IL42670A - 15-alkyl-15-hydroxy-prosta-4,5,13-trans-tienoic acid derivatives and process for their preparation - Google Patents

Description

naan^ τ^πητ n>a aB»la-pa-m-i 3f 5f4 trlenoic acid and procGBS for their preparation SYNTBX CORPORATION 0. 40763 42670/3 The present invention relates to certain novel prostaglandin derivatives and to a process for the production thereof.

More particularly, the present invention relates to prosta-4 , 5 , 13-trans-t ienoic acid derivatives having oxygenated functions at C-9 and C-15 or at C-9, C-ll and C-15 posi tions of the molecule, which are further substituted at C-15 by a methyl, ethyl or propyl group. Also encompassed are the corresponding pharmaceutically acceptable, non-toxic lower alkyl esters and salts.

Prostaglandins are members of a new hormonal system with a remarkable range of biological and pharmaceut cal properties. These compounds belong to a group of chemically related 20-carbon chain hydroxy fatty acids containing a five membered ring in the structure and different degrees of unsatu-ration, a number of which have been reported in the literature. For a review on prostaglandins and the definition of primary prostaglandins, see for example S. Bergstrom, Recent Progress in Hormone Research, 22, pp 153-175 (1966) and Science, 157, page 382 (1967 ) by the same author.. '"^^ Prostaglandins are widely distributed in mammalian tissues and have been isolated from natural sources in very small amounts. In addition, a number of the naturally ocurring prostaglandins have been prepared by chemical synthesis; note for example, J. Am. Chem. Soc. , 91, page 5675 (1969 ) ; , J. Am.

C em. Soc. 92, page 2586 (1970) and J. Am. Chem. Soc. , 93, pages 1489-1493 (1971) and references cited therein, . P.

Schneider et al . , J. Am. Chem. Soc. , 90, page 5895 (1968); U. Axen et al . , Chem. Commun. , page 303 (1969) and W.P. Schneider,' Chem. Commun. , page 304 (1969).

Because of the remarkable range of biological and pharmacological properties exhibited by this family of compounds a great deal of interest has focused upon such compounds , arid the preparation of analogs of such compounds; accordingly, we have discovered processes and intermediates for preparing modified prostaglandins and derivatives thereof.

The article in J.C.S. Chem. Communications pp. 904-5 (1972) discloses non-stereospecific C-15 hydroxy, C-15 desalkyl C-4,5 allenyl prostaglandins. The present application is directed to corresponding C-15 hydroxy C-15 alkyl compounds. It has been found that the present C-15 alkyl compounds are unexpectedly superior to the 15-desalkyl compounds of the cited article, by comparison for representative compounds of the results of bioassay tests designed to determine luteolytic activity.

The novel prostaglandin derivatives of the present invention can be represented by the following formula: 42670/3 wherein R represents hydrogen, hydroxy, acetoxy, tetrahydropyranyloxy or trimethyIsilyloxy ; 4 R represents hydrogen, a lower alkyl group or the pharmaceutically acceptable, non-toxic salts 4 of compounds in which R is hydrogen; R^ represents methyl, ethyl or propyl; R is oxo or a-hydroxy , -acetoxy, cx-tetrahydro- pyranyloxy or a-trimethylsilyloxy ; and the wavy lines (^) indicate the a or β con iguration, or mixtures thereof, 6 provided that when R is a, the hydrox 1 group, attached 6 6 to the same carbon atom as R , is β; and when R is β , the hydroxyl group, attached to the same carbon atom as R , is a.

The dotted lines shown in the above formulas and in the formulas below indicate that the substituents are in a configuration, i.e., below the plane of the cyclopentane ring.

The wavy lines ) indicate the a or β configura- tion, or mixtures thereof.

The double bond at C-13 in the compounds of the present invention has the same configuration as in natural pros tag3landin of the PGE1 , PGE2f PGF,lot or PGF2_a„ series, that is,' the trans configuration.

These novel compounds possess asymmetric centers and thus can be produced as racemic mixtures. The racemic mixtures can be resolved if desired, at appropriate stages by methods known to those skilled in the art, to obtain the respective individual antimers. It is to be understood that mixtures of both antimers are encompassed within the scope of the present invention.

Thus, compounds of formula (I) in which R-. is oxo are mixtures in equal proportions of the compounds of the indicated structure and its mirror image represented by. the formulas: (C-2) tures in equal proportions of compounds of formulas: 42670/2 and compounds of formula (I) in which R is -hydroxy are mixtures in equal proportions of compounds of the formulas: 42670/2 The compounds of the present invention are racemic mixtures and are produced starting from racemates.

For the sake of simplicity only one antimer of each pair will be depicted in the description of the process and Claims; however, it is to be understood that the mirror images for the racemic mixtures and the individual antimers are also encompassed thereby.

The use of the symbol "E" preceding a substituent designates the absolute stereochemistry of that substituent according to the Cahn-Ingold-Prelog rules [see Cahn et al., Angew. Chem. Inter. Edit., Vol. 5, p. 385 (1966), errata ,._/511 ; Cahn et al. , Angew. Chem. , Vol0 78, p. 413 (1966); Calm and Ingold, J. Chem. Soc. (London), 1951, p. 612; Cahn et al. , Ex erientia, Vol. 12, p. 81 (1956); Cahn. J. Chem. Educ. , Vol 41, p. 116 (1964)]. Because of the interrelation of the designated substituent with the other substituents in the compound having a or β prefixes, the designation of the absolute configuration of one substituent fixes the absolute configuration of all substituents in the compound and thus::the absolute con-figuration of the compound as a whole.

The term "conventionally hydrolyzable esters or ethers", as used herein, refers to those physiologically acceptable hydrolyzable ester and ether groups employed in the pharmaceutical art which do not significantly adversely affect the pharmaceutical properties of the parent compound. The conventionally hydrolyzable esters are derived from hydrocarbon carboxylic acids. The term "hydrocarbon carboxylic acid" defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess vary-ing degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from one to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain.

Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate , benzoate, phenylacetate , diphenylacetate , diethylacetate , trimethylacetate, t-butylacetate , trimethylhexanoate , methylneopentylacetate^ cy-clohexylacetate , cyclopentylpropionate , adamantoate , glycolate, methoxyacetate , hemisuccinate , hemiadipate , hemi-β , β-dimethyl-glutarate, acetoxyacetate , 2-chloro-4-nitro-benzoate , aminoace--tate, diethylaminoacetate , piperidinoacetate , β-chloropropionate trichloroacetate , β-chlorobutyrate , bicyclo-[ 2.2.2]-octane-l-carboxylate , 4-methyl-bicyclo-[ 2.202]-oct-2-ene-l-carboxylate , and the like. The preferred conventional hydrolyzable ester is acetate.

"Conventional hydrolyzable ethers" include the tetrahydrofuran-2-yl , tetrahydropyran-2-yl and 4-methoxytetra-hydropyran-4-yl ethers.

The addition salts are derived from pharmaceutically acceptable basic salts, including metal salts such as sodium, potassium, calcium, magnesium, aluminum and the like, as well as organic amine salts such as ammonium, triethylamine , 2-dimethylamino ethanol , 2-diethylamino ethanol , lysine, argi-nine, caffeine, procaine, N-ethylpiperidine , hydrabamine and the like. The term "pharmaceutically acceptable" refers to salts which do not significantly adversely affect the properties of the parent compound.

The novel prostaglandin derivatives of the present invention can be obtained by a process illustrated by the following sequence of reactions: OH COOCH, (XVI) (XVII) (XIX) (XVIII) 20 (XX) (XXI) NOH COOCH, XXII J ■COOCH COOCH, (XXV) (XXVI ) wherein R has the above indicated meaning; 11 R xs hydrogen or tetrahydropyranyloxy; 1" R is hydrogen or hydroxy; 4' R is hydrogen or methyl; 3 R xs hydrogen or trimethylsilyloxy; 7' R is hydrogen or trimethylsilyl and TMS is trimethylsilyl (Si [CH -.]-.) ; provided that when R is a, the hydroxyl g oup, attached to the same carbon atom as R , is p; and when is β, the hydr.oxyl group, attached to the same carbon atom as i In practicing the process illustrated above, a compound of formula XIVA (racemic or individual antimer) in which the hydroxyl group at C-15 is in a or β-configuration , or mixtures thereof, the β-isomer being prepared by the process described hereinbelow (I through VIII—^XII—>XIV) but starting from the corresponding 3" β-tetrahydropyranyloxy isomer of compound of formula I, is converted into an alkyl ester, preferably into the methyl ester, by reaction with diazomethane in ether solution, and thereafter the tetrahydropyranyloxy groups present hydrolyzed with 65% aqueous acetic acid-, as described hereinabove to yield the corresponding compound of formula XVI, (R^ = Me), in which the hydroxyl group at C-9 is. in a configuration. A compound of formula XVI is then selectively oxidized at C-15 with an excess of manganese dioxide or 2,3-dichloro-5 , 6-dicyano-l , 4-benzoquinone in a suitable inert organic solvent, e.g., chloroform, tetrahydrofuran , dioxane and the like to produce the corresponding 15-keto compound of formula XVII. V/hen manganese dioxide is used as reagent, this reaction is conducted at room temperature, for a period of time of about 18 to 40 hours, under vigorous stirring, using preferably chloroform or tetrahydro uran as . solvents „ The oxidizing agent is added portionwise at 4-6 hours intervals. When the oxidation is effected using 2 , 3-d ichloro-5 , 6 -dic}rano-l , 4-benzoquinone as reagent, the reaction is preferably conducted at a temperature above room temperature, i.e. , at about 40° to 50°C. using particularly dioxane as solvent, for a period ^f time of the order of 14 to 20 hours, preferably for about 18 hours,' In any case the course of the reaction can be followed' by thin layer chromatography or by periodic determination of the. ultraviolet spectrum. When the reaction is complete the oxidizing agent is separated by filtration and the reaction product isolated by conventional techniques such as evaporation of the solvent and purification of the residue by thin layer chromatography or chromatography on Florisil.

Compound XVII is then converted into the corresponding mono- or ditrimethylsilyl ether of formula XVIII by procedures known in the art, see for example Pierce, "Silyla-tion of. Organic Compounds", Pierce Chemical Co„ , Rockford , 111. (1968). Conveniently, this reaction can be done by using a mixture of hexamethyldisilazane and trimethylchlorosilane or N-trimethylsilyldiethylamine as etherifying agents.

Upon reaction of the trimethylsilyloxy compound with a slight molar excess of an alkyllithium or an alkylmag-nesium halide, using particularly methyl-, ethyl- or propylli-thium or methyl-, ethyl- or propylmagnesium bromides as reagents there are obtained the corresponding 15j -alkyl-15 -hydroxy compounds of formula XIX. In the preferred embodiments, the reaction is carried out using preferably 1.1 to 1.2 molar equivalents of the alkyllithium, or from 6 to 12 molar equivalents of the alkylmagnesium halide per molar equivalent of starting compound, using ether or tetrahydrofu an as solvent, at a temperature comprised between -78°C„ to room temperature, for a period of time of the order of 2 to 10 hours and under an inert atmosphere, preferably under argon atmosphere. The silyloxy groups of the crude mixture of alkylated compounds are immediately hydrolyzed to. afford the compounds of formula XX. This hydrolysis is effected by following known methods' for transforming silyl ethers into alcohols, and preferably by dissolving the compound- of formula XIX in a lower aliphatic alcohol-water mixture, eeg.f 50-80% aqueous methanol or ethanol , maintaining the solution at a temperature of between 0°C, to . room temperature for a period of time of about 18 hours to several days, the reaction time depending upon the temperature at which the hydrolysis takes place. This hydrolysis can be optionally done in the presence of a small amount of an organic or inorganic acid, or in the presence of carbon dioxide which will hasten the cleavage of the trimethylsilyloxy groups.

The mixture of 15a-hydroxy-15P-alkyl- and 15β-hydroxy-15 -alkyl compounds of formula XX is separated at this stage by thin-layer chromatographic techniques, and the methyl ester group in the individual isomers is in turn saponified by chemical or enzymatic methods, to yield the corresponding Γ5α-hydroxy-1 P-alkyl and 15P-hydroxy-15a-alkyl-prostatrienoic acids of formula XXI.

When this hydrolysis is effected chemically, the alkyl ester compound of formula XX is dissolved in a lower aliphatic alcohol such as methanol or ethanol and treated- with an aqueous solution of an alkali metal carbonate, e.g., sodium carbonate or potassium carbonate at a temperature above room temperature, of the order of about 30°C. to 50°Co , preferably at about 400C„ for a period of time of about 12 to 20 hours, preferably for about 16 hours, thus yielding, after acidi ication, the corresponding prostatrienoic acid compound of formula XXI. This hydrolysis is preferably conducted under an inert atmosphere i.e.,. under nitrogen or argon atmosphere.

Compound X can be alternatively hydrolyzed by using enzymes in aqueous solutions. For this enzymatic hydrolysis, there is preferably used a .crude pancreatic lipase commercially available (Sigma Steapsin) , however, other enzyme systems which are known as useful for the hydrolysis of compounds unstable to' alkaline or acid conditions can also be practical. Other lipases obtainable from bacterial sources, such as the partially purified lipase obtained from Corynebac-terium acnes culture supernatant can also be used, or a lipase of those that are known to act on water insoluble esters of long chain fatty acids (L. Sarda et al , Biochem. Biophys . Acta. 23:264 (1957)), or baker's yeast (C. Jo Sih et al. , J. C. S. Chem. Comm. 240 (1972)).

The hydrolysis of compound XX with the crude pancreatic lipase can be condicted in a buffered aqueous solution containing sodium chloride and calcium chloride, at a neutral or almost neutral pH, at a temperature of between 22° C. to 30°C. , preferably at about 25°C. to 27°C. , adjusting the pH of the reaction mixture to 7.2 to 7.4 by addition of, for example dilute sodium hydroxide solution, at intervals. Compound of formula XX is dissolved in the previously prepared buffered lipase aqueous solution by sonication at about 37 °C. using from about 0.5 ml. to about 1 ml. of the lipase solution per milligram of substrate. The methyl ester group is readily hydrolyzed within a short period of time, of the order of 5 minutes to 1 hour. The course of the reaction can be followed by thin layer chromatography; when the hydrolysis is complete, the free acid. can be isolated from the reaction mixture by conventional techniques, such as acidification with a dilute acid solution, e.g., using dilute hydrochloric acid, extraction with a solvent immiscible with water such as diethyl ether ethyl acetate, chloroform, methylene chloride, and the lilte, evaporation of the solvent and purification of the residue by column . chromatography, thin layer chromatography or liquid chromatography; good results in the separation of the acid XXI from the lipase have been obtained by column chromatography on Flo-risil.

By esterification of the carboxylic acid function of compounds of formula X or the l P-tetrahydropyranyloxy epi-mers (both represented by formula XA) , with an ethereal solution of diazomethane followed by hydrolysis of the tetrahydro-pyranyloxy functions present in the molecule with aqueous DCO acetic acid, as described hereinbe£©3^e , and protection of the 9-keto group as the oxime by lnown methods, i.e., by reaction with hydroxy!amine hydrochloride in aqueous methanol and in the presence of sodium acetate, conducting the reaction at. room temperature for about 16 to 24 hou s, there is. obtained the corresponding compound of formula XXII. This compound is then oxidized with manganese dioxide or 2 , 3-dich!oro-5 ,6-di-cyano-1 ,4-benzoquinone as described hereinabove in detail for the obtention of compound XVII, to produce the corresponding 15-lceto compound of formula XXIII „ By reaction of a compound of formula XXIII, (R = hydroxy) with a silylatmg agent, using particularly a mixture of hexamethyldisilazane and trimethylchlorosilane or N-trimethylsilyldiethylamine as reagent there is produced the corresponding trimethylsilyloxy derivative represented by formula XXIV.

Treatment of compound XXIII (E1 " = or compound XXIV with a. slight molar excess of an alkyl (methyl-, ethyl-or propyl) lithium or the corresponding alkylmagnesium halide, there is obtained the corresponding 15 j -alkyl-15^-hydroxyQ,om-pound of formula XXV. This reaction is preferably carried out in ether or tetrahydrofuran solution, using preferably from 1.1 to- 1.2 molar equivalents of the alkyllithium or from 6 to 12 molar equivalents of the alkylmagnesium halide per molar equivalent of starting compound. The reaction is effected at a temperature of between -78°C. to room temperature,- for a period of time of 2 to 10 hours, under an inert atmosphere.

The mixture of 15a-hydroxy-15P-alkyl and 15β-hydroxy-15a-alkyl compounds is separated into the individual isomers by thin layer chromatography, (previous hydrolysis of the trimethylsilyloxy group when present with aqueous methanol) and thereafter the oxime is hydrolyzed to regenerate the 9-keto function, thus producing the separated 9-keto-15a-hydroxy-15p-alkyl and 9-keto-15P-hydroxy-1 a-alkyl prostatrienoic acid ester compounds of formula XXVI. The deoximation reaction is effected under mild conditions, for example by the methods described by E. J. Corey et al. in J. Am. Chem. Soc, 92, 5276 (1970) or A. McKillop et al. J. Am. Chem. Soc. 93, 4918 (1971) and references cited therein.

The first method involves the conversion of the oxime into the 0-acetate derivative followed by reaction with an excess, using at least 2 molar equivalents, of chromous acetate in 90% aqueous tetrahydrofuran, at a temperature of the order of 25°C. to 65°C. for about 10 to 24 hours.

The second method comprises tre$¾nent of the oxime with thallium (III) nitrate, using about 1 to 1.1 molar equivalents of the reagent per mol of starting compound. The reaction is conducted at room temperature or below for a short period of time, of the order of 5 to 30 minutes, in an inert organic solvent, followed by filtration of the thallium (I nitrate which precipitates, and brief treatment of the filtrate with dilute acid to decompose the intermediate nitroso compound. In. accordance with our invention, this reaction is conducted in methanol solution, at about 20°C. using aqueous acetic acid to. ', decompose the nitroso intermediate.

Hydrolysis of the oxime can also be effected using titanium trichloride as described by Timms and Wilsmith, Tetrahedron Letters, 195 (1971).

Alternatively the compounds of formula XXVI (where -in R 1 " is hydrogen) are obtained by oxidation of the compomds of formula XX (wherein R is hydrogen) with chromium trioxide-dipyridine complex [prepared as described by J. C. Collins et al„ , Tetrahedron Letters, 3363 (1968)] Alternatively, the compounds of formula XXVI (wherein R1 is hydroxy!) are obtained by treating the compounds of formula XX (wherein R 1" i·s hydroxy! \) according to the m-ethod disclosed by E. ¥. Yankee et al. , J. A. C. S. , 94, 3651 (1972); namely, selective silylation at the 11-position of XX (wherein 1 M R is hydroxyl), followed by oxidation with Collins1 reagent and subsequent hydrolysis with aqueous methanol containing a trace of acetic acid to yield the compounds of formula XXVI (wherein R1" is hydroxyl).

Alternatively, the hydrolysis of the oxime can be effected on the mixture of the 15a and 15P-hydroxy isomers, separating the individual isomers afterwards by thin layer chromatography.

The alkyl ester group in compounds of formula XXVI is hydrolyzed by chemical or enzymatic methods, e.g., by reaction with potassium carbonate in aqueous methanol or with a crude pancreatic lipase, respectively, as described hereinbefore in detail for the 9a-hydroxylated com ounds, thus producing, the free acids of formula XXVII.

The hydroxyl groups in compounds of formulas XI and XV and the secondary hydroxyl groups in compounds of formulas XXI and XXVII can be esterified or etherified in a conventional manner, to produce mono-, di-, or triesters, or mono-, di- or triethers, depending upon the particular prostaglandin derivatives. Esterificat ion can be accomplished by reaction of the hydroxylated compound with a carboxylic acid anhydride or chloride of less than 12 carbon atoms in pyridine solution.

Etherification can also be carried out by conventional techniques. For example, reaction with dihydropyran , dihydrpfuran or 4-methoxy-5 , 6-dihyd o-2H-pyran in an inert solvent such as, for example, methylene chloride or benzene and in the presence of an acid catalyst . (e. g. p-toluenesulfonic acid, p-toluenesulfonyl chloride) produces the tetrahydropyran-2'-yloxy, tetrahydrofuran-2' -yloxy or 4' -methoxytetrahydropy-ran-4'-yloxy derivatives, respectively. · Although the esterifiqation or etherification reactions are usually effected using an excess of the esteri-fying or etherifying agents, it is preferable to use at least one molar equivalent of said reagents per hydroxyl group present in the starting compound.

The alkyl esters of the carboxylic acid function can be prepared by treatment of the free acid with an excess of a diazoalkane such as diazomethane , diazoethane or diazo-propane in ether or methylene chloride solution, in a conventional manner, or by reaction with the desired lower alkyl iodide i 'the presence of lithium carbonate, at room temperature.

The salt derivatives of the prostanoic acids of the present invention can be prepared by treating the corresponding free acids with about one molar equivalent of a pharmaceutically acceptable base per molar equivalent of free acid. Suitable pharmaceutically acceptable bases include, for example sodium hydroxide, trimethylamine, triethylamine , tripropyl-arnine, β-(dimethylamino) ethanol , p-(diethylamino) ethanol , argiriine, lysine, caffeine, procaine and the like. Typically, the reaction is conducted in an aqueous solution, alone or in combination with an inert water miscible organic solvent, at a temperature of about from 0° to 30° C preferably at room temperature. Typical inert, water miscible organic solvents include methanol, ethanol, isopropanol, butanol , dioxane and the like. When divalent metal salts are prepared such as the calcium salts or magnesium salts, the free acid starting material is treated with at least one half molar equivalent of, the pharmaceutically acceptable base.

The above-described processes are effected using racemic mixtures as starting materials. Consequently, each and every intermediate and final ' product will be a racemate.

The compounds of formulae XIVA and XA used as starting materials in the above described processes can be obtained by the following sequence of reactions:  (XIV) (XV) 11 1" wherein R and R have the above-indicated meaning; Ac is a lower acyl group containing from 1 to 4 carbon atoms, particularly acetyl and THP is tetrahydropyranyl.

In practicing the above illustrated process the starting materials of formula I (racemates or individual antimers) are treated with an excess of the dilithium salt of pent-4-yn-l-ol , in a suitable inert organic solvent to prodiuce the corresponding trihydroxyacetylenic compound of formula II.

The dilithium salt of pent-4-yn-l-ol reagent is used in amounts comprised between about 5 to about 15 molar equivalents per molar equivalent of starting hemiacetal, using preferably about 10 molar equivalents. This reagent is prepared by reaction of pent-4-yn-l-ol and methyllithium in ether solution, at a temperature of about -78°C to -50°C. , under an inert atmosphere, such as provided by nitrogen or argon, for a period of between 15 to 24 hours, preferably for about 18 hours The reagent thus prepared is combined with a solution of the hemiacetal of formula I in an ethereal solvent, maintaining, the reaction mixture at a temperature comprised between 10°C to 30°C for about 4 to 10 hours, the reaction time depending ■ upon the temperature used. In the preferred embodiments the reaction is conducted at room temperature (about 25°C. ) for approximately 6 hours „ Suitable solvents for this reactio are dimethyl ether, diethyl ether, dipropyl ether, dimethoxyethane and the like, particularly diethyl ether.

The product is isolated by dilution with water, extraction with an organic solvent immiscible with water and evaporation of the solvent under reduced pressure, talcing care that the temperature does not exceed 20°C. The trihydroxylat-ed compound is purified by column chromatography to separate it from the - uridesired non-polar by-products. There is obtain ed a mixture of the βα and ββ-hydroxy isomers, which can be separated into the individual isomers by thin layer chromatographic techniques, if desired.

The compound of formula II is then esterified . .... under conventional conditions, i.e., using a carboxylic acid chloride or carboxylic acid anhydride in pyridine solution to produce the corresponding triester, the compounds of formula III . The preferred ester ifying agent is acetyl chloride, conducting the reaction at room temperature for about 6 hours.

In the case of using a carboxylic anhydride, e.g.', acetic anhydride, the ester ificatibn is slower, requiring reaction times of the order of 12 to 18 hours or higher temperatures to obtain . complete esterification.

The allenic compounds of formula VIII, can be obtained by the reaction of/ a triacyloxy acetylenic compound of formula III with a lithium dialkylcopper reagent. The reaction is conducted under an inert atmosphere, i.e., under argon or nitrogen atmosphere in an ether solvent. The dialkylcopper reagents used are those wherein the alkyl moieties are the same, each alkyl group containing from 1 to 3 carbon atoms, e.g., lithium dimethylcopper , lithium diethylcopper , and lithium dipropylcopper , particularly lithium dimethylcopper. These reagents can be prepared by reaction of cuprous iodide with an alkyllithium in diethyl ether as solvent, as described for example by P. Rona et al. , in J. Am. Chem. Soc. 91, 3289 (1969).

In this transformation, the reaction conditions and the amount of the lithium dialkylcopper used determine the product obtained. Thus, when the reaction is conducted at very low temperatures, i.e., at temperatures of the order of -50°C to -78°C for about 3 to 7 hours, using four molar equivalents of the dialkylcopper reagent, employing especially lithium dimethylcopper as reagent, there is obtained the allenic compound VIII.

The reaction can be followed by t.l.c; at temperatures of about -70°C the reaction is complete within about 5 hours .

The allenic compounds are' isolated from the reaction mixture via conventional techniques, such as dilution with ammonium chloride solution, extraction, evaporation of the solvent and purification by chromatography, avoiding temperatures higher than room temperature.

The acyloxy groups in the allenic compounds represented by formula VIII are then hydrolyzed under alkaline conditions,, using a dilute solution of an alkali metal hydroxide or alkali metal carbonate in a lower aliphatic alcohol, at room temperature, or below for a period of time sufficient to complete the reaction, ranging from about 12 to about 24 hours. The preferred reagent used is anhydrous (calcinated) potassium carbonate using methanol as solvent, for a period of time of about 6 to 18 hours, thus obtaining the corresponding dihydroxy compound of formula IX.

Upon oxidation of a dihydroxy compound of formula IX with chromium trioxide, using particularly the stoichiometric' amount of an 8N solution of chromic acid in acetone solution in the presence of sulfuric acid (Jones' reagent) there is produced the corresponding keto acid derivative of formula X, 'whose tetrahydropyranyloxy groups are hydrolyzed under mild acidic conditions, to yield the prostatrienoic acid compounds of formula XI, e.g., racemic or individual antimer 9-keto-lla , 15a-dihydroxyprosta-4, 5 ,13-trans-trienoic acid ' and 9-keto-1 a-hydroxyprosta-4.5 ,13-trans-trienoic acid.- ·... ί This hydrolysis is carried out using a weak acid such as acetic acid, oxalic acid, tartaric acid, and the like, i the presence of water. Conveniently , the crude-compound of formula X is dissolved in an organic solvent mis-cible with water, e.g., tetrahydrof an , dioxane and the like-before addition of the acid reagent. The reaction is conducted at a temperature comprised between 20° C. to 50° C, for a period of time of about 4 to 18 hours, depending upon the temperature used. The preferred reagent is aqueous acetic acid, at concentrations of 40 to 80%. It is particularly convenient to use a 65:35 acetic acid-water mixture; however, other concentrations are also practical.

By reaction of the diacyloxy allenic compounds of formula VIII with 1.1 molar equivalents of anhydrous potassium carbonate in methanol solution, at about 0°C. , there is selectively saponified the primary acyloxy group. This selective hydrolysis can be followed by t.l.c. ; generally, it is complete in about 90 minutes to about 2 hours. The compounds of formula XII thus-obtained are oxidized with 8N chromic acid as described hereinabove for the dihydroxylated allenes, to produce the corresponding carboxylic acid, i.e., the compound of formula XIII. The protecting groups are in turn hydrolyzed by the above-described methods, i.e., the acyloxy group is hydrolyzed under alkaline conditions, using preferably anhydrous potassium carbonate in methanol, at room temperature or below, to yield the compounds of formula XIV, in which the te-trahydropyranyloxy groups are cleaved by mild acid treatment, using particularly 65% aqueous acetic acid,' thus obtaining the' trihydroxy prostatrienoic acid derivatives of formula XV, e.g., 9a ,11a ,15a-trihydroxyprosta-4 ,·5 , 13-trans-trienoic acid and 9a, 15a-dihydroxyprosta-4 , 5 ,13-trans-trienoic acid. " ' : In order to obtain the 9P-hydroxy isomers of compounds of formula XV, a compound of formula XI is esterified with ethereal diazomethane , in a conventional manner, and the methyl ester thus obtained reduced with sodium borohydride in a lower aliphatic alcohol such as methanol or ethanol, at about room temperature for a period of time of about 30 minutes to one hour, to produce a mixture of the corresponding 9a and 9β-hydroxy compounds, which are separated by chromatography on silica gel, obtaining approximately equal amounts of each isomer. The methyl ester group can be hydrolyzed by chemical or enzymatic methods, as described hereinafter in detail.

The compounds of formula I used as starting materials in the above described processes can be obtained by the following sequence of reactions: OTHP (IB) (16) (15) wherein Ru represents methyl or benzyl; 9 R represents hydrogen or p-phenylben oyl ; g I R represents p-phenylbenzoyl , represents sodium or thallium, and THP is as defined above.

In the above reaction scheme, compounds of formulas (8) through (I-A) and (7A) through (IB) can be in the form of racemates or as the corresponding individual antimers, in particular the R-antimers. The 1' R-antimers of 7A, (R = benzyl) and (_8) have been described by E„ J. Corey et al , in J. Am. Chem0 Soc. 93, 1491 (1971), while the l'R-antimer of o 7A, (R = methyl) has been described by E. J. Corey et al. , in J. Am. Chem. Soc. 92, 397 (1970).

Briefly, the method for the obtention of the starting materials comprises the reaction of cyclopentad enyl-sodium or cyclopentadienyl thallium (l), obtained by reaction of cyclo entadiene with sodium hydride or aqueous thallousjsul-fate in the presence of potassium hydroxide (E. J. Corey et al. , J. Am. Chem. Soc. 93, 1489 (1971)), with a slight excess of chloromethyl methyl ether or chloromethyl benzyl ether in te-trahydrofuran at approximately -55°C. , to yield respectively o the 5-methoxymethyl-l , 3-cyclopentadiene _2 (R = methyl) or 5-benzyloxymethyl-l , 3-cyclopentadiene , (R = benzyl) which are subjected to the Diels Alder reaction with an excess (about 5 molar equivalents) of 2-chloroacrylonitrile in the presence of cupric fluoroborate as catalyst to yield a mixture Q of the endo-exo cyano nitriles of formulas (3) and (4) (R = methyl or benzyl, respectively). This mixture of stereoisomer^ nitriles is treated with potassium hydroxide in dimethyl, sulfoxide to yield the ant i-bicyclic ketones of formula (5), 8 i.e., 7-syn-methoxymethyl-2-norbornen-5-one (R = methyl) or 8 7-syn-benzyloxymethyl-2-norbornen-5-one (R = benzyl) respectively, which upon reaction with a slight molar excess of m-chloroperbenzoic acid in methylene chloride in the presence of sodium bicarbonate results in selective Baeyer-Villiger oxidation to form the corresponding lactone. (_β) , namely 2-oxa-3-oxo- 5 8 Δ -8-syn-methoxy-methylbicyclo (3.2.1) octane^ (R = methyl) and 2-oxa-3-oxo-A -8-syn-benzyloxymethylbicyclo (3.2.1) octane o (R = benzyl). Saponification of the foregoing lactones of formula (6) with 2.5 equivalents of sodium hydroxide in aqieous methanol, followed by neutralization with carbon dioxide and treatment with 2.5 equivalents of aqueous potassium triiodide solution at 0-5°C. produce the respective hydroxy-iodolactones of formula (]_) , namely (2' α,4' a-dihydroxy-3' P-iodo-5' β-methoxy Q. methylcyclopent-1 ' -yl) -acetic acid 1,2' -lactone (R = methyl, ^ = H) and ( 2' , 4' -dihydroxy-3' P-iodo-5' P-benzyloxymethylcy- 8 Q clopent-11 α-yl ) -acetic acid 1,2' -lactone (R = benzyl, R =y'H) which are esterified with p-biphenylcarboxylic acid chloride, in pyridine, under conventional conditions to yield the co-rresponding p-phenylbenzoates (7, = p-phenylbenzoyl ) .

These compounds are then submitted to deiodina-tion using tri-n-butyl tin hydride in the presence of catalytic amounts of azobisisobutyronitrile in benzene solution, and thence to cleavage of the 51 β-benzyloxymethyl or 51 β-methoxy- ethyl group to produce the hydroxymethyl compound (_8).

The benzyloxymethyl group is cleaved by hydroge-nolysis in the presence of palladium-charcoal and perchloric acid as catalysts, in a suitable organic solvent; the methoxy-methyl group is hydrolyzed by reaction with boron tribromide in methylene chloride, at a temperature comprised between about -78°C to 0°C.

Oxidation of a racemic hydroxymethyl compound (8) with chromium trioxide-dipyridine complex (prepared as described by J. C. Collins et al. , in Tetrahedron Letters 3363 (1968) ) in methylene chloride, at about 0°C. affords the aldehyde (S , (racemic mixtures) which without purification is transformed stereospecifically into the corresponding trans-enone lactone of formula (10). This trans ormation involves a modified Wittig reaction, which comprises treatment of the aldehyde of formula (_9_) with the sodium anion of dimethyl-2-oxo-n-heptylphosphonate of the formula: 0 li CH3 ( CH2 )4 -C-CH2-P- ( OCH3 ) 2 0 in dimethoxy ethane solution. This reagent is conveniently prepared in accordance with the method described by E. J. Corey et al., in J. Am. Chem. Soc. 88, 5654 (1966) 42670/2 from dimethyl α-lithiomethanephosphonate and the methyl or ethyl ester of n-hexanoic acid, e.g., methyl n-hexanoate. The reaction is conducted at temperatures of the order of 0°C to 40°C, preferably at room temperature or below for about 1 to 4 hours, under an inert atmosphere, using at least one molar equivalent of the reagent per mole of aldehyde, and preferably 1.2 to 2 moles.

Treatment of the racemic enone (10) with an excess of zinc borohydride in dimethoxyethane , at room temperature for about 1 hour produces a mixture of the corresponding a and β-hydroxy compounds, which is separated by thin layer chromatography on silica gel to obtain the desired a-hydroxylated compound m pure form [11, E = p-phenylben-zoyl). The p-phenylbenzoyloxy group is then hydrolyzed under alkaline conditions, using preferably anhydrous potassium carbonate in methanol, and the diol is etherified with dihy-dropyran in methylene chloride solution and in the presence of p-tbluenesulfonic acid, to give the bistetrahydropyranyloxy compound (_12) , (racemic mixture) which by reduction with diisobutylaluminum hydride in toluene, at about -60°C produces the lactol of formula (IA) , [2 ' ct-hydroxy- ' -tetrahydropyranyloxy-5 ' β-( 3Ma-tetrahydropyranyloxyoct-1 " (t ) -en-1 "-yl ) -cyclopent-1 ' a-yl]-acetaldehyde-l , 21 -hemiacetal .

By 'reaction of a racemic hydroxy iodolactone of formula (7A) with freshly distilled phosphorous oxychloride in pyridine solution, first at 0°C and thereafter at room temperature there is obtained the corresponding dehydrolactone compound (racemic) of formula (13_) .

J In order to. prevent hydrogenolysis of the allylic hydroxyl during the reduction of the double bond, the lactone group in a compound of formula (13) is opened by treatment with 2N methanol ic sodium hydroxide followed by careful neutralization with 3N hydrochloric acid in ethyl acetate to pH 6, to produce the hydroxyacid (14) (racemic mixture).

Catalytic reduction of this hydroxyacid with Raney nickel in methanol solution followed by brief exposure to acid produces the corresponding lactone (l_5) , which is hydrolyzed to the corresponding hydroxymethyl compound (l_6) (racemic) by the above-mentioned methods, i.e., by hydrogenolysis o in the case of the benzyloxy ethyl compound (l_5, R = benzyl) or by reaction with boron tribromide for the methoxymethyl deriva- o tive (l_5, K = methyl).

A hydroxymethyl compound of formula (16) is then converted into the desired lactol of formula (IB) by oxidation with chromium t ioxide-dipy idine complex to the aldehyde, condensation of the aldehyde with the sodium anion of a dimethyl 2-oxo-n-alkylphosphonate of the type previously mentioned to produce the corresponding trans-enone lactone, selective reduction of the keto group with zinc borohydride to yield a mixture of the a and β-hydroxy isomers , separation of the isomers by thin layer chromatography, ethe ificat ion of the 3" -hydroxy compound with dihydropyran and reduction of the lactone ring with diisobutyl aluminum hydride, as described in detail hereinbefore with regard to the transformation of a compound {8) into a compound (LA) .

The compounds , esters and salts of the invention exhibit prostaglandin-like biological activities and thus are useful in the treatment of mammals where the use of prostaglandins are indicated. The compounds, esters and salts of the invention are bronchodilators and thus are useful in treating mammals for bronchial spasm or wherever strong bronchodilators are indicated. These compounds are also useful in controlling or palliating hypertension in mammals and further exhibit central nervous system depressant activity in mammals, and are useful as ■ sedatives . In addition, the compounds are useful for inducing labor, in pregnancy, and for inducing menses to correct or reduce menstrual abnormalities.

The compounds and/or salts, of the invention, can be administered in a wide variety of dosage forms, either alone or in combination with other pharmaceutically compatible medi-caments , in the form of pharmaceutical compositions suited for oral or parenteral administration or inhalation in the case of bronchodilators. The compounds are typically administered as pharmaceutical compositions consisting essentially of the compounds and/or salts, of the invention, and a pharmaceutical carrier. The pharmaceutical carrier can be either a solid material, liquid or aerosol, in which the compound and/or salt is dissolved, dispersed or suspended, and can optionally contain small amounts of preservatives and/or pH-buffering agents. Suitable preservatives which can be used include, for example, benzyl alcohol and the like. Suitable buffering agents include, for example, sodium acetate and pharmaceutical phosphate salts and the like.

The liquid compositions can, for example, be in the form of solutions , emulsions , suspensions , syrups , or elixirs „ The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. Suitable solid carriers include, for example, pharmaceutical grades of starch, lactose, sodium saccharin, talcum, sodium bisulfite and the like.

For inhalation administration, the compounds and/or salts can, for example, be administered as an aerosol comprising the compounds or salts in an inert propellant together with a cosolvent (e.g. ethanol) together with optional preservatives and buffering agents. Additional general information concerning the inhalation administration of aerosols can be had by reference to U„ S. Patents 2,868,691 and 3,095,355.

The compounds of this invention are typically ad-ministered in dosages of about from 0.01 to 10 mg. per Kg. of body weight. The precise effective dosage will, of course, vary depending upon the mode of administration, condition being treated and host.

The following Preparations and Examples illustrate the invention, but are not intended to limit its scope.

The abbreviation t.l.c. refers to thin-layer chromatography and all mixture ratios used with regard to liquids refer to volume ratios. Also, where necessary, preparations and examples are repeated to provide sufficient starting material for subsequent examples.

PREPARATION 1.

A. To a stirred solution of 125 g. of thallium sulfate and 50 g. of potassium hydroxide in 750 ml. of water are added, under an atmosphere of argon, 43 ml. of freshly distilled cyclopentadiene and the mixture is vigorously stirred for 10 minutes; the yellow precipitate formed is filtered off, washed with ice water, methanol and ether, to yield 132 g. of cyclopentadienylthallium.

B.. A mixture of 216.28 g. of benzyl alcohol, . 61.44 g. of paraformaldehyde,- 481.6 g. of anhydrous magnesium sulfate and 1,200 ml. of methylene chloride is cooled to a temperature of between -50°C. to -55°C. in a dry ice-acetonitrile ■ bath, and the stirred cold solution is saturated with anhydrous hydrogen chloride gas. The reaction mixture is kept at -50° C. to -55°C. for 10 minutes further, and the the excess of hydrogen chloride is eliminated by passing a stream of nitrogen during 30 minutes. The reaction mixture is filtered and the solid material washed well with pentane, and the combined filtrates are evaporated to dryness at a temperature below 30°C. , to produce an oil which is distilled under reduced pressure to yield chloromethyl benzyl ether„ C. A suspension of 132 g. of eye1ope tad ienyl- thallium in 200 ml. of anhydrous ether is cooled to -20° C. in a dry ice-carbon tetrachloride bath. To the cooled mixture are added under stirring and under an argon atmosphere, in a 15-mi- nute period, 90 g. of chloromethyl benzyl ether. The reaction mixture is stirred for 3 l/2 hours at -20°C. , it is then filtered in a filtration flask previously cooled to -78°C. and the solid precipitate washed with cold pentane (-78°C).

The filtered solution is immediately added to a mixture of 216 g. of anhydrous a-chloroacrylonitrile and 3^ g. of anhydrous cupric luoroborate , previously cooled to -78°C.

The reaction mixture is evaporated to half its original volume at a temperature not higher than 0°C. , and the concentrate is stirred at O°C. for 48 hours. The reaction mixture is then poured into 200 ml. of saturated sodium chloride solution, and extracted three times with ether. The combined extracts are washed with saturated sodium bicarbonate solution -(2 x 200 ml.) and saturated sodium chloride solution (2 x 200 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by filtration through 100 g0 of silica gel using benzene as eluant , thus ob- 5 taining the pure 2-chloro-2-cyano-A -7-syn-benzyloxymethylbi- o cyclo-(2.2. l)-heptane [mixture of (_3) and (4), R = benzyl], PREPARATION 2.

To a well-stirred slurry of 74„1 g. of cyclopen-tadienylthallium in 100 ml. of anhydrous ether cooled to .-20°C-to -22°C. (internal temperature) in a dry ice-carbon' tetrachloride bath under an argon atmosphere, are added dropwise, in a 15-minute period, 20.13 g. of chlo omethyl methyl ether and the slurry is stirred at -20°C. to -22°C. for 7 hours. The reaction mixture is then filtered into a precooled (-70°C . , dry ice-acetone) flask and the residue of thallium chloride washed with three 100 ml. portions of cold (-70°C) ether. The combined filtrate is added dropwise from a dropping funnel with a dry ice jacket to a suspension of 29.65 g„ of cupric tetrafluoro-borate in 87.5 g. of anhydrous a-chloroacrylonitrile maintained at 0°C. When the addition is complete, the mixture is stirred at 0°C. in the dark for 18 hours. One hundred milli- ' liters of saturated sodium chloride solution are then added' and the reaction mixture extracted with ether. The ether extracts are successively washed with saturated sodium bicarbonate (2 x 100 ml.) and sodium chloride (2 x 100 ml.), and dried over magnesium sulfate. Evaporation under reduced pres- 5 sure at room temperature gives 2-chloro-2-cyano-A ^-syn-methoxymethylbicyclo-^.2.l)-heptane [mixture of (_3) and (4), Q = methyl) as a clear pale yellow oil.

PREPARATION 3.

To a stirred solution of 100 g. of 2-chloro-2- cyano-A^-7 -syn-benzyloxymethylbicyclo-( 2 „ 2.1) -heptane in 368 ml of dimethylsulfoxide is added dropwise, in a 15-ininute period and under argon atmosphere, a hot solution of 105.2 g. of potas sium hydroxide in 52.6 ml„ of water. The reaction . mixture is stirred for 28 hours at room temperature, diluted to twice its volume with ice water and extracted several times with ether.

The combined organic extract is washed twice with saturated sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue is purified by distillation under high vacuum (0.6 mm.) to yield 7 -syn-benzyloxymethyl-2-norbornen 8 -5-one , (_5, R = benzyl), homogeneous on t.l.c.

By the same procedure but using 2-chloro-2-cyano-A^-7-syn-methoxymethylbicyclo-( 2„ 2.1 ) -heptane in lieu of 2-chloro-2-cyano-A^-7-syn-benzyloxymethylbicyclo-( .2.1) -heptane there is obtained 7-syn-methoxymethyl-2-norbornen-5-one (j_, R8 = methyl).

PREPARATION 4. ' To a suspension of 55 g. of m-chloroperbenzoic acid and 43.5 g. of sodium bicarbonate in 570 ml. of anhydrous methylene chloride are added 57 g. of 7 -syn-benzyloxy-methyl-2-norbornen-5-one , in a 15 minute period and under stirring, maintaining the temperature at about 25° C. The reaction mixture is stirred for three hours further and diluted with methylene chloride. The resulting mixture is vigorous ly stirred with 470 ml. of saturated aqueous sodium sulfite so lution, the organic layer is separated and washed with saturat ed sodium sulfite solution. The aqueous phase is extracted with methylene chloride and the combined organic methylene chloride extracts are dried. over magnesium sulfate and evaporated to dryness under reduced pressure, thus yielding 2-oxa 3-oxo-A^-8-syn-benzyloxymethylbicyclo-( 3.2.1 ) -octane as an . homogeneous oil, (6, R = benzyl).

By the same procedur-e but using 7-syn-methoxy-methyl-2-norbornen-5-one in place of 7-syn-benzyloxymethyl-2-norbornen-5-one there is obtained 2-oxa-3-oxo-A -8-syn-methoxy Q methylbicyclo-( 3.2.1) -octane, (6, R = methyl).

• PREPARATION 5.

To a solution of 60 g. of 2-oxa-3-oxo-A^-8-syn-benzyloxymethylbicyclo-( 3.2.1) -octane in 70 ml. of methanol is added, at 0°C. , a solution of 30 g. of sodium hydroxide in 247 ml. of water, and the resulting mixture is stirred at room temperature for three hours. The methanol is then evaporated under vacuo at a temperature below 30° C. , cooled to 0°C. and extracted with ether to eliminate the unsaponifiable products. The aqueous phase is neutralized with, .carbon dioxide and im- mediately treated wit a solution of 188.1 g. of iodine an* 369 g. of potassium iodide in 275 ml. of water. The reaction mixture is stirred for 48 hours at 0°Co'and diluted with sodium sulfite solution until complete decoloration. It is then saturated with sodium potassium tartrate and extracted wi methylene chloride. The organic extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue is crystallized from ether-methylene chloride, to yield the pure (21 , 4' a-dihydroxy-3' P-iodo-5' P-benzyloxymethylcyclopent-1 ' -yl )- acetic acid 1 , 2' -lactone, (7, R8 = benzyl, R9 = H).

Similarly, starting from 2-oxa-3-oxo-A -8-syn-methoxymethylbicyclo-( 3.2.1 ) octane there is obtained (2' ,4' dihydroxy-3' P-iodo-5' β-methoxymethylcyclopent-1 ' a-yl )- acetic acid 1,2' -lactone (7, R8 = methyl, R9 = H) .

PREPARATION 6.

To a solution of 39.45 g. of (21 a, ' a-dihydroxy-3' p-iodo-5' P-benzyloxymethylcyclopent-11 a-yl) -acetic .acid 1,2' lactone in 152 ml. of anhydrous pyridine is added 32.8 g. of p-bip enylcarboxylie acid chloride. The resulting solution is stirred at room temperature for one hour; 9 ml. of water are then added, and the mixture stirred for one hour to destroy the excess reagent. The solvents are eliminated under reduced pressure and the residue is dissolved in methylene chloride-cyclohexane (3:2). The organic solution is washed successively with 10% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated, to yield (2'a-hydroxy-4' a-p-phenylbenzoyloxy-3 ' p-iodo- 1 P-benzyloxymethyl- cyclopent-11 a-yl ) -acetic acid 1 ,2· -lactone, (7., R = benzy¾'; R = p-phenyl enzoyl ) which can be purified by crystallization.

By the same procedure, (2' α,4' a-dihydroxy-3 ' β-iodo-5' β-methoxymethylcyclopent-l ' -yl) -acetic acid 1,2' -lactone is converted into ( 2' a-hydroxy-4' a-p-phenylbenzoyloxy-3' β iodo-5' β-methoxymethylcyclopent-l 1 -yl) -acetic acid l,2'-lac-tone (7, R = methyl, R = p-phenylbenzoyl ) .

PREPARATION 7.

To a solution of 61 g. of ( 21 -hydroxy-4 ' -p-phenylbenzoyloxy-31 β-iodo-51 β-benzyloxymethylcyclopent-l ' a-yl ) -acetic acid 1,2 '-lactone in 610 ml. of benzene (dried over molecular sieves) is added 45.25 g. of tri-n-butyl tin hydride prepared according to the procedure of H.G. Kuivila and 0. F. Beumel , Jr., J. Am. C em. Soc. , 83, 1246 (1961) and 211 mg. of azobisisobutyronitrile. The mixture is stirred at 50°C. for 30 minutes. Then the benzene is removed by evaporation under reduced pressure, the oily residue is dissolved in 1.5 1. of ether and the ethereal solution is washed several times with 5% aqueous sodium hydroxide solution and then with saturated sodium chloride solution, dried over magnesium sulfate and evaporated unde vacuo. The residue is chromatographed on 915 g. of silica gel using as first eluant ether-hexane (l:l) to remove non-polar tin by-products. The fractions eluted with ethyl acetate afford the desired (2' a-hydroxy-41 -p-phenylbenzoyloxy- 1 β-benzyloxymethylcyclopent-l ' -yl ) -acetic acid 1 , 2' -lactone.

In a similar manner, (2' a-hydroxy-4' -p-phenylbenzoyloxy-3 ' β-ίοάο-5' β-methoxymethylcyclopent-l ' a-yl) -acetic acid 1,2' -lactone is converted into ( 2' -hydroxy-4' -p-phenyl- benzoyloxy-5 ' β-methoxymethylcyclopent-l 1 α-yl ) -acetic acid " 1 , ' -lactone.

PREPARATION 8.

A. To a prehydrogenated suspensio of 1 g. of 10% palladium charcoal catalyst in 200 ml. of anhydrous dime-thoxyethane are added 10 g„ of (2' a-hydroxy-4' a-p-phenylbenzo-yloxy-51 β-benzyloxymethylcyclopent-l ' -yl ) -acetic acid 1,2'-lactone and 1 ml. of perchloric acid, and the mixture is stirred under hydrogen atmosphere until the absorption of hydrogen ceases. The catalyst is then separated by filtration and washed with ether. The combined organic filtrates are washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crys tallization of the residue from chloroform, yields (2'a-hydroxy 41 a-p-phenylbenzoyloxy-5 ' β-hydroxymethylcyclopent-l ' -yl ) -acetic acid 1,2' -lactone (_8) .

B0 A stirred solution of 15 g. of ( 2 ' a-hydroxy-4' a-p-phenylbenzoyloxy-51 β-methoxymethylcyclopent-l ' -yl ) -acetic acid 1,2 '-lactone in 190 ml. of anhydrous methylene chloride is cooled to -78°C. in a dry ice-acetone bath and treated with 25 ml. of boron tribromide. The stirred mixture is allowed to warm rapidly to 0°C. and kept at this temperature for 50 minutes. To the resultant solution is then added 270 ml. of ether to decompose excess boron tribromide, maintaining the reaction mixture at 0°C. It is then poured into a vigorously stirred slurry of 95 g„ of sodium bicarbonate in 500 ml. of a saturated solution of sodium potassium tartrate; the organic layer is. separated and the aqueous phase extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified by crystallization from chloroform to afford ( 2 ' a-hydroxy-41 a-p-phenylbenzoyloxy-51 p-hydroxymethylcyclopent-l 1 a-yl ) -acetic acid 1 , 21 -lactone , identical to the product obtained in Part A.

C. To a suspension of 300 g. of Celite, diato-maceous earth (dried for 24 hours at 105°C) and 61.5 g. of chromium trioxide-dipyridine complex [prepared as described by J. C. Collins et al. , Tetrahedron Letters 3363 (1968)] in 610 ml. of anhydrous methylene chloride, cooled to -5°C. are added under stirring 10 g. of ( 21 -hydroxy-4 ' a-p-phenylbenzo-yloxy-51 β-hydroxymethylcyclopent-l 1 a-yl ) -acetic acid 1,2' -lactone dissolved in 60 ml. of methylene chloride and the mixture is stirred for 10 minutes further, maintaining the temperature between -5°C. and 0°C„ ; 100 g. of sodium bisulfite monohydrate are then added and the mixture is stirred for an additional 10-minute period, filtered through magnesium sulfate and the solids washed with methylene chloride, receiving the filtrate in a flask cooled to -60°C. in a dry ice-acetone bath. The combined filtrates are evaporated to dryness under reduced pressure, at a temperature below 0°C, obtaining ( 21 -hydroxy-4,a-p-phenylbenzoyloxy-5' β-formylcyclopent-1 ' -yl) -acetic acid 1,2' -lactone (9) as an homogeneous oil.

PREPARATION 9.

' A solution of 22 g. of ( 21 α , 4 ' a-dihydroxy-3 ' p-iodo-51 P-benzyloxymethylcyclopent-11 a-yl ) -acetic acid 1,2'-lactone in 60 ml. of anhydrous pyridine is cooled to 0°C. and treated. dropwise , under stirring, with a mixture of 8 ml. of phosphorous oxychloride and 20 ml. of pyridine. When the addition is complete, the reaction is stirred for 30 minutes at room temperature, and the solvent is eliminated under reduced pressure. The oily residue is dissolved in methylene chloride, and the organic solution, washed with 10% hydrochloric acid solution, reextracting the aqueous phases with methylene chloride.

The combined organic extracts are then washed with saturated sodium sulfite solution until complete decoloration,-dried over magnesium sulfate and evaporated to dryness under reduced pressure to yield ( 21 a-hydroxy-51 P-benzyloxymethylcy- o clopent-3' -en-1" a-yl) -acetic acid 1,2' -lactone (_13, R = benzyl) as a colorless oil.

In a similar manner, starting from (2' , 4' a-dihydroxy-3' p-iodo-5' β-methoxymethylcyclopent-l ' a-yl ) -acetic acid 1,2' -lactone there is obtained ( 2 ' a-hydroxy-5 ' β-methoxy-methylcyclopent-3' -en-1' -yl) -acetic acid 1,2' -lactone (13 , R = methyl) . 42670/2 PREPARATION 10.

A stirred solution of 13 g. of ( 21 (^hydroxys' P-benzyloxymethylcyclopent-31 -en-1 ' a-yl ) -acetic acid 1,2'-lactone in 20 ml. of methanol is cooled to 0°C. and treated dropwise with a solution of 6.5 g. of sodium hydroxide in 65 ml. of water; when the addition is complete the reaction mixture is stirred for one hour at room temperature. The methanol is then eliminated under reduced pressure at a temperature below 30°C. , and the resulting aqueous solution cooled to 0°C and extracted with ether, to eliminate the unsaponifiable ι products. The aqueous phase is carefully acidified to pH 5-6 with 3 hydrochloric acid at 0°C. , 100 ml. of ethyl acetate are then added and thereafter the reaction mixture is acidified to pH 2-3. The organic phase is separated and the aqueous phase is saturated with sodium chloride, extracting it with six 50 ml. portions of ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo. Crystallization of the residue from hexane-methylene chloride gives the pure ( 2 ' a-hydroxy- ' β-benzyloxymethylcy- o clopent-3' -en-1' α-yl) -acetic acid (14, R = benzyl).

In a similar manner ( 2 ' a-hydroxy-5' P-methoxyme-thylcyclopent-3' -en-11 -yl ) -acetic acid 1,2' -lactone is converted into ( 21 -hydroxy-51 p-methoxymethylcyclopent-31 -en-11 - 8 yl) -acetic acid (14, R = methyl).

PREPARATION 11.

To a prehydrogenated suspension of 10 g. of Raney nickel in 200 ml. of methanol is added 13 g. of (2'a-hydroxy-5' P-benzyloxymethylcyclopent-3' -en-1'a-yl ) -acetic acid, and the mixture is stirred under hydrogen atmosphere until the uptake of hydrogen ceases ; the catalyst is then separated by filtration and washed well with ether. The combined organic filtrates are evaporated to dryness under reduced pressure and the oily residue is dissolved in 200 ml. of ethyl-acetate. The resultant solution is then treated with 3N hydrochloric acid until a pH of 2-3 is obtained, stirring the reaction mixture for 30 additional minutes „ It is then neutralized with sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under vacuo, thus yielding (21 a-hydroxy-5' p-benzyloxymethylcyclopent-1 ' -yl ) -acetic acid 1,2'- o lactone, (15, R = benzyl) homogeneous on t.l.c.

In a similar manner, ( 21 a-hydroxy-5 ' P-methoxy-methylcyclopent-4 '-en-11 a-yl ) -acetic acid is converted into (2' -hydroxy-5' P-n-ethoxymethylcyclopent-l 1 a-yl ) -acetic acid Q 1,2' -lactone (15, R = methyl).

PREPARATION 12.

By following the method of Preparation 8, Parts A and B , respectively, ( 21 a-hydroxy-5 ' β-benzyloxy ethylcyclo-pent-1 ' -yl ) -acetic acid 1,2 '-lactone and (21 a-hydroxy-5 ' p-methoxymethylcyclopent-1 ' a-yl ) -acetic acid 1,2' -lactone are converted into ( 21 -hydroxy-51 β-hydroxymethylcyclopent-l 1 a-yl) -acetic acid 1 , 2 · -lactone , which upon oxidation with chromium trioxide-dipyridine complex, in accordance with the method of Part C of Preparation 8, affords ( 21 a-hydroxy-5 ' p- ormylcyclopent-11 a-yl ) -acetic acid 1 , 21 -lactone,, PREPARATION 13, A. A solution of 100 g. of dimethyl methylphos-phonate in 670 ml. of anhydrous tet ahyd ofuran is cooled to -78°C. under an argon atmosphere. To the cold solution are added dropwise under stirring and under argon atmosphere, 495 ml. of a 0„1M solution of n-butyllithium in tetrahydrofuran, maintaining the temperature at -70°C„ V7hen the addition is complete the reaction mixture is maintained under the same conditions for 10 additional minutes, a solution of 58 ml . ' of methyl caproate dissolved in 187 ml. of tetrahydrofu an is then carefully added, maintaining the temperature at -78°C.

The reaction mixture is stirred at -78°C„ for two hours followed by stirring for four hours at room temperature. The excess base is neutralized with acetic acid and the solvent is evaporated under high vacuo. The residue is dissolved in ether-water (1:1, 950 ml. each), the ethereal phase is separated, washed with water and dried over magnesium sulfate. The ether is evaporated and the residue is purified by vacuum distilla- e 42670/2 Β.' To a suspension of 1055 g. of sodium hydride (previously washed with pentane, under argon) in 355 ml. of dimethoxyethane freshly distilled from lithium aluminum hydride is added, under stirring and under an atmosphere of argon, a solution of 7.1 g. of dimethyl 2-oxoheptylphosphonate in 150 ml. of dimethoxyethane. The reaction mixture is stirred for 30 minutes at room temperature and 10 g. of ( 21 cc-hydroxy- 1 a-p-phenylbenzoyloxy-5 ' β-formylcyclopent-1 ' a-yl ) -acetic acid 1,2' -lactone are added. The reaction mixture is stirred at room temperature for two hours further, it is then carefully neutralized with acetic acid (to pH 7) and evaporated to dryness under reduced pressure at a temperature below 30°C. The solid residue is purified by chromatography on Florisil, using methylene chloride as eluant , to obtain [ 2 ' a-hydroxy-41 a-p-phenylbenzoyloxy-51 β-( 3"-oxo-oct-l " ( t )-en-l "-yl ) -cyclope t-1 ' a-yl]-acetic acid 1,2' -lactone (10) and a small amount of dimethyl 2-oxoheptylphosphonate.

• In a similar manner, ( 2' a-hydroxy-5' β-formylcyclopent-1' -yl) -acetic acid 1,2' -lactone is converted into [ 21 oc-hydroxy- ' β- ( 3"-oxo-oct-l " ( t ) -en-1 "-yl ) -cyclopent-1 ' a-yl] -acetic acid 1,2' -lactone and [ 2 ' a-hydroxy-5 ' β-( 3"-oxodec-l " (t ) -en-1 *'-yl ) -cyclopent-1" a-yl] -acetic acid 1 , 2 * -lactone. 42670/2 PREPARATION 14.

To a stirred solution of 5.34 g. of [ 2' cc-hydroxy-4 » a-p-phenylbenzoyloxy- ' β-( 3 "-oxo-oct-1 " ( t ) -en-1 "-yl ) -cyclo-pent-11 a-.yl] -acetic acid 1,2' -lactone in 36 ml. of dimethoxy-ethane freshly distilled from lithium aluminum hydride are added 9 ml. of zinc borohydride reagent in anhydrous dimetho-xyethane. The reaction mixture is stirred for an additional hour at room temperature, and treated with a saturated solution of sodium bitartrate until the evolution of gas ceases. It is then diluted with methylene chloride, dried over magnesium sulfate and evaporated to dryness under vacuo at a temperature below 30°C. to yield [ 2' a-hydroxy- 1 a-p-phenylbenzoyloxy-51 β-( 3"oc-hydroxyoct-l" (t )-en-l "-yl ) -cyclopent-1 ' a-yl]-acetic acid 1,2' -lactone (l_l, R 9 = p-phenylbenzoyl in mixture with the 3"P-hydroxy isomer.

The oily mixture is separated into the individual isomers by t.l.c. using a mixture of benzene-methylisobutyl ketone (2:l) as eluant.

Similarly the remaining 3"-oxo compound obtained in Preparation 13 is converted into the 3"-hydroxy compound, namely : [ 2' a-hydroxy- 1 β-( 3"a-hydroxyoct-l " ( t ) -en-1 "-yl ) -cyclopent-1 ' a-yl]-acetic acid 1 , 2 ' -lactone , in mixture with the corresponding 3"3-hydroxy isomer, which is separated by thin layer chromatography.

The zinc borohydride reagent is prepared from 0.025 mol of fused zinc chloride, 0.050 mol of sodium borohydride and 50 ml. of dimethoxyethane , stirring the mixture for 16 hours and filtering the insoluble material under argon at 42670/2 PREPARATION 15.

A solution of 3.7 g. of [ 2" a-hydroxy-4' a-p-phe-nylbenzoyloxy-5 ' P-( 3"a-hydroxyoct-1" (t ) -en-1 "-yl ) -cyclopent-11 a-yl]-acetic acid 1,2' -lactone in 37 ml. of anhydrous methanol is treated with 1.14 g„ of anhydrous potassium carbonate, and the reaction mixture stirred for two and one-half hours at room temperature. It is then cooled to 0°C. and adjusted with ION aqueous hydrochloric acid until a pH of 2-3 is obtained.' Ethyl acetate is added and the organic solution washed with saturated sodium bicarbonate solution and saturated sodium potassium bitartrate solution, dried over magnesium sulfate and evaporated to dryness under vacuo. The residue is purified by filtration through a Florisil column (130 g.). The fractions eluted with methylene chloride-ethyl acetate give methyl p-biphenylcarboxylate and the fractions eluted with ethyl acetate yield [21 α,4' a-dihydroxy-5 ' β-(3"α-hydroxyoct-1 " (t ) -en-l"-yl ) -cyclopent-11 a-yl]-acetic acid 1,2'-lactone (11 , R9 = H) . 42670/2 • ~< PREPARATION 16.

To a solution of 2.3 g. of [2' α,4' a-dihydroxy-51 β· ( 3 "a-hyd oxyoct-1 " ( t ) -en-1 " -yl ) -cyclopent-1 ' a-yl] -acetic acid 1,2' -lactone in 23 ml0 of methylene chloride are added 2.3 ml. of freshly distilled dihydropyran and.23 mg. of anhydrous p- toluehesulfonic acid. The reaction mixture is stirred for 15 minutes at room temperature, a. few drops of pyridine are added and diluted with ether. The ethereal solution is- washed with 100 ml. of 50% aqueous sodium chloride solution and then with saturated sodium chloride solution. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure, at approximately 0°C. , thus yielding [2' a-hydroxy-4' a-tetrahydropyranyloxy-51 p-(3"a-te- trahydropyranyloxyoct-1 " ( t ) -en-1 " -yl ) -cyclopent-1 ' a-yl] - acetic acid 1 , 2' -lactone , (.12) as an oil.

In a similar manner, [2' a-hydroxy-51 P-CS'Ot-hy-' droxyoct-l"(t)-en-l"-yl)-cyclopent-l' a-yl]-acetic acid 1,2«-lactone is converted into [21 a-hydroxy-5 ' β- (3 " a-tetrahydro-pyranyloxyoct-1" (t) -en-l"-yl) -cyclopent-1' a-yl] -acetic acid 1,2' -lactone.

PREPARATION 17. : . -.< One gram of [ 21 a-hydroxy-41 a-tetrahydropyranylr oxy-5 ' p-(3 "a-tetrahydropyranyloxyoct-1 " ( t ) -en-1 "-yl ) -cyclopent-l 1 ct-yl] -acetic acid 1,2' -lactone is dissolved in 20 ml. of anhydrous toluene. The solution is cooled to -60°C. and ■to the cold solution is added 3.43 ml. of a mixture of 1 ml. of diisobutyl aluminum hydride and 3 ml. of anhydrous toluene stirring the reaction mixture for 15 minutes at -60°C. It is then diluted with methanol until the evolution of gas ceases, the mixture is stirred for 15 minutes further at room temperature and diluted with ether. The organic phase is then separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness at about 0°C. to produce [ 2' a-hydroxy-4' a-tetrahydropyranyloxy- 51 β-( 3"a-tetrahydropyranyloxyoct-1 " ( t ) -en-1 "-yl ) -cyclopent- 1 ' a-yl]-acetaldehyde 1 , 2 ' -hemiacetal ( IA:) .

Similarly, the remaining compound obtained in Preparation 16 is converted into the lactol, namely: [ 2' a-hydroxy-5' p-(3"a-tetrahydropyranyloxyoct-l " (t)-en-l"-yl )-cyclopent-l 1 a-yl]-acetaldehyde 1 , 2' -hemiacetal .

PREPARATION 18.

In accordance with the methods described in Preparations 15, 16 and 17, 2 g. of [ 2' -hydroxy-4 ' a-p-phenylben-zoyloxy-5 ' P-(3"P-hydroxyoct-^1 " (t ) -en-1 "-yl ) -cyclopent-l ' a-yl] -acetic acid 1,2' -lactone are converted successively into [21 α,4' a-dihydroxy- 1 P-(3"P-hydroxyoct-1" (t)-en-l"-yl ) -cyclopent-l 1 a-yl]-acetic acid 1 , 2 ' -lactone, [ 2' a-hydroxy-4' a-tetrahydropyranyloxy-5' P-(3"p-tetrahydropy-ranyloxyoct-1 " (t ) -en-1 !,-yl ) -cyclopent-l ' a-ylJ-acetic acid 1,2' -lactone and 2' a-h drox - ' a-tetrah dro ran lox - ' - " - e - EXAMPLE 1.

A mixture of 2,14 g. of pent-4-yn-l-ol and 250 ml. of anhydrous ether is cooled under an- argon atmosphere to -70°C. in a dry ice-acetone bath. To the stirred cold mixture is added dropwise 26 „ 2 ml. of 2M methyllithium in ether. After addition of this reagent, the reaction mixture is allowed to attain room temperature, stirring for 18 hours further. A solution of 38O' mg. of [ 21 a-hydroxy-4 ' -te.trahydropy anyl0x3^- ' p-( 3"a-tetrahydropyranyloxyoct-l " ( t ) -en-l"-yl ) -cyclopent-11 cc-yl]-acetaldehyde 1 , 2 ' -hemiacetal (I, R1 = tetrahydropy-ranyloxy) in 5 ml. of anhydrous ether is added, and the mixture is stirred for six hours at room temperature.

It is then poured into ice water and extracted .several times with ether. The combined organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure, at a temperature not higher than 20°C. The residue is purified by chromatography on Florisil. The fractions eluted with ethyl acetate-methanol (90:10) give 1 ,6 , 9a-trihydroxy-ll , 15a-bistetrahydropyranyloxyprost — -yn-13-trans-ene (II, R1 = tetrahydropyranyloxy ) .

The 6a and δβ-hydroxy isomers can be separated by t.l.c. on silica gel, using a mixture of methylene chloride-ether (1:1) as eluant.

In a similar manner, [ 21 -hydroxy- ' β-( 3"a-tetra-hydropyranyloxyoct-1 " (t)-en-l"-yl)-cyclopent-l 1 a-yl]-acetal-dehyde 1 , 2' -hemiacetal is converted into 1 , 6 \ , 9a-tr hydroxy- 1 a-tetrahydropyranyloxyprost-4-yn-13-trans-ene (II, R 11 = H) .

EXAMPLE 2. ..^ A mixture of 300 mg. of 1 , 6 f , 9a-trihydroxy-lla,15a-bistetrahydropyranyloxyprost — -yri-13-trans-ene, 2 ml. of pyridine and 0.2 ml. of acetyl chloride is stirred at room temperature for six hours. It is then poured into water and extracted with ether. The organic extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo to yield l,6f,9a-triacetoxy-11 , 15 -bistetrahydropy any1oxyprost-4-y -13- ans-ene (III, R1 = tetrahydropyranyloxy) which can be purified by filtration through Fl'o isil.

By the same method 1 ,6 j ,9a-trihydroxy-15a-tetra-hydropyranyloxyprost-4-yn-13-trans-ene is converted into 1,6 ,9 -triacetoxy-15a-tetrahydropyranyloxyprost-4-yn-13-trans-ene (III, R1' = H) .

EXAMPLE 3.

• A stirred suspension of 117.5 mg. of cuprous iodide in 2 ml. of anhydrous ether is cooled to about -10°C. under an atmosphere of argon, and treated with two molar equivalents of a 2M solution of methyllithium in ether. The resultant colorless solution is cooled to -75°C. in a dry ice-acetone bath, a solution of 100 mg. of 1 , 6 ,9a-triacetoxy-11a, 15 -bistetrahydropyranyloxyprost-4-yn-13-tr ns-ene in 3 ml. of anhydrous ether is then added and the reaction mixture stirred at -75°C. for five hours. The temperature of the mixture is raised to -10°C. , saturated ammonium chloride solution is added and the mixture is stirred for one hour and extracted with ether. The organic extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified by chromatog aphy on Florisil. The fractions eluted with methylene chlo ide-ether (80: 20 ) afford the pure 1 , 9a-diacetoxy-lla, 15a-bistetrahydropyranyloxyprosta-4 ,-5 , 13-trans-triene (VIII, R = tetrahydropyranyloxy).' In a similar manner, but using 1 , 6 , 9 a-triacetoxy-15a-tetrahydropyranyloxyprost-4-yn-13-trans-ene , there is obtained: 1 , 9 -diacetoxy-15oc-tetrahydropyranyloxyprosta-4 , 5 , 13-trans--' triene .

EXAMPLE 4.

A mixture of 110 mg. of 1. , 9oc-diacetoxy-lla , 15a- istetrahydropyranyloxyprosta-4 , , 13-trans-triene, 50 mg. of . anhydrous potassium carbonate and 2 ml0 of anhydrous methanol is stirred at room temperature for 18 hours, under an argon atmosphere. The solvent is then eliminated under reduced pressure, water is added and the product extracted with ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo, thus yielding 1 , 9a-dihydroxy-lla, 15a-bis-tetrahydropyranyloxyprosta-4 , , 13-trans-triene (IX, R1 ' = tetrahydropyranyloxy) .

In a similar manner, the remaining 1 , 9a-diacetoxy compound obtained in Example 3 is converted into 1 , 9a-dihydroxy-15a-tetrahydropyranyloxyprosta-4 , 5 , 13-trans-triene . 42670/2 —( EXAMPLE 5. , A solution of 300 mg. of 1 ,9a-dihydroxy-lla,15a-bistetrahydropyranyloxypros ta-4 ,5,13-trans-t iene in 10 ml. of acetone is cooled to -10°C„ and treated under an atmosphere of nitrogen and with stirring, with 0,8 ml, of an 8N solution of. chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 ml. of concentrated sulfuric acid and diluting with water to 100 ml.). The reaction mixture is stirred for 90 minutes further at -10°C. , a few drops of isopropanol are then added to destroy the excess reagent, and the mixture diluted with ethyl acetate. The solution is immediately washed three times with sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. To the oily residue is added 2.4 ml. of a mixture of acetic acid-water (65:35), and the reaction mixture is stirred at room temperature for 18 hours, it is then evaporated to dryness under vacuo and the residue purified by t.l.c. using ethyl acetate as eluant , to give the pure 9-keto-lla,15a-dihydroxy-prosta- , 5 , 13-trans-trienoic acid (XI, R hydroxy ) .

Likewise, 1 ,9a-dihydroxy-1 ot-tetrahydropyranyl-oxyprosta-4 , ,13-trans-t iene , is converted into 9-keto-15a-hydroxyprosta-4 ,5 , 13-trans-trienoic acid.

EXAMPLE 6.

A. A mixture of 100· mg. of 1 , 9a-diacetoxy-lla,15a-bistetrahydropyranyloxyprosta-4 , 5 , 13-trans-triene , 27.5 mg. (1.1 molar equivalents) of anhydrous potassium carbonate and 2 ml. of anhydrous methanol is stirred at 0°C. for two hours, under an argon atmosphere. The solvent is then eliminated under reduced pressure, water is added and the product extracted with ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo. The residue is purified by t„l.c0, to produce the pure 9 a-aceto'xy-lla , 15a-bistetrahydropyranyloxyprosta-4 , 5 , 13-trans-trien-l-ol (XII , 1 ' R = tetrahydropyranyloxy) .

Upon oxidation of the foregoing compound with SIT chromic acid, in accordance with the method of Example 5, there is produced 9a-acetoxy-lla , 15a-bistetrahydropyranyloxypros ta-4 , , 13-trans-trienoic acid. The latter compound is then treated with anhydrous potassium carbonate (25 mg„ ) in methanol, in accordance with the method of Example 4, followed by acidification with oxalic acid to afford 9a-hyd oxy-11a , 15a-bistetra-hydropyranyloxyprosta-4 , 5 , 13-trans-trienoic acid (XIV, R11 = tetrahydropyranyloxy) .

B. A solution of 50 mg. of 9a-hydroxy-lla , 15a- ' bistetrahydropyranyloxyprosta-4 , , 13-trans-t ienoic acid in 0.15 ml. of tetrahydro uran is treated with 1.3 ml. of 650 aqueous acetic acid. The reaction mixture is stirred at 45°C. for four hours, cooled to 0°C. and evaporated to dryness under reduced pressure the oily residue is purified by t.l.c. using chloroform: methanol (9:1) as eluant , thus yielding the pure 9a , 11a , 15a-trihydroxyprosta-4 , , 13-trans-trienoic acid (XV, R1 = hydroxy).

In a similar manner but using 1 , 9a-diacetoxy-15a-tetrahydropyranyloxyprosta-4 , 5 ,13-trans-triene as starting compound there are successively obtained: 9a-acetoxy-15a-tetrahydropyranyloxyprosta-4 , 5 , 13-trans-trien-l-ol, 9a-acetoxy-15a-tetrahydropyranyloxyprosta-4 , 5 , 13-trans-t ienoic acid , 9a-hydroxy-15ci-tetrahydropyranyloxyprosta-4 , 5 ,13-trans-trien-oic acid and 1 " 9ar15a-dihydroxyprosta-4 , 5 ,13-trans-trienoic acid (XV, R = H) EXAMPLE 7'.

To a solution of 500' mg. of 9-keto-lla, 15a-dihy-d oxyprosta-4, 5 , 13-trans-trienoic acid in 10 ml. of methylene chloride is added an excess of ethereal diazomethane and the reaction mixture is kept at room temperature for 30 minutes. It is then evaporated to dryness under vacuo, to yield 9-keto-11a, 15a-dihydroxyprosta-4, 5 , 13-trans-trienoic acid methyl ester The foregoing crude compound is dissolved in 10 ml. of methanol and the resultant solution cooled to 0°C. To the cold solution are added 250 mg. of sodium borohydride, and the reaction mixture is stirred at room temperature for 30 minutes. The solvent is then eliminated under reduced pressure, water is added and the product extracted with ethyl acetate. The organic extract is washed with dilute hydrochloric acid solution and water to neutral, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica gel using methylene chloride-ethyl acetate mixtures to thus obtain 9a , 11a , 15a-trihydroxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester, and 9 β , 11α , 15a-trihydroxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester in approximately equal amounts (XVI, 1 " 41 R = hydroxy; R = methyl) .

In a similar manner, starting from 9-keto-15a-hydroxyprosta-4 , 5 , 13-trans-trienoic acid, there is obtained 9a,15a-dihydroxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester and 9 P, 15 -dihydroxyprosta-4, 5,13-trans-trienoic acid methyl ester .

EXAMPLE 8.

A mixture of 400 rag. of 9a-hydroxy-lla , 15a-bis-tetrahydropyranyloxyp osta-4 , , 13-trans-trienoic acid and 60 ml. of ethereal diaz.omethane is maintained at room temperature for 30 minutes. The solvent is then evaporated under vacuo, to yield 9a-hydrox3'-lla , 15a-bistetrahydropyranyloxy-prosta-4 ,5,13-trans-t ienoic acid methyl ester (XIV-A, R = tetrahydropyranyloxy) .

In a similar manner, from the corresponding free acid there is produced the following compounds: 9a-hydroxy-15a-tetrahydropyranyloxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester.

EXAMPLE 9.

H.

Examples 1,2,3, 6 (part A) and 8 are repeated but using [ 2 ' a-hydroxy-4 ' a-tetrahydropyranyloxy- ' p-(3"P-te- trahydropyranyloxyoct-1 " ( t ) -en-1 "-yl ) -cyclopent-1 ' a-yl] -ace- taldehyde 1 , 21 — hemiacetal as starting material, thus obtaining successively 1 ,6 *} ,9a-trihydroxy~lla,15P-bistetrahydropy- any1oxyp ost- -yn-13- rans -ene , 1 ,6\ ,9«-triacetoxy-ll ,15P-bistetrahydropyranylcxyp ost-4-yn- 13-trans-ene, 1 ,9a-diacetoxy-lla,15P-bistetrahydropyranyloxyprosta-4 ,5,13- trans-triene , 9 -acetox}'-lla , 15P-bistetrahydropyranyloxyprosta-4 , ,13-trans trien-l-ol , 9a-hydroxy-11o: , 1 p-bistetrahydropyrany1oxyprosta-4,5,13-tr ns trienoic acid, and 9a-hydroxy-lla , 15P-bistetrahydropyranyloxyprosta- ,5,13-trans trienoic acid nethyl ester (XIV-A, R = tetra- hydropyranylox}') .

EXAMPLE 10.

A solution of 500 mg. of 9a-hydroxy-lla,1 -bis-tetrahydropyrariyloxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester in 10 ml. of 65% aqueous acetic acid is stirred at room temperature for 18 hours. It is then evaporated to dryness under reduced pressure, the residue is dissolved in ethyl acetate and the solvent is eliminated by distillation under vacuo. The residue is purified by chromatography on 50 g. of Florisil. The fractions eluted with diethyl ether-ethyl acetate (80:20) yield the pure 9a , 11a , 15P-trihydroxyprosta- , 5 , 13-trans-trienoic acid metlryl ester (XVI, 1 " E = hydroxy) .

-{ EXAMPLE 11.

To a solution of 750 mg. of 9 , 11a , 15 β-trihydroxy- prosta-4 ,5,13-trans-trienoic acid methyl ester in 15 ml. of anhydrous tetrahydrof ran are added 3 g. of activated manganese dioxide, and the reaction mixture is stirred at room tempera- . ture for 6 hours, the manganese dioxide is filtered off and · ■ washed with acetone, the combined filtrates are evaporated to dryness under reduced pressure. The residue is redissolved in tetrahydrofuran and stirred with another 3 g. batch of manganese dioxide as above, repeating* the operation twice. After final evaporation of the solvent and purification of the residue by chromatography on Florisil there is obtained the pure 9a , ll -dihydroxy-1 -ketoprosta-4 , 5 , 13-1rans- rie oic ac d l " methyl ester (XVII, R = hydroxy).

By repeating the above procedure but using 9 , 11 , 15a-trihydroxyprosta-4 ,5,13-trans-trienoic acid methyl -ester as starting material there is also obtained 9a,lla-di- hydroxy-15-ketoprosta-4 , , 13-trans-trienoic acid methyl ester, In a similar manner, starting from 9a,15a-dihy- ■ droxyprosta- , , 13-trans-trienoic acid methyl ester, there is obtained 9a-hydroxy-15-ketoprosta-4 , 5 , 13-trans- trienoic acid methyl ester. 42670/2 EXAMPLE 12.

A0 To a stirred mixture of 6 ml. of hexamethyl-disilazane and 1,2 ml. of trirnethylchlorosilane there is added a solution of 200 mg„ of 9 , ila-dihyoroxy-15-ketoprosta-4 , 5 , 13-trans-tr ienoic acid methyl ester in 20 ml. of anhydrous tetrahydrofuran, under an argon atmosphere, and the resulting mixture is stirred at room temperature, under anhydrous conditions for 16 hours. It is then evaporated to dryness under reduced pressure. The residue is dissolved in 10 ml. of toluene and the solvent eliminated under vacuo, repeating the operation several times, thus obtaining the- crude 9a,lla-bis-( trimethylsilyloxy)-15-ketoprosta-4 , 5 , 13-trans-trienoic acid methyl ester (XVIII, R = trimethylsilyloxy) .

B. The foregoing crude product is dissolved in 20 ml. of anhydrous diethyl ether, and the resulting solution is cooled to -7S°C. in a dry ice-acetone bath. To the stirred cold solution is added dropvise an ether solution of 1.1 molar equivalents of methyllithium (2.8 ml. of 0.22M methyllithium' in ether) under stirring and under an argon atmosphere. The resulting stirred mixture is allowed to attain room temperature and stirred 2 additional hours at this temperature. It is then poured into a saturated solution of ammonium chloride, the ethereal phase is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo, thus obtaining the crude 9a,llc-bis-( t imethylsilyloxy ) -15? -hydroxy-15} -methylpros ta-4 ,5,13-t a s- CDCl trienoic acid methyl ester NMR : δΤΜ5 3 °·87 (3H,t), 1.26 (3H,s), 3.66 (3H,s), 3.60-3.90 (3H,s), 4.03-4.20 (lH,m) , 5.00-5.25 (2H,m) , 5.20-5.70 (2H,m) . (Mixture of 15 -hydroxy- 153-methyl and 156-hydroxy-15a-methyl compounds) . ( XI X , 6 3 R = methyl; R = trimethylsilyloxy).

C. A solution of 250 mg. of the crude 9a, 11a-bis-( trimethylsilyloxy ) -15{ -hydroxy-15} -methylprosta- ,5,13-trans -t ienoic acid methyl ester in 10 ml. of 70% aqueous methanol is lept at room temperature for 72 hours. The reaction mixture is then evaporated to dryness under reduced pressure and the residue containing a mixture of 9a,11a,15a- trihydroxy-15P-methylprosta-4.5 » 13-trans-trienoic acid methyl est and 9a ,11a , 15P-trihydroxy-15a-methylprosta-4 , 5 » 13-trans-trienoic acid methyl ester compounds , which mixture of compounds is an oi IR : vfilm 3350, 1955, 1745 cmT1; NMR : 6^∑3 0.78-0.96 (3H,t), max. i raa 1.25 (3H,s), 3.65 (3H,s), 3.75-4.04 (lH,m) , 413-4.40 (lH,m), 5.00-5.24 (2H,m) , 5.40-5160 (2H,m), purified by thin layer chromatography using ethyl acetate-ether (75:25) as eluant , thus obtaining the individual isomers, i.e. 9 , 11 , 15 -tri-hydroxy-15g-methylprosta-4 ,5, 13-trans-trienoic acid methyl ester, an oil; IR: vfllm 3400, 2955, 2940, 2870, 1970, 1745, max. . 1725 cmT1; NMR (carbon 13): δ^2^ 14.04 , 22.65, 23.82, 24.09, 27.34, 27.86, 32.28, 33.22, 42.59, 42.71, 42.91, .(50.03, 50.32)d, 51.72, 55.91, 72.91, 78.47, 89.82, 90.11, 91.09, 128.57, 139.36, 173.72, 204.32; Calcd. for C22 H3g 05 : C, 69.4; H, 9.5; Found: C, 69.39; H, 9.52 and 9a,lla,15e-trihydroxy-15a-methylprosta- 4, 5 , 13-trans-trienoic acid methyl ester, an oil;. IR: vfilm 3400, 2955, 2930, 2870, 1970, 1745, " ΓΠ3.Χ · 1725 cmT1; NMR (carbon 13): 14.01, 22.66 , 23.76 (23.83, 24.09)d, 27.34, 28.38, 32.28, 33.22, 42.62, 42.78, (50.13, 50.42)d, 51.72, 52.92, 72.89, 78.51, (89.82, 90.08)d, (90.99, 91.09)d, 128.48, 139.27, (173.73, 173.83)d, (204.26, 204.35)d; Calcd. for C22 H36 -05: C, 69.4; H, 9.5; Found: C, 69.61; H, 9.68, in pure form (XX, R1 = hydroxy; R6 = methyl) .

Similarly, there is obtained, for example, a residue containing a mixture of 9a, 11a, 15a-trihydroxy-156- ethylprosta-4 , 5 , 13-trans-trienoic acid methyl ester and 9a,- lla-15f5-trihydroxy-15a-ethylprosta-4 , 5 , 13-trans-trienoic acid methyl ester compounds, which mixture of compounds is an oil; IR: vi ΙΠαt.lΧm· 3600' 1955' !730 cmT1; NMR: ■ fiSin2e"L3 0.84 (3H,t), 0.85 (3H,t), 3.64 (3H,s), 3.82-4.02 (1H, m) , 4.18-4.34 (lH,m) , 5.00-5122 (2H,m) , 5.40-5.50 (2H,m) .

By repeating the procedures described in this Example but using as starting materials in part A the remaining compound produced in Example 11, there is obtained as final product! 9a,15a-dihydroxy-15p-methylprosta- , 5 > 13-trans-t ienoic acid methyl ester and 9a ,15p-dihydroxy-15a-methylprosta^-4 , 5 , 13-trans-t enoic acid meth l ester . -< EXAMPLE 13.

Twenty milligrams of 9a, 11a, 15a-trihydroxy-15P-methylprosta- , 5 , 13-trans-trienoic acid methyl ester are dissolved in a mixture of 2 ml. of methanol, 2 ml. of water and 90 mg. of potassium carbonate. The reaction mixture is maintained at 40°C for 16 hours under nitrogen atmosphere , 10 ml. of water are then added, and the reaction mixture is then evaporated under reduced pressiire to half volume. It is then acidified with 50% acetic acid and extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 9a, 11a, 15a-trihydroxy-15P-methylprosta- 1 " 4,5,13-trans-trienoic acid (XXI, R = hydroxy; R = methyl) .

In a similar manner 9a , 15a-dihydroxy-15 -methyl-prosta-4 , 5 , 13-trans-trienoic acid methyl ester is converted into the corresponding free acid.

Likewise there is obtained, for example, 9a, 15£-dihydroxy-15£-methylprosta-4 , 5 , 13-trans-trienoic acid, an oil; IR: vCHC13 3600, 1955, 1915 cmT1, and max. ' 9a, 11a, 15^ -trihydroxy-15^-methylpfosta-4 , 5", l"3-"trans-trienoic acid, an oil; IR: vfllm 3360, 1960, 1720 cmT1; N R: max. 6 MS 3 °·78-0·97 (3H,t), 1.27 (3H,s), 3.78-4.07 (lH,m) , 4.07-4.35 (ΐΗ,ιτι) , 4.95-5.29 (2H,m) , 5.40-5.63 (2H,m) ; MS: m/e 348 (M+-H20) 330 (M+-2H20) , 312 (M+-3H20) . -i EXAMPLE 14.

A. A suspension of 4 g„ of crude pancreatic lipase (Sigma L-3126) in 40 ml. of an 0.1M sodium chloride and 0.05M calcium chloride solution in water is stirred at 25°C. for one hour. The mixture is then cent ifuged for one hour at 5000 rev/min. and ■ at 25°C to 30°C. The supernatant is neutra--•lized with IN sodium hydroxide solution to pH 7.2 to 7.4 and used directly for the hydrolysis of the prostaglandin derivatives of the invention.

B. Forty-two milligrams of 9a,lla,15a-trihydroxy-15P-methylprosta—4 , 5 , 13-trans-trienoic acid methyl ester are dissolved by sonication at 37 °C for 20 minutes in 30 ml. of the lipase solution prepared as described in part A. The reaction mixture is magnetically stirred for 15 minutes at 25°C to 26°C, adjusting constantly the pH at 7.2 to 7.4 during the reaction period with IN sodium hydroxide soliition. The reaction mixture is then acidified to pH 2.5 using a 0.2N hydrochloric acid solution and the product extracted several times from the solution with ethyl acetate and ether. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness under vacuo. The residue is dissolved in methylene chloride and chromatographed on 3 g. of Flor sil. The column is elited successively with methylene chloride-di-ethyl ether mixtures, diethyl ether, diethyl ether-ethyl ace- ■ tate mixtures, pure ethyl acetate and ethyl acetate-metlianol (80:20). The fractions eluted with the latter solvent mixture afford the pure 9 , lla,1 a-trihydroxy-1 P-methylprosta-4 , , 13-trans-trienoic acid, identical to the product obtained in Example 13.

In a similar manner by following the above procedure, the remaining alkyl ester compounds obtained in Example 2β as final products are converted into the correspond ing free acids.

EXAMPLE 15.

To a solution of 500 mg. of 9-keto-lla,15a-bis-tetrahydropyranyloxyprosta- ,5,13-trans-trienoic acid methyl ester in 10 ml. of 65% aqueous acetic acid is stirred at room temperature for 18 hours. It is then evaporated to dryness under reduced pressure, the residue is dissolved in ethyl acetate and the solvent is eliminated by distillation under vacuo. The residue is purified by chromatography on 50 g. of Florisil. The fractions eluted with diethyl ether-ethyl acetate (80:20) yield the pure 9-keto-llct , 15a-dihydroxyprosta- 4 , 5 , 13-trans-trienoic acid methyl ester (Methyl ester of XI,· 1 " R = hydroxy) .

In a similar manner, starting from the corresponding 15a-monotetrahydropyranyloxy compound of Example 8 there is obtained 9-keto-15a-hydroxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester. ί' /' -( EXAMPLE 16.

To a solution of 400 mg. of 9-keto-lla , 15a-di-hydroxyprosta-4 , , 13-trans-trienoic acid jnethyl ester in 3 ml of methanol is added a solution of 400 mg. of hydrcxylamine hydrochloride and 500 mg. of sodium acetate in 10 ml. of methanol-wa er (l:l)„ The resulting reaction mixture is kept at room temperature for 18 hours under argon atmosphere and the solvent is then eliminated under reduced pressure. The residue is taken up in water and the mixture extracted wi.t ethyl acetate, the organic phase is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo, thus obtaining 9-hydroxyimino-lla, 15a-dihydroxyp osta-4 , 5 , 13-trans-trienoic 1" acid methyl ester. (XXII, R = hydroxy).

In a similar manner, starting from the remaining 9-keto compound obtained in Example 15, there is obtained the corresponding oxime , i.e., 9-hydroxyimino-15a-hydroxyprosta-4,5, 13-trans-trienoic acid methyl ester.

EXAMPLE 17.

To a solution of 250 mg. of 9-hydroxyimino-lla , 15a-dihydroxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester in 5 ml. of anhydrous tetrahydrofuran is added 1 g. of activated manganese dioxide, and the reaction mixture is stir red at room temperature for 6 hours, the manganese dioxide is filtered off and washed with acetone and the combined filtrates are evaporated to dryness under reduced pressure. The residue is redissolved in t etrahydrofuraii and stirred with another 1 g0 batch of manganese dioxide as above, repeating the operation twice. After final evaporation of the solvent and purification of the residue by chromatography on Florisil there is obtained the pure 9-hydroxyimino-lla-hydroxy-15-] eto-prosta-4 , 5 , 13-trans-tr ienoic acid methyl ester (XXIII, 1" R = hydroxy) .

By. repeating the above procedure but using as starting material the remaining 9-hydroxyimino compound obtained in Example 16, there is produced the corresponding 15-keto derivatives, 'namely: 9-hydroxyimino-15-ketoprosta-4 , 5 , 13-trans-t ienoic acid methyl ester . ■ EXAMPLE 18.

A. To a stirred mixture of 3 ml . of hexamethyl-disilazane and 0.6 ml „ of trimet ylchlorosilane there is added a solution of 200 mg. of 9-hydroxyimino-lla-hydroxy-15-keto-prosta-4 , 5 , 13-trans-t ienoic acid methyl ester in 15 ml. of anhydrous t etrahyd of ran , under an argon atmosphere and the resulting mixture is stirred at room temperature, under anhydrous conditions for 16 hours. It is then evaporated to dryness under reduced pressure. The residue is dissolved in 10 ml. of toluene and the solvent eliminated under vacuo, repeating the operation several times, thus obtaining the crude 9-tr imethyls ilyloxyimino-lla-trimethyls ilyloxy-15-keto-prosta-4 , 5 , 13-trans-trienoic acid methyl ester (XXIV) .

B„ The foregoing crude product is dissolved in 20 ml. of anh drous dieth l ether, and the resultin solution is cooled to -78°C in a dry ice-acetone bath. To the stirred cold solution is added dropwise an ether solution of 101 molar equivalents of methyllithium (2.7 ml. of 0.22M methyllithium in ether) under stirring and under an argon atmosphere. The resulting stirred mixture is allowed to attain room temperature, and stirred 2 additional hours at this temperature. It is then poured into saturated ammonium chloride solution, the ethereal phase is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo, thus obtaining the crude 9-tri-methylsilyloxyimino-lla-trimethylsilyloxy-151-hydroxy-15 -methylprosta- , 5 , 13-trans-trienoic acid methyl ester. (Mix-ture of 15a and 15β compounds) . (XXV, R = Me; 3 7 ' R = tnmethylsilyloxy ; R = trimethylsilyl) .

C. A solution of 250 mg. of the crude 9-tri-methyls ilyloxyimino-lla-tr imethyls ilyloxy-15 \ -hydroxy-15 -methylprosta-4 , 5 , 13-trans-trienoic acid methyl ester in 10 ml. of 70% aqueous methanol is kept at room temperature for 18 hours under carbon dioxide atmosphere. The reaction mixture is then evaporated to dryness under reduced pressure and the residue purified by thin layer chromatography using ethyl acetate-ether (75:25) as eluant , thus obtaining the individual isomers, i.e. , 9-hydroxyimino-lla,15a-dihydroxy-15p~methyl-prosta-4 , 5 , 13-trans-t ienoic acid methyl ester and 9-hydroxy-imino-11α , 15p-dihydroxy-15c-methylprosta- , 5 , 13-trans-t ienoic acid methyl ester in pure forrn0 D. To a stirred solution of 150 mg. of 9-hydroxy imino-lla , 15a-dihydroxy-15P-methylprosta- , 5 , 13-trans-trienoic acid methyl ester in 3 ml. of methanol is added a solution of 150 mg. of thallium (III) nitrate in 3 ml . of methanol. The reaction mixture is stirred at room temperature for 10 minu— tes, and the formed precipitate separated by filtration and ■ washed with methanol. To the filtrate are , added 5 ml. of dilute acetic acid and the mixture is stirred for 5 minutes, it is then extracted with ether and the organic extract washed . with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on Florisil. The fractions eluted with diethyl ether-ethyl acetate (9:1) afford the pure 9-keto-lla, 15a-dihydroxy-15P-methylprosta-4, 5 , 13-trans- 1 " trienoic acid methyl ester (XXVI, R ' = hydroxy; 6 = methyl) .

By repeating the procedures of parts B and D, using 9 -hydroxyimino-15-ketoprosta-4 , 5 , 13-tr_ans-trienoic acid methyl ester as starting material there is obtained a mixture of 9-keto-15a-hydroxy-15P-methylprosta-4 , , 13-tra s--trienoic acid methyl ester and the 15P-hydroxy-15 -methyl isomer, (XXVI, R1" = H; R6 = methyl) which is separated by chromatography on Florisil.

EXAMPLE 19.

In accordance with the method described In Example 14 , 9-keto-lla ,15a-dihydroxy-15P-methylprosta-4 ,5,13-trans -trienoic acid methyl ester is converted into 9-keto-lla , 15a-dihydroxy-15P-methylpros ta-4 ,5,13-trans-trienoic acid . (XXVII; R1" = hydroxy; R6 = methyl).

Likewise, the remaining compound obtained as final product in Example 18 is converted into the corresponding free acid.

EXAMPLE 20.

To a solution of 100 mg. of 9a , 11 , 1.5a-trihyar0xy-prosta-4 , 5 , 13-trans-trie oic acid in 5 ml . of methylene chloride is added an ethereal solution of diazomethane until the color of the reagent persists in the mixture. The reaction mixture is maintained at room temperature for 1 hour and is then evaporated to dryness under reduced pressure, thus obtaining 9a , 11a , 15a-trihydroxyprosta-4 , 5 , 13-tran≤-trienoic acid methyl ester.

In a similar manner, 9a , 15a-dihydroxyprosta-4,5, 13-trans-trienoic acid is converted into the corresponding methyl ester.

Similarly, there is obtained, for example, 9a, 15^-dihydroxy-15-methylprosta-4 , 5 , 13-trans-trienoic acid methyl ester, an oil; NMR : ¾MS °"86 i3H'fc)' 1,25 (3H,s), 3.66 (3H,s), 4.20-4.36 (lH,m) , 5.00-5.25 (2H,m) , 5.25-5.62 (2H,m).

Likewise, the ethyl esters of the foregoing acids are produced using diazoeth'ane i lieu of diazomethane.

In a like manner, using diazoisopropane in lieu of diazomethane/ there is obtained, for example, 9a, 11a, 15/-trihydroxy-15^ -methylprosta-4 , 5 , 13-trans-trienoic acid iso-propyl ester, an oil; IR: vfllm 3400, 1960, 1730 cm?1; NMR: max . rnn 6TMS 3 0,85 <3H't}' 1·20 <6H'd)' I·23 (3H,s), 3.75-4.00 (lH,m), 4.15-4.30 (lH,m), 4.98 (lH,m) , 5.00-5.20 (2H,m) , 5.40-5.70 (2H,m) .

EXAMPLE 21.

To a solution of 100 rug. of 9-keto-lla , 15a-dihy- droxyprosta-4 ,5,13-trans-trienoic acid in 10 ml. of methanol is added 2.6 ml. of a 0.1N solution of sodium hydroxide, and · the mixture is stirred at room temperature for 1 hour. It is then evaporated to dryness under reduced pressure, to give the sodium salt of 9-keto-lla , 15a-dihydrox}/prosta-4 , 5 , 13-• trans-trienoic acid.

By employing 1.1 molar equivalents of potassium hydroxide (in the form of a 0.1N solution) in ^place of sodium hydroxide in the above procedure the potassium salt of 9-keto- lla ,15a-dihydroxyprosta-4 , 5 , 13-trans-t ienoic acid is obtained.

Similarly, the sodium and potassium salts of the other prostatrienoic acid derivatives obtained in Examples 5, 6, 14 and 19 are produced.

EXAMPLE 22.

To a solution of 100 mg. of 9a,lla,15a-trihydroxy-prosta-4 ,5,13-trans-tr ienoic acid in 10 ml. of methanol is added a mixture of 3 ml. of concentrated ammonium hydroxide solution and 5 ml. of methanol. The resulting mixture is stirred for two hours at room temperature and then evaporated to dryness, to yield the ammonium salt of 9 , 11 , 15a-trihydroxy-prosta-4, 5 ,13-trans-trienoic acid.

By employing dimethylamine , diethylamine or di-propylamine in place of ammonium hydroxide in the above process the corresponding salts of 9 , 11a , 15a-t ihydroxyprosta-4 , 5 , 13-trans-trienoic acid are obtained.

In a similar manner, the ammonium, dimethylamine, diethylamine and dipropylamine salts of the other prostanoic - 9 , 15a-dihydroxyprosta-4 ,5 ,13-trans-trienoic acid, 9α , 15a-dihydroxy-1 P-methylprosta-4 ,5,13-trans-trienoic acid , 9-keto-ll , 15a-dihydroxy-1.P-methylprosta-4 ,5,13-trans-trienoic acid · EXAMPLE 23 , A mixture of 100 mg. of 9a , 11 , 1 a-trihydroxy-prosta-4 ,5,13-trans-trienoic acid methyl ester, 0.4 ml. of pyridine and 0.8 ml. of acetic anhydride is kept at room temperature for 1 hour. The reaction mixture is then evaporated to dryness under reduced pressure and the residue is dissolved in ethyl acetate. Fifty milligrams of sodium bisulfate are added and the solution is filtered through Celite, diato-maceous earth. The filtrate is evaporated to dryness under reduced pressure to yield 9a , 11a , 15a-triacetoxyprosta-4 , 5 , 13-trans-trienoic acid methyl ester.

In a similar manner, other prostatrienoic acid derivatives obtained in Examples 6 and 20 are converted into the corresponding diesters or triesters. 42670/2 EXAMPLE 24.

A solution of 100 mg. 'of 9a , lla-bis ( trimethyls i-lyloxy ) -15-ketoprosta-4 , 5 , 13-trans-tr ienoic acid methyl ester in 20 ml. of anhydrous ether is cooled to -20° C and treated dropwise, under stirring and under argon atmosphere with 6 molar equivalents of 3 methylmagnesium bromide solution in ether. The temperature of the reaction mixture is allowed to rise to 0°C, 6 additional molar equivalents of methylmagnesium bromide solution are added, and the resulting, mixture is stirred for 2 hours more, at .the end of which time there are added 5 ml. of methanol. The resulting mixture is diluted with ether and washed several times with saturated sodium chloride solution. The ethereal extract is then dried over magnesium sulfate and evaporated to dryness under vacuo to yield the crude 9a , lla-bis ( tr methylsilyloxy-15 ) -hydroxy-15 J-methylprosta-4 , 5 ,13-trans-trienoic acid methyl ester, which upon hydrolysis of the protecting tr imethyls ilyloxy groups and purifica-tion by thin layer cliromatography, as described in Example -2-6·, part C, gives rise to the pure 9 ,lla,15a-trihydroxy-15P-methylprosta- ,5,13-trans-tr ienoic acid methyl ester and 9a , 11a ,15P-trihydroxy-15a-methylprosta-4 , 5 , 13-trans-trienoic 6 acid methyl ester (XX, R 1 " = hydroxy; R = methyl) , identical to the compounds obtained in Example 12.

EXAMPLE 25.

To 280 mg. of 9a , lla-dihydroxy-15-ketoprosta-4 , 5 > 13-trans-trienoic acid methyl ester are added 6 ml. of a (1:1) mixture of -trimethylsilyldiethylamine and anhydrous acetone, and the. reaction mixture is kept at room temperature under argon atmosphere for 6 hours. The reaction mixture is then evaporated to dryness under reduced pressure and the oily residue is dissolved in 10 ml. of anhydrous tetrahydro-furan, The resulting solution is cooled to -78°C and treated dropwise, under argon atmosphere, with 1„4 ml. of 2N methyl-magnesium bromide in ether, maintaining the temperature of the reaction mixture below -60°C. The reaction mixture is stirred at -78°C for 5 hours further, diluted with saturated ammonium chloride solution and extracted with ether. The organic extract is washed with saturated ammonium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo. The residue is dissolved in 10 ml. of 70% •aqueous methanol and treated with 0.1 ml. of a mixture of acetic acid water (0.2:3), maintaining the reaction mixture at 0°C for 18 hours. It is then evaporated to dryness under vacuo and the residue purified by thin layer chromatography using a mixture of methylene chloride-ether-methanol" (50:45:5 as eluant , thus obtaining 9

Claims (14)

42670/2 CLAIMS :

1. A compound selected from the group consisting of racemic mixtures of those represented by the formula: wherein R represents hydrogen, hydroxy, acetoxy, tetrahydropyranyloxy or trimethylsilyloxy ; 4 R represents hydrogen, a lower alkyl group or the pharmaceutically acceptable, non-toxic salts 4 of compounds in which R is hydrogen; 6 R represents methyl, ethyl or propyl; 7 R is oxo or a-hydroxy, a-acetoxy, cx-tetrahydro- pyranyloxy or a-trimethylsilyloxy; and the wavy lines (^) indicate the a or p configurat io , or mixtures thereof, provided that when R is a, the hydroxyl group, attached 6 6 to the same carbon atom as R , is β; and when R is β, the hydroxyl g oup, attached to the same carbon atom as E , is a,

2. A compound according to Claim 1, wherein 4 . is hydroxy and R is hydrogen.

3. A compound^ccor^ing---to--jClaim_l,-Whexe.in R^" 4 and R are each hydrogen. T7 - --- 42670/2

4. A compound according to Claim 1, wherein the hydroxy group at C-15 is in the -configuration and the alkyl group R^ at said position is in the β-configuration.

5. A compound according to Claim 1 , wherein- the hydroxy group at C-15 is in the β-configuration and the alkyl group R^ at said position is in the a-configuration.

6. A compound according to Claim 1, wherein R^" is hydroxy, is hydrogen, R^ is β-methyl and R^ is oxo, i.e., 9-keto-lla,15a-dihydroxy-15$-methylprosta- 4 , 5 , 13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.

7. A compound according to Claim 1, wherein 1 4 6 7 R is hydroxy, R is hydrogen, R is β-methyl and R is a-hydroxy, i.e., 9a, lla,15a-trihydroxy-15f3-methylprosta-4,5, 13-trans-trienoic acid and the non-toxic pharmaceutically acceptable salts thereof.

8. A compound according to Claim 1, wherein 1 4 6 7

9. R and R are each hydrogen, R is β.-methyl and R is a-hydroxy, i.e., 9a,,15a-dihydroxy-15g-methylprosta-4 , 5 , 13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof. 42670/3 0. A process for producing a compound selected from the group consisting of racemic mixtures of compounds 7 of the formula I in Claim 1 in which R is oxo, which comprises the steps of: a) converting a racemic compound of the formula: 0 wherein

10. El ' is hydrogen or tetrahydropyranyloxy , i·nto an alkyl ester; b) hydrolyzing the tetrahydropyranyloxy groups; c) protecting the 9-keto group as the oxime; d) selectively oxidizing the hydroxyl group at C-15; e) protecting the hydroxyl group at C-ll when present as the trimethylsilyl ether; f) treating the 15-keto compound with at least 1.1 molar equivalents of an alkyllit ium or an alkyl ag- nesium halide in which the alkyl group ■ is methyl, ethyl or propyl to produce the corresponding 15{ -hy- drox2/-151 -alkyl derivatives; g) hydrolyzing the trimethylsilyloxy group when present; h) optionally separating the 15 -hydroxy-15 β-alkyl and 15 (3-hydroxy-15a-alkyl isomers; i) hydrolyzing the oxime to the corresponding keto compound ; j) hydrolyzing the alkyl ester group by chemical or 42670/2 enzymatic methods and k) optionally esterifying or etherifying the secondary hydroxy! group when present and/or converting the carboxylic acid function into the pharmaceutically acceptable salts.

11. A process for producing a compound selected from the group consisting of racemic mixtures of compounds 7 of the formula (I) in Claim 1, in which R is a-hydroxy, a-acetoxy, a-tetrahydroxpyranyloxy or a-trimethylsilyloxy , which comprises the steps of: a) selectively oxidizing the hydroxyl group at C-15 in a racemic compound of the formula: wherein R is hydrogen or tetrahydropyranyloxy; b) protecting the hydroxyl groups present as the tri- methylsilyl ethers; c) treating the trimethylsilyloxy-15-keto compound with at least 1.1 molar equivalents of an alkyllithiuin or an alkylmagnesium halide in which the alkyl group is methyl, ethyl or propyl, to produce the correspondin !5f -hydroxy-15$ -alkyl derivative; d) hydrolyzing the trimethylsilyloxy groups present; e) optionally separating the 15a-hydroxy-15g-alkyl and 15B-hydroxy-15ot-alkyl isomers; 42670/2 f) hydrolyzing the alkyl ester group by chemical or enzymatic methods, and g) optionally esterifying or etherifying the secondary hydroxyl groups present, and/or converting the carboxylic acid function into the pharmaceutically acceptable salts. 12. A process for producing a compound selected from the group consisting of racemic mixtures of compounds 7 of formula (I) in Claim 1, in which R is a-hydroxy, a-acetoxy, -tetrahydropyranyloxy or a-trimethylsilyloxy , which comprises the steps of: a) converting a racemic compound of the formula: 1 ' wherein R is hydrogen or tetrahydropyranyloxy into an alkyl ester; b) hydrolyzing the tetrahydropyranyloxy groups c) selectively oxidizing the hydroxyl group at C-15; d) protecting the hydroxyl groups present as the 42670/2 v- t imethylsilyl ethers; e) treating the trimethylsilyloxy-15-keto compound with about 1.1 molar equivalents of an alkyllithium or an alkylmagnesium hal de in which the alkyl group is methyl , ethyl or propyl , to prodv.ee the corresponding 15) -hydroxy-15^ -alkyl derivative-, f) hydrolyzing the tr imethyls ilyloxy groups present; optionally g ) /separating the 15o-hydroxy-15P-allcyl and 15P-hydroxy- 15a-alkyl isomers; h) hydrolyzing the alkyl ester group by chemical or enzymat c methods , and i) optionally esterifying or etherifying the secondary hydroxyl groups present, and/or converting the carboxylic acid function into the pharmaceutically acceptable salts.

12. The mixture of 9a,lla,15a-trihydroxy-15P-methylprosta-4 , 5 ,13-trans-trienoic acid methyl ester and 9α,11α,15β-trihydroxy-15oc-methylprosta-4, 5113-trans-trienoic acid methyl ester.

13. a , 11 , 15a-trihydroxy-15p-methylprosta-4 , 5 , 13-trans-trienoic acid methyl ester.

14. 9a , 11a , 15P-trihydr.oxy-15a-methylprosta- , 5 , 13-trans-trienoic acid methyl ester. ND:ed