JPS5929587B2 - Method for producing phenyl-substituted PGE↓ type 2 compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of making analogs of prostaglandins.

More specifically, the present invention is disclosed in Japanese Patent Application Publication No. 1973-
The present invention relates to a method for producing phenyl-substituted prostaglandin E2 (PGE2) type compounds described in No. 9465 (May 16, 1972). These phenyl-substituted prostaglandin analogs are represented by one of the following formulas, or a combination of that formula and its mirror image.

Formula 1 represents phenyl-substituted compounds of the PGE2 type.

In formula 1, M is t6H or paper)H, and R3 and R4 are hydrogen.

-C, H2, and a portion are lower alkylene. Represents lower alkylene. ^ Formula 1 encompasses the separate isomers when M is either R3'0H or K3)H, ie the side chain hydroxy is in the S (alpha) or R (epi to beta) configuration.

Regarding the numbering of prostanoic acid atoms, the attachment point is C-1
5, these epimers are referred to herein as C-15 epimers, regardless of the change in the C-1 to C-7 carbon chain. C-13 to C-14
In all of the compounds containing a double bond to R4, this carbon-carbon double bond is in the trans configuration and R4
The chain containing is attached in the beta configuration to the cyclopentane ring in the compounds encompassed by formula 1.

Like the natural prostaglandins mentioned above, these phenyl-substituted prostaglandin compounds have several asymmetric centers. These compounds include (a) compounds having the same stereochemistry as naturally occurring prostaglandins, and (b) racemic compounds of (a) plus one optically active enantiomer. Two structural formulas are required to accurately define these racemates. Formula 1 is intended to represent an optically active prostanoic acid analog having the same absolute configuration as naturally occurring prostaglandins. However, in the figures of this specification, for convenience,
It is used to define not only optically active types but also racemic compounds that generally undergo the same reaction. Phenyl-substituted PGE2 compounds encompassed by Formula 1 are made by the following reaction. Figure A illustrates a reaction system for making tricyclic lactone aldehydes by procedures known in the art.

See US Pat. No. 3,711,515. In this US patent, the reaction sequence to make the tricyclic lactone aldehyde is as follows. (a) Optically active or racemic [3.1.O]hex-2-ene-6-carboxaldehyde of the formula (in which ~ represents a bond in alpha or beta configuration) Convert to an active acetal, or its mirror image, or a racemate of this formula and its mirror image.
In the formula R2l and R22 are alkyl of 1 to 4 carbon atoms and when taken together (where R23, R24, R2
5, R26, R27, and R28 are hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl, provided that not more than 1 R'' is phenyl, and the total number of carbon atoms is 2 to 4.
10, x is O or 1), and ~ is as defined above].

(b) converting the optically active or racemic acetal into an optically active tricyclic mono- or dihaloketone of the formula, or a mirror image thereof, or a racemate of this formula and its mirror image [in the formula R2
l, R22, and ~ are as defined above;
R3O is bromo or chloro, and R3l is hydrogen,
bromo or chloro].

(c) Converting the optically active or racemic tricyclic mono- or di-ketone V into an optically active tricyclic ketone of the formula, or a mirror image thereof, or a racemic compound of this formula and its mirror image.
(d) an optically active or racemic tricyclic ketone as an optically active tricyclic lactone acetal, or a mirror image thereof, or a racemic combination of this formula and a mirror image thereof; oxidizes to a compound [in the formula, R2-R
22, and ~ as defined above].

(e) Hydrolyzing the optically active or racemic tricyclic lactone acetal to an optically active tricyclic lactone acetal of the formula, or a mirror image thereof, or a racemic compound of this formula and its mirror image [where ~ is above] As defined].

Bicyclic aldehydes of formula A exist in multiple isomeric forms.

Regarding the bond of the -CHO group, it has two isomeric forms,
Exists in exo and ending. Regarding the position of the cyclopentene double bond relative to the -CHO group, each of the exo type and the endo type exists in two optically active (d- or l-) types, resulting in a total of 4 isomers. Each of these isomers individually, or mixtures thereof, undergo reactions to produce prostaglandin intermediates and products. The unresolved isomers are used for racemic products. For optically active prostaglandins, the aldehyde or subsequent intermediate isomers are resolved and used to create the optically active product using methods disclosed in US Pat. No. 3,711,515.

To carry out step a, the bicyclic aldehyde is converted to an acetal by methods known in the art.

The aldehyde is thus reacted with an alcohol of 1 to 4 carbon atoms, such as methanol, ethanol, propanol or butanol, or their isomeric forms, or a mixture of these alcohols, or preferably a glycol of the formula.

In the formula, R23, R24, R25, R26, R27, and R28 are hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl, provided that not more than 1 R is phenyl, and the total number of carbon atoms is is from 2 to 10, and x is zero or 1. Examples of suitable glycols are ethylene glycol, 1,2-propanediol, 1,2-hexanediol, 1,3-butanediol, 2,3-pentanediol, 2,4-hexanediol, 3,4-octane. Diol, 3,5-nonanediol, 2,2-dimethyl 1,3-propanesyl, 3,3
-dimethyl 2,4-heptanediol, 4-ethyl-4
-Methyl-3,5-heptanediol, phenyl-1,
2-ethanediol, and 1-phenyl-1,2-propanediol. The reaction of step a is generally carried out under a variety of conditions using procedures known in the art.

The reactants are thus dissolved in benzene and the mixture is heated to remove the water that is formed azeotropically. To speed up the reaction, add an acid catalyst such as p-toluenesulfonic acid, trichloroacetic acid, zinc chloride, etc. Instead, the reactants are warmed to 40-100° C. with an acid catalyst and a water removing agent such as trimethyl orthoformate in an inert solvent such as benzene, toluene, chloroform, or carbon tetrachloride. The ratio of aldehyde to glycol is 1:1 to 1
:4 is preferred. To convert acetal to ketone,
Reactions known in the art for similar compounds are used.

To carry out step b, the acetal is converted into ketene R3OR3
lC-C=O, e.g. HBrC=C=O, HClC-C
-0. React with Br2C=C-0 or Cl2C1C-0. For convenience, ketene Cl2C-C1O is preferred. This involves adding a 0.5 to 2.0 fold excess of dichloroacetyl chloride to a tertiary amine, such as triethylamine.
00 to 70 in a solvent such as n-hexane, cyclohexane, or a mixture of isomeric hexanes (Skerisolve B) in the presence of tributylamine, pyridine, or 1,4-diazabicyclo[2.2.2]octane. Preferably, it is generated in situ by reaction at a temperature of .degree.

(For example, COrey et al., Tetrahedron Letters, No. 4)
No. 307310, 1970. ) Alternatively, ketene Cl2C=C=0 is made by adding trichloroacyl halide to zinc powder suspended in a reaction vessel, omitting the tertiary amine. To carry out step c, the mono- or dihaloketone V is dissolved in methanol,
With a 2- to 5-fold excess of zinc powder over the stoichiometric ratio of Zn:2C1 in the presence of sodium bicarbonate or sodium dihydrogen phosphate to acetic acid, ammonium chloride, etc. in ethanol, ethylene glycol, etc. Give back. Instead, the reaction is carried out with an aluminum amalgam at about 0 DEG to 50 DEG C. in a water-containing solvent such as methanol-diethyl ether water, tetrahydrofuran-water, or dioxane water.

To carry out step d, the tricyclic acetal ketone is oxidized by methods known in the art, for example in the presence of a base such as an alkali hydroxide, bicarbonate or orthophosphate. It is converted to the lactone by reaction with hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc. using a preferred molar ratio of agent to ketone of 1:1.
To carry out step e, the lactone acetal is converted to the aldehyde by acid hydrolysis known in the art, using dilute mineral acids, acetic acid, or formic acid, and the like.

Figure B shows a reaction sequence for converting tricyclic lactone aldehydes to bicyclic lactone diols.

Here, Q is -CtH2t-《》.

To carry out step a, an aldehyde is converted to an alkene of the formula by a ylide, such as in a Witteig reaction. Certain organic halides, such as chlorides and bromides, are the common tricyclic ketone moiety -CH=CH
It is necessary to make the Witteitsch reagent used to generate Q.

These organic halides, such as QCH2CH, Cl and QCH2CH2Br, are known in the art or can be made by methods known in the art. Witteig reagents are made by reacting these organic halides with triphenylphosphine in a known manner. For example, reacting 1-bromo-3-phenylprobane with triphenylphosphine yields 3-phenylpropane triphenylphosphonium bromide. To carry out step b, the alkene is hydroxylated to glycol x by procedures known in the art.

South African Patent No. 69/ issued on 3 July 1970
See No. 4809.

Hydroxylation of endo- or exo-alkenes, respectively, can result in a variety of isomers, depending on factors such as whether the -CH═CH moiety in it is cis or trans and whether a cis or trans hydroxylation reagent is used. of glycols are obtained. Thus, endocysolefins give a mixture of two isomeric erythroglycols of formula x by means of a cis-hydroxylating agent, such as osmium tetroxide. Similarly, endo-transolefins give similar mixtures of the same two erythroglycols with transhydroxylating agents such as hydrogen peroxide. Endocytic and endotrans olefins give similar mixtures of the two threoglycol isomers with trans and cis hydroxylating reagents, respectively. These various glycol mixtures are separated into individual isomers by silica gel chromatography. However, this separation is usually not necessary. Because each isomeric erythroglycol and each isomeric threoglycol can be prepared according to the method of the present invention and outlined in Figure B to form intermediate products of the formula This is because it is useful as an intermediate for producing the final product. Thus, mixtures of the various isomeric glycols encompassed by formula X made from the various isomeric olefins encompassed by the formula are all useful for these same purposes. To carry out step c, the optically active tricyclic lactone glycol an aralkyl of 7 to 12 carbon atoms substituted with ~3 halogen atoms, and R42 is methyl or ethyl], the optically active cyclic orthoester of formula M This produces an ester or a racemate of this formula and its mirror image.

7 To carry out step d, the cyclic orthoester M is reacted with formic acid,
This produces an optically active diol diester of the formula or a racemate of this formula and its mirror image. In carrying out step e, the acyl group of the diol diester 2 is replaced with hydrogen,
yielding bicyclic lactone diol x.

Up to now, the step of converting glycol x to diol
This is revealed in issue 5.

Example: For example, the glycol hydrogen atom of glycol x is replaced with an alkyl sulfone group and the product is subjected to hydrolysis. Instead, the mixture of isomeric glycols The conversion of glycol x to diol can be accomplished stereospecifically, thus providing high yields of the desired isomer via the cyclic orthoester.

Step C in Figure B. With reference to d and e, it will become clear how to achieve this. In step c of diagram B, tricyclic lactone glycol X is converted to cyclic orthoester M.

Glycol x exists in two erythro and two threo forms. [wherein R4l and R42 are as defined above]
obtained by reaction with orthoester.

The reaction proceeds smoothly at temperatures in the range of 50°C to +100°C, although 0°C to +50°C is generally preferred for convenience. 1.5 to 10 molar equivalents of orthoester are used with the acid catalyst. The amount of catalyst is usually a small fraction of the weight of the glycol, such as 1%, and typical catalysts include pyridine hydrochloride, formic acid, hydrochloric acid, p-toluenesulfonic acid, trichloroacetic acid, or trifluoroacetic acid. The reaction is a solvent,
Preference is given to working out, for example, in benzene, dichloromethane, ethyl acetate or diethyl ether. The reaction is generally complete in a few minutes and is conveniently followed by TLC (thin layer chromatography on basic silica gel plates). Orthoester reagents are known in the art or can be readily obtained by methods known in the art.

For example, S.M. McElvain (J.O.) starting from a suitable nitrile,
f. Am. Chem. SOc. ) Volume 64, Page 1925 (1
942).

Examples of useful orthoesters include: Trimethyl orthoformate Triethylorthoacetate Triethylorthopropionate Trimethylorthobutyrate Triethylorthovalerate Trimethylorthooctanoate Trimethylorthophenylacetate, and trimethylortho(acetate of 2,4-dichlorophenino).

Preferred are orthoesters when R4l is alkyl of 1 to 7 carbon atoms.

Particularly preferred are those when R4l is alkyl of 1 to 4 carbon atoms. The formula diester is in stage d,
Obtained by reaction of formula M cyclic orthoester with formic anhydride.

"Formic anhydride" means that it contains no more than 0.5% water. The reaction is carried out with an excess of formic acid, which itself serves as the reaction solvent. Solvents may be present, for example dichloromethane, benzene, or diethyl, ether, usually in an amount not exceeding 20% by volume of formic acid. Organic acid anhydrides useful as desiccants for formic acid, such as acetic anhydride, or alkyl orthoesters, such as trimethyl orthoformate, may also be present. The reaction will proceed over a wide range of temperatures, but is conveniently carried out at about 20-30°C and is usually complete within about 10 minutes. The product is then recovered and optionally purified by methods known in the art. Diols of formula X are obtained in step e by alcohol reaction of diesters of formula in the presence of a base.

Examples of bases are sodium or potassium carbonate or sodium or potassium alkoxides, including methoxides or ethoxides. The reaction is carried out using excess solvolysis reagent,
It is convenient, for example, to carry out in methanol or ethanol. The temperature range is -50°C to 100°C.
The time for completion of the reaction varies depending on the nature of R4l and the base.
In the case of alkali carbonates, the reaction proceeds in a few minutes when R4l is hydrogen, but takes up to several hours when R4l is, for example, ethyl. Referring to Figure C, another diester to diol route is shown.

In step a, diester to triolic acid Upon hydrolysis, the lactone is cleaved.

Hydrolysis occurs in the presence of a base such as sodium or potassium carbonate or hydroxide. In the case of alkali carbonates, water-containing solvents are used, such as methanol-water or tetrahydrofuran-water, whereas in the case of alkali hydroxides there is no need to add water. Thereafter, the triolic acid By lactonization, diol? converted to.

at a temperature above 100°C, e.g. in refluxing toluene,
Lactonization proceeds without acid catalyst.

Lacton formation is conveniently followed by TLC. Alternatively, when R4l is not hydrogen, the monoester of formula W is obtained in step b by selective alcoholysis of the formyl group of the diester.

Methanolysis with potassium bicarbonate or potassium carbonate is useful for this purpose. This intermediate W is prepared in step c by the above-mentioned alkaline hydrolysis or -C-R
It is useful to make triolic acid x either by alkaline alcoholysis for a time sufficient to remove the 4l portion.

The steps shown in Figure C are for 3S diols of formula.

Starting with the 3R diester corresponding to formula when the bond to C-3 is in the beta configuration, the same chemical conversion yields the 3R diols corresponding to formula x. The steps in Figure B yield 2R glycols of formula Xb or Xd to form 3R diols of formula X.

When a 3S formula x diol is desired, an epimerization procedure from any of the 2R glycols to the 2S glycol can be utilized.

For a discussion of the nomenclature of R and s, see, for example, R.S. Chan, J: Chem. Ed. 4l
See Vol. 116 (1964). Note that the designation 2S here refers to the s configuration of C-2, the second carbon of the side chain counting from the ring. Figure D shows the stages in which glycol X is epimerized to glycol XX.

In the glycol river, 2-hydroxy is in the R configuration and 1-hydroxy is in the R or S configuration.

In glycol XX, the 2-hydroxy is in the S configuration and the 1-hydroxy is in the same configuration as x. Thus in Figure D ~ indicates a bond to the side chain of the moiety in either the alpha or beta configuration. Further in Figure D, R43 and R44 are alkyl of 1 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or (1 to 2 halo, or 1 to 4 carbon atoms) phenyl (substituted with alkyl). When R43 is alkyl, it preferably has 3 or more carbon atoms. R43 and R4
4 can be the same or different. For example, when R44 is methyl, R43 can be n-butyl. In formula X, one of Bi and N is hydrogen, and the other is of formula -C(0)-R4
4 is an acyl group. Formula W is U.S. Patent No. 3,711,515
Formula XX includes both glycol Xb and glycol Xd obtained by the method described in Figure B and '
) will be understood to include both glycols Xa and glycols Xc useful in the preparation of diols by the steps of C. Continuing with Figure D, the formula x sulfonate is R4
The formula R43-SO3-Clτ where 3 is defined above
obtained in step a by reaction of the sulfonyl chloride of with glycol X.

To achieve selective activation of the C-2 hydroxyl, R
43 groups contain 3 or more carbon atoms,
For example, n-butyl, phenyl or p-tolyl are preferred. The reaction is carried out with about 3 molar equivalents of sulfonyl chloride in the presence of a tertiary amine. Preferably, a diethyl ether or dichloromethane solvent system containing about 33% by volume of a tertiary amine such as pyridine is used. The reaction is preferably carried out at about 0°C and is generally complete within 5 days as shown by TLC. Diester X is obtained in step b by reaction of an acid anhydride of formula (R44) 20 or an acyl halide of formula R44 halo (where halo is bromo or chloro) with sulfonate x.

Particularly useful for this purpose are acylated compounds in which R44 is alkyl of 1 to 3 carbon atoms, such as acetic anhydride or propionic anhydride. The mixed monoesters are obtained in step c by treating the diester 1x with a 90% aqueous acetic acid solution containing 4 molar equivalents of sodium acetate at 90°C.

The reaction is generally complete in a few hours. R.B. WOOdward et al., J. Am. C
hem. SOc. See Vol. 8O, p. 209 (1958). Finally, glycol XX is obtained in step d by removal of the acyl group.

This is preferably carried out with sodium methoxide in anhydrous methanol followed by quenching in aqueous acetic acid. the ? If 2N sodium hydroxide in methanol/water is used instead, lactone cleavage and hydrolysis of the acyl group occur simultaneously. Acidification to PH3 restores the lactone ring and allows recovery of glycol Xx. The steps shown in Figure D are for 2S glycols j of formula XX. If we start instead with a 2S glycol corresponding to formula
Produces R-glycol. Lactone diol X is converted to PGE2 or PGF2a type compounds by steps known in the art.

E.J. COrey et al., J.
Am. Chem. SOc. Volume 9l, page 5675 (1969
See ). Figure E shows the formula XX[V
PGF2. The compounds and steps leading to the formula XXPGE2 compound are shown. In diagram E, J is a blocking group as defined above, and the quality is either .

J of blocking group is substituted with hydrogen of hydroxyl group,
Any compound that is not as attacked by or reacts with the reagents used in the respective conversion as hydroxyls, and which is replaced by hydrogen in subsequent steps to produce prostaglandin-like products. It is the basis.

Several blocking groups are known in the art.

For example, tetrahydropyranyl, acetyl, and p-phenylbenzoyl (Coli et al., J.A.) M.Ch
em. SOc. 93, p. 1491 (1971)). Those found to be useful are (a) tetrahydropyranyl, (b) tetrahydrofuranyl, or (c
) includes groups of formula.

In the formula, Rl6 is alkyl of 1 to 18 carbon atoms, 3 to 1
cycloalkyl of 0 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or phenyl (substituted with 1, 2, or 3 alkyl of 1 to 4 carbon atoms), Rl7 and Rl8 are the same or different,
hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, or phenyl (substituted with 1, 2, or 3 of alkyl of 1 to 4 carbon atoms), or taking Rl7 and Rl8 together and one (CH2)h- or (CH2)i-0-(
CH2) j-, where h is 3, 4, or 5, i is 1, 2, 3, and j is 1, 2, or 3, but i+j is 2, 3, or 4; with the condition that there is,
and Rl5 is hydrogen or phenyl. When the blocking group is tetrahydropyranyl or tetrahydrofuranyl, suitable reagents such as 2,3-dihydropyran or 2
- Using 3-dihydrofuran in an inert solvent such as dichloromethane in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride.

Reagents are used in slight excess, preferably 1.0 to 1.0 of theory.
Use 2x. The reaction is carried out at about 20-50'C. The blocking group has the formula Rl6-0-C (
Rl7)-CHRl8Rl5, suitable reagents are vinyl ethers, such as isobutyl vinyl ether or those of the formula Rl6-0-C(Rl7)-CRl8Rl5
or any unsaturated cyclic or heterocyclic compound, such as 1-cyclohex-1-
Isomethyl ether 111 or 5,6-dihythro-4-methoxy-2H-pyran [T'].

C.B. Reese et al., J. A
nl. Chem. SOc. , vol. 89, p. 3366 (196
7). The reaction conditions for such vinyl ethers and unsaturates are similar to those for dihydropyran above. Particularly preferred blocking groups J are:
Tetrahydropyranyl and (α-ethoxy)ethyl. Referring to Figure E, compound XX is obtained from compound XX by introducing a blocking group J.

When the blocking group is tetrahydropyranyl or tetrahydrofuranyl, a suitable reagent such as 2,3-dihydropyran or 2,3-dihydrofuran is added to p-toluenesulfonic acid or pyridine hydrochloride in an inert solvent such as dichloromethane. Used in the presence of acid condensing agents such as salts. The reagent is in slight excess, preferably 1.0 to 1 of theory.
．． Used twice. The reaction is carried out at about 20-50°C. When the blocking group is of the formula Rl6-0C(Rl7)-CHRl8Rl5 as defined above, suitable reagents are vinyl ethers, such as isobutyl vinyl ether or formula Rl6-0-C(Rl7)-
CRl8Rl5 (wherein Rl6, Rl7, Rl8 and R
l5 is any vinyl ether (as defined above) or an unsaturated cyclic or heterocyclic compound, such as 1-cyclohex-1-yl methyl ether or 5,6-dihydro-4-methoxy-2H pyran .

Siichi, Biichi, Reese et al., J. Am. Chem. SOc.
See Vol. 89, p. 3366 (1967). The reaction conditions for such vinyl ethers and unsaturates are similar to those for dihydropyran above. Lactol X
is the formula X without reducing the 13,14-ethylene group.
Obtained by reduction of XI lactone.

Diisobutynoleanoleminium hydride is used for this purpose. Preferably, the reduction is carried out at -60 to 70°C. The stereochemistry of the side chain is preserved upon converting to XM and then to.

For example, a 3-alpha compound yields a 3-alpha compound X. The compound of formula x is a suitable ω-carboxyalkyltriphenylphosphonium bromide HOOC-A-CH
It is obtained from formula

Conveniently, the reaction is carried out in dimethyl sulfoxide at about 25°C. Phosphonium compounds are known in the art or are readily available, for example by reaction of omega-bromo fatty acids with triphenylphosphine. Compounds of formula XxnI can be prepared by removing the blocking group J by mild acid hydrolysis using, for example, acetic acid.
GF2.

Converted to compound XXIV. Formula X compounds are converted to formula XX compounds by Johns reagent, which are then converted to PGE2 compounds XXVI by mild acid hydrolysis.

Phenyl-substituted PGEa compounds encompassed by Formula 1 can also be made by other reaction sequences described in Figure F.

This procedure is carried out by steps similar to those known in the art. 1st Class Yishu Koli, J. Anl.
Chem. SOc. See Vol. 9l, p. 5675 (1969). Q in Figure F. M. M(R2, A, and J have the same meanings as defined above.

R5l is methyl or phenyl. Following the invention,
K. Mallion, in South African Patent Specification No. 724372, reported the synthesis of aryl-substituted prostanoic acid derivatives.

Compounds of formula XXVl are obtained by witeinohyalkylation of XXVIl.

A suitable sodium derivative of 2-oxophenyl alkylphosphonate can be used as the Witteitz reagent. Trans-enone lactone can be obtained stereospecifically (D. H. Wadsworth
), etc., Journal of Organic Chemistry (
J. Org. (See ChemO3O, Vol. 680, 1965). To make Formula XX compounds of Figure F, certain phosphonates can be used in the Wittig reaction.

These are general formulas.

where Q is as defined above and R52 is 1-8
alkyl of 5 carbon atoms, especially methyl. Phosphonates are made and used by methods known in the art. See above cited references in Wadsworth et al. Conveniently, a suitable phenyl-substituted fatty acid ester is condensed with dimethylmethylphosphonate in the presence of n-butyllithium. For this purpose, acids of the general formula Q-COOH are used in the form of their lower alkyl esters, preferably methyl or ethyl esters. For this purpose, methyl esters are readily prepared from acids by reaction with diazomethane. Fatty acids of various chain lengths with phenyl substitution within the range of Q defined above are known in the art or can be made by methods known in the art. Instead,
Sodium derivatives of phosphoranes of the formula where Q is as defined above can be used in the reaction.

These phospholanes are made and used by methods known in the art. A suitable ketone compound of the formula Q-CO-CH2-halo is condensed with triphenylphosphine and the condensation product is treated with an alkali to form the desired phosphorane compound. It is convenient.

Haloketone starting compounds are made by known methods. For example, reaction of an organic halide corresponding to a Q minus methylene group with an epihalohydrin yields a Q-CHCH2 halo, which is then oxidized with Johns' reagent to form the starting haloketone compound. Continuing with Figure F, compounds of formula XX[X are obtained as a mixture of alpha and beta isomers by reduction of XXVl.

This reduction uses ester or acid groups or any of the known ketonic carbonyl reducing agents that do not reduce carbon-carbon double bonds when such reduction is undesired. Examples of these are metal borohydrides, especially sodium, potassium, and zinc borohydrides, lithium (tri-tert-butoxy) aluminum hydride, metal trialkoxyborohydrides such as sodium trimethoxyborohydride, lithium borohydride, diisobutylaluminum hydride. , and when reduction of carbon-carbon double bonds is not a problem, boranes such as dicyamylborane. For the preparation of PG-type compounds of natural configuration, the desired 15-
The alpha type was determined by silica gel chromatography.
-separated from the beta isomer.

Compounds of formula
For example, bis(tetrahydropyranyl) ether Obtained by reaction.

Dihydropyran is added in excess, preferably from 4 to 10
Used in double doses. The reaction usually takes place at 20-30°C.
Will it end in 0 minutes? Lactol X is obtained by reduction of the formula XXl lactone or its 15β epimer without reduction of the 13,14-ethylene group.

Diisobutylaluminum hydride is used for this purpose. Preferably, the reaction is carried out at -60° to -70°C. The 15β epimer of formula XM lactone is readily obtained by the steps in Figure F using the 15β isomer of formula XX[X. Compounds of formula XXIn can be prepared in a Witteitsch reaction using a Witteitz reagent derived from the appropriate ω-carboxyalkyl triphenylphosphonium bromide, HOOC-A-CH2-P(C6H5)3Br, and sodium dimethylsulfinylcarbanide. It is obtained from the formula lactol.

It is convenient to carry out the reaction at about 25°C. This formula
The xIn compounds serve as intermediates to create PGF2a type or PGE2 type products (Figure E). Phosphonium compounds are known in the art or are readily available, for example by reaction of ω-bromo fatty acids with triphenylphosphine. The invention will be more fully understood from the following Preparations and Examples.

All temperatures are in degrees.

Infrared absorption spectrum is PerkinElmer model 42
1 infrared vector photometer.

Unless otherwise specified, undiluted (raw) samples are used. NMR spectra were recorded on a Varian A-60 spectrophotometer with deuterochloroform solutions using tetramethylsilane as internal standard (downfield).

Mass spectra were obtained using a TO-4 light source (ionization voltage 70ev).
) using an Atlas CH-4 mass spectrometer or using trimethylsilylated derivatives.
Recorded by an OB high-resolution mass spectrometer.

Chromatographic eluent fraction collection begins when the eluent front reaches the bottom of the column.

[Brine] herein refers to a saturated aqueous solution of sodium chloride. The A-solvent system used in thin layer chromatography (TLC) was developed by M. Hamber.
g) and B.Samuelson.
), J. BlOl. Chem. Volume 24l, page 257 (19
66) from ethyl acetate-acetic acid-2,2,4-trimethylpentane-water (90:20:50:100).

The ultraviolet spectra were recorded with a Cali Model 15 spectrophotometer.

[Skerisolve B] refers to mixed isomer hexanes. As used herein, silica gel chromatography refers to elution, collection of fractions, and collection of fractions shown by TLC (thin layer chromatography) to contain the desired product free of starting material and impurities. Understood as including fitting together.

Preparation Example 1 (3-Bromopropyl)benzene 597.37 and triphenylphosphine 7 in 1500 ml of (3-phenylpropyl)triphenylphosphonium bromide toluene
The solution of 867 is heated to reflux under nitrogen for 16 hours, then the mixture is cooled and the solid product is separated by filtration.

The solid was then slurried with toluene in a Warring blender, separated by filtration, and dried under vacuum at 70°C for 18 hours to yield (3-phenylpropyl)triphenylphosphonium bromide 10687. arise. Melting point 210.5-211.5°C o Preparation Example 2 (4-phenylbutyl)triphenylphosphonium bromide A. 4-Phenyl-1-butanol.

200 ml of 4-phenylbutyric acid in 1500 ml of anhydrous ether
The solution of 7 is added with stirring to a suspension of 46.3 y of lithium aluminum hydride in 1800 ml of anhydrous ether at a rate sufficient to maintain a gentle reflux while cooling the mixture in an ice bath. 15 minutes after the end of the addition, the mixture is carefully treated under nitrogen with 93 ml of water and then with 74 ml of 10% aqueous sodium hydroxide solution. The mixture was stirred at about 25°C for 18 hours, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-phenyl-1.
- yields butanol 1717. Infrared absorption is 3250
1298011610, 10601103017501
and 700? -10 NMR peaks are 7.30 (singlet), 3.61 (trifret), 2.65 (multiplet) and 2.75 (singlet) δ0b
．． (4-bromobutyl)benzene.

Phosphorus tribromide (40.5 mO) is added dropwise to 4-phenyl-1-1-butanol 1717 with cooling to maintain a temperature between 0°C and -5°C. The mixture is heated at 25°C for 16
Let stand for an hour and pour into a mixture of ice and aqueous sodium bicarbonate. The mixture is extracted with hexane and the extracts are washed with water, aqueous sodium bicarbonate, brine, dried over sodium sulfate, and concentrated under reduced pressure to yield (4-bromobutyl)benzene 1967. Distilling this yields 145.27
will occur.

The boiling point 103-103.5°C/16m7n0 NMR peaks are 7.19 (multiplet), 314 (triflet) and 2.45δ0c. (4-phenylbutyl)-
Triphenylphosphonium bromide. toluene 350
A solution of (4-bromobutyl)benzene 1457 and triphenylphosphine 1797 in m1 is heated to reflux under nitrogen for 16 hours. The mixture is then slowly cooled and ether is added resulting in the precipitation of the title compound. This is thoroughly washed with benzene/ether and dried at 50° C. under reduced pressure for 18 hours. 2687, mp 139-140'CO Preparation Example 3 (2-Phenylethyl)triphenylphosphonium bromide Following the procedure of Preparation Example 1, but using an equivalent amount of (2-bromoethyl)benzene instead of (3-bromopropyl)benzene. , the title compound is obtained.

Preparation Example 4 (2,2-dimethyl-3-phenylpropyl)triphenylphosphonium bromide A. (3-furomo-2,2-dimethylpropyl)benzene - Preparation Example 2b
(3-bromo-2,2-dimethylpropyl)-benzene is can get.

B. (2,2-dimethyl-3-phenylpropyl)triphenylphosphonium bromide - Following the procedure of Preparation Example 1, but replacing (3-bromopropyl)benzene with an equivalent amount of (3-bromo-2,2dimethylpropyl)benzene. The title compound is obtained using

Preparation Example 5 (2-Carboxyethyl)triphenylphosphonium bromide 3-bromopropionic acid 507, triphenylphosphine 85.87, and acetonitrile 250m
The mixture of 1 is heated under reflux for 23 hours and then 166 ml of acetonitrile are removed by distillation.

After cooling the remaining solution to room temperature, 250 ml of benzene are added and the mixture is left to stand for 16 hours. The solid that precipitates out is removed by filtration to yield the title compound 120.57.
Melting point 197-200; infrared absorption 2900, 261
01254011745, 162011585, 148
5, 1435, 1385, 1325, 12301111
017501725, and 690 (1-JMoV!-10
NMR peaks are 2.7-3.3 (broad range), 3.5-4
, 2 (broad range), and 7.6-7.9 (multiplet) δ.

Preparation Example 6 (a) (4-carboxybutyl)triphenylphosphonium bromide (b) (6-carboxyhexyl)
Triphenylphosphonium bromide (c) (8-carboxyoctyl)triphenylphosphonium bromide Following the procedure of Preparation Example 5, but instead of 3-bromopropionic acid, equivalents of (a) 5-bromopentanoic acid, (b) 7
-promoheptanoic acid, and (c) 9-promononanoic acid, the title compounds (a), (b) and (c) are obtained.

Preparation Example 7 3α-benzoyloxy-2β-carboxaldehyde-5
α-Hydroxy-1α-cyclopentaneacetic acid γ-lactone (Formula XX; R5l is phenyl) See Figure F.

1. levorotatory (-) in 135 ml of pyridine dry under nitrogen
3α-hydroxy-5α-hydroxy 4-iodo-2β
-Methoxy-methyl-1α-cyclopentaneacetic acid γ-lactone (I. Xu. Colli et al., J. Anl. Che
m. SOc. Volume 92, page 397 (1970)) 757
30.4 ml of benzoyl chloride are added to the mixture with cooling to maintain the temperature at about 20-400°C.

Continue stirring for another 30 minutes. Approximately 250 ml of toluene are added and the mixture is concentrated under reduced pressure.

The residue was dissolved in ethyl acetate, 11% sulfuric acid, brine,
Wash with saturated aqueous sodium bicarbonate solution and brine. The ethyl acetate solution is dried over sodium sulfate and concentrated under reduced pressure to produce oil 957. Crystallization of the oil yields the corresponding 3α-benzoyloxy compound. Melting point 84
~86°C: [α]. +7 (CHCl3); infrared spectral absorption is 1768, 1722, 1600, 1570
, 1490, 1275, 1265, 1180, 1125
, 10011060110301 and 710crrL
0NMR (nuclear magnetic resonance) peak is 2.1~. 45,
3.3, 358, 4.38, 5.12, 5, 51, 7.
18-7.58, and 7.83-8.05 δ02. The iodo group is removed as follows.

Approximately 60 watts of 2.2/-azobis-(2-methylpropionitrile) are added to a solution of the above benzoyloxy compound 607 in 240 ml of dry benzene. The mixture is cooled to 15 DEG C. and a solution of tributyltin hydride 757 in 600 ml of ether is added to it with stirring at such a rate as to maintain a sustained reaction at about 25 DEG C. When the reaction is complete as shown by TLC, the mixture is concentrated to an oil under reduced pressure. Mix the oil with 600 ml of Skellisolve B and 600 ml of water and stir for 30 minutes. The aqueous layer containing the product is separated and then combined with 450 ml of ethyl acetate and an amount of solid sodium chloride sufficient to saturate the aqueous phase. The ethyl acetate layer, which now contains the product, is separated, dried over magnesium sulfate, and concentrated to an oil under reduced pressure. Compound 397 that does not contain iodine. The analytical sample gives [α]D-99 (CHCl3). Infrared spectrum absorption is 1775, 1715, 160011585
, 149011315, 1275, 1180, 1110
, 1070, 1055, 1025, and 715 cm-
1: NMR peaks are 2.5-3.0, 3.25, 3
．． 34, 4.84~5.175.17~5.47.1~
7.5O●-) Rumor●) and 7.8~805δo The peaks in the mass spectrum are 2901168, 105, and 77
o{ 2β-methoxymethyl compound is converted to hydroxymethyl compound as follows.

Cold (0.5 m
g) A solution of 24.8 ml of boron tribromide in 320 ml of dichloromethane is added dropwise to the solution over 50 minutes with vigorous stirring at 0.about.5 m. Continue stirring and cooling for 1 hour. When the reaction is complete as shown by TLC, a solution of sodium carbonate (787, monohydrate) in 200 ml of water is added. Mixture at O~5, at 10~15
Stir, saturate with sodium chloride, and separate the ethyl acetate layer. Combine the additional ethyl acetate extract of the aqueous layer with the main ethyl acetate solution. Wash the combined solution with salt water,
Dry over sodium sulfate and concentrate under reduced pressure to an oil of 18.17% of the 2β-hydroxymethyl compound. The analytical sample had a melting point of 116-118°C; [α]D8OO (CHC
l3) ; Infrared spectrum absorption is 346011735
, 1708, 160011580, 1490, 1325
, 1315, 128011205, 1115, 1090
, 1070, 1035, 1025, 7301 and 72
00NMR peaks are 2.1-3.0, 3.58, 4,
83-5.12, 5.2-5.45, 7.15-7.5
5 and 7.8-80δ04. The title 2β-carboxaldehyde compound is made as follows.

150 ml of dry dichloromethane and Collins reagent (JC Collns et al., Tetrahedron Letters No. 3363 (1968) 28
7) to the mixture of dichloromethane under nitrogen at about 10 3
A cold (10) solution of the above hydroxymethyl compound 5.07 in 50 ml is added with vigorous stirring.

After stirring for another 5 minutes, add approximately 100ml of dry benzene.
is added, the mixture is filtered and the solution is concentrated under reduced pressure. Bring up the volume to approximately 150ml with benzene. A solution of the title compound is used directly. In repeated experiments, Collins' reagent was made on the spot and similar results were obtained. The procedure of Preparation Example 7 was followed, but instead of the optically active iodolactone, the corresponding racemic compound (Il.
hem. SOc. 9l, p. 5675 (1969)) to obtain the racemic compound for formula XX.

Preparation Example 8 To a solution of 115.57 of dimethyl 2-oxo-4-phenylbutylphosphonate in 2.111 of tetrahydrofuran was added 65.5% of dimethyl 2-oxo-4-phenylbutylphosphonate in hexane.
- 660 ml of a 1.6M solution of butyllithium are added, followed by a solution of 93.57 ml of ethylhydrocinnamate in 225 ml of tetrahydrofuran.

Stir the mixture at -65 Na for 2 hours, then at 25. Continue stirring for 16 hours. 70 ml of acetic acid are added, the solution is concentrated under reduced pressure and the residue is partitioned between methylene chloride and water. The organic layer is dried, concentrated and distilled over 2 mm to yield the title compound 121.57. Boiling point 184-195℃
, mass spectrum 256 (M+). Preparation Example 9 Dimethyl 3,3-dimethyl-2-oxo-4-phenylbutylphosphonate 1. To a solution of 101.27 ml of diisopropylamine in 125 ml of tetrahydrofuran at 0.00 m under nitrogen is added a solution of n-butyllithium in 625 ml of hexane and then 44 y of isobutyric acid.

Stir the mixture for 90 minutes at 00, then -15. benzyl chloride while keeping the temperature below -5°C.
Add m1. The mixture is stirred with 25 salt for 4 hours, then diluted with ether and washed with cold diluted hydrochloric acid. The organic phase is washed with brine, dried, concentrated and distilled to yield 2,2-dimethyl-3-phenylpropionic acid 487. 2. 1st
Part product 487 and thionyl chloride 827 are heated for 2 hours, then the mixture is concentrated, 50 ml of benzene is added, the mixture is concentrated and distilled to yield 2,2-dimethyl-3-phenylpropionyl chloride 4827. .

3 600 ml of tetrahydrofuran at -75 under nitrogen
1.6 in hexane while keeping the temperature below -55 °C.
Add 312 ml of Mn-butyllithium.

A solution of 2,2-dimethyl-3-phenylpropionyl chloride (Part 2, 4827) in tetrahydrofuran is added keeping the temperature below -60°C. The mixture is stirred at that temperature for 2 hours, then the temperature is allowed to rise to 25° C. and the mixture is stirred at this temperature for 16 hours. Acetic acid 2
0 ml is added, the mixture is concentrated and the residue is shaken with a mixture of diethyl ether-methylene chloride (3:1 v/v) and a cold dilute solution of sodium bicarbonate. Separate the organic layer, wash with brine, dry and concentrate. Crystallization of the residue from diethyl ether gives the title compound 62
7. Melting point 48-51, NMR peak 7.2
, 3.83, and 3.64, 3.28 and 2.9, 2.8 and 1.13δ.

Examples 1 to 12 below are shown in Figure B. C. This exemplifies the production of the compounds shown in D and E. Example 1 Endo-6-(4-phenylcis-1-butenyl)-exo-13-hydroxybicyclo[3.1.0]-hexane-
Exo-2-monoacetic acid, γ-lactone (formula: Q is -(CH2)
2C6H5) See Figure B.

Benzene 1,21f! Among them, endo-6-formyl-exo-3-hydroxy-bicyclo of lactonealdehyde [
R.C. Kelly
) et al., J. Anl. Chem. SOc. Volume 95 2746
(1973)) 1007. (3-Phenylpropyl)triphenylphosphonium bromide and benzene 31 are placed separately in separate flasks and 685 ml of a 15% solution of n-butyllithium in hexane is added dropwise at medium speed while stirring.

Stir the orange mixture for 15 hours after the addition is complete. After stopping the stirring, let the mixture settle, suck up the supernatant liquid, and add it to the benzene solution of lactone aldehyde at a rate of 800ml to 1000ml per hour while stirring.
Add at a rate of m1 until the red color persists. The progress of the reaction is checked by TLC and once the reaction is complete, the solution is concentrated and chromatographed on a silica gel column packed with 5% ethyl acetate in Scherisolve B (SSB).
Elution is carried out as follows. (1) 5% ethyl acetate in SSB 411 (2) 10% ethyl acetate in SSB 41, (
3) 10% ethyl acetate 61 in SSB, (4) 15% ethyl acetate 61 in SSB, and (5) 25 in SSB.
% Ethyl Acetate 810 Fractions (3), (4), and (5) containing the desired compound are combined and concentrated to yield the title compound 155V as an oil. IR absorption is 17
75, 160011495, 1230, 1175, 10
45, 1030, 9201745, 700c7n-1,
NMR peaks (CDCl3) are 7,08, 5.6, 4
．． 8, 4.4, 2.2-2.7, 1,92, 1.2-1
．． 58δo Following the procedure of Example 1, but using instead of the optically active tricyclic aldehyde lactone a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained. Example 2 Endo-6-[1(R)・2(S)-dihydroxy-4
-phenylbutyl]1-exo-13-hydroxybicyclo[3.1.O]-hexaneexo-2-monoacetic acid, γ-lactone (Formula X; Q is 1(CH2)2C6H,) See Diagram B.

To a solution of 155 V of the formula product of Example 1 in 500 ml of acetone and 50 ml of water was added 2.5 V of tetrahydrofuran.
Osmium tetroxide in m1 250 &! Add. A solution of N-methylmorpholine oxide hydrate 947 in 200 ml of acetone and 314 ul of water is added to the reaction mixture with stirring while maintaining the reaction temperature at 25 ml, and the mixture is stirred at that temperature for 6.5 hours and checked by TLC. Terminate the reaction as expected. The mixture is concentrated under vacuum in a 40 cup bath to remove most of the acetone. The residue is acidified with 10% hydrochloric acid to a pH of 3-4 and then extracted with ethyl acetate. The extract is washed with brine, dried and evaporated under reduced pressure. The residue is dissolved in methylene chloride and then chromatographed on a silica gel column packed with 60% ethyl acetate in Scherisolve B (SSB). Elution is carried out with ethyl acetate and SSB as follows. (1) SSB
60% ethyl acetate in (2) 80% in SSB
Ethyl acetate 1511 (3) 80% ethyl acetate in SSB 281, ((1) 80% ethyl acetate in SSB 41?,
(5) 80% ethyl acetate in SSB 81, Obi (6) 10% methanol in ethyl acetate 3510 fractions (
The title compound 887 is recovered from 3). Infrared absorption is 3430, 17601160011495145014
1513601335, 1295, 1260, 1230
1 1185, 1095, 10301925, 750170
5; NMR peak is (CDCl3)7,2,4.75
, 365, 2.5-3.1, 10-2.5δ and mass spectrum peaks are 302, 18011501149
, 121, 108, 1079392, 91, 790 Following the procedure of Example 2, but using instead of the optically active tricyclic lactone a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained. It will be done.

Example 3 Endo-6-[1(R)・2(S)-dihydroxy-4
-phenylbutyl ethyl orthopropionate] monoexo-13-hydroxybicyclo[3.1.0]-hexane-exo-2-monoacetic acid, r-lactone (formula M; Q is mono(C
H2) 2C6H5; R4l and R42 are -C2H5) Diagram B
See.

The β-glycol Formula X product 887 of Example 2 is dissolved in benzene 11 and then evaporated under vacuum. The residue contains 87 ml of triethylorthopropionate and 1 ml of benzene.
1 is added and then approximately 250 me of benzene is removed by evaporation under vacuum. 0.6y of pyridine hydrochloride is added and the mixture is left at 25°C for about 1 hour. Three drops of triethylamine are added and the reaction mixture is then evaporated under vacuum to yield the title compound 1107 as an oil. The title compound was prepared with an R of 0.57 on silica gel prespotted with triethylamine and developed in 50% ethyl acetate-cyclohexane.
It has an f value. Following the procedure of Example 3, but using instead of the optically active tricyclic lactone glycol a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained.

Example 4 3α-(formyloxy)-5α-hydroxy 2β-[(
3S)-3-propionyloxy-5 phenyl-trans-1-pentenyl] 1α-cyclopentaneacetic acid, γ-lactone (formula; Q is 1(CH2)2C6H5, R4l is -
C2H5) See Figure B.

440 ml of formic acid is stirred with 88 ml of acetic anhydride for 20 minutes. Flush the flask with dry nitrogen and cool to ca.
The crude cyclic orthopropionate Formula M product 1107 of Example 3 is then quickly poured into vigorously stirred formic acid and rinsed with about 40 ml of methylene chloride. Stirring is continued for 4 minutes, then sodium hydroxide (1N, 600ml) is added.
Pour the mixture into brine 1.5. dilute with e and extract with methylene chloride. The extract is washed with a saturated aqueous solution of sodium bicarbonate and then with brine. The mixture is dried and concentrated to yield an oil.
NMR peaks (CDCl3) are 7.87, 7.1,
5.5, 4.6-5.3, 2.2 and 1.10 This oil is used without purification in the following examples. Following the procedure of Example 4, but using instead of the optically active cyclic lactone orthopropionate a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained. Example 5 3α・5α-dihydroxy-2β-[(3S)3-hydroxy-5-phenyl-trans-1-pentenyl]-1
α-Cyclopentaneacetic acid, triolic acid (formula r: Q is one (CH2)2C6H5) See Figures B and C.

The crude lactone product of Example 4 was mixed with 875 ml of methanol, then 875 ml of 1N sodium hydroxide was added,
Stir the mixture for 1 hour at 25°C. The mixture is concentrated to about 900 ml in a 400 bath under reduced pressure. The mixture is then saturated with sodium chloride and cooled to approx. Cover the aqueous solution with ethyl acetate and stir constantly to cool the P.
Gradually acidify with 10% phosphoric acid to H5. Separate the phases and extract with ethyl acetate. The aqueous phase is covered again with ethyl acetate and further acidified to PH4 with 10% phosphoric acid. Separate the phases and extract again with ethyl acetate. The combined organic extracts are washed with brine, dried, filtered and concentrated on a rotary evaporator until crystallization is fully initiated. Mixture -10
Freeze at 0 for 16 hours. The crystals are filtered, washed with cold ethyl acetate Scherisolve B (3:1), and dried under vacuum at 500 °C to yield the title compound 57.5y. Melting point 125
~127℃. IR absorption (maru) is 339013260,
2730126601263011710, 1600,
1495, 135011340, 1305, 1275,
1240, 1195, 1125, 1075, 10501
1035, 995, 970, 965, 94017501
700 礪-1.

Following the procedure of Example 5, but using instead of the optically active lactone a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained.

·Example
63α・5α-dihydroxy-2β-[(3S)3-hydroxy-5-phenyl-trans-1-pentenyl]-
1α-cyclopentaneacetic acid γ-lactone (formula; Q is -(
CH2) 2C6H5) See Figure C.

Crystalline triolic acid obtained in Example 5 (14.47)
To a flask containing 450 ml of chloroform and 5 ml of a saturated solution of pyridine hydrochloride in methylene chloride are added.
Stir the mixture and check that the lactone formation is complete.
LC (acetic acid:methanol-lichloroform-10:10:
Heat to reflux until 80) is indicated. The mixture is then cooled to room temperature. The title compound is not isolated and the crude product is used directly in the next example. Its melting point is 51-53°C. IR
Absorption (maru) is 332011765, 1665, 162
5, 160011495, 116011085, 106
011040, 1000, 970, 700C! ! L-1
. Following the procedure of Example 6, but using instead of the optically active triolic acid a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained. Example 7 3α・5α-dihydroxy-2β-[(3S)-3-hydroxy-5-phenyl-trans-1-pentenyl]-
1α-cyclopentaneacetic acid, γ-lactone, 4・3′-
Bis(tetrahydropyranyl) ether (formula W; Q is -
(CH2)2C6H5, J is tetrahydropyranyl and -C- is -C)
u See Figure E.

25 to the product of Example 6 with 50 m of dihydroxypyran.
1 and a saturated solution of pyridine hydrochloride in 5 ml of methylene chloride are added.

The mixture is stirred for 25 minutes until the formation of bis-tetrahydropyranyl ether is complete as checked by TLC (50% ethyl acetate, Quelisolve B). The reaction mixture is washed with saturated sodium bicarbonate solution, then with brine, dried, filtered and the liquid is concentrated under vacuum. Oil 347 is obtained. IR absorption is 1775, 1440, 1425, 1
335, 1195, 1150, 1120, 1070, 1
030, 1015, 970, 910, 900, 865,
815, 755, and 705 cm−1. Following the procedure of Example 7, but using instead of the optically active lactone a racemic mixture of that compound and its mirror image, the corresponding mixture is obtained. Example 83α・5α-dihydroxy-2β-[(3S)-13-hydroxy-5-phenyl-trans-1-pentenyl]-1α-cyclobentane-acetaldehyde-γ-lactol, 4,3′-bis(
tetrahydropyranyl) ether (formula; Q is one (CH2
)2C6H5, J is tetrahydropyranyl and -C is -C)1' See Figure E.

To a solution of the product 347 of Example 7 in 150 ml toluene at -50C is added diisobutylaluminum hydride (10% solution in 150 ml toluene) over 15 minutes. The reaction mixture is stirred for an additional 10 minutes until the reaction is complete as checked by TLC (50% ethyl acetate-cyclohexane). The reaction mixture is removed from the cooling bath and a mixture of 60 ml of tetrahydrofuran and 60 ml of water is added slowly over 10-15 minutes. Stir until the mixture reaches room temperature. Filter the mixture and wash the filter cake with benzene. The filtrate is washed with brine, then dried and concentrated under vacuum. An oily lactol product 31f is obtained. IR absorption is 340-0,
1440, 13401120011175, 1120,
107011020, 9701870, 815, 735
, and following the procedure of 700CTIL-1 Example 8, but
Instead of an optically active compound, a racemic mixture of that compound and its mirror image is used to obtain the corresponding racemic mixture.

Example 9 17-phenyl-18,19,20-trinol-PG
F2.

・11,15-bis(tetrahydropyranyl) ether (formula XXnI; Q is -(CH2)2C6H5, J is tetrahydropyranyl, C- is -C, .R2 is H, .A is 1(CH2)3- ) See Figure E.

The oily lactol product of Example 8 (317) is dissolved in 35 ml of dimethyl sulfoxide. Separately, 320 ml of dimethyl sulfoxide was added with sodium hydride (
189f, 50% dispersion) with stirring and heat the mixture to react at 60-700 until the reaction is complete. The reaction mixture was cooled to 10°C, and carboxybutyltriphenylphosphonium bromide (Preparation Example 6, 87
y), while keeping the temperature below 35°C, forms a Witteig reaction solution. This solution was heated to 15°C.
cool to 150°C and then add the lactol solution dropwise over 15 minutes, maintaining the temperature between 15-300°C. The reaction mixture is stirred, mixed with 800 ml of benzene, cooled by adding ice, and then a solution of 60 t of potassium hydrogen sulfate in 650 mj of water is added with shaking. Separate the phases, remove the organic (top) phase, wash the aqueous phase with benben,
Combine the organic phases. The combined organic phases are washed with water, dried, filtered and concentrated. The resulting oily product is chromatographed on pickled silica gel 3507. Elution was (1) 33% ethyl acetate in SSB 1.751, (
2) 33% ethyl acetate in SSB 0.251, (3)S
40% ethyl acetate in SB 21, (4) 50 in SSB
% ethyl acetate 0.5. e, (5) 1.5 l of 50% ethyl acetate in SSB, and (6) 2 l of 60% ethyl acetate in SSB. Fractions (3) and (4) yield the title compound 257. Fractions (1) and (2
), and the recrystallized products from fractions (5) and (6) are rechromatographed under the same conditions to yield an additional 2.457 of the title compound. The desired product fractions are combined and concentrated under vacuum at 35-40°C;
26.47 g of pale yellow oil is obtained. NMR
Peaks (CDCl3) 7.2, 6.3, 5.3-5.
7, 4.7, and 3.3-4,2δ. Following the procedure of Example 9, but using instead of the optically active lactol product a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained. Example 10 17-phenyl-18,19,20-trino-PGF
2α (Formula XXIV; Q is 1(CH2)2C6H5, A is 1(CH2)3-) See Figure E.

6.957 ml of the 17-phenyl PGF2a bis(tetrahydropyranyl) ether product of Example 9 was added to 80 ml of acetic acid.
and dilute this solution with 40 ml of water and 4 ml of tetrahydrofuran.

The solution is heated to 40° C. and left at this temperature for 4 hours. The solution was then diluted with 450 ml of brine and 100 ml of chloroform.
Extract 4 times with 1 m aliquot. Combine the first three extracts,
Wash three times with salt water. Backwash the combined brine washes with a fourth chloroform extract. All the chloroform extracts are combined, dried, filtered and concentrated to yield an oil.
The oil is dissolved in methylene chloride and chromatographed on pickled silica gel 1507 packed with 50% ethyl acetate in SSB. Elution is carried out as follows. (1) 500 ml of 50% ethyl acetate in SSB, (2
) 500 ml of 75% ethyl acetate in SSB, (3) 10
0% ethyl acetate 500ml11 (4) ethyl acetate and 2.5
% methanol 250ml (5 ethyl acetate and 2.5% methanol 250ml (6) ethyl acetate and 5% methanol 500ml (7) ethyl acetate and 7.5% methanol 500ml, and (8) ethyl acetate and 10% methanol 500ml 10 fractions ( 5), (6), and (
7) is the desired 17-phenyl PGF2. Title product 1.
yields 9747. Rechromatography of fractions (4) and (8) yields the desired 17-phenyl PG
1.3027 of the F2a title compound is obtained.

The product after evaporation is a very viscous, almost colorless gum.
This is recrystallized from ethyl acetate-SSB. Melting point 79~
80'C, IR absorption (mal) is 3430, 334
0, 2950b1263011695, 1600114
95, 1275, 1245, 110011000197
5,695Cr1L-1. NMR peak (CDCl3
) are 7.2, 5.68, 5.45, and 4.1δ. Following the procedure of Example 10, but with optically active 17-phenyl PG
F2.

Instead of bis(tetrahydropyranyl) ether, using racemic mixtures of that compound and its mirror image,
The corresponding racemic mixture is obtained. Example 11 17-phenyl-18,19,20-trinol-PG
E2, 11.15-bis(tetrahydropyranyl) ether (formula XX; Q is (CH2)2C6H5, J is tetrahydropyranyl C- is -C-, A is one(CH2)3-
)p See Figure E.

17-phenyl PGF2 of Example 9.

Bis(tetrahydropyranino(ha)ether product5.
77 was dissolved in 100 ml of acetone and the solution was diluted to -100
Cool to While stirring the solution and keeping it at this temperature, add John's reagent (5 ml; C in 23 ml of H2SO4).
Mix rO326.7y and make up to 100 ml with water) and add dropwise over 5 minutes. The reaction mixture is stirred for 10 minutes until the reaction is complete as checked by TLC. Next, add 3ml of isopropyl alcohol,
Stir the reaction mixture for an additional 5 minutes. Next, 200ml of water
is added and the reaction mixture is extracted three times with methylene chloride. The combined extracts are washed with brine, dried, filtered and concentrated under reduced pressure. 5.97 g of the title compound as a yellow oil is obtained.
This is used without purification in the following examples. Following the procedure of Example 11, but using 17-phenyl PGF2a bis(
Using a racemic mixture of that compound and its mirror image instead of tetrahydropyranyl) ether, the corresponding racemic mixture is obtained.

Example 12 17-phenyl-18,19,20-trino-PGE
2 (formula XX; Q is one (CH2)2C6H5, C- is -C
- A is 1 (CH2)3-)1゛, see Figure E.

5.97 mL of the 17-phenyl PGE2 bis(tetrahydropyranyl) ether product of Example 11 is dissolved in 60 ml of acetic acid and this solution is diluted with 30 ml of water and 3 ml of tetrahydrofuran.

Heat the solution to 400 °C and leave at this temperature for 4 hours. The solution is then diluted with brine (350 ml) and extracted three times with 75 ml each of methylene chloride. 3. Combine the extracts and wash 3 times with salt water.

The combined methylene chloride extracts are dried, filtered and concentrated. The solution is chromatographed on pickled silica gel 100r packed with 50% ethyl acetate in SSB.
Elution is performed as follows. (1) 50% in SSB
500 ml of ethyl acetate, (2) 500 ml of 60% ethyl acetate in SSB, (3) 500 ml of 80% ethyl acetate in SSB
00me1 (4) 100% ethyl acetate 200m11 (5
) 100% ethyl acetate 100ml (6) 100% ethyl acetate 700ml (7) Ethyl acetate and 5% methanol 300ml (8) Ethyl acetate and 5% methanol 200ml
m11 and (9) ethyl acetate and 10% methanol 50
The 0ml fractions (6) and (7) contain the 17-phenyl PGE2 title compound. Recrystallization of this from anhydrous ether yields 1.23r. Fraction (5). (8). Re-chromatography of
．． Produces 26V. The combined product 1.49r is recrystallized from ethyl acetate-SSB using charcoal. Melting point: 95-96°C, NMR peak (CDCl3): 7.
2, 6.3, 5.6, 5.35, and 4.1δ. Reference example (15R)-15-methyl-17-phenyl 18.19
・20-trinor-PGF2a, methyl ester (15
S)-15-methyl-17-phenyl-18,19,2
0-trinor-PGF2.

, methyl ester 17 in 30 ml of 1,4-dioxane
-Phenyl-PGF2al. 2・3- in a solution of l657
Dichloro5,6-dicyano-1,4-benzoquinone 81
Add 7W9.

The reaction mixture is stirred at 257 for 72 hours under nitrogen atmosphere. Filter the mixture and wash the solid with methylene chloride. Concentrate the solution and mix with ethyl acetate and Scherisolve B (50:50)
Chromatography on pickled silica 1407 packed with Elution was carried out using (1) ethyl acetate and Scherisolve B (5
0:50) 31, (2) ethyl acetate 311 and (3)
31 parts of ethyl acetate and 11 parts of 10% methanol (100
me fraction). Eluent fractions 16-73 were combined and charcoal filtered to give 15-keto-17-
Phenyl-18, 19, 20-trinor-PGF2. l
．． Concentrate to O457. 15- in tetrahydrofuran
Keto-17-phenyl-PGF2. Add 22 ml of hexamethyldisilazane and 5 ml of trimethylchlorosilane to the solution of
is added and the mixture is stirred at 25° C. for 18 hours under nitrogen. Concentrate the solution, dissolve the residue in xylene, filter and concentrate to give an oily product, 17-phenyl 18.19
-Produces 1.6y, a trimethylsilyl derivative of 20-trinor-PGF2a. The oily product was dissolved in diethyl ether 5
0 ml, cooled to 0.0 ml under nitrogen and added 3 M
1.5 ml of ethereal methylmagnesium bromide are added dropwise.

Allow the reaction mixture to warm to room temperature and check by TLC that no ketone remains. The mixture is poured into saturated aqueous ammonium chloride solution and water and extracted with diethyl ether. The organic layer was washed with brine, dried and concentrated to yield 1.67 tertiary alcohols, namely the C-15 epimers (15R)-15-methyl-17-phenyl 18,19,20-trinor PGF2a and (15S )1
5-Methyl-17-phenyl-18,19,20-trinor-PGF2. yields a mixture of The epimer mixture is dissolved in 60 ml of ethanol, diluted with 40 ml of water and stirred for 3 hours at room temperature. The solution is concentrated to remove the ethanol (maximum temperature 35 l), potassium bisulfate is added to the residue and the mixture is then extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated, then esterified with ethereal diazomethane. The product was chromatographed on neutral silica 150y packed with 10% acetone and methylene chloride (1) 10% acetone and methylene chloride 31, (2) 40% acetone and methylene chloride 31
1, and (3) elute using 50% acetone and methylene chloride 21 (100 ml fractions).

When fractions 53 to 58 are combined, (15R)-
15-methyl-17-phenyl-18, 19, 20-
This yields trinol-PGF2O methyl ester 161m9. IR absorption is 3380, 1735, 1600, 149
5, 1455, 1440, 1370, 1225, 117
0, 1155, 1120) 1095, 1060) 1
030, 975, 925, 750) and 705cTn
-1. NMR peak (CDCl3) is 7.19, 5.
75~5.05, 4.30~3.70, 3.62,
1.32δo sustained elution yields the product 220~.

When this is recrystallized from ethyl acetate and Kelisolve B, 15(S)-15-methyl-17-phenyl-1
8.19.20=trinor PGF2d methyl ester 88m9. IR absorption is 3290, 1730,
1600) 1585, 1495, 1315, 1225
, 1175, 1105, 1040, 975, 910, 7
45, 740) and 700C7TL-1. NMR peak (CDCl3) is 7.45-7.10, 5.85
~5.30) 4.30~3.80, 3.68 and 1
．． 38δo The present invention is a method described in the claims, and includes the following aspects.

1. Step c) reacts a glycol with an orthoester to form an optically active cyclic orthoester or a racemate of this ester and its mirror image, and then reacts the cyclic orthoester with formic acid to form an optically active cyclic orthoester. 3. The method of claim 2, which comprises forming a racemate of the diol diester or its mirror image and replacing the acyl group of the diol diester with hydrogen.

2. The method of paragraph 1, wherein the glycol is in the endo configuration.

3. A claim in which step (c) comprises reacting the glycol with formic acid to produce an optically active diformate of the glycol, or a racemate of this compound and its mirror image, and then replacing the formyl group of the diformate with hydrogen. The method described in item 1 of the scope.

4. 4. The method of clause 3, wherein the glycol is in the endo configuration.

5. Step (c) comprises reacting the glycol with an orthoester to form an optically active cyclic orthoester or a racemate of this ester and its mirror image, and then reacting the cyclic orthoester with formic acid to form an optically active cyclic orthoester. 3. The method according to claim 2, which comprises preparing a racemic compound of the diol diester or its mirror image, and replacing the acyl group of the diol diester with hydrogen.

6. 6. The method of clause 5, wherein the glycol is in the endo configuration.

7. A patent in which step (c) comprises reacting a glycol with formic acid to form an optically active diformate of said glycol, or a racemate of this compound and its mirror image, and then replacing the formyl group of said diformate with hydrogen. The method according to claim 2.

8. The method of paragraph 7 above, wherein the glycol is in the endo configuration.

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is lower alkylene, Q is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (This -CtH_2
t- portion is lower alkylene), J is tetrahydropyranyl, and M' is ▲ has a mathematical formula, chemical formula, table, etc. ▼ or ▲ has a mathematical formula, chemical formula, table, etc. ▼ (J
is as defined above)] or a racemic compound of this formula and its mirror image, and the compound is subjected to conversion of the OJ group to a hydroxy group, with the formula ▲ mathematical formula, chemical formula, There are tables, etc. ▼ [In the formula, A and Q are as defined above, and M is ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲ Numerical formula, chemical formula,
There is a table, etc. for the production of the optically active compound of ▼ or the racemic compound of this formula and its mirror image. 2 (a) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, ~ indicates the bond of this part to the cyclopentane ring in the exo or endo configuration] as the formula φ_3P=C
H-Q [In the formula, Q is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where -CtH_2t- is lower alkylene,
φ is phenyl] to form an alkene, (b) hydroxylating the alkene to form a glycol, and (c) converting the glycol to form a bicyclic lactone of S and R configurations. (d) separating the diols in the S and R configurations; (e) replacing the hydrogen of the hydroxyl of the diol with a blocking group to form a bisether; (f) separating the lactone oxo group is reduced to a hydroxy group, and (g) the formula φ_3P=CH-A-COOH [in the formula φ
is as defined above and A represents lower alkylene], (h) oxidizes 9-hydroxy to oxo, and (i
) Consisting of the step of replacing a blocking group with hydrogen to generate a hydroxyl group, there are ▲mathematical formulas, chemical formulas, tables, etc. etc., where A and Q are as defined above] or a racemic compound of this formula and its mirror image.