US3899525A - 9{86 ,15{86 -Dihydroxy-11{60 -hydroxymethylprost-13(trans)-enoic acid derivatives - Google Patents

Abstract

Prostenoic acid derivative having the formula

WHEREIN A represents an alkylene group having from 4 to 8 carbon atoms, R1 represents an alkyl group having from 4 to 10 carbon atoms, R2 represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R3 represents hydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkyl moiety and pharmaceutically acceptable salts thereof. The compounds are useful as oxytocic agents and may be prepared by reducing the compound having the formula

WHEREIN A, R1, R2 and R3 have the meanings given above with a metal hydride complex, for example, sodium boron hydride and potassium boron hydride in the presence or absence of an inert organic solvent.

Description

United States Patent 11 1 Oda et al.

[ 1 Aug. 12, 1975 [54] 9,15-DIHYDROXY-1la-HYDROXYME- THYLPROST- l 3 TRANS -ENOIC ACID DERIVATIVES [75] Inventors: Osamu Oda; Kiyoshi Sakai; Takashi Yusa; Hamako Katano, all of Tokyo, Japan [73] Assignee: Sankyo Company Limited, Tokyo,

Japan 22 Filed: Aug. 27, 1973 21 Appl.No.: 392,113

[30] Foreign Application Priority Data Sept. 1, 1972 Japan 47-8817] [52] US. Cl ..260/463; 260/247.2 R, 260/243.65. 260/326.3, 260/343.2 R, 260/410.9 R.

260/468 D. 260/476, 260/268 R, 260/295 S. 260/390.9. 260/345.8, 260/413, 260/468 R.

[51] Int. Cl... C07C 61/32; CO7C 67/00; CO7C 69/74 [58] Field of Search .260/463. 468. 514

7,311,403 2/1974 Netherlands 260/468 Primary Examiner-Robert Gerstl Attorney, Agent, or Firm-Flynn & Frishauf [57] ABSTRACT Prostenoic acid derivative having the formula wherein A represents an alkylene group having from 4 to 8 carbon atoms, R represents an alkyl group having from 4 to 10 carbon atoms, R represents hydrogen atom or an alkyl group having from one to 6 carbon atoms and R represents hydrogen atom or an alkoxycarbonyl group having from one to 6 carbon atoms in the alkyl moiety and pharmaceutically acceptable salts thereof.

The compounds are useful as oxytocic agents and may be prepared by reducing the compound having the formula 3 R OH C wherein A, R, R and R have the meanings given above with a metal hydride complex, for example, sodium boron hydride and potassium boron hydride in the presence or absence of an inert organic solvent.

6 Claims, N0 Drawings 1 9,15-DIHYDROXY-11a-HYDROXYMETHYL- PROST- l 3(TRANS)-ENOIC ACID DERIVATIVES This invention relates to novel prostaglandin derivatives and a novel process for the preparation thereof.

More particulary, it relates to a 9g, l-dihydroxylla-hydroxymethylprost-l3(trans)-enoic acid derivatives having the formula atoms, preferably, pentamethylene, lmethylpentamethylene, Z-methylpentamethylene, hexamethylene, l-methylhexamethylene, 2- methylhexamethylene, heptamethylene and lmethylheptamethylene, R may be a straight or branched alkyl group having from 4 to 10 carbon atoms, preferably, n-butyl, isobutyl, n-pentyl, isopentyl, l-methylpentyl, Z-methylpentyl, 1 l -dimethylpentyl, 1,2-dimethylpentyl, n-hexyl, isohexyl, l-methylhexyl, 1,1-dimethylhexyl, 1,2-dimethylhexyl, n-heptyl, isoheptyl, n-octyl and isooctyl. R represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and the alkyl group may be straight or branched, preferably, methyl, ethyl and n-propyl. R represents hydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atoms, e.g., ethoxycarbonyl, npropoxycarbonyl and n-butoxycarbonyl.

A preferred group of the prostaglandin derivatives provided by the invention are those of the formula (I) wherein A represents hexamethylene group, i.e., those having the formula wherein R, R and R are the same as above and the pharmaceutically acceptable salts thereof.

In formulae (1) and (I-a), and elsewhere in this specification, a bond attached to the cyclopentane nucleus which is in the oz-configuration, i.e., extends below the plane of the cyclopentane ring, is represented by a dotted line, and a bond which is in the ,B-configuration, i.e., extends above the plane of the cyclopentane ring, is represented by a solid line. The wavy line indicates that either steric configuration is possible.

The pharmaceitucally acceptable salts of the acids of formulae (I) and (I-a) in which R is hydrogen atom include alkali and alkaline earth metal salts, e.g., the sodium, potassium, magnesium and calcium salts, quaternary ammonium salts, e.g., the ammonium, tetramethylammonium, tetraethylammonium, benzyltrimethylammonium and phenyltriethylammonium salts, aliphatic, alicyclic or aromatic amine salts, e.g., the methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine and ethylene diamine salts, heterocyclic amine salts, e.g., the piperidine, morpholine, pyrrolidine, piperazine, pyridine, l-methylpiperazine and 4-ethylmorpholine salts, salts of amines which are water-soluble or contain a hydrophilic group, e.g., the monoethanolamine, ethyldiethanolamine and Z-amino-l-butanol salts. Such salts may be prepared from the acids of formulae (I) and (I-a) in which R is hydrogen atom by the conventional techniques.

enoic acid dissolved in isotonic sodium chloride solution containing a small amount of sodium bicarbonate. Uterine activity was measured by recording changes in intraamniotic pressure from a balloon introduced into the amniotic cavity through the cervix.

Accordingly, the compounds of the invention are useful as oxytocic agents; and the invention provides pharmaceuticalcompositions comprising a compound of formula (I), or a pharmaceutically acceptable salts thereof, and a pharmaceutical carrier or diluent. The pharmaceutical compositions of the invention are generally formulated for parenteral administration. For example, the compounds of formula (I) may be administered by continuous intravenous infusion, dissolved in sterile, pyrogen-free isotonic sodium chloride solution. The optimum dosage of the compounds of the invention will vary with the body weight and age of the patient; but the parenteral total daily dosage for full-term pregnant women will generally be from about 0.5 g. to

According to the present invention, the compound having the formula (I) may be prepared by reducing a compound having the formula wherein A, R R and R are the same as above with a metal hydride complex in the presence or absence of an inert organic solvent.

The reduction maybe preferably carried out by contacting the compound (II), (III) or (IV) with the metal hydride complex in the presence of an inert organic solvent. Preferable examples of the metal hydride complex include alkali metal boron hydrides, e.g., sodium boron hydride, potassium boron hydride, lithium boron hydride, sodium cyano boron hydride, lithium 9b-boro-perhydrophenalene hydride; alkali metal aluminum hydrides, e.g., aluminum tri-tert.-butoxylithium hydride, aluminum trimethoxylithium hydride; and zinc boron hydride. Preferable examples of the inert organic solvent include alcohols, e.g., methanol and ethanol; ethers, e.g., diethyl ether, tetrahydrofuran, dioxane, diglyme; and dialkylformamides, e. g., dimethylformamide. The reduction is preferably carried out at relatively low temperatures, usually at a temperature from lOC. to room temperature. The reaction period will depend mainly upon the reaction temperature and a kind of the reducing agent. It is usually from about 30 minutes to 3 hours.

After completion of the reaction, the desired product may be recovered from the reaction mixture by conventional means. For instance, organic acids, e.g., formic acid and acetic acid, are added to the reaction mixture in order to decompose the excess reducing agent and the mixture is extracted with an organic solvent. The extract is washed with water and dried and the solvent is'distilled off to give the desired product. The product thus obtained may be further purified, if necessary, by conventional means, forv example, column chromatography or thin-layer chromatography.

The compounds of the formula (I) and their salts can exist as four different optical isomers, depending up n the configuration of the hydroxy groups attached to the cyclopentane nucleusand the side-chain. The racemic mixtures of these isomers can be resolved by "16 con.- ventional techniques. so as to obtain the desir ucts in he form of optically pure diastereoisomers formulae (I) and (l-a') are used to represent both diastereoisomeric forms. as well as the racemic mixtures. but the pure isomers are included within the scope of the invention, as well as their mixtures.

The hydroxyand carboxy-protecting group may be removed by conventional means, for example, by treating the compound (II), (III) or (IV) with an acid, e.g., acetic acid, hydrochloric acid or with a base, e.g., sodium hydroxide, sodium carbonate.

The compounds of the formulae (II), (III) and (IV), employed as starting materials in the preparation of the compounds of the invention. are also novel and can be prepared by the processes shown in the following reaction schemes.

Prepara tinn of the compounds (II) 0' o o o o x, 4 I 4 R ooc U co'oR R40OC COORS R 00c coon (V) (VI) J. Org. Chem. 36,

In the above scheme, A, R, R and R are the same as above, R R R, R R and R may be the same or different and each represents an alkyl group having from 1 to 6 carbon atoms. Each of theabove steps may be illustrated as follows: i v

The compound (VI) may be prepared by reacting the compound (V) with ethylene glycol in the presence of a Lewis acid, e.g., boron trifluoride. The reaction is preferably carried out in an inert organic solvent such as dichloromethane, chloroform or benzene at a temperature ranging from 0C. to room temperature.

The compound (VII) may be prepared by reacting the compound (VI) with an alkali metal compound, e.g., sodium methoxide, potassium ethoxide, sodium hydroxide. The reaction is preferably carried out in an inert organic solvent such as tetrahydrofuran, dioxane or methanol at a temperature ranging from OC.'to a reflux temperature of the reaction mixture. In this step, the bond of the group COOR is changed from B-configuration to a-con'figuration.

The compound (VIII) may be prepared by reducing the compound (VII) with a metal hydride compound such as sodium boron hydride, potassium boron hydride, lithium boron hydride, trimethoxylithium aluminum hydride or aluminum, lithium hydride. The reaction is preferably carried out in an inert organic solvent such as methanol, tetrahydrofuran or ether at a temperature ranging from 0C. to a reflux temperature of the reaction mixture.

The compound (IX) or (XVI) may be prepared respectively by reacting the compound (VIII) or (XV) with a compound having the formula X COOR or X COOR wherein R and R are the same as above and X and X represent a halogen atom, e.g., chlorine, bromine, iodine in the presence of a base such as sodium carbonate, sodium' bicarbonate, triethylamine, pyridine or N-methylpiperazine. The reaction is preferably carried out below room temperature.

The compound (X) may be prepared by reacting the compound (IX) with an acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid or sufuric acid. The reaction is preferably carried out in a solvent such as water, methanol, ether or acetone at a temperature ranging from 0C. to 60C.

The compound (XI) may be prepared by reacting the compound (X) with an alkali metal compound such as alkali metal alkoxides, e.g., sodium methoxide, potassium ethoxide, potassium tert.-butoxide; alkali metal hydrides, e.g., sodium hydride, potassium hydride; or alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide. The reaction is preferably carried out in an inert organic solvent such as tetrahydrofuran, ether and benzene at a temperature ranging from -50C. to 80C. in an inert gas atmosphere, for example in argon or helium atmosphere.

The compound (XII) may be prepared by reacting the compound (XI) with a compound having the formula X A COOR wherein A and R are the same as above and X represents a halogen atom, e.g., bromine, chlorine, in the presence of an alkali metal compound such as alkali metals, e.g., metallic sodium; alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide; or alkali metal alkoxides, e.g., sodium methoxide, potassium ethoxide.'The reaction is preferably carried out in an inert organic solvent, e.g., benzene, ether, tetrahydrofuran, dimethyl sulfoxide, below room temperature in an inert gas atmosphere, for example in argon or helium atmosphere.

The compound (XIII) may be prepared by reacting the compound (XII) with an alkali metal compound such as sodium hydroxide, potassium hydroxide, so-

dium carbonate or potassium carbonate. The reaction is preferably carried out in a solvent, e.g., water, methanol, ether, dioxane, a mixture of water and such an organic solvent, at a temperature ranging from room temperature to reflux temperature of the reaction mixture in an inert gas atmosphere, for example, in an argon or helium atmosphere.

The compound (XIV) may be prepared by contacting the compound (XIII) with an oxidizing agent such as chromic acid, chromic anhydride, chromic anhydride-pyridine complex, sodium bichromate dimethyl sulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride. The reaction is preferably carried out in a solvent such as acetic acid, dichloromethane and chloroform at a temperature ranging from 0C. to room temperature.

The compound (XV) may be prepared by contacting the compound (XIV) with an acid such as formic acid, acetic acid, hydrochloric acid or sulfric acid, or with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate. The reaction is preferably carried out in a solvent, e.g., water, methanol, ether at a temperature ranging from room temperature to reflux temperature of the reaction mixture.

The compound (XVII) may be prepared by reacting the compound (XV) with an alcohol, e.g., diazomethane and diazoethane.

The compound (II) may be prepared by reacting the compound (XIV), (XV), (XVI) or (XVII) with a Wittig reagent having the formula wherein R is the same as above and R represents an alkyl group having'from l to 6 carbon atoms or phenyl group. At least I mole of the Wittig reagent is used per mole of the compound (XIV), (XV), (XVI) or (XVII) and preferably from 2 to 10 moles of the Wittig agent is used. The reaction is generally carried out in an inert organic solvent such as ether, benzene, toluene, hexane, dimethyl sulfoxide, tetrahydrofuran, methylene chloride or chloroform, at a temperature ranging from O C. to a reflux temperature of the reaction mixture, preferably at room temperature or below and in an inert gas atmosphere, for example, in an argon or helium atmosphere. The reaction is carried out for a period of Shows to 30 hours depending on the temperature and concentration of the reaction mixture and the specific Wittig reagent used.

The product obtained in each step of the above processmay be recovered from the reaction mixture in a conventional manner, for example, by evaporating the solvent from the reaction mixture or by adding water and extracting with a water-immiscible solvent. The crude product can be purified by conventional means such as recrystallization or chromatography.

Preparation of the compounds (III) In the above scheme, A, R, R R", R and R are the same as above.

Each of the above steps may be illustrated as follows:

The compound (XVII) may be prepared by reacting the compound (XIII) with ethylene glycol in the presence of a Lewis acid, e.g., boron trifluoride. The reaction is preferably carried out in an inert organic solvent such as dichloromethane, chloroform or benzene at a temperature ranging from 0C. to room temperature.

The compound (XIX) may be prepared by contacting the compound (XVIII) with an oxidizing agent such as chromic acid, chromic anhydride, chromic anhydride-pyridine complex, sodium bichromate, dimethyl sulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride. The reaction is preferably carried out in a solvent such as acetic acid, dichloromethane, chloro- 60 perature of the reaction mixture.

The compound (XXI) may be prepared by reacting the compound (XIX) or (XX) with a Wittig reagent having the formula wherein R is the same as above and R represents an alkyl group having from 1 to 6 carbon atoms or phenyl group. At least 1 mole of the Wittig reagent is used per mole of the compound (XIX) or (XX) and preferably from 2 to 10 moles of the Wittig agent is used. The reaction is generally carried out in an inert organic solvent such as ether, benzene, toluene, hexane, dimethyl sulfoxide, tetrahydrofuran, methylene chloride or chloroform, at a temperature ranging from 0C. to reflux temperature of the reaction mixture, preferably at room temperature or below and in an inert gas atmosphere, for example, in an argon or helium atmosphere. The reaction is carried out for a period of'5 hours to 3O or dimethylforrnamide, at relatively low temperatures,

usually at a temperature ranging from -l0C. to room I group may be prepared by reacting the compound hours depending on the temperature andconcentrati'on of the reaction mixture and the specific Wittig reagent used.

The compound (XXII) may be prepared by reducing The reaction is preferably carried out in an inert organic solvent such'a's methanol, ethanol, ether, dioxane (XXII) with an acid and reacting the product thus obtained with a compound having the formula X COOR Preparation of the compounds (IV) 7 za-cooa A-COOR7 A-COOR R oocoH c c3 03 n oocoa c CHZO-THP x oocoagc CH2OTHP (XIII) (XXIII) (XXIV) C9 Q .v A-COOR7 a oocoa c ca -o 'rap a oocoa 'c ca on n oocon c cao VI) XXvII) v (XXV) R oocoa c (XXVIIZ same as above. R re resents an alkano l rou or benzoyl group. TI-IP represents tetrahydropyranyl group.

Each of the above steps may be illustrated as follows:

The compound (XXIII) may be prepared by reacting the compound (XIII) with dihydropyran in the presence of a mineral acid, e.g., hydrochloric acid, hydrobromic acid or an organic acid, e.g., p-toluenesulfonic acid. The reaction is preferably carried out in an inert organic solvent such as benzene, toluene or chloroform at a temperature ranging from C. to room temperature.

The compound (XXIV) may be prepared by reducing the compound (XXIII) with a metal hydride compound such as sodium boron hydride, potassium boron hydride, lithium boron hydride, trimethoxylithium aluminum hydride and aluminum lithium hydride. The reaction is preferably carried out in an inert organic solvent such as methanol, tetrahydrofuran or ether at a temperature ranging from 0C. to a reflux temperature of the reaction mixture.

The compound (XXV) may be prepared by contacting the compound (XXIV) with a halide or anhydride of an alkanoic acid or benzoic acid, e.g., acetic anhydride, acetyl chloride, benzoic anhydride, benzoyl chloride.

The compound (XXVI) may be prepared by contacting the compound (XXV) with a dilute acid solution, for example, a dilute solution of acetic acid, hydrochloric acid or sulfuric acid.

The compound (XXVII) may be prepared by contacting the compound (XXVI) with an oxidizing agent, e.g., chromic acid, dimethyl sulfoxide-chlorine complex, dimethylsulfoxide-acetic anhydride, N- bromoacetamide and aluminum tert.-butoxide. The reaction is carried out at a temperature ranging 20C. to room temperature in a solvent, e.g., benzene, acetic acid, dichloromethane and aqueous tert.-butanol.

The compound (XXVIII) may be prepared by reacting the compound (XXVII) with a Witting reagent having the formula (R P CH CO R wherein R is the same as above and R represents an alkyl group from I to 6 carbon atoms or phenyl group. At least 1 mole of the Wittig reagent is used per mole of the compound (XXVII) and preferably from 2 to 10 moles of the Wittig agent is used.

The compound (IV) in which R is an alkyl group and R is hydrogen atom may be prepared by contacting the compound (XXVIII) withan acid such as formic acid, acetic acid. hydrochloric acid or sulfuric acid or with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.

The compound (IV) in which R and R are hydrogen atom may be prepared by reacting the compound (XXVIII) with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.

The compound (IV) in which R is hydrogen atom and R is alkoxycarbonyl group may be prepared by reacting the compound (XXVIII) with an alkali metal compound and reacting the product thus obtained with a compound having the formula x cooR wherein X represents a halogen atom, e.g., chlorine, bromine, iodine and R represents an alkyl group having from 1 to 6 carbon atoms in the presence of an alkali metal compound such as sodium carbonate, sodium bicarbonate.

The product obtained in each step of the above process may be recovered from the reaction mixture in a conventional means, for example, by evaporating the solvent from the reaction mixture or by adding water and extracting with a water immiscible solvent.

The crude product can be purified by conventional means such as recrystallization or chromatography.

The following preparations and examples are given for the purpose of illustration of the present invention. Preparations l and 2 illustrate the preparation of the compound (II). Preparations 3 and 5 illustrate the preparation of the compound (III). Preparation 4 illustrates the preparation of the compound (IV). Examples 1 and 2 illustrate the preparation of the compound (I) from the compound (II). Example 3, 4, 6 and 7 illustrate the preparation of the compound (I) from the compound (III). Example 5 illustrates the preparation of the compound (I) from the compound (IV).

PREPARATION 1 Preparation of 9.5, dioxo-l la-hydroxymethylprost-l 3( trans eno ic acid 1 l-Ethylenedioxy-3,4-dimethoxycarbonylcyclopentane (VI) In 250 ml. of dichloromethane were dissolved I24 g. of 3,4-dimethoxycarbonylcyclopentanone and 155 g. of ethyle'neglycol and to the solution was added dropwise 94 g. of boron trifluoride etherate at O5C. After completion of the addition, the reaction mixture was stirred for 2 hours at l0-l6C. and next for 1.5 hours at 16-23C. After completion of the reaction, the re action mixture was added dropwise to 1.5 l. of a saturated aqueous sodium bicarbonate containing pieces of ice in order to decompose the excess of the boron trifluoride etherate. The mixture was extracted three times with l l. of ether. The extract was washedwith a saturated aqueous sodium chloride and a saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give 135.7 g. of the desired product as colorless oil.

l.R. (liquid film) vmax :l74l, 1438, 1329, 1200,

N.M.R. (CDCl Azppm 3.63, 3.69 (6H, each singlet, cis and trans COOCH 3.90 (4H, singlet,

2. l-Ethylenedioxy-trans-3,4-dimethoxycarbonylcyclopentane (VII) In 3200 ml of dry benzene was dissolved 178 g. of lethylenedioxy-3,4-dimethoxycarbonylcyclopentane and to the solution was added dropwise a sodium methylate solution prepared from 16.8 g. of metallic sodium and 730 ml. of absolute methanol in argon atmosphere at 5C. After completion of the addition, the solution was stirred for 2 hours at 5C. and next for 3 hours at 2022C. After completion of the reaction, the reaction mixture was cooled to 0C. and added to about 2.2 l. of ice-water containing 80 ml. of acetic acid under stirring. The reaction mixture was saturated with sodium chloride and the benzene layer was separated. The aqueous layer was extracted with 2 l. of ether and l l. of ethyl acetate. The extracts were combined, washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure to give 173 g. of pale yellow oil. The oil was subjected to vacuum distillation to give 155.8 g. of the pure desired product as oil boiling at 120123C. under 0.05 mm. pressure of mercury.

I.R'. (liquid film) vmax z 1741, 1438, 1329, 1200, 1030.

N.M.R. '(CCl A: ppm, 3.63 (6H, singlet, trans- COOC I I 3.83 (4H, singlet,

3. l -Ethylenedioxy-trans-3,4-dihydroxymethylcyclopentane (VIII) In 400 ml. of dry ether was dissolved 78 g. of 1- ethylenedioxy-trans-3,4-dimethoxycarbonylcyclopentane and the resulting solution was added dropwise to a suspension of 30.3 g. of lithium aluminum hydride in 300 ml. of dry ether at 5C. After completion of the addition, the mixture was stirred for 3 hours. After completion of the reaction, 500 ml. of ether saturated with water and 130 ml. of a saturated aqueous sodium chloride were added to the reaction mixture below 10C. to decompose the excess lithium aluminum hydride. The ether was separated from the reaction mixture by decantation. The aqueous layer was extracted with ether and further subjected to evaporation under reduced pressure. The residue was extracted with absolute ethanol. All of the extract were combined and dried over anhydrous sodium sulfate. The solvent was distilled off to give 68.4 g. of the desired product as pale yellow oil.

I.R. (liquid film) vmax 3400, 2900, 1433, 1141, 1013, 950.

N.M.R. (CC1 A: ppm, 3.l53.78 (4H, multiplet, CH OH); 3.80 (4H, singlet,

4.50 (2H, singlet, -Ol-I).

4. M l-Ethylenedioxy-trans-3 ,4- diethoxycarbonyloxymethylcyclopentane (IX) In 1 l. of dry pyridine was dissolved 113 g. of 1- ethylenedioxy-trans-dihydroxymethylcyclopentane and to the solution was added dropwise 250 g. of ethyl chloroformate (ClCOOC l-I below 5C. After completion of the addition, the reaction mixture was stirred for 30 minutes at that temperature and next for 2 hours at room temperature. After completion of the reaction, the reaction mixture was added to 2 l. of ice water and the mixture was extracted with ether. The extract was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 188.2 g. of the desired product as pale yellow oil.

I.R. (liquid film) vmax z 1750, 1469, 1403, 1372, 1260, 1010, 949, 875, 791.

N.M.R. (CDCl A: ppm, 1.15-1.50 (6H, triplet, -OCH Cl-l 3.88 (4H, singlet,

H CCH I 4.004.35 (8H, multiplet, Cl-I OCOOC H CI-I 5. Trans-3,4-diethoxycarb'6nyloxymethylcyclopentane-l-one (X) In a mixture of 800 ml. of acetone, 20 ml. of water and 2.5 ml. of 10 hydrochloric acid was dissolved 56.5 g of l -ethylenedioxy-trans-3 ,4- diethoxycarbonyloxymethylcyclopentane and the solution was stirred for one hour at room temperature and further for 2 hours at 50C. After addition of 2.0 g. of p-toluenesulfonic acid. After completion .of the reaction, the reaction mixture was added to 2 l. of ice water and saturated with sodium chloride. The mixture was extracted with benzene. The extract was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 51.0 g. of the desired product as pale yell'ow oil'. The oil was subjected to column chromatography using 250 g. of silica gel washed with hydrochloric acid and eluted some amounts of nhexane and next successively n-hexane-benzene (1:1)-benzene-ethylacetate (:5). The solvent was distilled off from the eluate to give 47.3 g. of the desired product as oil.

I.R. (liquid film) vmax"" 1748, 1469, 1408, 1376, 1260, 1009, 877, 792.

N.M.R. (CDCl A: ppm, 1.18-1.50 (6H, triplet, -OCH C I;I 4.30 (4H, singlet, Cl-I- OCOOCl-l Cl-1 4.02-4.41 (41-1, quartette, c"i+ OCOOC l -I CH 6. 2-Carboxy-3hydroxymethyl-4aethoxycarbonyloxymethylcyclopentan-1-one-2,3-(I)- lactone (XI) In 700 ml. of dry tetrahydrofuran was dissolved 28.83 g. of trans-3,4-diethoxycarbonyloxymethylcyclopentan-l-one and to the solution was added dropwise a solution of 16.9 g. of potassium tert.-butoxide in 900 ml. of dry tetrahydrofuran in an argon atmosphere at -45C. After completion of the addition. the reaction temperature was slowly elevated to C. The completion of the reaction was confirmed with chromatography. The reaction mixture was again cooled to -C. and added to about 2 1. of ice water containing 50 ml. of acetic acid under vigorous agitation. To the mixture was added sodium chloride and the mixture was extracted with ether and benzene. The extract was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 27.0 g. of pale yellow oil. To the oil was added ether-n-hexane and the mixture was allowed to cool to give 10.5 g. of the desired product as crystals. The mother liquor was subjected to column chromatography using silica gel and eluted with benzene to give 4.1 g. of crystals. The total yield was 14.6 g. melting point was 65-66C.

LR. (Nujol) V max""': 1772, 1747, 1290, 1283, 1258, 1168, 1150, 1029, 880, 790.

N.M.R. (CDCI A: ppm, 1.20-1 .46 (3H, triplet, OCH CH 3.00-3.45 (11-1, multiplet,

3.46-3.58 (1H, doublet 1 H cg coocog c 1 m Analysis:

Calculated for C H O C,54.54; H, 5.83

Found C,54.88; H,6.07.

7. 2-(6-Methoxycarbonylhexy1)-2-carboxy-3- hydroxymethy1-4aethoxycarbonyloxymethylcyclopentane-1-one-2,3-(l)- lactone (XII) In 60 ml. of dimethyl sulfoxide was dissolved 6.54 g. of 2-carboxy-3-hydroxymethyl-4- ethoxycarbonyloxymethylcyclopentane-1-one-2,3 (F )-lactone and to the solution was added 4.85 g. of potassium tert.-butoxide in argon atmosphere under cooling and the mixture was stirred for 60 minutes at room temperature. To the mixture was added 10.9 g. of methyl 7-iodoenanthate and the mixture was stirred for 6 hours at room temperature. After completion of the reaction, the reaction mixture was added to 500 ml. of ice-water containing 27 ml. of acetic acid and the mixture was extracted with ethyl acetate and benzene. The extract was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 1.5 g. of the pale yellow r: If .1

a I H 3.63 (3H, singlet, COOCH 4.05-4.6 (6H, multiplet,

H cg coocon c" 8. 2a-( 6-Methoxycarbonylhexyl)-3B-hydroxymethyl- 4a-ethoxycarbonyloxymethylcyclopentane- 1 -one (XIII) In a solution of 90 ml. of dioxane, 24 ml. of water and 2.43 g. of potassium carbonate was dissolved 6.12 g. of 2-( 6-methoxycarbonylhexyl )-2-carboxy-3- hydroxymethyl-4- ethoxycarbonyloxymethylcyclopentane-1-one-2,3(1)- lactone and the resulting solution was stirred in argon atmosphere for 3 days at room temperature. After completion of the reaction, the reaction mixture was added to 500 m1. of ice-water containing 10 ml. of acetic acid. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 6.1 g. of pale yellow oil. The oil was subjected to column chromatography using 48 g. of silica gel and eluted with some amounts of n-hexane and next successively with nhexane-benzene 1:2)-benzene-ethyl acetate (99:1 The eluates with n-hexane-benzene (1:2)-benzeneethyl acetate (99:1 were collected and the solvent was distilled off to give 4.50 g. of the desired product as oil.

LR. (liquid film) V max": 3540, 2940, 1742, 1440, 1370, 1258, 1172, 1008, 873, 792.

N.M.R. (CDCl Azppm: 0.90-1.34 (3H, triplet, OCH C I' I;;); 3.44 (3H, singlet, COOCH 3.50-4.20 (6H, multiplet, CH Q H and -CH- OCOOQI-I CH 5.30 (1H, singlet, C1-I O I-I). m

9. 2a-(6-Methoxycarbonylhexyl)-3B-formyl-4aethoxycarbonyloxymethylcyclopentane- 1 -one (XIV) In m1. of dichloromethane was dissolved 1.53 g. of 2a-( 6-methoxycarbonylhexyl)-3B-hydroxymethy1-4aethoxycarbonyloxymethylcyclopentane-l-one and to the solution was added 10 g. of chromic anhydridepyridine complex (Collins reagent). The mixture was stirred for 10 minutes at room temperature. After completion of the reaction, 100 ml. of ether was added to the reaction mixture and the mixture was stirred for a while and filtered with Hyflo Super Cel: (trade name of Johns Manville Sales Corp.). The precipitates was washed with ether and the washing was combined .with the filtrate. After cooling, the organiclayer was washed successively with a cooled 2% aqueous sodium hydroxide, a cooled 2% aqueous hydrochloric acid, a cooled aqueous sodium bicarbonate and a saturated aqueous sodium chloride, respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer to give 1.23 g. of the desired product as pale yellow oil.

l.R. (liquid film) vmax 2930, 1742, 1462, 1440, 1404, 1370, 1259, 1170, 1008,874, 792.

N.M.R. (CDCl3) A: ppm, 1.20-1.41 (3H, triplet, OCH C 1:1 3.68 (3H, singlet, -COOC I -I 4.06-4.43 (4H, multiplet, -CI-I OCOOCl-I CI-I 9.92 1H, singlet, cgo

10. 2a-(6-Carboxyhexy1)-3,8-formy1-4ahydroxymethylcyclopentane-1-one (XV) In a solution of 35 ml. of methanol, 7 ml. of water and 3.3 ml. of 10% aqueous potassium hydroxide was dissolved 712 mg. of 2a'-(6-methoxycarbonylhexyl)-3;8- formyl-4a-ethoxycarbonyloxymethylcyclopentanel-one and the resulting solution was stirred for 4 hours at room temperature in an argon atmosphere. After completion of the reaction, the reaction mixture was added to 200 ml. of ice water containing 2 ml. of acetic acid and extracted with ethyl acetate. The extract was washed with a small amount of an aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 315 mg. of the desired product as pale yellow oil.

I.R. (liquid film) 11 max""": 3470, 2700, 1720.

l 1 9, l5-Dioxo-l la-hydroxymethylprostl3(trans)enoic acid (II) In 15 ml. of ether was dissolved 310 mg. of 2a-(6- carboxyhexyl)-3,B-formyl-4a-hydroxymethylcyclopentane-l-one and to the solution was added 430 mg. of 2-oxoheptylidene tri-n-butylphosphorane. The mixture was stirred for 12 hours at room temperature in an argon atmosphere. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure to give 740 mg. of the desired product as yellowish orange oil. The oil was subjected to column chromatography using 6 g. of silica gel and eluted with benzene-benzene-ethyl acetate (95:5). The eluates with benzene-ethyl acetate (95:5) were collected and the solvent was distilled off to give 372 mg. of the desired product.

I.R. (liquid film) 11 max"" 3500, 2950, 1737, 1630, 1460, 1408, 1380, 1090, 981, 902, 725.

N.M.R. (CDCl Azppm, 0.80-1.05 (3H, triplet, CH C I-I 3.34-3.73 (2H, multiplet, -(;l-I OH); 5.78 (2H, singlet, -OI-I and COOH), 6.07-6.35 (1H, doublet,

PREPARATION 2 g Methyl 9, l S-dioxo-l la-ethoxycarbonyloxymethylprost- 13(trans )-enoate (II) In 45 ml. of ether was dissolved 1.20 g. of 2a-(6- methoxycarbonylhexyl 3 B-formyl-4aethoxycarbonyloxymethylcyclopentane- 1 -one (XIV) and to the solution was added 1.28 g. of 2- oxoheptylidenetri-n-butylphosphorane and the mixture was stirred for 17 hours at room temperature in an argon atmosphere. After completion of the reaction,

the solvent was distilled off from the reaction mixture under reduced pressure to give 2.52 g. of oil. The oil was subjected to column chromatography using 20 g. of silica gel and eluted successively with n-hexane-nhexane-benzene (5:1 The eluates were collected and the solvent was distilled to give 1.52 g. of the desired product as oil.

LR. (liquid film) v max"': 2940, 1745, 1700, 1678, 1631, 1460, 1405, 1370, 1256, 1169, 1008, 872, 791.

N.M.R. (CDCl Azpprn 0.80-1.10 (3H, triplet, -CI-I CH 1.16-1.41 (3H, triplet, -OCI-I C lj 3.68 (3H, si ri glet, -COOC I;I 4.03-4.40 (4H, multiplet, -CI OCOOCI CH 6.08-6.33 (1H, doublet,

6.55-6.94 (ll-l, quartette,

H ll 0 PREPARATION 3 Preparation of 9-oxo- 1 l a-hydroxymethyl- 1 5a( or,8)-hydroxyprostl3(trans)-enoic acid (111) l l-Ethylenedioxy-2oz-( 6-methoxycarbonylhexyl)- 3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane (XVIII) To a mixture of 2.02 g. of methoxycarbonylhexyl )-3 IS-hydroxymethyl-4aethoxycarbonyloxymethylcyclopentanel-one (XIII), 3.5 g. of ethylene glycol and 6 ml of dichloromethane was added dropwise 3.0 g of boron trifluoride diethyl ether complex under ice-cooling. After completion of the addition, the mixture was stirred for 2 hours at l 0C.-1 5C. and then for 3 hours at 0C. After completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium chloride containing pieces ice and the mixture was saturated with sodium chloride. The mixture was extracted with ether and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give 2.3 g. of pale yellow oils. The oilswere subjected to column chromatography using 12,5 g. of silica gel and eluted some amounts of n-hexane and next successively with nhexane benzene 2: l-l :l The eluates with nhexane benzene 2: 1-1 :1 were collected and the solvent was distilled to give 1.25 g. of the desired product as oil.

[.R. (liquid film) 11 max 3520. 2930, 1788. 1740. 14401370. 1255. 1100. 1010, 951. 874.791.

N.M.R. (CDCL A: ppm 3.70 (3H, singlet, COOC l;I cyclopentane-l-one (XIII), 3.5 g. of ethylene glycol and 6 ml. of dichloromethane was added dropwise 3.0 g. of boron trifluoride diethyl ether complex under ice-cooling. After completion of the addition, the mixture was stirred for 2 hours at 10)\ C.-lC. and then for 3 hours at 0C. After completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium chloride containing pieces ice and the mixture was saturated with sodium chloride. The mixture was extracted with ether and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give 2.3 g of pale yellow oils. The oils were subjected to column chromatography using 12.5 g. of silica gel and eluted some amounts of n-hexane and next successively with n-hexane-benzene 2:l-1 :1 (2: 1-1 :1 were collected and the solvent was distilled to give 1.25 g. of the desired product as oil.

I.R. (liquid film) 11 max"': 3520, 2930, 1788, 1740, 1440, 1370, 1255, 1100, 1010, 951, 874, 791.

N.M.R. (CDC1 A: ppm, 3.70 (3H, singlet, COOCII;,); 3.91 (4H, singlet,

4.00-4.50 (6H, multiplet, -C I -I OI-I and -C I:l O- COOC I-I CH 2. 1 -Ethylenedioxy-2a-( 6-methoxycarbonylhexyl)- 3/3-formyl-4a-ethoxycarbonyloxymethylcyclopentane(XlX) In 60 ml. of dichloromethane was dissolved 1.04 g. of l-ethylenedioxy-2a-( 6-methoxycarbonylhexyl )-3B- hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentame and to the solution was added 6.7 g. of anhydrous chromic acid-pyridine complex (Collins reagent) followed by stirring for 10 minutes at room temperature. After completion of the reaction, 100 ml. of ether was added to the reaction mixture followed by stirring and the mixture was .filtered with Hyflo Super Cel. The precipitates were washed with ether and the washing was combined with the filtrate. The organic layer was cooled andwashed successively with a cooled 2% aqueous sodium hydroxide, a cooled 2% aqueous hydrochloric acid, a cooled 5% aqueous sodium bicarbonate and a saturated aqueous sodium chloride, respectively, and dried over anhydrous sodium sulfate. The solvent was distilled ofi from the organic layer to give 935 mg. of the desired product as pale yellow oil.

I.R. (liquid film) 11 max" 2940, 1784, 1740, 1440, 1370, 1255, 1165, 1100, 1015, 951, 875, 791.

N.M.R. (CDCl A: ppm, 3.68 (3H, singlet, COOC I 3.92 (4H, singlet,

4.00-4.50 (4H, multiplet, Cfl OCOOCI-I CH 9.60-9.90 (ll-I, multiplet, CI I O The eluates with n-hexane-benzene LII 3. 1-Ethylenedioxy 2a-(6-carboxyhexyl )-3B-formyl- 4a-hydroxymethylcyclopentane (XX) In a mixture of m1. of methanol, 13 ml. of water and 7 ml. of a 10% aqueous potassium hydroxide was dissolved 1.60 g. of l-ethylenedioxy-2a-(6- methoxycarbonylhexyl )-3 a-formyl-4oeethoxycarbonyloxymethylcyclopentane followed by stirring for 4 hours at room temperature in an argon atmosphere. After completion of the reaction, the reaction mixture was added to ice water containing 4 ml. of acetic acid with vigorous agitation and the mixture was extracted with ethyl acetate. The extract was washed with a small amount of a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give 860 mg. of the desired product as a pale yellow oil.

I.R. (liquid film) 11 max ""1 3450, 2710, 1720.

4. 9-Ethylenedioxy-1 la-hydroxymethyll 5-oxoprostl3(trans)-enoic acid (XXI) In 30 ml. of ether was dissolved 620 mg. of lethylenedioxy-2o1-(6-carboxyhexyl)-3B-formyl-4ozhydroxymethylcyclopentane and to the solution was added 760 mg. of 2-oxoheptylidenetri-nbutylphosphorane followed by stirring for 13 hours at room temperature in an argon atmosphere. After completion of the reaction, the solvent was distilled 'off from the reaction mixture to give 1.49 g. of yellowish orange oils. The oil was subjected to column chromatography using 12 g. of silica gel and eluted with some amounts of benzene and next successively with benzene-ethyl acetate (99:198:2). The eluates with the latter solvent were collected and the solvent was distilled off to give 705 mg. of the desired product.

I.R. (liquid film) v max"'*: 3450, 1710, 1678, 1631. N.M.R. (CDCl A: ppm, 6.07-6.33 (1H, quartette,

6.56-6.93 (1H, quartette,

H r 11 H '5. 9-Ethylenedioxyl 1 a-hydroxymethyll S-hydroxy prostl 3-(trans)-enoic acid (XXII) In 25 ml. of ethanol was dissolved 615 mg. of 9- ethylenedioxy-l 1 oz-hydroxymethyll 5-oxoprost- 13(trans)-enoic acid and to the solution was added a mixture of 230 mg. of sodium boron hydride and 13 ml.

of ethanol under ice cooling followed by stirring for 2 hours at 05C. After completion of the reaction, the reaction mixture was poured into 100 ml. of ice water and the pH adjusted to 4.0 by addition of acetic acid. The reaction was extracted with ethylacetate and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give 603 mg. of the desired product as pale yellow oils.

LR. (liquid film) 11 max'": 3450, 2940, 1717, 1460, 1260, 1154, 1030, 972, 95.1.

N.M.R. (CDCl A: ppm, 0.60 l.10 (3H, triplet, CI-I C I;I 3.94 (4H, singlet,

5.90 (3H, singlet, O& and COO! -l 6. 9-Oxo-1 la-hydroxymethyl-lSa (or B)-hydroxyprost-13(trans)-enoic acid (lll) To a mixture of 12 ml. of acetone, 2.5 ml. of water and mg. of p-toluenesulphonic acid was added 596 mg. of 9-ethylenedioxy-1 la-hydroxymethyl-IS- hydroxyprost-l3(trans)-enoic acid followed by stirring for 1 hour at room temperature. After completion of the reaction, the reaction mixture was dried over 5 mg. of anhydrous sodium acetate and the solvent was distilled off. To the residue was added about ml. of ice water and the mixture was saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give 563 mg. of pale yellow oils. The oils were subjected to column chromatography using 5.6 g. of silica gel and eluted with some amounts of benzene and next with benzeneethylacetate (5:1 The eluates with the latter solvent were collected and the solvent was distilled off to give 163 mg. of 9-oxo-1 1a-hydroxymethyl-15a-hydroxyprost-13(trans)-enoic acid. The eluates with benzeneethyl acetate (3:2) were collected and the solvent was distilled off to give 150 mg. of the mixture of 9-oxo- 1 1 a-hydroxymethyl- 1 SB-hydroxyprost- 1 3(trans)-enoic acid and 9-oxo-1 1a-hydroxymethyl-15a-hydroxyprost- 13(trans)-enoic acid. The eluates with benzene-ethyl acetate (1:1) were collected and the solvent was distilled off to give 108 mg. of 9-oxo-1 loz-hydroxymethyl- ISa-hydroxyprost-l3(trans)-enoic acid. The infrared absorption spectrum and nuclear magnetic resonance of thus obtained 9-oxo-1 la-hydroxymethyl-l 5B- hydroxyprost- 1 3(trans)-enoic acid, 9-oxo-l lahydroxymethyll 5a-hydroxyprost- 1 3(trans)-enoic acid and the mixture thereof were in accordance with each other.

LR. (liquid film) 11 max"'': 3400, 2940, 1730, 1460, 1405, 1260, 1163, 1052, 1018, 972, 726.

N.M.R. (CD COCD A: ppm, 0.70-1.10 (3H, triplet, -CH C l:l 3) 3.204.3O (6H, multiplet, COO ll Cg0li, C l;l O); 5.54-5.75 (2H. multiplet,

9-Oxo-1 1 a-hydroxymethyl-l Sa-hydroxyprost- 13( trans)-enoic acid was obtained as semicrystals melting at 6567C. by allowance of cooling.

PREPARATION 4 Preparation of methyl 9 {-hydroxy-l la-hydroxymethyl-15-oxoprost-l3(trans)- enoate (1V) 1 1-Oxo-2oz-methoxycarbonylhexyl-3 ,8- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXlll) To 3.584 g. of 1-oxo-2a-methoxycarbonylhexyl-3B- hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane in 50 ml. of dry benzene were added 1.68 g. of dihydropyran and 15 mg. of p-toluenesulfonic acid and the mixture was stirred for 30 minutes under ice cooling and for 30 minutes at room temperature. To the mixture was added 10 ml. of 2% aqueous sodium carbonate. The benzene layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off to give 5.1 g. of oil. The oil was subjected to column chromatography using 50 g. of aluminum (grade ll, Voelm. Co.) and eluted with n-hexane-benzene (4:1)-benzene to give 4.12 g. of the desired product.

l.R. (liquid film) 11 max"" 1745, 1119, 1028.

N.M.R. (CDCl,,) :1: ppm, 4.72-4.58 (1H, multiplet,

3.65 (3H, singlet, Coocg 2. l fi-hydroxy-2a-methoxycarbonylhexyl-3B- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXlV) and 1f-acetoxy-2oz-methoxycarbonylhexyl-3 B- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXV) 4.10 g of tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane in 50 ml. of absolute methanol was reduced with 540 mg. of sodium boron hydride under ice cooling to give 4.19 g. of 15- hydroxy-Za-methoxycarbonyhexyl-3B- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane.

The product thus obtained was acetylated with 10 ml. of acetic anhydride in 50 ml. of dry pyridine at room temperature to give 4.82 g. of oil. The oil was subjected to column chromatography using 40 g. of silica gel and eluted with n-hexane-benzene (1:8)-benzene to give 4.01 g. of 1-acetoxy-Za-methoxycarbonylhexyl-3B- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane.

LR. (liquid film) v max"" 1742, 1120, 1030.

N.M.R. (CDCl A: ppm, 4.74-4.60 (1H, multiplet,

5.31-4.75 (ll-l, multiplet,

H OAC 1-oxo-2a-methoxycarbonyhexyl-3B- 2.00 (3H, singlet. OCCfi 3.67 (3H, singlet, cooc 1 &

3. 1E-Acetoxy-Za-methoxycarbonylhexyl-3,8-

hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane (XXVI) In a mixture of 40 m1. of acetic acid, 40 ml. of water and 6 ml. of tetrahydrofuran was dissolved 4.00 g. of 1f-acetoxy-2a-methoxycarbonylhexyl-3B- tetrahydropyranyloxymethyl-4w ethoxycarbonyloxymethylcyclopentane and the solution was stirred for 4.5 hours at 45C. The reaction mixture was poured into ice water and extracted with ethyl acetate, washed with a saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and the solvent was distilled off to give 3.86 g. of oil. The oil was subjected to column chromatography using 30 g. of silica gel and eluted with benzene-ethyl acetate (99:1 )-(90:l0) to give 3.01 g. of the desired product.

LR. (liquid film) v max z 3400, 1704.

N.M.R. (C DCl3) 6: ppm, 5.28-4.77 (1 H, multiplet.

3.67 (3H, singlet, -COOCfl 2.00 (3H, singlet, O- COCI I 1.100.78 (3H, triplet, -CH O-COOCH- 2 C l i 4. l-Acetoxy-Za-methoxycarbonylhexyl-3,8-formyl- 4a-ethoxycarbonyloxymethylcyclopentane (XXVII) and methyl 9lf-acetoxy-l la-ethoxycarbonyloxymethyl l5-oxoprost-13(trans)-enoate (XXVIII) To 3.00 g. of lg-acetoxy-Za-methoxycarbonylhexyl- 3B-hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane in 150 ml. of dry methylene chloride was added 19 g. of Collins reagent under ice cooling and stirred for minutes at room temperature. After completion of the reaction, 200 ml. of ether was added to the reaction mixture and mixture was filtered with Hyflo Super Cel. The precipitates were washed with ether and the washing was combined with the filtrate. The filtrate was washed with 5% aqueous sodium carbonate, 2% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and a saturated aqueous sodium chloride, respectively and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 2.76 g. of 1-acetoxy-2amethoxycarbonylhexyl-3/3-formyl-4aethoxycarbonyloxymethylcyclopentane (XXVII).

The product thus obtained was dissolved in 60 ml. of anhydrous ether and to the solution is added 2.80 g. of 2-oxoheptylidene-tri-n-butylphosphorane. The mixture was stirred at room temperature in an argon atmosphere for 15 hours. The solvent was distilled off under reduced pressure to give 5.51 g. of oil. The oil was subjected to column chromatography using 45 g. of silica gel and eluted with n-hexane nhexane -benzene (5: l to give 2.98 g. of methyl 9-acetoxy-l 1aethoxycarbonyloxymethyl-l5-oxoprost13(trans)- enoate (XXVIII).

l.R. (liquid film) 11 max"' 1745. 1676. 1630.

N.M.R. (CDC1;,) A: ppm. 6.946.52 (1H, quartette,

6.25-6.00 (1H. doublet,

n W l 3.67 (3H, singlet, COOCfi 2.00 (3H, singlet, O- COCH 5. methyl 9oz( and B)-hydroxy-l la-hydroxymethyll5-oxoprost-13(trans)-enoate (IV) In a mixture of 30 ml. of methanol, 10 ml. of water and 2.8 ml. of 20% aqueous potassium hydroxide was dissolved 1.02 g. of methyl 9fi-acetoxy-l 1ozethoxycarbonyloxymethyl-15-oxoprostl 3 trans enoate and the solution was stirred at room temperature for 2 hours. The reaction mixture was neutralized by addition of acetic acid. The product was reacted with diazomethane in acetic anhydride to give 810 mg. of oil. The oil was subjected to column chromatography using 8.0 g. of silica gel and eluted with benzene ethyl acetate (85:15) to give 351 mg. of methyl 9ahydroxy-l la-hydroxymethyl-l5-oxopr0st- 13(trans)enoate and with benzene ethyl acetate (60:40) to give 307 mg. of methyl 9a-hydroxy-11ahydroxymethyll 5-oxoprostl 3(trans)-enoate.

I.R. (liquid film) vmax' 3400, 1744, 1677, 1630.

N.M.R. (CDClflfizppm, 6.96-6.50 (1H, quartette.

6.266.02 l H, doublet,

3.68 (3H, singlet, COOCl-b) PREPARATION 5 Preparation of 9-0xo-l lwhydroxymethyl-15u(and 8)-hydroxy16.16-dimethylpr0st-13(trans)-enoic acid (III) 1. Methyl 9-ethylenedioxy-1 1aethoxycarbonyloxymethyl-15-oxo-16.16-dimethylprost- 1 3(trans)-enoate (XXI) Toa solution of 2.5 g. of l-ethylenedioxy-2a-(6- methoxycarbonylhexyl )-3 ,B-formyl-4aethoxycarbonyloxymethylcyclopentane in 40 ml. of dry tetrahydrofuran was added 2.8 g. of 2-oxo-3.3- dimethylheptylidene-tri-n-butylphosphorane and the mixture was refluxed for hours in an argon atmosphere. After completion of the reaction, the solvent was distilled off from the reaction mixture. The residue was subjected to column chromatography using 60 g. of silica gel and eluted with 5- 1 0% ethyl acetate in benzene to give the desired product.

[.R. (liquid film) v max"" 1740. 1695. 1625.

N.M.R. (CDCIQ) A: ppm. 3.70 (3H. singlet. (I11 1.10 (3H, singlet. 'Cljn); 1.05 (3H. singlet. -C

2. Methyl 9-ethylenedioxy-l 1aethoxycarbonyloxymethyl-15-hydr0xy-16.16- dimethylprost-l 3(trans)-enoate (XXII) To 1.91 g. of methyl 9-ethylenedioxy-1 1ozethoxycarbonyloxymethyl-l-oxo-16,1 6-dimethylprost-13(trans)enoate in 60 ml. of methanol was added 240 mg. of sodium boron hydride under ice cooling and the mixture was stirred for 2 hours at room temperature. After completion of the reaction, the mixture was made acidic by addition of acetic acid and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was subjected to column chromatography using 20 g. of silica gel and eluted with -20% ethyl acetate in benzene to give 1.8 g. ofthe desired product.

I.R. (liquid film) vmax"" 3500, 1740, 1260 N.M.R. (CDClg) A: ppm, 0.90 (3H, singlet, 3%,), 0.82 (3H, singlet, -CI;I

3. 9-Ethylenedioxy-1 la-hydroxymethyl- 1 5ghydroxy-l 6,16-dimethylprost-1 3(trans)-enoic acid (XXII) To a solution of 40 ml. of 5% aqueous sodium hydroxide and 60 ml. of methanol was added 1.68 g. of methyl 9-ethylenedioxy-l 1aethoxycarbonyloxymethyl-15-hydroxy-l 6,16- dimethylprost-13(trans)-enoate and the mixture was stirred for 2 hours at room temperature. After completion of the reaction, the mixture was made acidic by addition of acetic acid and extracted with ethyl acetate. The solvent was distilled off to give 1.4 g. of the desired product.

4. 9-Oxo-1 la-hydroxymethyl- 1 5a( and ,8)-hydroxy- 16,16-dimethylprost-13(trans)-enoic acid (ill) In a mixture of 15 ml. of acetic acid and 15 ml. of water was dissolved 1.33 g. of 9-ethylenedioxy-1 lozhydroxymethyl-l SE-hydroxy- 1 6, l 6-dimethylprost- 13(trans)-enoic acid and the solution was stirred for 2 hours at room temperature. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was subjected to column chromatography using g. of silica gel and eluted with 40-60% ethyl acetate in benzene to give 500 mg. of the ISa-hydroxy compound and 600 mg. of the ISB-hydroxycompound as oil.

ISa-hydroxy compound I.R. (liquid film) z/max 3450, 1740.

N.M.R. (CD COCD A: ppm, 5.7 (2H, broad); 0.91 (3H, singlet, -C I; I 0.88 (3H, singlet, {ll-l3)- ISB-hydroxy compound LR. (liquid film) 11 max": 3450, 1740.

N.M.R. (CD COCD A: ppm, 5.7 (2H, broad); 051 (31-1, singlet, -CH;;); 0.87 (3H. singlet, -CH

EXAMPLE 1 l 5-Dihydroxy-1 la-hydroxymethylprost- 1 3(trans enoic acid To a solution of 170 mg. of 9,15-diox o-l 1ahydroxymethylprost-l3(trans)-enoic acid in 8 of ethanol was added 70 mg. of sodium boron hydride in 4 ml. of ethanol under ice cooling and the mixture was stirred for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 3.5-4.0 by addition of acetic acid at 0C. and the solvent was distilled off from the reaction mixture under reduced EXAMPLE 2 Methyl 9g, 1 5-clihydroxy- 1 la-ethoxycarbonyloxymethylprost- 1 3 trans )-enoate To a solution of 400 mg. of methyl 9,15-dioxo-1 laethoxycarbonyloxymethylprost-l3(trans)-enoate in 20 ml. of ethanol was added 134 mg. of sodium boron hydride in 8 ml. of ethanol under ice cooling and the mixture was stirred for one hour. After completion of the reaction, about ml. of ice water containing 1.8 m1. of acetic acid was added to the reaction mixture. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give 425 mg. of the desired product as pale yellow oils.

LR. (liquid film) V max"": 3480, 3200, 2930, 1742, 1.624, 1400, 1330, 1250, 1090, 1008, 873, 791, 723.

N.M.R. (CDCl A: ppm, 0.80-1.05 (3H, multiplet, -C1-I Cfi 3.66 (3H, singlet, COOC I;I 3.80-4.80 (6H, multiplet, CHOH and CI-I OCOOCl-I CH 5.50 (2H, singlet, M m

EXAMPLE 3 (and B), 15 a-Dihydroxy- 1 1 ahydroxyrnethylprost- 1 3(trans)- enoic acid To a solution of 0.7 g. of methyl 9-oxo-1 1ahydroxymethyl- 1 Sa-hydroxyprostl 3(trans)-enoate in 20 m1. of absolute methanol was added 70 mg. of sodium boron hydride under ice cooling and the mixture was stirred for 1 hour in ice bath. After completion of the reaction, the reaction mixture was diluted with a cold 2% aqueous hydrochloric acid and subjected to salting out by addition of sodium chloride. The mixture was extracted three times with m1. of ethyl acetate. The organic layer was washed two times with saturated aqueous sodium chlroide and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.7 g. of methyl 9a (and B), l5oz-dihydroxy-11ahydroxymethylp rost-l3(trans)-enoate as oil. The oil was subjected to column chromatography using 21 g. of silica gel and eluted successively with 100-200 ml. of benzene-ethyl acetate (5:5, 4:6, 3:7, 2:8, 1:9, 0:10). The eluates with benzene-ethyl acetate (4:6-218) were collected and the solvent was distilled off. The

residue was recrystallized from ethyl acetate-n-hexane to give 210 mg. of methyl 9a. la-dihydroxy-1lahydroxymethylprostl 3(trans )-enoate melting at 68-69C. The eluates with benzene ethyl acetate (1:9-0110) were collected and the solvent was distilled off. The residue was recrystallized from acetate-nhexane to give 280 mg. of methyl 9B. l5a-dihydr0xyl la-hydroxymethlprost-l 3(trans)-enoate melting at 66.5-67.5C. 9a-hydroxy compound IR. (KBr) V max" 3300, 1741.

N.M.R. (CD COCD A: ppm, 5.46 (2H, multiplet,

4.07-3.95 (2H, multiplet,

I I--\ I" Oh j 7 I HO H 3.60 (3H, singlet, -COOCH 3.50 (2H, multiplet, qrg oH 0.90 (3H, triplet?C l- I 9B-hydroxy compound IR. (KBr) V max": 3300, 1740. N.M.R. (CD COCD Azppm, 5.46 (2H, multiplet,

4.00-3.80 (2H, multiplet,

nu :1 I

1 HO H 3.60 (3H, singlet, -COOCLI 3.45 (2H, multiplet, C l;l OH); 0.90 (3H, triplet, C l;l

2. 9a, 15a-Dihydroxy-lloz-hydroxymethylprostl3(trans)enoic acid In 10 ml. of methanol was dissolved 210 mg. of methyl 9a, l5a-dihydroxy-1 la-hydroxymethylprost- 13(trans)-enoate with stirring in ice bath. To the solution was added 10 ml. of 5% aqueous sodium hydroxide and the solution was stirred for 30 minutes at room temperature. Then, reaction mixture was diluted with 100 ml. of ice water, neutralized with diluted aqueous hydrochloric acid, subjected to salting out by addition of sodium chloride and extracted three times with ml. of ethyl acetate, respectively. The organic layer was 4.06 (2H, multiplet,

3.50 (2H, multiplet, C L1 OH), 0.90 (3H, triplet,

Mass spectram M 370 Using the above procedure, but replacing methyl 9a, 1 Sa-dihydroxy- 1 1 a-hydroxymethylprostl 3 (trans- )enoate by methyl 9oz, ISa-dihydroxy- 1 1ahydroxymethylprost-l3(trans)-enoate, there was ob tained 9,8. ISa-dihydroxy-l la-hydroxymethylprostl3(trans)enoic acid.

IR. (KBr) 11 max'" 3300. 2700. 1715, 975.

N.M.R. (CD COCD A: ppm, 5.46 (2H, multiplet,

3 .75 (2H, multiplet,

OH H

EXAMPLE 4 9oz( and ,8), 1 5 ,B-Dihydroxy-l la-hydroxymethylprost- 1 3(trans)- enoic acid 1. Methyl 9a(and B), ISB-dihydroxy-l 1ahydroxymethylprost- 1 3( trans)-enoate To a solution of 1.09 g. of methyl 9-oxo-11ahydroxymethyll 5 ,Bhydroxyprostl 3(trans)-enoate in 25 ml. of absolute methanol was added 109 mg. of sodium boron hydride under ice cooling and the mixture was stirred for 1 hour in ice bath. After completion of the reaction, the mixture was diluted with a cooled 2% aqueous hydrochloric acid and subjected to salting out by addition of sodium chloride. The mixture was extracted three times with ml. of ethyl acetate. The organic layer was washed two times with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 1.09 g. of methyl 95, ISB-dihydroxy-l la'hydroxymethylprost-l3(trans)-enoate as oil. The oil was subjected to column chromatography using 30 g. of silica gel and 4.10 (2H, multiplet.

so, m I

3.65 (3H, singlet, COOCLI 3.56 (2H, broad, singlet, C OH 2.56 (3H, broad, singlet, 30H); 0.90 (3H, triplet. C 9B-hydroxy compound LR. (liquid film) v max"" 3350. I740.

N.M.R. (CDCI A: ppm, 5.53 (2H, multiplet,

OH H

3.874. l 0 (2H. multiplet.

OH H

3.67 (3H, singlet, COOC ll 3.53 (2H, multiplet. C h- OH 2.40 (3H, broad singlet. 3.0H); 0.90 (3H, triplet. -C l ;l

2. 9a. 1 SB-Dihydroxy-l la-hydroxymethylprostl3(trans)-enoic acid In 10 ml. of methanol was dissolved 330 mg. of methyl 901. l SB-dihydroxyl l a-hydroxymethylprostl3(trans)-enoate with stirring in ice bath. To the solution was added 7 ml. of 5% aqueous sodium hydroxide and the solution was stirred for 1 hour at room temperature. The reaction mixture was diluted with 100 ml. of ice-water. neutralized with dilute hydrochloric acid, subjected to salting out by addition of sodium chloride and extracted three times with 50 ml. of ethyl acetate respectively. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was distilled off to give 340 mg. of oily residue. The residue was crystallized from ethyl acetate-n-hexane to give 283 mg. of the desired product as crystalls melting at 87.588.5C.

LR. (KBr) vmax"'" 3450, 3350, 2630. 1710, 1260, 963.

N.M.R. (CD COCD3) A: ppm, 5.50 (2H, multiplet.

4.10 (2H, multiplet,

3.50 (2H, multiplet, C&OH); 0.90 (3H, triplet, 1

Mass spectrum: M 370 Using the above procedure, but replacing methyl 9a,- ISB-dihydroxy-l la-hydroxymethylprostl 3 (trans)- enoate by methyl 9B,l5B-dihydroxy-l 1ahydroxymethylprost-l3(trans)-enoate. there was obtained 9,8,15B-dihydroxy-l la-hydroxymethylprostl3(trans)-enoic acid.

IR. (KBr) 11 max"" 3300. 2700, 1715, 975.

N.M.R. (CD COCD A: ppm, 5.48 (2H, multiplet,

3.65-4.05 (2H. multiplet.

3.47 (2H. multiplet. Cl ;I- OH); 0.90 (3H, triplet, 431.). Mass spectrum: M* 370 EXAMPLE 5 9a(and ,8),l5a(and B )-Dihydroxy-l la-hydroxymethylprostl 3 trans enoic acid 1. Methyl 9a (and B). 156! (and B)-dihydr0xy-l lahydroxymethylprostl 3(trans)-enoate To a solution of 347 mg. of methyl 9d-hydroxy-l lahydroxymethyll 5-oxoprostl 3(trans)-enoate in 20 ml. of ethanol was added 137 mg. of sodium boron hydride in 8 ml. of ethanol under ice cooling and the mixture was stirred for 1 hour. After completion of the reaction. the reaction mixture was poured into ice-water containing acetic acid and to the mixture was added saturated aqueous sodium chloride. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give 359 mg. of oil. The oil was subjected 5 to column chromatography using 5.0 g. of silica gel and eluted with benzene-ethyl acetate (6:4) to give 156 mg.

of methyl 9a,15B-dihydroxy-l la-hydroxymethylprostl3(trans) -enoate and with benzene-ethyl acetate (4:6)

to give 127 mg. of methyl 9a,15a-dihydroxy-1lahydroxymethylprost- 1 3 trans )enoate. 90:,1Sa-dihydroxy compound IR. (KBr) v max"'": 3300, 1741.

N.M.R. (CD COCD A: ppm 5.46 (2H, multiplet,

4.07-3.95 (2H, multiplet,

3.60 (3H, singlet, COOCE 3.50 (2H, multiplet, Cfl Ol-l). 9a,15B-hydroxy compound I.R. (liquid film) 11 max": 3350, 1740.

N.M.R. (CDCl A: ppm, 5.47 (2H, multiplet,

4.10 (2H, mutiplet,

3.80-4.00 (2H, multiplet,

so i. v I

3.87-4.10 (2H, multiplet,

HO H,

3.67 (3H, singlet, COOC I: 3.53 (2H, multiplet, C OH); 2.40 (3H, broad singlet, 3.0g).

2. 9a (and ,8), ISB-Dihydroxy-l la-hydroxymethylprostl 3(trans)-enoic acid In a mixture of 3.6 ml. of absolute methanol, 0.9 ml. of water and 1.5 ml. of 10% aqueous potassium hydroxide was dissolved 124 mg. of methyl 901,1 Sa-dihydroxylla-hydroxymethylprost-l3(trans)-enoate and the solution was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water containing acetic acid. The mixture was saturated aqueous sodium chloride and extracted with ethyl acetate. The extract was washed with aqueous saturated sodium chloride and dried over anhydrous sodium sulfate. the solvent was distilled off to give 101 mg. of crude crystal. The crystal was recrystallized from ethyl acetate-n-hexane to give mg. of 9oz,l5a'dihydroxy-1la-hydroxymethylprost-l3(trans)-enoic acid melting at 8l82C.

IR. (KBr) v max 3400, 2630, 1710, 1260, 965.

N.M.R. (CD COCD A: ppm 5.45 (2H, multiplet,

4.06 (2H, multiplet,

EXAMPLE6 90 (and 1 B), l Sa-Dihydroxy-l la-hydroxymethyl-'16,l 6-dime-.

thylprost-l3(trans)-enoic acid To a solution of 350 mg. of 9-oi o-l lahydroxymethyll Sa-hydroxy-l 6,1 6-dimethylprost' l3(trans)-enoic acid in. ml. of methanol was added 100 mg. of sodium boron hydrideunder ice cooling and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was made acidic by addition of acetic acid. The mixture was extracted with ethyl acetate and the solvent was distilled off. The residuewas subjected to column chromatography using 10 g. of silica gel and eluted with ethyl acetate-benzene 1:1) to give 1 mg. of 901,15adihydroxy l la-hydroxymethyll 6, l 6-dimethylprostl3(trans)-enoic acid and 95 mg. of 9,8,l5oz-dihydroxy- 1 la-hydroxymethyl- 1 6, lY6-dimethylprost-l 3(trans)-v enoic acid. v I 9 a( and ,8)-hydroxy compound LR. (CHCI 1 max"" 3240, 2400, 1710, 972.

N.M.R. (CD COCD Azppm, 5.5 (2H, multiplet,

EXAMPLE 7 9a( and B),l5 .-D ihydroxy-l l a-hydroxymethyll 6, 1 6-dimethylprostl3(trans)-enoic acid sin- To a solution of 295 mg. of ,9-oxo-l lahydroxymethybl SB-hydroxy-l 6, 1 6-dimethylprostl3(trans)enoic acid in 10 ml. of methanol was added 1 l5 mg.,of sodium'boron hydride under ice cooling and the mixture was stirred for minutes. After completion of the reaction, the reaction mixture was treated in the same procedure as in Example 3 to give 85 g. of 9a,15B-dihydroxy-l lea-hydroxymethyl-16,16-dimethylprost-l3(trans)-enoic acid and 70 mg. of 9,8,15B- dihydroxy-l la-hydroxymethyl- 1 6, l 6-dimethylprostl3(trans)-enoic acid.

Using the above procedure, but replacing 9-oxo-l lahydroxymethyll SB-hydroxyl 6, l 6-dimethylprostl3(trans)-enoic acid by methyl 9,15-dioxo-l laethoxycarbonyloxymethyll 6, l 6-dimethylprostl3(trans)-enoate and 9-hydroxy-l let-hydroxymethyll5-oxol 6, l6-dimethylprost-l 3(trans')-enoic acid, there were obtained methyl 9,l5-dihydroxy-l laethoxycarbonyl oxymethyll 6, l 6-dimethylprostwherein A represents an alkylene group having from 4 to 8 carbon atoms, R represents an alkyl group having 0 from 1 to 10 carbon atoms,-R represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R represents'hydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkyl moiety and pharmaceutically acceptable salts thereof.

2. Compounds having the'formula 2 (CH2) (R 3 R OH C wherein R represents an alkyl group having from 4 to 10 carbon atoms, R represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R represents hydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkyl moiety and pharmaceutically acceptable salts thereof.

3. 9 a(or B), l5a(or B)-Dihydroxy-l lax-hydroxymethylprost-l3(trans)-enoic acid.

4. Methylv 9a(or [3,),15 a(or B)-dihydroxy-l laethoxycarbonyloxymethylprostl 3( trans)-enoate.

5. v 9o (or' B),l5a(or B)-Dihydroxy-l lahydroxymethyll 6, 1 6-dimethylprostl 3(trans)-enoic acid. i V I i v 6. ,..Methyl 9a(or [3),1501 (or B)-dihydroxy-l lozhydroxymethyi-l 6, l 6-dimethylprostl 3(trans)-enoate.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFIQATE OF CORRECTION PATENT NO. 3 ,899,525 Page 1 of i DATED August 12, 1975 lNVENTOR(5) I Osamu Oda et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columns 5 and 6 In formulas IX, X, XI and XII, show a dotted line going from the ring structure to the group "R OOCOH C" with the dotted line attached to the last-mentioned "C" Column 6 In formula XII, show a dotted line going from the ring structure to the group "A-COOR with the dotted line attached to "A" Column 8, between lines 40 and 45 delete the formula and rewrite as ---(R P-cH-fi-R Column 10, last line, delete formula and rewrite as P-CH C-R Column 13, between lines 55 and 60, delete formula and rewrite as

Claims (6)

1. COMPOUNDS HAVNG THE FORMULA

2. Compounds having the formula

3. 9 Alpha (or Beta ), 15 Alpha (or Beta )-Dihydroxy-11 Alpha -hydroxymethylprost-13(trans)-enoic acid.

4. Methyl 9 Alpha (or Beta ),15 Alpha (or Beta )-dihydroxy-11 Alpha -ethoxycarbonyloxymethylprost-13(trans)-enoate.

5. 9 Alpha (or Beta ),15 Alpha (or Beta )-Dihydroxy-11 Alpha -hydroxymethyl-16,16-dimethylprost-13(trans)-enoic acid.

6. Methyl 9 Alpha (or Beta ),15 Alpha (or Beta )-dihydroxy-11 Alpha -hydroxymethyl-16,16-dimethylprost-13(trans)-enoate.