JPS5838433B2 - Method for producing phenyl-substituted PGF↓2-type compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of producing 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 and prostaglandin F2α (PGF2α) type compounds described in No. 9465 (May 16, 1972).

The phenyl-substituted prostaglandin analogs of Cholera 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 PGF2α type.

and R3 and R4 are hydrogen.

-C tH2 t portion is (a) lower alkylene.

Symbol A represents lower alkylene.

i.e. the side chain hydroxy is S (alpha) or R
Includes separate isomers in the (shrimp or beta) configuration.

Regarding the numbering of prostanoic acid atoms, the point of attachment is C-1
5, these epimers are referred to herein as C-15 epimers, despite the change in the carbon chain from C-1 to C-7.

In all compounds containing a C-13 to C-14 double bond, this carbon-carbon double bond is in the trans configuration, and the chain containing R4 is is attached in the beta configuration to the cyclopentane ring.

Like the natural prostaglandins mentioned above, these phenyl-substituted prostaglandin compounds have several asymmetric centers.

These compounds include (a) compounds with the same steric configuration as naturally occurring prostaglandins, and (bXa
) + its optically active enantiomeric racemic compounds.

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 perform the same reaction.

Phenyl-substituted PGF2α compounds encompassed by formula (1) are prepared by the following reaction.

? A illustrates a reaction system for making tricyclic lactone aldehyde 1 by procedures known in the art.

See US Pat. No. 3,711,515. In this US patent, the reaction sequence for making tricyclic lactone aldehyde ① is as follows.

(a) Optically active or racemic form of formula m (in the formula ~ represents a bond in alpha or beta configuration) [3.
1.O]hex-2-ene-6-carboxaldehyde is converted into an optically active acetanol of formula (1), or its mirror image, or a racemic compound of this formula and its mirror image [in the formula R2
and R22 are alkyl of 1 to 4 carbon atoms, and taken together (where R23, R24, R25, R26, R27 and R28 are hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl) with the proviso that not more than one R/ is phenyl, the total number of carbon atoms is from 2 to 10, X is 0 or 1), and K is as defined above ].

(b) The optically active form or racemic acetal ■ is expressed by the formula ■
into an optically active tricyclic mono- or dino-loketone, or a mirror image thereof, or a racemic compound of this formula and its mirror image, where R21, R22, and ~ are as defined above, and R30 is is bromo or chloro, and R3
1 is hydrogen, bromo, or chloro].

(c) Converting an optically active or racemic tricyclic mono- or dino-loketone (■) 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 [in the formula R2, , R22, and ~ are as defined above; (d) an optically active or racemic tricyclic ketone (■) as an optically active tricyclic lactone acetal (■), or a mirror image thereof, or a combination of this formula and a mirror image thereof; oxidize to the racemate, where R21, R22, and ~ are as defined above.

(e) an optically active or racemic tricyclic lactone acetal (■) as an optically active tricyclic lactone aldehyde of the formula (■);
or a mirror image thereof, or a racemic compound of this formula and its mirror image, where ~ is as defined above.

The bicyclic aldehyde of formula ■ in Figure A exists in a number of 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 one CHO group, each of the Echin type and the Endo type exists in two optically active (d- or 1-) types, resulting in a total of 4 isomers.

Each of these isomers, individually or in mixtures thereof, undergo reactions to produce prostaglandin intermediates and products.

For racemic products, unresolved isomers are used.

For optically active prostaglandins, aldehydes or subsequent intermediate isomers are resolved and used to create optically active bioactive compounds by the method disclosed in US Pat. No. 3,711,515.

To carry out step a, the bicyclic aldehyde (2) is converted to the acetal (2) by methods known in the art.

In this way, aldehyde
or butanol, or their isomeric forms, or mixtures of their alcohols, or preferably the formula? React with glycol.

In the formula, R23, R24, R25, R26, R2, and R
28 is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl, provided that not more than one R is phenyl, and the total number of carbon atoms is 2 to 10, and X is zero or one.

Examples of suitable glycols: ethylene glycol, 1 and 2
-Propanediol, 1,2-hexanediol, ■・
3-7”tanediol, 2,3-pentanediol,
2,4-hexanediol, 3,4-octanediol, 3.5-nonanediol, 2,2-dimethyl-1゜3
-propanediol, 3,3-dimethyl-2,4-hebutanediol, 4-ethyl-4-methyl-3,5-hebutanediol, 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 can be combined with an acid catalyst and a water scavenger such as trimethyl orthoformate, such as benzene, toluene,
Warm to 40-100°C in an inert solvent such as chloroform or carbon tetrachloride.

The ratio of aldehyde to glycol is preferably 1:1 to 1:4.

To convert the acetal (2) to the ketone (2), reactions known in the art for similar compounds are used.

To carry out step b, acetal ■ is converted into ketene R3oR
31C=C=01 e.g. HBrC=C=O, HCI=C
React with =O, Br, C=C=0, or Cl2C1C=O.

For convenience, ketene C1C=C=O is preferred.

This involves adding a 0.5- to 2.0-fold excess of dichloroacetyl chloride in the presence of a tertiary amine such as triethylamine, tributylamine, pyridine, or 1,4-diazabicyclo[2.2.2]octane. Preferably, it is generated in situ by reaction in a solvent such as n-hexane, cyclohexane or a mixture of isomeric hexanes (Skerisolve B) at temperatures between 00 and 70°C.

(For example, Corey et al., Tetrahedron Letters)
rs) No. 4, pp. 307-310, 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, a mono- or dino-loketone is added to a stoichiometric amount of Zn:2C1 in methanol, ethanol, ethylene glycol, etc. in the presence of acetic acid, ammonium chloride, sodium bicarbonate, or sodium dihydrogen phosphate. Reduction is carried out with a 2- to 5-fold excess of zinc powder over stoichiometry.

Alternatively, 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 treated with an oxidizing agent by methods known in the art, for example in the presence of a base such as an alkali hydroxide, bicarbonate, or orthophosphate. and ketone by reaction with hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc. using a preferred molar ratio of 1:1 of lactone and ketone.

To carry out step e, the lactone acetal (2) is converted to the aldehyde (2) by acid hydrolysis known in the art, using dilute mineral acids, acetic acid, or formic acid, etc.

Diagram B shows the reaction sequence for converting tricyclic lactone aldehyde (■) to bicyclic lactone diol (X).

To carry out a, the aldehyde ■ is converted to the formula ■ alkene by a ylide, such as in a Witteitsch reaction.

Certain organic halides, such as chlorides and bromides, are necessary to make Wittig's reagent, which is used to generate the general moiety 1CH1CHQ of the tricyclic ketone.

These organic halites, such as QCH2CH2Cl
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, 1-promo 3-phenylpropane reacts with triphenylphosphine to yield 3-phenylpropane triphenylphosphonium bromide.

To carry out step b, alkene I is hehydroxylated 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, involves the formation of various isomers, depending on factors such as whether the CH═CH moiety in ① is cis or trans and whether a cis or trans hydroxylation reagent is used. Glycols are obtained.

Thus, endocystic olefins 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 are prepared according to the method of the present invention and outlined in Figure B to form the intermediate compound of 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 derived from the various isomeric olefins encompassed by formula (1) are all useful for these same purposes.

To carry out step C, the optically active tricyclic lactone glycol 7-1 substituted with ~3 halogen atoms
aralkyl of 2 carbon atoms and R42 is methyl or ethyl], yields an optically active cyclic orthoester of formula M or a racemate of this formula and its mirror image.

To carry out step d, the cyclic orthoester M is reacted with formic acid to yield an optically active diol diester of formula (1) or a racemate of this formula and its mirror image.

In performing step e, the acyl group of the diol diester ① is replaced with hydrogen to yield the bicyclic lactone diol xm.

Until now, the step of converting glycol X to diol
This is revealed in issue 15.

For example, the glycol hydrogen atom of glycol X is replaced with an alkylsulfonyl group, and the product is subjected to hydrolysis.

Alternatively, the mixture of isomeric glycols

The conversion of glycol

With reference to steps c, d and e of Figure B, it will become clear how this can be achieved.

In step C of Figure B, tricyclic lactone glycol X is converted to cyclic orthoester ■.

Glycol X exists in two erythro and two threo forms.

These various glycols can be utilized by hydroxylation of the corresponding alkenes or alkenines, as disclosed, for example, in the above-referenced US Pat. No. 3,711,515.

Referring to Figure B, the formula M cyclic orthoester has step C
is obtained by reaction of glycol X with an orthoester of the formula where R41 and R42 are as defined above.

The reaction proceeds successfully at temperatures ranging from -50°C to +100°C, although temperatures from 0°C to +50°C are 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 glycol weight, e.g. 1%.
Typical catalysts are pyridine hydrochloride, formic acid, hydrochloric acid,
Includes p-toluenesulfonic acid, trichloroacetic acid, or trifluoroacetic acid.

The reaction is preferably carried out in a solvent such as benzene, dichloromethane, ethyl acetate or diethyl ether.

The reaction is already complete within a few minutes and is conveniently followed by TLC (thin layer chromatography on basic silica gel plates).

Are orthoester reagents known to this technology? or easily obtained by methods known in the art.

For example, starting from a suitable nitrile, S.M. McElvain et al., Journal of the American Chemical Society (J.
of. Am. Chem, Soc. ) Volume 64 19
See page 25 (1942).

Examples of useful orthoesters include:

Trimethyl orthoformate triethylorthoacetate triethylorthopropionate trimethylorthobutyrate 1 ethyl orthovalerate trimethylorthooctanoate trimethylorthophenylacetate, and trimethylortho(2,4-dichlorophenyl)acetate.

Preferred are orthoesters when R4 is alkyl of 1 to 7 carbon atoms.

Particularly preferred are those when R4 is alkyl of 1 to 4 carbon atoms.

The diester of the formula I is obtained in step d by the reaction of the cyclic orthoester of the formula M 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, such as dichloromethane, benzene, or diethyl ether, may be present, 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 1 are obtained in step e by alcoholysis of diesters of formula 1 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 conveniently carried out in an excess of solvolysis reagent, such as 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 R41 and the base.
In the case of alkali carbonates, the reaction proceeds in a few minutes when R41 is hydrogen, but takes up to several hours when R41 is, for example, ethyl.

Referring to Figure C, an alternative route from diester ■ to diol x ■ is shown.

In step a, the diester ■ is hydrolyzed to the triolic acid ■ and 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, but
In the case of alkali hydroxide, there is no need to add water.

Thereafter, the triolic acid It is converted to diol X■ by lactonization.

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 R41 is not hydrogen, the monoester of formula X is obtained in step b by selective alcoholysis of the formyl group of diester II.

Methanolysis with potassium bicarbonate or potassium carbonate is useful for this purpose.

This intermediate X is converted in step C to triolic acid X either by alkaline hydrolysis as described above or by alkaline alcoholysis for a time sufficient to remove the 1C R41 moiety. It is useful for

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

Starting with the 3R diester corresponding to formula ■ when the bond to C-3 is in the beta configuration, the same chemical conversion
3R diols corresponding to (2) are produced.

The steps in Figure B yield 2R glycols of formula xb or Xd to form 3R formula X diols.

When a 3S formula X diol is desired, an epimerization procedure from any of the 2R glycols to 28 glycol can be utilized.

A discussion of R and S nomenclature includes, for example, R.S. Chan, J. Chem. Ed
, Vol. 4, p. 116 (1964).

Note that the designation 28 here refers to the S configuration at C-2, which is the second carbon of the side chain counting from the ring.

Figure D shows the stages in which glycol XVI is epimerized to glycol XX.

In glycol XVI, the 2-hydroxy is in the R configuration and the 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 XVI.

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), or 1 to 4
phenyl substituted with alkyl of 5 carbon atoms.

When R43 is alkyl, it preferably has 3 or more carbon atoms.

R43 and R44 can be the same or different. For example, when R44 is methyl, R45 can be n-butyl.

In Formula XIX, one of Bi and A' is hydrogen, and the other is Formula 1C
(0) R44 is an acyl group.

Glycol xb and glycol
Formula XX encompasses both glycol Xa and glycol
It will be understood that both c.

Continuing with Figure D, the formula X■ sulfonate is R43
obtained in step a by reaction of a sulfonyl chloride of the formula R, 3-SO2-CI, with glycol XVI, where is defined above.

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-}! J le is 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 carried out at about 0° C. and is generally complete within 5 days as shown by TLC.

The diester ■ is in step b an acid anhydride of formula (R44)20, or a formula R44 halo (where halo is bromo or chloro)
is obtained by reaction of the acyl halide with sulfonate X■.

Particularly useful for this purpose are acylating agents in which R44 is alkyl of 1 to 3 carbon atoms, such as acetic anhydride or propionic anhydride.

The mixed monoester X■ is obtained in step C by treating the diester X■ 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. Chem. Soc, vol. 80, p. 209 (1
958).

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.

If 2N sodium hydroxide in methanol-water is used instead, lactone cleavage and hydrolysis of the acyl group occur simultaneously.

Acidification to pH 3 restores the lactone ring and allows recovery of glycol XX.

The steps shown in Figure D are for 28 glycols of formula XX.

If we start instead with a 2S glycol corresponding to formula
Produces R-glycol.

The lactone diol X■ is converted to a PGE2 or PGF2α type compound by steps known in the art.

E.J. Corey
et al., J. Am. See Chem, Soc, 9:1, p. 5675 (1969).

Figure E shows the formula XxIVPGF2 from lactone diol
The steps leading to the alpha compound and the formula XXVI PGE2 compound are shown.

It is not as attacked by or reacts with the reagents used in the respective conversion as hydroxyls, and is replaced by hydrogen in subsequent steps to produce prostaglandin-like products. Any group such as

Several blocking groups are known in the art.

For example, tetrahydropyranyl, acetyl, and p-phenylbenzoyl (Colley et al., J. Am. Ch.
em. Soc, 9 vol. 3 p. 1491 (1971)
).

Those found to be useful are (a) tetrahydropyranyl, (b) tetrahydrofuranyl, or (C) formula ? includes groups.

In the formula, R16 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), and R1 and R18 are the same or different and are hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, or (
phenyl substituted with 1, 2, or 3 alkyl of 1 to 4 carbon atoms, or when R1 and R18 are taken together -(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, with the proviso that i+j is 2, 3, or 4, and R15 is hydrogen or phenyl. be.

When the blocking group is tetrahydropyranyl or tetrahydrofuranyl, a suitable reagent such as 2,3-dihydropyran or 2,3-dihydrofuran is added in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. Used in an inert solvent such as dichloromethane.

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. Formula with blocking group defined above? 16-0 -C(R1)-CHR18R15, suitable reagents are vinyl ethers, such as isobutyl vinyl ether or those of the formula R160C(Rl)=CR18R15, where R16, R1, R18 and R15 are as defined above. or any unsaturated cyclic or heterocyclic compound, such as 1-cyclohex-1-iB,
Reese) et al., J. Am. Chem. So
c. , Vol. 89, p. 3366 (1967).

The reaction conditions for such vinyl ethers and unsaturates are similar to those for dihydropyran above.

Particularly preferred for blocking group J are tetrahydropyranyl and (α-ethoxy)ethyl.

Referring to Figure E, compound XX is obtained from compound X■ by introducing a blocking group J.

When the blocking group is tetrahydrofylanyl 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 an acid condensing agent such as

The reagent is used in a slight excess, preferably 1.0 to 1.
Used twice.

The reaction is carried out at about 20-50°C.

Formula with blocking group defined above? 1a -QC (R17) CHRts R
t 5 , suitable reagents are vinyl ethers, such as inbutyl vinyl ether or those of the formula R16-0 -C (R,.) =CR18R15
or any unsaturated cyclic or heterocyclic compound, such as 1-cyclohex-1-yl methyl ether or 5,6- It is dihydro-4-methoxy-2H pyran.

C.B. Reese et al., J. Am. Chem,
See Soc, Vol. 89, p. 3366 (1967).

The reaction conditions for such vinyl ethers and unsaturates are similar to those for dihydropyran above.

Lactol (2) can be obtained by reduction of the lactone of formula XX without reducing the 13,14-ethylene group.

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, 3-alpha compound (1) yields 3-alpha compound (2).

The compound of formula
It is obtained from the 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.

Formula xxm compounds are converted to the corresponding PGF2α compounds xxrv by removal of the flocking group J by mild acid hydrolysis using, for example, acetic acid.

The formula xxm compound is converted to the formula XX'v compound by Jones reagent, which is then converted to the PGE2 compound XX' by mild acid hydrolysis.

Phenyl-substituted PGFα 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.

E.G. Collie et al., J. Am. Chem,
Soc. 9, Vol. 1, p. 5675 (1969).

? In F Q, M, yrz R2, A, and J have the same meanings as defined above.

R5 is methyl or phenyl.

Following the invention, K. Malli
on) in South African Patent Specification No. 724372,
We reported the synthesis of aryl-substituted prostanoic acid derivatives.

Compounds of formula XX■ are obtained by Wittig alkylation of xxvn.

A suitable sodium derivative of 2-oxophenyl alkylphosphonate can be used as the Witteitz reagent.

Trans-enone lactone is obtained stereospecifically (D. H. Wadsworth).
), etc., Journal of Organic Chemistry (J. Org. Chem, ) Volume 30, 68
(see p. 0 (1965)).

To make the formula xxvnr compounds of Figure F, certain phosphonates can be used in the Witteig reaction.

These are general formulas belongs to.

Q in the formula is as defined above? and R5 is alkyl of 1 to 8 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.

Alternatively, 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.

Formula Q-CO-CH2 halo [in the formula, halo is chloro, bromo,
It is convenient to condense a suitable ketone compound (or iodine) with triphenylphosphine and treat the condensation product with an alkali to produce the desired phosphorane compound.

Haloketone starting compounds are made by known methods.

For example, reaction of the organic halide corresponding to the Q minus methylene group with epihalohydrin yields OH 1 halo, which is then converted into Jones Q -CH
Oxidation with a CH2 reagent creates the starting haloketone compound.

Continuing with Figure F, the formula plate compound is obtained as a mixture of alpha and beta isomers by reduction of XX■.

This reduction employs any of the known ketonic carbonyl reducing agents that do not reduce ester or acid groups or carbon-to-carbon double bonds when this is not desired.

Examples of these are metal borohydrides, especially sodium,
Potassium, and borohydride of zinc, 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, formula XXIX
The desired 15-alpha form of the compound is separated from the 15-beta isomer by silica gel chromatography.

The compound of formula XXI is then treated with an alkali metal carbonate such as potassium carbonate in methanol at about 25°C.
can be obtained by deacylating and subsequently introducing a blocking group to produce compound XM.

For example, bis(tetrahydropyranyl) ether XXI is obtained by reaction of dihydropyran in an inert solvent such as dichloromethane in the presence of an acid condensing agent such as p-}luenesulfonic acid or pyridine hydrochloride.

Dihydropyran is added in excess, preferably from 4 to 10
Used in double doses.

The reaction is usually completed in 15 to 30 minutes at 20 to 30°C.

Lactol X■ is obtained by reduction of the formula XX[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.

Formula XX [15β mono-epimer of lactone is 15β of formula n■
It is easily obtained by the steps in Figure F using the isomers.

Compounds of formula
It is obtained from the formula lactol by the Witteitz reaction using CH2-P(C6H5)Br, and Witteitz's reagent derived from sodium dimethylsulfinylcarbanide.

It is convenient to carry out the reaction at about 25°C. This formula x
The xm compound is a PGF2α type or PGE2 type product (Figure E
) is useful as an intermediate in the production of

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 by the following Preparations and Examples.

All temperatures are in Mr. Setsu's degrees.

Infrared absorption spectrum is PerkinElmer model 42
1 recorded by an infrared spectrophotometer.

Unless otherwise specified, undiluted (raw) samples are used.

NMR spectra were recorded on a Harian A-60 spectrophotometer with deuterochloroform solutions using tetramethylsilane as internal standard (downfield).

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

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

The term "salt water" as used herein refers to a saturated aqueous solution of sodium chloride.

The A■ solvent system used in thin layer chromatography (TLC) is M. Hamburg (M, Hamberg) and Bee. Samuelsson (B. Samuelsson)
, J, Biol, Chem, 2 4 Volume 1 25
7 (1966), ethyl acetate-2-acetate.
2,4-trimethylpentane) monohydrate (90:20:50
:100).

Ultraviolet spectra were recorded with a Carey Model 15 spectrophotometer.

"Skerinlube B" refers to mixed isomer hexanes.

As used herein, silica gel chromatography involves elution, collection of fractions, and bringing together fractions shown by TLC (thin layer chromatography) to contain the starting material and the desired product free of impurities. It is understood to include matching.

Preparation Example 1 (3-phenylglobil)triphenylphosphonium bromide (3-Flomopropyl)benzene 597.3y in toluene 1500ml I) A solution of phenylphosphine 7862 was heated to reflux under nitrogen for 16 hours. The mixture is then cooled and the solid product is separated by filtration.

The solid is then slurried with toluene in a Waring blender, separated by filtration, and dried under vacuum at 70°C for 18 hours to yield (3-phenylprobyl)trinoenylphosphonium furomide 10685'.

Melting point 210.5-211.5°co Preparation Example 2 (4-phenylbutyl)triphenylphosphonium bromide a. 4-phenyl-1-butanol.

20 4-phenylbutyric acid in 1500 rul of anhydrous ether
0? While stirring the solution, add 1800 rI of anhydrous ether.
The mixture is added to a suspension of 46.3 grams of lithium aluminum hydride in Ll at a rate sufficient to maintain a gentle reflux while cooling in a water bath.

15 minutes after the addition was complete, the mixture was poured under nitrogen with 93 mL of water.
r/Ll and then 10% aqueous sodium hydroxide solution 74r1
Process carefully with ll.

The mixture is stirred at about 25° C. for 18 hours, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 171 fI of 4-phenyl-1-butanol.

Infrared absorption is 325012980, 1610, 1060
11030, 750, and 700crrI. -1.

NMR peaks are 7.30 (singlet), 3.6
1 ( }replet), 2.65 (multiplet)
and 2.75 (singlet) δ.

b, (4-promobutyl)benzene.

Phosphorus tribromide (40.51 rLl) was cooled to maintain a temperature between 0°C and -5°C, then 4-phenyl-1
- Add dropwise to Butanol 1712.

The mixture is left at 25° C. for 16 hours and poured onto a mixture of ice and aqueous sodium bicarbonate.

The mixture was extracted with hexane, the extract was washed with water, aqueous sodium bicarbonate, brine, dried over sodium sulfate,
Concentration under reduced pressure yields (4-promobutyl)benzene 1
962 is generated.

Distilling this yields 1 4 5. 22.

Boiling point: 103-103.5°C/16°C.

NMR peaks are 71.9 (multiplet), 3.1
4(}replets) and 2.45δ.

c, (4-phenylbutyl)-}riphenylphosphonium furomide.

A solution of (4-furomobutyl)benzene 1451 and triphenylphosphine 1792 in 350 TL of toluene is heated to reflux under nitrogen for 16 hours.

The mixture is then slowly cooled and ether is added resulting in a precipitate of the title compound. This is thoroughly washed with benzene/ether and dried under reduced pressure at 50° C. for 18 hours.

268g, melting point 139-140°C.

Preparation Example 3 (2-phenylethyl)trinoenylphosphonium furomide Following the procedure of Example 10 but using an equivalent amount of (2-furomoethyl)benzene instead of (3-bromoprobyl)benzene, the title compound is obtained.

Preparation Example 4 (2,2-dimethyl-3-7enylprobyl)triphenylphosphonium bromide a. (3-furomo2,2-dimethylpropyl)benzene - Following the procedure of Preparation Example 2b, but using an equivalent amount of 2,2-dimethyl-3-phenyl-1-gropanol instead of 4-phenyl-1-butanol, ( 3- Fromo 2
・2-dimethylbucutyl)-benzene is obtained.

b, (2,2-dimethyl-3-phenylpropyl)triphenylphosphonium furomide Preparation Example 10 Procedure was followed, but instead of (3-bromopropyl)benzene, an equivalent amount of (3-bromo-2,2dimethylpropyl) was used. ) Using benzene, the title compound is obtained.

Preparation Example 5 (2-carboxyethyl)triphenylphosphonium bromide 3-promopropionic acid 50S', }rifenylphosphine 85.8P, and acetonitrile 250rIll
The mixture is heated under reflux for 23 hours and then 166 rfLl of acetonitrile is removed by distillation.

After cooling the remaining solution to room temperature, 250 TLl of benzene are added and the mixture is left to stand for 16 hours.

When the precipitated solid was removed by filtration, the title compound 1 was obtained.
yields 20.51.

Melting point 197-2000; infrared absorption 2900,26
10,2540,1745,1620,1585,14
85, 1435, 1385, 1325, 1230, 11
10, 750, 725, and 690crfL”.

The peak of Nagi ■ is 2.7-3.3 (wide area), 3.5-4.
2 (wide area), and 7.6 to 7.9 (multibullet)
δ.

Preparation Example 6 (a) (4-carboxybutyl)triphenylphosphonium bromide (b) (6-carboxyhexyl)triphenylphosphonium bromide (c) (8-carboxyoctyl)trinoenylphosphonium furomide Following the procedure of Example 50, but Instead of 3-fromopropionic acid, equivalents of (a) 5-fromopentanoic acid, (b) 7
-promohebutanoic acid, and (e) 9-promononanoic acid to prepare the title compounds (a), (b) and (e)
is obtained.

Preparation Example 7 3α-penzoyloxy-2β-carboxaldehyde 5
α-Hydroxy-1α-cyclopentaneacetic acid γ-lactone (Formula XXVII; R51 is phenyl) See Figure F.

1. Levorotatory (
c) 3α-hydroxy-5α-hydroxy-4-iodo-2β-methoxymethyl-1α-cyclopentaneacetic acid γ-lactone (E. J. Collie et al., J. Am
．． Chem, Soc. 9 Volume 2, page 397 (197
0 years)) 75? of penzoyl chloride with cooling to maintain the temperature at about 20-40°.
Add 4rrLl.

Continue stirring for another 30 minutes.

Approximately 250 rrLl of toluene are added and the mixture is concentrated under reduced pressure.

Dissolve the residue in 1 liter of ethyl acetate, add 10% 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 952.

Crystallization of the oil yields the corresponding 3α-penzoyloxy compound.

Melting point 84-86°C; [α]D+7° (CHCl3): Infrared spectral absorption is 1768, 1722, 160
0,1570,1490,1275,1265,11
80, 1125, 1090, 106011030, and 7 1 0crn'.

NMR (nuclear magnetic resonance) peak is 2.1-3.45
, 3.3, 3.58, 4.38, 5.12, 5.51,
7.18-7.58, and 7,83-8.05δ.

2. The iodo group is removed as follows.

The above penzoyloxy compound in 240 ml of dry benzene 60? About 60 mg of 2,2'-azobis-(2-methylpropionitrile) is added to the solution.

Cool the mixture to 15° and add 600wLl of ether to it.
The solution of tributyltin hydride 751 in the solution is added with stirring at a rate that maintains a sustained reaction at about 25°C.

When the reaction is complete as shown by TLC, the mixture is concentrated to an oil under reduced pressure.

Add oil to Skerisolve B 600rnl and water 600rrl
1 and stir for 30 minutes.

Separate the aqueous layer containing the product and then add 45 ml of ethyl acetate.
0rIll and sufficient solid sodium chloride to saturate the aqueous phase.

Separate the ethyl acetate layer that now contains the product;
Dry over magnesium sulfate and concentrate under reduced pressure to an oil.

Compound 391 that does not contain iodine. The analysis sample is [α, lD-
Gives 99° (CHCl s ).

Infrared spectrum absorption is 1775, 1715, 1600
, 1585, 1490, 1315, 1275, 1180
, 1110, 1070, 1055, 1025, and 7
15crrL'; NMR peak is 2.5-3.0,
3.25, 3.34, 4.84~5.17, 5.17~
5.4, 7.1-7.5 and 7.8-8.05δ.

Mass spectrum peaks are 290, 168, 105, and 77.

3.2β-Methoxymethyl compound is converted to hydroxymethyl compound as follows.

Cold (0
．． 5°) To the solution, a solution of 24.8 rul boron tribromide in 7320 ml of dikuoo meta is added dropwise at 0 to 5° over 50 minutes with vigorous stirring.

Continue stirring and cooling for 1 hour. When the reaction is complete as shown by TLC, a solution of sodium carbonate (78 g, monohydrate) in 200 rfLl of water is added.

The mixture is stirred at 0-5° for 10-15 minutes, saturated with sodium chloride and the ethyl acetate layer is separated.

Combine the additional ethyl acetate extract of the aqueous layer with the main ethyl acetate solution.

The combined solutions were washed with brine, dried over sodium sulfate, and the 2β-hydroxymethyl compound of the oil was extracted under reduced pressure.
8.1f! Concentrate to

The analysis sample has a melting point of 116-118℃: [α, lD-80°
(CHCl3): Infrared spectral absorption is 3460,1
735, 1708, 1600, 1580, 1490, 1
325, 1315, 1280, 1205, 1115, 1
090, 1070, 1035, 1025, 730, and 720o NMR peaks are 2.1-3.0, 3.58
, 4.83~5.12, 5.2~5.45, 7.15~
7.55 and 7.8-8.0 δ.

d. The title 2β-carboxaldehyde compound is made as follows.

150rfLl of dry dichloromethane and Collins reagent (J.C. Collins)
) and others, Tetrahedron Letters No. 3363 (19
To the mixture of 28 g) at about 100 °C under nitrogen and with vigorous stirring is added a cold (100) solution of 5.0 P of the above hydroxymethyl compound in 150 r/Ll of dichloromethane.

After stirring for another 5 minutes, add approximately 100 r/ml of dry benzene.
Add Ll, filter the mixture and concentrate the solution under reduced pressure.

Bring up the volume to approximately 150 rILl 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.

Preparation Example 70 procedure is followed, but instead of the optically active iodolactone, the corresponding racemic compound (E. J. Collie et al., J. Am. Chem. Soc, vol. 1, p. 5675)
(1969)) to obtain the racemic compound corresponding to formula XXVI[.

Preparation Example 8 Dimethyl 2-oxo 4-phenylbutylphosphonate 65° Tetrahydrofuran 2. To a solution of dimethylmethylphosphonate}115.5S' in IJ was added 660 rfLl of a 1.6M solution of n-butyllithium in hexane, followed by a solution of ethylhydrosinname}93.5P in tetrahydrofuran 225 Add.

The mixture is stirred at -65° for 2 hours, then stirring is continued at 25° for 16 hours.

70 rI'Ll of acetic acid is 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 121.5S'.

Boiling point 184-195, mass spectrum 256 (M+).

Preparation Example 9 Dimethyl 3,3-dimethyl-2-oxo-4phenylbutylphosphonate 1. To a solution of diisoprobylamine 101.2 P in 125 rrLl of tetrahydrofuran at 0.00 ml under nitrogen is added a solution of n-butyllithium in 625 TLl of hexane and then 442 isobutyric acid.

The mixture was stirred for 90 minutes at 00°C, then cooled to -15° and heated with benzyl chloride 60°C while keeping the temperature below -5°C.
Add rnl.

The mixture is stirred at 25° for 4 hours, then diluted with ether and washed with cold diluted salt.

The organic phase is washed with brine, dried, concentrated and distilled to give 2
-Produces 2-dimethyl-3-phenylpropionic acid 482.

2. 48 g of raw material from Part 1 and thionyl chloride 822 were heated for 2 hours, then the mixture was concentrated and benzene 5017LA
' was added and the mixture was concentrated and distilled to give 2,2-dimethyl-3-phenylpropionyl chloride 48.2S
' is produced.

3. Tetrahydrofuran 600 rI at -75° under nitrogen
In a solution of dimethylmethylphosphonate 631 in Ll,
1 in hexane while keeping the temperature below -55°.
．． 6 Add 312rILl of Mn-butyllithium.

A solution of 2,2-dimethyl-3-phenylpropionyl chloride (Part 2, 48.2S') in tetrahydrofuran is added keeping the temperature below -60<0>C.

Stir the mixture at that temperature for 2 hours, then reduce the temperature to 25°C.
The mixture is stirred at this temperature for 16 hours.

20 m of acetic acid are 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 yields the title compound 622.

Melting point 48-51°, NMR peaks 7.2, 3.83
and 3.64, 3.28 and 2.9, 2.8 and 1.13
δ.

Examples 1-12 below illustrate the preparation of the compounds shown in Figures B, C, D and E.

Example 1 Endo-6-(4-phenylcis-1-7'tenyl)-exo-3-hydroxybicyclo[3.1.O]-
Hexane-exo-2-acetic acid, gamma lactone (Formula ■: Q - (cH2)2C6H5) See Figure B.

Lactonaldehyde, endo-in 1.21 J of benzene
6-formyl-exo-3-hydroxy-bicyclo[3.
1.O]-hexane-exo-2-acetic acid γ-lactone (
(Formula ■) (U.S. Patent No. 3,711,515, January 26, 1973, Formula ■; R. C. Kelly (R, C.
Kelly) et al., J. Am. Chem. Soc.
．． 9, Vol. 5, p. 2746 (1973)) 101.

(3-phenylprobyl) triphenylphosphonium bromide and benzene 3J were placed separately in separate flasks,
To this was added a 15% solution of n-butyllithium in hexane 6
Add 85rrLl dropwise at medium speed while stirring.

Stir the orange mixture for 15 hours after the addition is complete.

After stirring is stopped, the mixture is allowed to settle, and the supernatant liquid is sucked up and added to the benzene solution of lactone aldehyde at a rate of 800 ml to 1000 rrLl per hour, while stirring, until the red color persists.

The progress of the reaction was checked by TLC, and after the reaction was completed,
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) 4 l of 5% ethyl acetate in SSB, (2) 4 l of 10% ethyl acetate in SSB
l, (3) 6 l of 10% ethyl acetate in SSB, (4)
6 l of 15% ethyl acetate in S S B, and (5) S
810 25% ethyl acetate in SB Fractions (3), (4), and (5) containing the desired compound are combined and concentrated to yield 155 g of the title compound as an oil.

IR absorption is 1775, 1 6 0 0, 1495, 12
30,1175,1045,10301920,745
, 700cm” NMR peak (CDCl3) is 7.0
8, 5.6, 4.8, 4.4, 2, 2-2.7, 1o9
2, 1.2-1.58δ.

Example 10 The procedure is followed, but instead of the optically active tricyclic aldehyde lactone, a racemic mixture of that compound and its mirror image is used to obtain the corresponding racemic mixture.

Example 2 Endo-6-(1@)・2(S) monodihydroxy-4-
phenylbutyl]-exo-3-hydroxybicyclo[
3.1.O]-hexane-exo-2-acetic acid, γ-lactone (Formula X: Q is -(CH2)2C6H5) See Figure B.

To a solution of the formula 1 product 155f of Example 1 in 500 wLl of acetone and 5 Qd of water was added 2.0 g of tetrahydrofuran.
Add 250m9 of osmium tetroxide in 5rfLl.

A solution of 942 d of N-methylmorpholine oxide hydrate in 200 d of acetone and 314 d of water was added to the reaction mixture with stirring while maintaining the reaction temperature at 25°, and the mixture was stirred at that temperature for 6.5 hours and checked by TLC. What if I let you? Terminate the reaction immediately.

The mixture is concentrated under vacuum in a 40° bath to remove most of the acetone.

The residue is acidified to a pH of 3-4 with 10% hydrochloric acid and then extracted with ethyl acetate.

The extract is washed with brine, dried and evaporated under reduced pressure.

The residue was dissolved in methylene chloride and then dissolved in Skellysolve B (
Chromatograph on a silica gel column packed with 60% ethyl acetate in SSB).

Elution is carried out with ethyl acetate and SSB as follows.

(1) 35 l 60% ethyl acetate in SSB, (2) S
80% ethyl acetate in SB 15,g, (3)S
28 l of 80% ethyl acetate in SB, (4) S S B
(5) 8 l of 80% ethyl acetate in SSB, and (6) 35 l of 10% methanol in ethyl acetate from 0 fractions (3) of the title compound 88
2 is collected.

Infrared absorption is 3430, 1760, 1600, 1495
, 1450, 1415, 1 3 6 011335, 1
295, 1260, 1230, 1185, 1095, 1
030, 925, 7501705; NMR peak is (
CDCI3) 7.2, 4.75, 3.65, 2.5-3
．． 1, 1. 0-2. 5δ and mass spectrum peaks are 302, 180, 150, 149, 121,
108, 107, 93, 92, 91, 79.

Example 20 procedure is followed, but instead of the optically active tricyclic lactone, a racemic mixture of that compound and its mirror image is used to obtain the corresponding racemic mixture.

Example 3 Endo-6-[1(R)·2(S)-dihydroxy-4
7enylpterethyl orthopropionate]-exo-3-hydroxybicyclo[3.1.0]-hexane-exo-2-acetic acid, γ-lactone (Formula XI; Q is
CH2)2CaH5: Ra and R42 are -C2
H,) See Figure B.

β-Glycol Formula X product of Example 2 88f! is dissolved in 1 l of benzene and then evaporated under vacuum.

Triethyl orthotopionate 87rrLl is added to the residue.
and 1 liter of benzene to 7 JOt, then about 250 benzene
The rfLl is debluened by evaporation under vacuum.

0.6 fI of pyridine hydrochloride is added and the mixture is left at 25° for about 1 hour.

Three drops of triethylamine are added and the reaction mixture is then evaporated under vacuum to yield the title compound 1102 as an oil.

The title compound was pre-spotted with triethylamine,
It has an Rf value of 0.57 on silica gel developed in 50% ethyl acetate-cyclohexane.

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-5-7enyl-trans-1-pentenyl]1α-cyclopentaneacetic acid, γ
-lactone (formula ■; Q - (CH2) 2 Ca
H5, R41 is -C2H5) See Figure B.

440 rfLl of formic acid was mixed with acetic anhydride 8. 8 rnl and 20
Stir for a minute.

Flush the flask with dry nitrogen and cool to approximately 10'.

The crude cyclic orthopropionate Formula M product 1101 of Example 3 is then quickly poured into vigorously stirred formic acid and rinsed with approximately 40 wL of methylene chloride.

Continue stirring for 4 minutes, then add sodium hydroxide (IN,
600rrLl).

The mixture is diluted with 1.5 l of brine and extracted 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 oil propionate 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)
-1α-cyclopentaneacetic acid, triolic acid (Formula XIV
: Q is -(CH2)2C6H5) See Figures B and C.

The crude lactone product of Example 4 was dissolved in methanol 875rIL.
l and then IN sodium hydroxide 875r/Ll
and stir the mixture for 1 hour at 25°C.

The mixture is concentrated under reduced pressure in a 40° bath to approximately 900 rrLl.

The mixture is then saturated with sodium chloride and cooled to approx.

The aqueous solution is covered with ethyl acetate and gradually acidified with 10% phosphoric acid to pH 5 with constant stirring and cooling.

Separate the phases and extract with ethyl acetate. The aqueous phase is covered again with ethyl acetate and further acidified to pH 4 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.

Freeze the mixture at -100 for 16 hours.

Filter the crystals and add cold ethyl acetate to Kelisolp B (3:1).
) and drying under vacuum at 50' to yield the title compound 57.59.

Melting point 125-127℃ oIR absorption (mal) 3390,
3260, 2730, 2660, 3630, 1710,
1600, 1495, 1350, 1340, 1305,
1275, 124011195, 1125, 1075,
1050, 1035, 995, 970, 965, 940
, 750, 700crrt'.

By following the procedure of Example 5, but using a racemic mixture of that compound and its mirror image in place of the optically active lactone, the corresponding racemic mixture was obtained.

Example 6 3α. 5α-dihydroxy-2β-((3S)-3-hydroxy-5-7enyl-trans-1-pentenyl)
-1α-Cyclopentaneacetic acid γ-lactone (formula ■; Q is (CH2) 2 Ca H5) See diagram C.

Crystalline triolic acid obtained in Example 5 (14.45'
) and 450 rrL of chloroform, add 5171A of a saturated solution of lysine hydrochloride in methylene chloride.
! Add.

The mixture was stirred and the formation of lactone X was confirmed by TLC: acetic acid:methanol:chloroform-10:
Heat to reflux until 10:80).

The mixture is then cooled to room temperature.

The title compound is not isolated and the crude material is used directly in the following examples.

Its melting point is 51-53°C.

IR absorption (mar) is 3320, 1765, 1665, l
625, 1600, 1495, 1160, 1085, 1
0 6 0,1040, 1000,970,700m
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 XX [
; Q is (CH2)2C6H5, J is tetrahydropyranyl and -C1 -C) See Figure E.

50 m of dihydroxypyran to the raw material of Example 6 at 25°
l and a saturated solution of pyridine hydrochloride in 5 lll of methylene chloride are added.

The mixture is stirred at 25° until the formation of bistetrahydropyranyl ether is complete as checked by TLC (50% ethyl acetate, Kelisolve B).

The reaction mixture is washed with saturated sodium bicarbonate solution, then with brine, dried, filtered and the liquid is concentrated under vacuum.

Oil 341 is obtained. IR absorption is 1775, 1440,
1425, 1335, 1195, 1150, 1120,
1070, 1030, 1015, 970, 910, 90
0, 865, 815, 755, and 705CIrL-
1.

Following the Example 70 procedure, but instead of the optically active sictone,
Using racemic mixtures of the compound and its mirror image, the corresponding mixtures are obtained.

Example 8 3α・5α-dihydroxy-2β-[(3S)-3-hydroxy-5-phenyl-trans=1-pentenyl]
-1α-cyclopentane-acetaldehyde γ-lactol, 4,3l-bis(tetrahydropyranyl ether (formula ■: Q is -(CH2)2Ca H5, J
See Tetrahydropyra Diagram E.

Example 7 in 150 rIll of toluene at -50°
Diisobutylaluminum hydride (150rfLl1 10% solution in toluene) is added over 15 minutes to a solution of product 34fI.

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 was removed from the cooling bath and diluted with tetrahydrofuran 6
A mixture of 0rfLl and 60r/Ll of water is added gradually 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.

31 g of oily lactol product are obtained.

IR absorption is 3400, 1440, 134011200,
1175, 1120, 1 0 7 0, 1020, 97
0, 870, 815, 735, and 700cnL'
.

The procedure of Example 80 is followed, but instead of the optically active Formula 1 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-trino-PG
F2α・11・15-bis(tetrahydropyranyl)ether (formula XX[II; Q is -(CH2)2C6H5,
J refers to Tetrahydropirani Diagram E.

Example 80 The oily lactol product (31P) is dissolved in 35rIll of dimethyl sulfoxide.

Separately, sodium hydride (18.9P, 50% dispersion) is added under nitrogen atmosphere to 320 ru of dimethyl sulfoxide with stirring, the mixture is heated and allowed to react at 60-70' until the reaction is complete.

The reaction mixture is cooled to 10° C. and carboxybutyltriphenylphosphonium bromide (Preparation Example 6, 87g) is added while maintaining the temperature below 35° to form a Witteig reaction solution.

The solution is cooled to 15° C. and then the lactol solution is added dropwise over 15 minutes, maintaining the temperature between 15° and 300° C.

The reaction mixture was stirred, mixed with 800 rIll of benzene, cooled by the addition of ice, and then added to 650 rIll of water.
A solution of 60 g of potassium hydrogen sulfate in Ll is added with shaking.

Separate the phases, remove the organic (top) phase, wash the aqueous phase with benzene, and combine the organic phases.

The combined organic phases are washed with water, dried, filtered and concentrated.

The resulting oily substance is chromatographed on pickled silica gel 3502.

Elution was (1) 33% ethyl acetate in SSB, 1.751;
(2) 33% ethyl acetate in SSB 0. 2 5 7,
(3) 2 l of 40% ethyl acetate in SSB, (4) S
0.5 l of 50% ethyl acetate in S B , (5) SSB
(6) 1.5 l of 50% ethyl acetate in SSB and 2 l of 60% ethyl acetate in SSB.

Fractions (3) and (4) yield the title compound 252.

fractions (1) and (2), and fraction (5
) and (6) are rechromatographed under the same conditions to yield an additional 2.459 of the title compound.

The desired product fractions are combined and concentrated under vacuum at 35-40°C to give 26.42 bluish-yellow oil.

NMR peak (CDCl3) is 7.2, 6.3
, 5.3-5.7, 4.7, and 3.3-4.2 δ
.

Following the procedure of Example 9, but using instead of the optically active lactol native a racemic mixture of that compound and its mirror image, the corresponding racemic mixture is obtained.

Example 10 17-7enyl-18,19,20-trinor-PGF
2α (formula XX[V; Q is -(CH2)2C6
H5, A is (CH2)3-) See Figure E.

6.95P of the 17-phenyl PGF2α bis(tetrahydropyranyl) ether product of Example 9 was dissolved in 80 ml of acetic acid, and this solution was mixed with 40 ml of water and 4 ml of tetrahydrone ether.
Dilute with rul.

The solution is heated to 40° C. and left at this temperature for 4 hours.

The solution is then diluted with 450 ml of brine and extracted 4 times with 100 portions of chloroform.

Combine the first three extracts and 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.

Pickled silica gel 150S' where the oil was dissolved in methylene chloride and packed with 50% ethyl acetate in SSB.
Chromatograph on top.

Elution is carried out as follows.

(1) 50% ethyl acetate in SSB 500rfLl1
(2) 500 TLl of 75% ethyl acetate in SSB,
(3) 100% ethyl acetate 500rrLl, (4) Acetic acid x -F-/l/to 2.5% methanol 250ml,
(5) ethyl acetate and 250 rul of 2.5% methanol,
(6) Ethyl acetate and 5% methanol 500-, (7) Ethyl acetate and 7.5% methanol 500rrLl, and (8) Ethyl acetate and 10% methanol 500TLl0 fractions (5), (6), and (7) desired 17
-Phenyl PGF2α yielding the title product 1.9 7 42.

Rechromatography of fractions (4) and (8) yields the desired 17-phenyl PGF2α title compound 1
．． 302P is obtained.

The raw product after evaporation is a very viscous, almost colorless gum.

This is recrystallized from ethyl acetate-SSB.

It has a melting point of 79-80'C and an IR absorption (mal) of 343
0, 3340, 2950b, 2630, 1695, 16
001 1495, 1275, 1245, 1100,1
000,975,695CTL 0NMR peak (CDCl3) is 7.

2, 5.68-, 5.45, and 4.1δ.

Example 100 procedure is followed, but optically active 17-phenyl P
Instead of GF2α bis(tetrahydrohyranyl) ether, a racemic mixture of that compound and its mirror image is used to obtain the corresponding racemic mixture.

Reference example 1 (15R)-15-methyl-17-phenyl-18.1
9,20-trino-PGF2α-methylesterhenol(15S)-15-methyl-17-phenyl-18,1
To a solution of 1.165 17-phenyl-PGF2α in 30 liters of 1,4-dioxane was added 2,3-dichloro-5.
6-dicyano-1,4-penzoquinone 8 1 71n9
Add.

The reaction mixture is stirred at 25° under nitrogen atmosphere for 72 hours.

Filter the mixture and wash the solid with methylene chloride.

The solution was concentrated and diluted with ethyl acetate and Schellisolp B (50:5).
0) packed with pickled silica 140? Chromatograph on top.

Elution was performed using (1) ethyl acetate and Scherisolve B (5o:5o
) 3J, (2) ethyl acetate 3J, and (3) ethyl acetate 3L and 10% methanol 1. e (100rrL
l fraction).

Elution fractions 16-73 were combined and charcoal filtered to remove 15-keto-17-7enyl-18.19.
・Concentrate to 1.045 g of 20-trino-PGF2α.

22 rnl of hexamethyldisilazane to a solution of 15-keto-17-phenyl-PGF2α in tetrahydrofuran.
! and 5rIll of trimethylchlorosilane are added and the mixture is stirred at 25° C. under nitrogen for 18 hours.

Concentrate the solution, dissolve the residue in xylene, filter and concentrate to give an oily product, 17-phenyl-18.19
-Produces 1.62 of the trimethylsilyl derivative of 20-trino-PGF2α.

The oily product is dissolved in 50 TrLl of diethyl ether, cooled to 000 ml under nitrogen, and to this is added dropwise 1.5 rILl of 3M ethereal methylmagnesium furomide.

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 1.62 tertiary alcohols, i.e. (1
5R)-1 5-methyl-17-phenyl-18,19
・20-trinor PGF2α and (15S)-15-methyl-l7-phenyl-18,19,20-trino-P
A mixture of GF2α is produced.

The epimer mixture was dissolved in 60 ml of ethanol,
Dilute with 40ml of water and stir at room temperature for 3 hours.

Concentrate the solution to remove ethanol (maximum temperature 3
5°), 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 raw material was chromatographed on neutral silica 1502 packed with 10% acetone and methylene chloride.
) 10% acetone and 3 l methylene chloride, (2) 40% acetone and 3 l methylene chloride, and (3) 50% acetone and 2 l methylene chloride to elute (100 wL).
l fraction).

When fractions 53 to 58 are combined, (15R)
-15-Methyl-17-phenyl-18.19.20-trino-FGF2α methyl ester 161 ml is produced.

IR absorption is 3380, 1735, 1600, 1495,
1455, 1440, 1370, 1225, 1170,
1155, 1120, 1095, 1060, 1030,
975, 925, 750, and 705crIL”
.

NMR peak (CDC13) is 7.19, 5.75~
5.05, 4.30-3,70, 3.62, ■. 32δ
.

Continued elution yields 220 kg of raw material.

When this is recrystallized from ethyl acetate and Kelisolve B, 15(S)-15-methyl-17-7enyl-18.
19/20-trinor PGF2α methyl ester 88■
will occur.

IR absorption is 3290, 1730, 1600, 1585,
1495, 1315, 1225, 1175, 1105,
1040, 975, 910, 745, 740, and 700cIrL'. NMR peak (CDC13) is 7.45-7, 10, 5.85-5.3 0, 4.3
0 to 3.8 0, 3.6 8 and 1.38 δ.

The present invention is a method as described in the claims, and includes the following embodiments.

1. 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. 2. A process according to claim 1, comprising forming a racemic compound of the diol diester or its mirror image and replacing the acyl group of said 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 (e) comprises reacting the glycol with an orthoester to form an optically active cyclic orthoester or a racemate of the 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 (e) comprises reacting a glycol with formic acid to form an optically active diformate of said glycol, or a racemate of said compound and its mirror image, and then replacing the formyl group of said diformate with hydrogen. The method according to claim 2.

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

Claims (1)

[Scope of Claims] Starting from an optically active compound of formula 1 (lower alkylene), lofuranil, M/ is J is tetrahydride (as defined above)] or a racemic compound of this formula and its mirror image and converting the compound from an OJ group to a hydroxyl group, wherein A, Q are as defined above, and M is /
~, or 7・\ (R3 is the above definition R3 0H
R3 0H )] or a process for producing a racemic compound of this formula and its mirror image. 2(a) where -CtH2t- is lower alkylene and φ is phenyl] reacting with a reagent to form an alkene; (b) hydroxylating the alkene to form a glycol; (e) converting the glycol to form a bicyclic lactone diol of S and R configuration; ) S
(e) replacing the hydroxyl hydrogen of the diol with a blocking group to form a bisether; (f) reducing the ochyne group of the lactone to a hydroxyl group; g) carrying out Uiteits hyalkylation with a compound of the formula φ3P=CH-A-COOH C, where φ is as defined above and A represents lower alkylene; (h) substituting the blocking group with hydrogen; A process for preparing an optically active compound of the formula (wherein hydrogen is hydrogen) and A and Q are as previously defined, or a racemic compound of this formula and its mirror image, comprising the steps of: