JPS6013035B2 - PGD type compound - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel compositions of matter. The present invention also provides new methods of making compositions of these materials. The present invention also provides novel chemical intermediates useful in the above methods. In particular, the present invention uses hydrogen at C-11, for example. PGFQ, PGF which is substituted with xyl (hydroxyl group) or deoxygenated at C-9 or both
Novel analogues of some of the known prostaglandins corresponding in that they contain a modified cyclobentane structure exhibiting an oxo substitution at the C-11 position, in marked contrast to PGE. Known prostaglandins include PGE compounds, such as prostaglandin E,
(PGE,), prostaglandin E2 (PGE2),
Includes prostaglandin E3 (PGE3) and dihydroprostaglandin E, (dihydroPGE,). Known prostaglandins include PGFQ compounds, such as prostaglandin F. Q (PGF, Q), Brawl Stars Grand Jin F2Q (PGF20),
Prostaglandin F3Q (PGF3Q) and dihydroprostaglandin F. Q (dihydro PGF
, Q). Known prostaglandins are PGF
3 compounds, such as prostaglandin F,8 (PGF
, P), Prostag Grandin F28
(PGF28), prostaglandin F38 (PGF3
3) and dihydroprostaglandin F, 3 (dihydro PGF, 8). Known prostaglandins include PGA compounds, such as brostaglandin A, (PGA,), prostaglandin A2 (PGA2), prostaglandin A3 (PG
A3) and dihydroprostaglandin A, (dihydro-PGA,). Known prostaglandins include PCB compounds such as prostaglandin B (PGB, ), prostaglandin B2 (PGB2), prostaglandin B3 (PCB3),
) and dihydroprostaglandin B (dihydro-PG
B,). The above-mentioned known prostaglandins (P
Each of class G) is a derivative of prostanoic acid with the following structure and numbering of atoms. For example, Bergstrom et al., P.
harmacol. Rev. 2 Hajime 1 page (196 mother sheep)
and references cited therein. The systematic name of prostanoic acid is 7-[(28-octyl)-cyclobent-IQ-yl]hebutanoic acid. P
GE, has the following structure. PGE2 has the following structure. PGE3 has the following structure. Dihydro PGE has the following structure. FGF,Q has the following structure. PGF2Q has the following structure. PGF3Q has the following structure. Dihydro PGF,Q has the following structure. PGF,8 has the following structure. PGF23 has the following structure. OGF33 has the following structure. Dihydro-PGF,B has the following structure. PGA, has the following structure. PGA2 has the following structure. PGA3 has the following structure. Dihydro-PGA has the following structure. PCB, has the following structure. PCB2 has the following structure. PGB3 has the following structure. Dihydro PCB has the following structure. In the above formula as well as the formulas described below, a dashed bond to the cyclobentane ring indicates an alpha configuration, ie a substituent below the plane of the cyclobentane ring. A thick solid bond to the cyclobentane ring indicates a beta configuration, ie a substituent above the plane of the cyclobentane ring. Wavy line (~) in this specification
The use of indicates attachment of a substituent in either the alpha or beta configuration, or a mixture of alpha and beta configurations. In the above formula, the side chain hydroxy at C-15 is in the S configuration. For a discussion of the stereochemistry of prostaglandins, see Nature Ken, 212, p. 38 (1966). C-9,C
-11. An expression such as C-1 refers to a carbon atom in a prostaglandin at a position corresponding to the same numbered position in brostanic acid. Molecules of known prostaglandins each have several asymmetric centers and can exist in either a racemic form (optically inactive type) or two enantiomeric forms (optically active type), dextrorotatory and levorotatory. As illustrated, each of the above formulas is a prostaglandin obtained from, or obtained from, some mercenary tissue, such as sheep minor vesicles, pig lungs, or human sputum. Represents a specific optically active form of prostaglandin obtained by reduction of the carbonyl and/or double bond of prostaglandin. For example, Bergst quoted above. See Mu et al.
The mirror image of each of these formulas represents the other enantiomer of that prostaglandin. Racemic forms of prostaglandins contain the same number of molecules of both enantiomers, and one of the above formulas and a mirror image of that formula are required to correctly represent the corresponding racemic prostaglandin. For convenience below, the use of the term prostaglandin or PG etc. refers to the optically active form of that prostaglandin with the same absolute configuration as PGE obtained from mammalian tissue. When a reference to the racemic form of these prostaglandins is intended, the word "racemic" or "dl" is prefixed to the prostaglandin name. As used herein, the term "prostaglandin-type" (PG-type) compounds refers to
Any cyclobentane derivative useful for at least one of the same pharmacological purposes as the prostaglandins indicated herein. As used herein, the term "prostaglandin-type intermediate" refers to any cyclobentane derivative useful in making prostaglandin-type compounds. Each of the formulas illustrated herein depicting a prostaglandin-type compound or an intermediate useful in making a prostaglandin-type compound may be compared with the corresponding prostaglandin obtained from mammalian tissue. Represents a particular stereoisomer of a prostaglandin-type compound that is of the same relative stereochemical configuration, or a particular stereoisomer of an intermediate useful in making the above stereoisomers of a prostaglandin-type compound. As used herein, the term "prostaglandin derivatives" refers to prostaglandin-type compounds that are of the same relative stereochemical configuration as the corresponding prostaglandin obtained from mammalian tissues. It represents a stereoisomer, a mixture of this stereoisomer and its enantiomer, or its enantiomer. Particularly when a formula is used herein to describe a prostaglandin-type compound, the term prostaglandin refers to a compound of that formula or a mixture of this compound and its enantiomers. .
The various PGs named above, their wastes,
Acylates and pharmacologically acceptable salts are highly effective in eliciting a variety of biological responses. These compounds are therefore useful for pharmacological purposes. For example, Bergström et al., Pharmacol.
Rev. 20, p. 1 (1968) and references cited therein. For PGE compounds, biological responses include:

[a} Smooth muscle stimulation (e.g. guinea pig ileum, rabbit
(as shown by duodenal or gerbil intestine tests),
'b} Effect on lipolytic activity (isolated sleeping fat
Epinephrine-induced glycerol release from fat aggregation
(indicated by seedling resistance), [c} Suppression of gastric juice secretion and
Gastrointestinal effects caused by systemic administration of rostaglandiso synthase inhibitor
reduction of undesirable effects on [d} Suppression of attacks and promotion of breathing in patients with acute respiratory symptoms. [el Decongestion of the nasal cavity. target Platelet adhesion (platelet
(indicated by adhesion to glass), and various
Physical stimuli (e.g. arterial damage) or chemical stimuli (e.g.
ATP, ADP, serotonin, thrombin, and cola
inhibition of platelet aggregation and thrombus formation induced by (g) Parturition inducing agents, abortifacients, cervical dilators, estrous phase adjustment
Effects on mammalian reproductive organs as a menstrual cycle regulator
and (h) promoting the growth of epidermal cells and keratin in animals.
. For PGFQ, biological responses include:
[a} Smooth muscle stimulation (guinea pig ileum, rabbit ileum
(as shown by tests on the denum or the progeny of the jarpil). 'b} Suppression of gastric juice secretion and prostaglandin synthase
Reduction of undesirable gastrointestinal effects due to systemic administration of inhibitors
Few. {c' Nasal decongestion. Wind Blood 4/Plate adhesion (depending on the adhesion of platelets to glass)
) and various physical stimuli (e.g. motion).
pulse damage) and chemical stimuli (e.g. ATP, ADP,
tonin, thrompin, and collagen) induced blood
Inhibition of platelet aggregation and thrombus formation. {e' Labor induction agents, abortifacients, cervical dilators, estrous phase regulators
, and its impact on the reproductive organs of mammals as a menstrual cycle regulator.
sound. For PGF3 compounds the following responses are included: {a'Smooth muscle stimulation (guinea pig ileum, rabbit duodenum)
(as shown by tests on the intestine or japiral intestine). [b' Suppression of gastric juice secretion and inhibition of prostaglandin synthase]
Reduction of undesirable gastrointestinal effects due to systemic drug administration
. [c' Suppression of seizures and promotion of breathing in patients with asthma symptoms. 'd} Decongestion of nasal passages. {eー (to platelet glass)
decreased platelet adhesion (as indicated by the adhesion of
physical stimuli (e.g. vascular damage) or chemical stimuli (e.g.
For example, ADP, ATP, serotonin, etc. platelet aggregation caused by
Prevention of blood clot formation. 'f - Parturition inducers, abortifacients, cervical enlargement
Use of milkweeds as tonic agents, estrus regulators and menstrual cycle regulators
Effects on reproductive organs. Biological responses to PGA compounds include:
. {a} Smooth muscle stimulation (guinea pig ileum, rabbit ileum
(as shown by tests in the denum or gerbil stripes). [b} Suppression of gastric juice secretion and prostaglandin synthase
Mitigation of undesirable gastrointestinal effects from systemic administration of inhibitors
Decreased. {c} Suppression of attacks and promotion of breathing in patients with acute breathing symptoms. {d- decongestion of nasal passages and 'c} increase renal blood flow
. For PGB compounds, the biological responses include:
. 'a} (Guinea pig's kaiyo, rabbit's duodenum or rabbit's
smooth muscle stimulation (as shown in studies on the erbil colon)
. [b} Promotion of epidermal cell and keratin growth in animals. Because of these biological responses, these known prostags
Langins are used in birds and humans, useful livestock, pets, and
mammals, including animal specimens, as well as laboratory animals, e.g.
Wide range of effects in mice, mice, rabbits, and monkeys
research, prevention and control of diseases and undesirable physiological symptoms;
is useful for mitigation. Extremely effective in stimulating smooth muscle
The compounds listed above as being powerful also have other
Known smooth muscle stimulants such as oxytocin and derivatives
and various ergot alkaloids, including
It has high activity in synergizing labor stimulants. These compounds therefore include, for example, these known smooth muscle stimulants.
instead of or in combination with smaller amounts than their usual amounts
, to reduce symptoms of paralytic intestinal obstruction, including abortion or postpartum treatment.
Placental expulsion and delivery to control or prevent tonic uterine bleeding.
It is useful as an aid during the marriage period. For the latter purpose, abortion or
Immediately after delivery, about 0.01 to about 50 French per kilogram of body weight per minute
g of Prostag until the desired effect is achieved.
Randin is administered by intravenous infusion. subsequent throws
The dosage is 0.01 to 2 per kilogram of body weight per day during the period of childbirth.
For intravenous, subcutaneous, or intramuscular injection or infusion in a range of 9
The exact dose depends on the age of the patient or animal.
Varies depending on age, weight, and symptoms. PG as above
E compounds inhibit epinephrine-induced fatty acid mobilization.
It is a powerful anti-inflammatory agent. For this reason, this compound has been used in experimental medicine.
Regarding mammals including humans, rabbits, and mice
, diseases involving abnormal lipid mobilization and high levels of free fatty acids, e.g.
For example, understanding and predicting diabetes, vascular disease, and thyroid disease.
Tests intended to prevent, alleviate symptoms, and treat
Useful for in vitro and in vivo studies. humans and species
of useful animals, such as mammals including dogs and pigs, with excess
Reduces and inhibits gastric juice secretion, thereby causing gastrointestinal scar formation
reduce or avoid these substances already present in the gastrointestinal tract.
It has been cited above as useful in promoting the healing of una usin bran.
The prostaglandins used are for this purpose
Approximately 0.1 French g to approximately 500 mg per kg of body weight, or 1
Sum in the range of 9 from about 0.1 to about 20 per kg of body weight per day
Inject the compound intravenously, subcutaneously, or intramuscularly at a dosage range of
The exact dose is determined by the patient or animal.
depending on age, weight, symptoms, and number and route of administration. These compounds are involved in anti-inflammatory prostaglandin synthesis enzymes.
Undesirable effects on the gastrointestinal tract resulting from systemic administration of anti-inflammatory drugs
It is useful for reducing noise and is also used for this purpose.
Taglandins and anti-inflammatory prostaglandin synthases
Used with simultaneous administration of suppressants. induced by certain non-steroidal anti-inflammatory drugs in mice.
The concentrated explosive biological effects that occur are PGE, , PGE2, PGE3,1
3,14-dihydro PGE and the corresponding 11-deo
E and A series including xy-PGE and PGA compounds
suppressed by simultaneous oral administration of prostaglandins.
Regarding the disclosure that
See U.S. Patent No. 3,781,42y.
Prostaglandins include, for example, indomethacin,
caused by systemic administration of nilftazone and aspirin.
It is also useful in reducing the undesirable gastrointestinal effects of
be. These are non-steroidal anti-inflammatory drugs that Partridge et al.
This is a substance specifically mentioned as an agent. But these are pros
It is also known to be a grandin synthase inhibitor.
Anti-inflammatory synthetic enzyme inhibitors, such as indomethacin, aspirin
Phosphorus, or phenylbutazone, is a compound known in the art.
to reduce inflammatory conditions in any way, e.g.
and by any known systemic route of administration. Prostaglandin is an anti-inflammatory prostaglandin synthesis enzyme
with a primary inhibitor, either by the same route of administration or by a separate route.
is also administered. For example, as described in U.S. Pat. No. 3,545,439,
When administering anti-inflammatory substances orally, such as
Grandin can also be administered orally or alternatively as a suppository.
from the rectum in the form of a suppository, or into the knee in the form of a suppository in women.
For slow release it is administered in the form of an intra-knee device. the
Alternatively, if a proinflammatory substance is administered rectally, prosthetic
Grandins can also be administered rectally or alternatively orally,
Alternatively, in the case of women, it is given internally. The route of administration is anti-inflammatory.
Made the same for both substances and prostaglandins
Sometimes it is especially advantageous to combine both in a single dosage form.
This is the case. Appropriate intake of prostaglandin through this treatment
The type, age, weight, gender and medical condition of the mammal
, the nature of anti-inflammatory synthetic enzyme inhibitors administered to mammals.
Appropriate intake, relative to specific synthetic enzyme inhibitors regarding gastrointestinal effects.
the susceptibility of certain individual mammals, as well as the
due to a variety of factors, including certain prostaglandins that
Will. For example, everyone who needs an anti-inflammatory substance
Those who experience the same adverse gastrointestinal effects when ingesting
do not have. The type and extent of the effects on the gastrointestinal tract are currently unknown.
will change. However, administration of anti-inflammatory substances to humans or
Causes undesirable gastrointestinal effects in animal subjects
to reduce these undesirable effects and implement them in the next
Prescribe an effective dose of brostaglandin to qualitatively eliminate
It is within the skill of the attending physician or veterinarian to do so. half-breath
Prostagra, cited above as being useful in the treatment of
Ginseng is used as a bronchodilator or as an antigen-antibody body.
Therefore, SRS-A released from activated cells and human
Useful as an inhibitor of inclusions such as stamine. For this reason, these compounds may cause bronchial breath, bronchitis,
Symptoms like bronchiectasis, pneumonia, and emphysema
to suppress seizures and make breathing easier. For these purposes,
These compounds may be in tablet, capsule or liquid form, for example.
Orally, rectally in the form of suppositories, and in emergencies intravenously.
It is preferable to administer nepra, parenterally, subcutaneously or intramuscularly.
by inhalation in the form of an aerosol or solution, or as a powder.
It can be administered in a variety of dosage formats, such as by insufflation in powder form.
Ru. Dosing in the range of about 0.01 to 5 kg/k9 body weight
The dose is administered 1 to 4 times a day, but the exact dose depends on the patient's age.
Depends on age, weight, symptoms, and number and route of administration. for above
During the process, these prostaglandins are stimulated by sympathetic nerves.
drugs (isoproterenol, phenylephrine, epinef)
phosphorus, etc.), xanthine derivatives (theophylline and amino
phyllin), and corchicosteroids (ACT day and
In combination with other asthma treatments such as prednisolone (prednisolone)
It is advantageous to do so. Regarding the use of these compounds
is M.E. Rosenthal.
See U.S. Pat.
. Useful in mammals, including humans, as a nasal decongestant.
The prostaglandins cited above as
Pharmacologically suitable liquid vehicle or aerosol dispersion for the purpose
Administering from about 10 mg to about 10 c as a liquid.
Both are used for topical application. Platelet aggregation
The pros mentioned above are useful when you want to suppress
Staglandins have been found in animals including humans, rabbits, and mice.
Decreases platelet adhesion and thrombosis formation in mammals
It is useful for eliminating or preventing. For example, these compounds can be used for the treatment and prevention of cardiovascular infarctions,
Treatment and prevention of postoperative thrombosis, opening of vascular grafts after surgery
and atherosclerosis, arteriosclerosis, fat
Symptoms such as blood coagulation failure due to bloodemia, and other underlying symptoms
The etiology is combined with fat imbalance or hyperlipidemia
It is useful in the treatment of clinical conditions such as For these purposes
, administering these compounds systemically, e.g. intravenously, subcutaneously, intramuscularly.
Administered intramuscularly and in the form of sterile implants for sustained action.
give Intravenous administration is recommended, especially for rapid response in emergencies.
A given path is preferred. Approximately 0.005 per kg of body weight per day
None, then use a dosage range of about 20 females, but do not know the exact
The dosage depends on the age, weight, and condition of the patient or animal.
depending on the number of doses and route of administration. Furthermore, these compounds are
Isolated body parts, such as limbs and organs, are returned to the original body.
Combined or separated and stored or prepared for transplantation
state or being joined to a new body.
Artificial extracorporeal circulation and respiratory flow in these body parts
blood, blood products, blood substitutes, and other
Useful as an additive to fluids. During these circulations and perfusions, clotted platelets interact with blood vessels.
There is a mirror side that closes the circulation system part. The presence of these compounds
This blockage is avoided by the presence of the For this purpose, the compound
at a constant rate of approximately 0.001 to 10 mm per liter of circulating fluid.
At regular doses, it enters the circulating blood, the blood of donor animals, binds or
to the severed body part, to the recipient, or to the
Add gradually or once or multiple times to two or all
do. Due to new methods and techniques for organ and limb transplantation,
For these purposes, experimental animals such as cats, dogs, rabbits, monkeys, and rats are used.
It is particularly useful to use these compounds in Oxy
It is said that it is useful for inducing labor as a substitute for 1)
The prostaglandins cited above are
Avoid contact with humans, cows, pregnant female animals including sheep, pigs, or
is when a fetus dies in the womb from about 20 weeks to term.
Used in pregnant animals. For this purpose, the compound
at a dose of 0.01 to 50 Ag/kg body weight per minute.
, until or near the end of the second stage of labor, i.e. expulsion of the fetus.
Inject intravenously until If the female animal has been waiting for a week or more
When the natural delivery does not start after the due date, or when the amniotic sac
Natural childbirth still does not begin 12 to 6 hours after the rupture.
These compounds are particularly useful when they are not available. already
One route of administration is oral. These compounds are
to regulate the reproductive cycle of ovulating dianto-mammalian mammals, including
Useful. A female mammal that ovulates has enough time to ovulate.
have reached maturity, but are not old enough to stop ovulating normally.
It refers to ugly animals. For this purpose, prostaglandins
Advantageously starting at the time of ovulation and starting at about the time of menstruation or shortly thereafter.
9 of 0.01 per kilogram of body weight of female mammals during the period ending before
to about 20° C. for systemic administration. camp
Intra- and intrauterine routes are alternative methods of administration. others
during the first and second trimesters of normal cornemallian gestation.
With similar presentation of the compound, expulsion of the bulwark or fetus may be achieved.
It will be done. Furthermore, these compounds have been shown to be useful in obstetrics and gynecology.
Pregnant and non-pregnant female mammals have offspring for the above purposes.
It is useful in causing cervical dilatation. Places of labor induction and clinical miscarriage caused by these compounds
Cervical dilatation is also observed in some cases. In case of infertility, this
Cervical dilatation caused by these compounds inhibits sperm movement into the uterus.
useful in helping. D and C (cervical dilatation and uterine scraping)
Mechanical dilation is also used in surgical gynecology, such as
May cause uterine perforation, cervical laceration, or infection
, cervical dilation with prostaglandins is useful.
This is also useful for diagnostic procedures that require dilation for tissue examination.
be. For these purposes, prostaglandins can be locally
or administered systemically. For example, prostaglandins
About 5 to 50 doses per treatment for adult women
It is administered orally or intravenously in 1 to 5 treatments per 2 hours.
given. Instead of that. Staglandin is a one-time treatment
Administered intramuscularly or subcutaneously at a dose of approximately 1 to 25 females per day.
Ru. The exact dosage for these purposes is determined by the patient or animal.
Depending on age, weight and condition. These compounds are
It is used as an abortifacient in livestock (especially for multiparous cows in feedlots).
It can be used as an auxiliary means for detecting the estrus period, and for regulating or regulating the estrus period.
is useful for synchronization purposes. Domestic animals include horses, cows, sheep and pigs. Regulation of the estrus period
occur at the same time, forcing livestock farmers to do so at short, predetermined intervals.
By allowing all female animals to give birth
This allows for more efficient management of pregnancy and childbirth. this
Synchronization produces a higher rate of life than would be possible with natural regulation.
becomes. Prostaglandin 0.1-100 per animal
Either injected or mixed into the feed at a dose of 9.
may be combined with other drugs such as steroids.
Dosage regimens will vary depending on the species being treated. for example,
Give prostaglandins to mares 5 to 8 days after ovulation.
Then, we return to the heat cycle. All cows are advantageously in heat at the same time.
In order to arrive on time, follow regular training over a period of 3 weeks.
Pupils look at intervals. PGA compounds and their derivatives and salts
species increase blood flow in the kidneys of mammals, thereby
Increase urine output and its electrolyte content. For this reason, PGA compounds have been shown to cause vascular dysfunction, especially vascular dysfunction.
Useful in the management of cases involving floor obstruction. example
PGA compounds are used to treat edema resulting from extensive burns.
Useful in alleviating and correcting symptoms and overcoming shock.
For this purpose, first, add 10 to 1,000 Buddhag per kg of body weight.
or by intravenous injection at doses in the range of k9 body weight per minute.
by intravenous infusion at doses ranging from 0.1 to 20 mg per day.
and then administer the PGA compound until the desired effect is achieved.
is preferred. The subsequent dosage is 0/k9 body weight per day.
．． Intravenous, intramuscular, or subcutaneous administration in the range of 05 none, 2 females
Given by injection or infusion. Growth of epidermal cells and keratin
The compounds cited above as promoting growth are
Including useful livestock, pet animals, zoological specimens, and laboratory animals.
It is useful for this purpose in cultivated animals. For this reason, these compounds can be used for example in burns, trauma,
Accelerates the healing of injured skin from scratches or after surgery
It is useful for These compounds are effective in skin autografts.
skin by outward growth, especially later than early
to cover missing areas or delay rejection of autografts.
small, deep (Davis) implants with the intention of
It is useful in promoting fragment cohesion and growth. for the purpose above
is placed in or near areas where cell growth and keratinization are desired.
Topically, advantageously as an aerosol solution or a fine powder dusting agent
, as an isotonic aqueous solution in the case of wet dressings, or as a conventional preparation.
lotions in combination with pharmaceutically acceptable diluents;
Administering these compounds as a cream or ointment
It is preferable to In some cases, for example due to extensive burns or other causes.
When there is substantial loss of body fluids, as in the case of skin loss due to
separate from the normal injection of blood, blood acid, or a substitute thereof.
or in combination with systemic administration by intravenous injection or infusion.
It is advantageous to give. An alternative route of administration is to
Subcutaneous or intramuscular, oral, sublingual, buccal, rectal, or intravenous
It is within. The exact dose depends on the route of administration, the age of the patient,
Factors like weight, and symptoms come into play. For example, skin
Second and/or third degree fire with a skin area of 5 to 26 square centimeters
Wet dressings applied topically to wounds weigh between 1 and 500 French grams.
Using an isotonic aqueous solution containing brostaglandin of
It has been found that it is advantageous. Especially for topical use,
These prostaglandins are treated with antibiotics, e.g.
perilla, neomycin, polymyxin, bacitra
Syn, Svectinomycin, and Oxytetracycline
and other antibacterial agents such as mafenide hydrochloride, sulfur
Phadiazine, Furazolium Chloride, and Nitrof
lasone, and corticochoid stethroids such as high
Drococcizoso, Prednisolone, Methylprednisolo
It is useful in combination with
However, each of these can be used alone in this combination.
It is used at a normal concentration suitable for Prostaglan of the present invention
Certain prostaglans are structurally related to gin-type compounds.
Jin-type compounds are known in the prior art. For example, Belgian patent 767,704Q (Darwentoff
Armdoc CP176109J-B), this is 9
-deoxy-POD type compounds are disclosed. Also the United States
Patent No. 3,878,23 (April 15, 1973)
(Published), which is a methyl at C-15 or C-16.
Thus, certain PGD analogues that have been studied are disclosed. P
For disclosure of GD or PGD2, Nagtalen et al.
ug to ren) Rec. Trav. Chim. Pays
1 Bas. 85, 104 (1966), Glance
Trom et al. (Gra ship trom), J. Bio
l. Chem. 243,4104 (19 Iso), Shi Shiichi
(C. Sih) BioChem. 11,227 (19
72), J. 0rg. Chem. , 38, 215 (19
73) and prostaglandins such as Nishizawa9,109
(1975). 9-deoxy-PG after death
For F-type compounds see the following references, Gluwe
Ntof Arm Dock CPI Number 7643$-B:210
9-B; 39100U-8; 21092r-B; 1 total
43U-8; 13929U-B; and 4999-B.
The present invention provides novel prostaglandin analogs, analogs thereof
esters, pharmacologically acceptable salts of their analogues.
provide. The present invention also provides new methods of making these analogs. The present invention provides lower alkanoates of these analogs.
Ru. The present invention further provides novel methods for making these analogs.
do. The present invention further provides novel novelties useful in making these analogs.
Provides regulatory chemical intermediates. prostaglandin analogs of
has been disclosed and claimed as a patent. In the formula, D is
H-CQ-, provided that Y is FCH-C ratio unity only when ○ is, and Z is [1' system].
-CH=CH-C ratio-(CH2)6-CF2-, ■cis
-CH=CH-C Koichi (CH2)6-CH2-, glue cis
-C ratio -CH=CH-(CH2)g-CH2-. [41
CH2-C horse-(CH2)3-CH2-,'6-also
is '61, where g is 1, 2 or 3, M, or..., R5 and R6 are hydrogen or methyl, but one of R5 and R6
It is methyl only when the other is hydrogen, and R7 is '
1'-(C ratio)m-CH3, where m is 1 to 5.
R, is hydrogen, or lower alkyl, or pharmacologically acceptable
It is a cation that can be formed, and further '11 When R6 is methyl
Only D is, Z is cis-CH=CH-(CH2)3-, R7 is-(CH2)3-C,
Y is trans-CH=CH1 and one or more of R3 and R5
are both methyl, and '2) D only when R6 is methyl
, Z is cis-CH=CH- (CH2)3-, R7 is one (CH2)3-CH3,
Y is trans-CH=CH-, and R3, R4 and R5
is all hydrogen. B is Sisu CH=CH-C ratio-(CH2)g-CH2-
, or cis-CH=CH-CH2-(CH2)8-CF
21 is designated as "PQ" compounds. The latter compounds are further converted into "2,2-difluoro" PG type.
Characterized as a compound. When g is 2 or 3, the
The prostaglandin analogs described in
” or “Matsu, Wataru dihomo” compounds. That's that
In case the carboxy-terminal side chain is contained in PGE, 7
This is because it contains 8 or 9 carbon atoms instead of carbon atoms.
Ru. These additional carbon atoms may be located at the C-2 and C-3 positions.
It can be thought of as if it were inserted between the two. Therefore these
The additional carbon atoms are counted from C-2 to C-3 and are C- and
It is said to be C-. Furthermore, Z is -(C Buddha) 3-(CH2)
6-CH2- or one (C French) 3-(CH2)g-CF2
When g is as defined above)
The compounds described in are "PG," compounds. When g is 2 or 3, “2-homo” and “Matsu, Sajji homo”
Compounds are described as discussed in the previous section. Z, is
-CH2-○1CH2-(CH2)91C Yamaichi's time
The compounds described in the above are "5-oxa-PG," compounds.
It is named as a thing. When g is 2 or 3, compounds so described are discussed above.
``2-homo'' or ``ne, young-dihomo'' respectively.
” Compounds. ZI is -(CH2)2-. -(CH2)g・CH2-(ko) where g is defined above
), then the compounds so described are "
It is named as 4-oxa-PG, a class of compounds. g is bifurcated
3 The compounds so described were discussed earlier.
``Z-homo'' or ``Matsu, Sha-dihomo'' compound, respectively.
additionally characterized as a thing. Z is one (CH2) 3
−○−(CH2)g−(ko) where g is as defined above
), then the compounds so described are "3-
Oxa-PG," compounds. When g is 2 or 3, compounds so described are further
``Z-homo'' or ``笈,'' respectively, as discussed above.
It is characterized as a class of "juvenile dihomo" compounds. B is sis
-CH2-CH=CH-(CH2)s-(CH2)-,
(in this), g is as defined above), then
Compounds described as “cis-4,5-didehydro
-PG,” compounds. When g is 2 or 3, the compounds so described further include
As previously discussed, “2-homo” or
-dihomo" compounds. 3-O when g is 1 for the novel compound of the present invention when B is or
Xa-3,7-inter m-phenylene-4,5,6-
trinol, or 3,7-inter-m-phenylene-4
, 5,6-trinol-PG-type products are described. When g is 2 or 3, the above compounds are additionally each "2-
Homo” or “dihomo” PG type compounds
It will be posted. Cis-CH=CH at C-13 to C-14 position
- novel prostaglandin analogues of this invention comprising the moiety
are therefore referred to as "cis-13" compounds. -CQC
When part of day 2 exists between C-13 and C-14,
The compounds described in ``13,14-dihydro'' compounds
It is a thing. C-13 to C-14 part Y = CHC string
The compounds so described are as discussed above.
Named according to the cyclobentane ring structure. Therefore, “12,13-dihydro-13,14-dihydro
' Compounds are described. As depicted here, 12
, 13-didehydro-13,14-dihydro compounds
The formula represented is a double bond attached to a carbon atom that is not part of a ring.
State the possible geometric isomers of the ring carbon atoms present.
The E and Z nomenclature is used to represent the E geometric isomer. subordinate
Therefore, these compounds are additionally "12,13-(E)
-didehydro-13,14-dihydro” as a PG analogue
It is characterized by Blackwood Z.I. etc. (Bla
ckwoodJ. E. etal) J. ofChem. D
M. 8, 30 (1968). R7 is -(C
ratio) m-CH3 (this) where m is as defined above.
), the compounds so described are each m
1, 2, 4 or 5 "19,20-dinol""20
-nol” “20-methyl” or “20-ethyl” compound
Named as a thing. When R7 is (this) and T and s are as defined above), write it as such.
When s is zero, the compounds obtained are “17-phenyl-181
920-trinol" compounds. When s is 1, 2 or 3, the corresponding compounds are
phenyl)-18,1320-trinol compounds and
It is named after R? (T and s are as defined above) when R3 and R4 are
Not methyl. Compounds so described are ``16-phere'' when s is zero.
Noxy 17,1 & 19,20-tetranol” compound
It is a thing. When s is 1, 2, or 3, the corresponding compound is “1
6-(Substituted Fe/xy)-17,1 & 1920-tet
It is named as "ranol" compound. One of R3 and R4 is
And one length is methyl or both R3 and R4 are methyl
What to do when R7 is as defined in this section
The compound is “16-phenoxy or 16-(substituted phenoxy)”
c)-18 19,20-trinols” compound or “1
6-methyl-16-phenoxy or 16-(substituted
xy)-1 & 1920-trinols” compounds and their
Each is named. R7 is cis-CH=CH-CH2-C
Compounds so defined when H3, Z, is R2
is hydrogen or fluoro, cis-CH=CH-(
Day 2) Whether it is g-C(R2)2- or another part
Therefore, “PG31 or “cis-17,18-didehydro
” in each compound. When at least one of R3 and R4 is not hydrogen, then (as above)
(apart from the case of the 16-phenoxy compounds discussed)
"16-methyl" (one of R3 and R4 and one length is medium)
methyl), “16,16-dimethyl” (both R3 and R4 are
co-methyl), “16-fluoro” (one of R3 and R4 is
and one length is fluoro), "10 16-difluoro"
(both R3 and R4 are fluoro) compounds are described. For these compounds where R3 and R4 are different, the
The prostaglandin analog shown in
Contains a uniform carbon atom. Therefore, the two Epimer configurations
Possible positions are ``16'' and ``1 pulse.'' Furthermore, according to the present invention
A C-16 epimer mixture "1 Iso S" is described. R
When 5 is methyl, the compound described as such is ``15-methyl''.
These compounds are named "chill" compounds. When R6 is methyl, the compound so described is “15-
The compound is named methyl ether. will be described later
The formulas of some of the 13-cis-cyclobentane derivatives are
Contains the expression part. In this), the cyclobentane ring is variously substituted, and M is as defined herein.
Various definitions are given by the numbers given below.
, L, and R7 are defined above and Y is cis-CH=CH-
It is. Optionally, the above formula allows one or both of L and M to be combined.
*Depicted with one or both of L and M on the carbon
Photographed. For example, as follows. The above expression is used
Please indicate the following rules regarding the display of cis-13 double bonds.
Nico) is defined as Furthermore, in using this convention, for example, M is or
When the corresponding indication is or is intended, respectively. -Therefore, this book represents 13cis cyclobentane derivatives.
All formulas in the specification are drawn as follows:
It is drawn by the same convention as for PGE. mosquito
Therefore, by this convention, 131 PGE, (1$
)-hydroxy is in the beta configuration. Hydroxy at C-15 in alpha configuration
or illustrated herein as having methoxy
The cis-131PG-type compound is cis-131PGE,
The stereochemical configuration of is the opposite relative at C-15.
It is of stereochemical configuration. Therefore, 15epy compound
be named as a thing. Beta hydroxy or methoxy configuration
This special representation of stereochemistry does not give any
I can't do it. Therefore, 15-ep-1016-difluoro
Cis-13-PGD2 is depicted as follows. S
Sue 131 PGE, alternate display is alpha or beta
As a hydroxyl, it affects the contribution of C-15. Thus
Cis-13-PGE, by any indication to the contrary to this Agreement, shall:
It appears like. Therefore, C-15 carbon atom is appropriately expressed.
That is to say, all Sisu 13-15-EP PG
As used herein, cis-131P is 15Q-OH.
Care should be taken to consistently illustrate the formulas of Type G compounds.
Must be taken. 1314-trans or saturated cyclobentane derivatives containing the moiety (where cycloben
The tan ring is variously substituted, where M is as given herein.
are variously substituted according to the numbers listed below. In this), L, and R7 are as defined above, and in this)
and Y is trans-CH=CH- or -CH2CH2-)
It is. When this indication is used C-13 to C-14
The following conventions regarding the display of parts are indicated in each section).
defined. or similarly when using this agreement, M.
For example, when is , a corresponding representation for transformer 13 or then 13, 14 is saturated or respectively intended. Therefore trans-13 or 1314-saturated cyclobenta
All formulas herein that represent carbon derivatives are as described above.
The same convention as for PGE, as illustrated in
Therefore, it is described. Finally, the 12,13(E)-didehydro shown in
-13,14-dihydroPG-type compounds are 13,14-dihydroPG-type compounds.
- as described above for the depiction of saturated cyclobentane derivatives.
Follow the same conventions. Thus everything as illustrated in
trans-13 or 13,14-dihydro-PG-type of
The 15Q-hydroxy configuration for the compound is similar to
Relative C-15 stereochemistry of PGE, as obtained from
Corresponds to the target configuration. What special C-15 stereo to name these compounds?
No chemical labeling is provided. C-15 (i.e. 158
- Hydroxy) in the opposite stereochemical configuration
The designation "15-epi" is used for the compound. 1no
Examples of alkyls of up to 12 carbon atoms are methyl, ethyl, and
lopyl, butyl, besotyl, hexyl, heptyl, octyl
Tyl, nonyl, decyl are of the usodecyl and isomeric forms. Examples of cycloalkyl of 3 to 1 hard carbon atoms are cyclo
propyl and 2-methylcyclopropyl. Examples of aralkyl of 7 to 12 carbon atoms are penzyl,
2-phenylethyl and 1-phenylethyl. 1 to 3 of chloro or alkyl of 1 to 4 carbon atoms
Examples of phenyl substituted with p-chlorophenyl and m
- Chlorophenyl. (In the formula, T is alkyl of 1 to 3 carbon atoms, fluoro, chloro, trifluoromethyl
, or alkoxy of 1 to 3 carbon atoms, s is zero 1,
2 or 3 but not more than 2 T is other than alkyl
Examples of phenyl, (o-, m-, or p-)
triyl, (o-, m-, or p-)ethylphenyl,
2-ethyl-p-tolyl, 4-ethyl-o-tolyl
, 5-ethyl-m-triyl, (o-, m-, or p-
Propylphenyl, 2-propyl-(o-?m-, or
p-) Triyl, 4-isopropyl-2,6-xylyl
, 3-propyl-4-ethylphenyl, (2,3,4-
, 2, 3, 5 - 2, 3, 6 - or 2, 4, 5 - tri
Methylphenyl, (o-, m-, or p-)fluorophenyl
enyl, 2-fluoro(o-, m-, or p-)tri
yl, 4-fluoro-2,5-xylyl “(2,4-,
2,5-, 2,6-, 3,4- or 3,5-) difluoro
Lofenyl, (o-, m, -, or p-)-chlorophene
Nyl, 2-chlorop-tolyl, (3-,4-,5-oryl
is 6-)chloro-o-tolyl, 4-chloro-2-pro
Pyrphenyl, 2-isopropyl-4-chlorophenyl
, 4-chloro-3,5-xylyl, (2,3-,2,4
1, 2, 5-, 2, 6-, 3, 4-, or 3, 5-
Chlorophenyl, 4-chloro-3-fluorophenyl,
(3- or 4-)methyl-2-fluorophenyl, (
o-, m, or p-) trifluoromethylphenyl, (
o-, m-, or p-)methoxyphenyl "(o-, m-
mono- or p-)ethoxyphenyl and (4- or 5-)
It is chloro-2-methoxyphenyl. The novel prostaglandin analogs of the present invention
Rostaglandin analogs have prostaglandin-like activity
It corresponds to each of the above prostaglandins in that it shows
. More specifically, the novel prostagrange of the present invention
Each of these novel analogs can be
For each of the above uses in which prostaglandins are used.
Corresponds to prostaglandins in that they are useful as
The same as the corresponding prostaglandin as discussed in
used in different ways. The prostaglandins are diverse even at low doses.
All are effective in producing biological responses. Furthermore, these prostaglandins for many applications
have an inconveniently short period of biological activity
. In sharp contrast, the novel prostaglandin analogs of the present invention
When the body mounts a prostaglandin-like biological response
Substantially more selective with respect to potency and substantially more
Has a long period of biological activity. Therefore, these new
Each of the rostaglandin analogs is
The few mentioned above for the latter than one of the taglandins.
surprisingly and unexpectedly for a single pharmacological purpose.
It is very useful. It is more than any known prostaglandin.
Has a different and narrower subectrum biological efficacy
and therefore more specific in its activity and more prostatic.
smaller than when a grunge was used for the same purpose
This is because the length causes fewer side effects than the previous one. the
Novel prostagrange for its prolonged activity
Smaller and lower dosages of analogues are often desired.
Effective in getting results. New prostagura of the present invention
Other advantages of the ginsin analogs are defined herein below, among others.
Another advantage of the preferred PG analogues is that the corresponding prosthesis
Compared to grandins, these new PG analogs
These prostaglandins
Intravenous, intramuscular, and subcutaneous injections as listed above
or when effective only by injection administration.
Administer orally, sublingually, intracranially, bucally, rectally
be done. These alternative routes of administration suggest that they are less
these compounds in the body at short or small doses of
Makes it easy for patients to maintain a uniform level of self-care
This is because it enables administration. Therefore, the novel product of the present invention
Staglandin analogs can be administered in different ways for different purposes.
given. For example, intravenously, intramuscularly, subcutaneously, orally,
Internally, rectally, bucally, sublingually, topically, and
It is administered in the form of sterile implants for its prolonging and prolonging action. intravenous injection
Alternatively, sterile isotonic aqueous solutions are preferred for injection. For that purpose
Due to increased aqueous solubility, R in the novel compounds of the present invention is
Preferably, it is an element or a pharmacologically acceptable cation.
Yes. For subcutaneous or intramuscular injection, the acid in an aqueous or non-aqueous medium.
, salt or ester type disinfectant solutions or suspensions are used.
. Tablets, capsules and syrups, eliquidyl, and
Liquid formulations such as simple solutions can be administered orally with common pharmaceutical carriers.
Used for sublingual administration. For rectal or intramuscular administration
Suppositories made using this technique as known
is used. Tissue transplants may contain or contain substances.
Sterile tablets or silicone rubber capsules impregnated with
other things are used. The novel PG analogs of the present invention are free
The above in acid form, ester form, and pharmacologically acceptable salt form.
used for a purpose. When the ester form is used, the ester is the above definition of R,
Any of those within. However, Esther is Ichino.
Preferably it is alkyl of up to 12 carbon atoms.
Among the alkyl esters, methyl and ethyl and especially meth
specific for optimal absorption of the compound by the body or experimental animal system.
preferable. Straight chain octyl, nonyl, decyl, undecyl
and dodecyl have been shown to have prolonged effects in the body and in experimental animals.
Particularly preferred for activity. The present invention useful for the above purpose
Pharmacological recognition of novel prostaglandin analogues of compounds
Acceptable salts include pharmacologically acceptable metal cations,
ammonium, amine cation or quaternary ammonium cation
It is a salt with ions. Particularly preferable dominant metal ions include lithium, sodium ions,
and alkali metals such as potassium, e.g.
Derived from alkali metals such as sium and calcium
It is something that will be done. Although other metals such as aluminum, zinc and iron
Also within the scope of this invention are enteric ions of the genus. pharmacologically acceptable
The resulting amine enteric ions are primary, secondary and tertiary amines.
It is derived from Examples of suitable amines are methylamine, dimethylamine,
Trimethylamine, ethylamine, dibutylamine, trimethylamine
lyisopropylamine, N-methylhexylamine,
Cylamine, dodecylamine, allylamine, crotyl
Amine, cyclobesothylamine, dicyclohexylamine
Penzylamine, Dibenzylamine, Alfaaf
enylethylamine, beta-phenylethylamine,
Approximately 18 items such as ethylenediamine, diethylenetriamine, etc.
Aliphatic, cycloaliphatic, containing up to and 18 carbon atoms
Tsuku, Ararifuatetsukuamines, and Piverizine,
Morpholytho, pyrrolidine, piperazine and their lower
alkyl derivatives such as 1-methylpiveridine, 4-methyl
Tylmorpholine, 1-inpropylpyrrolidine, 2-
Methylpyrrolidine, 1,4-dimethylpiverazine, 2-
Enomoto cyclic amines such as methylpiveridine, and water-soluble
In other words, amines containing hydrophilic stems such as mono-, di-,
and triethanolamine, ethyldiethanolamine
, N-butylethanolamine, 2-amino-1-buta
Nor, 2-amino-2-ethyl-1,3-butyletha
nolamine, 2-amino-1-butanol, 2-amino
No 2-ethyl-1,3-propanediol, 2-amino
Nor-2-methyl-1-propanol, tris(hydroxy)
dimethyl) aminometho, N-phenitalethanola
Min, N-(p-tertiary amyl-phenyl)-diethanol
Galamine, N-methyldicamine, N-methyldicamine,
Chilglucosamine, efuedrin, phenyl efuedrin
These include epinephrine, epinephrine, and procaine. 0 Appropriate medicine
Examples of physically acceptable quaternary ammonium cations are
Tetramethylammonium, 7traethylammonium
, benzyltrimethylammonium, phenyltriethyl
ammonium etc. Free hydroxy type or hydroxy moiety is lower alkanoate
used for the above purpose in the form of a
The novel PG analogs of the present invention are acetoxy, propionyl
Oxy, petyriloxy, valeryloxy, hexanoyl
rooxy, heptanoyloxy, octanoyloxy and
and branched-chain alkanoyloxy isomers of these moieties.
. Among these alkanoates, particularly preferred for the above purpose are
Preferred are acetoxy compounds. These free
All droxy and alkanoyloxy compounds are as described above.
Used as free acid as ester and in salt form as
be done. biological response specificity, efficacy and activity
Certain compounds within the scope of the present invention may be used to obtain suitable combinations.
preferable. It is preferable that g is 1 or 3 on the carpoxy terminal side.
It is especially preferable that g is 1. In other words, the chain is of the natural chain length of prostaglandins.
That is. Furthermore, when R7 is -(CH2)m-CH3, m is
It is preferable that it is 3. For those compounds where R is or, s is drop or 1 and T is chloro, fluoro. Or trifluoromethyl is preferred. R3 and R
These compounds in which at least one of 4 is methyl or fluoro
Preferably, both R5 and R6 are hydrogen for the compound.
Yes. These compounds in which at least one of R5 and R6 is methyl
It is preferred that R3 and R4 are both hydrogen for
. For those compounds where R is or, R3, R4, R5, and R6 are all hydrogen.
It is preferable. Oxa is used instead of methylene (i.e. -C ratio
- instead of -○-), these compounds have such
It is preferable that substitutions occur at C-5 rather than C-3 and C-4.
Yes. 15-hydroxy or 15-methoxy in alpha configuration
In this specification, it is assumed that the
15 for the novel cis-131PG analogue as shown.
-epi configuration, non-cis-1 sphere G analogues are considered
when it is not in the 15-epi configuration
preferable. The charts herein are based on the novel products disclosed herein.
A method by which rostaglandin analogs are made is described. Figure A Box B Figure C Figure D Figure E Figure F Box G Figure Date Figure 1 Figure J Box K Figure L Figure M Box N Figure 〇Figure P Box Q Regarding this chart, T and s are as defined above.
, R, is as defined above, but herein the species
For each conversion, R is a pharmacologically acceptable cation.
Rather, it is hydrogen or ester. R2 is hydrogen or fluoro, R53 is hydrogen or methyl,
R3, R4, R5, R6 and R7 are as defined above.
, R9 is an acyl protecting group and R and o are protecting groups
. R22 and R26 are hydrocarbyl such as alkyl,
These include chloroalkyl, aralkyl, etc. Preferred R22 and
R26 is alkyl, lower alkyl (e.g. methyl or ethyl)
Chill) is most preferred. R5, is R30-S02)
and R3o is alkyl, cycloalkyl, aralkyl,
phenyl, or phenyl substituted with alkyl or halogen
It is le. Preferred R3o is methyl or p-tolyl.
be. R55 and R56 are alkyl groups of 1 to 4 carbon atoms;
A group of time expressions taken together with the same thing or danced things
appear. In this) R57, R mother, R59, R6o, R61 and R62
is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl,
are the same or different, but R57, R5
8, R59, R6o, R6, and one or more of R62 are
R57, R58, R59, R6. , and R
The total number of carbon atoms in 62 is 2 to 10, and h is 0 or 1.
The condition is that R63 is carboxyacyl of the formula, where R64 is hydrogen of 1 to 19 carbon atoms.
Alkyl is an aralkyl of 7 to 12 carbon atoms.
In ri, ko), the above alkyl or aralkyl is at least 3
is substituted with fluoro, chloro, promo or iodo. R66 is hydrogen or a blocking group by R65. of the present invention
R65 blocking groups useful for this purpose include those listed herein.
All blocking groups by R, o as above and additionally
- Contains Si(Gi)3. In this), ○, is 1 to 4 carbons
atomic alkyl, cycloalkyl of 3 to 1 carbon atoms
kyl, aralkylphenyl of 7 to 12 carbon atoms (
Chloro, fluoro or alkyl of 1 to 4 carbon atoms
) is substituted with one or two of the following. to R65
Preparation of reagents necessary for use of these silyl capping groups by
and hydroxy hydrogens are substituted with these silyl capping groups and then
A suitable reaction to hydrolyze these silyl capping groups with
Methods known in this art for conditions are used
. R68 is hydrogen, carboxyacyl by R63 is R9
is an acyl protecting group. R69 is hydrogen or 1 to 4
alkyl of 4 carbon atoms, R7o is hydrogen, 1 to 4 carbon atoms
alkyl, C, of the carbon atom of has the formula as defined above
-Si(G,)3 silyl. 2x is the formula thioketal or
Straight chain alkyl of 3 to 3 carbon atoms. -Si(G2)3 is t-butyldimethylsilyl
is preferable. Y and Z are as defined above. Z2 is cis-CH2CHCH2-(CH2)8-C(R
2) 2-, cis-CH2-CH-CH-(CH2)g-
CH2-(CH2)3-(C ratio)6-C(R2)2
-, 1CH2 101C Koichi (CH2)g-CH2-, or
is one (CH2)31○-(CH2)g-deko) and R2
g is as defined above. Z is each oxa
Or methylene, i.e. -01 or -C Koichi. Z4 is
In this), h is 2 to 4, preferably 3. L, M, and M9 are as defined above, Earth is Ha, and R, o is as defined above. Pigeon is a mixture of or. Pigeon is a mixture of or. M7 is or. In this case, R65 is as defined above. Buddha is or. R. o is as defined above. M. 8 is or. where R and o are as defined above. The acyl protecting group by R9 is [a}penzoyl, {b'
Alkyl of 1 to 4 carbon atoms 7 to 1 hard carbon atom
phenylalkyl or nitro 1,2,3,4 or
Penzoyl substituted with 5 but with 2 substituents
A carbon atom in a substituent even if the above is other than alkyl
provided that the total number of does not exceed lq carbon atoms,
provided further that the substituents may be the same or different.
Ru. {c) A carbon atom with 2 to 5 alkoxycarbonyl moieties
Pen substituted with alkoxycarbonyl that is child
Zoyl. [d Saftyl, 'e-1 to 4 carbon atoms
alkyl, phenylalkyl of 7 to 1 carbon atoms
Naphthyl substituted with 1 to 9 of ole or nitro, provided that
Do not exceed one solid carbon atom on any of the naphthyl rings.
provided that the various substituents are the same or
provided that they may be different. 'f}2 to 12 pieces
Alkanoyl of carbon atoms, etc. are included. Hydroxy-containing
herein to make these acyl derivatives of compounds.
Methods commonly known in the art are used. Thus, for example, when R9 is defined above,
Aromatic acids (e.g. benzoic acid) on the day of the ceremony are used as dehydrating agents e.g.
Hydrogen in the presence of sulfuric acid, zinc chloride or phosfloryl chloride
Reacted with droxy-containing compounds. or alternatively the expression
(R9) Anhydrides of 20 aromatic acids (e.g. benzoic anhydride
) is used. However, those mentioned in the above section
The method uses a suitable acyl halide, e.g.
By using R9HAL when lomo or iodo
It is preferable to proceed. For example, penzoyl chloride is a hydrogen chloride scavenger, e.g.
Presence of tertiary amines such as pyridine, diethylamine, etc.
with a hydroxy-containing compound. The reaction is
Various procedures are performed using procedures commonly used in this technique.
carried out under conditions. Generally mild conditions are used
Ru. 2pi~60℃. in a liquid medium (e.g. excess pyridine or benzene,
in an inert solvent such as ene or chloroform).
Contact of reactants. The acylating agent may be present in stoichiometric or substantial amounts.
Used either in stoichiometric excess. As an example of R9
The following compounds are acid (R90H), anhydride (RQ) 20,
or acyl chloride (R9CI), benzoyl, substituted penzo
It can be used as a file. For example (21, 31, or 4-
)-methylbenzoyl, (2-, 3-, or 4-)
Tylbenzoyl, (2-, 3-, or 4-)-isopro
Pyrbenzoyl, (2-, 3-, or 4-)-tertiary-
Butylbenzoyl, 2,4-dimethylbenzoyl, 3,
5-dimethylbenzoyl, 2-isopropyltolyl,
2.4,5-trimethylbenzoyl, pentamethylben
Zoyl, alpha-phenyl-(2-, 3-, or 4-
)-toluyl, (2-, 3-, or 4-)-phenethyl
Benzoyl, (2-, 3-, or 4-)nitrobenzo
yl, (2,4-,2,5- or 2,3-)-dinito
Benzoyl, 2,3-dimethyl-2-nitrobenzoyl
, 4,5-dimethyl-2-nitrobenzoyl, 2-dimethyl
Thoro-6-phenethylbenzoyl, 3-nitro-2-phenzoyl
Enethylbenzoyl, 2nitro-6-phenethylben
Zoyl, 3-nitro-12-phenethyl-penzoyl,
Noesterified phthaloyl, isophthaloyl or terephthaloyl
royl, 1- or 2-naphthoyl, substituted naphthoyl, e.g.
For example (2-1, 3-, 4-, 5-, 6-1, or 7-1)
Chi-1 naphthoyl, (21 or 4-)ethyl-1-
naphthoyl, 2-isopropyl-1 naphthoyl, 4,
5-dimethyl-1 naphthoyl, 6-isobropyru-4
-Methyl-1-naphthoyl, 8-pendiyl-1-naphthoyl
Toyl, (3-, 4-, 5-, or 8-)-nitro-1
-naphthoyl, 4,5-dinitro-1-naphthoyl, (
3-1, 4-1, 6-1, 7-1, or 8-) methyl-1-naph
toyl, 4-ethyl-2-naphthyl and (5- or 8
1) Nitro-2 naphthoyl and acetyl. Therefore chloride
Penzoyl, 4-nitrobenzoyl chloride, 3,5-chloride
dinitrobenzoyl, etc., that is, R9C corresponding to the above R9 group
I compounds can be used. If acyl chloride is not available, this technique
Correspondingly, it is made from acid and phosphorus pentachloride.
Ru. R90 days, (R9)20 or R9CI reactants are
For example, on both ring carbon atoms adjacent to the bondyl attachment point.
It does not have substituents that cause major hindrances such as the third pull.
is preferable. Acyl protecting group with R9 can be used for deacylation
Therefore, it is excluded. Alkali metal carbonates are effectively used for this purpose at ambient temperatures.
used. For example, potassium carbonate in methanol is approximately 2500
used to advantage. These blocking groups within R,o are
Any group that replaces hydroxy hydrogen, used in this)
hydroxyl is less aggressive to the reagents used in the conversion.
not responsive or responsive, then brawl grunge
In the production of carbon-type compounds, hydrogen is exchanged.
. Several blocking groups are known in the art. For example, Tet
Lahydropyranyl and substituted tetrahydropyranyl, reference
Tamee, Ze, Corey, Proceedings of the
robert eiwelch foundation kunghua
Rency on Chemical Research 12, Organic Synthesis
E.○.Corey, Proceedings o.
f the RobenWelch Foundation
on Conferences on Chemica
lResearch, 12, gobukuro nicShada esis
), pp. 51-79 (1969). Useful things
These blocking groups were found to include: [a
'Tetrahydropyranyl' b1 Tetrahydrofuranyl and
and [c'formula-C(OR,.)(R,2)-CH(R,3
)(R,4), in which R, . has 1 to 18 carbon atoms
Child alkyl, cycloalkyl of 3 to 1 carbon atoms
aralkyl of 7 to 12 carbon atoms, phenyl or
is substituted with 1 to 3 alkyl of 1 to 4 carbon atoms
phenyl, R,2 and R. 3 is 1 to 4 carbon atoms
Child alkyl, phenyl, alkyl of 1 to 4 carbon atoms
Phenyl substituted with 1 to 3 of Kyl or R, 2 and R
, 3 taken together -(CH2)a- or one(CH
2) b-○-(C ratio) c-, a is 3, 4, or 5
or b is 1, 2 or 3 and c is 1, 2 or 3, provided that
b and c are 2, 3, or 4, and furthermore, R
,2 and R,3 may be the same or different.
with the proviso that R,4 is hydrogen or phenyl. Seal
Chain basis,. When is tetrahydropyranyl, in this specification
Tetrahydrof any hydroxy moiety of the PG-type intermediate
Pyranyl ether derivatives inactivate hydroxy-containing compounds
p-toluenesulfur in a neutral solvent such as dichloromethane.
2, in the presence of an acid condensing agent such as phosphoric acid or pyridine hydrochloride.
Obtained by reacting with 3-dihydropyran. dihydropi
Ran is preferably in large stoichiometric excess, preferably in stoichiometric excess.
It is used in 4 to 10 pitches. The reaction is usually 20 to 5
Complete within 1 hour at 0°C. The blocking group is tetrahydrof
When ranyl, 2,3-dihydropi as described in the previous section
2,3-dihydrofuran is used instead of ran. The blocking group has the formula -C(OR,.)(R,2)-CH(R,3
)(R,4) (in the formula R,.,R,2,R
,3 and R,4 are as defined above), as appropriate
The reagent is a vinyl ether, such as isobutyl vinyl ether.
or formula C(OR,.)(R,2)=C(R,3)(
R, 4) (in the formula, R, ., R, 2, R, 3 and R, 4 are the above
in any vinyl ether (as defined in )
some or unsaturated cyclic or heterocyclic compounds such as monocyclic
Chlohexen-1-ylmethyl ether, or 5,6-
Dihydro-4-methoxy-2-pyran. C. C.B. Reese, etal J
okawa MI of the Chemical S ratio
See 89, 3366 (1967). Like that
Reaction conditions for vinyl ethers and unsaturated compounds
is similar to that for dihydropyran above. R,o
The blocking group is removed by mild acidic hydrolysis.
Ru. For example {1} hydrochloric acid in methanol, {2) acetic acid, water and
Mixture of tetrahydrofuran or '3'tetrahydrofuran
Reaction with aqueous (citric acid) or aqueous phosphoric acid during the run.
Hydrolysis of the blocking group is achieved at temperatures below zero. Specification
The charts in this book represent the novel compounds disclosed in this specification.
describes the method by which it is prepared. For each starting material and resulting product in the chart
Such compounds may be present in enantiomerically pure form or in
obtained as a mixture of nanomers or
As such, by the means available in
I can get bored. Chart A is disclosed herein.
Bicyclic lactol useful in the production of POD type compounds
The method by which the intermediate is made is given. The starting materials for formulas are those well known in the art or
easily produced by methods known in the art.
For example, JomM10ftheAmehcanChemi
See calS ratio ity931490 (1971)
thing. The compound of formula × is then converted into the corresponding formula or formula
It is converted into a compound. The formula fox compound is derived from the formula phantom compound, for example by Collins reagent or
Produced by oxidation using John's reagent. This technique
Conventional reaction conditions known in the art are used. Formula x W
using methods known in the art from the formula x compound.
is produced by silylation. For example, neve chloride
Tyldimethylsilyl. For reference, Pierce
e) Silylation of organic compounds, Pierce Chemical
Pani (Pierce Chemical Co) Rock Huo
See code (R ratio k phantom rd) m (19 spots). Shikikari
The compound is then converted to the formula foxketone by thioketalization.
It is converted to ×m. Reagents such as 1,2-ethanediol are used for this purpose.
Used in the presence of Lewis acids such as boron fluoride etherate
be done. The reaction is conveniently carried out at room temperature and usually takes place within a few hours.
Proceed to completion. The formula x V primary alcohol is
is made from either a compound of formula xW or a compound of formula Xm.
Preparation is by methods known in the art.
It progresses through the splitting of the ether. For example, this technique
As is known in the art, boron tribromide is convenient for this purpose.
commonly used. The reaction is methylene chloride or n-pentane
Proceeds advantageously at temperatures below 0°C in diluents such as
do. Corey in the conversion of formula x W to formula x V compound
(Corey) etc.JomM10f enemy American
Chemical Society94, 6190 (19
72) method is used. The alcohol in the formula x V is
The aldehyde of the corresponding formula × is transformed by oxidation.
Ru. This oxidation involves
Lin's reagent is advantageously used. The compound of formula × town is formula ×
Produced from the compound W by Wittetsu alkylation
Ru. Reagents known in this technology or in this technology
Reagents made by known methods are used. Trance
Enone lactone is obtained stereospecifically. D. Sex
D. Japan Wa ship wonhetal
) Jo Yamahada 1 of Organic Chemist
See H 30, Total 0 (1965) for reference.
In the production of formula × skin compounds, certain phosphonates are
Used in Itetsuhi reaction. These phosphonates are of the general formula. ) where L and R7 are defined above (but cis-CH=CH
(not one CH2CH3) and R,5 is 1 to 8 carbons
It is an elementary alkyl atom. The above single-pronged phosphone
The sheets are made by methods known in the art. Above
See Wadsworth et al. cited. appropriate fat
Esters of acids of the group are made using n-butyllithium.
Condensation with the anion of dimethylmethylphosphonate
It is convenient to be For this purpose acids of the general formula are preferred in the form of lower alkyl esters.
Preferably it is used in the form of methyl or ethyl ester. For example, the interaction of the acid corresponding to methyl ester with diazomethane
Easily obtained by reaction. For example, R? When , then T and s are as defined above, and R3 and R4 of the L part are
Both are hydrogen, but the corresponding phenoxy or substituted
phenoxyacetic acid is known or readily available in the art.
can be obtained using this technology. What is known in this technology is that the R7 section is
This includes cases where it is something like . Phenoxy
, (o-, m-, or p-)triyloxy, (o-,
m-, or p-)ethylphenoxy, 4-ethyl o-
Triyloxy, (o-, m-, or p-)bropylf
Phenoxy-, (o-, m-, or p-)-t-butylph
phenoxy, (o-, m-, or p-)fluoropheno
xy, 4-fluoro2,5-xylylooxy, (o
1, m-, or p-)chlorophenoxy, (2,3-
,2.4-,2,5-,2,6-,3,4-1, or 3,
5-) dichlorophenoxy, (o-, m-, or p-
) trifluoromethylphenoxy, or (o1.m-
, or p-)methoxyphenoxy-. even more 2-fs
Phenoxy- or substituted phenoxyprobionic acids are readily available.
Therefore, only one of R3 and R4 of the L part is methyl.
and R7 is phenoxy or substituted phenoxy
It is useful for producing acids of the above formula. These 2-pheno
The xy- or 2-monosubstituted phenoxypropionic acids are R? Department
The minute is p-fluorophenoxy-, (o-, m-, or p-fluorophenoxy-, (o-, m-, or p-fluorophenoxy-,
-) chlorophenoxy-, (2,3-,2,4-,2,
5-,2,6-,3,4-, or 3,5-) dichlorof
phenoxy, (4- or 6-)chloro
C-, phenoxy, (o-, m-, or p-)trilo
xyloxy, 3,5-xylyloxy or m-trifluoro
Including those for methylphenoxy. Finally, many
2-methyl-2-phenoxy- or (2-layer fusumapheno
xy)propionic acids are obtained. Both R3 and R4 of the L portion are methyl, and R7
is phenoxy or substituted phenoxy.
It is useful for coming. These 2-methyl-2-pheno
xy- or (two-layer) phenoxypropionic acid is R
7 is phenoxy-, (0-, m-"or p-") chlorophyll
Enoxy-, (2,3-,2,4-,2,5-,2,6
1, 3, 4, or 3, 5) dichlorophenoxy
Including those of the case. Other phenoxy-substituted acids
For example, Q-halo fats can be prepared by methods known in the art.
Sodium phenoxide or substitution of aliphatic acids or esters
Ether utensils for use with sodium phenoxide
It can be easily obtained by Williamson synthesis. In this way, (T)s-substituted sodium phenoxide is used as an example.
For example, Q-chloroaliphatic acid or its alkyl ester derivative
When reacted with a conductor while heating, it produces the acid of the general formula above.
It can be recovered from the reaction mixture by conventional purification techniques.
be done. Furthermore, when R7 is penzyl or substituted penzyl
Phenyl substituted acids of the above formula are available. For example, when R3 and R4 of the L portion are both hydrogen, the following
of phenyl or substituted phenylpropionic acids are available.
Ru. (o-, m-, or p-)chlorophenyl-, p-fluor
olophenyl, m-trifluoromethylphenyl,
(o-, m-, or p-)methylphenyl-, (o-,
m- or p-)methoxyphenyl, (2,4-,2
,5- or 3,4-)dichlorophenyl, (2,3-,
2,4-,2,5-,2,6- or 3,4-dimethyl
Phenyl-, or (2,3-,2,4-,2,5-,2
, 6-, 3, 4-, or 3, 5-) dimethoxyphenyl
−. When only one of R3 and R4 in L, min is methyl,
For example, the following 2-methyl-3-phenyl or substituted phenyl
Propionic acids are obtained. i.e. phenyl, o-k. lophenyl-, (o- or
p-)methylphenyl-, (o-, m-, or p-)methyl
Toxyphenyl-, (2,4- or 3,4-)difluoro
lophenyl-~2,3-dimethylphenyl-, and (2
．． 3-,3,4- or 4,5-)dimethoxyphenyl-
. When R3 and R4 are both methyl, for example, the following 2,
2-dimethyl-3-phenyl or substituted phenylpropio
Acids are available. i.e. phenyl- and p-methylphenyl oR3 and R
When only one of 4 is fluoro, for example, 2-fluoro
-3-phenylpropionic acid is obtained. Phenyl-substituted acids (above when R7 is pendyl)
can be prepared by methods known in the art, e.g. with the appropriate methyl
- or fluoroacetic acid, secondary amines (e.g. diiso
propylamine), n-phthyllithium and organic diluent
(e.g. tetrahydrofuran) with appropriate substitution.
obtained by reacting with pendyl chloride. The above acid can thus be obtained by the following reaction. upper cloth
The reaction normally proceeds smoothly at 0°C. The product acid is recovered using conventional methods. R7 is
For the acid of the above formula in the case of n-alkyl, many such
Acids are readily available. For example, L, part R3 and R4 are
When both are hydrogen, butyric acid, bentanoic acid, hexanoic acid,
Hebutanoic acid and octanoic acid are available. For example, when only one of R3 and R4 of L, moiety is methyl,
The following 2-methylalkanoic acids are available. i.e. butyric acid, bentanoic acid, hexanoic acid, heptanoic acid,
and octanoic acid. For example, one of R3 and R4 of L, part
When is fluoro, the following 2-fluoroalkanoic acids are
Available. i.e. butyric acid, bentanoic acid, hexanoic acid, hebutanoic acid and
Bioctanoic acid. R7 is alkyl, R3 and R4 of the L part
The acids of the above general formula when is fluoro are the corresponding 2-
Oxoalkanoic acids i.e. butyric acid, bentanoic acid, hexoalkanoic acids
Conveniently derived from Sans, heptanoic acid, and octanoic acid
It will be done. From these 2-oxoalkanoic acids, the corresponding 2,2
- Conversion to difluoroalkanoic acid
proceed by methods known in the art using chemical reagents.
nothing. For example, using MoF8・BF3 for fluorination is
It's advantageous. When R7 is 1-butenyl, the formula x W28
-Carboxaldehyde corresponding to 28-(2-formyl
-trans-1-ethenyl) compound, followed by
By the Grignard reaction using the reagents produced, the formula ×
The suppressor compound is made from the formula xW compound. Next, a (class S)-3-hydroxy compound corresponding to the formula ×W
, and optionally transform it into the formula x skin compound using Collins reagent.
Upon oxidation, Y is trans-CH=CH-, R5 and R
The formula for 6 hydrogens is converted into a skin compound. Y is sissu
For CH=CH-, the formula × style compound follows photoisomerization.
by separation of the resulting mixture of trans-cis isomers.
able to make. Photoisomerization is about 2800 to 4000 angstroms.
A conventional photon source that can produce photons with wavelengths between
Proceed using. Wavelength of approximately 3500 angstroms
using a conventional photon source capable of producing
It is preferable to Equilibrium mixture of cis and trans isomers
Irradiation continues until . The progress of photoisomerization is according to the conventional method
methods such as silica gel thin layer chromatography (TLC)
Matched using Then, using the conventional method, the resulting
The equilibrium mixture is separated. For example, silica gel chromatography
It is advantageous to use graphics. Y is -CH2C mountain
The formula
It is advantageous to make it by catalytic hydrogenation using
. However, when X is a thioketal, an extremely large amount of catalyst
or preferably NaB in methanol
4 must be used at ambient temperature. Formula XX compound is
By converting the 3-oxo moiety to the M5 moiety, the formula ×W3
-Made from oxo-bicyclic lactones. The above 3-oxo bicyclic lactone (formula x W) is
Following reduction of the so moiety, 3Q- and 38-hydroxy
By separation of Pima-classes, the corresponding 3 in case of or
Q- or 38-hydroxybicyclic lactone. This reduction involves esters or acid groups or carbon-carbon double bonds.
(when such a reduction is undesirable)
If a known ketotic carbonyl reducing agent is used that does not
It will be done. Examples of these reagents are metal borohydrides, esp.
Sodium, potassium and zinc borohydride,
thium (tritertiary poxy) aluminum hydride
metal trialkylboronohydride, e.g.
Lithium trimethoxyborohydride, lithium borohydride/
・Idride etc. Reducing carbon-carbon double bonds
If it is not necessary to use borane, e.g.
Ran (bis-3-methyl-2-butylborane) as its substitute.
Use instead. c-15 is an epimerically pure protein
Taglandin is manufactured by methods known in the art.
The 15-epi compound is separated from the mixture. For example, it is useful to use silica gel chromatography.
It is advantageous. The corresponding 3- from the 3-oxo bicyclic lactone
For conversion to methoxy bicyclic lactone,
The 3-hydroxy moiety of the 3-hydroxy dihydrolactone
Alkylation by methods known in the art. The alkylation mentioned in the previous section is preferably carried out by, for example, a Lewis acid.
(e.g. trifluoride shelving ether compounds, aluminum chloride
or a fluoroside acid).
Proceeds by reaction between chthon and diazomethane. For reference, please refer to Fieser et al.'s "Organic Synthesis Reagent" (Reag.
Enji for 0rhokon ni S skin thesis), Jo
Nwiley & Sons, New York, New York
See York (1967), especially p. 191. appropriate inactivity
diazo in a diluent, preferably diethyl ether.
3-Hydroxybicyclic R produced above with a solution of methane.
The reaction is carried out by mixing with chthone. this
The reaction proceeds at approximately 25°C. Alkyl of 3-hydroxy compounds
One alternative to trifluoride etherification is fluorine trifluoride etherification.
By reaction with methanol in the presence of compounds. Thus, methanol and trifluoride shelf ether compounds
was reacted with a 3-hydroxy compound at 25oo, and the reaction
Verify the response by thin layer chromatography (TLC)
It is convenient. 3-oxo bicyclic lactone is this
and Grignard reagent CH3Mg halo (where halo is chloro,
The corresponding (S)-3-methyl bicyclic lactone when the pigeon is a mixture with
converted to. Then, as is known in the art, e.g.
Hydrolyzing Grignard Sentai using a saturated aqueous solution of
do. 3-oxo compound (S)-3-methyl compound
Another method for converting to is the 3-oxobicyclic lacto
By the reaction between aluminum and trimethylaluminum. To separate these (S)-3-methylepimers,
A preferred method is to prepare the corresponding C-
By separation of 15 epimers. Therefore, the corresponding PG type
Silica gel chromatography or high pressure liquid
body chromatography (HPLC), thereby
The C-15 epimer is separated. Next, the formula XX compound is
The above procedure converts any free hydroxy moieties into R,o
From a compound of formula
I can't believe it. Next, the formula ×XI compound can be obtained from the formula ×× lactone by its corresponding
By reduction to lactol, compound of formula
It will be created. Using methods known to the art. example
For example, diisobutylaluminum hydride is
It is used in Shi-7pi0. Diagram B is created according to diagram A.
The formula ×XVI lactol is expressed as
We provide a method for converting into a Kisser PG intermediate. formula
×XVO compound is (carbalkoxy-methylene)
Triphenylphosphorane R crab00C-CH=P(C6&
)3, where R2 is as defined above.
It is obtained from the formula ×XVI lactol by the H reaction. React at 25°C using methods and reagents known in the art.
It is advantageous to carry out The compound of formula ×XVm is then
obtained by reduction of the ethylene group in the carboxyl-containing side chain.
It will be done. For this purpose, reduction of Y or R7 (such reduction
Reducing agents, such as water
of palladium on carbon or rhodium on alumina
used in the presence of a catalyst such as Mild conditions are sufficient.
and separate the product mixture by chromatography.
It is convenient. The formula x XIX alcohol is, for example,
Thiium aluminum hydride or lithium trimeth
By reduction with xyaluminum hydride, the formula
Obtained from Vm compound. Jethyl ether or tetra
It is convenient to use solvents such as hydrofuran
. Formula ×XX compound is prepared by formula ×XIX alco in the presence of a base.
haloalkanoate, halo(CH2)gCOOR
, (where halo is chloro, furomo, or iodo;
R, is as defined above).
Obtained by Liamson synthesis. Examples of bases include n-butyllithium, phenyllithium
triphenylmethyllithium, sodium hydride,
Or use potassium t-poxide. 1 molar equivalent
It is preferable to use the same base. Alkanoates are used in approximately 100% stoichiometric excess
be done. Instead of haloalkanoic acid esters, salts, e.g.
For example, lithium chloroacetate is useful. After condensation,
Convert the salt to a compound of formula XX by methods known in the art.
Ru. dimethylformamide, tetrahydrofuran, dimethyl
Tylsulfoxide or hexamethylphosphoramide
It is convenient to carry out the condensation in such a solvent. In figure C
converts the formula x XXIlactol into the corresponding formula x XXm5-o
Methods are provided for converting to Kisser PG type intermediates. The formula ×XXO alcohol is produced by ring cleavage of lactol.
The hydroxyadehyde type and the resulting alkaline
The dehyde, e.g. methanolic or ethanolic sodium
Mborono Hydraid'Kyotte Expression x XXO First Class Al
Obtained by reducing to call. Instead
Preferably, the compound of formula
lithium aluminum hydride or dihydride at a range of temperatures.
Formula x XXI lactone by isobutylaluminum
Bound by gradual reduction. Create a compound with the formula ×XXm
uses Williamson synthesis. For example, the formula ×XX
O compound halo C Koichi (CH2)g-CH2-COO
R, [where halo is chloro, bromo, or iodo, and g is
haloalkanoic acids within the range [as defined in] or suitable
Condense with haloester. Usually, the reaction is n-butyllithium, phenyllithium,
trimethyllithium, sodium or potassium hydride
-butoxide is carried out in the presence of a base such as -butoxide. the
Alternatively, ortho-4-bromoalkanoene is preferably used.
Use Is such a reagent available or is there anyone familiar with this technology?
By method, a suitable halonite, e.g.
From Lil through the corresponding iminoester hydrohalide
It is made by Tetrahydrofuran or dimethylsulfo
oxides, and especially when using organolithium compounds.
is preferably dimethylformamide or hexamethyl
Condensation in phosphoramide is convenient. The reaction proceeds smoothly at -20 to 5,000 ℃, but it cannot be carried out at ambient temperature.
Now is preferable. Diagram D corresponds to the formula ×XXVI compound
Formula × Lm4-oxer PG type intermediate or formula × LW series
Method for converting to su-4,5-didehydro-PG type intermediate
is provided. When the formula×XXW compound is condensed, the formula×
Produces XXVO enols. For this purpose, hydrocarbyloxy, preferably alkaline
Koxymethylenetriphenylphosphorane is useful.
For reference, see Levin (Levi ship), J. Am. Che
m. S-like. See Vol. 80, p. 6150 ($19). base
, for example in butyllithium or phenyllithium
from a quaternary phosphonium halide, preferably at low temperature.
It is convenient to prepare the reagents at temperatures below -10°C. formula
×XXVI Lactol is mixed with the above reagent and 30 qo
The condensation proceeds smoothly within a temperature range of 13 to 10 degrees. higher
The reagent is unstable at high temperatures, while the condensation rate slows down at low temperatures.
undesirably slow. Preferred alkoxy for the above purposes
Examples of methylenetriphenylphosphoranes include methoxy
, etoxy, propoxy, isopropoxy, buto
xy, isobutoxy, s-butoxy, and t-butoxy
Toximethylenetriphenylphosphorane. arbitrarily
Alternative to alkoxymethylene trivenyl phosphoranes
and therefore the formula when R26 is hydrocarbyl
×XXVarious hydrogens such as those useful in the production of VO intermediates
Locarpyroxymethylenetriphenylphosphoranes are
Alkoxy, aralkoxy, cycloalkoxy,
and aryloxymethylenetriphenylphosphoranes
include. These hydrocarbyloxytriphenylpho
Examples of sulfolanes are 2-methyl-butyroxy, isobe
antiloxy, hebutyloxy, octyloxy, noni
Roxy, tridecyloxy, octadecyloxy, base
ndiloxy, phenethyloxy, p-methyl phenethyloxy
Roxy, 1-methyl-3-phenylpropyloxy,
Cyclohexyloxy, phenoxy, and p-methyl
Phue/xy, phenoxymethylene triphenyl phosphor
It's a run. For reference, see "Organic reaction" (R on 0r scales).
eactio ship) Volume 14, pp. 346-348, John Woo
Iley & Sons, Inc. (New York, New York)
(1969). Next, the formula x XXVO enols
The intermediate is hydrolyzed to lactols of formula xXXVm.
This hydrolysis is carried out under acidic conditions, e.g. perchloric acid or vinegar.
It is done with acid. Tetrahydrofuran does this reaction
A diluent passed through the mixture. 100 to 100 qo
Use reaction temperature. The length of time required for hydrolysis is partially determined by the hydrolysis temperature.
Determined by For example, acetic acid-water-tetrahydrofuran
at approximately 60 qo and several hours are sufficient to achieve hydrolysis.
It's a minute. Next, the formula × XXIX compound is the formula × XXVO la
Oxidation of cutol to lactone leads to formula ×XXVm
Made from a compound. This conversion is carried out using silver oxide as a converting agent, followed by
Treat with pyridine salt. Then the formula x XXIX lactone is
, follow the steps mentioned above for these changes.
Converting the free hydroxyl moiety to a blocking group with R,o
may be converted to the formula ×L ether by Next, the formula × LI compound is obtained from the formula × L lactone to lactol
is made from a compound of formula ×L by reduction to . for example
, as mentioned above regarding the reduction of lactone to lactol.
Use diisobutylaluminum hydride.
The formula x LI lactol thus created is the formula XLm or
is used instead for the production of XLIV compounds. formula
For the production of the ×L-dish compound, first, the formula XLI lactol is
By reducing the lactol ring, the formula x LI lactol becomes the formula x L
Converted to O compound. The formula × LO compound can be obtained by Williamson synthesis.
It is converted to a compound of formula ×Lm. Formula x LI compound to formula
× Conversion to LO and subsequent formula × LO compound to formula
×Methods and corresponding reagents used for conversion to Lm compounds
is the conversion of a compound of formula ×XXI to a compound of formula ×XXO and
and then conversion from formula XXXO compound to formula ×XXm compound.
This is similar to the method proposed for Thus the formula ×
L-blood 4-oxer PG type intermediate is produced. Formula × LIV compounds are suitable (-carboxyalkyl)
Triphenylphosphonium bromide HOOC-CH2
-(CH2)g-CH2-P(C6day5)3Br[Here
and g is as defined above]
is made from a compound of formula x LI by chemical reaction. The reaction, as is generally known in this technology, begins with the environment.
(■-carpoxyalkyl)triphenyl at appropriate temperature
Sodium dimethyl sulfuric acid to phosphonium bromide
Mix the nylcarbanide and add the formula x LI lactol to this mixture.
Proceed by adding it to the compound. Then form like this
The carboxy hydrogen of the compound that is
Therefore, it is converted to R, part. In this way, the formula x LIV sissu
A 4,5-didehydro-PG type intermediate is produced. Diagram E
is the formula × LVI compound by the corresponding formula × LVOPG type intermediate
Provides a method for converting into a compound or formula x LVmPG type intermediate.
Ru. Compounds of the formula
xyalkyl) triphenylphosphonium. My HOOC-C(R2)2-(CH2)g1C ratio1
using P-(C6Tsuru)3Br, followed by carbonization as below.
By converting the carboxy hydrogen to the R, moiety, the formula ×
Made from LVI compounds. The formula x LVm compound is
By catalytic hydrogenation of the su-5,6 single double bond, the formula ×LV
Made from O compounds. Hydrogenation known to this technology
method, but when X is a thioketal, very high
amount of catalyst is required. The mixture of compounds thus created
The compounds are conveniently separated by silica gel chromatography.
be separated. In Figure F, a PC-type intermediate of formula LI is shown herein.
The corresponding new formula LVOPGD-also revealed in
A method for converting into 98-PGD type compounds is provided.
Ru. Compounds of formula LI can be converted to corresponding compounds of formula LO by oxidation.
be transformed. Reagents suitable for this purpose may be used as known in the art.
Jones reagent or Collins reagent used.
The formula Lm compound is then converted to formula LO by ring carbonyl reduction.
Made from chemical compounds. Known prostaglandin derivatives
The method used for the ring carbonyl reduction of
It is. Following this reduction, 9Q produced in the reduction step
- and 98-hydroxyepimer chromatography
Perform separation by Prostaglandin cycloventa
The carbon ring carponyl reduction is performed using known prostanoic acids as described above.
using methods known in the art for the ring carponyl reduction of
carried out using For example, Bergström et al., A.
Water iv. Kemi. , vol. 19, p. 563 (1963 prison),
Acta. Chem. Scand. Volume 16, page 969 (1
962) and British Patent Specification No. 1097533.
reference. Does not react with carbon-carbon double bonds or ester groups
Use any reducing agent such as The preferred reagent is hydrogenation
Lithium (tritert-butoxy) aluminum, metal shelf water
hydrides, especially sodium, potassium, and zinc shelf hydrogenations
metal trialkoxy shelchloride, e.g.
Rimethoxyborohydride. As above, C-
The above mixture of alpha and beta hydroxy isomers at position 9
The compound is an acid oxyconductor of the known isomeric prostanglandins.
separation of similar pairs of classes by methods known in the art.
Thus, it is separated into the individual alpha or beta isomers. For example, Bergström and Glans cited in the previous section
Grans et al., J. Biol. Ch
em. Volume 240, page 456 (1965), and Green
(Green) et al., J. LipidResea [ch nephew
See Kago page 117 (19 Mu). Instead, the useful amount
The separation method is a partition chromatography procedure (normal phase and reversed phase).
(also), preparative thin layer chromatography and countercurrent distribution procedures.
be. Formula LW compounds are then of formula Lm or formula LI compounds.
Substituting a 9-hydroxy hydrogen with a blocking group by R,o
made from a formula L compound or a formula LI compound by
Ru. Directions for use include substitution of hydroxy hydrogen by blocking group.
This is what was mentioned above. When X is -Si(G2)3
Formula LW compounds have a tertiary group than any blocking group by R,o.
By selective hydrolysis of the petyl-dimethylsilyl group,
Converted to the corresponding formula LV compound. This selection of silyl groups
Selective removal is accomplished by methods known in the art.
Ru. For reference, Collie et al., J. Am. Chem. S.M.
See Vol. 94, p. 6190 (King 1972). specifically for this purpose
A useful reagent is tetra-n fluoride in tetrahydrofuran.
-butyl ammonium. Then you can get it like this
When a 11-hydroxy compound is oxidized at the C-11 position,
, yielding the corresponding 11-oxo compound. Familiar with this technology
Use the procedures provided. For example, Tetrahedron reta
See 2235 (1974). useful for this purpose
The reagent herein refers to a brostaglandin type product or
Hydroxy moiety attached to the cyclobentane ring of the intermediate
Oxidizing agents discussed as useful for oxidizing
(e.g. Jones reagent). In addition, formula L
The V compound has the formula L when X represents a thioketal moiety
It is produced from N compounds by dethioketalization. This conversion involves several dethioketries known in the art.
Any one of the following is useful. For example, “1972
``Organic Synthesis Report'' (Ann female I Report is i
n ○r scales n s skin thesisssl972), Jay
・McMurray and R. P. Miller (J. McMu)
nyand R. B. Mmer) line, academic play
New York, NY, 1973 King, 11
See references cited on pages 2-114. Therefore
A very useful procedure for this purpose is the use of chlorinated and oxidized steels.
consisting of reacting a compound of formula LW in a mixture with copper
. Dethioketalization progresses to completion within a few hours, but a thin layer of
Verify by chromatography and run the reaction at ambient temperature.
is convenient. The compound of formula LW then has an assignment by R,o.
created from a compound of formula LV by removal of the desired blocking group.
Ru. Reaction conditions described above for removal of blocking groups by R,o
and using reagents. In the previous stage of Figure F and the preceding figure
At this stage, it is better to make X a silyl than a thioketal.
preferable. Furthermore, when X is a thioketal, the blocking group is blocked by R and o.
Optionally omit introduction (LI or LO to LW). subordinate
Therefore, removal of such a blocking group, ie, removal of L from LV.
is also omitted. Next, the formula L skin compound has R5 as the main
Any C-15 present in the compound of formula LW when chilled
made from a compound of formula LW by separation of an epimer mixture.
It will be done. For this separation, R is methyl and a conventional silica gel is used.
using liquid chromatography or high pressure liquid chromatography.
It is preferable to use Figures G, Day, 1, and J are 3-O
Kisser 3,7-interm-phenylene-4,5,6-
tri/ru or 3,7-interm-phenylene-4,
Provides a method for making 5,6-trino-PG type intermediates
are doing. For Figure G and Day, R7 is one (C ratio) m CH3 or
is preferably (m, T, s are as defined above)
stomach. In Figure 1 or J, R7 is preferably cis-CH=CH-
CH2-CH3 or (T and s as defined above)
Provided are methods for making the novel compounds herein when
has been done. Therefore, Figures G-J show all inter m-phenylene
Methods for making useful intermediates for making PG-type compounds
is provided. In Figure G, bicyclohexene LXI
Both endo and exo types are available or compatible with this technology.
racemic or enantiomeric forms by known methods.
It is made in its pure form. See US Pat. No. 3,711,515. By the method in Figure G
Thus, the endo or exo starting material is in the final part of formula LXXm.
Produces an interstitial body. Oxetaso LXm, Formula XLI Picyclo
Hexene and the formula [wherein R63 is hydroxyacyl of the formula, R64 is hydrogen,
alkyl of elementary atoms or aral of 7 to 12 carbon atoms
However, alkyl or aralkyl has 0 to 3 ha
[substituted by atom] with an aldehyde
can be obtained. Are the above pendylaldehydes available or available?
easily made by methods known in the art. Examples of such compounds within this range are:
and the formation of formula LXO oxetane is achieved by the formation of
Achieved by photolysis of a mixture of hexene and aldehyde
be done. Bicyclohexene in excess of molar equivalents, e.g.
It is preferable to use the base at 2 to 4 times the stoichiometric amount. The solvent is
A photochemically inert organic liquid, such as benzene or hexafluoride.
liquid hydrocarbons, including san, 1,4-dioxane, and
It is Jethyl Ether. The reaction takes place under environmental conditions, e.g.
It is conveniently carried out at q0, but about
It is carried out over a wide temperature range up to the boiling point. low or medium pressure
Mercury vapor lamp, e.g. one with a peak of 3500A
Irradiation is performed by Such a light source is
Southern New England, Middletown, Texas
Available from LutraViolet. Instead, wide
It emits a wavelength of a wide spectrum, but the input voltage is 3000~3700A.
Use a lamp with a filter that allows only the light to pass through.
You may. For consideration of photolysis, D.R.A.
Nord (D.R. ~ Hada ld) “Advances in photochemistry” (Adv
ancesinPhotochemist), Volume 6,
W. A. Noyes et al.
Willy Interscience, New York 19th year
, pp. 301-423. Formula LXO compound to formula LX
The cleavage of the oxetane ring to create the m-compound is a primary
achieved with alkali metals in the presence of amines or alcohols
It will be done. Preferred is 1'thium or butyl in ethylamine.
Sodium in alcohol. L.G.A.L.
L.J. AItman et al., Synthesis 129
(197 Mountain Year). Cleavage conversion is performed using ethyl acetate or ethyl acetate.
Inert metal catalysts in ethanol, e.g. Pd on carbon
It is also achieved by catalytic hydrogenation. The compound of formula LXN is
, preferably two hydroxyl groups are replaced by R63.
boxacyl group, i.e.
is obtained from the formula LXm diol by blocking it as
It will be done. For example, diols can be mixed with acid anhydrides such as acetic anhydride, or
Treatment with acyl halide in tertiary amine. in pyridine
Particularly preferred is pivaloyl chloride. Resources useful for this transformation
Other carboxyacylating agents are known to this technology.
or easily obtained by methods known in the art.
carboxyacyl halides are preferred.
or chlorides, bromides, or fluorides
, that is, R64C(0)CI, R64C(0)Br,
or R64C(0)F, and carboxylic acid anhydride (R64
C-)20 (R-Europe is as defined above). Preferred reagents are acid anhydrides. No acids useful for this purpose.
Examples of hydrates include acetic anhydride, propionic anhydride, butyric anhydride,
Pentanoic anhydride, anhydrous/nanic acid, tridecanoic anhydride, anhydrous
Water stearic acid, anhydrous (mono, di, or tri) chloroacetic acid
acid, 3-chlorovaleric anhydride, 3-chlorovaleric anhydride (2-promoethyl anhydride)
)-4,8-dimethylnonanoic acid, cyclopropane anhydride
Acetic acid, 3-cycloheptanepropionic anhydride, anhydride 13
- Cyclobentane tridecanoic acid, phenylacetic anhydride, no
Water (2 or 3)-phenylpropionic acid, 13-phenyl anhydride
Phenyltridecanoic acid, phenoxyacetic anhydride, benzoic anhydride
Acid, anhydride (o, m, or p)-promobenzoic acid, anhydride 2
, 4(or 3,4)-dichlorobenzoic acid, p-trianhydride
Fluoromethylbenzoic acid, 2-chloro-3-nitro anhydride
Benzoic acid, (o, m, or p)-nitrobenzoic anhydride,
(o, m, p)-tolylic anhydride, 4-methyl anhydride
3-nitrobenzoic acid, 4-octylbenzoic anhydride, anhydrous
(2, 3, or 5)-biphenylcarboxylic acid, anhydride 3-
Chloro-4-piphenylcarboxylic acid, 5-isoproanhydride
Pyr-6 nitro-3-biphenylcarbosoic acid, and
Water (1 or 2)-naphthoic acid. The choice of anhydride is
Varies depending on the R64 content in the final acylated product
. For example, when R64 is methyl, acetic anhydride is used.
Ru. When R64 is 2-chlorobutyl, anhydrous 3-chlorobutyl
Use rosaceous acid. When R64 is hydrogen, it is formyl. Formylation can be carried out using procedures known in the art, e.g.
compound and mixed anhydride of acetic acid and formic acid, or formyl
It is carried out by reaction with midazole. For example, fee
Zar et al. "Organic Synthesis Reagents" John Wiley &
pp. 4 and 40 (1967) and cited therein.
See references. Instead, use the formula LXm diol
2 equivalents of sodium hydride followed by excess ethyl formate
Make it react. In the formula LXW, R68 is penzoyl, a substituted compound.
ndzoyl, monoesterified phthaloyl, and substituted or unsubstituted
Capping groups are also represented, including substituted naphthyls. Methods known in the art can be used to introduce these blocking groups.
Use. If such R63 is as defined above
Formula R630 Aromatic acids such as benzoic acid are used as dehydrating agents.
For example, in the presence of zinc chloride or phosphoryl chloride, a compound of formula LXm
or the aromatic acid of formula (R63)20.
A hydrate is used, for example benzoic anhydride. but preferably
is an acyl halide R63CI such as penzoyl chloride.
, pyridine, tertiary amines such as triethylamine etc.
is reacted with a compound of formula LXO in the presence of . Reactions can be carried out in various ways using general procedures known in the art.
carried out under conditions. Generally mild conditions e.g. 20-6
Using 0°C, the reactants are placed in a liquid medium, e.g.
Lysine, or benzene, toluene, or chloroform
The contact is carried out in an inert solvent such as Acylating agent is stoichiometric
Use in stoichiometric amount or in excess. For the purposes of this invention, R mother
Examples of reagents provided include “Regarding the use of acyl protecting groups”.
See discussion above. Formula LXIV acetal is prepared using dilute mineral acids, acetic acid or formic acid, etc.
aldehyde by acid hydrolysis known to this technology.
Converted to LXV. Like acetone, dioxane, and tetrahydrofuran
Use a suitable solvent. To convert from LXV to LXIX,
R66 is hydrogen, but is it a blocking group as defined below?
is optional. For efficient use of Wittig reagent, R66 can be used as a blocking group.
It is preferable to do so. Formula LXIV when R68 is hydrogen
When using a compound, the formula LXV intermediate has hydrogen at R66.
have. When R66 is a blocking group, LXV to L
Prior to conversion to XVI, reaction with appropriate reagents as described below.
This is easily provided by the application. The blocking group R mirror is
The hydrogen of the droxyl group is exchanged with hydrogen, and as much as the hydroxyl group
It is not attacked by the reagents used in each conversion and is reactive.
and later production of prostaglandin-like products.
Any group that can replace hydrogen at a later stage in the formation
. Some blocking groups such as tetrahydropyranyl, acetyl
, and p-phenylbenzoyl are known to the art.
(Colley et al., J. Am. CheSM. 9 mirror cover 1491
(1971). ). What was found to be useful was [R6 on a'
carboxyacyl, i.e. acetyl, within the range of 5;
Blockade with 'b'R, o, penzoyl, naphthoyl, etc.
group, and [c}-Si(G,)3 (G, as defined above)
). The hydrogen atom of the hydroxyl group is
To replace the oxyacyl capping group, use a method known to the art.
method is used. Reagents and conditions for R68 on compounds of formula LXIV
is discussed above. When the blocking group is R, o, suitable
The appropriate reagents and conditions are as defined above. blocking group
When is a silyl of formula 1 Si(G,)3, we know this technique.
By the procedure described, formula LXV compounds can be converted into silica of formula LXV.
is converted into a derivative. For example, Pierce (Pierce) ``Silyl of Organic Compounds''
Pierce Chemical Company, Rockford, Illinois
See (196 Mother Prison). The silylation required for these conversions
The agent is known to the art or known to the art.
It is made using the same method. For example, post
rSilicones and other silicone compounds "Rainhole"
Do Publisher, New York, New York (194g King)
See. These reagents contain tertiary bases such as pyridine.
used at temperatures ranging from about oo to 150 qo in the presence of
be done. Tri-substituted monochlorosilanes for this purpose
Examples are chlorotrimethylsilane, chlorotriisobutylene
Lucilan, chlorotriphenylsilane, chlorotris (
p-chlorophenyl) silane, chlorotri-m-tolyl
silane, and tribenzylchlorosilane. That cost
Instead, chlorosilane is used together with the corresponding disilazane.
do. Other silylations suitable for the production of formula LXV intermediates
Examples of agents are bentamethylsilylamine, bentaethylsilylamine,
Rylamine, N-trimethylsilyldiethylamine, 1
,1,1 triethyl-N,N-dimethylsilylamine
, N,N-diisopropyl-1,1,1-trimethylsilyl
Rylamine, 1,1,1 tributyl-N,N-dimethy
Lucilylamine, N,N-dibutyl-1,1,1-tri
Methylsilylamine, 1-isobutyl-N. N, 1, 1
-tetramethylsilylamine, N-penzyl-N-ethyl
-1,1,1-trimethylsilylamine, N,N,1
, 1-tetramethyl-1-phenylsilylamine, N,
N-diethyl-1,1-dimethyl-1-phenylsilyl
Amine, N,N-diethyl-1-methyl-1,1-diph
enylsilylamine, N,N-dipyl-1,1,1-
triphenylsilylamine, and 1-methyl-N,N,
Includes 1,1-tetraphenylsilylamine. Formula L
To convert the XV compound to the formula LXW compound, Witty
The aldehyde group is converted to a moiety of formula by a H reaction. For this purpose, or (wherein L, , R7, and R53 are as defined above)
Phosphonyl prepared from organic chloride or bromide
Use um salt. These organic chlorides or bromides are not known to the art.
or made by any method known in the art.
. For example German published patent publication No. 2209 identified above
See No. 990. For the Wittig reaction, for example,
US Pat. No. 3,776,941 and cited therein
See literature. Compounds of formula LXW can be prepared by deblocking if necessary.
That's what you get. When the R muscle is damaged by carpoxyacyl, phenol
R66 on the base hydroxyl is hydroxyl in ethanol-water
For hydrolysis with sodium or potassium or carbonates
Therefore, hydrogen is selectively substituted. mix with other water
solvents such as 1,4-dioxane, tetrahydrofura
or 1,2-dimethoxychetane can be substituted. choice
It is best to carry out the hydrolysis at -15o to 25o
preferable. Higher temperatures may be used, but selectivity
It will decrease somewhat. Addition of the entire R muscle blocking group on a compound of formula LXW
Water decomposition is performed at 25°C when R66 is carboxyacyl.
Alkali alcohol in alcoholic solvent at a temperature of ~50°C
oxide, preferably sodium methoxy in methanol
This is achieved by When R66 is trialkylsilyl, acid or base water soluble
The liquid is used at 25°C to 50qo. Continue on Figure G
and using William synthesis to obtain the formula LX skin compound.
Ru. Halo(CH2)g-COOR formula LX skin phenol,
(Here halo is chloro, furomo, or iodo; g
and R, as defined above).
condensate with Usually n-butyllithium, Fe
Nillithium, triphenylmethyllithium, sodium hydride
Thorium, potassium t-topoxide, sodium hydroxide
, or carry out the reaction in the presence of a base such as potassium hydroxide.
Now. *． From formula LX style compound to formula LXK
Conversion can occur by any one of several routes known to the art.
achieved by. U.S. Patent No. 3,711,515
reference. In this way, alkenes LXW are converted to glycols LXR.
Droxylated. For this purpose, osmium tetroxide e.g.
For example, N-methylmorpholine oxide hydrogen peroxide and
The combination is a suitable reagent (Fieser et al., ``
Organic Synthesis Reagents” 690 pages, John Wiley &
Sands, New York (1967)). next
Several methods can be applied to obtain formula LXX products.
In one method, the glycol is converted into pis (alkanesulfonic acid).
) into Esther and then by the methods known to this technology.
Therefore, it is hydrolyzed to a compound of formula LXX (for example,
Patent Publication No. 1936676, Derwent Farr
(See Mudok total 6 pitches). Another method is glycol
via difluorates due to formolysis of
(See National Patent No. 3711515). Yet another person
The method is via cyclic orthoester. For this purpose
Cole LXK is reacted with orthoester of formula. During the ceremony
R? 4 is hydrogen, alkyl of 1 to 1 carbon atoms, or
Aralkyl of 7 to 12 carbon atoms, wherein alkyl
and aralkyl are substituted with 0 to 3 halo atoms,
Moreover, R75 is methyl or ethyl. The next lady style oar
A tester is created. In the formula, g, R,, R53, R6
6, R74, R direction, L, and R are as defined above.
be. The reaction progressed smoothly in the temperature range of -50o~1100℃
However, for convenience, 00°C to 150°C is generally preferred.
Ru. 1.5 to 10 molar equivalents of orthoeste with acid catalyst
use the file. The amount of catalyst is usually a small portion of the glycol weight.
For example, about 1%, a typical catalyst is pyridine hydrochloride.
, formic acid, hydrogen chloride, p-toluenesulfonic acid, trichloro
fluoroacetic acid or trifluoroacetic acid. Solvent the reaction
Among them, for example, benzene, dichloromethane, ethyl acetate,
Alternatively, it is preferably carried out in diethyl ether. generally
Finished in 2-3 minutes, TLC (basic silica gel Sakagami thin film)
Conveniently, verification is performed by layer chromatography). O
Lutester reagents are known to the art or
can be easily obtained by methods known in the art. For example, S.M. maque starting from a suitable nitrile
S.M. McElvain et al., JAm. Ch
em. S ratio. See Vol. 64, p. 1925 (p. 1942).
Examples of useful orthoesters include: bird
Methyl orthofluormate, triethyl orthoacetate
triethylorthopropionate, trimethylorthobutyrate, trimethylorthovalerate, trimethylorthooctanoate, trimethylorthophenylacetate, and trimethyl
Ortho(2,4-dichlorophenyl)acetate. o when R74 is alkyl of 1 to 7 carbon atoms;
Lutester is preferred, R74 is 1 to 4 carbon atoms
Particularly preferred are alkyl. Next, react the cyclic orthoester exemplified above with formic anhydride.
When applied, the formula [in the formula g, R,, R7, R53, R66
and L, as defined above]
arise. Formic anhydride refers to formic acid containing not more than 0.5% water.
That's true. The reaction is carried out with an excess of formic acid;
itself acts as a reaction solvent. Solvent e.g. dichloro
Methaso, benzene, or diethyl ether is usually
It may be present in amounts not exceeding 2% by volume of formic acid. Also
Organic acid anhydrides, such as acetic anhydride or alkyl orthophosphate
Steles such as trimethyl orthofluormate exist.
These are useful as desiccants for formic acid. anti
The reaction proceeds over a wide temperature range, but is performed at approximately 20 to 30 qo.
This is convenient and usually takes about 1 minute. last
The diol gestal above is suitable for those who are familiar with this technology.
by method, e.g. in the presence of a base in an alcoholic medium.
Converted to product LXX by hydrolysis. Examples of bases are sodium or potassium carbonate, or methoxycarbonate.
Sodium or potassium alkaline salts, including acid and ethoxide
It is a coxide. The reaction is carried out using a solvated decomposition reagent, e.g. methane.
This is conveniently carried out in an excess of alcohol or ethanol.
Ru. The temperature range is -50oo to 100oO. anti
The reaction completion time varies depending on the properties of R74 and the base, and
In the case of potash carbonate, when R74 is hydrogen, it progresses in 2 to 3 minutes.
However, when R74 is ethyl, it takes several hours. solvent
When chemical decomposition is allowed to proceed for too long or when conditions are
If too much, the ester group (R,) is removed now.
. However, these can be easily achieved by methods known in the art.
is replaced by See discussion below. Formula LXXI compound
is caused by the oxidation of C-15 hydroxy to 15-oxo.
is made from a compound of formula LXX. Therefore, as known in the art, 2,3-dichloro
5,6-dicyano-1,4-benzoquinone, activated diacid
It is advantageous to use manganese chloride or nickel peroxide.
(Feeser et al. ``Organic Synthesis Reagents'' John Wiley)
& Sons, Inc., New York 21, New York
(see pages 637 and 731). Then the formula LXXI compound
Silyl derivatives of C-9 and C-11 hydroxy hydrogens
produced from 15-oxo compounds by conversion to
It will be done. Using procedures known in the art. For reference
Pierce “Silylation of Organic Compounds” Pierce Chemical
Inc., Rockford, IL (1968).
To use silylation, proceed the reaction to completion.
Sufficient silylating agent must be used. This transformation requires
The necessary silylation reagents are known to the art or can be
made by methods known in the art. For reference
Post “Silicones and other silicon compounds” Rainho
Old Publishing, New York, NY (194g
King). Next, in the compound of formula LXX, first Y is cis
Photoisomerizing the compound of formula LXXI when -CH=CH-
, then e.g. Grignard reagent or (15-methyl intermediate
(when trying to make trimethylaluminum)
convert the C-15 oxo to the M5 moiety using
-When trying to make hydroxy compounds, carbonyl
15-methyl ether by reduction to alcohol.
When trying to make alcohol, alcohol is extracted from carbonyl.
Following reduction to
from a compound of formula LXXI by alkylation of the compound
It will be done. After this, the silyl group is mixed with water such as ethanol.
in the solvent (enough liquid to create a homogeneous reaction mixture).
Hydrolyzed using a dilute aqueous solution of acetic acid in water. 25
At °C, hydrolysis is usually completed in 2 to 1 hour. Further hydrolysis is carried out under an inert atmosphere, e.g. nitrogen or argon.
Preferably, it is carried out inside. Formula LXXm compounds have Y
When trans-CH=CH-1 and M and M9 are the same,
It is represented by the formula LXX compound. Instead, compounds of formula LXXm are of C-15 epimers.
It is made from formula LXXO compounds by separation. This way
Una separation is the method mentioned to achieve this goal in the previous figure.
(e.g. thin layer chromatography or high pressure liquid chromatography)
Proceed by Lahui). Regarding the figure date, the formula LXXW bisi
For example, clohexene has a well-developed side chain.
[In the formula, oxa or methylene] Oxetane (formula LXX
skin) and finally into the formula LXXXN compound.
It is shown. In the figure, R69 is hydrogen or an alkyl group of 1 to 4 carbon atoms.
and R7o is hydrogen, alkyl of 1 to 4 carbon atoms.
or the formula (G,)bui (where ○ is as defined above)
It is (original). To convert LXXW to LXXW in the figure
is the alkaline of the formula [Formula ヰZ3 and R69 are as defined above]
Use dehyde. Are such aldehydes available or known to this technology?
It is easily made by a method that For example, this transformation
The conditions are the corresponding stages in Figure G (i.e. from LXI to LXU)
is essentially the same as for The preparation of compounds of formula LXXXI is then carried out in the corresponding steps in Figure G (i.e.
(i.e. from LXO to LXVI)
However, the conversion from LXXW to LXXW is carried out catalytically.
is preferable. Next, convert LXXXI to LXXXW
The stages proceed in the same way and are the same as the corresponding fur stage in Figure G above.
Use the same or similar reagents and conditions. See Figure 1 below.
Then, the aldehyde LXXX in the figure is converted to 17,18-tet
Radehydro-PG intermediate (formula LXXXK) and 17,1
Method for converting to 8-didehydro-FG intermediate (formula ×C)
The stages are indicated. In Figure 1, the Wittig reagent is changed from LXXXW to LXXX skin.
, which is a haloalkyl compound of the formula or where R53 and L are as defined above.
made from the phosphonium salts of
U.Axen et al., ChemComm. 196 deities
(See King 303 and 197th King 602). Then the 17,18-tetrahydro compound LXXXK is produced.
In subsequent transformations, experiments similar to the corresponding reactions shown in the figure
Using drugs and conditions. Formula ×C conversion from formula LXXXK compound
Conversion to the compound -C3C is carried out as known in the art.
catalyzes hydrogenation from 1 to only cis-CH=CH-
By hydrogenation of product LXXXM using a catalyst such as
achieved. For example, "Feaser R Organic Synthesis Reagent" pages 566-56,
John Wiley & Sons, New York (
(1967). Rindler catalysis in the presence of quinoline
medium is preferred. References cited above the accent
reference. As stated above, Figure J is similar to Figure G or Figure H'.
The formula created by × the formula corresponding to the PG-type intermediate of CI ×
How to convert CW16-fa/xy PG type intermediate
providing. The compound of the formula
By cleavage of the 13,14-trans double bond by
, made from a compound of formula ×CI. Ozonolysis uses dry oxygen containing approximately 3% ozone.
Mixing Formula x CI Compounds in a Suitable Non-Reactive Diluent
Proceed by letting things bubble. For example, n-heki
It is advantageous to use sun. Ozone is familiar with this technology.
generated using the method described. For example, Feeser et al.
``Organic Synthesis Reagents'' John Wiley & Sons Company
(1967), pp. 773-77. The reaction is an analogy
Indication of termination by silica gel thin layer chromatography
or until the reaction mixture is rapidly diluted with a dilute solution of bromine in acetic acid.
Reaction conditions are maintained until there is no longer a color change. Then the formula ×
The Cm compound is prepared by blocking with the R65 blocking group and then by blocking the formula [
where R, 5, L, , T and s are as defined above]
made from a compound of formula × CO using a phosphonate of
It will be done. Phosphonates of this general formula can be prepared by methods known in the art.
Therefore, it is created. Although manufacturing and Wittig reactions proceed
See the above description of attached Figure A for a discussion of suitable reaction conditions.
Light. Formula × CW compound has 15-oxo moiety to M, moiety
is made from a compound of formula ×Cm by conversion to . Up
In particular, use the notation method described in Figures G and 2. Appropriate
Using phosphonates, various other R7 moieties can be expressed as
The method in Figure J is optionally used to introduce ×CO into the compound.
It will be done. Figure K is disclosed herein following the procedure of Figures L and M.
to create new PGD- and 98-PGD type compounds.
The corresponding formula × CRPGF2Q type intermediate is useful for formula
×CV Proposes a method for converting bicyclic lactone aldehyde
I'm offering it. Formula xCV compounds are known in the art. The compound is present in its two pure enantiomers, or
Any mixture consisting of both of these enantiomers
It can be obtained as Formula × CW compound is a compound of formula ×
Reagents and conditions similar to the preparation of the formula XXI compound of Figure A from
is made from the formula x CV compound using like this
, using methods commonly known in the art. Then the formula ×
The C skin compound is produced by formula ×XX compound from formula ×XW compound.
structure (Figure B), from formula × XXI compound to formula × XXm compound
Preparation (Figure C) of formula LXW compound from formula ×XXW compound
Manufacture (Figure D) or from a compound of formula ×L to a compound of formula ×L
using reaction conditions and reagents similar to the preparation of (Figure B)
, made from a compound of formula XC. Next, the formula x C-side compound
First (using the steps and methods described above), R,. by
Hydrolyze any blocking group and then when R5 is methyl
By separating the C-15 epimer the formula x CW compound
made from things. Methods described herein (e.g., serial
Kagel chromatography or high pressure liquid chromatography
). Formula XCK compounds are, for example, Jones or
First, use Collins reagent to calculate C-9 of the formula ×C skin compound.
Oxidize the hydroxyl and then the 9-
Ring carbonal reduction on the oxoPG-type intermediate is carried out, and this
From the 9-epimer mixture thus prepared, 98-hydro
Separate the quichepimer and finally from the formula XC skin compound above.
Following the procedure described for the conversion to a compound of formula ×C,
It is made from a compound of the formula x CW. Ring carbonyl reduction on
, and the 9-epimer mixture produced thereby.
The subsequent separation is performed by those familiar with this technique as described above.
Implemented by law. Diagram L is intermediate of formula CIPGFQ type
into the corresponding novel compounds of formula CVPGD type of the present invention.
provide a method to do so. Formula CI compounds are made by the methods and procedures described above.
Ru. CO compounds are cyclo(alkyl boronization)
) from formula CI compounds. Therefore, bicyclic formula CO compounds are somewhat similar to formula CI compounds.
Reaction with stoichiometric excess of butylboronic acid
created by. Silica gel thin layer chromatography of reaction process
It is convenient to check the reaction by
Preference is given to carrying out at reflux temperature with vigorous stirring.
The preferred reaction diluent for this conversion is methylene chloride, but
, and other suitable organic solvents may be used as well. instructor
Formula CV compounds made with free hydroxyl of M9 moiety
By replacing silium hydrogen with a blocking group by R, o,
Tell. Advantageously, the procedure described above is used. next
Compounds of formula CW can be prepared by decycloboronization to give formula
It is made from Cm compound. For this purpose, alkali gold
hydroxides (e.g. sodium hydroxide, lithium, or
potassium) with water to produce a homogeneous reaction mixture.
Formula Cm in a diluent (e.g. methanol or ethanol)
Combine the compounds and dilute the resulting solution with a dilute aqueous solution of hydrogen peroxide.
Process. Compounds of formula CV can then be prepared in one of two ways:
is the formula CI (when R5 or R6 is methyl) or the formula CN (
When R5 and R8 are hydrogen)
It will be done. According to the first method, e.g. using Jones reagent
using a compound of formula CI or CN at the C-9 position
selectively oxidized in step 11. To achieve a high degree of selectivity, reactions were carried out at -200 and -6
It is desirable to carry out the test between 020 and 020. -5y or -
A reaction temperature of 30 oo is particularly preferred. Therefore the product mix
Separation of the product yields a pure product of formula CVPGD type.
It will be done. According to the second procedure, a compound of formula CV is first prepared with formula
C-11 rather than C-9 hydroxy of CI or CW compounds
By selectively silylating the hydroxy, formula C
I or CW compound. It is advantageous to use a silyl group of the formula -Si(0,)3.
be. For selective monosilylation procedures, U.S. Pat.
No. 22303 (Registered July 2nd, 197 Puou), Germany
Published Patent Publication No. 2259195, Derwent Fur
Mudoc CP136457U-B or Dutch Patent No.
No. 7214142, Derwent Farm Dock CP1
See 26221U-B. Next, the silicate made in this way
The converted compound has R,o instead of 9-hydroxy.
to the corresponding C-9 ether using a blocking group with
be converted into Next, the C-11 silyl moiety was removed by the above method.
Hydrolyze the resulting 11-hydroxy compound using the above procedure.
When oxidized by
Cheating. Formula CV compounds are then optionally blocked by R,o
By replacing the group with hydroxy hydrogen, this 11-oxo compound
made from things. Diagram M shows the PGFQ-type intermediate of formula C.
How to convert to the corresponding compound of formula CX93-PGD type
providing. The formula CW compound is made as illustrated in the previous figure.
. Next, the formula C skin compound is converted from the formula CW compound to formula CI in Figure L.
Following the procedure described for making the compound from the formula CW
Made from a compound. Next, the formula C skin compound is shown in Figure L'
In the explanation above, we will explain how to convert a formula CV compound from a formula CW compound.
Selective silylation as described for the second method
made from formula C skin compounds by. quoted there
See references provided. Next, the formula CX compound is first prepared as follows:
9-oxo compound corresponding to the C-9 hydroxy of the compound
The 9-oxo compound thus produced is then oxidized to
Reduction to a mixture of 9Q and 8-hydroxyepimers
and is made from a formula C skin compound. Then the formula CK
The compound is a mixture of 93-hydroxyepimer and this epimer.
It is created by separating it from a compound. Then the formula CX
The compound is from formula Lm to formula L when X is silyloxy in Figure F.
It is made by the method described for the production of skin compounds, but
The separation of the C-15 epimer mixture is then omitted. Figure N is
, the PGD type compound of formula CXI is of formula CXO9-deoxy-
9,10-didehydro-PGD type compound, formula CXm9-
Deoxy-PGF or 9-deoxy-113-PGF type
compound, or formula CX skin 9-deoxy-POD type compound
Various methods of conversion are provided. Formula CXO compounds are prepared by mild acid catalysis of formula CXI compounds.
is made from a compound of formula CXI by dehydration. Acetic acid, trifluoroacetic acid, citric acid, oxalic acid, or p-t
Organic acids such as luenesulfonic acid are useful for this purpose.
Ru. Tetrahydrofuran, methanol, ethanol, or
effectively uses a diluent such as water. However, homogeneous
It is preferred to use a diluent that results in a reaction mixture.
Yes. Dehydration occurs rapidly at temperatures between ambient and 40:00.
Proceed to. Instead, a compound of formula CXI can be washed with acid.
placed on a column of licagel, which normally yields 1
Dehydrates to formula CXO product within ~5 days. Then the formula CXm
The compound is prepared by reduction of the formula CXO compound followed by
By separation of the C-11 ebimer mixture produced, formula C
Made from XO compounds. This reduction is an endocyclic double
1 by selectively reducing bonds without affecting side chain unsaturation.
Converting 1-oxo to 11-hydroxy. for this purpose
is an alkali metal borohydride, e.g. sodium,
Potassium or lithium borohydride in alcohol
Use effectively in solution. The reaction was carried out at approximately -20°C.
This usually takes 2 to 3 minutes. Any subsequent separation
using conventional methods, e.g. silica gel chromatography, high pressure
The process proceeds by liquid chromatography, etc. Formula CXO conversion
The compound is produced by selective catalytic hydrogenation of the endocyclic double bond.
is optionally converted to a formula CX skin compound. This conversion is carried out selectively without destroying side chain unsaturation.
For this purpose, forceps, alumina, or other suitable materials may be used.
A 5-10% palladium or rhodium catalyst on a support is used.
used. This reaction is performed using ethyl acetate, methanol, and ethanol.
any suitable organic solvent such as alcohol or diethyl ether
Temperature of 130 to 150 and atmospheric pressure or higher
carried out at a pressure of Finally, the formula CXO compound has M,
By substituting the moiety with the M7 moiety, a compound of formula CXW
converted to. This substitution is applied to R65 when R6 of the M moiety is hydrogen.
requires the introduction of a blocking group. The above method for this conversion
use. Next, is a compound of formula CXV a compound of formula CXO?
to the compound of formula CXm by reduction as described above.
It is made from a compound of formula CXW. Compounds of formula CXVI are then prepared by oxidation of the cyclobentane ring.
is made from the compound of formula CXV. For this purpose,
Oxidizing agents such as Jones reagent (acidified chromic acid)
use. For reference, J. Chem. S ratio. 39(1)
See King 946). Secondary hydroxy of formula CXV compound
Slightly more stoichiometrically than the amount needed to oxidize one of the groups
Use excess. Acetone is a useful diluent for this purpose.
be. Reaction temperatures as low as at least about 0°C are useful.
Ru. The preferred reaction temperature is in the range of -10 to -5 pi
. A particularly useful reagent for this purpose is Collins' reagent (pyridine
Chromium trioxide). For reference, J.C.
J.C. Coilins et al., Tetrahedo
Ron. See Letters paper line (19th year). Dichlorometh
is a suitable diluent for this purpose. Lower than 30pm
Reaction temperatures are preferred. Particularly preferred are reaction temperatures in the range of -10, -11 and -○.
stomach. This oxidation proceeds rapidly and is complete within a few minutes. pure
The product can be prepared by conventional methods such as silica gel chromatography.
It is solely nourished by i. Other oxidations useful in this conversion
An example of a reagent is a chromium trioxide mixture in pyridine (J.A.
m. Chem. Sw. 7 Shenxuan 422 pages (1953 King))
, tert-butylchromate in pyridine (Biologc
aI Chemical Jo Abu et al. 1, 8 subvol. 195 pages (1
962 King)), 3 in pyridine and dimethyl sulfoxide
Sulfur oxide mixture (J. Am. ChemS ratio. 8 period lid, 5
505 (1967)) and dicyclohexylcarpo
Mixture of diimide and dimethyl sulfoxide (J.Am
．． Chem. S.M. Volume 87, page 5661 (1965))
It is. Formula CX skin compounds are then blocked by R65 as described above.
Created from formula CXW compounds by hydrolysis of the group. Figure 0 shows the formula CX side PGFQ type compound with the corresponding formula CXX
W9-deoxy-PGF compound, formula CXXVm9-deo
xyPOD type compounds, or formula CXXIX9-deoxy
-113-PGF type compounds are provided.
Ru. From the formula CX skin compound to the corresponding formula CXIX compound
conversion, and then from the formula CXIX compound to the corresponding formula CXX
The conversion to a compound of formula CXXI is shown in Figure L.
The conversion to the formula CN compound proceeds as described above.
Ru. Formula CXXD compounds then have C-1 hydroxy rather than C-9 hydroxy.
By selective monosilylation of 1 hydroxy, formula CXX
I or a compound of formula CX. used for this step
The methods and reagents used are known in the art. For reference
No. 3,822,303 (July 2, 1974)
(Registered in Japan), German Published Patent Application No. 2259195,
Wendt Farm Dock CP136457U-B, also
is Dutch Patent No. 7214142, Derwent Fa.
See Mudoc CP126221U-B.・This purpose
For example, trimethylsilyldethylamine is useful for
It is a reagent. A compound of formula CXXm is then a compound of formula CXXO
converting compounds into 9-hydrocarbylsulfonyl derivatives.
is made from a compound of formula CXX by Bases are suitable for this purpose, especially tertiary amines (e.g.
For example, methanesulfonyl chloride
or P-toluenesulfonyl chloride with the formula CXXO
Condense with a compound. The reaction is preferably carried out using 10 qo or
The process progresses to completion in a few minutes at temperatures below that temperature. complete the reaction
slightly overstoichiometrically to ensure that the
Using excess hydrocarbylsulfonyl chloride reagent
Ru. The compound of formula CXXW is then hydrated at the 11-silyl moiety.
It is made from a compound of formula CXXm by decomposition. Hydrolysis is an organic acid combined with water, or water and ethanol.
It proceeds conveniently in water-miscible organic solvents such as alcohols. example
For example, using a 2% aqueous solution of citric acid in methanol
It is advantageous to have one. Then formula C from the formula CXXW compound
The preparation of XXV compounds can be accomplished by several methods known in the art.
9 of the formula CXXW compound using any of the general methods
- Proceeds by cleavage of the hydrocarbylsulfonyloxy moiety
nothing. Thus, some methods use aprotic solvents (e.g.
metal borohydride (dimethyl sulfoxide)
e.g. sodium borohydride) or metal cyanohydride)
lonohydride (e.g. sodium shea/porohydride)
The cleavage proceeds using a reducing agent such as Ride). The second method follows reduction with lithium aluminum hydride.
an aqueous suspension of platinum dioxide previously reduced with hydrogen (
Adams Catalyst, Feeser & Feeser “Organic
"Synthetic Reagents", New York, New York, 1967,
(page 890), the primary alcohol formed using
requires conversion to carboxy free acid. This anti
Another method of reaction is the use of lithium bromide (bromide).
(for the production of lomo derivatives) followed by dilution of the resulting product.
Methylformamide aqueous solution and galvanizing agent (ethylene diamide
treatment with chromium(0) perchlorate in a tank). Compounds of formula CXX can be prepared by hydrolysis of any blocking group.
Made from compounds of formula CXXV. It is advantageous to use the above method. Instead, one
Formula CXXV compounds are used to make Formula CXX skin compounds
be done. When used in this way, for example, from a compound of formula CXV to a compound of formula
Using the oxidizing agents mentioned above to make CXW compounds
, a compound of formula CXXV is oxidized. Next, any blocking group
By hydrolysis of formula CXX style compound, formula CXX style compound
made from things. The method described above is used. Next, the above method (for example, converting the formula to LO)
Using diagram F) when converting a compound into a compound of formula Lm
By cyclobentane ring carbonyl reduction, formula CXXI
The X compound is made from the formula CXX skin compound. Then, by conventional separation techniques, 118-hydroxyepi
The epimers are separated from the resulting epimer mixture. For example,
Silica gel chromatography or high pressure liquid chromatography
Use the separation of To make a compound of formula CXXW,
Instead of the formula CXXO compound, the corresponding 11,15-bis
Ether compounds, that is, [in the formula R,, Z, R, M6,
L, and R7 as defined above] are optionally used.
. These 1L 15-bisethers are known to the art.
or conveniently by the method described in Figure K.
It will be done. Diagram P shows the case where Y is trans-CH=CH-
Various novel prostagranges disclosed herein
analogues of the corresponding novel 1 disclosed herein.
2,13-didehydro 13.14-dihydro PG type
It provides a method for converting into compounds. The formula CXXXI compound made above can be prepared by reaction with a mild base.
By processing, it becomes a compound of formula CXXX or CXXXD.
be transformed. When a substantial amount of a compound of formula CXXXO is desired, tri-
Ethylamine or 1,5-diazobicyclo [4.3.0
．． ] with a mild base such as -non-5-ene (DBN)
Preferably, compounds of formula CXXXI are treated. DBN
Lorisil, or a salt such as potassium acetate in methanol
When using the group, the major amount of E epimer is produced.
However, triethylamine substantially eliminates the EZepimer mixture.
arise. Instead, "formula CXXX b or formula CXX
As mentioned for the preparation of the X melon compound, the formula CXXXm
Compounds of formula CXXX can be prepared by treatment with a mild base.
made from things. Also, a compound of formula CXXXW is (as stated in Figure N)
Used to make XXXV compounds. This latter transformation
The compound can be prepared using the above base treatment to form a compound of formula CXXXW.
It is useful for making. Instead, the formula CXXXW compound
A compound of formula CXXXm can be prepared by the method described above in Figure N.
made from things. Box Q has the formula 9-deoxy of XLIX
-9,10-didehydro-PGD type compounds are preferred.
provides a new method. With respect to Figure Q, the PGF2Q type compound of formula CXLI is this
known to art or created by the above ten thousand laws.
Ru. Then formula CXL0, formula CXLm, and formula CXXXW compounds
The class is cyclo(alkyl boronization), optical C-
15 etherification, and 9.11 l-n-alkylborone
It is produced by hydrolysis of a derivative. Previous diagram, illustration
For example, Figure L (particularly from formula CI compounds to formula CD, formula Cm, and formula
The method used for (conversion to CIV compound) is used.
The compound of formula CXLIV is then prepared by 1,9-lactonization.
is converted into a compound of formula CXLV. To achieve 1,9-lactonization, formula CXLI or formula
The CXLIV compound was dissolved in 2-pyridyldisa in benzene solvent.
Mix with Rufuaid and stir for 3 to 2 minutes. Additional benzene solvent is then added until the lactonization is complete.
Reaction mixture until indicated for use (silica gel TLC)
Heat to reflux. The compound of formula CXLVI is then
Oxidation of droxy to 11-oxo gives formula CXLV
Made from chemical compounds. For this purpose, the above oxidation method
methods and reagents are useful. For example, a compound of formula CIV can be converted into a compound of formula C
See Figure L for conversion to V compound. Formula CXLVO conversion
Compounds of formula CXLVI were deposited on silica gel at various times.
or by applying a mild acid to a compound of formula CXLVI
made from things. For example, a compound of formula CXLVI can be washed with silica gel or acid.
Leave it on a column of silica gel for 1 to 5 days, thereby
to make a compound of formula CXLVD. The compound of formula CXLVm is
, by hydrolysis of any blocking group using the above procedure.
is made from a compound of formula CXLVO. A compound of formula CXLIX is then prepared using the method described below.
By converting the lupoxy acid to the R, moiety, the formula CX
Made from LVm compounds. Let's make C-15 tertiary alcohol (R5 is methyl)
To use the above method as a C-15 blocking group, it is necessary to use
There's no need. Therefore, at the stage shown in the above diagram, the introduction and addition of the blocking group
Water splitting is omitted in the preferred method. Some types of figure A
(Anchor S)-3-methyl lactones are silica gel chroma
separation by high-pressure liquid chromatography or high-pressure liquid chromatography techniques.
Therefore, it is separated into each (station) and ($) Epima. This route is preferred if such separation is possible. subordinate
Thus, in these cases, separation is effective, where the side is or and the pigeon is or (R, o are blocking groups). Therefore, when using any lactone separation, the corresponding fraction
The release procedure is omitted. According to the method steps in the diagram above, the optically active PG-type product is
obtained from chemically active intermediates. Similarly, following the steps in the figure above, the PG form of the enantiomer
Are the compounds PG-type intermediates of the corresponding enantiomers?
obtained from When using a racemic intermediate in the above reaction,
A racemic product is obtained. These products in racemic form
or optically according to procedures known in the art.
It is resolved as active enantiomers. For example, PG type
When the free acid is obtained, its racemic form can be obtained by known procedures.
to convert the free acid into an optically active base (e.g. brucine or stryxine).
This technology was made known by reacting with
can be separated depending on the procedure (separate dia are separated by fractional crystallization)
of two diastereomers), resulting in a salt of two diastereomers
By producing a mixture, it is separated into type d and type 1.
Ru. Next, the optically active acid is
Made from salt according to the order. All of the above reactions produce
The product is separated from starting materials and impurities by conventional means.
Ru. For example, silica gel matched by thin layer chromatography
By using chromatography, the various stages in the above diagram
The product is separated from the corresponding materials and impurities. Up
As described above, the methods described herein can be used to obtain acid from various routes.
(R, is hydrogen) or esters. If an alkyl ester is obtained and an acid is desired, P
This technique is known for GF-type prostaglasosin.
Saponification procedures may be used. The saponification step may lead to unwanted desorption of the brostaglandin analogs.
When water can be generated, use methods known in the art.
enzymatic methods are used to convert the esters to their acid forms.
It is possible. For reference, E.G. Daniels (E.G.
Daniels' process for producing esterases, U.S. Patent No.
See No. 3761356. Acid is created and Al
Desiring kill, cycloalkyl, or aralkyl esters
Sometimes esterification involves a phase between an acid and a suitable diazo hydrocarbon.
Advantageously achieved by interaction. For example, when using diazomethane, the methyl ester
I can't believe it. For example, diazoethane, diazobutane, 1-di
Same for azo-2-ethylhexane and diazodecane.
used for ethyl, butyl, and 2-ethylhexyl, respectively.
Sil, and decyl esters are obtained. Similarly, Gia
Zocyclohexane and phenyldiazomethane are each
Produces cyclohexyl and pendyl esters. Gia
Esterification with hydrocarbons can be carried out using a suitable inert solvent,
A solution of the diazo hydrocarbon, preferably in diethyl ether
with the acid reactant, advantageously in the same or another inert diluent.
It is carried out by mixing. After the esterification reaction is completed, the solvent is removed by evaporation.
and optionally by conventional methods, preferably chromatography.
Refine Esther with Fi. of unwanted molecules
Contacting the acid reactant with the diazo hydrocarbon to reduce the change
for a longer time than necessary to effect the desired esterification.
Do not overheat, preferably for about 1 minute to about 10 minutes.
is preferred. Diazo hydrocarbons are not known to this technology.
or can be made by methods known to the art.
Ru. For example, "organic reaction"
Hajon Willey & Sons, New York
,N. Y. , Vol. 8, pp. 389-394 (1954 Wang)
reference. Alkyl and cycloalkyl in the carboxyl part of acid compounds
An alternative method to kill or aralkyl esterification is to use the free acid
to the corresponding silver salt, followed by the conversion of this salt with an alkyl iodide.
Consists of interaction with Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide.
isoptyl iodide, tert-butyl iodide, cyclopropyl iodide
Pill, cyclobentyl iodide, penzyl iodide, phene iodide
Chill et al. Silver salts can be prepared using conventional methods, such as diluted with cold acid.
Dissolve in ammonia aqueous solution and remove excess ammonia under reduced pressure.
by evaporation and then adding a stoichiometric amount of silver nitrate.
It is made by Although the yield and purity of the product varies
, corresponding aromatic alcohols and free acid PG compounds
phenyl or substituted phenyl within the scope of the invention
A variety of methods are available for making tell compounds. like this
According to the method described in
mixed acid anhydride when reacted with pivaloyl halide
which is then reacted with an aromatic alcohol. As an alternative, instead of pivaloyl halide, p
-alkyl or toluenesulfonyl chloride
Use phenylsulfonyl halide. For example, bell
Gee Patent No. 755106 and No. 776294, Dow
Ent Farm Dock No. 33705T and 39011
See T. Another method is to dilute the coupling reagent.
By using cyclohexylcarbodiimide. Fieser et al., “Organic Synthesis Reagents (Re
``OrganicSynthesis''
pp. 231-236, John Wiley & Sons
See Inc., New York (1967). PG type compound
from 2 to 10 molar equivalents of disiloxane in pyridine as a solvent.
In the presence of chlorhexylcarbodiimide, 1 to 10 mol
React with an equivalent amount of aromatic alcohol. However, these
A preferred new method for producing esters of
PG type compound and isobutyl chloro in the presence of tertiary amine
form a mixed anhydride with formate and anhydride of [2]
The step of reacting something with a suitable aromatic alcohol
Consisting of The above mixed anhydrides can
-400 to +60 qo to minimize reaction.
, preferably within the range of -1oo to +10qo.
It is easily made in degrees. Isobutyl chloroformate
Reagent in excess, e.g. 1.2 per mole of PG-type compound
It is preferred to use a molar equivalent of from to 4.0. anti
It is preferable to carry out the reaction in a solvent (acetate is preferred for this purpose).
However, acetonitrile, dichloromethane
and other relatively non-polar solvents such as chloroform
is used. The reaction occurs with tertiary amines, e.g. triethyl
It is carried out in the presence of an amine and normally produces a co-produced amine.
Mine hydrochloride precipitates, but needs to be removed for the next step
There isn't. Ensures that all mixed anhydride is converted to ester
As such, molar equivalents or substantial chemical amounts of aromatic alcohols
Preferably, it is used in logical excess. The excess aromatic alcohol is as described herein or
The product by methods known in the art, e.g. crystallization
separated from Tertiary amines are salts for esterification
It is not only a basic catalyst but also a convenient solvent.
Other examples of tertiary amines useful for this purpose are N-methyl
Lumorpholine, triethylamine, diisopropylethyl
amine, and dimethylaniline. these are
Although effectively used, 2-methylpyridine and quinoli
ion produces only a slow response. 2,6-dimethylpi
Highly sterically hindered amines such as lysine are
It is not useful because the response is slow. The reaction with anhydride proceeds smoothly at room temperature (approximately 20 to 3030 °C).
can be tracked by conventional methods using thin layer chromatography.
Ru. The reaction mixture is worked up according to methods known in the art.
and the product is chromatographed on silica gel, for example.
Refined by graphics. Solid esters include ethyl acetate, tetrahydrofuran, and methane.
For crystallization from various solvents including tanol and acetone
Cool or evaporate the saturated solution of ester in the solvent.
or mixtures such as diethyl ether, hexane or water.
Free-flowing crystalline form by adding a colander non-solvent
converted to. The crystals are then removed using conventional techniques such as filtration or lotus
Collected by heart separation, washed with a small amount of solvent and dried under vacuum.
Ru. Warm these in a nitrogen or argon stream or approx.
It may be dried by heating to 75 qo. The crystal is
Although typically of sufficient purity for many applications, each
Same general procedure to achieve improved purity after crystallization
These may be recrystallized by By the method of the present invention
The compounds of the present invention prepared in free form by
Neutralization with appropriate amounts of organic or organic bases may result in pharmaceutically acceptable
It is converted into salts that can be added. Examples of these bases are the enteric ions and amino acids listed above.
This corresponds to the These conversions result in inorganic salts, i.e. metals.
or generally useful in the production of ammonium salts.
This can be carried out by various procedures known in the art. procedure
The choice of salt depends in part on the solubility characteristics of the particular salt being made.
Varies depending on gender. In the case of inorganic salts,
the stoichiometric amount of the corresponding hydroxide, carbonate, or bicarbonate.
It is usually suitable to dissolve the acid of the invention in water containing
ing. For example, sodium hydroxide, sodium carbonate, or
When using sodium bicarbonate in this way, sodium
produces a murine salt solution. Water evaporation or medium polarity water
Miscible solvents, such as lower alkanols or lower alkalis/
If a solid inorganic salt form is desired due to the addition of
Produces a cigarette mold. To make the amine salt, the acid of the invention
is dissolved in a suitable solvent of medium or low aptitude. Examples of the former are ethanol, acetone, and ethyl acetate.
Ru. Examples of the latter are diethyl ether and benzene.
at least a stoichiometric amount of amine corresponding to the next desired cation
Add the stoichiometric amount to this solution. If the resulting salt does not precipitate
by the addition of a less polar miscible diluent or by evaporation.
Therefore, it is usually obtained in solid form. Amines are relatively volatile
If the
Can be removed. Stoichiometry of less volatile amines
It is preferable to use The cation is quaternary ammonium
salts, the corresponding quaternary ammonium in aqueous solution when
A stoichiometric amount of aluminum hydroxide is mixed with the acid of the present invention, followed by
It is made by evaporating water. Acids or agents of the present invention produced by the method of the present invention
Steles are free hydroxy compounds and carboxyacyl
oxidizing agent, preferably lower alkanoic acids, i.e. 2 to 8
by the interaction of the carbon atoms of the alkanoic acid anhydride with
Converted to lower alkanoates. For example, using acetic anhydride produces the corresponding acetate.
Cheating. Similarly, propionic anhydride, isobutyric anhydride, or
When using water-hexanoic acid, the corresponding carboxyacyl
It gives rise to Carpoxyacylation is preferably carried out using pyridine.
in the presence of a tertiary amine such as triethylamine or triethylamine.
By mixing a hydroxy compound and an acid anhydride,
This will be done to your advantage. A substantial excess of anhydride, preferably hydroxy compound,
About 10 to about 10,000 moles of anhydride per mole of reactant
use things Excess anhydride acts as a diluent and solvent for the reaction.
fulfill the role of Inert organic diluent, e.g.
Sun can also be added. The carboxylic acid produced by the reaction,
and any free carbon present in the hydroxy compound reactants.
a sufficient amount of tertiary amine to neutralize the carboxyl groups.
It is preferable to use The carpoxyacylation reaction is approximately 0
Preferably, the temperature is between 0 and about 100°C.
The required reaction time depends on the reaction temperature and the anhydride and tertiary amine.
It depends on factors such as the nature of the reactants. acetic anhydride,
For pyridine and a reaction temperature of 25°C, 12 to 2 h
reaction time is used. Carpoxyacylated products are
isolated from the reaction mixture by conventional methods. For example, if an excess amount of anhydride is decomposed with water and the resulting mixture is
acidified and then extracted with a solvent such as diethyl ether
do. Desired carpoxy acylate is removed by evaporation.
Recovered from ether extract. Next, carboxylic
The rate is determined by conventional methods, advantageously by chromatography or
is purified by crystallization. The present invention includes the following preparation examples and
A more complete understanding can be provided by the following examples. temperature is everything
, in degrees Celsius. Infrared absorption spectrum (IR) is Birkin Elmer
・Model 421 Infrared Svector Otometer - Described above.
recorded. undiluted (unadulterated), except when otherwise specified
sample is used. Ultraviolet spectrum UV carries
– Recorded on a Model 15 vector otometer
ing. Nuclear magnetic resonance (NMR) spectra of dunarochloro
Tetramethylsilane was used as an internal standard (download) in a form solution.
(field), Balian A 16 stop A-6 mark D
or recorded on a T-60 vector otometer.
There is. Mass spectra are CEG Model 11 vessel bifocal
High-resolution mass spectrometer or LKB model 90
00 Kass chromatograph - on mass spectrometer
recorded. Trimethylsilyl derivatives unless otherwise indicated
are using. Here, “salt water” refers to salt water saturated with sodium chloride.
It refers to aqueous solution. A-IX used during thin layer chromatography (TLC)
The solvent system was M Hamburg (ratio m is rg) and B.
Samuelsson, J. BioIChem. ,2
According to Volume 41, 25 Tokan (1966), ethyl acetate
Acetic acid-2,2,4-trimethylbentane-water (90:2
0:50:100). Skerisolve B (SSB) is a mixed isomer hexane.
It is about. Silica gel as used herein. Matography consists of elution, fraction collection, and TL
The pure product (all
i.e. free of starting materials and impurities).
including combining the indicated fractions.
It is understood as The melting point (MP) is
Fisher Johns or Thomas
- Melting point measuring device of Hoover (Momas-Nikka version)
It is measured by DDQ is 2,3-dichloro-5,6-dicyano-1,
4-penzoquinone. THF is tetrahydrofuran. Specific optical rotation [Q] is Birkin Elmer model 141
An automatic polarimeter measures the temperature of the specified solution at ambient temperature.
Measured for a solution of the compound in a medium. Preparation Example 1 Dimethyl-3,3-dimethyl-2-oxo-4-phenylene
Luptylphosphonate, A Tetrahydride at 0°C under nitrogen
Lofuran 125 must-hit diisopropylamine 101.2
The solution in the evening should be cooled (using an ice-methanol tank).
Dropwise addition of n-butyllithium 625' in hexane
do. Isobutyric acid 46.5 is added dropwise to the resulting solution while cooling.
Ru. This mixture was stirred for 90 minutes at 0°C, then at -15°C.
Cool to o. such as keeping the reaction temperature below -5℃
At high speed, add 60' of penzyl chloride while stirring.
. The resulting mixture is then stirred at ambient temperature for 4 hours. child
Stirred mixture with ethyl ether and excess cold diluted
Dilute with hydrochloric acid. The organic layer was washed with brine, dried and concentrated.
and the residue is distilled under vacuum. Thus, 2,2-
Dimethyl-3-phenylpropionic acid is produced. B
A mixture of 48 parts of the product of Part A of this example and 82 parts of thionyl chloride.
Heat the mixture on a steam stove for 2 hours while stirring. The mixture is then concentrated under vacuum. Then add dry benzene.
The resulting mixture was concentrated again to remove traces of thionyl chloride.
Exclude all. Distillation of this residue was performed using 2,2-dimethyl-
3-phenylpropionyl chloride yields 48.2
Ru. C dimethylmethane in tetrahydrofuran 600
A solution of tylphosphonate 63 at -75q0 under nitrogen
1.6 molar n-butyllithium 31 in hexane
Add 2'. Make sure the reaction temperature stays below 55℃
Adjust the addition rate accordingly. One generation after addition ends
, at a rate that maintains the reaction temperature below -6000C.
Example Part B reaction product 48.2 and tetrahydrofuran
Release 50' drops. The resulting mixture was then mixed at -75 pm.
Stir for 2 hours and overnight at ambient temperature. Next, 20 acetic acid
the resulting mixture is distilled under vacuum, thereby
to remove most of the tetrahydrofuran. then chloride
Diethyl ether (3:1) and sodium bicarbonate in methylene
Shake the residue with cold dilute thorium solution. Next
Wash the organic layer with brine, dry and concentrate. Jetil the residue
Crystallization from ether gives the title compound dimethyl 3,
3-dimethyl-2-oxo-4-phenylbutylphosphor
The 54th birthday is born. Melting point 48-5 pi○. Preparation example 1
Follow the procedure, but instead of penzyl chloride, use the formula [where T is fluoride]
fluoro, chloro, trifluoromethyl, 1 to 3 carbons
alkyl of atoms or alkoxy of 1 to 3 carbon atoms
and s is 〇, 1, 2 or 3, provided that 2
provided that T not exceeded is other than alkyl, and further
provided that the various T's are the same or different]
Substituted penzyl chloride is used to convert the corresponding dimethyl
3,3-dimethyl-2-oxo-4-(substituted phenyl)
Butylphosphonate is produced. For example, this procedure allows dimethyl 3,3-dimethyl
2-4-(p-fluorophenyl)butylphosphonate
is created. Further following the procedure of Preparation Example 1, but with Preparation Example 1
．． When propionic acid is used instead of isobutyric acid in part A,
Dimethyl 3-methyl-2-oxo-4-phenylbutyl
Phosphonates are produced. Following the procedure of Preparation Example 1, but using the above instead of penzyl chloride.
Substituted pendyl chloride and propiopropyl chloride instead of isobutyric acid.
species when the phenyl substitution is as above using
dimethyl 3-methyl-2-oxo-4-(substituted phenol)
nyl)butylphosphonates are produced. Further preparation examples
1, but using the isobutyric acid used in Part A of Preparation Example 1.
Using acetic acid instead of dimethyl 2-oxo-4...
Phenylbutylphosphonate is produced. Various substituted pendyl chlorides as described above according to the procedure of Preparation Example 1
and acetic acid, the phenyl substituent is
Various dimethyl 2-oxo-4-(substituted
nyl)butylphosphonate is produced. Furthermore, Preparation Example 1
However, the isobutyric acid used in Part A of Preparation Example 1 was
Using 2,2-difluoroacetic acid instead, dimethyl
3,3-difluoro-2-oxo-4-phenylbutyl
Phosphonates are produced. Further following the procedure of Preparation Example 1, but with the above substituted pendyl chloride
Using 2,2-difluoroacetic acid combined with silk, phenyl
The corresponding dimethyl 3,3-
Difluoro-2-oxo-4-(substituted phenyl)butyl
Phosphonates are produced. Further follow the procedure of Preparation Example 1.
However, using 2-fluoroacetic acid instead of isobutyric acid,
Dimethyl 3-fluoro-2-oxo-4-phenylbutylene
phosphonate is produced. 2-fluoroacetic acid and the above species according to the procedure of Preparation Example 1.
The phenyl substituent is
Various dimethyl 3-fluoro-2-o
Xo-4-(substituted phenyl)butylphosphonates
I can't believe it. According to the procedure of Japanese Patent Application No. 0018-45y
, 3Q-t-butyldimethylsilyloxy 5Q-hydro
xy28-carboxaldehyde-IQ-cyclobenta
Y-lactone acetate is 3Q-t-butyldimethylsilyl
xy-5Q-hydroxy-28-(2-formylutora)
1-ethenyl)-IQ-cyclobentaneacetic acid
-converted to lactones. This product has the formula cis-BrM or 2-CH=CH-CQ.
When reacted with Grignard reagent of C day 3, 3Q-buti
dimethylsilyloxy-5Q-hydroxy-28-[(
S)-3-hydroxy-trans-1,cis-5-o
[cutadienyl]-IQ-cyclobentaneacetic acid-lacto
is created. Finally, this Grignard reaction product is oxidized with Collins reagent.
Then, 3Q-t-butyldimethylsilyloxy 5Q-hyperoxy
Droxy28-[3-oxotrans-1, cis]
5-octadienyl]-IQ-cyclobentanacetic acid y-
Lactones are produced. Further, following the procedure in the previous section, but using a Grignard reagent of formula or (corresponding 1-methyl or 1,1-dimethyl)
Manufactured from chiru-1-bromosis-2-1 (bentenes)
) to make the corresponding y-lactones. Preparation example 22,2-difluoro-5-promobentanoic acid
triphenylphosphonium salt Br(C6day5)P-(
CH2)3-CF2-COOHA methyl fluorate
Dissolve in 180' methanol. Then add 5% palladium on charcoal for one night. this mixture
is hydrogenated at 1 to 3 atm. After 4 hours, hydrogen 0.7
9 moles are consumed. Filter the black mixture through Celite and add to the reaction flask.
and use 50' of methanol to wash the filter.
. Evaporating the filtrate at a temperature of 40-50 qo under reduced pressure
, producing a yellow oil of 51 mm. Next, this is distilled and 32~
Collect the fractions that are incubated at 35°C. In this way,
46.7 hours of tiltetrahydrofurate is produced.
B in 50' of acetic anhydride until a specific gravity of 1.3 is obtained.
Whisk in the hydrobromic anhydride while cooling. This reagent was then added to the Part A reaction product of this example for water drainage.
Stir and add while cooling. Oysters in Hiyunaka
Continue stirring for 15 minutes, then leave the mixture at room temperature overnight.
. Next, stir the reaction mixture into crushed ice and 600 g of water.
Pour and extract with jelly ether. ether extract
Washed with aqueous sodium hydroxide solution and dried over sodium sulfate.
Dry, filter and then evaporate under reduced pressure to give a pale yellow oil 3
8th evening occurs. When this is distilled in a high vacuum, methyl 2-
Acetoxy-5-furomo-pentanoate 31.6 hours
arise. B of this example in C methanol 200
A solution of 60 parts of the reaction product was saturated with hydrobromic acid at 0°C.
methanol 10 with a specific gravity of 1.3 before addition.
Add 0 and. The reaction mixture is left at room temperature overnight. Then remove the solvent under reduced pressure
Evaporate at a temperature of 35°C and add 400 g of toluene.
Evaporate the solvent again. This residue was dissolved in ethyl acetate.
Dissolved in 5% aqueous sodium hydroxide solution and sodium chloride
solution and then dried over sodium sulfate.
Oil 42 by filtration and solvent evaporation under reduced pressure at 45o0
Distillation under high vacuum yields methyl 2-hydrohydride.
Roxy-5-promobentanoate yields 28.8 days
. D Reaction product 34.4 of part C of this example and acetone
Add the joe to the 400' solution while stirring and cooling.
Lens reagent (concentrated sulfuric acid 23% C of 326.73% water)
diluted to 100%) at a reaction temperature of 30%
Add at a rate such that it is maintained between 0 and 40 qo. The reaction ends in about 2 pieces. After this, the reaction mixture was prepared in 1.
Stir for 5 hours. Next, inpropyl alcohol 150
Add the secretion gradually over 30 minutes while stirring. reaction mixture
Dilute the material with 1.8 sleeves of water and extract with 2.4 sleeves of methylene chloride.
Ru. These extracts were washed with brine and dried over sodium sulfate.
dry Filtration and solvent evaporation under reduced pressure
- Light yellow oil containing 5-bromobentanoate 30
．． 8th evening occurs. This oil can be used in the following example without further refining.
used in the stages of E Exclude moisture under nitrogen atmosphere
While dry ice of MoF61BF3195
Cool in an acetone bath. The reaction product of Step D of this example was 30.8 ml and methylene chloride 4 ml.
0' solution dropwise with stirring for IB minutes. anti
The response temperature is maintained between -35o and -45o. dry
Continue stirring ice-acetone Yuchu for 1 hour, then
Remove the cooling bath and pour the reaction mixture into 200 g of methylene chloride.
Dilute with 400ml of water. Separate the organic and aqueous layers and add water
Methylene chloride extraction where the layers were extracted with methylene chloride and combined.
250M of water, 250M of 5% potassium bicarbonate aqueous solution,
Wash with 250' of brine and dry over sodium sulfate.
Filtration and solvent evaporation yielded a dark brown oil of 31.1 mm. child
Distillation of this under high vacuum yields methyl 2,2-difluoro-
5-bromobentanoate is produced. F In this example
The reaction product 28 of Part E was dissolved in an aqueous hydrobromic acid solution (specific gravity 1.
71) Stir at room temperature for 3 hours in 175 ml. The reaction mixture was cooled in an ice bath and dimethyl ether 130
Dilute with 0 units. Separate the organic and aqueous layers and drain the aqueous layer.
Extract with Luther. Add the combined ether extracts to water.
Wash and backwash the aqueous layer with 400 g of diethyl ether. one
The combined ether solutions are dried over sodium sulfate.
Filtration and solvent evaporation yielded a pale yellow oil 2,2-difluoro-5
- yielding 27.7 g of bromobentanoic acid. This further
It is used in the next step of this example without further purification. G Part F of this example
reaction product 15.2 minutes, acetonitrile 8 [and
While stirring with the mixture of 22 evenings of Riphenylphosphine.
Heat to reflux for 30 hours. The reaction mixture was then heated to 110 qo and added 160 qo of toluene.
Stir the mixture gradually at room temperature.
Leave to cool. The reaction mixture was then stored at 5°C for 2 hours.
do. Collect the precipitate, wash with 50 ml of toluene, and store in a vacuum chamber.
Dry at warm temperature. Thereby the title compound of this example 20.9
You can get evening. Preparation example 3 (6-carpoxyhexyl)
Triphenylphosphonium bromide 7-bromohebuta
acid muscle. 6 evenings, triphenylphosphine 80 evenings and acetic acid
A mixture of 30' of tonitrile is refluxed for 6 hours. After this, 200% of acetonitrile was removed by distillation.
Ru. Cool the remaining solution to room temperature and then add 30% of benzene.
Add while stirring the top. Let the mixture stand for 1 hour
. A solid precipitates out and is collected by filtration, with a melting point of 1
85-1870, yielding 134.1 hours of product. Preparation example
3 but instead of 7-bromoheptanoic acid 3
-bromopropionic acid, 4-bromobutanoic acid, 5-bro
using moventanoic acid or 6-bromohexanoic acid,
The corresponding (-carboxyalkyl)triphenylphos
Honium bromide is produced. Preparation example 4 3-oxo 5Q-hydroxy-26-pendyloxime
Chi-IQ-cyclobentanacetic acid y-lactone 3-(E)
tylenethioketal) (Formula x〇)See Figure A. 3Q,5Q-dihydroxy-28-pendyloxymethyl
-IQ-cyclobentanacetic acid y-lactone (formula x 1 "1
2.43 pm) and acetone 400 ml under nitrogen atmosphere.
Combine while cooling at °C. Add Jones reagent (21.3 secretion, chromium trioxide) to this solution.
66.8 hours and concentrated sulfuric acid 57.5 hours with water to a total volume of 250'
diluted). The resulting solution was heated at 0°C for 20 minutes.
Stir, then add isopropanol 5, then stir until solidified.
Add body weight sodium carbonate to adjust pH to 7. reaction mixture
Filter, concentrate, wash with brine, and extract with ethyl acetate.
Ru. The organic extract was washed with brine and dried over sodium sulfate.
Upon concentration, crude 3-oxo-5Q-hydroxy-28
-Pendyloxymethyl-IQ-Cyclobesotasoacetic acid y-
This yields 12.74 lactones as a pale yellow oil. next
The oil in the previous section (formula x O) is converted to carbon tetrachloride 200' and 1,2
-Dissolved in ethanedithiol 30'. After setting up an oxygen-free atmosphere,
Add 0.75 I of the compound to the reaction mixture. The resulting confusion
The mixture was stirred for 2 hours at 290°C, then
Add an additional portion of 0.25' of tel compound. Another 1 o'clock
Continue stirring and then mix the reaction mixture with brine and 5% hydroxide.
Add to the mixture with aqueous sodium solution (ice-cold) 300'
Ru. The resulting aqueous phase was extracted with chloroform and the organic flux
Do it with John. Combine the combined fractions with salt water
% aqueous sodium hydroxide solution (ice-cooled) and brine
and dry over magnesium sulfate. reaction mixture
Concentration yields a pale yellow oil of 20.81 g of the lees product.
Ru. Silica gel chromatography (10% ethyl acetate and
(using a column packed with Schellisolp B)
and dissolved in 10-60% ethyl acetate in Scherisolve B.
The product is then pure as a cool-colored crystalline solid 9.72
Produces evening. Reconsolidation from ethyl acetate and Skellisolve B
The crystals give a melting point of 115.3 to 117.3°C. NMR
Absorption is 2.07-3.0, 3.27, 3.6-3. chick,
Found in 4.52, 4.77-517 and 7.326
. Infrared absorption is 1765, 1 spot 0, 1495, 1165
, 1090, 104-li, 750 and 700-1
It will be done. The mass spectrum is 330 308 24fu 20
2, 17 127, 92, 91, 6fu 61 and 44
shows the income. Preparation Example 5 3Q-(t-butyldimethylsilyloxy)-5Q-hydro
Roxy28-(3-oxotrans-1-octenylene)
l)-IQ-cyclobentanacetic acid-lactone [formula x V
R3 and R4 of the O:L portion are hydrogen, R7 is n-butyl, and
and X is H/, OSi(G2)3 (where -OSi(G2)3 is
Roxy)] See Figure A. A 3Q,5Q-dihydroxy-23-pendyloxime
Chil-IQ-cyclobentanacetic acid y-fuctone (formula x,
2.03 evening), N,N-dimethylformamide 4 skin, t
-butyldimethylsilyl chloride 0.40m, and i
Midazol 1.32 hours with 1 bait at 3yC while stirring the evening
Let's do it together for a while. The mixture is then cooled to ambient temperature and diluted with 300% salt water.
, extracted with jetyl ether. 1. is hydrochloric acid aqueous solution, heavy
Wash the ether extract with saturated aqueous sodium carbonate solution and brine.
and dry over magnesium sulfate. Concentration under reduced pressure yields a pale brown oil, which is allowed to stand for 30 minutes.
and crystallize. Recrystallization from n-hexane gives pure
Product 2. Produces paper evening. Further recrystallization lowers the melting point to 43.
7-44. gets a ○. NMR absorption is 0.03, 0.8
6, 1.86-2.97, 3.35 4.15, 4.4
7, 4.9Q and 7.326. Infrared absorption is
3060, 3040, 1755, 1600, 1 group 1
500, 135fu 125i l180, 1175, 1
125, 1110, 1095, 1030, 965, 89
-1 of 0, 840, 780, 750, and 700
It will be done. Mass spectrum is 370 319 181, 92
,? Peaks are shown at 7, 75 and 73. B Part A above
reaction product 1.00 g, tetrahydrofuran 30 g,
and 10% palladium on charcoal at ambient temperature.
Hydrogenate at 16 pounds per square inch per hour. The resulting mixture was filtered through Celite and concentrated under reduced pressure.
This yields 0.89 g of a light brown solid. n-hexa
and recrystallization from ethyl acetate gives a melting point of 67.2-69
．． This yields colorless plate-like crystals of 93° and 0.55 m. NMR
Absorption is 0.05, 0.87, 1.67-3.083.6
4.1& and 4.976. mass spectrum
is 286, 271, Shigeru 9, 211, 194, 183, 1
68, 170, 137, 111, 105, 9391, 7
Peaks are shown at 5 and 73. Tet cooled to CO
Hydrogenation of 57% of lahydrofuran 65' under nitrogen atmosphere
Combine with 0.46 g of sodium dispersion. To this mixture was added 10 dimethyl dimethyl (
Add 2.49 g of 2-oxoheptyl)phosphonate dropwise.
Ru. Allow the reaction mixture to warm to ambient temperature, approximately 1.
Leave it for a while. The resulting mixture was cooled to 0°C and
Therefore, make Wittig reagent. chloride under nitrogen atmosphere.
Combine 82% of tyrene with 5.19% of pyridine. While cooling this mixture to 0°C, chromium trioxide 3.2
7. Gradually add the mixture while stirring, and the resulting mixture
Allow to warm up to temperature. After cooling to 0℃,
While stirring, methylene chloride 10 formula x V alco
Add rule 1.56 evening. The resulting mixture was stirred at ambient temperature for 30 minutes, then poured on top.
Combine with the supplied Wittig reagent. After 1 hour, reaction
Add 50 volumes of saturated aqueous sodium bisulfate solution to the mixture.
Therefore, it is stopped, diluted with brine and extracted with methylene chloride.
. Next, add the combined organic extracts to 1. is an aqueous solution of hydrochloric acid, bicarbonate
Sodium saturated aqueous solution, washed with salt water and magnesium sulfate
Dry on a dry cloth. Concentration under reduced pressure produces a dark colored oil 3.62
Produces evening. This oil (10% acetic acid in Skellisolve B)
Chromatography on silica gel (packed with ethyl)
Dissolve with 10-50% ethyl acetate and Suke IJ Solv B.
Refute. Crude from 50% ethyl acetate in Schellisolp
A yellow oil of 2.2 mm was obtained, which was further chromatographed.
Purification by filtration yields 1.78 g of pure product. n
-Crystallization from hexane produces colorless needles. melting point
is 61.3-62.4℃. NMR absorption is 0.03, 0.
86, 0.67-3.07, 4.07, 4.97, and
5.93 to 6.876. The mass spectrum is 3
24 32311 included 99 75 73, 71, 594
Peaks are shown at 3 and 41. Following the procedure of Preparation Example 5, but
Instead of dimethyl 2-oxoheptylphosphonate
Use any of the various dimethylphosphonates listed above
Then, 28-(3-oxygen) optionally substituted as follows:
(so-trans-1-alkenyl) substituent
3q-t-butyldimethylsilyloxy-50-hydro
xy-IQ-cyclobentanacetic acid y-lactones are formed
It will be done. 4,4-difluorohexenyl, 4,4-difluorohexenyl
putenyl, 4,4-difluorooctenyl, 4,4-di
Fluorononenyl, 4,4-difluorodecenyl, 4-
Fluorohexenyl, 4-fluoroheptenyl, 4-f
fluorooctenyl, 4-fluorononenyl, 4-fluoro
Lodecenyl, 4,4-dimethylhexenyl, 4,4-di
Methylheptenyl, 4.4-dimethyloctenyl, 4,
4-dimethylnonenyl, 4,4-dimethyldecenyl, 4
-Methylhexenyl, 4-methylheptenyl, 4-methy
luoctenyl, 4-methylnonenyl, 4-methyldecenyl
hexenyl, heptenyl /nenyl, decenyl,
5-phenylbentenyl, 5-(m-trifluoromethyl)
fluorophenyl)-bentenyl, 5-(m-fluorophenyl)
-bentenyl, 5-(m-chlorophenyl)-bentenyl
Tenyl, 5-(p-trifluoromethylphenyl)-be
pentenyl, 5-(p-fluorophenyl)-pentenyl
, 5-(p-chlorophenyl)-pentenyl, 4-methy
-5-phenylbentenyl, 4-methyl-5-(m-
trifluoromethylphenyl)-bentenyl, 4-methy
-5-(m-fluorophenyl)pentenyl, 4-mer
Thyl-5-(p-trifluoromethylphenyl)-ben
thenyl, 4-methyl-5-(p-fluorophenyl)-
Pentenyl, 4-methyl-5-(p-chlorophenyl)
-bentenyl, 4,4-dimethyl-5-(m-triflu
(omethylphenyl)-pentenyl, 4,4-dimethyl
-5-(m-fluorophenyl)-pentenyl, 4,4
-difluoro-5-(m-chlorophenyl)-pentenyl
4,4-dimethyl 5-(p-trifluoromethyl fluoride)
enyl)-pentenyl, 4,4-dimethyl-5-(p-
fluorophenyl)-bentenyl, 4,4-dimethyl-
5-(p-chlorophenyl)pentenyl, 4-fluoro
-5-phenylbentenyl, 4-fluoro-5-(m-
trifluoromethylphenyl)-bentenyl, 4-fluor
o-5-(m-fluorophenyl)-bentenyl, 4
-Fluo○-151 (m-chlorophenyl)pentenyl,
4-fluoro-5-(p-trifluoromethylphenyl
)-bentenyl, 4-fluoro-5-(p-fluorof
enyl)-bentenyl, 4-fluoro0-5-(p-chloro
(lofenyl)-pentenyl, 4,4-difluoro-5-
Phenylbentenyl, 4,4 difluoro5-
(lifluoromethylphenyl)-pentenyl, 4,4-di
Fluoro-5-(m-fluorophenyl)pentenyl,
4,4-difluoro5-(m-chlorophenyl) pen
thenyl, 4,4-difluoro-5-(p-trifluoro
methylphenyl)-pentenyl, 4,4-difluoro
5-(p-fluorophenyl)-pentenyl, 4,4-
Difluoro-5-(p-chlorophenyl)-pentenyl
, 4-phenoxybutenyl, 4-(m-trifluoromethane)
tylphenoxy)-butenyl, 4-(p-fluorophene)
noxy)-putenyl, 4-(m-chlorophenoxy)-
Butenyl, 4-(m-trifluoromethylphenoxy)
-butenyl, 4-(p-fluorophenoxy)-butenyl
4-(p-chlorophenoxy)-butenyl, 4-methyl
Chil-4-phenoxyputenyl, 4-methyl-4-(m
- Trifluo. Methylphenoxy)-butenyl, 4-methyl-4-(m
-Fluorophenoxy)-butenyl, 4-methyl-4-
(m-chlorophene/xy)-butenyl, 4-methyl-4
-(p-trifluoromethylphenoxy)-putenyl,
4-methyl-4-(p-fluorophenoxy)putenyl
, 4-methyl-4-(p-chlorophenoxy)-butenyl
4,4-dimethyl-4-phenoxybutenyl, 4,
4-dimethyl-4-(trifluoromethylphenoxy)
-putenyl, 4,4-dimethyl-4-(m-fluorophore)
enoxy)-butenyl, 4,4-dimethyl-4-(m-
Chlorophenoxy)-butenyl, 4,4-dimethyl-4
-(p-trifluoromethylphenoxy)-butenyl,
4,4-dimethyl-4-(p-fluorophenoxy)-
Butenyl, 4,4-dimethyl-4-(p-chlorophenol)
xy)-butenyl etc. Preparation example 6 3-oxo-5Q-hydroxy-23-(3-oxo
trans-1-octenyl)-IQ-cyclobentane vinegar
Acid Y-Lactone, 3-(Ethylenethioketal) (Formula ×
W: L, R3 and R4 of the moiety are hydrogen, R7 is n-butyl,
(X is ethylene thioketal) See diagram A. A Using chlorine tribromide, 3-oxo 5Q-hydro
xy-28-benzyloxymethyl-IQ-cyclobenta
Acetic acid y-lactone 3-(ethylene thioketal) (preparation)
When etherification of Preparation Example 4, 9.75 yen) was carried out, the 3-key
Otho-5Q-hydroxy-28-hydroxymethyl-I
Q-cyclobentanacetic acid y-lactone 3-(ethylenethiol)
(Oketal) 5.64 evenings occur. NMR absorption is 1.95-3.27, 2.30 3.33
3.9 skins and 4.73 to 5.2561 skins can be seen. red
External radiation absorption is 3430, 1770, 1745, 122
1190, 1160 and 1245. mass spec
Kutle is 246, 21 & 147, 118, 61, 59
, 9i4541 and 27. B Preparation Example 5
Following the procedure in Part C, the title compound. is a colorless solid
It will be made (2.17 evening). Melting point 65.4-67.4°C. NMR absorption is 0.90, 0
．． 9-1.9, 3.25 4.77-5.18, and 6
．． Found in 05-7.106. Infrared absorption is 1775
, 1675, 1635, 1250, 122fu 1190
"1040, and 980 go-1. Mass spec.
Toru is 34u 312, 279, 241, 174.99
95 71, 5-4 showing absorption in 41, 29 and 27
vinegar. Follow the instructions in Preparation Example 6, but as described after Preparation Example 5.
31 (described after Preparation Example 5) using various reagents.
t-butyldimethylsilyl ethers)
3-(ethylene thioketal) compounds are produced.
. Preparation Example 7 3Q-(t-butyldimethylsilyloxy)-5Q-hydro
Roxy 28-(3-oxosis-1-octenyl)
-IQ-cyclobentanacetic acid-lactone (formula x V plate:
L, R3 and R4 of the moiety are hydrogen, R7 is n-butyl, and X is
H no... -Si(G2)3 (wherein -OSi(G2)3 is t-butyl
dimethylcycloxy) and Y is cis-CH=CH-)
See Figure A. Reaction product of Example 2 in acetone 1 16.3
Add the diluted solution (bubble nitrogen into the solution and stir).
Knot photochemical reactor (using 8 RPR-208 lamps)
irradiate for 3 hours in a In this case, the emission spectrum is 3500 angstroms.
It shows substantial intensity at wavelengths at or near that wavelength. evaporate the solvent
and the residue was dissolved in 10% ethyl acetate in cyclohexane.
For chromatography on silica gel 1.5k9 packed with
put on. 10%, 15%, 20% in cyclohexane,
4 each of 25%, 30%, 35% and 40% ethyl acetate
．． Elute for 5 days and collect the 1.5 taf fraction.
Starting material and crude 3Q-t-butyldimethylsilyloxy
5Q-hydroxy-28-(3-oxo-cis-1-o)
ctenyl)-IQ-cyclobentanacetic acid y-lactone
arise. Further purification by chromatography yields pure
Gives cis isomer. Following the procedure of Example 4, but using dimethylene
Instead of 2-oxo-beptyl phosphonate,
Any of the various dimethylphosphonates described in
28-(3-oxy), optionally substituted as follows:
corresponding 3 with substituents (1-alkenyl)
Q-t-butyldimethylcycloxy-5Q-hydroxy
-lq-cyclobentanacetic acid y-lactones are produced.
Ru. 4.4-difluorohexenyl, 4.4-difluorohexenyl
putenyl, 4,4-difluorooctenyl, 4,4-di
Fluorononenyl, 4,4-difluorodecenyl, 4-
Fluorohexenyl, 4-fluorohebtenyl, 4-phenyl
fluorooctenyl, 4-fluorononenyl, 4-fluoro
Lodecenyl, 4,4-dimethylhexenyl, 4,4-di
Methylheptenyl, 4,4-dimethyloctenyl, 4,
4-dimethylnonenyl, 4,4-dimethyldecenyl, 4
-Methylhexenyl, 4-methylheptenyl, 4-methy
luoctenyl, 4-methylnonenyl, 4-methyldecenyl
ru, hexenyl, heptenyl, nonenyl, decenyl, 5
-phenylbentenyl, 5-(m-trifluoromethyl
phenyl)-bentenyl, 5-(m-fluorophenyl
)-pentenyl, 5-(m-koo phenyl)-bente
Nyl, 5-(p-trifluoromethylphenyl)-pen
tenyl, 5-(p-fluorophenyl)-bentenyl,
5-(p-chlorophenyl)-bentenyl, 4-methyl
-5-phenylbentenyl, 4-methyl -5-(m-t
Refluo. methylphenyl)-bentenyl, 4-methyl-5-(m
-fluorophenyl)-pentenyl, 4-methyl-5-
(p-trifluoromethylphenyl)-bentenyl, 4
-Methyl-5-(p-fluorophenyl)pentenyl,
4-Methyl-5-(p-oo phenyl)-pentenyl
, 4,4-dimethyl-5-(m-trifluoromethylphthalate)
enyl)-bentenyl, 4,4-dimethyl-5-(m-
fluorophenyl)-bentenyl, 4,4-difluoro
-5-(m-chlorophenyl)-pentenyl, 4,4-
Dimethyl-5-(p-trifluoromethylphenyl)-
Bentenyl, 4,4-dimethyl-5-(p-fluorophore)
enyl)-bentenyl, 4,4-dimethyl-5-(p-
chlorophenyl)-bentenyl, 4-fluoro-5-
enylbentenyl, 4-fluoro5-(m-trifluor
(oromethylphenyl)-bentenyl, 4-fluoro5
-(m-fluorophenyl)-bentenyl, 4-fluoro
R-5-(m-chlorophenyl)-bentenyl, 4-phenyl
Luoreau 5-(p-trifluoromethylphenyl)-be
fluorophenyl, 4-fluoro-5-(p-fluorophenyl)
)-pentenyl, 4-fluoro-5-(p-chlorophene
Bentenyl)-bentenyl, 4,4-difluoro-5-phenylated
Rubentenyl, 4,4-difluoro-5-(m-trif
(fluoromethylphenyl)-pentenyl, 4,4-diflu
Olow-5-(m-fluorophenyl)-bentenyl, 4
,4-difluoro-5-(m-chlorophenyl)-pen
thenyl, 4,4-difluoro5-(p-trifluoro
methylphenyl)-pentenyl, 4,4-difluoro
5-(p-fluorophenyl)-bentenyl, 4,4-
Difluoro-5-(p-chlorophenyl)-pentenyl
, 4-phenoxybutenyl, 4-(m-trifluoromethane)
Tylphenoxy)-butenyl, 4-(p-fluorophene)
noxy)-butenyl, 4-(m-c.lophenoxy)-
Butenyl, 4-(m-trifluoromethylphenoxy)
-butenyl, 4-(p-fluorophenoxy)-butenyl
4-(p-chlorophenoxy)-butenyl, 4-mer
Chi-4-phenoxybutenyl, 4-methyl-4-(m
-trifluoromethylphenoxy)-butenyl, 4-mer
Thyl-4-(m-fluorophenoxy)-putenyl, 4
-methyl-4-(m-chlorophenoxy)-butenyl,
4-Methyl-4-(p-trifluoromethylphenoxy)
-butenyl, 4-methyl-4-(p-fluorophenophenoxylate)
c)-butenyl, 4-methyl-4-(p-chlorophenol)
xy)-butenyl, 4,4-dimethyl-4-phenoxy
Butenyl, 4,4-dimethyl-4-(trifluoromethyl)
ruphenoxy)-butenyl, 4,4-dimethyl-4-(
m-fluorophenoxy)-butenyl, 4,4-dimethy
Ru-4-(m-chlorophenoxy)-butenyl, 4,4
-dimethyl-4-(p-trifluoromethylphenoxy
)-butenyl, 4,4-dimethyl-4-(p-fluoro
phenoxy)-butenyl, 4,4-dimethyl-4-(p
-chlorophenoxy)-butenyl, etc. Follow the steps in Preparation Example 7
However, dimethyl 2-oxoheptyl phosphatide of Preparation Example 5
dimethyl 2-oxosis-4- instead of phonate
Using putenyl phosphonate, 3Q-t-butyldi
Methylsilyloxy 5Q-hydroxy-28-(3-o)
xosis, cis-1,5-octadienyl)-IQ-
Cyclobentaneacetic acid y-lactone is produced. This cis, cis-1,5-octadienyl compound is
Prepared by the chromatographic separation method described in the specification.
Cis, cis-1,5 produced by photoisomerization as described in Example 7
and trans-1-cis-5-geometric isomer mixtures?
separated from 28-(3-oxosis, cis-1,
5-octagenyl) substituents, e.g. 4-fluoro, 4
-methyl, 4,4-dimethyl and 4,4-difluoro
Various other 3Q-t-butyldimethylsilyl
xy-5Q-hydroxy-IQ-cyclobentanacetic acid y
-Lactones are similarly produced. Preparation Example 8 3Q t-butyldimethylsilyloxy 5Q-hydro. xy-28-(3-oxooctyl)-lq-cyclo
Bentaneacetic acid y-lactone [Formula x W: R3 and R of the L part
4 is hydrogen, R7 is n-butyl, Y is -CQCH2-, and
and X is Hノ・,OSikuG2)3 (where -OSi
(G2) 3 is t-butyldimethylsilyloxy)] Figure A
reference. Reaction product of Preparation Example 5 in methanol and water and methanol
Mixing of sodium borohydride in tanol
Stir the material at ambient temperature under nitrogen for 20 minutes. Next, add acetic acid, water, and citric acid one after another to adjust the pH to 3.
adjust. The product was then isolated and subjected to Collins test at -20°C.
Treat with medicine for 20 minutes. Finally, the reaction is stopped and pure
Collect the product. Follow the procedure of Preparation Example 7 or 8, but
The compound of Preparation Example 6 was used instead of the compound of Preparation Example 5 as a starting material.
3-(5-butyldidi) of Preparation Example 7 or 8 using
3-(ethylether) corresponding to the methylsilyl ether) product.
thioketal) product is produced. Following the procedure of Preparation Example 8, but using dimethyl 2-oxoheptyl
Various dimethyl phosphonates listed above can be used in place of the phosphonates.
Use any of the
with a substituted 23-(3-oxoalkyl) substituent
The corresponding 3Q-t-butyldimethylsilyloxy-5Q
-Hydroxy-IQ-Sik. Pentaneacetic acid y-lactone
A class is created. 4,4-difluorohexyl, 4,4
-difluoroheptyl, 4,4-difluorooctyl,
4.4-difluorononyl, 4,4-difluorodecyl
, 4-fluorohexyl, 4-fluorohbutyl, 4-
Fluorooctyl, 4-fluorononyl, 4-fluoro
Decyl, 4,4-dimethylhexyl, 4,4-dimethyl
heptyl, 4,4-dimethyloctyl, 4,4-dimethy
Lunonyl, 4,4-dimethyldecyl, 4-methylhexy
4-methylheptyl, 4-methyloctyl, 4-methyl
thylnonyl, 4-methyldecyl, hexyl, heptyl,
Nonyl “decyl, 5-phenylbentyl, 5-(m-t)
(lifluoromethylphenyl)-bentyl, 5-(m-phenyl)
5-(m-chlorophenyl)-pentyl,
-bentyl, 5-(p-trifluoromethylphenylene)
)-pentyl, 5-(p-fluorophenyl)-ben
methyl, 5-(p-chlorophenyl)-pentyl, 4-methyl
methyl-5-phenylbentyl, 4-methyl-5-(m-
trifluoromethylphenyl)-pentyl, 4-methyl
-5-(m-fluorophenyl)-pentyl, 4-methy
Ru-5-(p-trifluoromethylphenyl)-pentylene
4-methyl-5-(p-fluorophenyl)-ben
Chil, 4-methyl-5-(p-chlorophenyl)-ben
methyl, 4,4-dimethyl-5-(m-trifluoromethyl
(ruphenyl)-pentyl, 4,4-dimethyl-5-(m
-Fluorophenyl)-bentyl, 4,4-difluoro
-5-(m-chlorophenyl)-bentyl, 4,4-di
Methyl-5-(p-trifluoro-methylphenyl)-pe
4,4-dimethyl-5-(p-fluorophenyl)
-bentyl, 4,4-dimethyl-5-(p-chloro)
phenyl)-bentyl, 4-fluoro-bentyl,
trifluoromethyl, 4-fluoro5-(m-trifluoromethyl
phenyl)-bentyl, 4-fluoro5-(m-fluor
olophenyl)-bentyl, 4-fluoro-5-(m-
phenyl)-pentyl, 4-fluoro5-(p
-trifluoromethylphenyl)-bentyl, 4-fluor
Oro-5-(p-fluorophenyl)-bentyl, 4-
Fluoro-5-(p-chlorophenyl)-bentyl, 4
, 4-difluoro-5-phenylbentyl, 4,4-di
Fluoro-5-(m-trifluoromethylphenyl)-
Bentyl, 4,4-difluoro-5-(m-fluorof)
enyl)-bentyl, 4,4-difluoro5-(m-
chlorophenyl)-pentyl, 4,4-difluoro5
-(p-trifluoromethylphenyl)-bentyl, 4
,4-difluoro5-(p-fluorophenyl)-pe
4,4-difluoro-5-(p-chlorophenylene)
-bentyl, 4-phenoxybutyl, 4-bentyl,
Lifluoromethylphenoxy)-butyl, 4-(p-fu)
fluorophenoxy)-butyl, 4-(m-chlorophenoxy)-butyl,
xy)-butyl, 4-(m-trifluoromethylphenol)
xy)-butyl, 4-(p-fluorophenoxy)-butyl
methyl, 4-(p-chlorophenoxy)-butyl, 4-methyl
methyl-4-phenoxybutyl, 4-methyl-4-(m-
trifluoromethylphenoxy)-butyl, 4-methyl
-4-(m-fluorophenoxy)-butyl, 4-methy
Ru-4-(m-chlorophenoxy)-butyl, 4-methy
-4-(p-trifluoromethylphenoxy)-petite
4-methyl-4-(p-fluorophenoxy)ben
Chyl, 4-methyl-4-(p-c.lophenoxy)-butyl, 4,4-dimethyl-4-phene
Noxybutyl, 4,4-dimethyl-4-(trifluoro)
methylphenoxy)-butyl, 4,4-dimethyl-4-
(m-fluorophenoxy)-butyl, 4,4-dimethy
Leu-4-(m-chlorophenoxy)-butyl, 4,4-
Dimethyl-4-(p-trifluoromethylphenoxy)
-butyl, 4,4-dimethyl-4-(p-fluorophene)
noxy)-butyl, 4,4-dimethyl-4-(p-chloro)
rophenoxy)-butyl, etc. Following the procedure of Preparation Example 8, but
28-(3-oxotrans-1,cis-5-
octadienyl)-compounds.
Tyldimethylsilyloxy-5Q-hydroxy-28-(
3-oxosis-5-octenyl)-IQ-cyclobe
Thoractone acetate is produced. This cis-5-octenyl compound was described in Example 5.
Chromatography from a mixture of compounds created by reduction
Separated by separation. 23-(3-oxo-5-o)
Various other 3Q-t-petite with ctenyl) substituents
dimethylsilyloxy-5Q-hydroxy-IQ-sic
Robentane acetate-lactones, e.g. 4-fluoro-
4-methyl, 4,4-dimethyl and 4,4-difluoro
Compounds are made similarly. Preparation Example 9 3Q-(t-butyldimethylsilyloxy)-5Q-hydro
Roxy28-[($)-3-hydroxy-trans-
1-octenyl]-IQ-cyclobentanacetic acid y-lac
[Formula × IX: L, R3 and R4 of the moiety are hydrogen, R7 is
n-butyl, M5 and X (where -OSi(G2)
3 is t-butyldimethylsilyloxy)] or its (station)
Epimer - See Diagram A. Sodium borohydride 0.23 hours under nitrogen atmosphere
was combined with 25' of anhydrous methanol and cooled to -25°C.
To the resulting mixture was added 10' of methanol and
The title compound of Example 2 in hydrofuran 8 [1.64]
Add evening. The mixture was heated to -25 qo 2. Stir for a while, add acetic acid (1/2
yo) Add 1.3'. Then bring the reaction mixture to ambient temperature.
Leave to warm until 200 ml of brine, concentrate under reduced pressure
' and 200 ml of ethyl acetate. organic frac
2M potassium bisulfate, saturated sodium bicarbonate,
Wash with brine and dry over magnesium sulfate. concentration under reduced pressure
The shrinkage produced a pale yellow oil of 1.71 g, which was quenched with silica.
35% in Skelisorp B by gel chromatography
Dissolve with ethyl acetate. Pure title raw as colorless oil
The result was 1.00 evenings and (station) Epima - 0.72 evenings.
Ru. The title compound is 0.03, 0.86, 0.62-3.
00, 3.80-4.25 4.97 and 5.38-5
．． 686 shows NMR absorption. (Station) - About Epimar
Rf is 0.26 (silica gel TLC, scale
50% ethyl acetate in Resolve B). Follow the steps in Preparation Example 9.
but using the compound of Preparation Example 6 instead of the compound of Preparation Example 5.
31 of Example 6 (t-butyldimethylsilica) using
31 (ethylene thioketal) corresponding to
A product is created. Similarly, a corresponding (station) -Epima- will be created. ($)
-For epimer, NM old absorption is 0.90, 0.9~
1.85, 2.25~3.07, 3.27, 3.93~
4.35, 4.68-513 and 5.63-5.806
seen in Infrared absorption is 3450, 1775, 142
0, 1245, 117 stop 1040, and 97&re-1
seen in The mass spectrum shows the parent peak at 414.1709.
Indicates peak absorption. (Explanation) Regarding Epima, NMR
Absorption is 0.90, 0.9-1.80 2.3-3.08
, 3.27, 3.93-4.38, 4.70-5.13
and 572-5.806. Infrared absorption is me 5
0177u1420 124fu 117fu1160 1
Seen in 035 and 97&re-1. The mass spectrum is
Parent peak absorption at 414.1713, and 399, spot 6
, 343, 286, 199 and 173 other peaks
shows. Following the procedure of Example 6, but used there
3Q-t-butyldimethylsilyloxy 5Q-hydroxy
C28-(3-oxotrans-1-octenyl)
-IQ-cyclobentaneacetic acid y-fuctone starting material price
Instead, various 3Q-t-butyl-dimethylsilyloxy
-5Q-hydroxy-28-(3-oxo-cis- or
trans-1,1-alkenyl, cis or trans-1,
cis-5-alkagenyl, alkyl, or substituted alke
(alkagenyl, or alkadienyl, or alkyl)
Using clobentanacetic acid y-lactones, the corresponding
A (station)- or (mori)-hydroxy product is created.
For example, the (class) or ($) type 28 side chain is from
3Q-t-butyl-dimethylsilyloxy-5Q
-Hydroxy-IQ-cyclobentanacetic acid-lactone
can be obtained. That is, 3-hydroxy-trans-1-hexenyl,
3-hydroxy-trans-1-heptenyl, 3-hydro
Roxytrans-1-nonenyl, 3-hydroxyate
trans-1-decenyl, 3-hydroxy-trans-1
, cis-5-octadienyl, 3-hydroxy-4-methane
Chill-trans-1-octenyl, 3-hydroxy-4
,4-dimethyl-trans-1,cis-5-octadie
Nyl, 3-hydroxy-4,4-difluorotrans
-1, cis-5-octadienyl, 3-hydroxy-4
-Fluorotrans-1-octenyl, 3-hydroxy
C-4,4-difluorotrans-1-octenyl,
3-Hydroxy-5-phenyl-trans-1-pente
Nyl, 3-hydroxy-5-(p-fluorophenyl)
-trans-1-bentenyl, 3-hydroxy-5-(
m-chlorophenyl)-trans-1-bentenyl, 3
-Hydroxy-5-(m-trifluoromethylphenyl
)-trans-1-pentenyl, 3-hydroxy-4,
4-dimethyl-5-phenyl-trans-1-benteny
3-hydroxy-4,4-dimethyl-5-(p-fu)
(fluorophenyl)-trans-1-pentenyl, 3-hypolyphenyl
Droxy-4,4-dimethyl-5-(m-chlorophenylene)
)-trans-1-pentenyl, 3-hydroxy-4
,4-dimethyl-5-(m-trifluoromethylphenylene)
)-trans-1-bentenyl, 3-hydroxy-4
,4-difluoro-5-phenyl-trans-1-pene
thenyl, 3-hydroxy-4,4-difluoro5-(
p-fluorophenyl)-trans-1-bentenyl,
3-Hydroxy-4,4-difluoro-5-(m-chloro)
loofenyl)-trans-1-bentenyl, 3-hydro
xy-4,4-difluoro-5-(m-trifluoromethane)
tylphenyl)-trans-1-pentenyl, 3-hydro
Roxy-4-phenoxytrans-1-butenyl, 3
-Hydroxy-4-(p-fluorophenoxy)-tra
Nence-1-butenyl, 3-hydroxy-4-(m-chloro)
rophenoxy)-trans-1-butenyl, 3-hydro
xy-4-(m-trifluoromethylphenoxy)-t
Lance-1-1-putenyl, 3-hydroxy-4,4-dime
Thyl-4-phenoxy-trans-1-putenyl, 3-
Hydroxy-4,4-dimethyl-4-(p-fluorophore)
enoxy)-trans-1-putenyl, 3-hydroxy
-4,4-dimethyl-4-(m-chlorophenoxy)-
trans-1-butenyl, 3-hydroxy-4,4-di
Methyl-4-(m-trifluoromethylphenoxy)-
Trasos-1-butenyl, 3-hydroxysis-1-
hexenyl, 3-hydroxysis-1-heptenyl,
3-hydroxysis-1-octenyl, 3-hydroxy
cis-1-nonenyl, 3-hydroxy-cis-1-
Decenyl, 3-hydroxysis, cis-1,5-oc
Tadienyl, 3-hydroxy-4-methylcis-1-
Octenyl, 3-hydroxy-4,4-dimethyl-cis
-1-octenyl, 3-hydroxy-4-fluorosy
Su-1-octenyl, 3-hydroxy-4,4-diflu
Orosis-1-octenyl, 3-hydroxy-5-phenyl
enylcis-1-pentenyl, 3-hydroxy-5-
(p-fluorophenyl)cis-1-bentenyl, 3
-Hydroxy-5-(m-chlorophenyl)-cis-1
-bentenyl, 3-hydroxy-5-(m-trifluoro
(romethylphenyl)-cis-1-pentenyl, 3-hydro
Roxy-4,4-dimethyl-5-phenylcys-1-
bentenyl, 3-hydroxy-4,4-dimethyl-5-
(p-Fluorophenyl)-cis-1-bentenyl, 3
-Hydroxy-4,4-dimethyl-5-(m-chloroph)
enyl)-cis-1-pentenyl, 3-hydroxy-4
,4-dimethyl-5-(m-trifluoromethylphenylene)
)-cis-1-pentenyl, 3-hydroxy-4,4
-difluoro0-5-phenylcis-1-bentenyl,
3-Hydroxy-4,4-difluoro5-(p-fluor
olophenyl)-cis-1-bentenyl, 3-hydroxy
C4,4-difluoro5-(m-chlorophenyl)
-cis-1-bentenyl, 3-hydroxy-4,4-di
Fluoro-5-(m-trifluoromethylphenyl)-
cis-1-bentenyl, 3-hydroxy-4-phenoxylene
cis-1-butenyl, 3-hydroxy-4-(p-
Fluorophenoxy)-cis-1-butenyl, 3-hydro
Roxy-4-(m-chlorophenoxy)-cis-1-p
thenyl, 3-hydroxy-4-(m-trifluoromethyl
ruphenoxy) cis-1-putenyl, 3-hydroxy
-4,4-dimethyl-4-phenoxysis-1-pute
Nyl, 3-hydroxy-4,4-dimethyl-4-(p-
Fluorophenoxy)-cis-1-butenyl, 3-hydro
Roxy 4,4-dimethyl-4-(m-chlorophyne
c) cis-1-putenyl, 3-hydroxy-4,4-
Dimethyl-4-(m-trifluoromethylphenoxy)
cis-1-butenyl, 3-hydroxy-hexyl, 3
-hydroxy-beptyl, 3-hydroxy-octyl,
3-hydroxynonyl, 3-hydroxydecyl, 3
-hydroxycis-5-octenyl, 3-hydro. Kishi
-4-methyl-octyl, 3-hydroxy-4,4-di
Methylcis-5-octenyl, 3-hydroxy-4,
4-difluorosis-5-octenyl, 3-hydroxy
C-4,4-dimethyl-octyl, 3-hydroxy-4
-Fluorooctyl, 3-hydroxy-4,4-diph
Luoroooctyl, 3-hydroxy-5-phenylube
3-hydroxy-5-(p-fluorophenyl)
)-pentyl, 3-hydroxy-5-(m-chlorophene)
nyl)-bentyl, 3-hydroxy-5-(m trif)
(fluoromethylphenyl)-pentyl, 3-hydroxy
4,4-dimethyl-5-phenyl-pentyl, 3-hydro
Roxy-4,4-dimethyl-5-(p-fluorophene)
)-pentyl, 3-hydroxy-4,4-dimethyl-
5-(m-chlorophenyl)-pentyl, 3-hydroxy
C4.4-dimethyl-5-(m-trifluoromethyl
phenyl) pentyl, 3-hydroxy-4,4-diflu
Oro-5-benylbentyl, 3-hydroxy-4,4
-difluoro-5-(p-fluorophenyl)-pliers
3-hydroxy-4,4-difluoro-5-(m-
chlorophenyl)-bentyl, 3-hydroxy-4,4
-difluoro-5-(m-trifluoromethylphenyl
)-bentyl, 3-hydroxy-4-phenoxybutyl
3-hydroxy-4-(p-fluorophenoxy)
-butyl, 3-hydroxy-4-(m-chlorophenol)
c)-butyl, 3-hydroxy-4-(m-trifluoro
lomethylphenoxy)-butyl, 3-hydroxy-4,
4-dimethyl-4-phenoxybutyl, 3-hydroxy
C-4,4-dimethyl-4-(p-fluorophenoxy)
)-butyl, 3-hydroxy-4,4-dimethyl-4-
(m-chlorophenoxy)-butyl, 3-hydroxy
4,4-dimethyl-4-(m-trifluoromethylfluorocarbon
/xy)-butyl etc. Preparation Example 10 3Q-(t-butyldimethylsilyloxy)-5Q-hydroxy-28-[($)-3-meth
xytrans-1-octenyl]-IQ-cycloben
Tanacetic acid y-lactone [Formula x IX: L, R3 and R of the moiety
4 is hydrogen, R7 is n-butyl, M5 is Y is trans-C
H: CH1, X is (here -OSi(Q)3 is t-butyl
dimethylsilyloxy)] or its (wave) -epima- diagram
See A. Title compound of Example 6 in 50% methyl iodide 1.
Stir 91% of silver oxide and 4.08% of silver oxide under reflux for a while.
heat. Then add 25 parts of chloroform and filter the mixture. filtrate
Concentrate it to an oil and take it into chloroform for 50 minutes.
Ru. This solution was washed with salt water and dried over magnesium sulfate.
Concentrate to oil. Next, silica gel chromatography
The title product was decomposed from the resulting mixture and purified with ethyl acetate.
and eluted with Skellysolve B. Similarly (fox) - Epima
The product is obtained from the epimer starting material. Sequential reaction with NaH and CH31 results in Example 6.
3-(ethylene thioketal) starting material listed below
The material was the corresponding 31 (t-butyldimethylsilane) of Preparation Example 10.
3-(ethylene thioketal) corresponding to
) is converted to product. Following the procedure of Preparation Example 10, but using the 3Q-t-
Butyldimethylsilyloxy 5Q-hydroxy-23-
[(station) or ($)-hydroxy-trans-1-oc
[thenyl]-IQ-cyclobentanacetic acid y-lactone starting
In place of the material, various 3Q-t-butyl dimethyl silica
Roxy 5Q-hydroxy-23- [(bi) or ($)
-hydroxycis- or trans-1-alkenyl:
Cis- or trans-1,cis-5-alkadienyl:
or alkyl; or substituted alkenyl; alkadienyl:
or alkyl)]-IQ-cyclobentanacetic acid
Using tons, the corresponding (class)- or ($)-meth
Oxygen products are produced. For example, (station) or ($) type
26-3Q-t-p if the temporal region consists of the following:
Tyldimethylsilyloxy 5Q-hyde. Kishi IQ-shi
Clobentanacetic acid y-lactones are obtained. 3-meth
xytrans-1-hexenyl, 3-methoxyethra
trans-1-hebutenyl, 3-methoxytrans-1-
octenyl, 3-methoxytrans-1-nonenyl,
3-methoxytrans-1-decenyl, 3-methoxy
-trans-1,cis-5-octadienyl,3-meth
x-4-methyl-trans-1-octenyl, 3-methyl
Toxy-4,4-dimethyl-trans-1-octenyl
, 3-methoxy4,4-dimethyl-trans-1,cy
5-octadienyl, 3-methoxy-4,4-diph
Luorotrans-1,cis-5-octadienyl, 3
-Methoxy-4-fluorothrasos-1-octenyl
, 3-methoxy4,4-difluorotrans-1-
Octenyl, 3-methoxy-5-phenyltrans-
1-pentenyl, 3-methoxy 5-(p-fluorophore
enyl)-trans-1-pentenyl, 3-methoxy-
5-(m-chlorophenyl)-trans-1-benteny
3-methoxy5-(m-trifluoromethylphenylene)
nyl)-trans-1-bentenyl, 3-methoxy-4
,4-dimethyl-5-phenyl-trans-1-vente
Nyl, 3-methoxy-4,4-dimethyl-5-(p-phenyl)
(fluorophenyl)-trans-1-bentenyl, 3-methane
Toxi-4,4-dimethyl-5-(m-chlorophenyl
)-trans-1-bentenyl, 3-methoxy4,4
-dimethyl-5-(m-trifluoromethylphenyl)
-trans-1-pentenyl, 3-methoxy4,4-
Difluoro-5-phenyl-trans-1-bentenyl
, 3-methoxy4,4-difluoro5-(p-fluor
olophenyl)-trans-1-bentenyl, 3-meth
xy-4,4-difluoro5-(m-chlorophenyl
)-trans-1-bentenyl “3-methoxy4,4
-difluoro-5-(m-trifluoromethylphenyl
)-trans-1-pentenyl, 3-methoxy-4-ph
Enoxytrans-1-butenyl, 3-methoxy4
-(p-fluorophenoxy)-trans-1-butenyl
3-methoxy4-(m-chlorophenoxy)-t
Lance-1-1-butenyl, 3-methoxy-4-(m-tri
Fluoromethylphenoxy)-trans-1-butenyl
, 3-methoxy4,4-dimethyl-4-phenoxy
trans-1-butenyl, 3-methoxy4,4-dime
Chiru-4-(p-fluorophenoxy)-trans-1
-putenyl, 3-methoxy4,4-dimethyl-4-(
m-chlorophenoxy)-trans-1-putenyl, 3
-methoxy-4,4-dimethyl-4-(m-trifluoro
methylphenoxy)-trans-1-butenyl, 3-
Methoxy-cis-1-hexenyl, 3-methoxysis
-1-heptenyl, 3-methoxy-cis-1-octenyl
L, 3-methoxycis-1-/nenyl, 3-methoxy
cis-1-decenyl, 3-methoxysis, cis-1
,5-octadienyl,3-methoxy-4-methylcy
1-octenyl, 3-methoxy-4,4-dimethyl
cis-1-octenyl, 3-methoxy-4,4-dime
Thirsis, cis-1,5-octadienyl, 3-meth
cis-4,4-difluorosis, cis-1,5-oc
Tadienyl, 3-methoxy-4-fluorosis-1-
Octenyl, 3-methoxy-4,4-difluorosis
-1-octenyl, 3-methoxy-5-phenylsis
-1-pentenyl, 3-methoxy-5-(p-fluoro
phenyl) cis-1-bentenyl, 3-methoxy5
-(m-chlorophenyl)-cis-1-bentenyl, 3
-Methoxy-5-(m-trifluoromethylphenyl)
-cis-1-bentenyl, 3-methoxy4,4-dime
Thiru-5-phenylysis-1-pentenyl, 3-meth
xy4,4-dimethyl-5-(p-fluoro.phenyl)cis-1-pentenyl, 3-methoxy4
,4-dimethyl-5-(m-chlorophenyl)cis-
1-bentenyl, 3-methoxy4,4-dimethyl-5
-(m-trifluoromethylphenyl)cis-1-be
3-methoxy-4,4-difluoro-5-tenyl, 3-methoxy-4,4-difluoro-5-
enyl-cis-1-pentenyl, 3-methoxy4,4
-difluoro5-(p-fluorophenyl)-cis-
1-bentenyl, 3-methoxy 4,4-difluoro
5-(m-chlorophenyl)-cis-1-bentenyl,
3-Methoxy4,4-difluoro5-(m-trif)
methylphenyl)cis-1-bentenyl, 3-
Methoxy-4-phenoxy-1-butenyl, 3-
Methoxy-4-1 (pn fluorophenoxy)-1
-Ptenyl, 3-methoxy-4-(m-chlorophenol)
c) cis-1-butenyl, 3-methoxy4-(m-
trifluoromethylphenoxy)-cis-1-butenyl
, 3-methoxy4,4-dimethyl-4-phenoxy
cis-1-butenyl, 3-methoxy-4,4-dimethyl
-4-(p-fluorophenoxy)-cis-1-buteny
3-methoxy-4,4-dimethyl-4-(m-chloro)
rophenoxy) cis-1-butenyl, 3-methoxy
4,4-dimethyl-4-(m-trifluoromethylphene)
(noxy)-cis-1-butenyl, 3-methoxy-hexy
3-methoxy-beptyl, 3-methoxyoctyl
, 3-methoxynonyl, 3-methoxydecyl, 3-
Methoxysis-5-octenyl, 3-methoxy-4-
Methyl-octyl, 3-methoxy-4,4-dimethyl-
Octyl, 3-methoxy-4,4-dimethylcys-5
-octenyl, 3-methoxy-4,4-difluorosy
Su-5-octenyl, 3-methoxy4-fluoro
Cutyl, 3-methoxy-4,4-difluorooctyl
, 3-methoxy-5-phenylrubentyl, 3-methoxy
C-5-(p-fluorophenyl)-pentyl, 3-methane
Toxi 5-(m-chlorophenyl)-bentyl, 3-
Methoxy-5-(m-trifluoromethylphenyl)-
Pentyl, 3-methoxy-4,4-dimethyl-5-phene
Nylubentyl, 3-methoxy4,4-dimethyl-5
-(p-fluorophenyl)-bentyl, 3-methoxy
-4,4-dimethyl-5-(m-chlorophenyl)-be
methyl, 3-methoxy4,4-dimethyl-5-(m-
trifluoromethylphenyl)pentyl, 3-methoxy
-4,4-difluoro-5-phenylbentyl, 3-methyl
Toxicity 4,4-difluoro-5-(p-fluorofluoride)
nyl)-pentyl, 3-methoxy4,4-difluoro
-5-(m-chlorophenyl)-pentyl, 3-methoxy
C-4,4-difluoro-5-(m-trifluoromethyl
(ruphenyl)-bentyl, 3-methoxy4-phenoxylene
She-butyl, 3-methoxy-4-(p-fluoropheno)
xy)-butyl, 3-methoxy-4-(m-chlorophene)
noxy)-butyl, 3-methoxy-4-(m-triful)
(oromethylphenoxy)-butyl, 3-methoxy4,
4-dimethyl-4-phenoxybutyl, 3-methoxy
-4,4-dimethyl-4-(p-fluorophe/xy)
-butyl, 3-methoxy-4,4-dimethyl-4-(m
-chlorophenoxy)-butyl, 3-methoxy4,4
-dimethyl-4-(m-trifluoromethylphenoxy
)-butyl etc. Preparation Example 11 3Q-t-butyldimethylsilyloxy-5Q-hydroxy
C-28-[(S)-3-hydroxy-3-methyl-
trans-1-octenyl]-IQ-cyclobentane vinegar
Acid solactone (formula x IX: L, R3 and R4 of the moiety are water
R7 is a mixture of n-butyl and doto, and Y is trans-CH! CH-1, and
X is (where -OSi(G2)3 is t-butyldimethyl
silyloxy) See Figure A. 3Q-tert-butyldimethyl in dry benzene 890'
Silyloxy-5Q-hydroxy-20-(3-oxo
cis-1-octenyl)-IQ-cyclobentaneacetic acid
Cool the solution of -lactone 18 to 9°C under nitrogen atmosphere.
Ru. A solution of trimethylaluminum in toluene yields 60'
Add to the mixture over 4 minutes. 20 minutes of this mixture
Stir at ~25°C for 1.5 hours, then cool to 10q C.
do. Saturate at a rate that maintains the reaction mixture at ambient temperature.
Gradually add 370M ammonium chloride. 0.5 o'clock
After that, the reaction mixture was diluted with acetic ether and water and filtered.
Wash the filter cake with ethyl acetate-water solvent. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were salted.
Wash with water, dry over magnesium sulfate and evaporate.
Produces 20 tons of oil. Add this to 10% vinegar in Skerisolve B.
Chromatograph on silica gel lk9 packed in ethyl acid
Add 10-16% ethyl acetate in Skellisolve B.
18 sleeves, thereby producing pure 3(RS)-raw
produce a product. Follow the procedure in Preparation Example 10, but use
3Q-t-butyldimethylsilyloxy 5Q-hydro
roxy-28-(3-oxo-trans-1-octenylene)
)-IQ-cyclobentaneacetic acid-lactone starting material
Instead of various 30-t-butyldimethylsilyloxane
C-5Q-hydroxy-23-(3-oxosis-also
is trans-alkenyl; cis- or trans-1, cy
Su-5-alkagenyl: alkyl or substituted alkenyl
alkadienyl; or alkyl)-IQ-cyclobene
The corresponding 3-methane
A chill-(S)-hydroxy product is created. For example, if the 28-side chain of type (S) consists of the following:
3Q-t-butyldimethylsilyloxy-5Q-
Hydroxy-IQ-cyclobentanacetic acid lactones
is obtained. That is, 3-methyl-3-hydroxy-trans-1-
hexenyl, 3-methyl-3-hydroxy-trans-
1-heptenyl, 3-methyl-3-hydroxy-tran
Su-1 nonenyl, 3-methyl-3-hydroxyetra
ence-1-1-decenyl, 3-methyl-31-hydroxyate
Lance-1, cis-5-octadienyl, 3-methyl-
3-Hydroxy-4-methyl-trans-1-octeny
3-methyl-3-hydroxy-4,4-dimethyl-
trans-1-octenyl, 3-methyl-3-hydroxy
C-4,4-dimethyl-trans-1,cis-5-oc
Tadienyl, 3-methyl-3-hydroxy-4,4-di
fluorotrans-1,cis-5-octadienyl,
3-methyl-3-hydroxy-4-fluorotrans
-1-octenyl, 3-methyl-3-hydroxy-4,
4-difluoro-trans-1-octenyl, 3-methy
-3-hydroxy-5-phenyl-trans-1-pe
tenyl, 3-methyl-3-hydroxy-5-(p-fu)
phenyl)-trans-1-bentenyl, 3-mer
Chiru-3-hydroxy-5-(m-chlorophenyl)-
trans-1-pentenyl, 3-methyl-3-hydroxy
C-5-(m-trifluoromethylphenyl)-tran
Su-1-pentenyl, 3-methyl-3-hydroxy-4
,4-dimethyl-5-phenyl-trans-1-vente
Nil, 3-methyl-3-hydroxy-4,4-dimethyl
-5-(p-fluorophenyl)-trans-1-ben
thenyl, 3-methyl-3-hydroxy-4,4-dimethy
5-(m-chlorophenyl)-trans-1-ben
thenyl, 3-methyl-3-hydroxy-4,4-dimethy
-5-(m-trifluoromethylphenyl)-tran
Sub-1-bentenyl, 3-methyl-3-hydroxy-4
,4-difluoro-5-phenyltrans-1-pene
thenyl, 3-methyl-3-hydroxy-4,4-diflu
Oro-5-(p-fluorophenyl)-trans-1-
Pentenyl, 3-methyl-3-hydroxy-4,4-di
Fluoro-5-(m-chlorophenyl)-trans-1
-bentenyl, 3-methyl-3-hydroxy-4,4-
Difluoro-5-4 (m-trifluoromethylphenyl
)-trans-1-pentenyl, 3-methyl-3-hydro
Roxy-4-phenoxytrans-1-butenyl, 3
-Methyl-3-hydroxy-4-(p-fluoropheno
xy)-trans-1-butenyl, 3-methyl-3-hy
Droxy-4-(m-chlorophenoxy)-trans-
1-butenyl, 3-methyl-3-hydroxy-4-(m
-trifluoromethylphenoxy)-trans-1-butyl
thenyl, 3-methyl-3-hydroxy-4,4-dimethy
4-phenoxytrans-1-butenyl, 3-methyl
Thyl-3-hydroxy-4,4-dimethyl-4-(p-
fluorophenoxy)-trans-1-ptenyl, 3-
Methyl-3-hydroxy-4,4-dimethyl-4-(m
-chlorophenoxy)-trans-1-butenyl, 3-
Methyl-3-hydroxy-4,4-dimethyl-4-(m
-trifluoromethylphenoxy)-trans-1-p
thenyl, 3-methyl-3-hydroxycis-1-hexyl
Cenyl, 3-methyl-3-hydroxycis-1-heb
thenyl, 3-methyl-3-hydroxycis-1-oc
thenyl, 3-methyl-3-hydroxycis-1-/ne
Nyl, 3-methyl-3-hydro. Kisisi-1-Deseni
3-methyl-3-hydroxysis. Sisu 1,5
-octadienyl, 3-methyl-3-hydroxy-4-
Methyl-cis-1-octenyl, 3-methyl-3-hydro
Roxy-4,4-dimethylcis-1-octenyl, 3
-Methyl-3-hydroxy-4,4-dimethylsis,
Cis-1,5-octadienyl, 3-methyl-3-hydro
Roxy-4,4-difluorosis, cis-1,5-o
Cutadienyl, 3-methyl-3-hydroxy-4-fur
Orosis-1-octenyl, 3-methyl-3-hydro
xy-4,4-difluorosis-1-octenyl, 3
-Methyl-3-hydroxy-5-phenylsis-1-
Bentenyl, 3-methyl-3-hydroxy-5-(p-
fluorophenyl) cis-1-pentenyl, 3-methy
-3-hydroxy-5-(m-chlorophenyl)-cy
Sub-1-bentenyl, 3-methyl-3-hydroxy-5
-(m-trifluoromethylphenyl)cis-1-pe
Tenyl, 3-methyl-3-hydroxy-4,4-dimethyl
Thiru-5-phenylcis-1-pentenyl, 3-methy
-3-hydroxy-4,4-dimethyl-5-(p-phthalate)
fluorophenyl)-cis-1-bentenyl, 3-methyl
-3-hydroxy-4,4-dimethyl-5-(m-chloro)
lofuenyl) cis-1-bentenyl, 3-methyl-3
-Hydroxy-4,4-dimethyl-5-(m-triful)
methylphenyl) cis-1-bentenyl, 3-methyl
Thyl-3-hydroxy-4,4-difluoro-5-phene
Nylcis-1-bentenyl, 3-methyl-3-hydro
Kisii 4,4-difluo. -5-(p-fluorophene
) cis-1-pentenyl, 3-methyl-3-hydro
xy4.4-difluoro5-(m-chlorophenyl
)-cis-1-bentenyl, 3-methyl-3-hydroxy
C-4,4-difluoro-5-(m-trifluoromethyl)
(ruphenyl)-cis-1-bentenyl, 3-methyl-3
-hydroxy-4-phenoxycis-1-butenyl,
3-methyl-3-hydroxy-4-(p-fluorophe
noxy)cis-1-putenyl, 3-methyl-3-hydro
Roxy-4-(m-chlorophenoxy)cis-1-b
thenyl, 3-methyl-3-hydroxy-4-(m-tri
fluoromethylphenoxy)cis-1-butenyl, 3
-Methyl-3-hydroxy-4,4-dimethyl-4-
Enoxisis-1-putenyl, 3-methyl-3-hydro
Roxy-4,4-dimethyl-4-(p-fluoropheno
xy)cis-1-butenyl, 3-methyl-3-hydro
xy-4,4-dimethyl-4-(m-chlorophenoxy
)-cis-1-butenyl, 3-methyl-3-hydroxy
-4,4-dimethyl-4-(m-trifluoromethylphthalate)
enoxy)-cis-1-butenyl, 3-methyl-3-hy-
Droxyhexyl, 3-methyl-3-hydroxybe
butyl, 3-methyl-3-hydroxy-octyl, 3-
Methyl-3-hydroxynonyl, 3-methyl-3-h
Droxy-decyl, 3-methyl-3-hydroxysis
-5-octenyl, 3-methyl-3-hydroxy-4-
Methyl-octyl, 3-methyl-3-hydro. Ki-4,
4-dimethylcis-5-octenyl, 3-methyl-3
-Hydroxy-4,4-difluor. -cis-5-octe
Nyl, 3-methyl-3-hydroxy-4,4-dimethyl
-octyl, 3-methyl-3-hydroxy-4-fluoro
. -octyl, 3-methyl-3-hydroxy-4,4-
Difluorooctyl, 3-methyl-3-hydroxy-
5-phenylubentyl, 3-methyl-3-hydroxy
-5-(p-fluorophenyl)-pentyl, 3-methy
-3-hydroxy-5-(m-chlorophenyl)-pe
methyl, 3-methyl-3-hydroxy-5-(m-tri
Fluoromethylphenyl)-bentyl, 3-methyl-3
-Hydroxy-4,4-dimethyl-5-phenylruben
Chil, 3-methyl-3-hydroxy-4,4-dimethyl
-5-(p-fluorophenyl)-pentyl, 3-methy
-3-hydroxy-4,4-dimethyl-5-(m-k
rolophenyl)-bentyl, 3-methyl-3-hydroxy
4,4-dimethyl-5-(m-trifluoromethyl)
phenyl)-bentyl, 3-methyl-3-hydroxy
4,4-difluoro-5-phenylbentyl, 3-methy
-3-hydroxy-4,4-difluoro-5-(p-
fluorophenyl)-pentyl, 3-methyl-3-hydro
Roxy-4,4-difluoro-5-(m-chlorophenylene)
-bentyl, 3-methyl-3-hydroxy-4,4
-difluoro-5-(m-trifluoromethylphenyl
)-pentyl, 3-methyl-3-hydroxy-4-phene
Noxybutyl, 3-methyl-3-hydroxy-4-(
p-fluorophenoxy)-butyl, 3-methyl-3-
Hydroxy-4-(m-k.〇phenoxy)-butyl,
3-methyl-3-hydroxy-4-(m-trifluoro
methylphenoxy)-butyl, 3-methyl-3-hydro
xy-4,4-dimethyl-4-phenoxybutyl, 3
-Methyl-3-hydroxy-4,4-dimethyl-4-(
p-fluorophenoxy)-butyl, 3-methyl-3-
Hydroxy-4,4-dimethyl-4-(m-chlorophene)
noxy)-butyl, 3-methyl-3-day hydroxy-4,
4-dimethyl-4-(m-trifluoromethylphenoxy)
c)-butyl etc. Preparation Example 12 3Q-(t-butyldimethylsilyloxy)-5Q-hydro
Roxy-28-[($)-3-hydroxy-trans-
1-octenyl]-IQ-cyc0pentasoacetalde
Hydrolactol 3-(tetrahydropyranylethe)
) (Formula x XI: R3 and R4 of the L part are both hydrogen, M6
R7 is n-butyl, Y is trans-CH:CH-, and
and X (where -OSi(G2)3 is t-butyldimethylene
luciriloxy)] or its (plaque) epimer. See Figure A. A Title product of Preparation 9 1.00 tm, methylene chloride 2
0', dihydropyran 1.5 minutes, and pyridine hydrochloride
Keep it together for 2 days at ambient temperature with stirring for 0.15 tns.
, then 300 mL of ethyl acetate and saturated sodium bicarbonate
and the top of the aqueous solution 300. Wash the organic fraction with brine and dry over sodium sulfate.
and concentrated under reduced pressure to yield 1.36 kg of crude product oil.
Ru. This was packed in 10% ethyl acetate in Scherisolve B.
Purified on 60 ml of silica gel and purified in Suke 1" Solv B.
Dissolve with 10-30% ethyl acetate. In this way pure
3Q-(t-butyldimethylsilyloxy)-5Q-hydro
Roxy-26-[($)-3-hydroxy-trans-
1-octenyl]-IQ-cyclobentanacetic acid y-lac
Ton 31 (tetrahydropyranyl ether) 1.19 evening
is obtained as an oil. NMR absorption is ○-03, 0.86
,0-63~3-08.3-17~4-33 4.65
, 4.93, and 5.28-5.686. B
1.19 hours of the reaction product of Step A above was added under nitrogen atmosphere.
to -7800C with toluene 15%.
Ru. 10% diisobutyl hydride in toluene 7.6'
Add the aluminum solution dropwise over 5-10 minutes. reaction temperature
After 1.5 hours while maintaining the temperature at -78℃,
Carefully add 10' of Lofuran and water (2:1)
Destroy excess hydride. Do not stir the reaction mixture.
Allow to warm to ambient temperature and filter through Celite.
diluted with 300% ethyl acetate and 2M potassium bisulfate.
in aqueous solution, saturated aqueous sodium bicarbonate solution and brine one after another.
wash. The mixture was dried over sodium sulfate and concentrated under reduced pressure.
Condensation yields the title compound as a colorless oil.
. This gradually solidifies. The Rf value is in Schellisolp B.
0.19 and 0.24 with 25% ethyl acetate, also with skeliso
0.54 and 0.59 (series) in 50% ethyl acetate in
Lycagel TLC). Following the procedure of Preparation Example 12, but
The 3Q-t-butyldimethylsilyloxy used there
-5Q-hydroxy-23-[($)-3-hydroxy
-trans-1-octenyl]-IQ-cyclobentane
Instead of the acetate y-lactone starting material, after Example 6
Various 3Q-t-butyldimethylsilyloxy-
5o-hydroxy-28-[(arc)1 or ($)-3-
Hydroxysis or trans-1-alkenyl: cis
- or trans-1,cis-5-alkagenyl;
or substituted alkenyl; or substituted alkenyl; or substituted alkenyl; or substituted alkenyl;
[Kyl]-IQ-cyclobentanacetic acid y-lactones
of the (iso)- or ($)-3-hydroxy product using
The corresponding 3-(tetrahydropyranyl ethers)
I can't believe it. For example, the 28-side chain of the (station) or ($) type is as follows:
When consisting of 3-(tetrahydropyranylable)
The above-mentioned 3q-t-butyldimethylsilyloxy-5Q-hyron
Droxy IQ-Cyclobentaneacetaldehyde y-
Lactol 3-(tetrahydropyranyl ethers)
can get. That is, 3-hydroxy-trans-1-hexenyl
, 3-hydroxy-trans-1-heptenyl, 3-hydroxy
Droxytrans-1-nonenyl, 3-hydroxy
trans-1-decenyl, 3-hydroxy-trans-
1, cis-5-octadienyl, 3-hydroxy-4-
Methyl-trans-1-octenyl, 3-hydroxy
4-methyl-trans-1-octenyl, 3-hydroxy
C-4,4-dimethyl-trans-1,cis-5-oc
Tadienyl, 3-hydroxy-4,4-difluoro-
lance-1, cis-5-octadienyl, 3-hydroxy
C4-Fluoro-trans-1-octenyl, 3-H
Droxy-4,4-difluorotrans-1-octe
Nyl, 3-hydroxy-5-phenyl-trans-1-
Bentenyl, 3-hydroxy-5-(p-fluorophene)
nyl)-trans-1-pentenyl, 3-hydroxy-
5-(m-chlorophenyl)-trans-1-bentenyl
3-hydroxy-5-(m-trifluoromethyl fluoride)
enyl)-trans-1-bentenyl, 3-hydroxy
-4,4-dimethyl-5-phenyl-trans-1-pe
enthenyl, 3-hydroxy-4,4-dimethyl-5-(
p-fluorophenyl)-trans-1-pentenyl,
3-hydroxy-4,4-dimethyl-5-(m-chloro
phenyl)-trans-1-pentenyl, 3-hydroxy
C-4,4-dimethyl-5-(m-trifluoromethyl
phenyl)-trans-1-pentenyl, 3-hydroxy
C-4,4-difluoro-5-phenyltrans-1
-bentenyl, 3-hydroxy-4,4-difluoro-
5-(p-fluorophenyl)-trans-1-bente
Nyl, 3-hydroxy-4,4-difluoro5-(m
-chlorophenyl)-trans-1-bentenyl, 3-
Hydroxy-4,4-difluoro-5-(m-trifluor
(oromethylphenyl)-trans-1-pentenyl, 3
-Hydroxy-4-phenoxytrans-1-butene
3-hydroxy-4-(p-fluorophenoxy)
-trans-1-butenyl, 3-hydroxy-4-(m
-chlorophenoxy)-trans-1-butenyl, 3-
Hydroxy-4-(m-trifluoromethylphenoxy)
)-trans-1-butenyl, 3-hydroxy-4,4
-dimethyl-4-phenoxytrans-1-butenyl
, 3-hydroxy-4,4-dimethyl-4-(p-flu
(olophenoxy)-trans-1-butenyl, 3-hydro
Roxy-4,4-dimethyl-4-(m-chlorophenoxy)
c)-trans-1-butenyl, 3-hydroxy-4,
4-dimethyl-4-(m-trifluoromethylphenoxylene)
C)-trans-1-butenyl, 3-hydroxysis
-1-hexenyl, 3-hydroxysis-1-hepte
Nyl, 3-hydroxysis-1-octenyl, 3-H
droxysis-1 nonenyl, 3-hydroxy-cis
-1-decenyl, 3-hydroxysis, cis-1,5
-octadienyl, 3-hydroxy-4-methylosis
-1-octenyl, 3-hydroxy-4,4-dimethyl
cis-1-octenyl, 3-hydroxy-4-fluoro
low-cis-1-octenyl, 3-hydroxy-4,4-
Difluorosis-1-octenyl, 3-hydroxy-
5-phenylcis-1-pentenyl, 3-hydroxy
-5-(p-fluorophenyl)-cis-1-benteny
3-hydroxy-5-(m-chlorophenyl)-
-1-pentenyl, 3-hydroxy-5-(m-tri
fluoromethylphenyl)cis-1-bentenyl, 3
-Hydroxy-4,4-dimethyl-5-phenyl-cis
-1-bentenyl, 3-hydroxy-4,4-dimethyl
-5-(p-fluorophenyl)-cis-1-besotenyl
3-hydroxy-4,4-dimethyl-5-(m-k)
rolophenyl)-cis-1-pentenyl, 3-hydroxy
C-4,4-dimethyl-5-(m-trifluoromethyl
phenyl)-cis-1-pentenyl, 3-hydroxy-
4,4-difluoro-5-phenylycis-1-besote
Nyl, 3-hydroxy-4,4-difluoro-5-(p
-fluorophenyl)-cis-1-bentenyl, 3-h
Droxy-4,4-difluoro-5-(m-chlorophene)
Nyl)-cis-1-bentenyl, 3-hydroxy-4,
4-difluoro-5-(m-trifluoromethylphenylene)
)cis-1-bentenyl, 3-hydroxy-4-bentenyl
enoxy-1-butenyl, 3-hydroxy-4-
(p-fluorophe/xy)-cis-1-butenyl, 3
-Hydroxy-4-(m-chlorophenoxy)-cis
1-butenyl, 3-hydroxy-4-(m-trifluoro)
methylphenoxy) cis-1-butenyl, 3-hydro
Roxy-4,4-dimethyl-4-phenoxysis-1
-butenyl, 3-hydroxy-4,4-dimethyl-4-
(p-fluorophenoxy)-cis-1-butenyl, 3
-Hydroxy-4,4-dimethyl-4-(m-chloroph)
enoxy)cis-1-butenyl, 3-hydroxy-4
,4-dimethyl-4-(m-trifluoromethylphenol)
cis-1-butenyl, 3-hydroxyhexy
3-hydroxy-beptyl, 3-hydroxy-octyl
Chil, 3-hydroxy-nonyl, 3-hydroxy-decyl
L, 3-hydroxycis-5-octenyl, 3-hydro
Roxy-4-methyl-octenyl, 3-hydroxy-4
, 4-difluorosis-5-octenyl, 3-hydro
xy-4,4-dimethyl-octyl, 3-hydroxy-
4-fluorooctyl, 3-hydroxy-4,4-di
Fluoroooctyl, 3-hydroxy-5-phenyl-
Pentyl, 3-hydroxy-5-(p-fluorophenyl)
)-bentyl, 3-hydroxy-5-(m-koo f)
enyl)-bentyl, 3-hydroxy-5-(m-tri
Fluoromethylphenyl)-pentyl, 3-hydroxy
-4,4-dimethyl-5-phenyl-pentyl, 3-h
Droxy-4,4-dimethyl-5-(p-fluorophene)
nyl)-pentyl, 3-hydroxy-4,4-dimethyl
-5-(m-chlorophenyl)-pentyl, 3-hydro
x-4,4-dimethyl-5-(m-trifluoromethyl)
(ruphenyl)-bentyl, 3-hydroxy-4,4-di
Fluoro-5-phenylbentyl, 3-hydroxy-4
,4-difluoro5-(p-fluorophenyl)-be
ethyl, 3-hydroxy-4,4-difluoro-5-(
m-chlorophenyl)-pentyl, 3-hydroxy-4
,4-difluoro-5-(m-trifluoromethylphene)
nyl)-bentyl, 3-hydroxy-4-phenoxy
butyl, 3-hydroxy-4-(p-fluorophene)
c)-butyl, 3-hydroxy-4-(m-chlorophene)
noxy)-butyl, 3-hydroxy-4,4-dimethyl
-4-phenoxy-butyl, 3-hydroxy-4,4-
dimethyl-4-(p-fluorophenoxy)-butyl,
3-Hydroxy-4,4-dimethyl-4-(m-chloro
Phenoxy)-butyl, 3-hydroxy-4,4-dimethyl
Chiru-4-(m-trifluoromethylphenoxy)-b
Chill et al. Follow the procedure of Step B of Preparation Example 12, but use
The used 3q-t-butyldimethylsilyloxy-5o-
Hydroxy-28-[(station)-or ($)-3mhydro
xytrans-1-octenyl]-IQ-cycloben
Preparation Example 10 instead of tanacetic acid y-lactone starting material
Various 3Q-t-butyldimethylsilyl compounds mentioned after
5Q-Hydroxy-28-[(grade)- or ($)
-3-methoxy- or trans-1-alkenyl
: cis- or trans-1, cis-5-alkagenyl
;alkyl; or substituted alkenyl: alkagenyl; or
is alkyl]-IQ-cyclobentanacetic acid y-lactone
using the corresponding (station) - or ($) -3-meth
An xy product is obtained. For example, the 28-side chain in the (class) or ($) type is as follows:
The above 3Q-t-butyldimethylsilyloxy
C-5Q-Hydroxy-IQ-cyclobentanaceto
Rudehyde lactols are obtained. That is, 3-methoxytrans-1-hexenyl,
3-methoxytrans-1-heptenyl, 3-methoxy
C-trans-1-octenyl, 3-methoxytotran
Su-1-nonenyl, 3-methoxy-trans-1-dec
nyl, 3-methoxytrans-1, cis-5-octa
dienyl, 3-methoxy-4-methyl-trans-1-
Octenyl, 3-methoxy-4,4-dimethyl-tran
1,cis-5-octadienyl, 3-methoxy-4
,4-difluorotrans-1,cis-5-octadi
enyl, 3-methoxy-4-methyl-trans-1-o
Ctenyl, 3-methoxy-4,4-dimethyl-trans
-1-octenyl, 3-methoxy-4,4-difluoro
-trans-1-octenyl, 3-methoxy4-fur
orotrans-1-octenyl, 3-methoxy5-
Phenyl-trans-1-bentenyl, 3-methoxy
5-(p-fluorophenyl)-trans-1-vente
Nyl, 3-methoxy-5-(m-chlorophenyl)to
Rance 1-bentenyl, 3-methoxy 5-(m-t)
(rifluoro-methylphenyl)-trans-1-pentenyl
3-methoxy-4,4-dimethyl-5-phenyl-
trans-1-pentenyl, 3-methoxy-4,4-di
Methyl-5-(p-fluorophenyl)-trans-1
-bentenyl, 3-methoxy-4,4-dimethyl-5-
(m-chlorophenyl)-trans-1-pentenyl,
3-methoxy-4,4-dimethyl-5-(m-triflu
(oromethylphenyl)-trans-1-bentenyl, 3
-Methoxy-4,4-difluoro-5-phenyltra
ence-1-pentenyl, 3-methoxy-4,4-diflu
oro-5-(p-fluorophenyl)-trans-1-
bentenyl, 3-methoxy-4,4-difluoro-5-
(m-chlorophenyl)-trans-1-pentenyl,
3-Methoxy-4,4-difluoro-5-(m trif)
(fluoromethylphenyl)-trans-1-pentenyl,
3-methoxy4-phenoxytrans-1-putenyl
3-methoxy4-(p-fluorophenoxy)-
trans-1-butenyl, 3-methoxy-4-(m-k
rolophenoxy)-trans-1-putenyl, 3-meth
xy-4-(m-trifluoromethylphenoxy)ate
Lance-1-butenyl, 3-methoxy-4,4-dimethy
Le-4-phenoxytrans-1-butenyl, 3-mer
Toxi-4,4-dimethyl-4-(p-fluoropheno
xy)-trans-1-butenyl, 3-methoxy4,
4-dimethyl-4-(m-chlorophenoxy)-tran
Sub-1-butenyl, 3-methoxy4,4-dimethyl-
4-(m-trifluoromethylphenoxy)-trans
-1-butenyl, 3-methoxysis-1-hexenyl
, 3-methoxycis-1-heptenyl, 3-methoxy
cis-1-octenyl, 3-methoxy-cis-1no
nenyl, 3-methoxycis-1-decenyl, 3-meth
xysis, cis-1,5-octadienyl, 3-meth
xy-4-methylcis-1-octenyl, 3-methoxy
C-4,4-dimethylcis-1-octenyl, 3-methyl
Toxi-4,4-dimethylsis, cis-1,5-oc
Tadienyl, 3-methoxy-4,4-difluorosis
, cis-1,5-octadienyl, 3-methoxy4-
Methylcis-1-octenyl, 3-methoxy4-f
Fluorosis-1-octenyl, 3-methoxy4,4
-difluorosis-1-octenyl, 3-methoxy
5-phenylcis-1-pentenyl, 3-methoxy
5-(p-fluorophenyl)cis-1-besotenyl
, 3-methoxy-5-(m-chlorophenyl)-cis-
1-pentenyl, 3-methoxy5-(m-trifluoro)
(romethylphenyl) cis-1-pentenyl, 3-meth
xy-4,4-dimethyl-5-phenylcis-1-be
enthenyl, 3-methoxy4,4-dimethyl-5-(p
-fluorophenyl) cis-1-pentenyl, 3-methane
Toxi-4,4-dimethyl-5-(m-chlorophenyl
)-cis-1-bentenyl, 3-methoxy-4,4-di
Methyl-5-(m-trifluoromethylphenyl)-cy
Sub-1-bentenyl, 3-methoxy 4,4-difluoro
Lo-5-phenylcis-1-bentenyl, 3-methoxy
C-4,4-difluoro-5-(p-fluorophenyl)
)-cis-1-bentenyl, 3-methoxy-4,4-di
Fluoro-5-(m-chlorophenyl)-cis-1-be
tenyl, 3-methoxy-4,4-difluoro5-(
m-trifluoromethylphenyl)cis-1-vente
Nil, 3-methoxy-4-phenoxy-1-pute
Nyl, 3-methoxy-4-(p-fluorophenoxy)
-cis-1-butenyl, 3-methoxy4-(m-chloro
rophenoxy)-cis-1-butenyl, 3-methoxy
4-(m-trifluoromethylphenoxy)cis-1
-putenyl, 3-methoxy4,4-dimethyl-4-phenyl
enoxysis-1-butenyl, 3-methoxy-4,4
-dimethyl-4-(p-fluorophe/xy)cis-
1-butenyl, 3-methoxy4,4-dimethyl-4-
(m-chlorophenoxy)cis-1-putenyl, 3-
Methoxy-4,4-dimethyl-4-(m-trifluoro
methylphenoxy)cis-1-putenyl, 3-methoxy
Cyhexyl, 3-methoxy-bebutyl, 3-methoxy
-octyl, 3-methoxy-/nyl, 3-methoxyde
sil, 3-methoxysis-5-octenyl, 3-meth
xy-4-methyl-octyl, 3-methoxy-4,4-
Dimethylcis-5-octenyl, 3-methoxy4,
4-difluorosis-5-octenyl, 3-methoxy
-4,4-dimethyl-octyl, 3-methoxy-4-f
Luoroooctyl, 3-methoxy-4,4-difluoro
-octyl, 3-methoxy-5-phenylrubentyl,
3-Methoxy-5-(p-fluorophenyl)-benchi
3-methoxy5-(m-chlorophenyl)-pene
methyl, 3-methoxy-5-(m-trifluoromethylphthalate)
enyl)-bentyl, 3-methoxy4,4-dimethyl
-5-phenyl-pentyl, 3-methoxy-4,4-di
Methyl-5-(p-fluorophenyl)-bentyl, 3
-Methoxy-4,4-dimethyl-5-(m-chlorophene)
nyl)-bentyl, 3-methoxy4,4-dimethyl-
5-(m-trifluoromethylphenyl)-bentyl,
3-Methoxy-4,4-difluoro-5-phenylben
Chil, 3-methoxy-4,4-difluoro-5-(p-
fluorophenyl)-bentyl, 3-methoxy-4,4
-difluoro5-(m-chlorophenyl)-bentyl
, 3-methoxy4,4-difluoro-5-(m-trifluoro)
Fluoro-methylphenyl)-bentyl, 3-methoxy
4-phenoxybutyl, 3-methoxy-4-(p-fu)
fluorophenoxy)-butyl, 3-methoxy4-(m
-chlorophene/xy)-butyl, 3-methoxy-4-(
m-trifluoromethylphenoxy)-butyl, 3-methyl
Toxy-4,4-dimethyl-4-phenoxybutyl,
3-Methoxy4,4-dimethyl-4-(p-fluoro
phenoxy)-butyl, 3-methoxy-4,4-dimethy
Ru-4-(m-chlorophenoxy)-butyl, 3-meth
xy-4,4-dimethyl-4-(m-trifluoromethyl)
lufenoxy)-butyl et al. Preparation Example 12 Step B Procedure
However, the 3Q-t-butyldimethyl used therein
Silyloxy-5Q-hydroxy-28-[($)-3-
hydroxy-trans-1-octenyl]-IQ-sic
In place of the lobentane acetate-lactone starting material, the preparation
The various 3Q-t-butyl dimethane described after Example 11
Tylsilyloxy-5Q-hydroxy-28- [(S)
-3-methyl-3-hydroxy-cis- or trans-
1-alkenyl; cis- or trans-1, cis-5-
Alkadienyl; alkyl: or substituted alkenyl;
Cajenyl; or alkyl)-IQ-cyclobentane vinegar
(S)-3-methyl-
The corresponding 3-(tetrahydropi) of the 3-hydroxy product
ranyl ethers) are produced. For example, the 23-side chain in the (station S) type is the 3-(
The above when consisting of tetrahydropyranyl ethers)
3Q-t-butyldimethylsilyloxy 5Q-hydroxy
C-IQ-cyclobentanacetaldehyde y-lacto
− rules are obtained. 3-methyl-3-hydroxy-trans-1-hexenyl
3-methyl-3-hydroxy-trans-1-hep
thenyl, 3-methyl-3-hydroxy-trans-1-
Octenyl, 3-methyl-3-hydroxy-trans-
1-nonenyl, 3-methyl-3-hydroxy-trans
-1-decenyl, 3-methyl-3-hydroxytotran
-1,cis-5-octadienyl,3-methyl-3-
hydroxy-4-methyl-trans-1-octenyl,
3-methyl-3-hydroxy-4,4-dimethyl-tra
nce-1, cis-5-octadienyl, 3-methyl-3
-Hydroxy-4,4-difluoro-trans-1,cy
Su-5-octadienyl, 3-methyl-3-hydroxy
-4-fluoro-trans-1-octenyl, 3-methy
-3-hydroxy-4,4-difluorotrans-
1-octenyl, 3-methyl-3-hydroxy-5-
enyl-trans-1-pentenyl, 3-methyl-3-
Hydroxy-5-(p-fluorophenyl)-trans
-1-pentenyl, 3-methyl-3-hydroxy-5-
(m-chlorophenyl)-trans-1-pentenyl,
3-methyl-3-hydroxy-5-(m-trifluoro
methylphenyl)-trans-1-bentenyl, 3-methyl
Thiru-3-hydroxy-4,4-dimethyl-5-phenylene
Le-trans-1-pentenyl, 3-methyl-3-hydro
Roxy 4,4-dimethyl-5-(p-fluorophene
-trans-1-bentenyl, 3-methyl-3-h
Droxy-4,4-dimethyl-5-(m-chlorophenylene)
)-trans-1-pentenyl, 3-methyl-3-h
Droxy-4,4-dimethyl-5-(m-trifluoro
methylphenyl)-trans-1-bentenyl, 3-methyl
Chil-3-hydroxy-4,4-difluoro-5-phene
Nyl-trans-1-bentenyl, 3-methyl-3-h
Droxy-4,4-difluoro-5-(p-fluorof)
enyl)-trans-1-bentenyl, 3-methyl-3
-Hydroxy-4,4-difluoro-5-(m-chloro
phenyl)-trans-1-bentenyl, 3-methyl-
3-Hydroxy-4,4-difluoro-5-(m-tri
Fluoromethylphenyl)-trans-1-pentenyl
, 3-methyl-3-hydroxy-4-phenoxytra
nce-1-putenyl, 3-methyl-3-hydroxy-4
-(p-fluorophenoxy)-trans-1-buteny
3-methyl-3-hydroxy-4-(m-chlorophyle)
enoxy)-trans-1-butenyl, 3-methyl-3
-Hydroxy-4-(m-trifluoromethylphenoxy)
c)-trans-1-butenyl, 3-methyl-3-hydro
Roxy-4,4-dimethyl-4-phenoxytrans
-1-putenyl, 3-methyl-3-hydroxy-4,4
-dimethyl-4-(p-fluorophenoxy)-tolan
Su-1-butenyl, 3-methyl-3-hydroxy-4,
4-dimethyl-4-(m-chlorophenoxy)-tran
-1-butenyl, 3-methyl-3-hydroxy-4,
4-dimethyl-4-(m-trifluoromethylphenoxylate)
c)-trans-1-putenyl, 3-methyl-3-hydro
roxisis-1-hexenyl, 3-methyl-3-hydro
Roxy-cis-1-heptenyl, 3-methyl-3-hydro
Roxy-1-octenyl, 3-methyl-3-hydro
Roxisis-1-nonenyl, 3-methyl-3-hydro
xysis-1-decenyl, 3-methyl-3-hydroxy
cis, cis-1,5-octadienyl, 3-methyl
-3-hydroxy-4-methylcis-1-octenyl
, 3-methyl-3-hydroxy-4,4-dimethyl-
1-octenyl, 3-methyl-3-hydroxy-4
,4-dimethyl-cis,cis-1,5-octadienyl
, 3-methyl-3-hydroxy-4,4-difluoro
cis, cis-1,5-octadienyl, 3-methyl-3
-Hydroxy-4,4-dimethylcis-1-octeny
3-methyl-3-hydroxy-4-fluorosis
-1-octenyl, 3-methyl-3-hydroxy-4,
4-difluorosis-1-octenyl, 3-methyl-
3-Hydroxy-5-phenyl-cis-1-bentenyl
, 3-methyl-3-hydroxy-5-(p-fluorophore)
(enyl) cis-1-pentenyl, 3-methyl-3-hy
droxy-5-(m-chlorophenyl)cis-1-pe
tenyl, 3-methyl-3-hydroxy-5-(m-t)
(lifluoromethylphenyl) cis-1-pentenyl,
3-methyl-3-hydroxy-4,4-dimethyl-5-
Phenylcis-1-pentenyl, 3-methyl-3-hy
Dooxy-4,4-dimethyl-5-(p-fluorophene)
Nyl)-cis-1-pentenyl, 3-methyl-3-hydro
Roxy 4,4-dimethyl-5-(m-chlorophenyl
)-cis-1-pentenyl, 3-methyl-3-hydroxy
C-4,4-dimethyl-5-(m-trifluoromethyl
phenyl)-cis-1-bentenyl, 3-methyl-3-
Hydroxy-4,4-difluoro-5-phenylsis
-1-pentenyl, 3-methyl-3-hydroxy-4,
4-difluoro-5-(p-fluorophenyl)sis
-1-bentenyl, 3-methyl-3-hydroxy-4,
4-difluoro-5-(m-chlorophenyl)cis-
1-pentenyl, 3-methyl-3-hydroxy-4,4
-difluoro-5-(m-trifluoromethylphenyl
)-cis-1-pentenyl, 3-methyl-3-hydroxy
C-4-phenoxysis-1-butenyl, 3-methyl
-3-Hydroxy-4-(p-fluorophenoxy)-
cis-1-butenyl, 3-methyl-3-hydroxy-4
-(m-chlorophenoxy)cis-1-putenyl, 3
-Methyl-3-hydroxy-4-(m-trifluoromethane)
tylphenoxy)-cis-1-butenyl, 3-methyl-
3-Hydroxy-4,4-dimethyl-4-phenoxy
cis-1-butenyl, 3-methyl-3-hydroxy-4
．． 4-dimethyl-4-(p-fluorophenoxy)-cy
su-1-butenyl, 3-methyl-3-hydroxy-4,
4-dimethyl-4-(m-chlorophenoxy)-cis-
1-putenyl, 3-methyl-3-hydroxy-4,4-
Dimethyl-4-(m-trifluoromethylphenoxy)
cis-1-butenyl, 3-methyl-3-hydroxy-
hexyl, 3-methyl-3-hydroxy-beptyl, 3
-methyl-3-hydroxy-octyl, 3-methyl-3
-Hydroxynonyl, 3-methyl-3-hydroxy
Decyl, 3-methyl-3-hydroxycis-5-oc
thenyl, 3-methyl-3-hydroxy-4-methyl-o
Cutyl, 3-methyl-3-hydroxy-4,4-dimethy
Lucis-5-octenyl, 3-methyl-3-hydroxy
C4,4-difluorosis-5-octenyl,3-
Methyl-3-hydroxy-4,4-dimethyl-octyl
, 3-methyl-3-hydroxy-4-fluorooctyl
3-methyl-3-hydroxy-4,4-difluoro
-octyl, 3-methyl-3-hydroxy-5-phenylene
Rubentyl, 3-methyl-3-hydroxy-5-(p
-fluorophenyl)-pentyl, 3-methyl-3-hydroxy
Droxy-5-(m-chlorophenyl)-bentyl, 3
-Methyl-3-hydroxy-5-(m-trifluorome)
tylphenyl)-pentyl, 3-methyl-3-hydroxy
C-4,4-dimethyl-5-phenyl-pentyl, 3-
Methyl-3-hydroxy-4,4-dimethyl-5-(p
-Fluorophenyl)-bentyl, 3-methyl-3-hy
Droxy-4,4-dimethyl-5-(m-chlorophenylene)
)-bentyl, 3-methyl-3-hydroxy-4,4
-dimethyl-5-(m-trifluoromethylphenyl)
-pentyl, 3-methyl-3-hydroxy-4,4-di
Fluoro-5-phenylbentyl, 3-methyl-3-h
Droxy-4,4-difluoro-5-(p-fluorophore)
enyl)-bentyl, 3-methyl-3-hydroxy-4
,4-difluoro-5-(m-chlorophenyl)-ben
Chil, 3-methyl-3-hydroxy-4,4-difluoro
Rho 5-(m-trifluoromethylphenyl)-bench
3-methyl-3-hydroxy-4-phenoxieb
Chil, 3-methyl-3-hydroxy-4-(p-fluoro
lophenoxy)-butyl, 3-methyl-3-hydroxy
-4-(m-chlorophenoxy)-butyl, 3-methyl
-3-Hydroxy-4-(m-trifluoromethylphenylene)
noxy)-butyl, 3-methyl-3-hydroxy-4,
4-dimethyl-4-phenoxybutyl, 3-methyl-
3-hydroxy-4,4-dimethyl-4-(p-flu
olophenoxy)-butyl, 3-methyl-3-hydroxy
C-4,4-dimethyl-4-(m-chlorophenoxy)
-butyl, 3-methyl-3-hydroxy-4,4-dimethyl
Tyl-4-(m-trifluoromethylphenoxy)ben
Chill et al. Following the procedure of Example 9, but using Example 6-3 as starting material
- Implementation corresponding to tert-butyldimethylsilyloxy compounds
3-ethylene thioketal compound described after Example 6
The following compounds are made using each of the following: (1} 3-oxo-5Q-hydroxy-23-[(3
S) monohydroxy-trans-1'-octenyl]-I
Q-cyclobesotanacetic acid y-lactone 3-(ethylenethiol)
oketal), 3'-(tetrahydropyranyl ether)
). (NM old absorption is 0.90, 0.90~2.3, 2.3~
3.1, 3.27, 3.1-4.3, 4.58-5.1
5, and 5.40 to 5.856. Infrared absorption 1780,
1250, 1195 1185, 1160, 1130,
1115, 1080, 1035, 1020, 975, 9
05-1. The mass spectrum peak is 426.191
9 (parent peak), 396, 342, 324, 314, 2
90 and 214 skin [2] 3-oxo 5Q-hydroxy
C28-[(3S)-3-hydroxy-trans-1
'-octenyl]-IQ-cyclobentanacetalde
Hydroy-lactol 3-(ethylenethioketal) 3-
(tetrahydropyranyl ether) (Rf (silica gel)
Chromatography) was performed using 25% ethyl acetate in Skellisolve B.
0 in chill. pine). Similarly, as described after Preparation Example 12,
Species corresponding to the tert-butyldimethylsilyloxy compound
Each ethylene thioketal was prepared according to the procedure of Preparation Example 12.
It is made. Reference example 1 3-oxer PGF, QII-(t-butyldimethylsiloxane)
(lyl ether) 15-(tetrahydropyranyl ether)
) Methyl ester [Formula x XX: R, is methyl, g is 1,
L, R3 and R4 of the part are hydrogen, R7 of the pigeon is n-butyl,
X is (where -OSi(G2)3 is t-butyldimethylsil
Y is trans-CH=CH-] or its 15
- epimer or corresponding free acid See diagram B. A: Add 10.0 mg of the title compound of Preparation Example 12 (3 drops of acetic acid)
(containing) must be dissolved in 150 ml of absolute ethanol. Add carbethoxymethylene triphenyl phosphor to this solution.
Add orchid for 10 hours and stir the mixture at ambient temperature for 7 hours.
Zeru. The resulting mixture is concentrated under reduced pressure to a volume of approximately 35 volumes.
and ethyl acetate, mixed with ice and dilute sodium bicarbonate solution.
Shake with water. Wash the organic phase with brine and soak in magnesium sulfate.
Drying over sium and concentrating yields a residue. residue
Slurry and filter in Jetyl Ether 100
do. Concentrate the filtrate to a residue. Silica gel residue
20-4 in Scherisolve B by chromatography.
Elute with 0% ethyl acetate. Formula XX skin compound 2,3,
4-trinor-PGF2Q ethyl ester 11-(t-
butyldimethylsilyl ether) 15-(tetrahydro
pyranyl ether) is obtained. 8 Reaction of step A above
The product was dissolved in 5% palladium on charcoal in 30' of ethyl acetate.
The mixture was mixed with 0.3 liters of aluminum catalyst and hydrogenated under atmospheric pressure. Filter the catalyst when approximately 41' of hydrogen is consumed and the filtrate
When concentrated under reduced pressure, 2,3,4-t of the formula XX skin compound is obtained.
Linol-PGF, Q ethyl ester, 11-(t-butylene
15-(tetrahydropisilyl ether), 15-(tetrahydropisilyl ether),
Rani ether). C Diethyl ether 30
The reaction product 1.1 of step B above in Z of
Ether 60 surefire lithium aluminum hydride 0.3
Add 000 to the evening mixture while stirring. Addition continues over a period of 10 minutes. Let the mixture sit for 2 hours.
Allow to warm up to room temperature, then cool to 0°C and add 0.3
5. Carefully add and process. Next, 15% sodium hydroxide
Add 0.35 ml of thorium aqueous solution, then add 1 ml of water.
Add. The solids were removed by filtration and the filtrate was concentrated under reduced pressure.
When condensed, 2-decarboxy-2-hydroxymethyl-
2,3,4-trino-PGF, QII-(t-butyl
dimethylsilyl ether) 15-(tetrahydropirani
ether). D 1.7 mL of the reaction product from step C above was dissolved in dimethyl sulfonate.
With oxide 15 secretion and tetrahydrofuran 5',
1.6 mol n- in hexane with stirring and cooling
Treat with 2.28% of butyllithium. After 5 minutes, the moisture
Add chillformamide 5-chloride. The resulting solution is stirred and cooled to 0°C. Then lithium
Add 0.7 ml of chloroacetate. Mixture at 0℃
time, and stir at about 25 qC for 22 hours. what happens next
Dilute the solution with 20 parts of ice water and add 3 parts of dilute acetic acid to 50 parts of water.
Acidify with a cold solution of ' and then extract with dichloromethane
do. The organic phase was washed with cold water and brine and poured onto magnesium sulfate.
Dry with. Thus 3-oxer PGF, QII-(
t-butyldimethylsilyl ether) 15-(tetrahydryl ether)
Dropyranyl ether) is produced. E solution above (
Add excess ethereal diazomethane to step D) for a few minutes
Afterward, excess reagent is destroyed with acetic acid. Wash the mixture with a mixture of sodium bicarbonate solution and salt water
, then wash with salt water. Dry the resulting solution and concentrate under reduced pressure.
do. The resulting residue was chromatographed on silica gel.
Roughly coat and remove with ethyl acetate and Scherisolve B.
gives the title compound. Following the procedure of Reference Example 1,
(Interpretation) Using the starting materials, the corresponding 15-epi products
is obtained. Follow the procedure of Reference Example 1, but add Ester 〇 stage (part E).
If omitted, the free acid form of the compound is obtained. Reference example 1 move
Following the order, it is used in Step D of Reference Example 1 and
Lithium t-butylpropio instead of loloacetate
using nate or lithium t-butyl butyrate,
Corresponding 3-oxer PGFIQ when g is 2 or 3
Type 1 11 (t-butyldimethylsilyl ether) 15
- (tetrahydropyranyl ether) compounds, i.e.
Chi2-Homo- or Z. Sadihomo compounds are created
. Follow the procedure of Reference Example 1, but as described after Preparation Example 12.
(1 station) - or (
IS) corresponding 3-oxa-9GF, QII-(t
-butyldimethylsilylable) or 3-oxa-P
GF, QII-(t-butyldimethylsilyl ether)
15-(tetrahydropyranyl ether) is in free acid form or
is obtained in the methyl ester form. Reference example 2 5-oxer PGF, Q methyl ester 11
(tyl dimethyl ether) 15-(tetrahydropyranyl
ether) [Formula x XXm: g is 1, R3 and R4 of the L part
is hydrogen, M6 is X (where -OSi(Q)3 is t-butyldimethylsilyl
(oxy), R is methyl, R7 is n-butyl, and Y is to
Lance 1 CH=CH-] or its 15-epima-diagram C
reference. A Title product of Preparation 12 or its (wave)epimer 6
．． A mixture of 50' and 95% ethanol at 0 °C for 3 min.
While stirring, dissolve the sodium chloride in the top of the water.
Treat with Dryd (added every minute). Stir the resulting mixture at 0°C for 10 min, then add 10 ml of water
Shake with 250 g of ethyl acetate, and 150 g of brine.
I will use it. The organic phase is washed with brine, dried and concentrated under reduced pressure.
Then, the 2-decarboxy-2-hydro of the compound of formula
Roxymethyl-2,3,4,5,6-pentanol-PG
F,QII-(t-butyldimethylsilyl ether)1
51 (tetrahydropyranyl ether) or its (1 sphere)
) gives rise to epima. B Tetrahydrofuran 30% guaranteed
A solution of 1.77 g of potassium tert-butoxide at 0°C.
While stirring, add 30 ml of tetrahydrofuran.
The reaction product of stage A is mixed with the solution of 5.8 hours. The resulting mixture was stirred for 5 minutes at 0°C, then trimethyl
Add the top of ortho-4-promobutyrate 5. Scratch
It can be read for 2 hours at 0℃ and 1 hour at about 25℃. this
Add 30 g of dimethylformamide and 1 t of potassium to the mixture.
Add 0.5 ml of epoxide. The resulting mixture was fed twice.
Stir for a while. Remove some of the solvent under reduced pressure and remove the remaining
Dimethyl ether and dichloromethane (3:1) with water.
). Wash the organic phase with water and brine and dry.
and concentrate. The residue containing orthoester was heated to 0°C.
Dissolve 6' of methanol in cold water containing 2 drops of acetic acid
Process with 15 skin. Stir the resulting key compound at 0°C for 5 minutes.
200 jetyl ether, 50 dichloromethane
', and 20 parts of salt water. Salt the organic phase
Wash with water, dry and concentrate under reduced pressure. Silica residue
Gel chromatography yields the title compound methyleth.
generates tell. C trimethylortho-4-butyrate
Create as follows. S.M McEldian et al., J.M. McEldian et al. Am. Chem. S.M. 6
See Volume 4, page 1825 (King 1942). 4-furomobutyronitrile 74 minutes, methanol 21 hours
', and a mixture of 150' of diethyl ether at 0°C.
Treat with hydrogen bromide for 40 minutes while stirring. Stir the mixture for another 4 hours at 0°C and add 100 g of hexane.
Add. Filter the precipitated iminoester hydrobromide
Jethylate in hexane separated from the liquid by
Wash with 400 ml of water (1:1). Add iminoester salt
Ethyl ether 250 methanol 50' and methanol underground
A stirrer is added to the top of the chillorthoformate 25.
Process for 2 hours at about 25 oo. The resulting mixture is approx.
The ambromide solution is cooled to zero and the organic solution is thus formed.
Separate from monium. Next, Jethyl Ether 100
[Add. Immediately and quickly pour the resulting solution into potassium carbonate.
An ice-cold solution made from 20 ml of water and 300 ml of salt water.
wash. The organic phase was washed with brine, treated with 3 drops of pyridine and
Dry over magnesium sulfate. Concentrate the solution under reduced pressure
dilute with 150 g of benzene and concentrate again. residue
Distillation produces the title ortho-4-bromoptylate.
Cheating. Follow the procedure of Step C of Reference Example 2, but with 5-promove
Use tantanonitrile or 6-promohexanonitrile
and trimethylortho-5-bromobentanoate or
is attached to trimethylortho-6-bromohexanoate.
It will be done. Follow the procedure of Reference Example 2, but add the species mentioned after Preparation Example 12.
Using each of the various lactols, the corresponding 5-oxygen
SirPGF, Q-type methyl ester 11-(t-butyl di
methyl silyl ether) or 11-(t-butyl dimethy
(tetrahydropyranyl ether) 15-(tetrahydropyranyl ether)
(tell) is created. Further, the procedure of Reference Example 2 is followed, but trimethylortho-5-
Bromobentanoate or trimethyl ortho-6-pro
(1 arc) or (1$) type using mohexanoate
The corresponding 5-oxa-PGF when g is 2 or 3,
Q-type methyl ester 11-(t-butyldimethylsilyl
ether) 15-(tetrahydropyranyl ether)
able to make. Reference example 3 3Q-(t-butyldimethylsilyloxy)5Q-hydro
xy28-[($)-3-hydroxy-trans-1
'-octenyl]-IQ-cyclobentanepropionia
aldehyde 8-lactol 3-(tetrahydropyranyl ether)
) [Formula x LI: L, R3 and R4 of the moiety are hydrogen, M
6 is R7 is n-butyl, Y is trans-CH=CH-,
and X is (where -OSi(G2)3 is t-butyldimethyl
tyrsilyloxy)] or its (3'R)epimer diagram D
reference. A Methoxymethyl in tetrahydrofuran 150
Suspension of triphenylphosphonium chloride 32.4 hours
Cool the liquid to -15°C. Add 45% of tetrahydrofuran to the suspension.
n-butyllithium at a 1.6 molar concentration in
Add. After 30 minutes, in 90% of tetrahydrofuran
3Q-(t-butyldimethylsilyloxy)-5Q-dihy
Droxy 28-[($)-3-hydroxy-trans
-1-octenyl]-IQ-cyclobentanacetal
Dehyde y-lactol 3'-(tetrahydropyranyle)
Add the solution of Preparation Example 12.10. Stir for 1 hour while warming the mixture to 25°C.
Concentrate the solution under reduced pressure. Residue in dichloromethane
and water, dry and concentrate the organic phase. this
The dry residue was chromatographed on silica gel;
Elute with cyclohexane-ethyl acetate (2:1). Thin
Formula x XXVO product pure by layer chromatography
Combine the fractions shown to contain.
B Above step A in 20' of tetrahydrofuran
The reaction product of is diluted with 50' of 66% acetic acid aqueous solution to approx.
2 at 35°C. Insect time hydrolyzes. Reduce pressure on the resulting mixture
Concentrate below. Add toluene to the residue and reconcentrate the solution.
Shrink. Finally chromatograph the residue on silica gel
and dissolved in acid with chloroform-methanol (6:1).
do. In this way, thin-layer chromatography produces pure raw materials.
The fractions shown to contain the compound were combined.
The pure product is obtained by concentration. subordinate
The corresponding formula x XXVm6-lactol is obtained.
C 1.14 g of silver nitrate in 3 g of water with 2 N sodium hydroxide
Lium solution6. Add it dropwise to make silver oxide. A precipitate forms. Precipitate tetrahydro in an ice water bath
Furaso 4 in the upper stage B of lactol 1 night
Add. Once the addition is complete, remove the ice cube and allow the reaction mixture to ring.
Allow to warm up to ambient temperature. Thin layer chromatography (
Chloroform-methanol 9:1) as indicated
After the reaction is complete, remove the pure product by filtration
do. The filtrate is then extracted with diethyl ether. water layer
Cool in an ice bath and dilute with 10% potassium bisulfate solution to a concentration of less than 2.
Acidify to pH. Jetilete this aqueous mixture
Extract with file. Combine the ether extracts and wash with salt water.
, dried over magnesium sulfate, filtered and evaporated under reduced pressure.
yielding the formula xXXIX6-lactone. D above
The formula x XXIX lactone made in Step C is Example 9
The 3'-(tetrahydride)
ropyranyl ether) derivatives. E Example
Created in step D above using the procedure described in step B of 9.
The corresponding 8-lactol 3-(t-b) compound of formula XL
methyldimethylsilyether)3'-(tetrahydropyra
Reduction to (Nyl ether) yields the pure title compound.
Ru. Following the procedure of Reference Example 3, but substituting (3'S) starting material
Using the (3'R) starting material corresponding to (3'R), the corresponding (
3′R)-6-lactol is obtained. Following the procedure of Reference Example 3, but starting with formula x XXVI lactol
Instead of materials, various formulas described after Example 9
Using the XVI lactols, the corresponding 6-lactol
The results are as follows: Reference example 4 Cis-4,5-didehyde o-PGF, QII-(t-butyl
(tyl dimethyl silyl ether) 15- (tetrahydropi
Ranyl ether) (Formula x LIV: g is 1, R3 in the L part
and R4 are hydrogen, M6 is R, is hydrogen, R7 is n-butyl,
Y is (where -osi(G2)3 is t-butyldimethylsil
Loquin), and Y is trans-CH=CH-) or its
15-Epimer. See Figure 3-Carboxypropyltriphenylphosphonium bromine
Mide (4-promobutyric acid and triphenylphot in benzene)
Heating the sphine under reflux for one hour before purification
10 sides of sodium hydride (2
．． 0 chicks, 57%) and dimethyl sulfoxide 30'.
Sodium methylsulfinylcarbamide made from
Add to. The resulting Wittig reagent can be converted to the formula LI in the title of Reference Example 3 above.
lactol and dimethyl sulfoxide 20
do. Stir the mixture overnight, add about 200' of benzene
Dilute and wash with potassium hydrogen sulfate solution. The two lower layers are
Wash with chloromethane, combine the organic phases, and wash with brine.
Dry and concentrate under reduced pressure. Silica with residue washed with acid
Chromatography on gel ethyl acetate-isomers
Remove with hexane (3:1). thin layer chromatography
The file shown to contain the desired compound by
Combining the fractions yields the pure product. three
Follow the procedure in Example 4, but use ($) instead of starting material
(station) using the starting materials, the corresponding 15-ebi
PGF, Q-type 11-(t-butyldimethylsilyether
) 15-(tetrahydropyranyl ether) is obtained
. Follow the procedure of Reference Example 4, but using 3-carboxypropyltritri
Phenylphosphoniumb. 4-carboxybutyl triphenyl instead of amide
Phosphonium bromide or 5-carboxybentilt
Using liphenylphosphonium furomide, g is 2
or the corresponding formula x LIV compound in case 3 is made
. Further, the procedure of Reference Example 4 is followed, but the formula 〆LI starting material is replaced.
Instead, the various formulas mentioned after Reference Example 3
using the corresponding cis-4,5-didehydro-
PGF, Q-type 11-(t-butyldimethylsilyl ether
) 15-(tetrahydropyranyl ethers) or 1
11 (t-butyldimethylsilyl ethers) is made
It will be done. Reference example 5 4-oxer PGF, Q methyl ester 11-
methyldimethylsilyl ether) 15-(tetrahydropi
Ranyl ether [formula x Lm: g is 1, R3 and R of the L part
4 is hydrogen, M6 is R, is hydrogen, R7 is n-butyl, X is (here -osi(G2)3 is t-butyldimethylsil
Roxy) and Y is trans-CH:CH-]. A According to the procedure of Step A of Example 11, the formula ×L16-
Lactol (Reference Example 3) is the corresponding formula x L lo 2-decal
Boxy 2-hydroxymethyl-2.3.4.5-tet
Ranol-PGF, QII-(t-butyldimethylsilyl
ether) to 15-(tetrahydropyranyl ether)
be transformed. B Follow the steps in Step B of Reference Example 2 to
trimethylortho-4-promobutyrate instead of trimethylortho-4-promobutyrate
Using methyl ortho-3-furomopropionate,
The product of Step A of this example is converted to the title compound. Following the procedure of Reference Example 5, but using the (dis)lactol starting material
(1 station) to produce a product. Furthermore, the substitute for trimethylortho-3-promopropionate
Instead, trimethyl ortho-4-promobutyrate or trimethyl ortho-4-promobutyrate
using remethylortho-5-promobentanoate
, when g is 2 or 3, a compound of formula xLm is obtained. Most
Afterwards, follow the steps in Reference Example 5, and optionally add one of the earlier clauses.
However, the various formulas described after Reference Example 3 are used.
Using 〆LIlactol, the corresponding products are obtained.
Ru. Reference example 6 PGF2QII-(t-butyldimethylsilyl ether
), 15-tetrahydropyranyl ether) [Formula x L skin
:g is 1, R3 and R4 of the L part are hydrogen, pigeon is R, is hydrogen
, R2 is hydrogen, R7 is n-butyl, X is (where -os
i(G2)3 is t-butyldimethylsilyloxy), and
Y is trans-CH=CH-] or its 15-epimer
. See Figure E A Sodium methylsulfinyl methide (dimethylsulfinyl methide)
Sodium hydride in sulfoxide 10' (0.4 hiragi,
4-carbo
Xyptyltriphenylphosphonium bromide 2.2
Add to the rudder. The corresponding mixture is kept at 25° C. for 30 minutes with stirring.
Preparation Example 12 in dimethyl sulfoxide 10'
Add the title compound 1.2 bee solution. Environment the reaction mixture
Stir at temperature for 14 hours and dilute with 200 g of benzene.
. Gradually add potassium bisulfate (2 parts to 3 parts of water).
The reaction temperature was maintained at 10°C or lower, and the pH was adjusted to 2.
acidic until Extract the aqueous layer with 100% of benzene,
Before combining the organic extracts, add 50 ml of water and 50 ml of salt water.
Wash one after another, dry and evaporate to 2.5 glugs of oil. oil
Wash with acid packed in 10% ethyl acetate and Schellisolve B.
Chromatography was performed on 100% silica gel.
Melt with 10-35% ethyl acetate and Scherisolve B
yields 1.27 g of pure product (colorless oil). NM old absorption is 0.05, 0.87, 0. Total ~2.86,
3.20-4.48, 4.75 and 5.20-5.87
Seen in 6. Follow the procedure of Reference Example 6, but with the corresponding 3-1
Using the ethylene thioketal starting material 0.7
The corresponding product PGD2,11-(ethylene thioketal
), 15-(tetrahydropyranyl ether) 0.43
g is produced as a colorless oil. NMR absorption is 0.90, 0.90-2.93, 3.18
, 3.02-4.38, , 4.72, 5.23-5.7
8 and 6.526. Following the steps in Reference Example 6,
, using the corresponding (class)-lactol starting material.
The corresponding 15-epipeline product is produced. Procedure of reference example 6
However, 5-carboxybentyltriphenylphosphor
nium bromide or 6-carboxyhexyltriphene
Using nylphosphonium furomide, g is 2 or 3
The corresponding formula ×L skin compounds for the case are created. Finally, following the procedure in Reference Example 6, optionally perform the various reactions in the previous section.
The lactol described after Preparation Example 12 is used.
using each of the corresponding PGF2Q types 11-(t
-butyldimethylsilyl ether) 15-(tetrahydride
ropyranyl ethers) or PGF2Q type 11-(t-
butyldimethylsilyl ethers) are produced. Reference example 7 POD2 (formula LVO: R, is hydrogen, L, parts R3 and R
4, and R5 and R6 of the M portion are hydrogen, and R7 is n
-butyl, Y is trans-CH=CH-, and Z is cis
-CH=CH1 (CH2) 31) or its (1 ball) pipe
See map F. A PGF2QII with 10% methylene chloride (t-bu)
(tyl dimethyl silyl ether) 15- (tetrahydropi
Ranyl ether) 1.27g, dihydropyran 0.9g
, and 0.1 ml of pyridine hydrochloride together at ambient temperature.
Stir overnight. Next, 200% of a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added.
Add 200 ml of ethyl acetate together and
Wash the solution with salt water, dry over sodium sulfate, and
Concentration in vacuo yields a pale yellow oil of Formula 11V. B
Add the product from step A above to 25 ml of tetrahydrofuran.
Dissolve 10% tetrahydrofuran
Treated with a solution of tylammonium fluoride 1.2.
Ru. This corresponding mixture was stirred at 65°C for 2 hours, then 25q.
Cool to o. The resulting product is concentrated under vacuum and washed with brine.
Dilute and extract with ethyl acetate. Combine the organic extracts
, washed with 2M potassium bisulfate aqueous solution and salt water, and washed with sulfuric acid magne.
Dry on sium. Concentrate under reduced pressure to give a yellow-brown oil
will occur. Place this oil in methanol-water (9:1)
Dissolved in 35' of 5% potassium hydroxide and stirred for 2 hours.
Mix. The reaction mixture was cooled to 25 qo and concentrated under reduced pressure.
diluted with water and acidified with 2M potassium bisulfate and ice.
Ru. After dilution with brine, the fraction containing the aqueous solution was evaporated with acetic acid.
Extract with chill, wash the combined organic extracts with salt water, and sulfurize.
Drying over magnesium chloride and concentrating in vacuo yields a yellow ointment.
Microwave oil yields 1.0 female. Add this oil to Skerisolve B.
Purified with 6 puffs of silica gel packed with 10% ethyl acetate.
and eluted with 10-50% ethyl acetate in Scherisolve B.
do. Combine pure chromatographic fractions
Then, PGF2Q, 9.15-bis(tetrahydropipropylene)
Ranil ether) yields 0.2 crabs. NMR absorption is 0.
89 0.8-2.86, 4.77 and 5.22-5.
Found in 976. C Acetone 10 [Book inside]
The reaction product of step B of the example 0.2 crabs was purged with nitrogen.
, cooled to 1 liter 5 qo, then added Jones reagent (0.2
0', 1.7 equivalents). The reaction mixture was stirred at -1yo for 3M minutes, then the excess diluted
Stop the Jones reagent with 0.25' of isopropanol.
let The reaction mixture was diluted with brine and extracted with ethyl acetate.
Ru. Wash the organic extract with brine and dry over sodium sulfate.
and concentrated under reduced pressure to yield 0.2 whistles of oil of formula IV.
. ○ Dissolve the above oil in acetic acid-water (2:1) mixture,
Stir and heat to 3 hours for 3 hours. The reaction mixture was then cooled to 25 qo and diluted with 100 ml of water.
Upon dilution and lyophilization, 0.16 g of the crude title product was obtained.
arise. This product was dissolved in 10% ethyl acetate in Skellisolve B.
Chromatograph on one side of pickled silica gel packed in chill
Pour over the fin. 10-70% acetic acid in Skellisolve B
Solving on chill yields 0.1 total of pure title product.
. Instead, the title product is written to the prostagr as follows:
Engine D211-(ethylene thiol), 15-(
(tetrahydropyranyl ether). A Starting material 0.2 cranes is mixed with acetic acid, water and tetrahydrofura
(6:3:1) Combine with 9 [ and make it 37-4000.
Heat for 2 hours. The reaction mixture was then cooled, diluted with 15 parts of water, and lyophilized.
This produces a 0.1 speck of crude product. Skelesol this
Pickled silica gel packed with 20% ethyl acetate in BuB 1
2 in Skellysolve B by chromatography on the surface
Elute with 0-35% ethyl acetate. This allows P.G.D.
211-(ethylene thioketal) is obtained. NMR
Absorption is 0.90 0.9-3.00, 3.234.02
~4.50, and 4.93 to 5.956. red
External radiation absorption is 340u3000, 292u 285026
5 or more 1710, 14551425, 1410, 127
1240, 1050, 1020, and 970 skin-1
It will be done. Mass of tris-(trimethylsilyl) conductor
The spectrum shows a mass peak absorption at 644.3257. B Add 0.5% of water-acetone (1:49) mixture
The corresponding product in the previous section is oxidized to 0.017 ml of secondary steel.
and 0.013 total cupric chloride dihydrate. Birth
Stir the mixture at ambient temperature for 2 hours, then add the corresponding mixture.
The mixture was diluted with water and extracted with ethyl acetate. organic extract
Dry over magnesium sulfate and filter through Celite.
, when concentrated using a stream of nitrogen, contains the title compound.
Produces a yellow-orange oil. Following the procedure of Reference Example 7,
(1 station) Using materials from Eppima I, 15-Eppi P
GD2 is created. Follow the procedure of Reference Example 7, but apply Reference Examples 1, 2, 4, 5, and
Using each of the various compounds mentioned in and after 6.
A corresponding PGD-type product is produced. Reference example 8 93-PGD2 (formula L skin: R. is hydrogen, L, part R3
and R4 and M, R5 and R6 of the part are hydrogen, and R7 is n-b.
chill, Y-trans-CH=CH-, and Z2 is cis-
CH2CH1(CH2)31)A in acetone 10'
PGF2qll-(t-butyl) of the compound of Reference Example 6 in
15-(tetrahydropimethyldimethylsilyl ether)
Ranyl ether) 0.4 string is cooled to 0°C. Next, use Jones reagent (no
Hydrochromic acid 2.1 is on water 6 and concentrated sulfuric acid 17)
Add. Next, add 2-3 drops of isopropanol to deal with the problem.
Stop and concentrate the resulting mixture under reduced pressure. thus
The resulting residue is partitioned between dichloromethane and water,
The organic phase is dried and concentrated to yield the formula LO compound.
B Ice-cold methanol 6 must-have sodium boro/hydra
Add the solution of Id 300 9 to 30% methanol at -5°C.
Solution of reaction product 650 of Step A of this example in
Add to. The reaction mixture was stirred for an additional 5 minutes and diluted by addition of dilute acetic acid.
Make slightly acidic and concentrate under reduced pressure. the residue obtained
is extracted with dichloromethane. Dichloromethane extract
Wash with water, dilute aqueous sodium bicarbonate solution, salt water, sodium sulfate
Dry over aluminum and concentrate under reduced pressure. silica gel
Chromatography shows pure 98-epima-((formula Lm))
arise. C Following the procedure of Reference Example 7, the steps of this example
The reaction product of B is converted to the title product. The procedure of Reference Example 8 is followed, but the various procedures mentioned after Reference Example 6 are followed.
using any of the LI intermediates to produce the corresponding product
is obtained. Reference example 9 2,2-difluoro-POD2 methyl ester A Reference
Following the procedure of Example 6, but with 4-carboxybutyltriphenyl
3,3-difluoride instead of phosphonium bromide
rho-4-carpoxybutyltriphenylphosphonium salt
2,2-difluoro PGF2Q using Romide
, 11-(t-butyldimethylsilyl ether) 15-
(tetrahydropyranyl ether) is produced. B Follow the procedure of Reference Example 7, but PGF2QII-(t-
butyldimethylsilyl ether), 15-(tetrahydride)
(ropyranil ether) produces the title product.
Ru. C Follow the procedure of Reference Example 9, but starting with lactol in step A.
Various lactates mentioned after Preparation Example 12 in place of the materials
Using each of the 2,2-difluoro
- A PGD type 2 product is produced. Reference Example 1OPGD, a solution of PGD2 (Reference Example 17) in ethyl acetate was dissolved in water charcoal.
in the presence of 5% palladium catalyst above at ambient temperature of about 1 atm.
Shake with pressure hydrogen. When 1 equivalent of hydrogen is absorbed per 1 equivalent of PGD2, water
Stop adding elements. Remove the catalyst by filtration and reduce the pressure of the filtrate
Concentrate and chromatograph the residue on silica gel.
Elute with ethyl acetate and Sketch IJ Solp B.
fractions shown to contain pure product.
Together they give the title compound. Follow the steps in Reference Example 10
However, pale-homo or Z. Using Sajhomo-PGD2
using, 2-homo or ne, fox-dihomo-POD, gatsu
I can't believe it. Furthermore, the procedure of Reference Example 10 is followed, but the procedure described after Reference Example 7 is
The various PGD type 2 compounds described in and after Reference Example 8
Beta 981 PGD type 2 compounds, or in Example 18
The 2,2-difluoro-PGD type 2 chemical compounds mentioned later
using the corresponding PCD, mono- or 2.2-difluoro
-PGD, type products are produced. Example 13-o
Kisser 3,7-interm-phenylene-4,5,6-
Trinor-PGD, (Formula CV: R, hydrogen, L, moiety
R3 and R4, and R5 and R6 of the M portion are all hydrogen,
R7 is n-butyl, Z, or 3,7-interm-f
Phenylene-4,5,6-trino-PCD, (formula CV:
R, is hydrogen, R3 and R4 of L, part, and R of M, part
5 and R8 are all hydrogen, R7 is n-butyl, and Z is
See G, Day, and L. A Optically active bicyclo[31.0]-hex-2-ene
-6-endocarboxaldehyde. According to the procedure of Preparation Example 1 of U.S. Pat. No. 3,711,515.
Therefore, to racemic bicyclo[3.1.0]
En-6-endocarboxaldehyde is bicyclo[2
．． 2.1] Made from hepta-2.5-diene and peracetic acid
It will be done. The racemic compound was produced in accordance with U.S. Pat. No. 3,711,515.
When divided according to the procedure of Example 13, oxa
Produces zolidine. Racemic Bisik. [3.1.0] Hekis-2-hen-6-endocarbo
12.3g xaldehyde and 16.5g 1-ephedrine
Approximately 150 benzene is dissolved in the soil. Benzene under vacuum
and remove the residue with approximately 150% isopropyl ether.
will be featured in Filter the solution and then cool to one lyo
and 2-endopicyclo-[3.1.0] to kiss-2
-en-6-yl-3,4-dimethyl-5-phenyl
11.1g of oxazolidine crystals, melting point 90-92℃,
arise. Recrystallized three times from isopropyl ether and its
When cooled to about 12°C each time, as shown by NMR, the current
The degree of oxazolidine crystal is essentially a single isomeric form.
2. Produces males. Melting point 100-1030. recrystallization on
Oxazolidine 1. Dissolve the female in dichloromethane number
Dissolved, charged into a 2-layer silica gel column, and dichloromethane
Make lacquerware with a lacquer. Silica gel is chromatographic grade (mel
The grain size is between 0.05 and 0.2 (manufactured by K.K.) and water per 10 females.
It has about 4~Satoshi. Collect the eluent fractions and dilute
Desired compound by layer chromatography (TLC)
Combine fractions shown to contain
Let the oil evaporate until 360 pm. This oil was determined by NMR.
Substantially free of ephedrine, with virtually no single optical activity.
The desired title compound is shown to be in the isomeric form.
Ru. The point on the circular dichroism curve (y is nm, 8) is 350
,0:322.5,4,854:312,15,Paper 3;
302,5,14,854;269,0;250,2,
368:240,0; and 210,134,600. B I-bicyclo[3.1.0]hekis-2-en-6
- Endocarboxaldehyde neobentyl glycol
Acetal (Formula XI: R55 and R56 taken together are one
CH2-C(CH3)2-CH2-, and ~ is endo)
2,2-dimethyl-1,3-propanediol 900g
Reflux a mixture of 3', benzene, and 85% phosphoric acid
Heat down. In addition, optically active bicyclo [3.1.0
]Hex-2-ene-6-endocarboxaldehyde
(Floor A, 50 females) solution was added for 1.5 hours. azeotropic vaporization
Deen the retained water. Stark. for removal with a trap
to do something After 3 hours, the mixture was cooled and diluted with 5% sodium bicarbonate.
Extract with Rium 2 sleeves. Dry the organic phase over sodium sulfate and concentrate under reduced pressure.
. The resulting semi-solid residue was taken up in methanol and diluted with 60% water.
Recrystallized using a total of 120' of metal including 0.
and then cooled to -13:00 to give the title compound 30 females.
arise. Melting point 52-55°C. NMR peak is 0.60
1.2ri 0.83-2.65, 317-3.8, 3.9
and 5.47 to 5.886. [Q] o-227o (me
c=0.8976) in tanol, and Rfo. 60(
Mixed isomer hexanes in 25% ethyl acetate
TLC on silica gel). Further, when finishing the mother liquor, add
Produce 50-10 females. C d-8-(m-ace
(toxyphenyl)-7-oxatricyclo[4.2
0. Pi,4]-octane-6-endocarboxal
Dehyde neobentyl glycol acetal (formula LXO;
When R55 and R56 are taken together, -CH2-C(CH3)
2-CH2-, R63 is and ~ is endo) and the formula LXI〆-bicyclo[3
．． 1.0]Hex-2-en-6-endo-carboxa
Rudehyde neobentyl glycol acetal (stage B,
5.8) and m-acetoxybenzaldehyde 1.
6. Bamboo solution is heated using a submersible water-cooled finger-shaped cooler and a floating water cooler.
Pyrex photolysis vessel with rounded gas inlet tube
Pour into a container. Remove dissolved oxygen by bubbling nitrogen into the solution.
Ru. Rayonet equipped with 6 RUL3500A lamps
Photochemical reactor for RS preparation (Middleta, CT)
Un's Southern. New England. Ultra/I
The mixture was irradiated with 35 ml of blood according to Oret. 2
After 4 hours, the photolysis products were reduced to a pale yellow oil under reduced pressure.
Concentrate. This is subjected to silica gel chromatography. skeliso
16-70% acetic acid in Lube B (isomeric hexane mixture)
When scaled with ethyl, the starting materials recovered and the formula LXO table
Separate fractions of the title compound with a light yellow oil of 0.8 g.
will occur. For the latter, the peak of NM calm is 0. Thigh・1.20,
0.8-2.5, 2.28, 2.99, 3.12-3.
88, 3.4 & 4.97~5.52, and 6.78~
7.606. Infrared absorption bands are 3040, 2950, 28
60, 2840, 1765, 161 1590, 148
514701370, 1205, 1115, 10201
050, 990790 and 700 enemies-1. mass spectrum
There are 3 peaks: 357, 116, 115, 108,
107, 79, 70, 69, 45, 43, and 41. [
Q] D155o (c=0.750 in 95% ethanol
5). Rfo. 18 (25% in mixed isomer hexanes)
TLC on silica gel with ethyl acetate). ○ d-2
-exo-[m-(pivaloyloxy)penzyl]-3-
Exopiparoloxy)-Bisik-o-[31.0]
Xane-6-endo-carboxaldehyde neobentyl
Glycol acetal (formula LXN: R$ and R56 together)
Taking it as -C Buddha -C(CH3)2-CQ, R58
is and ~ is the end). Ethylamine 70's inner layer
A mixture of 0.2 mm is made at 0°C and cooled to 0.
Ru. Formula LX0d-81 (m-
Acetoxyphenyl)-7-oxatricyclo[4.
2.0. 4]-octane-6-endo-carboxy
Saldehyde neobentyl glycol acetal (in stages)
．． 1.8 total) solution was added dropwise over about 5 minutes. -78qo
After stirring for approximately 3.5 hours, the reaction was terminated with solid ammonia chloride.
and water-tetrahydrofuran. unrebelled
removing the reactive lithium and gradually warming the mixture to about 260 °C;
Remove ethylamine. Neutralize crab meat with dilute acetic acid and salt
Mix with 200 ml of water and extract with ethyl acetate. organic phase
of brine, and brine and saturated aqueous sodium bicarbonate solution (
1:1) mixture and dry over sodium sulfate.
Concentration under reduced pressure converts the formula LXm diol into a light tan color.
Produced as a foamy oil of about 1.6 ml. Rfo. 03 (mixed
Silica gel with 25% ethyl acetate in isomer hexane
TLC above). Dissolve the product from the previous section in pyridine 30 skin.
pivaloyl chloride at about 25° C. for 2 hours.
Process with [5]. The reaction mixture was washed with water and then brine and extracted with ethyl acetate.
Ru. The organic phase was dissolved in brine, water, a saturated aqueous solution of cupric sulfate, and bicarbonate.
Washed successively with saturated sodium solution and brine, and washed with sodium sulfate.
Dry over thorium. Concentration under reduced pressure leaves a residue of 2.
Yields 53g. Apply this to silica gel chromatography
This yields 1.87 g of the formula LXW title compound. N
MR peak is 0.71, 1.2, 1.33, 0.9~
3.1, 3.28-4.00, 4.17, 4.7-5.
2, and 677-7.586. mass spectrum peaks
is 486, 485, 115, 73, 72, 57, 44
43, 42, 41, 30, 29, 15. [Q]o+19
0 (c=0.9340 in ethanol). Rfo. 50
(Siliconization with 25% ethyl acetate in mixed isomer hexane)
TLC on Kagel). E 2-exo-[m-(pivalo)
yloxy)penzyl]-3-exo-(pivaloyloxy)
)-bicyclo[3.1.0]hexane-6-endoka
Ruboxaldehyde (formula LXV: R is and ~ is endo) Formula L×N acetal or d-2-exo (m-pi
valoyoxy)penzyl]-3-exo-(pivaloiro)
xy)-bicyclo [3.1.0] hexane-6-end
-Carboxaldehyde neobentyl glycol acetate
(stage ○, 0.4 total) with 88% formic acid 25 secretion at 0℃.
Process for 4 hours. Dilute the mixture with 200ml of brine and extract with ethyl acetate.
. The organic phase was washed with brine and saturated aqueous sodium bicarbonate solution;
Dry over magnesium sulfate. Concentration under reduced pressure produces 0.0% oil.
5 spots were generated, which were subjected to silica gel chromatography.
Ru. Elute with 5-15% ethyl acetate in Scherisolve B.
yields the formula LXV title compound as 0.37 g of oil.
. The peak of NM town is 1.20 1.33, 0.6-3.
2, 5.1-5.56.6-7.5 and 9.736. R
fo. 50 (25% ethyl acetate in mixed isomeric hexanes)
(TLC on silica gel). F2-exo [
m-pivaloyloxy)penzyl]-3-exo-(piva
(royloxy)-6-endo-(cis-1-hebutenyl)
-bicyclo[3.1.0]hexane (formula LXW: L, part
Both R3 and R4 are hydrogen, R is n-butyl, and R is
R53 is hydrogen, ~ is endo), and 2-exo-(
m-hydroxybenzyl)-3-exo-hydroxy
6-endo-(cis-1-heptenyl)bicyclo [3.
1.0] Hexane (formula LX skin: R3 and R4 of the L part are the same)
is hydrogen, R7 is n-butyl, R53 and R66 are hydrogen, and
bi~ha end). n-hexyl triphenyl phosphor of benzene 10
Niromide 0.79 light and n-butyl lithium (0.79 light)
6', 2.32M solution in hexane) at about 260
0. Make Witihillide reagent during insect time. precipitated
After the lithium bromide has settled, remove the solution and
Cooling of LXV aldehyde (stage E. 0.37 g), (0
°C) Add to slurry. After 1 game, Aceton 1.0 machine
and heat the mixture to 60°C for 1 hour. The mixture is concentrated under reduced pressure. Remove the residue in Skellisolve B
of 10% ethyl acetate and the washings were converted to the formula LXW title compound.
Oil of things 0. Concentrate to paper g. NMR peak outside 1.1
&1.33, 0.6-3.2, 4.5-6. Stop and 6.
67-7.626. Rfo. 78 (in Skellysolve B)
TLC on silica gel with 25% ethyl acetate). previous section
The product of sodium methoxide (methanol
2.5% solution of [)] for 4 hours, followed by solidification.
body sodium methoxide 0. Add demon and 1 with 2yo
for an hour, then by stirring under reflux for 6 hours.
, converted to the formula LX skin diol. The mixture was cooled, mixed with 300 g of brine and diluted with ethyl acetate.
Extract. The organic phase was washed with brine and poured over magnesium sulfate.
Dry and concentrate under reduced pressure to a residue of 0.27 g. residual
Subject the material to silica gel chromatography and apply Skellisolve.
When melted with 25-35% ethyl acetate in B, Shikito X skin
The title compound was dissolved in oil o. Yields as 21g. NMR P
Ku is 0.87, 0.6-3.2fu 3.88-4.35
4.82-5.92, and 6.47-7.336. Rf
o. 13 (with 25% ethyl acetate in Scherisolve B)
TLC on silica gel). G 2-exo {m1 [(
hydroxyl)methoxy]-3-exohydroxy
6-endo-(cis-1-heptenyl)bicyclo [3.
1.0] Hexane (formula LX: L, parts R3 and R4 are
Both are hydrogen, g is 1, R7 is n-butyl, R, and R53
R66 is hydrogen, and ~ is endo) formula JX skin diol.
2-exo(m-hydroxybenzyl)-3-exo
So-hydroxy-1-6-endo-(cis-1-heptenyl)
) picyclo[3.1.0]hexane (stage F, 0.1 group
) in dioxane 8 with 0.61 g of bromoacetic acid and IN
Treat with 6 parts of aqueous sodium hydroxide solution. Add sodium hydroxide as necessary to maintain pH at approximately 10.
The mixture was heated under reflux for 3 hours while adding the solution of
From there, cool the mixture, dilute with 100' of water and add
Extract with Luther. acidifying the aqueous phase to pH ˜2;
Extraction with ethyl acetate gives a pale yellow color of the formula LX skin title compound.
of oil yields 0.2 females. The recovered formula LXW diol is
, obtained from the diethyl ether organic phase by drying and concentration.
It will be done. 0.025&day 3-oxa-3.7-interm-phenylene*
-4.5.6-trino-PGF,Q (formula LXXm:L
, R3 and R4 of the part, and R5 and R6 of the L part are all
is hydrogen, R7 is n-butyl, g is 1, and R, is water
element). The trick revealed in U.S. Patent No. 3,711,515
Applying the procedure, the formula LXW alkene is converted to the title compound.
It will be done. Thus, by the procedure of Example 6 of this patent, the triacid
Osmium chloride alone or N-methylmorpholine oxide
Compound L can be used in combination with hydrogen monoperoxide rust.
Cape X (stage G) is converted to the formula LXK glycol in Figure G.
Ru. Next, add glycol to '11, for example Example 7 of this patent.
Create bismesylate by sulfonation by applying the procedure of
and hydrolyze the title compound and its 15-epimer.
or '21 Examples 20 and 2 of this patent.
Applying the procedure in step 1, treat with essentially 100% formic acid.
, make LX breast difluormate and then hydrolyze it.
to a mixture of the title compound and its 15-epimer.
Understand. epimers by silica gel chromatography.
separation yields the title compound and its 15-epimer.
Ru. The third path from glycol LXK to compound LXXm
The road is a cyclic orthoester [in the formula R74, R? 5, and
~ as defined above]. Glycol as a 1-20% solution in benzene, approx.
Trimethyl orthoformate (1.5-10
molar equivalent) and a catalytic amount (1% of the weight of the glycol) of pyri
Treat with gin hydrochloride. The reaction was analyzed using TLC (thin layer chromatography).
Raffi) and finish in a few minutes. In this way, the ring
Lutester is obtained in 100% yield. ring ester
is treated with 100% formic acid at a volume of approximately 2%. The reaction mixture was dissolved in water or alkaline bicarbonate solution for about 10 minutes.
Stop and extract with dichloromethane. 5% organic phase
Shake with aqueous sodium bicarbonate solution and over sodium sulfate.
Drying and concentration yields the corresponding gestal.
Add 10 to 5 volumes of absolute methanol and its
With 10-20% of potassium carbonate by weight at about 25°C,
Contact is made until the tel group is removed. thus obtained
Separation of a mixture of 15-epimers yields a compound of formula LXXm
or its 15-epimer. 1 2-exo- [
m-(2-ruboxyethyl)penzyl]-3-exo
-Hydroxy-6-endo(cis-1-heptenyl)bi
Cyclo-[3.1.0]hexane (Z3 is methylene, g
is 1, L. R3 and R4 of the moiety are hydrogen, R7 is n-butyl
, R, and R53 are hydrogen, and ~ is endo). Regarding the date of the figure, first the formula LXXW oxetane was created.
Ru. Following the procedure of Step C, but with m-acetoxybenz of Step C
Instead of the aldehyde, the formula [wherein R69 is defined above]
A well-developed temporal region using aldehydes
The corresponding formula LXX skin oxetanes are obtained. Next
follows the procedure of steps D, E, and F, but the formula LX of step D
Instead of O-oxetane, use the procedure in the previous section of this step.
Using the resulting oxetane, the corresponding formula LXXXI is prepared.
A product is obtained. Finally, the blocking group on each LXXXI compound is
removed by methods described in the book or known in the art.
This results in a compound of formula XXXO. J 3,7-inter m-phenylene-4,5,6-to
Linol-PGF, Q (Formula LXXXW: R, is hydrogen, L,
R2 and R3 of the moiety and M, R5 and R6 of the moiety are hydrogen,
R7 is n-butyl, g is 1, Y is trans-CH! CH
1, and Z is -CH2). According to the step date procedure, the formula LXXX Roalkene is several steps
is converted to a compound of formula LXXXW. K 3,7-in
ter-m-phenylene or 3-oxer 3,7-inter
-m-phenylene-4,5,6-trino-PGF,Q
15-(tetrahydropyranyl ether). Reference example 12
Step A procedure is followed, but with the step date or step as the starting material.
A compound of formula CIV is made using a compound of formula J. L 3,7-inter m-phenylene- or 3-oxa
-3,7-inter-m-phenylene-4,5,6-tri
nor-PGD, 15-(tetrahydropyranyl ether
). Following the procedure of Step B of Reference Example 12, but using Step B as the starting material.
Compounds of rank K are used to make the corresponding products.
. M 3,7-interm-phenylene- or 3-oxa
-3,7-interm-phenylene-4,5,6-tri
Nor-FGDI. Following the procedure of Step C of Reference Example 12, but using Step C as the starting material
Using the compound of stage L, the corresponding title compound is obtained.
Ru. Following the procedure described in Example 20, but with various alternative intermediate
using the bodies and starting materials disclosed herein.
Various 3-oxa-3,7-inter m-phenylenes
or 3,7-inter m-phenylene 4,5,6-tri
Noru-PGD type 2 compounds are created. Reference example 11 9, ]0-didehyde o-9-deoxy-PGD, (formula C
XLK: R, is hydrogen, Z, is cis-CH=CH-(CH
2) 31, Y is trans-1 CH=CH1, M, and L part
R3, R4, R5 and R6 are all hydrogen, and R7 is
n-butyl) See Figure Q. A Convert PGF2o in methylene chloride to n-butyl
Mix with Polonic acid 688 c. The reaction mixture was heated under reflux with vigorous stirring.
, methylene chloride was added in an amount of 5 to compensate for the evaporation.
I can do it. After about 28 minutes, 10' of dihydropyran was added to pyridine.
Add the hydrochloride salt to the reaction mixture along with 150 g of the hydrochloride salt. Approximately 2q hours
After a while, esterification is completed and methylene chloride is removed under reduced pressure.
do. The residue was diluted with 30% methanol and potassium hydroxide.
dilute with aqueous solution. The resulting clear yellow solution was allowed to stand for 2 hours.
Then add 5ml of a 30% solution of hydrogen peroxide in 30ml of water.
Process with. The methanol was then removed under reduced pressure and the aqueous residue
The distillate was diluted with 10 parts of water and extracted twice with diethyl ether.
put out Make the aqueous layer acidic with 25% potassium bisulfate aqueous solution.
and extract with ethyl acetate. Salt the combined organic extracts.
Wash with water and dry over sodium sulfate. Solvent under reduced pressure
When you remove oil 3. Produces verticality. This is washed with acid.
Apply Lycagel 10 to chromatography. Hexa
Pure formula CX was eluted with 75% ethyl acetate in
LN PGF2Q15-(tetrahydropyranylethe)
l) 2.0 oysters are obtained. B Benzene without oxygen
11.3 g of reaction product of Step A in 200 kg,
10.13 g of liphenylphosphine and 2-pyridyl
Disulfide 8. Acid solution under nitrogen atmosphere at ambient temperature
Stir for 3 hours. The resulting solution is dried and oxygenated.
Dilute with 300 ml of benzene to make the total volume 500 ml.
Ru. The solution is refluxed for 2 hours. After cooling, the mixture
Concentrate to an oil and dissolve in 50% ethyl acetate in n-hexane.
Chromatography on packed neutral silica gel 1.5k9
and eluting with 60% ethyl acetate in hexane. child
Thus the formula CXLV compound 6. is obtained. C Aceto
5. Reaction product of Step B in 100% chick solution
Cool to -35oo. Next, add Jones reagent 3.3' and reduce the solution to -35q
Hold at o. A few hours later, ``isopropanol 6W [was used].
Add while stirring. Pour the resulting mixture into 600 g of ice-cold brine.
and extracted with diethyl ether-hexane (1:2).
put out The combined organic solutions were washed with brine and poured onto magnesium sulfate.
dried, concentrated and chromatographed (hexane).
Marine Cloth CC- packed with 10% ethyl acetate in a bottle
4 silica gel). Elute with 25% ethyl acetate in hexane
Then the product of formula CXL 3. Produced from bamboo as oil. D
Tetrahydrofuran-water monoacetic acid (1:3:6) 100 units
2.0 g of the reaction product of step C of this example in '
Stir the solution at 40-45 oo for 1 hour. The solution was then cooled, poured into brine and ethyl acetate-hexane.
Extract at a ratio of (1:3). Pour the combined organic solution into salt water and ice.
Wash with cold sodium bicarbonate. Wash the hexane layer with salt water,
Drying over sodium sulfate and concentration yields the crude product 1.
Produces 2 chicks. Packed in 20% ethyl acetate in hexane
Chromatographed on 20 ml of silica gel.
30% ethyl acetate and 60% ethyl acetate in Sun, 1% vinegar
When scaled with acid, 1.17 g of the pure product is a yellow oil.
It can be obtained by Infrared absorption is 3450, 2980, 29
00, 2700, 1740・1720, 1600,, 1
460, 1440, 1410, 1350, 1240, 1
170, 102fu Seen in 970ka-1. . NMR
Absorption is 0.90, 4.15 5.6ri 6.20, and 7
．． Found in 656. Mass spectrum is 478.291
2 shows the basic peak absorption. The title compound is instead
PGD2 was left on a silica gel column, thus obtained
The impure product produced by silica gel chromatography
It is produced by refining it. Following the procedure of Reference Example 11,
using any of the PGFQ type compounds mentioned therein.
, the corresponding 9-deoxy-9,10-didehydro-PG
Type D compounds are created. Reference Example 12 See PGD2 or PGD2 methyl ester diagram L. A PGF2Q2. Cough and methylene chloride 50m'
Process with Chirpolonik Ashid 6-layer fence. Stir the reaction mixture vigorously to compensate for losses due to evaporation.
Under reflux while adding methylene chloride in step 5
Heat to. Add about 20-25' methylene chloride.
Continue this procedure for about 25 minutes. The resulting distillation product is clear
become. Next, 10w of dihydropyran was added to the reaction mixture.
Then add 150 g of pyridine hydrochloride. 2 hours
After that, the reaction was completed and the methylene chloride was removed under reduced pressure and the remaining
Dilute the distillate with 30 ml of methanol and 1 ml of potassium hydroxide aqueous solution.
3 Do it with me. The resulting solution was allowed to stand for 2 hours, then 30% hydrogen oxide
Treat with 30' of secretion and water. Then add methanol under reduced pressure.
Remove and dilute the aqueous residue with 100% water and dilute
Extract twice with ether. Next, drain the aqueous layer with potassium bisulfate.
Acidify with 25 ml of aqueous solution and extract with ethyl acetate. one
Combine the combined acetate extracts, wash with salt water, and
Dry over sodium hydrosulfate. Solvent removal under reduced pressure
3. ※, which was then washed with a cloth on 10 pieces of pickled silica gel.
Apply to matography. Column is 75% vinegar in hexane
Load and elute with ethyl acid. Thus the formula CW PGF2
Q15-tetrahydropyranyl ether is obtained. B
PGF2Q15-(tetrahydro) on acetone 75
Fupirani ether) Shigeru is cooled to -45qo, and Joe
Treat with Lens reagent 1.2. Stir the mixture for 30 minutes at -35 to -45°C.
and then treated with 0.5 ml of isopropanol for an additional 15 minutes.
Stir. Pour the reaction mixture on ice, water and diethyl ether.
The combined ether extracts were washed with salt water and soaked with sulfuric acid.
Dry over sodium chloride. After filtration, solvent removal is done by rotary evaporation.
Proceed by starting. The crude product thus obtained 1. total
Acid-washed silica gel 360 was rumored to be subjected to chromatography.
, scaled with 45% ethyl acetate in hexane. PGD2
15-(tetrahydropyranyl ether) 80 product c is this
It can be obtained by C: Add 20 parts of acetic acid and 10 parts of water.
PGD215-tetrahydropyranyl ether) 80
Heat 8 of 0 for 2 hours at 4 pm and dilute with 100 ml of water.
, then lyophilized. Pickling the residue with 20% ethyl acetate in hexane
Chromatograph on silica gel 5. Hexa
When dissolved in 35-65% ethyl acetate in water, a colorless oil is produced.
It produces 500 melons 9 and crystallizes when left to stand. Melting point 62.8
~63.3℃. Infrared absorption is 338, 3000, 272
0,268ri174fu1725・1710,1435,
140fu 132fu 1315, 1270, 1240, 1
2001155, 1080, 1040, 1025, 10
15, 990, Satoshi Q96fu 935, 73fu and 705 enemy
-1. NMR absorption is 0.894.14, 4.5 5.5
3 and 5736. The mass spectrum is 33 and 3
Peaks are shown at 1024 and 190. D Excessive A
When esterified with diazomethane, the title methyl
Occurs with stealthization. The procedure of Reference Example 12 is followed, but the various P described therein are
Using any of the GF-type compounds, the corresponding PO
A type D compound is created. Reference example 1315-methyl-POD2 methyl ester a
15-methyl-PGF2Q methyl ester in setone 10
Cool the solution of Stell 200 to -4 and 0, and
Add 0.15' of Z's reagent. Stir the solution at -3.0°C. Then isopropano
Add the solution at 0.1' and stir the solution for 15 minutes. mixture
Pour the thing into a mixture of ice and salt water and add it with jelly ether.
Extract. The ether extract was dissolved in saturated sodium bicarbonate water.
Wash with liquid and brine, dry over sodium sulfate and concentrate.
This yields 0.2 g of oil. The crude product thus obtained
Silica gel packed with 30% ethyl acetate in hexane 1
30-6 in hexane by chromatography on whiskers.
Drain with 0% ethyl acetate. 0.12 of pure product was obtained.
It will be done. Infrared absorption is 3440, 2940, 2860,
1735, 1440, 1375, 1315, 1240,
1220, 1200, 1170, 1075 10551
Seen in 035, 975c Sou-1. NMR absorption is 0.
891.25, 3.65, 4.50, and 5.508
Can be seen. Follow the procedure in Reference Example 13, but with the species mentioned therein.
Using various 15-methyl-PGF type compounds,
A 15-methyl-PGD type compound is produced. Reference example 141616-dimethyl-FGD2 (formula CV:
R, is hydrogen, O is cis-CH=CH-(CH2)31,
Y is trans-CH=CH-1, R3 and R4 of the L part are both
methyl, M, R5 and R6 of the moiety are both hydrogen, and R7
(n-butyl) or its methyl ester. See Figure L. A IG 16-dimethyl-PGF2ql. 6 He is real
IG16-dimethyl-according to the procedure of Step A of Example 22
PGF2Q15-(tetrahydropyranyl able) 1
．． Converted to 0 end. NMR absorption is 0.87, 0.67-2. Total, 3.25~
4.3〆 4.73, 5.12 and 5.2 to 5.86
Can be seen. Infrared absorption is 3400, 2940, 2870
1710, 120 stop 113fu 1115, 1075, 10
Found in 50, 102, 100, and 975-1.
B 4.35 g of the corresponding product from step A above and 15 g of acetone
0' together and purge with nitrogen for several minutes. Then this
The mixture was cooled to -4 pC and 2.67M Jones reagent
Add solution 2.83 dropwise over 10 minutes while stirring,
The corresponding temperature is maintained at -35 to -4500. 60 minutes later,
The reaction is stopped by the addition of isopropanol 2.
. The reaction mixture is diluted with brine and extracted with ethyl acetate. one
The combined organic extracts were washed with brine and poured over magnesium sulfate.
and concentrated under reduced pressure to yield the crude product 4. cause a mistake
. 2.40 g of the crude product was dissolved in 90% of acetic acid-water (2:1).
Dilute. The resulting solution was heated to 35°C for 3 hours while stirring.
Heat for a while. Next, cool to ambient temperature and place on a table with 200 ml of water.
Dilute and lyophilize. This method produces the remaining crude product
2. Repeat for honey. Freeze-dried residue together
This yielded 3.5% crude product, which was dissolved in 25% ethyl acetate and
Use silica gel 50 female packed in Bisuke IJ Solve B
and refine it. 25-75% of Skellisolve B
When released with ethyl butyrate, pure 10-16-dimethyl
21.57 g of Chill-POD are obtained. Naamo Chromato
Graphical purification yields pure product 1.3
. NMR absorption is 0.83, 0.87, 0.68-3.2
3, 3.86, 4.50, 4. total, and 5.2-6.0
Seen in 6.0. Infrared absorption is 3430, 2950,
2920, 2860, 266 stop 1735, 171513
851235, 1165, 1110, 106fu 102fu
Seen in 99 Fu and 975 En-1. Torisu (Torime)
The mass spectrum of the tylsilyl derivative is 590497,
500410407, showing peaks at 35 and 201
. High-resolution mass spectrum shows demethylation peaks at 1.3
502. C The reaction product of step B is stoichiometrically
When treated with a slight excess of ethereal diazomethane, 16
, 16-dimethyl-POD2 methyl ester.
NMR absorption is 0.7-3.1, 3.67, 3.7-3.
94.3-4.6 and 5.3-5.76. fruit
Example 22,2-difluoro-13,14-dihydro-
POD2 methyl ester (formula CV: R, is methyl, Z,
is cis-CH=CH-(Cri)2-CF2-, Y is -C
QC day 21, R3 and R4 of L part and Rs of M, part
R6 is hydrogen, R7 is n-butyl). See Figures K and L. A 13,14-dihydro-2,2-difluoro PG
F2Q methyl ester (formula x C group: R, is methyl, Z is
cis-CH-CH-(CH2)2-CF2-, Y is -C
From H -, R3 and R4 of L part and R5 and R of M, part
6 is all hydrogen, M7 is n-butyl) as follows.
to make. 3 of formula XCV compound using penzoyl chloride, 5Q
Dihydroxy-28-carboxaldehyde-IQ-Sic
Acylation of lobentane acetate-lactone, thereby
3Q-benzoyloxy-5Q-hydroxy-23-ka
ruboxaldehyde IQ-cyclobentanacetic acid y-lac
make tons. This 3Q-penzyloxy compound was tested using an appropriate Wittig test.
3Q-benzoyloxy-5
Q-Hydroxy-20-(3-oxotrans-1-
octenyl)-IQ-cyclobentanacetic acid y-lactone
Create. Following the procedure of Preparation Example 8, the above compound was converted to 3Q
-penzyloxy-5Q-hydroxy-23-(3-o
(xo-octyl)-IQ-cyclobentanacetic acid
Converted to tons. Following the procedure of Preparation Example 9, the unsaturation on
The lactone is converted into 3Q-penzyloxy-5Q-hydroxy-
28-[$)-3-hydroxy-octyl]-IQ-cy
Convert to clobentane acetate-fuctone. Next this transformation
The compound was deacylated according to the procedure of Preparation Example 12 to form an ester.
, thereby converting the corresponding formula CM compound 8Q. 5
Q-dihydroxy-28 [($)-3-hydroxyoc
]-IQ-cyclobentanacetic acid y-lactone bis-
(Tetrahydropyranyl ether) is made. This compound
Wittig reagent 3,3-difluoro-4 of Reference Example 9
- Ruboxybutyltriphenylphosphonium. My
alkylated by C, thereby forming the formula C skin compound.
2,2-difluoro-13.14-dihydro-PGF
2QII. 15-bis-(tetrahydropyranylethe
(Le) Add the above compound in slight stoichiometric excess.
esterification in esteric diazomethane, thereby
2,2-difluoro-1314-dihydromethyleste
11,15-pis (tetrahydropyranyl ether)
Create. The title compound is then converted to 11,15-pis(te).
by mild acid hydrolysis of trahydropyranyl ether).
It is made. B Reaction product 1 of step A of this example
．． 5 females were treated with 2,2-
Difluoro-1314-dihydro PGF2Q methyl ester
ster, converted to 15-(tetrahydropyranyl(M-tel))
be converted into C The product of the next step B is the procedure of step B of Reference Example 12.
2,2-difluoro-13,14-dihyde. -to PGD215-(tetrahydropyranyl ether)
be transformed. D Next, follow the steps in Step C of Reference Example 12.
The reaction product of Step C is hydrolyzed to the title compound.
. The mass spectrum has a fundamental peak absorption at 485.3196,
533477, 458443387, 371, 36&2
Other peaks are shown at 81 and 173. Infrared absorption is
3420, 3000, 2970・2860, 1765,
1735, 14451350, 1320127121
5, 1200, 1150, and 1090. fruit
Example 3 2, ga-pihomo PGD2 (formula L skin: R, is hydrogen, Z is
cis-CH=CH-(CH2)5-, Y is trans-C
H=CH-, R3 and R4 of L moiety are both hydrogen, M, moiety
R5 and R6 are both hydrogen, and R7 is n-butyl) Figure E
and F. A According to the procedure of Reference Example 6, 4-carboxybutyltritri
6-carpo instead of phenylphosphonium bromide
Xyhexyltriphenylphosphonium bromide 4.
3 female, and 3Q-(t-butylmethylsilyloxy)-5
q-hydroxy-28-(3Q-hydroxy-trans
-1-octenyl)-IQ-cyclobentanacetal
Dehydeturactol 3-(tetrahydropyranyl)
Tel) Using 1.0, Saichi Dihomo PGF2
qll-(t-butyldimethylsilyl ether), 15
-(Tetrahydropyranyl ether 0.91 number
It will be done. B Follow the procedure of Reference Example 7, but use this example as the starting material.
Using the product of Step A of Matsu, Sha-dihomo-PGF
2Q9,15-bis(tetrahydropyranyl ether)
0.5 males and 0.2 males of the title compound are successively produced. NMR absorption is 0.90, 0.7-3.17, 4.12,
, 4.52, and 5.576. Trisu(to)
The mass spectrum of the (dimethylsilyl) concession is 596.3
The parent peak absorption is shown at 764. Reference example 4 Young-dihomo PGD215-methyl ether (formula C
V:R. is hydrogen, O is cis-CH=CH- (C ratio) 5-
, Y is trans-CH=CH-, R3 and R4 of the L part are
Hydrogen, M, R5 and R6 of the moiety are hydrogen and methyl respectively,
and R7 is n-butyl) See Figure L. A, Sadihomo-PGF2o15-methyl ether1.
Cool the female and acetone 25 skin in an ice-methanol bath. Jones reagent (1', 2.67 mmol of chromium trioxide)
) for 1 minute. Heat the mixture at -2 pi○ for 20 minutes.
Stir and start the reaction by adding 1 part of isopropanol.
make it stop. Stir the mixture for another 10 minutes at -20°C.
, dilute with 100' of water and extract with ethyl ether.
. Wash the ether extract with water and brine and add magnesium sulfate.
Dry on top. The mixture was concentrated under reduced pressure with 40 CO
, producing water-laden oil. Add 75' of benzene and steam.
Emission yields 0.87 g of orange oil. water phase
Extract with dichloromethane and wash the dichloromethane extract with water.
and dry over magnesium sulfate. Steam at 40℃ under reduced pressure.
Emission produces 1.0 g of orange oil. these
Combine the oils and place on a column of 10 pieces of pickled silica gel.
Apply to chromatography. 25~ in Skellysolve B
Dissolution with 75% ethyl acetate reveals the title compound as a pale yellow color.
Obtained as Oil 197:9. Mass spectrum is 394
, 392, 370 362, 344, 321, 289 and
Peaks are shown at and 273. Infrared spectrum I00,3
000, 2930, 2860, 2670, 1735, 1
710, 1460, 1410 1380, 127fu 1
20Q Absorb to IO95, 1 female 0, and 975 enemy-1
show. NMR absorption is 0.7-1.01.1-2.0 2
．． 6-32, 3.33.4-3. Yeah, 4.4~4.64
, 5.38-5.62, and 025-6856
Ru. Reference example 5PGD, (formula CV: R. is hydrogen, Z, is
-(CH2)5-, Y is trans-CH=CH-, L,
Part R3 and R4 are hydrogen, M, part R5 and R6 are hydrogen
, and R7 is n-butyl) see Figure L. A According to the procedure of Step A of Reference Example 12, PGF, Q,
2.0g1 PGF, Q15-tetrahydropyranyle
-tel)2. transformed into a female. B Generation of step A according to the procedure of step B of Reference Example 12
The substance is PGD, 15-(tetrahydropyranyl ether)
0.9 converted to female. C Reaction of Step B according to the procedure of Step C of Reference Example 12
The product is converted to the title compound 210. 1314-dihydro-PGD. Add a solution of POD 20.20 in ethanol 15 to 1
10% palladium catalyst on charcoal under hydrogen atmosphere at atmospheric pressure 4
Stir in the presence of 0 evening. After 35 minutes, the reaction is complete and the suspension is filtered through Celite.
pass Concentrate the filtrate to yield 0.2 volumes of oil. Remove this oil
On 20g of silica gel packed with 20% ethyl acetate in Sun
chromatography with 60% ethyl acetate in hexane.
Melt with chill. Fraction containing pure product
taken together yields the title compound. Infrared absorption is 3
450, 2 group 0, 2900, 1740, 1725146
0 Found in 1400, 1170 and 1070ka-1
. NMR absorption is 0.90, 3.55, 4.5u 5.2
Seen in 6. Mass spectrum is 501,,482,4
Absorption is shown at 67, 411, group 3, and 173. Example
5 Cis-4,5-didehydro-PGD, or 15-ip
cis-4,5-didehydroPGD, (formula CV: R,
Hydrogen, Z, is cis-CH2-CH=CH-(CH2)2
1, Y is trans-1 CH=CH1, R3 and R4 of the L part
is hydrogen, M, R5 and R6 of the moiety are hydrogen, and R7 is n-
Butyl) A 15 according to the procedure of Step A of Reference Example 12
-Epis-4,5-didehydro-PGF, QO. 9
7th evening is 15-episis-4,5-didehydro PGF
, Q15-(tetrahydropyranyl ether)1. To the public
be transformed. B The reaction of Step A according to the procedure of Step B of Reference Example 12
0.6 of the product is 15-epis-4,5-didehyde
Rho PGD, 15-(tetrahydropyranyl ether)
It will be converted to 0.9. C Reaction of Step B according to the procedure of Step C of Reference Example 12
The product compound is converted to the 15-epipeline title compound by hydrolysis.
converted to. 9 of 150 products are thus obtained. silylated
The mass spectrum of the derivative is 640. Basic peak in total 13
Indicates absorption. Follow steps A to C above, but (1$)
Reacting title using a starting material with an Ebimer configuration
The compound cis-4,5-didehydroPGD was obtained.
Ru. Infrared absorption is 3420, 3000, 2920, 2
860, 2660, 1735 "1715, 1450,
1390, 1165, 1135 1075, and 970
Seen in arc-1. The mass spectrum of the silylated concession is
Basic peak absorption at 568.3431, 5 spheres, 550, 4
97, 478, 4 lines, 407, birthmark, 350 and 29
9 shows other absorptions. NM old absorption is 0.6-1.8
2.3-2. 4.4-447, 5.2-5.76
It will be done. Example 6 Cis-4,5-didehydro PGD, methyl ester table
The title compound was added to the product of Example 5 in excess of ethereal dia.
Produced by methylesterification using zomethane
Ru. Infrared absorption is 34403010, 2930, 2860,
1740, 1440, 1360, 1255, 1235,
1200 1165 1135 1030 985 9
Seen in 70 enemies-1. Mass spectra of silylated derivatives
The fundamental peak absorption is at 410,3204, 595,5
79, 420, 405, 340, 199 and 173.
shows other absorption of. NM broadside absorption is 0.6 to 2.5, 2.
5-37, 3.68, 3.8-4.2, 4.3-4.0
and 5.1 to 5.68. Example 7 Cis-4,5-didehydro POD, Methyl Ester 1
5-Methyl ether Following the procedure of Step B of Reference Example 12,
Cis-4,5-didehydro PGF,Q methyl ester
15-Methyl ether is converted to the title compound. Mass spectrum is 380, 365 362, 349, 3
48, 309, 291, 277, 259227, 141
, and peaks at 105 are shown. Infrared absorption is 3440,
2930, 2860, 1730, 1440, 1250,
1190, 117010851035, 980 enemy-1
Can be seen. NM liver absorption is 0.7-1.1, 1.1-3.
1, 3.29, 3.35-3.6i, 3.8L 4.4
5-4. Paper, and found in 5.3-5.66. Example
8 Cis-4,5-didehydro-15-methyl-POD, Methyl
Following the procedure of Step B of Tyl Ester Reference Example 12, the cis
-4,5-didehydro-15-methyl-PGF, o-methy
200 females are converted to the title product 0.0
. The mass spectrum has a fundamental peak absorption at 524.3465.
, and 509500 453434 and 363 others
shows the peak of NMR absorption is 0.901.27, 3.
66, 4.56, and 5.3-5.926.
The characteristic infrared absorption is 4-175Q and 0-1.
Can be seen. Example 95-oxa-PGD, methyleth
(Formula CV: R, is methyl, Z is -CH2-0-(C
ratio) 3-, Y is trans-CH=CH-, L, R of the part
3 and R4 are both hydrogen, M, R5 and R6 of the part are both hydrogen
, and R? is n-butyl)A Step A of Reference Example 12
According to the order, 5-oxer PGF, Q methyl ester 0
．． 85 eroded 5-oxer PGF,Q methyl ester 15
1 (tetrahydropyranyl ether) converted into 0.5 base
It will be done. NMR absorption is 0.8 & 0.8~2.6, 2.8 & 3
．． 48, 3.67, 3.2-4.4, 4.7 and 5.2
8 to 5.656. Infrared absorption is 3430,1
740, 1440, 1365, 1320, 126 stop 1
200, 1170, 1115, 1075, 1020, and
and 985 Kite-1. Pisu (trimethylsilyl)
) The mass spectrum of the derivative is the parent peak at 600.3847.
shows absorption. 8 Follow the steps in Step B of Reference Example 12
, step A reaction product 1.0 female is 5-oxer POD,
Methyl ester 15-(tetrahydropyranyl ether)
) Converted to 0.4 ship. NMR absorption is 0.87, 0.7~3.05 3.05~
4.28 3.64 4.47, 4.72 and 5.17
~5.786. C The title compound is Reference Example 1
Produced by hydrolysis as described in step C of 2.
Ru. Thus, 0.4 chicks of the reaction product of Step B are 0.4 chicks of the title product.
Produces 2 females. NMR absorption is 0.87, 3.50 3.
Found in 63, 4.05, 4.47, and 5.476
. Infrared absorption is 344 2930, 286u174
1440, 1370, 1255, 122fu 1195, 1
175111fu 101i Found in 970ka-1.
The mass spectrum of pis-(trimethylsilyl) derivative is
Parent peak at 514.3112 and 49949044
Enter 42fu 424353334199 and 173 and others
shows the peak of Example 10 9-deoxy-POD2 (formula CXXW: R, is hydrogen, Z
is cis-CH=CH-(CH2)3-, Y is trans-
CH=CH-, R3 and R4 of L, part, and M, part
R5 and R6 are all hydrogen, and R7 is n-butyl) Figure 0
See. A Dichloromethane 150 PGF2Q methyl ester secreted
Teru 6.0g and n-butyl poronic acid 2.13
Heat g to reflux. Evaporate 75 ml of dichloromethane and add 15 ml each
Replace with 75% of dichloromethane. Then the solution
Cool and filter out excess n-butylboronic acid.
do. Next, dihydropyran 30 [and pyridine hydrochloride 0
．． 4 and stir the resulting mixture for 20 hours. Next
The mixture was concentrated to an oil, which was diluted with 1 ml of tetrahydrofuran.
Featured in the top 50. 30% hydrogen peroxide reacts with 15 secretions
Add to the mixture followed by 40 ml of sodium bicarbonate in water.
Add. The reaction mixture was stirred for 90 minutes and concentrated to approximately 1/2 volume.
, poured into brine and extracted with ethyl acetate. Ethyl acetate extraction
Wash the extract with brine, dry over sodium sulfate and concentrate.
Then, crude product 11. Produces a rudder. in Skellysolve B
Clothes on 600 g of silica gel packed with 50% ethyl acetate.
50 to 100 in Skellysolve B
When eluted with % ethyl acetate, PGF2Q15-(tetra
hydropyranyl ether) methyl ester 7.1 several millimeters
It will be done. Infrared absorption is 350 298Q2900174
0, 1420, 1370, 131$ 1200, 111
0, 1075, 1020, 97091 870 and 8
1 & Pine-1. B in dry acetone 100'
A solution of the reaction product of Step A of this example at -40
Cool down at midnight. Next, n-trimethylsilyldethyl acetate
Add Min 18 Z under nitrogen atmosphere. After 2 hours, reaction
is completed and the reaction mixture is cooled to -78o0. This cooled mixture is pre-cooled (17 is ○).
Sodium bicarbonate diluted with Rether 150 and chilled on ice
Pour 200 ml of um saturated solution into the secretion. Separate the layers and dilute the aqueous phase.
Extract with a mixture of ethyl ether and hexane. together
The organic extract was dissolved in saturated aqueous sodium bicarbonate solution and salts.
After washing with water, drying over magnesium sulfate, and concentrating, the crude
PGF2QII-(trimethylsilyl ether) 15
-(tetrahydropyranyl ether) methyl ester 5
．． Produced as oil from seaweed. C Reaction product of step B5. Abbreviation and dichloromethane 80 secretion
Cool the solution to -25°C. Add 1.83M triethylamine followed by methanesulfate.
Add Honyl Chloride 1.0. After 10 minutes, additional
Triethylamine 0.55' and methanesulfonyl
Lolide 0. Add paper. After IQ minutes, the resulting mixture was saturated with ice-cold ammonium chloride.
200' of solution and separate the resulting layers. water phase
Extracted twice with dichloromethane and combined dikuoo meta
The extract was washed with saturated sodium bicarbonate solution and brine and sulfurized.
Drying over magnesium acid and concentrating yields a crude yellow
Oil PGF2Q9-mesylate 11-(trimethylsilyl
ether) 15-(tetrahydropyranyl ether)
Tyl ester 5. Produces warmth. Trimethic acid of the product of the previous section
Lucilyl ether is produced by mixing the crude oil obtained above with methanol.
70' and cooling the resulting mixture to 0°C.
Therefore, it is removed. Next, add 30 pillows of 2% citric acid aqueous solution, and after 1 hour
Pour the mixture into 300ml of chilled brine and add ethyl acetate.
Extract with chill. Ethyl acetate extract with sodium bicarbonate
Wash with saturated solution and brine, dry over sodium sulfate and concentrate
This product was then mixed with 50 g of crude product, yielding 5.0 g of crude product.
Silica gel packed with % ethyl acetate and Skellisolve B 3
Chromatographed on 5 cells in Skellisolve B.
Dissolve with 70% ethyl acetate. PGF2Q9-mesire
15-(tetrahydropyranyl ether) methyl es
Ter 3.8 crab is thus obtained. Infrared absorption is 350
0, 2 jobs 0, 2920, 1740, 1440, 1350
, 1200, 11801110, 1 female 1040102
0, me 0, 91 mountains seen in 870 and 815 enemy-1
. NMR absorption is 3.05, 3.654.70, 5.10
and 5.56. D Dried jetyl ether 1
Lithium aluminum hydride in 1.1 female of 00
Stir at ambient temperature in an elementary atmosphere. Next, dry Jetil
Reaction product 3 of step C above in [in] ether 25
．． The base solution is added dropwise over 18 minutes. Another 30 minutes later
, the reaction ends. Then carefully add 2.2 parts of water,
Then add 1.75% of 10% potassium hydroxide aqueous solution.
Ru. After stirring for 3 hours, the suspension turns white. This resulting mixture was mixed with 10% sodium tartrate in brine.
00Pour into the skin. Separate the layers and jelly ether the aqueous phase.
Extract twice. Wash the combined ether solution with salt water
, dried over magnesium sulfate and concentrated to give the crude product
As oil 2. Create a connection. Skellisolve this crude product.
on silica gel packed with 40% ethyl acetate in B.
Apply to chromatography. In this way, pure 2-deoxy
C-21(hydroxymethyl)-9-deoxy-PGF
2Q,15-(tetrahydropyranyl ether)2.1
The total is obtained. Infrared absorption is 350Q2 spots 0, 148u
146 1 1350, 13201260, 121
0119 1120, 1080, 1040, 1005
Found in 980, 910, 87li and 81&umi-1.
NMR absorption is 2.7f 3.603.9u 4.7f and 5
．． Seen in 406. E Distilled water 50 Platinum dioxide underground
Make 0.50g of suspension and bubble hydrogen into it.
This creates a catalyst. Flush the mixture successively with nitrogen and oxygen until the catalyst is slightly
Oxygen is bubbled into the liquid until it is dispersed into particles. next
Add 0.7 kg of sodium bicarbonate and raise the reaction temperature to 60°C.
enhance Next, the reaction product of step ○ above is 0. Until my father and water.
Add acetone (4:1) and 30 parts of the mixture. after a few minutes
A lump appears. Next, add 53 pieces of 12% acetone in water.
Add. After about 4 hours, the catalyst was dispersed into fine particles and
After 4 hours, the starting material is completely consumed. reaction mixture
Cool to ambient temperature and filter through Celite to remove the aqueous filtrate.
Acidify with 50% sodium bisulfate. Vinegar the aqueous phase
Extract with ethyl acetate three times, then add the ethyl acetate extract to brine.
washed with water, dried over sodium sulfate, and concentrated to obtain the crude
Yields 0.30 g of product oil. The crude product in hexane
Chroma on 20 g of silica gel packed in 10% ethyl acetate
Tograph and dissolve in 30% ethyl acetate in hexane.
Let go. Therefore, pure 9-deoxy-PGF2Q, 1
5-(tetrahydropyranyl ether) 0.20 mi bound
It will be done. Infrared absorption is 3450, 2980, 2920,
1720, 1460, 144 or above 1*0, 1200113
Li 1110, 1080, 1020, and 980 arc-1
Can be seen. NMR absorption is 4.0, 4.755.40 and
6. Seen in 706. F Collins reagent is dichloromethane.
Dry chlorine trioxide to 0.69' of pyridine
It is made by adding 0.427g of mu. This suspension was heated to 0°C.
to ambient temperature. dichloromethane 2
The reaction product of step E of this example in a sure shot is 0.1
Add. After 40 minutes, the mixture was filtered through Celite and
Chromatographed on 4-layer silica gel with ethyl acetate.
Melt scales with ru. The resulting ethyl acetate solution was concentrated to yield crude 9
-deoxy-PGD215-(tetrahydropyranyle
ter). This crude product was mixed with 6 parts of acetic acid and 3 parts of water.
Dissolve in a mixture with. The resulting mixture was heated to 400 ml for 90 minutes.
warm. Then add 25' of water and freeze dry the mixture.
. The lyophilized residue was dissolved in 20% ethyl acetate in hexane.
Chromatograph on 20 g of pickled silica gel packed with
and eluted with 50% ethyl acetate in hexane.
Thus 0.06 g of the pure title product was obtained as a colorless oil.
It will be done. Infrared absorption is 3500, 2 groups 0, 2920, 1
740, 17251460, 140 123 1160
, 1125, 1120, 970 and 76 ratio S-1
It will be done. NM old absorption is 0. Iso, 4.15 5.5 and 6.
Seen in 706. High resolution mass spectrum is 480.3
The basic peak is shown at 069. Following the procedure of Example 35
, known to the art or produced as starting materials.
Various PGF-type compounds whose structures are described herein
using any of the corresponding 9-deoxy-PG
Type D compounds are created. Therefore, as described herein
9-deoxy-PGD corresponding to each SOD type compound
type compounds are created. Example 11 9-deoxy-9,10-didehydro-PGD2 (formula C
XO: R, is hydrogen, Z, is cis-CH=CH- (C ratio)
3-, Y is trans-CH=CH-, R3 and R of the L part
4, and R5 and R6 of the M portion are all hydrogen, and R7 is n
- Butyl Refer to diagram N. Remove the total amount of PGD2 from the solution fraction. PGD2
) until a less polar impurity of approximately 3.92% is obtained.
Apply to licage gel chromatography. Less polar impurities were removed with 5% acetone in methylene chloride.
For chromatography on silica gel 1.2 [9] packed with
and dissolve in 10-15% acetone in methylene chloride.
Ru. The partially purified title product thus obtained -
Neutral packed in methanol chloroform (1:1:18)
Chromatography on 200 g of silica gel. child
of acetic acid monomethanol-chloroform (1:1:
48) Wash with 800 ml of
Add the product. Acetic acid-methanol-chloroform
(1:1:48) to give 0.5 cm of pure product.
Obtained as a yellow oil. Infrared absorption is 50 for me and 0 for group 2.
, 2900, 2700, 1740, 1720, 1600
,1460,14401410,135ri1240,1
Found in 170, 1025, and 970 skin-1. N.M.
R absorption is 0.9 or more 4.1f 5.60, 6.60, and
and 7.65 Matsu-1. Mass spectrum is 478
．． 2912 shows the basic peak absorption. Procedure for Example 36
Accordingly, each of the PGD-type compounds mentioned above has a corresponding
9-deoxy-9,10-didehydro POD type
It is converted into a compound. Reference example 179-deoxy-9,1
0-didehydro-13 14-dihydro PGD2 (formula
CXO: R, is hydrogen, Z, is cis-CH=CH-(CH
2) 3-, Y is -CQC day 2-, L, part R3 and R4
are both hydrogen, M, R5 and R6 of the moiety are both hydrogen, and R7 is
n-Butyl A According to the procedure of Reference Example 12, 13 14
-dihydro PGF2Q is 13,14-dihydro PO
Converted to D2. , B This implementation was carried out according to the procedure of Example 12.
The product of Step A of the example is converted to the title compound. Example 12 9-deoxy-9,10-didehydro-2,2-diflu
Oro-13 14-dihydro PGD2 methyl ester
(Formula CX RO: R, is methyl, O is cis-CH=CH-(
CH2) 2-CF2-, Y is-CQC day 2-1, L, part
Both R3 and R4 are hydrogen, M, and R5 and R6 are both hydrogen.
For hydrogen, R7, see n-butyl diagram N. Following the procedure of Example 12, but using Example 2 as starting material.
The title compound of this example was made using the title compound.
It will be done. The mass spectrum of the silylated derivative is 458.2664.
Basic peak, 443 387, 3 total, 358330, and
and 173 show other peaks. The infrared spectrum is
3440, 3020, 2920, 2860, 1770,
1705, 1590, 1545, 1350, 1315,
1270, 1215 1195, 1090, 1050,
and shows absorption at 975-1. Example 13 13 14-dihydro 12,13-(E)-didehyde
POD2 (Formula CXXXO: R, is hydrogen, Z, is cis
CH=CH-(CH2)3-, and L, R3 of the part and
and R4, and M, R5 and R6 of the part are all hydrogen, R7
(n-butyl) See Figure P. Chloroform 3.5' and triethylamine 3.5'
The solution of PGD2300 inside was kept at ambient temperature for 72 hours.
Mix it up. The resulting mixture is diluted with brine and potassium bisulfate.
The resulting mixture was extracted with ethyl acetate and the ethyl acetate extract
is washed with salt water, dried over sodium sulfate, and concentrated.
This yields 0.3 g of a yellow oil as crude product. This crude production
Pickling the material with 30% ethyl acetate in n-hexane
Chromatography on silica gel 3 sprays and n-hexyl
Elute with 30-3% ethyl serpentine in San. In this way, pure
A pure product 150 c is obtained. Infrared absorption is 340
0, 3010, 2 spots 0, 2860, 2660, 1710
, 1645, 1575, 1405124 stop 118QI0
Found in 80 and 103 Renne-1. NM old absorption is 0.
89, 3.75, 4.50, 5.70, and 6.706
Following the procedure of Example 13 as found in C-13 or C
-Various cases where the 14 moiety is trans-CH=CH-
Each of the PGD-type compounds has a corresponding 12,131 (
E)-didehydro-13,14-dihydro-PGD type raw material
converted into synthetic products. Example 14 15-methyl-12,13-(B)-didehyde o-13
14-dihydroPGD2-methylester (formula CXX
XO: R, and R5 are methyl, Z, is cis-CH=CH-
(CH2)3-, R3 and R4 of the L portion, and M
, R5 and R6 of the moiety are all hydrogen, and R7 is n-b
9-deoxy-9,10-didehydro-12
,13-(E)-didehydro-13,14-dihydro
15-Methyl-PGD2 methyl ester (formula CXXXO
:R. is methyl, Z, is cis-CH=CH-(CH2)
3-, R3 and R4 of L part, and R5 and R6 of M, part
are all hydrogen and R7 is n-butyl) See diagram P. Add 1 female slurry of Florisil in 30 ethyl acetate to 15
Methyl-POD2 methyl ester (Example 23, 1.0
foundation). The resulting suspension is stirred at ambient temperature for 48 hours. Next
Add 1 female Florisil and stir the suspension for another 2 hours.
Mix. The Florisil was then filtered, washed with ethyl acetate,
The filtrate is concentrated under reduced pressure to yield 1 g of crude product. this
The phase products were packed with 30% ethyl acetate in n-hexane.
Chromatographed on 100% silica gel and
- Elute with 30-60% ethyl acetate in hexane. Thus pure 15-methyl-12,13(E)-dide
Hydro-13,14-didehydro POD2 methyleth
0.3 and 9-deoxy-9,10-didehydro
-15-methyl-12,13-(E)-didehydro 13
14-dihydro 15-methyl-PGD2 methyleth
The result is 0.17 ge. 15 methyl-12,13-
(E)-didehydro-13 14-dihydro-PGD2
For methylester, the infrared absorption is 3430,2
930, 286u1720 1 fishing 1455, 1440
137 fu 124 u 1225 117 stop 115 fu and
Found in 1185. NMR absorption is 1.15, 3.70, 4.40, 5.50
, and 6756. 9-deoxy-9,10-
didehydro-12,13-(E)-didehydro-13,
14-dihydro-15-methyl-POD2 methylester
Infrared absorption is 3450, 2930, 28
60, 1740, 1700, 1650, 1580, 14
55, 1435, 1375, 1430, 1310, 12
80, 124 mountains 12151170115 to 109010
Found in 50 and 1015 skin-1. NMR absorption is 3.6f, 4.4f, 6.70, and 7.5
Seen in 56. Example 15 9-deoxy-POF2Q methylester (formula CXXW
;R, is methyl, Z, is cis-CH=CH-(C ratio)3
1, Y is trans-CH=CH-, L, R of moiety
3 and R4, and R5 and R6 of the M portion are all hydrogen, R
7 is n-butyl) See Figure 0. A.O. PGF2QI1,15 in the top of Tanol 20
(tetrahydropyranyl ether) 1. Pass the plaque solution
Treat the remainder with ethereal diazomethane. 5 minutes later at 000
, add acetic acid to destroy excess diazomethane. The methanol was then removed under reduced pressure and the residue was
- Dilute with 100% of the solution. This ether solution is mixed with water,
Wash with aqueous sodium bicarbonate solution and dry over sodium sulfate.
dry Removal of the solvent under rotary evaporation yields the crude PGF2
Q Methyl ester 11,15-bis-(tetrahydropi
It produces Rani ether). Sprinkle this with 20 ml of silica gel.
40% of Scherisolve B
Elute with ethyl acetate, whereby PGF2Q, methyl
ester, 11.15-pis-(tetrahydropyranyl
Etel) 1. Produces a rudder. B. The opposite of step A of this example.
The reaction product was dissolved in anhydrous pyridine and recrystallized.
and p-toluenesulfonyl chloride. After 1 hour at ambient temperature, the reaction mixture was poured into ice, brine, and water.
ether and potassium bisulfate in a mixture of 70'
pour. The resulting mixture is thoroughly extracted with ether. A
The extract was dissolved in a cold dilute aqueous solution of potassium bisulfate, water and sodium bicarbonate.
Wash with aqueous solution of sodium chloride and salt water, and wash with anhydrous sodium sulfate.
dry. Removal of the solvent under reduced pressure yields the crude PGF2Q
Methyl ester 9Q tosylate 11,15-bis-(
Tetrahydropyranyl ether) produces nutrients. This inside
Chromatography on 20% silica gel. mosquito
Pack the rum with 30% ethyl acetate and Skellisolve B, and
When this is eluted, pure tosylate 1. Causes spots. C
Step B above in dimethyl sulfoxide 15
1.3 g of reaction product and sodium boronohydrite
1. Stir the solution under nitrogen atmosphere at ambient temperature for 72 hours.
Mix. Mixing ice, water, potassium bisulfate, and diethyl ether
Pour the reaction mixture into the container. Jetilete this mixture
The combined ether extracts were extracted with bicarbonate.
Wash with sodium aqueous solution, water, and brine, anhydrous sodium sulfate
Dry on a rack. When the solvent is removed, 9-deoxy
-PGF2 methyl ester 11,15-bis-(tetra
yielding 1.1 g of hydropyranyl ether). This crude
The product was packed with 5% ethyl acetate and Scherisolve B.
Chromatographed on 25 ml of silica gel, 20
% ethyl acetate and Skellysolve B. thus
A pure product is obtained. NMR absorption is 3.6f32~
3.8470 and 5.25-5.706. D
36' of tetrahydrofuran, 30' of water, and 85'
A solution of the reaction product of step C above in 6% phosphoric acid
Stir for 3 hours at 4pi○. ice, water, diethyl ether, and sodium bicarbonate in water
Pour the reaction product into the liquid mixture and dilute with diethyl ether.
Extract. The combined ether extracts were washed with salt water and soaked with sulfuric acid.
Dry over sodium chloride. Removing the solvent under reduced pressure
, yielding 450 o of crude product. 8 in hexane
Chroma on neutral silica gel 8 mustache packed with 0% ethyl acetate
and elute with this. Thus a pure table
Title compound 208 females are obtained. Infrared absorption is 3420,
174fu 1435, 117i 108stop and 970-1
seen in NMR absorption is 0.88, 2.80, 3.6
It is seen in 3.6-4.2 and 5.25-5.66.
Ru. The mass spectrum is 352, 33431030i2
Peaks are shown at 9Q263 and 245. Reference example 18 PGD31016-dimethyl-PGD3 and 1616-
Difluoro PGD3A Magnesium Kezuri Calendar 1-
Bromosis-2-bentene, 1-promo-1,1-di
Methylcis-2-bentene or 1-iod-1,1-
By reacting with difluorosis-2-pentene
Make a Grignard reagent. 1-iodo-1,1-difluorosis-2-bentene
is created as follows. 2,2-difluoro-acetic acid with excess ethereal diazome
Asterize with Tan. Next, the resulting methyl 2,2-difluoroacetate is
Trahedron. Letters 3995 (1971) Procedure
(For example, adding lithium diisopropylamine to the starting material)
methyl 2, by subsequent treatment with iodine)
Iodination to 2-difluoro-2-iodoacetate
Ru. Next, 17 is diisobutylaluminum hydride at o.
to convert this product into the corresponding aldehyde 2,2-di
Reduction to fluoro-2-iodoacetaldehyde.
Iridethyltriphenylphosphorane (Cpan5)3P=
This aldehyde is converted to Witteich using CH-CH3.
When alkylated by alkylation, the iodide of the title
will occur. B. The Grignard reagent from Step A is mixed with 3Q-t.
dimethylsilyloxy-5q-hydroxy-23-(2
-formyl-trans-1-ethenyl)-lq-cyclo
by reacting with bentaneacetic acid y-lactone, thereby
Corresponding 28-[(S)-13-hydroxy-trans-1
1, cis-5-octasogenyl] compound, and
This was determined by silica gel chromatography.
) separates into epimer. C Following the procedure of the example above, the reaction product of step B is
Converted to POD3. Follow the procedure in steps B and C above, but with methyl or fluoro
Using a substituted Grignard reagent, the corresponding 1016 dime
Chilu PGD3 or 16,16-difluoro PGD3
is created. Following the procedure of Example 15, but as described herein or herein
Using various PGF-type compounds known in the art,
Corresponding 9-deoxy-PGF type compounds are created
.

Claims (1)

[Claims] 1 D in the prostaglandin analogue formula of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Y is cis-CH=CH-, -CH_2CH_2- or =CH-CH_2-, provided that Y is D is ▲ formula,
There are chemical formulas, tables, etc. ▼ Only when , the condition is that =CH-CH_2-, and Z_1 is (
1) Cis-CH=CH-CH_2-(CH_2)_g-
CF_2-, (2) cis-CH=CH-CH_2-(C
H_2)_g-CH_2-, (3) cis-CH_2-C
H=CH-(CH_2)_g-CH_2-, (4) CH
_2-O-CH_2-(CH_2)_g-CH_2-,
(5) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ where g is 1, 2 or 3 and M_1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ So, R_5 and R_6 are hydrogen or methyl, but R_5 and R_
One of 6 is methyl only when the other is hydrogen,
R_7 is (1)-(CH_2)_m-CH_3, where m is 1 to 5, R_1 is hydrogen, or lower alkyl, or a pharmacologically acceptable cation;
) Only when R_6 is methyl, D is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and Z_1 is cis-CH=CH- (CH_2)_3-, and R_7 is -(CH_2)_3-
In CH_3, Y is trans-CH=CH- and R_3
and one or both of R_5 is methyl, and (2) R_
Only when 6 is methyl, D is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and Z_1 is cis-CH=CH-(CH_2)_3-, and R
The conditions are that _7 is -(CH_2)_3-CH_3, Y is trans-CH=CH-, and R_3, R_4 and R_3 are all hydrogen.