JPS6034552B2 - 3-oxo-4-oxa-cis-bicyclo[4.3.0]nonane derivative - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel 3-oxo-4-oxacis-bicyclo[4.3.0]nonane derivative having the general formula (1). In the above formula, A represents a hydroxyl group, a protected hydroxyl group, a carboxyl group, or a protected carboxyl group, × represents a hydrogen atom, Y represents a hydroxyl group or a protected hydroxyl group, and X and Y together represents a protected carbonyl group formed by In the general formula (1), A is preferably a hydroxyl group, 2-
Tetrahydropyranyloxy group, 2-tetrahydrofuryl group, 1-methoxyethoxy, ethoxy group having a lower alkoxy group at the Q position such as 1-ethoxyshethoxy, carboxyl group, methoxycarbonyl, ethoxycarbonyl, n-po poxycarbonyl, Lower alkoxycarbonyl groups such as isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, halogenoethoxycarbonyl groups or penzyloxycarbonyl such as 2,2,2-trichloroethoxycarbonyl, 2,2-dibromoethoxycarbonyl A group or base, a halogen atom such as bromine, a penzyloxycarbonyl group having a nitro group as a substituent, X represents a hydrogen atom, and Y represents a hydroxyl group or acetoxy, n-propionyloxy, n-butyryloxy, iso Indicates a lower alkanoyloxy group such as butyryloxy, and further indicates an ethylenedioxy group or ethylenedithio group formed by X and Y together, and a particularly preferred compound is one in which A is 2-tetrahydropyranyl. A compound that represents an oxy group, an ethylene dithioxy group formed by X and Y together, and A represents a carboxyl group, and X represents a hydrogen atom,
Examples include compounds in which Y represents a hydroxyl group or an acetoxy group. In the compound having the general formula (1), syn- and anti-stereoisomers based on substituents on the five-membered ring moiety and optical isomers based on non-satile carbon atoms exist. Therefore, in producing the target compound, each isomer can be obtained by stereoselective synthesis in an appropriate step or by optical resolution using a conventional method. In the compound having the general formula (1), stereoisomers, optical isomers, and mixtures of optical isomers are all represented by a single formula, but this limits the scope of the description of the present invention. isn't it. It has been known that prostaglandins (hereinafter abbreviated as PG) have various powerful physiological effects, but the side chains at positions 8 and 12 in their chemical structure are cis-type. -isoPGs exhibit more selective physiological effects. For example, 8-iso-PGE, which is obtained by biosynthesis from all-cis-8,11,14-icosatrienoic acid, has weaker smooth muscle contracting and blood pressure lowering effects than PGE, but has an antilipid release effect. Action (antilipol×ic
CTs) and platelet aggregation inhibiting effects are known to exhibit the same strong level. [E. ○． iniel
sePl. ;J. Amer. Chem. Soc. ,90
, 5894 (1968)] In the same article, 8-iso-PCE, , E2 are produced when PGE, , E2 are treated with potassium carbonate in ethanol, but the raw material PCE
G.E. , E2 is 9 and 8-iso-PG is an equilibrium mixture of 12, so the synthesis method for 8-iso-PG is inefficient and difficult to separate. Furthermore, an 8-iso type PC
Two total syntheses of E. have been reported, but both start from intermediates obtained as by-products during the synthesis of husbandrylated PGs, and are not advantageous methods. [W. P. Schne
ider ene1. ;J. Amer. Chem. Soc.
．． , 91, 5372 (1969) and M. Mi secretion no
,M. A. S planning; J. ○rg. , Chem. 4
0, 1748 (1975)]. As a result of repeated research on methods for stereoselectively obtaining 8-isoPGs, the present inventors discovered a novel 3-oxo-4 represented by the general formula (1).
The present invention was completed by discovering that -oxa-cis-bicyclo[43.0]nonane derivatives are important compounds as intermediates for their synthesis. Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below. '1} 3-oxo-4-oxer7-syn-ruboxy-9-syn-acetoxycys-bicyclo [4.3.
0] Nonane (2) 3-oxo 4-oxa-7-syn-methoxycarbonyl-9-syn-acetoxysis-
Bicyclo[4.3.0]nonane '3' 3-oxo-4
-oxa-7-syn-penzyloxycarbonyl-9-
Syn-hydroxy-cis-bicyclo[4.3.0]nonane (4' 3-oxo-4-oxer-7-syn-benzyloxycarbonyl-9,9-ethylenedioxycis-bicyclo[4.3.0]nonane

[5) 3-oxo4
-oxa-7-syn-ruboxy-9,9-ethylenedioxycys-bicyclo[4.3.0]nonane (61
3-oxo 4-oxa-7-syn-hydroxy-9,
9-Ethylenedioxycyc. [4.3.0] Nonane [7] 3-oxo-4-oxa-7-syn-(tetrahydropyran-2-yl)oxy-9,9-ethylenedioxycis-bicyclo ``4.3
．． 0] Nonane {8) 3-oxo4-oxa-7-syn-(2,2,2-trichloro)ethoxycarbonyl-
9,9-ethylene dithiosis-bicyclo[4,3.0
] Nonane side 3-oxo 4-oxer 7-syn-carboxy-
9,9-ethylene dithiosis-bicyclo [4.3.0
] Nonane Q0 3-oxo-4-oxa-7-syn-(
1-ethoxy)ethoxy-9,9-ethylenedioxybicyclo[4.3.0]nonane of the general formula (
The novel compound having 1) can be produced by the method shown below. (D) (m) (W) (V) (W) (Skin) (Skin) (R) (X) (Phantom) In the above formula, R1, R2 and R3 are methyl, ethyl, n
-fu. Lopil, Aesop. It represents a lower alkyl group such as pyru, n-butyl, isobutyl, and R4 represents a lower alkyl group such as pyru, n-butyl, isobutyl, 2,2,2-trichloroethyl, 2,2. Chlorine in the halogenoethyl group or aromatic ring, such as dibromoethyl,
It represents a halogen atom such as bromine, a penzyl group with or without a nitro group as a substituent, and R5 is a 2-tetrahydropyranyl group, a 2-tetrahydrofuryl group, or a 1-methoxyethoxy, 1-ethoxyethoxy, etc. represents an ethoxy group having a lower alkoxy group at the Q position, and Z
represents an oxygen atom or a sulfur atom, and n represents an integer of 2 or 3. Also, in the above formula, cis-bicyclo [4
．． 3.0]/The substituent at the 7th position of the Nan ring shows a compound having a syn configuration, but its stereoisomer, a compound having an anti configuration, can also be reacted in the same manner. The first step is to prepare a compound having the general formula (m), that is, a compound having the general formula (1).
) in which A represents a carboxyl group, X represents a hydrogen atom, and Y represents a lower alkanoyloxy group. This is carried out by heating and reacting with a lower fatty acid having R3COO (in the formula, R3 has the same meaning as described above). There are no particular limitations on the key acid used, but
Sulfuric acid and nitric acid are preferred. The reaction temperature is 50 to 150°C, preferably 85°C.
It is desirable to carry out at 110 oo to 110 oo. The reaction time varies depending on the reaction temperature, etc., but is usually 2 to 6 hours.
The second step is to prepare a compound having the general formula (W), that is, A in the general formula (1) has a lower alkoxycarbonyl group, a halogenoethoxycarbonyl group, or a halogen atom or a nitro group as a substituent in the aromatic ring. Indicates a penzyl group that is not
is a process for producing a compound in which the general formula (m) represents a hydroxyl group;
This is carried out by esterifying the carboxyl group of a compound having , and solvolyzing the alkanoyloxy group. In the reaction of this step, the compound having the general formula (m) is reacted with diazomethane according to a conventional method to form a methyl ester conductor, and then the obtained methyl ester is reacted with, for example, 2 , 2,2-trichloroethanol or pendyl alcohol at around room temperature, or by treating the compound having the general formula (m) with hydrochloric acid, sulfuric acid, or P-toluenesulfonic acid in a conventional manner. This can be carried out by heating the above-mentioned various alcohols to around 80 to 20,000 in the presence of an acid such as. The reaction time varies depending on the type of alcohol used, reaction temperature, etc., but is usually 8 hours to 6 days. The third step is a step of producing the compound having the general formula (V), and is carried out by oxidizing the compound having the general formula (W). The oxidizing agent used is not particularly limited as long as it does not involve side reactions such as cleavage of the lactone ring, but chromic acid-pyridine is preferably used. The reaction is preferably carried out in the presence of a solvent, including inert organic solvents such as methylene chloride,
Mention may be made of halogenated hydrocarbons such as ethylene dichloride. The reaction temperature is preferably relatively low in order to suppress side reactions, and is preferably carried out at around 0°C. The reaction time is usually 5 to 3 minutes. The fourth step is a compound having the general formula (W), that is, A in the general formula (1) has or does not have a lower alkoxycarbonyl group, a halogenoethoxycarbonyl group, or a halogen atom or a nitro group in the aromatic ring. In the process of producing a compound exhibiting a penzyl group and a lower alkylene dioxy group or a lower alkylene dithio group formed by X and Y together, the carbonyl group of the compound having the general formula (V) is ketalized or This is done by thioketalization. The reaction of this step is to convert the compound having the general formula (V) into an alkylene diol or alkylene having the general formula (Xm) (wherein Z and n have the same meanings as described above) in the presence of an acidic catalyst. This can be carried out by reacting with dithiols.
The acidic catalyst used is not particularly limited as long as it is used in ordinary ketalization reactions, but triboron etherate, P-toluenesulfonic acid, and the like are preferably used. The reaction temperature is preferably around room temperature when using boron trifluoride etherate, and under heating under reflux in the presence of an inert organic solvent such as benzene or toluene when using P-toluenesulfonic acid. . The reaction time varies depending on the reaction temperature and the type of acidic catalyst used, but is usually 1 to 4 hours. The fifth step is the general formula (
W), that is, a compound in which A in the general formula (1) represents a carboxyl group and X and Y together represent a lower alkylene dioxy group or a lower alkylene dithio group, General formula (W)
It is carried out by removing the protecting group of the carboxyl group of. In the case where the carboxyl group protecting group of the compound having the general formula (W) is a pendyl group with or without a halogen atom or a nitro group in the aromatic ring, the reaction in this step is carried out using a contact method such as palladium on carbon. It can be carried out by reacting with hydrogen at normal pressure in an alcohol such as methanol or ethyl alcohol using a reduction catalyst, and the protecting group of the carboxyl group is 2,2,2-trichloro. When the compound is a halogenoethyl group such as ethyl and Z is a thioketal compound in which Z represents a sulfur atom, it can be treated with a reducing agent such as zinc-acetic acid at around room temperature. When is a lower alkyl group, it can be treated under mild conditions near room temperature using a base such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as sodium carbonate or potassium carbonate. It can be carried out by hydrolysis. The reaction time varies depending on the type of reaction reagent, but is usually 0.5
Or it's two-man time. The sixth step is a step of producing a compound having the general formula (wind), and is carried out by converting the compound having the general formula (skin) into an acid chloride derivative, and then methylating this. The reaction in this step is carried out by reacting the compound having the above general formula (W) or the corresponding potassium salt treated with potassium bicarbonate with oxalyl chloride in benzene or thionyl chloride in carbon tetrachloride at around room temperature according to a conventional method. The resulting acid chloride derivative is methylated with dimethyl steel lithium, dimethyl cadmium, dimethyl zinc, methyl magnesium bromide-cuprous iodide, etc. in an inert organic solvent such as ether-methylene chloride. It can be carried out by reacting with a reagent at around -50°C. The reaction time for the methylation reaction is usually 18 minutes to 1 hour. The seventh step is a step of producing a compound having the general formula (K), and is carried out by oxidizing a compound having the general formula (and others). The reaction of this process is the so-called Bayer-Villiger (mother eye).
r-Vmi bag r) reaction, and the oxidizing agent used is preferably an organic peracid, particularly pertrifluoroacetic acid. The reaction is preferably carried out in the presence of a solvent with the addition of an alkali metal diphosphate such as dibasic sodium phosphate;
Solvents used include inert organic solvents such as halogenated hydrocarbons such as methylene chloride and ethylene dichloride. The reaction temperature is preferably from 0° C. to around room temperature in order to suppress side reactions. The reaction time is usually 6 to 2 hours. The eighth step is the general formula (
X), that is, a compound in which A in the general formula (1) represents a hydroxyl group and X and Y together represent a lower alkylene dioxy group or a lower alkylene dithio group. This is carried out by solvolysis of the acetoxy group of the compound having formula (K). The reaction in this step can be carried out by treating the compound having the general formula (K) with an alkali metal carbonate such as potassium carbonate or sodium carbonate in an alcohol such as methanol or ethanol at around room temperature according to a conventional method. can. The reaction time is usually 1 to 2 hours. The ninth step is to prepare a compound having the general formula (phantom), that is, the general formula (1
) in which A is a 2-tetrahydropyranyloxy group, 2
- A process for producing a compound that represents a tetrahydrofuryloxy group or an ethoxy group having a lower alkoxy group at the Q position, and a lower alkylene dioxy group or a lower alkylene dithio group formed by X and Y together. (
This is carried out by etherifying the hydroxyl group of a compound having X). The reaction of this step is to react dihydropyran, dihydrofuran, methyl vinyl ether, ethyl pinylene, etc. in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, or P-toluenesulfonic acid at around room temperature according to a conventional method. The reaction can be carried out by reacting with a Q,8-unsaturated ether compound such as ether. The reaction time is usually about 1 to 2 hours. In each of the above steps, each target compound is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the reaction mixture is extracted using an appropriate organic solvent, the resulting organic solvent layer is washed and dried, and then the solvent is distilled off from the extract. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, column chromatography, etc., but it can also be used as a raw material for the next step without any purification operation. In carrying out this method, the compound having the general formula (b) used as a raw material is a new compound, and can be produced, for example, by the method shown in the reaction route below. (XW) (XV) (X's) (XW) (X leg) Ku. ) In the above formula, RI and R2 have the same meanings as described above. The first step is a step of producing an ester derivative having the general formula (XV), in which 7,7-dibromosis-bicyclo[3.2.0]oct-2-en-6-one [W. T. Brady; J. Chg. Chem
．． , 31, 2676 (1966)] with the general formula RIOM
(XK) (wherein RI has the same meaning as defined above, and M represents an alkali metal atom such as sodium or potassium) and an alkali metal alkoxide having the general formula RI
This is carried out by reacting with an alcohol having OH (XX) (wherein RI has the same meaning as defined above), and then isomerizing the resulting cis form of the ester to the trans form. The ring-opening reaction in this step can be suitably carried out using a methanol solution of sodium methoxide, and the reaction temperature is preferably relatively low in order to suppress side reactions. suitable. The reaction time is preferably about 0.5 to 1 hour. Next, the isomerization of the cis-ester derivative to the trans-ester derivative can be carried out by maintaining the reaction temperature at around -5 to 0°C for 1 to 3 hours. In addition, if sissuester is desired, the reaction temperature is -1
The purpose can be achieved by keeping the value below 000. The second step is a step of producing a monopromoester derivative having the general formula (XW), and is a step of producing a monopromoester derivative having the general formula (XW).
XV) by reacting the ester derivative with 1 equivalent of tributyltin hydride. The reaction in this step is preferably performed at a relatively low temperature in order to suppress side reactions, and can be suitably carried out at a reaction temperature of 0 to 20 qo. The reaction time is usually 4 to 1 field hour. The third step is a step of producing a triester derivative having the general formula (X skin), in which a monobromoester derivative having the general formula (XW) is converted into a monobromoester derivative having the general formula (XM) (wherein R2 is the same as the above-mentioned one). It is carried out by reacting a malonic acid monosilver salt with a lower alkyl ester having the following meaning. The reaction in this step is preferably carried out in the presence of a solvent, and examples of the solvent used include polar organic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoramide. The reaction can be suitably carried out under heating at a temperature of 70 to 100°C. The reaction time varies depending on the reaction temperature, etc., but is usually 2 to 1 hour. The fourth step is to produce a diazoester derivative having the general formula (X leg), and is carried out by reacting a triester derivative having the general formula (X leg) with P-toluenesulfonyl azide. The reaction in this step is preferably carried out in the presence of a solvent, and examples of the solvent used include polar organic solvents such as acetonitrile, dimethylformamide, and dimethyl sulfoxide, and the presence of organic amines such as triethylamine and triptylamiso. It can be suitably carried out below. The reaction temperature is preferably relatively low in order to suppress side reactions, and is preferably around room temperature. The reaction time is usually about 8 to 1
It's muscle time. The fifth step is tricyclo[4.3.0. [P, 9] A process for producing a nonane humble conductor, which is carried out by subjecting a diazoester derivative having the general formula (X-leg) to a heating reaction in the presence of a metal catalyst. The metal catalysts used in the reaction in this step include steel powder, copper catalysts such as steel chloride, cupric chloride, cupric sulfate, trimethyl phosphite-cuprous iodide, and palladium chloride, palladium acetate. Examples include palladium catalysts such as, and copper powder is particularly suitable. Solvents used include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, n-heph.
80 such as tane, n-octane, tetrachloroethane
Aliphatic hydrocarbons having a boiling point of 0 or higher are suitable. The heating reaction temperature is usually 80 to 140 pm. The reaction time varies depending on the metal catalyst used, reaction temperature, etc., but is usually 1 to 4 hours. In each of the above steps, each target compound can be obtained by treating the reaction mixture in a conventional manner after the reaction is completed. The obtained target compound can be further purified, if necessary, using conventional methods such as recrystallization, vacuum distillation, and column chromatography. As mentioned above, the compound represented by the general formula (1) obtained by the present invention is a compound useful as a synthetic intermediate for 8-isoPG. For example, 8-iso PGE and E2 can be synthesized in good yield by the method described below. (X-kari) (
XXm) (XXW) (XXV) (XXW) (XX skin) (XXK) (XXX) (XX phantom) (XX fox) That is, substituent A in the general formula (1) is a 2-tetrahydropyranyloxy group. The compound obtained in the present invention (X pond), which is an ethylenedioxy group formed by X and Y together, is used as a starting material, and this is -6000
When reduced with diisobutylaluminum hydride near (
1st step), quantitatively the corresponding lactol (XXm) is obtained. Compound (XXm) is reacted with a dimethyl sulfoxide solution of ylide (XXW) prepared from triphenylphosphoniovalerate bromide, and the product is esterified with diazomethane (second step) to obtain compound (XXV).
Compound (XXV) is catalytically reduced through hydrogen gas in methanol in the presence of 10% palladium-carbon (third step) to give a saturated product (XXW). When the compound (XX) is oxidized in methylene chloride using a chromic acid-pyridiso anchor (fourth step), an aldehyde (XX skin) is obtained. When the compound (XXW) is condensed with 2-oxoheptylidene butylphosphorane (XX style) (step 5), the enone body (XXK) is obtained. Compound (XX melon)
is reduced with sodium borohydride in anhydrous methanol, and the product is separated by silica gel chromatography (step 6) to obtain 15Q-alcohol (XXX). Compound (XXX) is hydrolyzed in an aqueous methanol solution of sodium hydroxide to give the free acid, and further treated with an aqueous acetic acid solution to remove the protecting groups at positions 9 and 11 (step 7), resulting in the desired 8 -isoPGE, (XX phantom)
is obtained. In addition, if the same reaction as in the fourth step and subsequent steps is carried out without ringing compound (XXV), the desired 8
-iso PGE2 (XX cut) is obtained. Furthermore, the compound obtained in the present invention can be used as an intermediate.
8-isoPGs and 8-isoPGFs having a carpoxyl group or hydroxymethyl group at the 1-position can also be synthesized. Next, the present invention will be explained in more detail with reference to production examples and reference examples. (Production Example 1) 38-dibromomethyl-4Q-methoxycarbonylcyclobentene 7,7-dibromo-cis-bicyclo [3.2
．． Oct-2-en-6-one (186.2 ml) was dissolved in 350 ml of anhydrous methanol and cooled to 130 qo. Sodium (23 yen) in anhydrous methanol (350 yen)
A sodium methoxide solution prepared by dissolving the solution was added dropwise over a period of 45 minutes. Keep the internal temperature below -1oo0. -5~0℃
After boiling for 1.5 hours, add 42% of acetic acid and add 15% of ice water.
Pour into a bowl and extract twice with ether. The extract is washed with water, dried and concentrated, and the residue is distilled under reduced pressure to obtain the desired ester as a colorless liquid with a boiling point of 87-90 pm. Yield: 173.0 yen. Elemental analysis: C8 days, calculated value as oBr202; C, 32.24: days, 3. Paper; Br, 53.63 Actual value; C, 32.33; Day, 3.60; Br, 53.19. (Production Example 2) 429.5 ml of 38-dibromomethyl-4Q-methoxycarbonylcyclobentene was cooled to 5 to 7°C in an ice bath,
Add 430 ml of tributyltin hydride all at once after cooling it on ice. After praying for 4 hours at 5 to 700, it will be lighted for 1 year at 20 pm. Pass through a column containing 3 kg of silica gel and wash with 8 sleeves of hexane, then elute with 4 sleeves of ethyl acetate. Concentrate the eluate and distill the light, which has a boiling point of 103 to 106 oo
The desired monobromester 280.8 ml is obtained as a pale yellow liquid with 8 ml. Elemental analysis: C8 days. Br0
Calculated value as 2: C, 43.86: day, 5.06: Br, 36.48 Actual value: C, 43.63: day, 5.28: Br, 36.43. (Production Example 3) 38-[(Ethoxycarbonylacetoxy)methyl]-14Q-methoxycarbonylcyclobentenemalonic acid monopotassium salt 618.4 parts of ethyl ester was dissolved in 1 part of water, and 617.2 parts of silver nitrate was dissolved in 1 part of water. ) Add the solution. The resulting salt was collected by passing it through a vacuum oven, washed with two coats of water and dried. The silver salt thus obtained, 690 g, is suspended in 6.0 g of acetonitrile and heated to reflux. 36-bromomethyl-4Q-methoxycarbonylcyclobentene 286.1
Dissolve 600ml of acetonitrile in 500ml of acetonitrile and drip over 40 minutes. The mixture was refluxed for a further 6 hours, left to cool, and then filtered to remove the liquid from the furnace. Two ethers were added to the residue, and the impurities were removed by the furnace. The ether was distilled off, and the residue was subjected to column chromatography using silica gel 3k9. The desired ester of 160.5% was obtained as a pale yellow liquid from the fractions eluted with 15-25% ethyl acetate-hexane. NMR spectrum (deuterated chloroform solution): 5.63p
pm, m. , is (-CH=CH-)4.18P
Pm'q. , J=7HZ, but (CH3 from -CO)4
．． 18PPm'd. , J=7HZ, Spot, (-C ratio OCO
CH2C02Et) 3.67 ppm, s. ，
Chihito, (1C02CH3) 3.33ppm, s. ,but,
(-OCO-CQC02Et) 1.25PPm't. ，
J=7HZ, 3 days, (1C02CQC day 3) (manufacturing example
4) 38-[(ethoxycarbonyldiazoacetoxy)
Dissolve 38-[(ethoxycarbonylacetoxy)methyl]-4Q-methoxycarbonylcyclobentene 142.9 and P-toluenesulfonyl azide I04-3 in 70% of triethylamine. Add 80.3 evenings and leave the lamp at room temperature for 16 hours. The solvent was distilled off, 1 portion of ether was added to the residue, and the mixture was washed twice with 3% potassium hydroxide solution 800% and twice with brine, and the ether solution was dried and concentrated to give the desired diazoester 154.
．． 8 evenings are obtained. This product can be used in the next step without purification. NMR spectrum (deuterated chloroform solution):
5.63ppm, m. , 2 days, (1CH=CH-
)4.28PPm'q. , 2 days, J=7HZ, (1C0
2CH2CH. )4.25ppm, d. , 2 days, J=6
Hz, (-CH20-CCN2-C.2Et))A 3.67ppm, s. , 3rd (1C02C
H3) 3.35ppm,
m. , IH<>CH-CH2-C. 11,3 Cape Pm' t. , J=7 days 2, (1 C02 C days 2 CH3) (Production Example 5) 2-Ethoxycarbonyl-3-oxo-4-oxa-7-syn-methoxycarbonyltrisic. [4.3.0. Pi'9] Nonane 38-[(ethoxycarbonyldiazoacetoxy)methyl]-4Q-methoxycarbonylcyclobentene 15.06, copper powder 0.75
120-125 qC of mixture of xylene and 600 qC
Heat on an oil bath for 2.5 hours. After cooling, the solvent was removed and the semi-crystalline residue was recrystallized from ethyl acetate-hexane to give a melting point of 118.500-119.
．． The desired trienotic lactone is obtained as 500 prismatic crystals. Yield: 4.7 mackerel. Elemental analysis: C, 3 days, calculated value as 606; C, 58.20; day 6.01 Actual value; C, 58.47: day 6.09. (Production Example 6) 3-oxo4-oxa-7-syn-carboxy-9-syn-acetoxycys-bicyclo[4.3.0] 2 in a mixture of 30% of nonaneacetic acid and 0.75% of concentrated sulfuric acid. −
Ethoxycarbonyl-3-oxo-4-oxer-7-syn-methoxycarbonyrotricyclo[4.3.0. 9] Dissolve 2.75 liters of nonane and heat at 115 qo for 2 hours or at 8500 ℃ for 6 hours. After cooling, dilute with 200 ml of water and extract 5 times with ethyl acetate. The extract is washed with saturated brine, dried, and the solvent is distilled off to obtain the desired carboxylic acid as a pale yellow viscous oil. This acid is used in the next step without purification.
IR spectrum (liquid film): 3000-2500cm-1 (1 COOH) 1740c
-1 (one OAC, six-membered lactone) I7IOC -1 (
-COOH) (Production Example 7) 3-oxo4-oxer7-syn-methoxycarbonyl-9-syn-acetoxycys-picyclo [4.3.
0] Dissolve 7.95 g of the crude carboxylic acid shown in Nonane Production Example 6 in ethyl acetate, and add an ether solution of diazomethane under ice cooling until no nitrogen gas is generated. The solvent was distilled off, and the residue was subjected to column chromatography using 100% silica gel. The fractions eluted with ethyl acetate give the desired ester of 7.10 min as a colorless oil. NMR spectrum (deuterated chloroform solution): 4.8 imitation pm' m. , IH <> Manipulation Ac) 4.
27ppm, m. , crime, (-CH2-0-CO-)3
．． 71 ppm, s. , is (-C02CH3
)2.03ppm, s. , 3rd, (one OCO
CH3) (Production Example 8) 3-oxo4-oxa-7-
Syn-benzyloxycarbonyl-9-syn-hydroxycys-bicyclo[4.3.0] Nonane 25 g of crude ester produced as in Example 7 was dissolved in 200 g of pendyl alcohol, and 10 g of potassium carbonate was dissolved. Add and incubate at room temperature for 6 days. Add 200 parts of water containing 9.6 parts of acetic acid and extract with 300 parts of ethyl acetate. The extract was washed with 5% aqueous sodium bicarbonate and saturated brine, dried, and the solvent was distilled off. The remaining liquid was subjected to column chromatography using 250 days of silica gel. A fraction eluted with ethyl acetate-hexane (3:1) yields 20.4% of the desired pendyl ester. N.M.
R spectrum (star chloroform solution): 7.33ppm
, S●, Mother's Day (C6th, 51st) 5.15ppm, s. ,2
Sun (Ph-CH2-) 4.2 Cape pm, d.
, J = 3 ppm, 2 days, 〉CH℃day 2 "n[C. 1 (Production Example 9) 3-oxo-4-oxer7-syn-benzyloxycarbonyl-9,9-ethylenedioxycis-bicyclo[4 .3.0] A solution of 51.53 chromic anhydride dissolved in 1.3 ml of methylene chloride containing 83.3 nonanepyridine was cooled on ice, and 3-oxo4-oxo7-cysobenzyloxycarbonyl Add all at once a solution of 18.70% of 9-syn-hydroxycys-bicyclo[4.3.0]nonane dissolved in 50% of methylene chloride. After cooling on ice for 20 minutes, add 2.5% of ether. evening and water 1
Add that and separate the liquids. The organic layer is washed successively with cold 3% potassium carbonate solution, cold 3% hydrochloric acid, 5% sodium bicarbonate solution and saturated saline, and after drying, the solvent is removed. Dissolve the remaining 16.33 kg of ketone in a mixture of 100 methylene chloride and 50 kg of ethylene glycol,
Add trifluoroboron etherate 15 at °C. After lighting for 2 hours at room temperature, pour the reaction solution into 250 ml of 5% sodium bicarbonate solution. Extract with ethyl acetate, wash the extract with water, and dry.
Removal of the solvent yields 18.94 g of the desired cyclic acetal as a crystalline solid. Recrystallization from ethyl acetate-hexane gives white needle-like crystals with a melting point of 74-750°.
Elemental analysis: C, 8 days 2. Calculated value as 06; C, 65.05; day, 6.07 Actual value; C, 65.05: day, 6.08 (Production Example 10) 3-oxo-4-oxer 7-syn-carboxy9.
9-ethylenedioxycybicyclo[4.3.0]
18.94 liters of the crude product shown in Example 9 is dissolved in 350 ml of methanol and mixed with 3.2 ml of 10% palladium on carbon previously reduced in 100 ml of methanol. Introduce hydrogen gas at normal pressure and shake koji for 1 hour. benzene 5
00 was added to remove the catalyst through the Celite layer.
When the solvent is distilled off, the desired carboxylic acid 13 is obtained as a white solid. When recrystallized from acetone, the melting point is 18.
It becomes a white plate crystal of 2 to 184 oo. Elemental analysis: C,.
Calculated value as day, 406: C, 54.54: day, 5.83 Actual value: C, 54.60; day, 5.80 (Production row 11) 3-oxo 4-oxa-7-syn-acetyl 9,9
-Ethylenedioxycys-bicyclo[4.3.0]nonane 3-oxo4-oxer7-syn-forceboxy9,9-ethylenedioxycys-bicyclo[4.3.
0] Add 25 parts of water to a mixture of 9.465 parts of nonane, 3.907 parts of potassium bicarbonate, and 12 parts of methanol to make a homogeneous solution. The solvent is dried, the residue is suspended in 200 g of hot water benzene, 28 g of oxalic acid dichloride is added, and the mixture is incubated for 2.5 hours. The reaction solution that became clear was evaporated to dryness, and the residue was dissolved in 400 methylene chloride. Literature [E. Pietai, R
．． J. Keziere, Canadian Jour ship
of Chemistry, 47, 137 (1969)]
A solution of dimethyl steel lithium prepared from 600 g of ether and 200 g of methyl lithium ether solution (containing 0.5 mole of methyl lithium) was cooled to -78 °C, Add the above methylene chloride solution all at once. 1 powder and 12 ethyl acetate
Add 0M and pour the reaction solution into 800ml of water containing 25ml of acetic acid. The impurities are removed in an oven through a Celite layer, and sodium thiosulfate is added to the aqueous layer overnight to separate the layers. The aqueous layer is extracted three more times with chloroform. The organic layers are combined, dried, and the solvent is distilled off to obtain the desired ketone 9.34 as a pale white solid.
When recrystallized from acetosohexane, the melting point is 139-1
It becomes white needle-like crystals at 40°C. Elemental analysis: C, 2 days, 60
Calculated value as 5; C, 59.99: day, 6.71 Actual value: C, 60. Female: day, 6.72 (Production example 12) 3-oxo 4-oxer 7-syn-acetoxy 9,
9-ethylenedioxycys-bicyclo [4.3.0]
Nonane 3-oxo-4-oxer 7-syn-acetyl-9,9-ethylenedioxycys-bicyclo [4.3.
[M.
F. Hamhome, W. ○． Emmons and
K. S. MC Canyama, J. Am. Chem. SM
．． '80, 6396 (1958)] are added to the solution. After clarifying for 5 hours, the same amount of peracid solution was added, and the mixture was immediately incubated at room temperature (15-20 qo) for 3 hours. Add 400 ml of ethyl acetate, filter through a suction furnace, and reduce the furnace liquid to 5%.
Wash sequentially with a sodium bicarbonate solution, a 3% potassium iodo solution, a 2% sodium thiosulfate solution, and a saline solution. After drying, the solvent is distilled off to obtain the desired acetyl compound as a white solid. When recrystallized from acetone-hexane, the melting point is 152-153o.
It becomes white needle-like crystals of o. Elemental analysis: C. Calculated value as 2 days, 606; C, 56.24: days, 6.29 Actual value; C, 56.26: days, 6.32 (Production example 13) 3-oxo 4-oxa-7-syn-hydroxy-9 ，
9-ethylenedioxycys-bicyclo [4.3.0]
Nonane 3-oxo 4-oxa 7-syn-acetoxy-9,9-ethylenedioxycys-bicyclo[4.3
．． 0] A mixture of 6.965% of nonane, 7.0% of potassium carbonate, and 400% of anhydrous methanol at 20°C. Immediately worship the hawk. Add 3.4 g of acetic acid and stir, then add 5.0 g of baking soda. Methanol is removed and the residue is extracted with ethyl acetate. Removal of the solvent yields 5.63 g of the desired alcohol as a white solid. When recrystallized from acetone-hexane, it becomes white long needle-shaped crystals with a melting point of 116-1170. Elemental analysis: C. Calculated value as mountain, 405; C, 56.07H; 6.59 Actual value; C, 56.21; day, 6.53 (Production Example 14) 3-oxo-4-oxa-7-syn-(tetrahydropyran-2- yl)oxy-9,9-ethylenedioxycis-bicyclo[4.3.0]nonane 3-oxo-4-
Oxer-7-syn-hydroxy-9,9-ethylenedioxy-bicyclo[4,3.0)nonane and dihydropyran were dissolved in 100 g of methylene chloride, and p-toluenesulfonic acid was dissolved in 0.1 g of dihydropyran. Add to the mixture and let it stand at room temperature for 2 hours. Add 200% of ethyl acetate, wash with 5% sodium bicarbonate solution and brine, dry and evaporate the solvent to obtain the desired pyranyl compound 6.17
5% is obtained as a white solid. Recrystallization from ethyl acetate-hexane gives white needle-shaped crystals, with a melting point of 105-1
1yo, and is presumed to be a mixture of two diastereomers. NMR spectrum (deuterated chloroform solution): 4
．． 63 ppm, m. , IH4.25ppm, d. , J=
5Hz, 2nd ()CH-. CH2 ratio 0) 3.97ppm, s. , 4 days, (1OCH2CH201) (Reference example 1) 71 [(28-hydroxymethyl-3
Q-(tetrahydropyran-2-yl)oxy-5,5
-ethylenedioxycyclobentan-IB-yl]-cis-5-heptenoic acid methyl sodium hydride (50%)
5. A solution prepared by dissolving 28.4 parts of triphenylphosphoniovaleric acid bromide in 100 parts of dimethyl sulfoxide was added dropwise in an argon stream to an anion solution prepared by heating and dissolving the solution in 100 parts of dimethyl sulfoxide. A red ylide solution is thus obtained. On the other hand, 2.39 g of 3-oxo-4-oxa-7-syn(tetrahydropyran-2-yl)oxy-9,9-ethylenedioxycys-picyclo[4.3.0]nonane was dissolved in tolueso 50' to -6000. Cooling. Hexane solution of diisobutylaluminum hydride (25 minutes/100 minutes)
6. Add 9' and stir for 20 minutes. Add a mixture of 40 parts of tetrahydrofuraso and 20 parts of water, and return the reaction solution to room temperature. Add 20 parts of ethyl acetate and remove impurities in the oven.
After washing with water, the solvent was distilled off to obtain an oily substance of 2.57 cm. Add 2.39 ml of this crude product to the above IJ solution and incubate at 22-25 ml for 1 hour. 1. Pour the reaction solution into ice water and extract with ethyl acetate. Add 4 parts of acetic acid to the sodium bicarbonate and extract 3 times with ethyl acetate.
An ether solution of diazomethane is added to this second extract under ice until no nitrogen gas bubbles are generated. After drying, the solvent was distilled off and the remaining 13.4 mL was poured into 150 ml of silica gel.
The mixture is subjected to column chromatography using chromatography. 10%
From the fraction eluted with ether-benzene, 2.64 g of the desired hydroxyester is obtained as a colorless oil. NMR spectrum (deuterated chloroform solution): 5.45P
pm, m. , 2 days, (1CH=CH-)4.7 pm, m. , IH, 4.3 Cape pm, m. ,IH(
>CAROTHp)3.9pm, s. ,4th,(
1 OCH2C day 201) 3.7 temporary pm, s
．． , is (-C02CH3) (Reference example 2) 7-[28-
Hydroxymethyl-3Q-(tetrahydropyran-2-
10% palladium on carbon was mixed with 4 parts of methanol and shaken over hydrogen. After hydrogen absorption is completed, 7-[28-hydroxymethyl-3Q-(tetrahydropyran-2-yl)oxy-5
, 5-ethylenedioxycyclobent-18-yl]cis-5-heptenoate was dissolved in methanol and added to the solution, and the mixture was bubbled with hydrogen and shaken for 30 minutes. 13
After the hydrogen above is absorbed, the catalyst is evaporated and the solvent is distilled off to yield the desired saturated ester 180 as a colorless oil. NMR spectrum (deuterated chloroform solution): 4.53P
Pm'4.13PPm' 3.80ppm, s. , 4th (○ from 1OCH)
-)3. Spot ppm, s. , Mother's Day (1C0
2CH3) (Reference Example 3) 9,9-ethylenedioxy-11Q-(tetrahydropyran-2-yl)oxy-1
A solution of 400 o of chromic anhydride dissolved in 30 methylene chloride containing 632 mg of methyl pyridine 5-oxo 8-isoprostol 13-transenoate was cooled on ice, and 7-[28-hydroxymethyl-3Q-1 (tetrahydropyran- Methyl 2-yl)oxy-5,5-ethylenedioxycyclobento-18-yl]hebutanoate 18
Methylenenk the evening of 0. Dissolve in lido 2 secretion and add. After worshiping for 3 minutes under ice-cooling, add 40 units each of ether and ethyl acetate, add water and cool for 1 hour.
．． Wash sequentially with 5% sodium carbonate solution, 1.5% hydrochloric acid, 5% sodium bicarbonate solution, and water again. After drying, the solvent was distilled off, the residue was dissolved in 10 parts of anhydrous ether, and 9 parts of 2-oxohebtylidenetriphenylphosphorane was added to give 22-24
qo has a 24 hour light frame. The solvent is distilled off, and the residue is subjected to column chromatography using silica gel.
The desired enone 194 female is obtained as a colorless oil from the fractions eluted with 4% ethyl acetate-benzene. NMR spectrum (deuterated chloroform solution): 6.75p
pm, dd, J, = 16, J2 = 9 HZ, IH (C, 3
-H) 6.03ppm, dd, J, = 16, J2 = 3H
Z, IH (C, 4-H) 4.57 ppm, m, IH,
3.90ppm, s, 4 days, (1 OCH2C day 20
1) 3.63ppm, s, 3 days, (1C02
CH3) 0.93 ppm, m, 9 days, (1C4-CH3) (Reference example 4) 9,9-ethylenedioxy-
11Q-(tetrahydropyran-2-yl)oxy-1
5Q-Hydroxy-8-isobrostol 13-trans-Methyl enoate Anhydrous methanol 8
il) Oxy-15-Oxo-8-Isobrost-1
Methyl 3-transenoate 191 Dissolve the palisade, 120
Cool to oC. Add 50 parts of sodium borohydride and incubate for 2 hours, then add 20 parts of water containing 0.4 parts of acetic acid. Next, add 5% hydroxide and extract twice with ethyl acetate.
The extract is washed with water, dried, and concentrated, and the residual liquid 187 is subjected to column chromatography using silica gel. 8
158-hydroxy form 7 with ethyl acetate-benzene
After 9 of 8 was eluted, the desired 15Q of 71 was extracted from the fraction eluted with 10-12% ethyl acetate-benzene.
-The alcohol is obtained as a cool colored oil. NMR spectrum (deuterated chloroform solution): 5.53p
pm, m, 2 days, (1CH=CH-)4.56P
Pm'm'3.83ppm, s, 4 days (one OCH
2CH20-)3.6 Cape pm, s, Pan(-C
02CH3) 0.87ppm, m, lees (1C4 melon-CH3) (Reference example 5) d1-8-isoprostaglandein E, 9,9-ethylenedioxy-11Q-tetrahydropyranyl in methanol 2 Oxy-15
- Oxo 8-isobrost 13-Methyl trans-enoate 5 Dissolve product 9, cool on ice, and add 5% sodium hydroxide solution 1. After heating the mixture for 4 hours at room temperature, add 4 parts of saline solution and adjust the pH to 3-4 by adding acetic acid dropwise. Extract twice with ethyl acetate, wash with water and remove the drying solvent. 51 parts of the residue was dissolved in a mixture of 2 parts of acetic acid, 1 part of water, and 0.3 parts of tetrahydrofuran and allowed to stand at room temperature for 2 hours. Add 6 parts of brine and extract twice with ethyl acetate. After drying, the solvent was distilled off and the crystalline residue was recrystallized from ether-hexane to give a melting point of 88.
dl-8-isoPGE is obtained as white needles at ~89°C. Yield: 21 females. Although the melting point of this product is different from the literature value (melting point 101-1020), the 8-isoPGE obtained here shows a single spot in thin layer chromatography using three solvent systems. By treatment with caryetanol acetate, melting point 112.5-11
dl-POE, at 3.5°C, which is the same as the known dl-POE.
l-PGE. The melting point and various spectra are the same. (
Reference Example 6) dl-8,15bisiso-PGE, 9,9-ethylenedioxy-11Q- obtained as shown in Reference Example 4
Tetrahydropyranyloxy-158-hydroxy-8
-iso. P. Reference Example 5
By operating in the same manner as described above, dl-8,15-bisiso-PGE, 39, is obtained as a colorless oil.
Oily dl can be obtained by treatment with karyl acetate.
-15 isoPGE, which has completely identical spectra to known standard products. (Reference Example 7) Methyl 9,9-ethylenedioxy-11Q-(tetrahydropyran-2-yl)oxy-15-oxo-8-isoprost-5-cis-13-transogenate 7
When 1.332% of 1[28-hydroxymethyl-3Q-(tetrahydropyran-2-yl)oxy-5,5-ethylenedioxycyclobentan-18-yl]cis-5-heptenoic acid was treated in the same manner as in Reference Example 3, 1.472 kg of the desired enone is obtained as a colorless oil. NMR
Spectrum (deuterated chloroform solution): 6.93 ppm,
dd, (J]=16, J2=9Hz), IH, (C, 3
1H) 6.2 pm, dd, (J, = 16, J2 = 3H
Z), IH, (C,4-H)5.43ppm, m,
2 days, (C5-day, C6-H) 4.66 ppm, m,
IH, 4.0 pm, s, 4th, (○ from 1 OCH
-) 3.73 ppm, s, 3 days (1C02
CH3) 0.93ppm, m, (C4 is -
CH3) (Reference Example 8) 9,9-ethylenedioxy-1
1Q-(tetrahydropyran-2-yl)oxy-15
Q-Hydroxy-8-isoprostose-5-cis-13
-Methyl transgenate 9,9-ethylenedioxy-11Q-(tetrahydropyran-2-yl)oxy-15-oxo-8-isobrostol 5-13-
The crude product prepared by the procedure in Reference Example 4 using 1.472 mm of methyl transgenate was subjected to column chromatography on 75 mm of silica gel. The desired 15Q-alcohol 576-9 is obtained as a colorless oil from the fractions eluted with 25-35% benzene-ethyl acetate. NMR spectrum (deuterated chloroform solution): 5.1-6
．． Blood pm, m, 4 days (1CH=CH1) 4.73p
pm, m, IH3.95ppm, s, Misaki (-O
CH2C ratio 0-) 4.73 ppm, s, insect day (1 C02 CH3) 0.9 snake pm, m, 3 days (1 C4 戊-CH3) (Reference example 9) 8-isoprostaglandin E4 9,9- When methyl ethylenedioxy-11Q-(tetrahydropyran-2-yl)oxy-15Q-hydroxy-8-isoprost-5-cis-13-transgenate is hydrolyzed as in Reference Example 5, the desired 8-yl SoPGE2 is obtained as white feathery crystals with a melting point of 90-920. 0o elemental analysis value of yield 143: Calculated value as C2 side 3205; C, 68.15: day, 9.15 Actual value: C, mottled. 41: Sun, 9.11 This product, when treated with potassium acetate in the same manner as described in Reference Example 5, gives PGE2 which is identical in all respects to the authentic product.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A represents a hydroxyl group, a protected hydroxyl group, a carboxyl group or a protected carboxyl group, and X represents a hydrogen atom, Y represents a hydroxyl group or a protected hydroxyl group,
Furthermore, it shows a protected carbonyl group formed by X and Y together. ) with 3-oxo-4-oxa-cis-bicyclo [
4.3.0] Nonane derivatives. 2 In general formula (I), A is a hydroxyl group, 2-tetrahydropyranyloxy group, 2
- a tetrahydrofuryloxy group, an ethoxy group having a lower alkoxy group at the α-position, a carboxyl group, a lower alkoxycarbonyl group, a halogenoethoxycarbonyl group, or a benzyloxycarbonyl group that is unsubstituted or has a halogen atom or a nitro group as a substituent, 3 of Claim 1, wherein X is a hydroxyl atom, Y is a hydroxyl group or a lower alkanoyloxy group, and furthermore, X and Y together form an ethylenedioxy group or an ethylenedithio group. -oxo-4-oxa-cis-bicyclo[4.3.0]nonane derivative.