DE2342004A1 - PROSTAGLANDIN DERIVATIVES - Google Patents

Description

PATENT LAWYERS
DR. W. KINZEBACH - DIPL.-ING. O. HELLEBRAND

8 Munich 80 20. A ^- Ug. 1973 Walpurgisstraße 6 Telephone: 0811/4705034 Telegrams: Hekipat (Munich)

GASES: AHP-5811

AMERICAN HOME PRODUCTS CORPORATION 685 Third Avenue, New York, N.Y. 10017, USA.

Prostaglandin derivatives.

The invention relates to prostaglandin _s in which the 11-position (it will be the numbering system of Prcstansäure used) is variously substituted with chemical moieties which vrurden not found in nature. These compounds have bronohodilatierenda mA hvpo ^ uiisive effectiveness, they are ouch PG-A ₂ UNAE ihröü esters IMD 15 Ipimeren made.

The prostaglandins are a group of hormone-like substances that can be regarded as prostanoic acid derivatives. Man found that various prostaglandins are widely distributed in mammalian tissues and are isolated from this source been. These prostaglandins have been shown to have a variety of biological properties, including bronchodilating Effect, ability to gastric secretion

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decrease, modify muscle tone, and increase or decrease pressure.

Summary of the invention

The prostaglandin derivatives according to the invention have the general my formula:

00R-

(i) X represents the oxo radical,

Y stands for a cis double bond,

Z stands for a trans double bond, R nitromethyl, vinyl, phenyl, methyl, benzyl, cyano, mercapto, (Lower) alkylthio, phenylthio, carboxycyanomethyl, carb (lower) alkoxyeyanomethyl, dicarboxymethyl, dicarb (low) alkoxymethyl, Means dicyanomethyl or garbamoylcyanomethyl,

2
R is hydroxy, tetrahydropyranyloxy or acetoxy, R ^{5 is} hydrogen or (lower) alkyl and R ^ "is hydrogen or

(il) 1 füi. " Ethyl tmoloxy stands,

Y stands for an eiB double mouth,

Z stands for a trans double oil bond, R cyano, carboxy, carbamoyl, formyl, hydroxymethyl, acetyl, 1-hydroxyethyl or nitromethyl denotes, R denotes hydroxy or acetoxy,

R ^ is hydrogen or lower alkyl and

R ^ represents hydrogen or

(iii) X is oxo,

Y stands for a cis double bond,

Z stands for a trans double bond,

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R carboxy, acetyl, carbamoyl, hydroxymethyl or 1-hydroxyethyl "means,

ρ
R means hydroxy

R and R represent hydrogen or

(iv) X stands for ethylenedioxy,

Y stands for a cis double bond,

Z is a trans double bond, R is nitromethyl or cyano, R and R together represent the oxo radical and R * stands for hydrogen or

(v) X stands for ethylenedioxy,

Y stands for a cis double bond,

Z is a trans double bond, R is nitromethyl or cyano,

ρ
R is methyl or phenyl, R is hydrogen and R ^ is hydroxy or

(vi) X is oxo,

Y stands for a cis double bond,

Z is a trans double bond, R is nitromethyl or cyano, R is methyl or phenyl, R is hydrogen and

R is hydroxy or

(vii) X is oxo,

Y and Z stand for single bonds,

R denotes nitromethyl or cyano,

2
R is methyl or phenyl,

B? Represents hydrogen and

4th
R is hydroxy or

(viii) X is Oxo,

Y and Z stand for single bonds,

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R carbamoyl, methyl, carboxy, benzyl, nitromethyl, phenyl, Cyano, carb (low) alkoxycyanomethyl, carboxycyanomethyl, Dicarb (lower) alkoxymethyl, dicarboxymethyl, hydroxymethyl, Means acetyl or 1-hydroxyethyl,

ρ
R is hydroxy, tetrahydropyranyloxy or acetoxy, R ^ is hydrogen or (lower) alkyl and

R represents hydrogen or

(ix) X stands for <^ _H ,

Y stands for a cis double bond,

Z stands for a trans double bond,

1
R is mercapto, nitromethyl, vinyl, phenyl, methyl, benzyl, cyano, (lower) alkylthio, phenylthio, carboxycyanomethyl, dicarboxymethyl, dicyanomethyl or carbamoylcyanomethyl,

ρ
R is hydroxy or tetrahydropyranyloxy, R ^ is hydrogen or (lower) alkyl and R ^{4 is} hydrogen.

In a first embodiment, the invention relates to prostaglandins the general formula:

OOR '

II

wherein R denotes nitromethyl, vinyl, phenyl, methyl, benzyl, cyano, mercapto, (lower) alkylthio, phenylthio, carboxycyanomethyl, carb (lower) alkoxycyanomethyl, dicarboxymethyl, dicarb (lower) alkoxymethyl, dicyanomethyl or carbamoylcyanomethyl; R represents hydroxy, tetrahydropyranyloxy or acetoxy; and R ^{5 represents} hydrogen or (lower) alkyl.

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* "23A20Q4

The real connections of this first embodiment are clear to yellow oils, essentially insoluble in water and generally soluble in organic solvents such as Ethyl acetate and ether. The study of the compounds prepared according to the procedure described below shows using infrared, HMR and mass spectrographs Analysis of spectral data bearing the molecular structure given above. Confirm the above-mentioned physical characteristics together with the nature of the starting material, the type of synthesis and the elemental analysis, the structure of the invention Links.

The real compounds of this first embodiment of the invention have bronchodilating and hypotensive effects when used, when administered of warm-blooded creatures. This is shown by pharmacological investigations based on standardized test procedures. Also suitable they can be used as intermediates for the preparation of other products according to the invention Links.

In a second embodiment, the invention relates to prostaglandins of the general formula V:

0 p

where R is cyano, carboxy, carbamoyl, formyl, hydroxymethyl, Is acetyl, 1-hydroxyethyl or nitromethyl;

2
R is hydroxy or acetoxy and R ^- ^ is hydrogen or lower alkyl.

The real connections of the second embodiment according to the invention

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^G ? 3 A? O O A

form are either crystalline solids or clear up Applied oils are essentially insoluble in water and generally soluble in polar solvents such as ethyl acetate and ether. The investigation of the compounds produced by the method described below shows, according to the infrared, NMR and mass spectral analysis spectral data bearing the molecular structure given above. The above physical characteristics confirm together with the Nature of the starting materials, the type of synthesis and the elemental analysis, the structure of the compounds according to the invention.

The real compounds of the second embodiment of the invention have the property in use that they are bronchodilator when administered to warm-blooded living beings and exert hypotensive effects. This is shown by phannacological Investigations according to standardized test procedures. aside from that eie are suitable as intermediates for the synthesis of other compounds according to the invention.

In a third embodiment, the present invention relates to Prostaglandins of the general formula VI:

COOH

VI

wherein R is carboxy, acetyl, carbamoyl, hydroxymethyl or 1-hydroxyethyl means.

The real connections of the third embodiment of the invention are clear to yellow oils, are essentially insoluble in water and generally soluble in polar solvents, like 'ethyl acetate and ether. The investigation of according to the connection produced using the method described below

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fertilize shows according to the infrared, KM and mass spectrographic Analysis of spectral data showing the molecular structure given above wear. The above-mentioned physical characteristics, together with the nature of the starting material, confirm the nature of the synthesis and the elemental analysis the structure of the compounds according to the invention.

The real compounds of the third embodiment of the invention show bronchodilating and hypotensive effects when administered to warm-blooded animals. This showed pharmacological examinations according to standardized test procedures, they are also suitable as intermediates for the synthesis of other compounds according to the invention.

A fourth embodiment of the invention relates to prostaglandins of the general formula VII:

VII

wherein R is nitromethyl or cyano.

The real compounds of the fourth embodiment are either crystalline powder substances or clear to yellow oils, they are essentially insoluble in water and generally soluble in polar solvents such as ethyl acetate and ether. An investigation of compounds following the one described below Process has been prepared shows spectral data after infrared, NMR and mass spectrographic analysis, which have the molecular structure given above. The above-mentioned physical characteristics together confirm with the nature of the starting material, the type of synthesis and the elemental analysis, the structure of the invention Links.

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The real compounds of this fourth embodiment are suitable as intermediates for the synthesis of other compounds according to the invention Links.

A fifth embodiment of the invention relates to prostaglandins of the general formula VIII:

VIII ²

HO R

1 2

where R is nitromethyl or cyano and R is methyl or phenyl.

The real connections of this fifth embodiment are clear to yellow oils, they are essentially insoluble in water and generally soluble in polar solvents, like ethyl acetate and ether. Examination of compounds prepared by the method described below shows the infrared, NMR and mass spectral analysis spectral data bearing the molecular structure indicated above. The above-mentioned physical characteristics, together with the nature of the starting material, confirm the type of Synthesis and elemental analysis of the structure of the compounds according to the invention.

The compounds of this fifth embodiment serve as intermediates for the synthesis of others according to the invention Links.

A sixth embodiment of the invention relates to prostaglandins the general formula IX:

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IX

1 2

where R is nitromethyl or cyano and R is methyl or phenyl.

The real compounds of this sixth embodiment are clear to yellow oils, they are essentially insoluble in Water and generally soluble in polar solvents such as ethyl acetate and ether. The investigation of connections, prepared by the procedure described below showed by infrared, HMR and mass spectrographic Analysis of spectral data bearing the molecular structure given above. The physical characteristics mentioned above confirm together with the nature of the starting material, the type of synthesis and the elemental analysis, the structure of the compounds according to the invention.

The compounds of this sixth embodiment have bronchodilators when administered to warm-blooded animals and hypotensive properties. This is shown by pharmacological Investigations according to standardized test procedures; they are also suitable as intermediates for the synthesis of others compounds according to the invention.

A seventh embodiment of the present invention relates to prostaglandins of the general formula X:

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where R is nitromethyl or cyano and R is methyl or phenyl.

The compounds of this seventh embodiment are clear to yellow oils, they are essentially insoluble in water and generally soluble in polar solvents such as ethyl acetate and ether. The study of compounds following by the method described below by infrared, NMR and mass spectrometry Analysis of spectral data bearing the molecular structure given above. Confirm the above-mentioned physical properties together with the nature of the starting material, the type of synthesis and the elemental analysis, the structure of this Links.

The real compounds of this seventh embodiment have bronchodilators when administered to warm-blooded animals and hypotensive effects, such as pharmacological studies according to standardized test procedures show that they are also suitable as intermediates for synthesis other compounds of the invention.

An eighth embodiment of the present invention relates to prostaglandins of the general formula IV:

COOR ³

IV

where R is carbamoyl, methyl, carboxy, benzyl, nitromethyl, phenyl, Cyano, carb (low) alkoxycyanomethyl, carboxycyanomethyl, dicarb (low) alkoxymethyl, Means dicarboxymethyl, hydroxymethyl, acetyl or 1-hydroxyethyl;

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lyloxy or acetoxy R ^{3 represents} hydrogen or (lower) alkyl.

R represents hydroxy, tetrahydropyranyloxy or acetoxy and

The real connections of this eighth embodiment are clear to yellow oils, they are essentially insoluble in water and generally soluble in polar solvents, like ethyl acetate and ether. The study of compounds produced by the method described below has been determined by infrared, NMR and mass spectrographs Analysis of spectral data bearing the specified molecular structure. The physical characteristics mentioned above confirm together with the nature of the starting material, the type of synthesis and the elemental analysis, the structure of the compounds according to the invention.

The real connections of this eighth embodiment work bronchodilating and hypotensive when administered to warm-blooded organisms, as shown by pharmacological studies show standardized test methods and they are also suitable as intermediates for the synthesis of other inventive methods Links.

A ninth embodiment of the present invention relates to prostaglandins of the general formula III:

COOR ³

III

wherein R is mercapto, nitromethyl, vinyl, phenyl, methyl, benzyl, cyano, (lower) alkylthio, phenylthio, carboxycyanomethyl, dicarboxymethyl, dicyanomethyl or carbamoylcyanomethyl; R is hydroxy or tetrahydropyranyloxy and R ^{5 is} hydrogen or (lower) alkyl.

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The real compounds of this ninth embodiment are also clear to yellow oils, they are essentially insoluble in water and generally soluble in polar solvents such as ethyl acetate and ether. The study of compounds which have been prepared by the method described below , gives after infrared, WiR and mass spectrographic analysis spectral data bearing the molecular structure indicated.The above-mentioned physical characteristics, together with the nature of the starting material, the type of synthesis and the elemental analysis, confirm the structure of the compounds according to the invention.

The compounds of this ninth embodiment have bronchodilators when administered to warm-blooded animals and hypotensive effects such as pharmacological studies show according to standardized test methods and are also suitable as intermediates for the synthesis of other products according to the invention Links.

When describing the synthesis of the compounds according to the invention Reference is made to the following figure, in which the formulas which make up the various inventive Represent embodiments are provided with Roman numerals for identification. These numbers are the same which were used in the summary and the

12 3

Definitions of the radicals R, R and R are the same as the were assigned to the corresponding embodiments.

The starting materials of Formula I are either known compounds or simple derivatives thereof which can be readily prepared in ways known to those skilled in the art. Thus, the starting materials 15-biprostaglandin-A ₂ and its methyl ester and acetate can be isolated from Plexaura homomalla, as has been described by Weinheimer and Spraggins, Tetrahedron Letters, 5,9, 5185 (1969); Prostaglandin ^

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(VII)

COOH

Ib

(in)

C00R ^v

CX)

ClX)

-J3 -

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(Prostaglandins, Bergstrom et al., Interseience Publishers, 1967) and Prostaglandin-A ₂ , methyl ester (Bundy et al., Annals of the NY Academy of Sciences, 180 , 76 / ΐ 971 /) are also known. Starting materials in which R means tetrahydropyranyloxy can easily be prepared by, for example, reacting the corresponding 15-hydroxy starting material with dihydropyran in the presence of p-toluenesulfonic acid and prostaglandin Ag methyl ester acetate can be obtained from prostaglandin A2 methyl ester, for example by treatment with acetic anhydride in the presence can be made from pyridine.

Compounds of the formula II are prepared from the starting materials (I) by 1,4-conjugate addition to the of, ) -unsaturated ketone system. This addition is achieved either by treatment with Grignard reagents in the presence of a Xupfer-I compound such as copper-I chloride, or by treatment with a donor for a Michael reaction in the presence of a strong base, or by treatment with a thiolating agent such as sodium sulfide, Thxophenol or atanthiol. If the compounds of the formula II contain ester or ether groups, these can be hydrolyzed so that the corresponding free hydroxy acid compounds are obtained.

Compounds of formula III are made appropriate by treatment Compounds of Formula II with a hydride reducing agent such as sodium borohydride prepared. The connections of formula IV are obtained by hydrogenation of the corresponding compounds of formula II or formula VI, e.g., by hydrogenation in the presence of palladium on carbon.

Ketal compounds of the formula V are produced by ketalization in a manner known per se, e.g. by treatment with ethylene glycol in the presence of p-toluenesulfonic acid. Are the compounds of the formula V ester, they can be hydrolyzed, e.g. with ethanolic sodium hydroxide, thereby obtained

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the corresponding free hydroxy acids, compounds of the formula V in which R is carbamoyl or carboxyl, are obtained by hydrolysis of compounds of the formula V in which R is cyano, for example by hydrolysis with aqueous methanolic sodium hydroxide at reflux temperature and subsequent separation of the two products, for example by chromatography on silica gel. Compounds of the formula V in which R is hydroxymethyl are prepared by treating compounds of the formula V _f in which R is cyano with triethoxyhydride and then hydrolyzed in water, preferably acidic, so that compounds of the formula V are obtained in which R stands for formyl, followed by reduction, for example with sodium borohydride. Compounds of the formula V ₁ . in which R is acetyl, are prepared by treating compounds of the formula V in which R is cyano with methylmagnesium bromide and subsequent treatment with aqueous acid. The acetyl compound can be reduced, for example with sodium borohydride, to compounds of the formula V in which R is 1-hydroxyethyl.

Compounds of the formula VI are by Beketalisierung of Compounds of formula V, in a manner known per se, e.g. by treatment with hydrochloric acid in tetrahydrofuran, manufactured. The 15-keto compounds of formula VII are produced by oxidation of compounds of formula V with Jones reagent. Compounds of formula VIII are made by reaction of compounds of the formula VII with methyl or phenyl Grignard reagent. Compounds of Formula IX are by decetalization of compounds of the formula VIII, e.g. with hydrochloric acid or perchloric acid in tetrahydrofuran. Compounds of formula X are made by Hydrogenation of compounds of formula IX, e.g., by hydrogenation in the presence of palladium on carbon.

It is clear to the person skilled in the art that the carbon atoms to which the

1 2
Substituents R and R are bonded in the invention

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^{/ 6} 2 3 Λ 2 GOA

Compounds represent asymmetric carbon atoms and as a result, two epimeric configurations occur. Da3 symbol ^ "is intended to indicate that both possible configu rations in each individual position are meant. The substituents R are introduced in the preparation of the compounds of the invention and their introduction leads to formation a mixture of the two epimeric forms, based on this position. In the compounds of the formulas VIII, IX and X also become in previously non-asymmetric centers

ρ
Substituents R introduced and in turn both possible configurations are formed in a mixture. In the other compounds according to the invention, the 15-position (where R is bound) in the starting material is asymmetrical and remains so during the formation of the desired product; As a result, the configuration in this position in the product depends on the configuration of the starting material. Where epimeric mixtures are formed in the present invention, they can, if desired, be separated in a variety of known ways, such as by chromatography.

Various compounds according to the invention carry hydroxyl or carboxyl groups, which are formed smoothly in a known manner can be esterified by simple esters; likewise, various compounds carry and can carry carboxyl groups smoothly into their alkali metal salts or a salt of a pharmacologically acceptable cation, that of ammonia or a basic amine originates, transferred v / earth. All such esters and salts are perfect equivalents of the specific claimed connections.

Where the terms "(lower) alkyl" and "(lower) alk-" are used, they include straight and branched chain hydrocarbon radicals having 1 to about 6 carbon atoms.

When using the compounds according to the invention for the production bronchodilating effects in warm-blooded living

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being, they can be administered in a variety of dosage forms, including forms for oral administration, injectable administration and oral inhalation. Oral inhalation is a preferred mode of administration because of its rapid onset of action, the powerful effect and the specificity of the effect. The specific dose to achieve the bronchodilator effect will vary depending on the particular compound used, the individual living being and the desired degree of bronchodilation. In guinea pigs, the oral inhalation dose for producing a bronchodilator is about 0.2 micrograms to about 100 micrograms, preferably about 5 to 50 micrograms. The bronchodilatation produced as a result of the oral inhalation can be determined by the method of Rosenthale et al., Int. Arch. Pharmacol., 172 . 91 (1968) can be observed.

When using the compounds according to the invention to produce hypotensive effects in warm-blooded animals administration by injection is preferred, preferably intravenous injection.

The following examples are provided for further illustration the invention.

example 1

7- / 2- (3 "-S-hydroxy-1-octenyl) -5-oxo-3-cyclopenten-1-yl7-5-heptenoic acid, methyl ester

A solution of 16.0 g of PG ₂ in 200 ml of ether is treated with excess diazomethane in ether and held at 25 for 1 hour. The excess diazomethane is decomposed with acetic acid and the mixture is diluted with ether, washed with water and dried over sodium sulfate. When the solvent evaporates, 17.0 g of the compound mentioned in the title are obtained as an oil, λ PiIm 3.0, 3.45, 5.75, 5.85 μ.

XUcLa.

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Example 2

7- / 2- (3-S- / tetrahydropyran-2-yloxy7-1-octenyl) -5-oxo-3-cyclo -penten-1-yl7-5-heptenic acid

A solution of 10.0 g PGit ,, 4.0 g dihydropyran and 0.06 g p-toluenesulfonic acid in 300 ml benzene is stirred for one hour at 25 °. The reaction mixture is diluted with ether, washed with water and dried over sodium sulfate. After evaporation and chromatography of the residue on silica with 3056 ethyl acetate in hexane, 4.4 g of the compound mentioned in the title are obtained as an oil, X _mv film 3.45, 5.85, 6.3, 9.8, OK, 3juiA _max 9556 EtOH 218 mju (E. 9600).

Example 3

7- / 2- (3-S- / tetrahydropyran-2-yloxy7-1-octenyl) -5-oxo-3-cyclo -penten-1-yl7-5-heptenoic acid, methyl ester

A solution of 1.0 g of 7- / 2- (3-S- / tetrahydropyran-2-yloxy / -1-octenyl-5-oxo-3-cyclopenten-1-yl / -5-heptenoic acid in 20 ml of ether becomes Treated with excess diazomethane in ether and the mixture is kept for 1/2 hour at 25 ° After the destruction of the excess diazomethane with acetic acid, the solution is washed with water and dried over sodium sulfate g of the compound named in the heading as oil, λ-3.45, 5.8, 5.9, 9.7, 10.3 ^ i X _ffiax 95% EtOH 218 η μ (i 96CG). MR: b 7 , 55 (dd, J = 1.5, 6.0, 11 -H), 6.20 (dd, J = 2.2, 6.0, IG-H), 5.50 (K, 4, olefinic ), 4.68 (M, 1,0-CH-O), 3.68 (s, 3, OCH ₃ ) ppm.Mass spectrum: M ⁺ at m / e 432 (theoretical 432), K ⁺ -OCE, at m / e 401.2746 (theoretical 401.2690).

Example 4

7- / 2- (3-R- / tetrahydropyran-2-yloxy7-1-0ctenyl) -5-oxo-3-cyclo -penten-1-yl7-5-heptenoic acid

A solution of 3.936 g of 15-epi-PGA ₂ and 1.5 g of dihydropyran in 100 ml of benzene is treated with 25 mg of p-toluenesulfonic acid and

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the mixture is stirred for 1 hour at 25 ° under nitrogen. The reaction mixture is diluted with ether, washed with water and dried over sodium sulfate. The solvent is evaporated and the residue chromatograpniert on silica, eluted with 3O? & Ethylacetate in hexane and obtained 3.75 g of the compound of the title product as an oil, A _"o" Film 3.4,

ITlCLJ ¹ L

5.8, 6.3, 9.8, 10.25 µ; Λ 95 # EtOH 219 mu (89800).

_A ' max'

KIiR: t 7.55 (dd, J = 2.2, 6.0, 11-H), 6.25 (dd, J = 1.5, 6.0, 10-E), 5.48 (M. , 4, olefinic), 4.72 (bs, 1,0-CH-O) ppm. Mass spectrum: M ⁺ -OPy at m / e 317.2099 (theoretical 317.2116).

Example 5

7 / 2- (3-S-hydroxy-1-octenyl) -5-oxo-3-cyclopenten-1-yl / -5-hepten- , methyl ester, acetate

A solution of 17.0 g of 7- / 2- (3-S-hydroxy-1-octenyl) -5-oxo-3-cyclopenten-i-ylZ-S-heptenoic acid methyl ester in 300 ml of pyridine and 30 ml of acetic anhydride is stirred at 25 ° for 6 hours. The reaction mixture is concentrated in vacuo, diluted with ether, washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 15% ethyl acetate in hexane gives 15.3 g of the compound named in the title as an oil, \ _max Pilm 3.45, 5.7, 5.8, 6.3, 8, 0, 9.25, 10.25 and the like

Example 6

7- / 2- (3-R-Hydroxy-1-octenyl) -3-nitromethyl-5-oxocyclopentyl7-5 -heptenoic acid methyl ester, acetate

A solution of 13.4 g of 15-epi-PGAp methyl ester, acetate and 37.3 ml of nitromethane in 250 ml of methanol is mixed with 1.485 g of xatrium methylate treated and the mixture is stirred under nitrogen for 2 hours at 25 °. The reaction mixture is diluted with ether, wash with water and dry over sodium sulfate. Evaporation and chromatography of the residue on silica with 40 # ethyl acetate in hexane gives 8.9 g of that in the title

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named compound as oil, λ. Film 3.4, 5.7, 6.4, 8.0,

9.8, 10.3 ju. Mffi: 5 5.60 (M, 2; 13 and H-H), 5.37 (M, 3, ·

5-6-15-H), 4.45 (M, 2, CH ₂ NO ₂ ), 3.67 (S, 3, OCH ₅ ), 2.06 (s, acetate) ppm.

Example 7

7 - / ^ (3-R-Hydroxy-1-octenyl) -3-nitromethyl-5-oxocyclopentyl7-5-heptenoic acid

A solution of 0.60 g of 7- / 2- (3-R-hydroxy-1-octenyl) -3-nitromethyl-5-oxocyclopentyl7-5-heptenoic acid methyl ester, acetate in 20 ml of methanol is mixed with 15 ml of a 1 η Treated sodium hydroxide solution and the mixture is stirred under nitrogen for 1/2 hour at 25 °. The reaction mixture is added to water, acidified with hydrochloric acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. When eluting with 30 $ ethyl acetate in hexane, 0.653 g of the product named in the heading is obtained as oil, X """film 3.0 (shoulder), 3.4, 5.7, 5.8, 6.4, 7 , 2, 10.3 µ. NMR: δ6.7O (s, 2, OH), 5.60 (M, 2; 13 and HH), 5.40 (M, 2; 5 and 6-H), 4.45 (M, 2, CH ₂ NO ₂ ), 4.15 (M, 1j 15-H) ppm. Mass spectrum: M ⁺ at / e 395 (theoretical 395), M ⁺ -H ₂ O at m / e 377.2224 (theoretical 377.2201).

Example 8

7- / 2- (3-R- / tetrahydropyran-2-yloxy7-1-octenyl) -5-oxo-3-vinyl cyclopentyl7-5-heptenoic acid

5.75 ml of a 3.35 M vinyl magnesium chloride solution in 15 ml of TH5 ¹ are added dropwise to an ice-cold mixture of 0.65 g of 7- / 2- (3-R-Z-tetrahydropyran-2-yloxy7-1-octenyl) -5- oxo-3-cyclopenten-1-yl7-5-heptenoic acid and 1.27 g of copper (I) chloride in 25 ml of THP, while stirring under nitrogen. After stirring at 0 for one hour, the reaction mixture is added to an aqueous ammonium chloride solution and extracted with ether. After washing with water and drying over sodium sulfate, the

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The extract was evaporated and the residue was chromatographed on silica. It is eluted with 20% ethyl acetate in Kexan and 0.27 g of the product named in the title is obtained as an oil, λ PiIm 3.45, 5.75, 5.85, 6.1, 9.8, 10.25, 11 , OjU. MR: S 4.7-5.7 (M, 7, olefinic), 4.75 (bs, O-CH-O) ppm. Mass spectrum: M ⁺ -OPy "at m / e 345.2433 (theoretical 345.2429).

Example 9

7- / 2- (3-R-Hydroxy-1-octenyl) -5-oxo-3-vinylcyclopentyl7-5-heptenic acid

An ice-cold solution of 0.30 g of 7- / ~ 2- (3-R- / Tetrahydropyran-2-yloxy_7-1-octenyl) -5-oxo-3-vinylcyclopentyl7-5-heptenoic acid in 20 ml of THP is mixed with 5, 0 ml of hydrochloric acid "and the mixture is stirred at 0 ° C. under nitrogen for 5 minutes. The reaction mixture is diluted with water, extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation and chromatography of the residue on silica 30 $ ethyl acetate in hexane gives 0.13 g of the product named in the heading as an oil, ^ - _max PiIm 3.0, 3.45, 5.8, 6.1, 10.3 10.95 yes KMR: - 4.8-5.9 (M, 7, olefinic), 4.2 (M, 1, 15-H) ppm.Mass spectrum: M ⁺ at m / e 362 (theoretical 362).

Example 10

7- / l> - (3-R - hydroxy-1-octenyl) -5-OXo ^ -Ph enylcyclopentylJ-S- heptenoic acid

3.84 ml of a 2.5m phenylmagnesium chloride solution in 15 ml of THP are added dropwise to an ice-cold mixture of 0.62 g of 7- / 2- (3-R- / tetrahydropyran-2-yloxy / -1-octenyl) -5- oxo-3-cyclopenten-1-yl7-5-heptenoic acid and 0.61 g of copper (I) chloride in 20 ml of THP and stirred under nitrogen for 1/2 hour at 0 ^° C. The reaction mixture is added to aqueous ammonium chloride solution and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated

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and the residue on silica chromatograph! Eluting with 20% ethyl acetate in hexane gives 0.26 g of an oil which is dissolved in 20% . 20% hydrochloric acid is dissolved in TKP at ⁰ ° C. for 10 minutes. The mixture is diluted with water, extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 30% ethyl acetate in hexane gives 0.13 g of the product named in the title as an oil, ^ _max Pilm 3.0 (shoulder), 3.45, 5.8, 10.35 , 13.2, 14.3ju. NMR: S 7.18 (s, 5, aromatic), 6.25 (s, 2, OH), 5.42 (M, 4, olefinic), 4.02 (M, 1, 15-H) ppm. Mass spectrum: M ⁺ at m / e 412.2587 (theoretical 412.2613).

Example 11

7- / 2- (3-S- / tetrahydropyran-2-yloxy7-1-octenyl-5-oxo-3-vinyl-

cyclopentyl7-5-heptenoic acid

9.0 ml of a 3.35m vinyl magnesium chloride solution in 40 sil T hydrofuran are added dropwise with stirring and nitrogen to an ice-cold mixture of 1.0 g of 7- / 2- (3-S- / tetrahydropyran-2-yloxy / -1- octenyl) -5-oxo-3-cyclopenten-1-yl / -5-heptenoic acid and 2.0 g of copper (I) chloride in 40 ml of tetrahydrofuran. After stirring at 0 ° for 1/2 hour, the reaction mixture is added to aqueous ammonium chloride solution and extracted with ether. After washing with water and drying over magnesium sulfate, the extract is evaporated and the Poickstar-d is chromatographed on silica. Eluting with 20 $ ethyl acetate in hexane gives 0.3 g of the product named in the title as an oil, χ _max film 3.45, 5.75, 5.85, 6.1, 9.8, 10.25, 11, 0; u.

Example 12

7V ~ 2- (3-S-hydroxy-1-octenyl) -5-oxo-3-vinylcycloper ^ yl / -5-heptenoic acid

An ice-cold solution of 0.30 g of 7- / ~ 2- (3-S- / Tetrahydropyrar.-2-yloxy_7-octenyl) -5-oxo-3-vinylcyclopentyl7-5-heptenoic acid in 20 ml of THP is mixed with 5.0 ml of hydrochloric acid treated and

- 22 -409810 / 117S

AHP-5811

the mixture is stirred for 5 minutes at 0 °. The reaction mixture is diluted with water, extracted with ether, the extract is washed with water and dried over magnesium sulfate. Evaporation and chromatography of the residue on silica with 30% ethyl acetate in hexane gives 0.10 g of the product named in the title as an oil, λ _max film 3.0, 3.45, 5.8, 6.1, 10.35, 11 , 0 & KKR: 5 4.5-5.8 (M, 7, olefinic H), 4.08 (K, 1, 15-H) ppm. Mass spectrum: M ⁺ -H ₂ O at m / e 344.2342 (theoretical 344.2350).

Example 13

7- / 2- (3-S-hydroxy-1-octenyl) -3-nitromethyl-5-oxocyclopentyl7-5-heptenoic acid

A solution of 0.70 g of PGA ₂ and 2.26 ml of liitromethane in 25 ml of dry methanol is treated with 0.303 g of sodium methylate and stirred at 25 ° under nitrogen for 2 hours. The reaction mixture is added to water, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue on silica chromatograph? "Tt. Eluting with 50 $ ethyl acetate / hexane gives C, 61 g of the compound named in the title as an oil, λ _max film 3.0 (shoulder), 3.4, 5.75, 5.85, 6.45, 10.3 μ NMR:. b6,42 (s, 2 OH), 5.60 (M, 2, 13, and HH), 5.40 (K, 2, 5 and 6-H), 4.47 (M , 2, CH ₂ NO ₂ ), 4.15 (M, 1, 15-H) ^{ppm.Mass spectrum: M +} -HgO at m / e 377.2225 (theoretical 377.2201).

Example U

7- / 2- (3-S-hydroxy-1-octenyl) -3-methyl-5-oxocyelopentyl7-5-heptenoic acid

A solution of 0.515 g of PGA ₂ in 20 ml of THF is added dropwise over the course of 20 minutes to an ice-cooled, stirred mixture of 7.5 ml of 3m MeMgSr / ether and 1.58 g of CuCl in 25 ml of TH? under nitrogen. The mixture is stirred at 0 ° for 15 minutes and "at 25 ° for 15 minutes. The reaction mixture is diluted

- 23 -

A09810 / 1 175

ΑΉΡ-581 1

mixture with aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 40% ethyl acetate in hexane gives 0.311 g of the product named in the title as an oil (solidifies on standing, mp = 63-68 °), λ _max KBr 3.0, 3.5, 5.8, 8.5 , 10.25 µ, NMR: S 6.57 (s, 2, OH), 5.45 (M, 4, olefinic), 4.15 (M, 1, 15-H) ppm. Mass spectrum: M ⁺ at m / e 350.2556 (theoretical 350.2456).

Example 15

7 / OI ^ Cf ΤΤτΓί ~ Ι Ύ * · ΛντΓ ι ^ m Γ \ O * ί ~ O ΥΊ ΊΤ 1 I «μ ^ ^ · Ο Υ /" ΐ η ^ · ™ ΤΛrl OTl TΓ I Γ * ~ \ Τ V * ι (~ \ Ύ \ &"* ~ Ί " ί ~ ΛΛ I / - · ^ ^ m ■ · ■ ι ^ • ^mm I _J "· ™ O Xi. y KX. X. kJ-fw ν ^^ * U LJ ί / ti I J. y J- y ^^ ^) ^^ \ j Jr ^ XJ ^ x ^^ UXXOXX y J. ν yw J- W UCiI »-Y ~ -J ^^ J ^^

heptenic acid

Add 5.2 ml of a 2.5m phenylmagnesium bromide solution in 15 ml TKE add dropwise over 15 minutes with stirring to an ice-cold mixture of 0.60 g PGAp and 0.92 g copper-I-chloride, the mixture is stirred under nitrogen for 1 hour at 0 °. The mixture is added dropwise to an aqueous one Ammonium chloride solution and extracted with ether. After this Washing * with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 30% ethyl acetate in hexane gives 0.13 g of the product named in the title as an oil, A film 3.0

XUcLjC

(Shoulder), 3.45, 5.8, 10.3, 13.3, H, 3 yes. KMR: S 7.22 (s, 5, aromatic), 5.42 (M, 4, olefinic), 4.02 (M, 1, 15-H) ppm. Mass spectrum: M ⁺ -H ₉ O at 394.2496 (theoretical 394.2507).

C.

Example 16

7- / 3-Benzyl-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-

heptenic acid

An ice-cold mixture of 1.14 g of PGA ₂ and 1.75 g of copper (I) chloride in 50 ml of THF is treated with 10.3 ml of a 2.4 M benzyl magnesium chloride solution in THF and the mixture is stirred at 0 ° for 1 hour under nitrogen. The reaction mixture is given

- 24 409810/1175

to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. Elution with 30 % ethyl acetate in hexane gives 0.35 g of the product named in the title as an oil, λ film 3.0 (shoulder), 3.45, 5.8, 6.2, 10.3, 13.3 , 14.2 µ. NMR: S 7.26 (s, 5, aromatic), 5.98 (s, 2, OH), 5.62 (M, 2, 13 and HH), 5.42 (M, 2; 5 and 6- H), 4.17 (M, 1, 15-H), 2.29 (d, J = 6, benzylic protons) ppm. Mass spectrum: M ⁺ at m / e 426.2749 (theoretical 426.2768).

Example 17

7- / 3-Cyano-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-heptenic acid, methyl ester, acetate

A solution of 15.0 g of 7- / 2- (3 ~ S-hydroxy-1-octenyi) -5-oxo-3-eyelopenten-1-yl / -5-heptenoic acid methyl ester, acetate, 3.4 g Zaliumcyanid and 1.9 g of ammonium chloride in 500 ml of dimethylformamide and 100 ml of water is stirred at 10O ⁰ 90-- g under nitrogen for 1 hour. After cooling, the mixture is diluted with water, extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent gives 15.5 g of the compound named in the heading as an oil, λ _v PiIm 3.45, 5.75, 7.3, 8.05,

IHcLX.

9.85, 10.3ju.
Example 18

7Z5.y-2- (3 ~ S / tetrahydropyran-2-yloxy7- ¹ -oct enyl) -5-oxo c.yclopentyl7-5-heptenoic acid, methylester

A solution of 0.51 g of 7- / 2- (3-S- / tetrahydropyran-2-yloxy7-1-octenyl) -5-oxo-3-cyclopenten-1-yL ^ 5-heptenoic acid methyl ester, 0.115 g of potassium cyanide and 0.081 g of ammonium chloride in 25 ml of dimethylformamide and 5 ml of water is stirred under nitrogen at 90-100 ° C. for 1 hour. After cooling down to 25, the Mix to water and extract with ether. After washing with water and drying over sodium sulfate, the. extract

- 25 40981 0/1175

BATH

evaporated and the residue chromatographed on silica. Elution with 50% ethyl acetate in hexane gives 0.237 g of the product named in the title as an oil, λ Fi:; .. 3.4, 4.45, 5.7, 8.6, 9.17, 10.2, 11 , 5 µ. KKR: £ 5.1-5.9 (K, 4, olefinic), 4.70 (K, 1, 0-CH-O), 3.80 (s, 3, CCH ₅ ) ppm. Checkout spectrum: M ⁺ at m / e 459 (theoretical 459), K ⁺ -OPy at ra / e 358.2423 (theoretical 358.2381).

Example 19

7- / 3-cyano-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl -5-heptenoic acid

An ice-cold solution of 0.57 g of 7- / 3-cyano-2- (3-S- / tetrahydropyran-2-yloxy7-1-octenyl) -5-oxocyclopentyl7-5-h.epteri5ä.uremethylester in 40 ml of THP v / is treated with 10 ml of hydrochloric acid and the mixture is stirred at 0 ° for 10 minutes. Kan added the reaction mixture to water, extracted with ether, washed the extract with water and dried over sodium sulfate. Evaporation of the solvent gives an oil, CaG ir; 50 ml of 0.5N sodium hydroxide in aqueous methanol gölüst u; .d is kept at 25 1/2 hour. The solution is diluted with water, acidified with hydrochloric acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 50% ethyl acetate in hexane, 0.172 g of the "compound mentioned in the title" is obtained as an oil, λ PiIm 3.0 (shoulder), 3.45, 4.45, 5.75, 7.1, 8.1, 10.3 μ. NKR: ό 6.50 (s, 2, OH), 5.82 (M, 2, 13 and HH), 5.42 (M, 2 \ 5 and 6-H), 4.28 (K, 1, 15-H) ppm. Mass spectrum: K ⁺ at m / e 361 (theoretically 361).

Example 20

7- / 2- (3-S-hydroxy-1-octenyl) -3-mercapto-5-oxo-cyclopentyl / -5- heptenoic acid

A solution of 1.12 g of PG-Ap in 8 ml of dry tetrahydrofuran is ^{treated at 0} ° C. with 1.5 g of sodium sulfide in 6 ml of water

- 26 409810/1175

-and stirred for ^{1 hour at 0} ° C. under nitrogen. The reaction mixture is added to water, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract is evaporated and the residue is chromatographed on silica. When eluting with 25% ethyl acetate in hexane, 0.42 g of the product named in the title is obtained as an oil, ^ " _ην film 3.00 (shoulder), 3.40, / ,, 00 (shoulder), 5.70, 5.85, 7.10, 8.10, 10.3 m. KKR: ^ö 4.30 (K, 1, 15-H), 5.50 (M, 2, 5 and 6-Ii), 5, 75 (M, 2, 13 and HH), 7.15 (s, 2, -OH) ppm. Checkout spectrum: K ⁺ at m / e 368.1960 (theoretical 368.2020).

Example 21

7- / ^r 3-ethylthiol-2- (3-S-hydroxy-1-octenyl) -5-oxo-cyclopentyl7-5- heptenoic acid

A solution of 0.5 g of PGA ₂ in 2 ml Äthantnioi is treated with 0.1 ml of piperidine and stirred at 25 ⁰ C for 20 hours. All of the solvent is removed in vacuo, giving 0.61 g of the product mentioned in the heading as an oil, · _max Pilia 3.00 (shoulder), 3.50, 5.75, 5.85, 7, 20, 8.10, 10.4Ou. XaR: S 4.20 (M, 1, 15-H), 5.42 (M, 2, 5 and 6-H), 5.70 (K, 2, 13 and HH), 6.76 (s, 2, -OH) ppm.Cash spectrum: K ⁺ at m / e 396 (theoretical 396), M ⁺ -H ₂ O at m / e 378.2241 (theoretical 378.2228) .

Example 22

7- / 2- (3-S-Hydroxy-1-octenyl) -5-oxo-3- (phenylthio) -cyclopentyl / -5 -heT) tene acid

A solution of 0.5 g of PGA and 0.2 g of thiophenol in 6 ml of dry benzene is treated with 0.1 ml of piperidine and ^{stirred at 25 °} C. under nitrogen for 20 hours. The reaction mixture is evaporated and the residue is dissolved with ether. After washing with water and drying over magnesium sulfate, the ether solution is evaporated and the residue is put on a silica chromatograph.

- 27 409810/1175

k era

Xt

Eluting with 30 $ ethyl acetate in hexane gives 0.62 g of the product named in the title as an oil, ~ ^ _max film 3.00 (shoulder), 3.50, 5.75, 5.85, 6.30, 10, 40, 13.40, 14.50 µ. NMR: δ 4.12 (M, 1, 15-Η), 5.39 (M, 2, 5 and 6-H), 5.65 (M, 2, 13 and HH), 6.00 (S, 2, -OH), 7.35 (M, 5, aromatic-H) ppm. Mass spectrum: M ⁺ at m / e 444.2334 (theoretical 444.2381).

Example 23

3- (6-Carboxy-2-hexenyl) -ci-cyano-2- (3-S-hydroxy-1-octenyl) -4-oxo-cyclopentan-essiftaäure-ethyl ester

A solution of 0.58 g PGA _? and 0.185 ml of ethyl cyanoacetate in 25 ml of dimethylformamide is treated with 0.167 g of a 50% sodium hydride oil dispersion and the mixture is stirred under nitrogen at 25 ° for 1/2 hour. IVian dilutes the mixture with water, acidifies with acetic acid and extracts with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. When eluting with 30 $ ethyl acetate in hexane, 0.435 g of the product named in the title is obtained as an oil, film 3.0 (shoulder), 3.5, 4.3

IUcLX-

and 4.45 (weak shoulder), 5.8, 8.0, 9.7, 10.3 ju. NMR: S 6.38 (S, 2, OH), 5.70 (M, 2, 13 and HH), 5.55 (m, 2, 5 and 6-H), 4.38 and 3.58 ( q, J = 7.5, OCH ₂ ), 1.25 (t, J = 7.5, ester-CH ₃ ) ppm. Mass spectrum: M ⁺ at m / e 447 (theoretical 447), M ⁺ -HpO at m / e 429.2529 (theoretical 429.25H).

Example 24

3- (6-Carboxy-2-hexenyl) -oc-cyano-2- (3-S-hydroxy-1-octenyl) -4-oxocyolopentane-acetic acid

A solution of 1.424 g of 3- (6-carboxy-2-hexenyl) -. Cc-cyano-2- (3-S-hydroxy-1-octenyl) -4-oxocyclopentane-acetic acid ethyl ester in 100 ml of 0.5N sodium hydroxide in aqueous methanol is stirred at 25 ° for 1 hour. The solution is diluted with water, acidify to pH 1 with hydrochloric acid and extract with ether. After washing with water and drying over sodium

- 28 4098 10/1175

sulfate, the extract is evaporated and 1.19 g of the product mentioned in the title are obtained as an oil, λ. Pilin 3.4, 4.3 and 4.45 (weak shoulder), 5.8, 7.1, 8.3, 10.3 and IiKR: S 7.45 (S, 3, OH), 5, 70 (M, 2, 13 and HH), 5.48 (M, 2, 5 and 6-H), 4.25 (M, 1, 15-H), 3.95 (d, J = 6, NC -CH-CO) ppm. Mass spectrum: M ⁺ -CO ₂ at m / e 375 (theoretical 375), M ⁺ -CO ₂ -H ₂ O at m / e 356.2217 (theoretical 356.2225).

Example 25

/ 3- (6-CarlDoxy-2-hexenyl) -2- (3-S-hydroxy-1-oetenyl) -4-oxocyclo-

pentyl7-malonic acid 1,3-diethyl ester

A solution of 1.126 g of PGAp and 0.51 ml of diethyl malonate in 50 ml of dimethylacetamide is treated with 0.334 g of a 50% sodium hydride oil dispersion and the mixture is stirred at 25 ° for 0.5 hours under nitrogen. After dilution with water and acidification with acetic acid, the mixture is extracted with ether and the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 40% ethyl acetate in hexane gives 0.36 g of the product named in the title as an oil, "λ _e " PiIm 3.0 (shoulder), 3.5, 5.85, 8 , 7, 9.7, 10.4 ju.NMR: S 5.3-5.7 (M, 4, olefinic), 4.22 (q, J = 7.5, OCH ₂ ), 3.55 ( M, 1, CO-CH-CO), 1.25 (t, J = 7.5, Sster-CH ₃ ) ppm.Mass spectrum: M ⁺ at m / e 494 (theoretical 494), M ⁺ -HpO at m / e 476.2773 (theoretical 476.2773).

Example 26

/ ^ - (ö-Carboxy ^^ h
-pentyl / malonic acid

A solution of 0.28 g / 3- (6-carboxy-2-hexenyl) -2- (3-S-hydroxy-1-octenyl) -4-oxocyclopentyl7-malonic acid 1,3-diethyl ester in 50 ml of 0.5N sodium hydroxide in aqueous methanol is at 25 Stirred for 16 hours. The solution is diluted with water, acidified to pH 4 with acetic acid and washed with ether. the Solution is then acidified to pH 1 with hydrochloric acid.

- 29 409810/1175

and extracted with ether. After washing with water / water and drying over sodium sulphate, the extract is evaporated, 0.164 g of the compound named in the title being obtained as an oil (solidifies on standing), λ. , 3.5, 5.9, 7.15, 10.35 & KMR: - 5.3-5.6 (M, 4, olefinic), 3.95 (M, 1, 15-H), 3 , 52 (M, 1, CO-CH-CO) ppm. Kassenspektrua: M ⁺ -CO ₂ at m / e 394 (theoretical 394), K ⁺ -CO ₂ -H ₂ O at m / e 376.2231 (theoretical 276.2248).

Example 27

7- / 3-Mcyanomethyl-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopeni; yl / -

5-heptenoic acid

A solution of 1.0 g of ¹ ^ A ₂ " ¹ ^ ¹⁰ - °» ² 4 S potassium nitrile in 50 ml of dimethylformamide is treated with 0.28 g of 50% sodium hydride oil dispersion and the mixture is, under nitrogen at 25 ° 1 / Stirred for 2 hours. The mixture is diluted with water, acidified with acetic acid and extracted with ether. After washing with water , drying over sodium sulphate, the extract is evaporated and the residue is chromatographed on silica. Sluicing with 35% Ethyl acetate in hexane gives 0.8 g of the product named in the title as an oil, A _max film 3.0 (shoulder), 3.5, 4.47, 5.8, 7.12, 8.65, 10, 3 ju.NMR: h 5.78 (M, 2, 13 and 14-H), 5.48 (M, 2, 5 and 6-H), 4.25 (M, 2, 15-H and CN- CH-CN) ppm.Mass spectrum: M ⁺ at m / e 400 (theoretical 400), M ⁺ -H ₂ O at m / e 382.2279 (theoretical 382.2255).

Example 28

7 - / ^ 3-Cyanocarbamoy ^ methyl-2- (3-S-hydroxy-1-octenyl) -5-oxocyelG- pentyl / -5-heptenoic acid

A solution of 1.2 g of HxA ₂ and 0.3 g of 2-cyanoacetamide in 5C si dimethylformamide is treated with 0.34 g of 50% sodium hydride oil dispersion and the mixture is stirred under nitrogen at 25 ° for 1/2 hour. The mixture is diluted with water, acidified with acetic acid and extracted with ether.

- 30 409810/1175

AliP-5811

23A2004

After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. When eluting with ethyl acetate, 0.58 g of the product named in the title is obtained as an oil, f ^ _mnv film 3.2 (shoulder), 3.5, 5.9, 7.45, 10.35 μ. MR: ό 7.58 (bs, 1, KH), 7.12 (bs, 1, NH), 5.25-5.65 (M, 4, olefinic), 3.95 (K, 2, 15- H and CN-CH-CO) ppm. Mass spectrum: M ⁺ -H ₂ O at m / e 400 (theoretical 400), M ⁺ -H ₂ O-GONH _{2 at} m / e 356.2234 (theoretical 356.2225).

Example 29

7- / 3-Cyano-2- (3-R-hydroxy-1-octenyl) -5-oxocyclopentyi / -5- heptenoic acid-niethyl ester-acetate

A solution of 1.06 g of ^ -epi-PCJAg methyl ester acetate and 0.25 g of aluminum cyanide in 25 ml of dimethylformamide is treated with a solution of 0.18 g of ammonium chloride in 7.0 ml of water, and the mixture is heated to 100% Stirred for 1.5 hours under nitrogen. After cooling, the reaction mixture is added to water, acidified with hydrochloric acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue on aluminum oxide (activity 3 When eluting with ethyl acetate in hexane, 0.77 g of the product named in the title is obtained as an oil, λ PiIm 3.4, 4.5, 5.7, 8.0, 9.75, 10, 25 / z, NMR: δ 5.60-5.95 (M, 2, 5 and 6-H), 5.05-5.60 (M, 3; 13, H and 15-H), 3.70 (S, 3, OGH ₃ ), 2.10 (S, 3, acetate-GH,) ppm. Mass spectrum: M ⁺ -CH ₅ COOH "at m / e 557 (theoretical 357).

Example 30

7- / 2- (3-S-hydroxy-1-octenyl) -S-hydroxy-1-mercapto-cyclopentyl / -5-Iieptenic acid

A solution of 0.2 g of 7- / 2- (3-S-Hydroxy-1-octenyl) -3-mercapto-5-oxo-cyclopentyl7-5-heptenoic acid in 20 ml of methanol is at " ^{0 0} C with 0, 6 g of sodium borohydride in 10 ml of methanol "treated and

- 31 40981 0/1175

-Vl-

"stirred for 1 hour at ⁰ ° C. It is the reaction mixture into water, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract is evaporated and the residue chromatographed on silica. Elution with 30 Ethyl acetate in hexane gives 0.09 g of the product named in the heading as an oil, λ _β film 3.00 (shoulder), 3.40, 3.90 (shoulder), 5.85, 7.10, -8 , 20, 10.30 ju.NMR: b 4.22 (M, 2, 9 and 15-H), 5.02 (S, 2, -OH), 5.53 (M, 4, olefinic -H) ppm.Mass spectrum: M ⁺ at m / e 370 (theoretical 370), M ⁺ -H ₂ O at m / e 352.2139 (theoretical 352.2071).

See example 51

3-carbamoyl-2- (3-S-hydroxyoctanyl) -5-oxocyclopentyl-heptanoic acid

A solution of 0.565 g of 7-Z3-carbamoyl-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-heptenoic acid in 30 ml of ethyl acetate is added to a prehydrogenated mixture of 0.06 g of 10 $ palladium on charcoal in 30 ml of ethyl acetate and hydrogenated the mixture "at 25 ° and atmospheric pressure until 2 equivalents of hydrogen have been absorbed. After the catalyst has been filtered off, the solution is evaporated and the residue is chromatographed on silica. Eluting with ethyl acetate gives 0.075 S des Product named in the heading as oil, ^ - EiIm 3.0, 3.5, 6.0, 7.0, 9.6 / i. Mass spectrum: M ⁺ at m / e 383 (theoretically 383), M ⁺ - H ₂ O at m / e 365.2589 (theoretical 365.2566).

Example 32 3-Methyl-2- (3-S- hydroxyoctyl) -5-oxocyclopentyl-heptanoic acid

A solution of 0.222 g of 7- / 3-methyl-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-heptenoic acid in 20 ml of ethyl acetate are added to a prehydrogenated mixture of 0.045 g of 10% palladium Charcoal in 20 ml of ethyl acetate and hydrogenated the mixture at 25 ° and atmospheric pressure to 2 equivalents of hydrogen

- 32 409810/1175

-Vb-

-b ° 11

have been absorbed. After filtering off the catalyst, the solution is evaporated and the residue is chromatographed on silica. When eluting with 25 $ ethyl acetate in hexane, 0.085 g of the compound named in the title is obtained as an oil (solidifies on standing), λ Έ ± 1ΐη 3.0, 3.5,

- Max

5.8, 6.85, 8.5 ju. NMR: *> 6.12 (M, OH), 3.68 (M, 15-H), 1.12 (d, J = 5.3, 11-OH ₅ ) ppm, mass spectrum: M ⁺ at m / e 354.2807 (theoretical 354.2768).

Example 33 3-carboxy-2- (3-S-hydroxyoctyl) -5-oxocyclopentyl-heptanoic acid

A solution of 0.26 g of 7- / 3-carboxy-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl / -5-heptenoic acid in 20 ml of ethyl acetate is added to a prehydrogenated mixture of 0.05 10 g of palladium on carbon in 20 ml of ethyl acetate and hydrogenated at 25 ° and atmospheric pressure until 2 equivalents of hydrogen have been absorbed. After the catalyst has been filtered off, the solution is evaporated and the residue is chromatographed on silica. When eluting with 40% ethyl acetate in hexane, 0.09 g of the compound named in the title is obtained as an oil, ~ ^ _mQV film

ISaX

3.0 (shoulder), 3.45, 5.8, 7.1 ju. NMR: S 7.88 & 7.68 (M, OH), 3.68 (M, 15-H) ppm. Mass spectrum: M ⁺ at m / e (theoretical 284), M ⁺ -H ₂ O at m / e 366.2368 (theoretical 366.2405).

Example 34 3-Benzyl-2- (3-S-hydroxyoctyl) -5-oxocyclopentyl "-heptanoic acid

A solution of 0.175 g of 7- / * 3-benzyl-2- (3-S-hydroxy-1-octenyl) - '5-oxocyclopentyl / -5-heptenoic acid in 15 ml of ethyl acetate are added to a prehydrogenated mixture of 0.035 g of 10 $ palladium Charcoal in 15 ml of ethyl acetate and hydrogenated the mixture at 25 ° and atmospheric pressure to 2 equivalents of hydrogen have been absorbed. After filtering off the catalyst, the solution is evaporated and the residue is silica

- 33 -409810 / 1 17 p

23A2004

chromatographed. Obtained on elution with $ 30 ethyl acetate one 0.082 g of the compound named in the title as

^oil » ^A n, o _V ^pllm 5.0 (shoulder), 3.5, 5.8, 6.23, 6.67, 6.88, max

13.4 H, 34 jx. MMR: ο 7.30 (S, aromatic-H), 6.42 (s, QH), 3.65 (M, 15-H) "ppm. Mass spectrum: M ⁺ at m / e 430.3098 (theoretical 430 , 3082).

Example 35

7- / 8-cyano-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4 / non-

6-yl7-5-hepten3 acid methyl ester acetate '

A solution of 15.3 g of 7- / 3-cyano-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-heptenoic acid methyl ester acetate and 0.94 g of p-toluenesulphonic acid in 920 ml Benzene and 92 ml of ethylene glycol are refluxed for 24 hours using a water separator. After cooling, the reaction mixture is diluted with ether, washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica dss with 20 $ ethyl acetate in hexane gives 12.0 g of the title product as Gl, ~ k film _mav 3.4, 4.45, 5.73 ,, 8, 1, 8.63, 9.7, 10.3 µ.

B e ί β τ) ie 1 ge

7- / 8-cyano-7- (3-S-hydroxy-1-ootenyl) -1,4-dioxaspiro / 4,4 / non- 7

A solution of 12.0 g of 7- / 8-cyano-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid ethyl acetate in 330 ml of methanol and 330 ml of 1N sodium hydroxide is stirred for 1 hour. The reaction mixture is diluted with water, acidified with acetic acid and extracted with ether. After washing with Viasser and drying over sodium sulfate the extract is evaporated and the residue is chromatographed on silica. When eluting with 33 $ ethyl acetate in hexane 9.4 g of the product named in the title are obtained

- 34 409810/117 p

as oil, λ _ηαν film 3.0 (shoulder), 3.45, 4.45, 5.8, 8.65, 9.65, 10.3 Ju. NMR: c 7.1 (S, 2, OH), 5.70 (K, 2, 13 and HH), 5.40 (M, 2, 5 and 6-H), 4.15 (M, 1, 15-K), 3.92 (S, 4, ketal H) ppm. Mass spectrum: M ⁺ at m / e 405.2582 (theoretical 405.25H).

Example 37

7- / 8-carboxy-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non- 6-yl7-5-heptenoic acid

7- / 8-Gar'bamoyl-7- (3-S-hydroxy-1-octeny]) -1 ^ -dioxaspiro / ^^ non- 6-yl / -5-heptenoic acid

A solution of 0.28 g of 7- / S-cyano-7- (3-S-hydroxy-1-octenyl) -1 ^ -dioxaspiro / ^^ Jnon-o-ylZ-S-heptenoic acid in 60 ml of 0.5N Sodium hydroxide in aqueous methanol is refluxed under nitrogen for 5 hours. The mixture is cooled, diluted with water, acidified with acetic acid and extracted with ether. After washing with water / water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. When eluting with 50 / »ethyl acetate in hexane, 0.115 g of the product first named in the title is obtained as an oil, λ _v film 3.0 (shoulder), 3.45, 5.85, 8.7, 9.65, 10.3 Yes. NMR: S 5.68 (M, 4, olefinic), 4.12 (M, 15-H), x 3.98 (S, 4, ketal) ppm. Mass spectrum: M ⁺ at m / e 424.2462 (theoretical 424.2460).

Further elution with 1: 2: 97 acetic acid: methanol: ethyl acetate gives 0.10 g of the second "product mentioned heading as an oil (solidifies on standing), ^ _" in the film _v 3.0 (shoulder), 3.45 , 5.8, 8.7, 9.6, 10.3 yes. NMR: S 6.4-7.3 (M, 4, OH and NH), 5.60 (M, 4, olefinic), 4 .05 (M, 5, 15-H and Ketal E) ^{ppm.Mass spectrum: M +} at m / e 423.2674 (theoretical 423.2620).

Example 38

7- / 8-Formyl-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non- 6-yl7-5-heptenoic acid

A solution of 0.405 g of 7- / 8-cyano ~ 7- (3-S-hydroxy-1-octenyi) -

- 35 -

409810/1 1 7 p
BATH ORIGINAL

• AHP-5S11

1,4-dioxaspiro / 4,47non-6-yl7-5-heptenic acid and 0.096 g of 50% sodium hydride oil dispersion in 10 ml of THF are added to a mixture of 5.0 ml of 1M lithium aluminum hydride and 0.73 ml of ethyl acetate in 1 , 70 ml THF and stir under nitrogen for 1 hour. The reaction mixture is treated with 5 ml of methanol, diluted with water, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated, 0.35 g of the product named in the title being obtained as an oil, ^ _max film 3.0, 3.45, 5.8, 8.7, 9.7, 10.3 µ. NMR: S 9.50 (M, aldehyde H), 5.62 (M, 2, 13 and HH), 5.42 (M, 2, and 6-H), 4.10 (M, 1, 15- H), 3.92 (S, 4, Ketal H) ppm.

Example 39

7- / 8-hydroxymethyl-7- (3-S-hydroxy-1-octenyl-1,4-dioxaspiro / 4,47- non-6-yl-7-5-heptenoic acid

A solution of 0.25 g of 7- / 8-formyl-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6-yl7-5-heptenoic acid in 20 ml of methanol is treated with a solution of 0.90 g of sodium borohydride in 70 ml of methanol and the mixture is at 25 ° for 1 hour long stirred. After concentrating the mixture at 40 ° under vacuum, the residue is diluted with water, washed with ether, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate the ether extract is evaporated and yields 0.125 g of the product named in the heading as an oil, ^ "film 3.25

ΙΠ S a

(Shoulder), 3.5, 5.9, 7.2, 8.2 μ. Mass spectrum: M m / e 410.2724 (theoretical 410.2666).

Example 40

7- / 8-acetyl-7- (3-S-hydroxy-1-octenyl-1,4-dioxaspiro / 4, 4_7non- 6-yl7-5-heptenoic acid '

A solution of 0.623 g of 7- / 8-cyano-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yo_7-5-heptenoic acid in 35 ml of THF is treated with 2.54 ml of 3m methylmagnesium bromide in ether and

- 36 409810 / 117S

*. '■ AHP-5811

the mixture is refluxed under nitrogen for 1 hour. After cooling, the mixture is diluted with water, acidified with acetic acid and extracted with ether. After evaporation of the ether, the residue is redissolved in 10 ml of THF and 100 ml of 0.5N sodium hydroxide. The solution is washed with ither, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica, eluting with Aöfo ethyl acetate in hexane gives 0.10 g of the product named in the title as an oil, λ _max film 3.0 , 3.4, 5.75, 8.55, 9.5 yes. NMR: S 5.88 (M, 2, OH), 5.68 (M, 2, 13 and HH), 5.42 (M , 2, 5 and 6-H), 4.10 (M, 1, 15-H), 3.95 (S, 4, ketal), 2.15 (S, COCH ₃ ) ppm. Mass spectrum: M ⁺ at m / e 422.2658 (theoretical 422.2666).

Example 41

7- / 8- (1-hydroxyethyl) -7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro- / ^{4,47 non-} 6-yl7-5-heptenoic acid

An ice-cold solution of 0.63 g of 7- / 8-acetyl-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4 / non-6-yl / -5-heptenoic acid in 40 ml of methanol is treated with a cold solution of 1.87 g of sodium borohydride in 150 ml of methanol and the mixture is stirred at 25 ° for 1 hour. After the mixture has been concentrated at 40 ° in vacuo, the residue is diluted with water with Acetic acid acidified and extracted with ether., After the Washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. When eluting with 60 # ethyl acetate in hexane, 0.46 g is obtained ties in the headline named product as oil,.) film 3.2, 3.5, 5.9, 9.7, 10.35 / 1. Mass spectrum: M at m / e 424 (theoretically 424).

Example 42

7- / 8-Nitromethyl-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4, Aj non-6-yl7-5-heptenoic acid methyl ester acetate A solution of 1.0 g 7- / 2- (3-R-hydroxy-1-octenyl) -3-nitromethyl-

-37-4QS810 / 117S

S-oxocyclopentylZ-S-heptenoic acid methyl ester acetate and Ο, ". 25 g of p-toluenesulfonic acid in 125 ml of benzene and 12.0 ml of ethylene glycol are refluxed with a water separator for 20 hours. After cooling, the mixture is diluted with Ether, washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 30 $ ethyl acetate in hexane gives 0.685 g of the product named in the title as an oil, λ film 3.45, 5.8, 6, 5, 7.0, 7.35, 8.15, 9.9, 10.35 yes, NMR: δ 5.0-5.6 (M, 5, olefinic and 15-H), 4.28 (m , 2, CH ₂ NO ₂ ), 3.90 (S, 4, ketal), 3.68 (S, 3, OCH ₅ ), 2.02 (S, COCH,) ppm.Mass spectrum: K ⁺ at m / e 495 (theoretical 495), M-CH ₃ COOH at m / e 435.2636 (theoretical 435.2620).

Example 43

7- / 8-nitromethyl-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4 / -

non-6-yl7-5-heptenic acid

A solution of 4.5 g of 7- / 8-nitromethyl-7- (3-R-hydroxy-1-octenyl) -1 ^ -dioxaspiro / ^, 4 / non-6-yl7-5-heptenoic acid methyleoter acetate in 150 ml of methanol and 120 ml of 1N sodium hydroxide is stirred under nitrogen at 25 ° for 1 hour. The solution is diluted with water, acidified with acetic acid and extracted with ether. After washing with water / water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 30 $ ethyl acetate in hexane gives 3.68 g of the product named in the title as an oil (solidifies on standing), A _max KBr 3.0, 3.45, 5.85, 6.45, 6.9, 7.95, 9.15, 10.25, etc. NMR: S 6.55 (S, 2, OH), 5.62 (M, 4, olefinic), 4.30 (M, 3, 15-H and CH ₂ NO ₂ ), 3.92 (S, 4 , Ketal) ppm. Mass spectrum: M ⁺ at m / e 439 (theoretical 439), M ⁺ -NO ₂ at m / e 393.2651 (theoretical 393.2639).

- 38 40981G / 1175

Example 44

7- / 8 * -Cyano-7- (3-R-hydroxy-1-octenyl) -1, 4-dioxaspiro / 4,4_ / non- 6-yl / -5-heptenoic acid - methyl3ter acetate and

7- / 8J-cyano-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_ / non-

6-yl / -5-heptenic acid »methyl ester acetate

A solution of 3.4 g of 7- / ~ 3-oyano-2- (3-R-hydroxy-1-octenyl) -5-oxoeyclopentylZ-S-heptenoic acid methyl ester acetate and 0.55 g of p-toluenesulfonic acid in 150 ml of benzene and 15 ml of ethylene glycol is refluxed for 22 hours using a water separator. After cooling, the reaction mixture is diluted with ether, washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 25% ethyl acetate in hexane gives 1.19 g of γοη the product first mentioned in the heading as an oil, Ä _max PiIm 3.45, 4.5, 5.75, 8.1, 9.8, 10.3 Ji. KMR: £ 5.5-5.7 (M, 2, 5 and 6-H), 5.0-5.5 (M, 3; 13, U and 15-H), 3.93 (S, 4 Ketal), 3.68 (S, 3, OCH ₅ ), 2.03 (S, acetate CH ₅ ) ppm. Mass spectrum: M ⁺ at m / e 461 (theoretical 461), M ⁺ -HC ₂ H ₅ O ₂ at m / e 401.2557 (theoretical 401.2565).

A further elution with 25% ethyl acetate in hexane gives 0.93 g of the second product named in the title as an oil, A _max film'3.45, 4.5, 5.75, 8.1, 9.8, 10 , 3ju. NMR: 8 5.55-5.95 (M, 2, 5 and 6-H>, 5.05-5.55 (M, 3; 13, H and 15-H), 3.92 (S, 4 , Ketal), 3.68 (S, 3, OCH ₃ ), 3.07 (q, J = 7.5, HH), 2.05 (S, acetate CH,) ppm.Mass spectrum: M ⁺ at m / e 461 (theoretical 461), M-HC ₂ H ₅ O ₂ at m / e 401.2532 (theoretical 401.2565).

Example 45

7- / 8cC-cyano- (3-R-hydroxy-1-octenyl) -1,4-dioxaspir 0 / 4,4 / non- 6-yl7-5-heptenoic acid

(A) A solution of 1.10 g of 7- / 8cC-cyano-7- (3-R-hydroxy-

1-octenyl) -1,4-dioxaspiro / 4,4 / non-6-yl7-5-heptenoic acid methyl ester acetate in 25 ml of methanol is mixed with 25 ml of 1N sodium

- 39 -409810/1 175

Hydroxide and the mixture is stirred for 1 hour at 25 ° under nitrogen. The mixture is diluted with water, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is evaporated Chromatographed silica, eluting with 30% ethyl acetate in hexane and subsequent crystallization from ethyl acetate and pentane gives 0.37 g of the product named in the title, Pp = 88.5-89.5 °, miso melting point with the 8j3 isomer = 75-80 , ^A max ^{KBr 5} ' ¹⁵ ' ³ · ⁴⁵ ' ⁴ ' ⁰ ' ⁵ ' ⁸⁵ ' ⁷ ' ² ' ⁸ ' ¹ ' ⁸ ' ⁷ ' ⁹ ' ⁶ ' ¹⁰ ' ^{4 '11} »°» 14.2 µ, NMR : & 7.35 (s, 2, OH), 5.1-5.9 (M, 4, olefinic ^ H), 4.12 (M, 1, 15-H), 3.95 (S, 4 , Ketal H) ppm.Mass spectrum: M ⁺ at m / e 405 (theoretical 405), M ⁺ -H ₂ O at m / e 387.2379 (theoretical 387.2409).

(B) A solution of 0.20 g of 7- / 8β-cyano-7- (3-R-hydroxy-1-octenyl) -1 _f 4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid in 20 ml of tert-butyl alcohol is treated with 0.28 g of potassium tert-butoxide and the mixture is stirred at 25 ° under nitrogen for 16 hours. After dilution with water and acidification with acetic acid, the mixture is extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography on silica with 5% ethyl acetate in hexane gives 0.16 g of the product named in the title as white crystals. A recrystallized sample (ethyl acetate / pentane) shows a melting point of 84-86 °, mixed melting point with the authentic 8oc isomer = 87-89 and the mixed melting point with the 8β isomer = 73-76 °.

Example 46

7- / 8β-Gyano-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,47non- 6-yl / -5-heptenoic acid

A solution of 0.83 g of 7- / 8/3-cyano-7- (3-R-hydroxy-1-oetenyl) -1,4-dioxaspiro / 4f 47non-6-yl7-5-heptenoic acid methyl ester acetate in 25 ml of methanol is treated with 25 ml of 1 n sodium hydroxide

- 40 -409810/1 1.7B

23-2004

and the mixture is stirred at 25 ° under nitrogen for 1 hour. The solution is diluted with water, acidified with acetic acid and extracted with ether. After washing with water and drying over sodium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 30 $ ethyl acetate / hexane and subsequent crystallization from ethyl acetate and pentane gives 0.23 g of the product named in the title, Pp = 88-89 °, miso melting point with the 8oc isomer = 75-80 °, Ά _max KBr 3 , 1, 3.45, 5.95, 7.55, 7.65, 7.85, 8.7, 9.6, 10.35, 11.0, 13.25 yes · ^{Mi δ 7} » ²⁵ < ^s » ² » ^0H ) »5.70 (M, 2; 5 and 6-H), 5.45 (M, 2, 13 and 14-H), 4.20 (M, 1, 15-H), 3.95 (S, 4, Ketal-H), 3.08 (q, J = 7.3, 11-H) ppm. Mass spectrum: M ⁺ at m / e 405 (theoretical 405), M ⁺ -H ₂ O 387.2417 (theoretical 387.2409).

Example 47

7- / IM3arboxy-2- (3-S-hydroxy-1-octenyl-5-oxocyclopentyl / -5- heptenoic acid

A solution of 0.70 g of 7- / 8-carboxy-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenic acid in 50 ml of THP and 5.0 ml of hydrochloric acid is stirred at 25 ° for 1/2 hour. The mixture is diluted with water, extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 50% ethyl acetate in hexane gives 0.45 g of the product named in the title as an oil, λ _mav PiIm 3.5, 5.85, 7.15, 8.2, 10 , 4 & NMR: 8 5.68 (M, 2, -13 and 14-H), 5.45 (M, 2; 5 and 6-H), 4.20 (M, 1, 15-H) ppm. Mass spectrum: M ⁺ at m / e 380 (theoretical 380), M ⁺ -H ₂ O at m / e 362.2123 (theoretical 362.2093).

Example 48

7- / 3-Carbamoyl-2- (3-S-hydroxy-1-oetenyl) -5-OXOCyClQPe ^ yIZ-S- heptenoic acid

A solution of 0.51 g of 7-Z8-carbamoyl-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4 / i ^l on-6-yl7-5-heptenoic acid in 50 ml THP and

- 41 409810/1175

AHP-J> 8'1

5.0 ml of hydrochloric acid is stirred at 25 ° for 1/2 hour. The mixture is diluted with water, extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 1: 2: 97 acetic acid: methanol: ethyl acetate gives 0.38 g of the product named in the title as an oil, ^ _x film 3.0, 3.4, 5.7 , 5.9, 6.1 (shoulder), 8.0, 10.3 yes. NMR: S 6.4-6.9 (M, 4, OH and NH), 5.65 (M, 2, 13 and HH), 5.42 (M, 2; 5 and 6-H), 4, 15 (M, 1, 15-H) ppm. Mass spectrum: M ⁺ at m / e 379 (theoretical), M ⁺ -ZK ₂ O at m / e 343.2155 (theoretical 343.2146).

Example 49

7-Z3-hydroxymethyl-2- (3-S-hydroxy-1-octenyl-5-oxocyclopentyl7-5 -heptenoic acid

An ice-cold solution of 0.255 g of 7- / 8-hydroxymethyl-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro $, 4 / non-6-yl / -5-heptenoic acid in 25 ml of THP is treated with 2.5 ml of hydrochloric acid and the mixture is stirred at 0 ° for 0.5 hour. The reaction mixture is diluted with ether, washed with water, dried over sodium sulfate and evaporated. Chromatography of the residue on silica with 70 $ ethyl acetate in hexane gives 0.056 g of the product named in the title as an oil, i ^ max film 3.0, 3.45, 5.8, 7.1, 8.1, 10, 3 yes. NMR: S 5.1-5.8 (M, 7, 4-olefinic H, 3-OH), 4.12 (M, 1, 15-H), 3.72 (M, x 2, 0-CH ₂ ) ppm. Mass spectrum: M ⁺ at m / e 366 (theoretical 366), M ⁺ -C ₅ H ₁₁ at m / e 295.1551 (theoretical 295.1544).

Example 50

7- / iHU2etyl-2- (3-S-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-heptenoic acid

A solution of 0.16 g of 7- / 8-acetyl-7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl / 5-heptenoic acid in 15 ml of THF and 1.5 ml of hydrochloric acid is stirred at 25 ° for 1/2 hour. The mixture is diluted with water and extracted with

- 42 409810/1175

Α! ΙΡ-5811

Ether, wash the extract with water and dry over sodium sulfate. After evaporation and chromatography of the residue on silica with 40% ethyl acetate in hexane, 0.13 g of the product named in the title is obtained as an oil, X _max film 3.0, 3.45, 5.8, 7.1 , 8.6, 10.3 µ. NMR: S 6.12 (S, 2, OH), 5.68 (M, 2; 13 and HH), 5.42 (M, 2; 5 and 6-H), 4.20 (M, 1; 15-H), 2.20 (S, COCH,) ppm. Mass spectrum: M ⁺ at m / e 378.2438 (theoretical 378.3405).

Example 51

7- / 3- (1-hydroxyethyl) -7- (3-S-hydroxy-1-octenyl) -5-oxocyelopentyl7-5 -heptenoic acid

A solution of 0.46 g of 7- / 8- (1-hydroxyethyl) -7- (3-S-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6-yl7-5-heptenoic acid in 30 ml of THi ¹ and 3.0 ml of hydrochloric acid are stirred at 25 ° for 1/2 hour. The mixture is diluted with water, extracted with ether, the extract is washed with water and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 50% ethyl acetate in hexane gives 0.14 g of the product named in the title as an oil, A _max 3 μm 3.0, 3.5, 5.85, 7.15 , 8.2, 10.4 & NMR: £ 5.50 (M, 4, olefinic), 4.02 (M, 2, 0-CH), 1.20 (d, J = 6, Me-CH ) ppm. Mass spectrum: 'M ⁺ -H ₃ O at m / e 362 (theoretical 362), M ⁺ -2H ₂ 0 at m / e 344.2367 (theoretical 344.2350),

Example 52

7- / 8-Nitromethyl-7- (3-0X0-1-octenyl) -1,4-dioxaspiro / 4.47n ° ⁿ -6- yl7-5-heptenoic acid

A solution of 0.2 g of 7- / 8-nitromethyl-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6-yl7-5-heptenoic acid in 5 ml of acetone becomes treated at -10 ° with 0.1 ml of Jones reagent and ^{stirred at 0} ° C. for 15 minutes. After adding 1 ml of methanol, the reaction mixture is made basic with aqueous sodium bicarbonate solution, acidified with acetic acid and with

- 43 -409810/1175

Ether extracted. After washing with water and drying with magnesium sulfate, the extract is evaporated and the residue is chromatographed on silica * eluting with 30% ethyl acetate in hexane gives Ό, 17 g of the product named in the heading as a semi-solid substance, ^ _mnv film 3.50 5.87, 6.15

Max

(Shoulder), 6.45, 7.25 µ. NMR: ο 3.95 (S, 4, ketal), 4.30 (M, 2, -CH ₂ NO ₂ ), 5.20-5.80 (M, 3, * 5, 6, and HH), 6.20-2.90 (M, 1, 13-H), 8.28 (S, 1, OH) ppm. UV λ _max EtOH 223 mji (E 8740). Mass spectrum: M ⁺ at m / e 437.2456 (theoretical 437.2480).

Example 53

7- / 8cc-cyano-7- (3-OXO-1-octenyl) -1, 4-dioxaspiro / ~ 4,4_7non-6-yl7-5 -heptenoic acid

A solution of 1.0 g of 7- / 8oC-cyano-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6-yl7-5-heptenoic acid in 50 ml of acetone becomes treated at 0 ° with 3.4 ml 1.2m Jones reagent and stirred for 3/4 hours ⁰ C under nitrogen at O. The reaction mixture is treated with 3 ml of ethanol and neutralized with aqueous sodium bicarbonate solution. After acidification with acetic acid, the mixture is extracted with ether, the extract is washed with brine and dried with magnesium sulfate. The extract is evaporated and the residue is chromatographed on silica. Elixing with 35% ethyl acetate / hexane gives 0.95 g of the product named in the title as an oil, λ, film

' Max

3.5, 4.5, 5.8 (shoulder), 5.85, 6.10, 8.60, 9.70ju. UV ^ _max EtOH 225 mji (613,000). NMR: δ 3.95 (S, 4, ketal), 5.42 (M, 2, 5 and 6-H), 6.42 (M, 2, 13 and HH), 9.65 (M, 1, -OH) ppm. Mass spectrum: M ⁺ at m / e 403.2334 (theoretical 403.2357).

Example 54

7- / 8f3-cyano-7- (3-oxD-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6-yl7-5-heptenoic acid

A solution of 4.05 g of 7- / 8β-cyano-7- (3-R-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6-yl7-5-heptenoic acid in 50 ml of acetone

- 44 -0 9 810/11 7 p

ΑΗΡ-5β11

is treated at OC with 3.5 ml of Jones reagent and stirred 1.2m 3/4 hours at ⁰ C O. The reaction mixture is treated with 3 ml of ethanol and neutralized with aqueous sodium bicarbonate solution. After acidification with acetic acid, the mixture is extracted with ether, the extract is washed with brine and dried with magnesium sulfate. Evaporation of the dried ether extract yields 4.00 g of the the title product as Pestsubstanz, which is recrystallized from ether / pentane to obtain white crystals having a melting point of 52 - 54 results in ⁰ C, ^ _max Piim 3.45, 4.50 , 5.70

(Shoulder), 5.85, 6.10, 8.70, 9.7Ou. UVX ", _ev EtOH 225 am r ~ c max '

(C 11 000) '. NMR: δ 3.21 (q, J = 7.5, HH), 4.00 (S, 4, ketal), 5.46 (M, 2; 5 and 6-H), 6.22 (d, J = 16, HH), 6.98 (dd, J = 9, 16, 13-H), mass spectrum: M ⁺ at m / e 403.2357 (theoretical 403.2357).

Example 55

7- / 8-Nitromethyl-7- (3-methyl-3-hydroxy-1-octenyl) -1,4-dioxa spiro / 4 _< 4_7non-6-yi7-5-heptenoic acid

A solution of 1.72 g of 7- / 8-nitromethyl-7- (3-oxo-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl / -5-heptenoic acid in 80 ml of tetrahydrofuran is at -10 ⁰ C treated with 9.7 ml of 3m methylmagnesium bromide in tetrahydrofuran and stirred at 0 C for 1 hour. The reaction mixture is added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over magnesium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 30 $ ethyl acetate in hexane gives 0.26 g of the product named in the heading as an oil, λ ^ _v PiIm 3.00 (shoulder), 3.45, 5.80 (shoulder), 5.85, 6, 45, 7.25, 10.30;!. NMR: S 1.32 (S, 15-methyl), 4.01 (S, 4, ketal), 4.40 (M, 2, CH ₂ NO ₂ ), 5.22 (M, 2, 5 and 6 -H), 5.63 (M, 2, 13 and 14-H) ppm. Mass spectrum: M ⁺ at m / e 453, (theoretical 453), M ⁺ -H ₂ O at m / e 435.2571 (theoretical 435.2620).

- 45 _ 4098 10/1175

Example 56

AhP-5811

7- / 8-Nitromethyl-7- (3-hydroxy-3-phenyl-1-octenyl) -1,4-dioxa spiro / 4,47non-6-yl7-5-heptenoic acid

A solution of 1.88 g of 7- / 8-nitromethyl-7- (3-oxo-1 ~ octenyi) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid in 80 ml of tetrahydrofuran is 1O ⁰ C treated with 6.6 ml of 3M Phenylmagnesiumbroinid in tetrahydrofuran and stirred for 1 hour at ⁰ C O. The reaction mixture is added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 30 $ ethyl acetate in Kexan gives 0.90 g of the product named in the heading as an oil, λ _max PiIm 3.00 (shoulder), 3.50, 5.88, 6.28, 6.47, 6, 95, 7.25, 13.30, 14.35 µ. NMR: S 3.93 (s, 4, ketal), 4.35 (M, 2, -CH ₂ NO ₂ ), 5.15-6.05 (M, 4, olefinic -H), 5.88 ( S, 2, -OH), 7.45 (Mj 5, aromatic-HO) ppm. Mass spectrum: I4 ⁺ at m / e 515 (theoretical 515), M ⁺ -H ₃ O at m / e 497.2776 (theoretical 497.2776).

Example 57

7- / 8oc-cyano-7- (3-methyl-3-hydroxy-1-octenyl) -1,4-dioxaspiro- / 4,4_7non-6-yl7-5-heptenoic acid

A solution of 0.98 g of 7- / 8oC-cyano-7- (3-oxo-1-octenyl) -1,4-dioxaspiro / 4,4-7non-6-yl7-5-heptenoic acid in 35 ml of dry tetrahydrofuran is treated under nitrogen at -10 ⁰ C with 5 ml of 3M methyl magnesium bromide in tetrahydrofuran and stirred at -10 ⁰ C for 1 1/2 hours. The reaction mixture is added to 20 ml of saturated aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with salt solution and drying with magnesium sulfate, the ether extract is evaporated and 1.02 g of the product named in the heading is obtained as an oil, \ _max PiIm 3.0 (shoulder), 3.5, 4.4, 5.8, 8.7, 9.4 µ. NMR: S 1.32 (S, 15-CH ₃ ),

- 46 409810/1175

ΑΗΡ-5811

4.01 (S, 4, ketal), 5.5O-5.8O. (M, 4, olefinic H), 6.88 (S, 2, -OH) ppm. Mass spectrum: M ⁺ "at m / e 419.2679 (theoretical 419.2671).

Example 58

7- / 83-cyano-7- (3-hydroxy-3-methyl-1-octenyl) -1,4-dioxaspiro- / 4,4 / non-6-yl7-5-heptenoic acid

A solution of 0.87 g of 7- / 8β-cyano-7- (3-oxo-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid in 35 ml of THP is added under nitrogen ⁰ C treated with 5 ml of 3M methyl magnesium bromide in THF at O and stirred for 1 1/2 hours at ⁰ C O. The reaction mixture is added to 20 ml of saturated aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with salt solution and drying with magnesium sulfate, the ether extract is evaporated and the residue is chromatographed on silica. Eluting with 20 $ ethyl acetate / hexane gives 0.54 g of 7- / 8oc-cyano-7- (3-hydroxy-3-methyl-1-octenyl) 1,4-dioxaspiro / 4,4_7non-6-yl7-5 -heptenic acid. Further elution with 20 $ ethyl acetate / hexane gives 0.08 g of the product named in the title as an oil, λ _max PiIm 2.95 (shoulder), 3.40, 4.40, 5.80, 8.65, 9 , 60 µ. NMR: S 1.30 (S, 15-methyl), 3.10 (q, J-7.5, 11-H), 3.92 (S, 4, ketal), 5.40 (M, 2, 5 and 6-H), 5.70- (d, 2, J = 4, 13 and HH), 6.10 (S, 2, -OH). Mass spectrum: M ⁺ at m / e 419 (theoretical), M ⁺ -HpO at m / e 401.2557 (theoretical 401.2565).

Example 59

7- / 2- (3-Hydroxy-3-methyl-1-octenyl) -3-nitromethyl-5-oxocyclo pentyi / -5-heptenoic acid

A solution of 0.20 g of 7- / 8-nitromethyl-7- (3-methyl-3-hydroxy-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid in 4 ml tetrahydrofuran is treated acid at ⁰ ° C with 0.4 ml of concentrated hydrogen chloride and stirred for 1.5 hours at ⁰ C O. The reaction mixture is added to water and extracted with ether. After washing with water and drying over

- 47 -409810/1175

Magnesium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 15% ethyl acetate in hexane gives 0.11 g of the compound named in the title as an oil, λ _max PiIm 3.00 (shoulder), 3.50, 5.80, 6.45, 7.25, 10.30 Yes. NMR: 8 1.32 (S, 15-methyl), 4.49 (M, 2, -CH ₂ KO ₂ ), 5.80 (M, 4, olefinic-H), 5.92 (S, 2, OH) ppm. Mass spectrum: M ⁺ -H ₂ O at m / e 391.2402 (theoretical 391.2358).

Example 60

7- / 2- (3-Hydroxy-3-phenyl-1-octenyl) -3-nitromethyl-5-oxo-cyclo pentyJ7-5-heptenoic acid

A solution of 0.3 g of 7- / 8-nitromethyl-7- (3-hydroxy-3-phenyl-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid in 6 ml of dry tetrahydrofuran is treated with 0.6 ml of concentrated hydrochloric acid at OC and ^{stirred at 0 °} C. for 1.5 hours. The reaction mixture is added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract is evaporated and the residue is chromatographed on silica. Eluting with 32% ethyl acetate in hexane gives 0.08 g of the product named in the title as an oil, A _max film 3.00 (shoulder), 3.40, 5.75, 6.40, 7.20, 10, 20, 13.20, 14.18 yes. NMR: & 4.45 (m, 2, -CH ₂ NO ₂ ), 5.40 (m, 2; 5 and 6-H), 5.85 (m, 2, 13 and HH), 5.90 ( s, 2, OH), 7.40 (s, 5, aromatic -H) ppm. Mass spectrum: M ⁺ "at m / e 471 (theoretical 471), M ⁺ -H ₂ O at m / e 453 (theoretical 453).

Example 61

7 - /! Fcc-cyano-2- (3-hydroxy-3-methyl-1-octenyl) -5-oxocyclopentyl7-5 -heptenoic acid

A solution of 0.30 g of 7- / 8cC-cyano-7- (3-hydroxy-3 ~ methyl-1-octenyl) -1,4-dioxaspiro / 4,47non-6-yl7-5-heptenoic acid in 12 ml of THF is under nitrogen at 25 ° with 2.8 ml of 3m perchloric acid treated and stirred for 6 hours. The reaction mixture is added to water and extracted with ether. After this Washing with saline solution and drying with magnesium sulfate will

- 48 409810/1 17S

AHP-5811

the ether extract evaporated and the residue chromatographed on silica. Eluting with 30 $ ethyl acetate in hexane gives 0.18 g of the product named in the heading as an oil, ^ _max PiIm 3.0 (shoulder), 3.4, 4.45, 5.75, 8.75, 10, 3 / i. NMR δ 1.33 (S, 15-methyl), 5.54 (M, 2, -5 and 6H), 5.82 (M, 2i 13 and HH), 6.70 (M, 2, -OH ) ppm. Mass spectrum: M ⁺ at m / e 375 (theoretical 375), M ⁺ -HgO at m / e 357.2303 (theoretical 357.23H).

Example 62

7- / 3β-cyano-2- (3-hydroxy-3-methyl-1-octenyl) -5-oxocyclopentyl7-5 -heptenoic acid

A solution of 0.8 g of 7- / 8ß-cyano-7- (3-hydroxy-3-methyl-1-octenyl) -1,4-dioxaspifo / 4., 47non-6-yl7-5-heptenoic acid in 16 ml of TEP is treated with 4 ml of 3M perchloric acid at 25 ° under nitrogen and stirred for 10 hours. The reaction mixture is added to water and then extracted with ether. After washing with salt solution and drying with magnesium sulfate, the ether extract is evaporated and the residue is chromatographed on silica. Eluting with 35% ethyl acetate in hexane gives 0.68 g of the product named in the title as an oil, λ PiIm 2.95 (shoulder), 3.40, 4.40, 5.75, 7.00, 8.50 , 10.1571. HMR: 6 1.35 (S, 15 ^ ethyl), 3.40 (M, 1, 11-H), 5.49 (M, 2, 5 and 6-H), 5.88 (d, J = 4, 13 and HH), 6.41 (S, 2, -OH) ppm. Mass spectrum: M ⁺ at m / e 375.2347 (theoretical 375.2409).

Example 63 3o: -Cyano-2- (3-hydroxy-3-methyl-octyl-5-oxo-cyclopentyl-heptanoic acid

A solution of 0.29 g of 7- / 3oC-cyano-2- (3-hydroxy-3-methyl-1-octenyl) -5-oxocyclopentyl / -5-heptenoic acid in 15 ml of ethyl acetate are added to a pre-hydrogenated mixture of 0.18 10 ^? d / C in 15 ml of ethyl acetate and hydrogenate the mixture at 25 ° and atmospheric Pressure until two equivalents of hydrogen have been absorbed. After filtering, the solution is evaporated

- 49 409810/1178

and the residue is chromatographed on silica. Sluice in 30 $ ethyl acetate in hexane gives 0.18 g of that in the upper writing named product as oil, A film 3.0 (shoulder),

' Max ' ''

3.4, 4.4, 5.7, 6.J5, 8.1, 8.55, 10.7 µ. KMR: δ 6.10 (S, 2, GK), 1.22 (S, 15-CH ₂ ) ppm. Mass spectrum: M ⁺ -H ₂ O at m / e 561.2579 (theoretical 361.2617).

Example 64 3 _ι ^ -Cyano-2- (3-hydrox.y-3-IΓ.ethyl-octyl ·) -5-oxocyclopen · tyl-hept ^ r.s ^ l-J.l- ^ ΰ

A solution of 0.18 g of 7-Z3: - Cyano-2- (3-hydroxy-3-methyl-1-octenyl) -5-oxocyclopentyl / -5-heptanoic acid in 20 ml of ethyl acetate is added to a prehydrogenated mixture of 0.08 g of 10 $ d / C in 10 ml of ethyl acetate and hydrogenate the mixture at 25 ° and atmospheric pressure until 2 equivalents of hydrogen have been absorbed. After filtering, the solution is evaporated and the residue is chromatographed on silica. Eluting with 30 $ ethyl acetate in hexane gives 0.15 g of the product named in the title as an oil, / 'film 3.0 (shoulder), 3.45, 4.45, 5.80, 6.80, 8 , 60, 10.9 µ. HMR: S 1.25 (S, 15-Kethyl), 3.41 (M, 1, 11-H), 6.10 (S, 2, -OH) ppm. Mass spectrum: K ⁺ -K ₂ O at m / e 361.2601 (theoretical 361.2617).

Example 65

7-Z2i ^; - / X3S) -3-Hydroxy-trans-1-octeny3j-3oC-methyl-5-oxo-1oc- cyclopentyl7-cis-5-heptenoic acid

and
7- / 2ß- / X3S_-3-hydroxy-trans-1-octenyl73ß-methyl-5-oxo-1o: -cyclo-

pentyl7cis-5-heptenoic acid

A solution of 3.0 g of PGA ₂ in 60 ml of tetrahydrofuran (THi ¹⁾ is added dropwise to a mixture of 24 ml eigekühlten 3e methylmagnesium bromide and 5.0 g of cuprous chloride in 120 ml IEF and stirred at ⁰ ° C. 1 For hours. The mixture is added to an aqueous ammonium chloride solution and extracted with ether. After washing with water and drying over magnesium sulfate, the extract is concentrated to give a crystalline material.

- 50 409810/1176

-5Ί-

.23A2004

It is filtered and then crystallized from ether / pentane, thus obtaining 1.2 g of the first-mentioned title product, mp = 68 -. 70 ⁰ C, "λ KBr, 3.0 (shoulder), 3,5, 5 , 8, 6.9 * 7.6, 8.05, 8.55, 10.3 µ. EKR: δ 6.93 (β, 2, OH), 5.54 (m, 13 and HH), 5.38 (m, 5 and 6-H), 4.16 (m, 1, 15-H) . Checkout spectrum: M ⁺ "at m / e 350.2476 (theoretical 350.2455).

Evaporation of the filtrate and chromatography of the residue on silica with 30 $ ethyl acetate in hexane and subsequent recrystallization from ether / pentane gives 0.09 g of the second compound mentioned in the title, Pp = 72-74 ⁰ C, A _mo film 3, 0 (shoulder), 3.5, 5.8 (shoulder), 5.9, 7.0, 8.15, 8.45, 10.4; i. MKR: S 7.05-6.22 (m, 2, OH), 5.48 (m, 4, olefinic), 4.15 (m, 1 _f 15-H) ppm. Checkout spectrum: K ⁺ at m / e 350.2460 (theoretical 350.2455).

Example 66

2p- / X3S) -3-hydroxyoctyl / -3c * -methyl-5-oxo-1 (rt-cyclopentane-heptanoic acid

A solution of 0.9 g of 7- (2; 3 - / "(3S) -3-hydroxy-trans-octenyl7-3Ä'-methyl-5-oxo-1cf-cyclopentyl) -cis-5-heptenoic acid in 10 ml Methanol is added to a pre-hydrogenated mixture of 0.2 g of 5 % Pd / C in 155 ml of ethanol and the mixture is hydrogenated at 25 ° and atmospheric pressure until 2 equivalents of hydrogen have been absorbed and the residue chromatographed on silica elution with 25% ethyl acetate in hexane and crystallized from ethyl acetate / hexane, thus obtaining 0.25 g of the the title product, mp = 43.5 -. 44.5 ⁰ C, λ KBr

IHcLX

3.0, 3.5, 5.8, 6.85, 8.5, 8.9 yes. HMR: S 6.81 (s, 2, OH), 3.65 (m, 1, 15-H) ppm. Mass spectrum: M ⁺ at m / e 354.2771 (theoretical 354.2768).

- 51 - 40981 0/1175

:,. ΑΗΡ-5β11

Example 67

7- (5oC-Hydroxy-2ß - / "(3S) -3-hydroxy-trans-1 -oc t enyl7-3oc-methyl-tv · -

cyclopentyl) ice-5-heptenoic acid '

7- (5, '3-Hydroxy-2 | 3 - / "(3S) -3-hydroxy-1-octenyl73of-niethyl-1oc- cyclopentyl) -cis-5-heptenoic acid

An ice-cold solution of 7.8 g of 7- (2; ^ - / ~ (3S) -3-hydroxy-trans-1-octenyl7-3oC-methyl-5-oxo-1oC-cyclopentyl) -cis-5-heptenoic acid in 150 ml of methanol is treated with 3.5 g of lithium borohydride and ^{stirred at 0} ° C. for 2 hours. The mixture is diluted with water and acidified with acetic acid. Extraction of the mixture obtained with ether and subsequent washing, drying and evaporation of the extract gives the crude product. Chromatography on silica with 30 $ ethyl acetate in hexane gives 3.5 g of the product first mentioned in the title as an oil, X _max film 3.0, 3.5, 5.85, 6.9, 7.15, 8 , 1, 8.9, 9.8, 10.35; NMR: S 5.57 (s, 3, OH), 6.0-5.17 (m, 4, olefinic), 4.21 (m, 2, 9 and 15-H), 1.01 (d, J = 4.5, 11-methyl) ppm. Mass spectrum: M ⁺ at m / e 352.2670 (theoretical 352.2613).

Further elution with 30 $ ethyl acetate in hexane gives 3.0 g of the product named in the second heading as an oil,% ax ^{Pilm 3} ' ⁰ ' ³ ' ⁵ * ⁵ ' ⁸⁵ ' ⁶ » ⁹ ' ⁷ ' ¹⁵ ' ⁸ ' ^{2 '10} » ⁴ P' ^{mR: S 5 '61} (s, 3, OH), 5.52 (s, 4, olefinic), 4.10 (m, 2, 9 and 15-H), 0.91 ( d, J = 4.5, 11-methyl) ppm. Mass spectrum: M ⁺ at m / e 352 (theoretical 352), M ⁺ - ^ HpO at m / e 334.2564 (theoretical 334.2507).

7- / 8oc-cyano-7p - ((3S) -3-hydroxy-trans-1-octenyl) -1,4-dioxaspiro-

A solution of 10.0 g of 7- / 8-Cyano-7 - ((3S) -3-hydroxy-trans-1-octenyl) -1,4-dioxaspiro / 4,4_7non-6oC-yl7-cis-5- heptenic acid and 13.0 g of potassium t-butoxide in 700 ml of t-butanol is taken at 25 ° below Stirred nitrogen for 40 hours. The reaction mixture is diluted with water, acidified with acetic acid and extracted with ether. After washing and drying, the extract becomes

- 52 409810 / 117S

AHF-581.1

evaporated and the residue chromatographed on silica. 'Eluting with 35 $ ethyl acetate in hexane followed by recrystallization from ether / pentane gives 3.0 g of the the title product, Pp = 58.5 to 61 ⁰ G, λ KBr 3.0 3.4, 5.8 , 8.5, 8.9, 9.65, 10.3 µ. NKR: 6 6.72 (S, 2, OH), 5.65 (M, 2, 13 and HH), 5.40 (M, 2, 5 and 6-H), 4.18 (M, 1, 15-H), 3.92 (S, 4, ketal) ppm. Mass spectrum: M ⁺ "at m / e 405.2492 (theoretical 405.25H).

7-Z3öf-Cyano-2- ((3S) -3-hydroxy-trans-1-octenyl) -5-oxo ~ 1oC-. _C yclo-

pentyl7-cis- »5-heptenoic acid

An ice-cold solution of 0.5 g of 7- / 8oc-cyano-7 - ((5S) -3-hydroxy 1 -trans-1 -octenyl) -1,4-dioxaspiro / 4,4_7non-6oc-yl / - cis-5-heptenoic acid in 50 ml of tetrahydrofuran is treated with 12.5 ml of hydrochloric acid and ^{stirred at 0} ° C. for 1 hour. The mixture is diluted with water, extracted with ether, the extract is washed, dried and evaporated residue obtained on silica with 35 $ ethyl acetate in hexane followed by recrystallization from ether / hexane gives 0.26 g of the the title product, Pp = 71-73 ⁰ C, A _max KBr 3,0, 3,4, 5 , 7, 7.9, 8.55, 9.8, 10.3 yes.

MR: S 7 _? o (S, 2, OH), 5.82 (M, 2, 13 and HH), 5.50 (M, 2, 5 and 6-H), 4.28 (M, 1, 15-H) ppm . Calculated for C 1 H 1 O 4 N: C, 69.77; H, 8.63; W, $ 3.86. Found: C, 69.69; H, 8.83; N, $ 3.62.

3öC-Cyano-2p - / "(3S) -3-hydr oxyoc tylJ-S-oxo-ioC-cyclopentane-heptanoic acid

- A solution of 0.48 g of 7- / 3 <* - cyano-2 - ((3S) -3-hydroxy-trans-1 octenyl) -5-oxo-ioC-cyclopentyl7-cis-5-heptenoic acid in 20 ml are ethyl acetate is added to a pre-hydrogenated suspension of 0.22 g of 5 $ Pd / C in 20 ml ethyl acetate and hydrogenated at 25 ⁰ C and atmospheric pressure to 2 equivalents V / absorbed on Hydrogen. The reaction mixture is filtered, evaporated and chromatographed on silica, which contains silver nitrate to the extent of 20%

- 53 409810/1175

-5-V-

ΑΗϊ-5811

Eluting sr.it with 5Ο ^ ό ethyl acetate in hexane gives 0.164 g of the product named in the title, • A _raax film 3.45 (shoulder), 3.4, 4.45, 5.75, 6 , 85, 7.1, 8.65 µ.NMR : S 3.60 (M, 1,15-H), 5.70 (S, 2, OH, removed with D ₃ O) ppn mass spectrum: M ⁺ at m / e 365.2566 (theoretically 365.2566).

- 54 -4Q981 0/1175

Claims (2)

GASES: AHP-5811 PATENT CLAIMS Prostaglandin compounds of the general formula: COOR ⁵ (i) X is oxo, Y stands for a cis double bond, Z stands for a trans double bond, R nitromethyl, vinyl, phenyl, kethyl, benzyl, cyano, mercapto, (Lower) alkylthio, phenylthio, carboxycyanomethyl, carb (lower) alkoxycyanomethyl 1, dicarboxyinethyl, dicarb (lower) alkoxymethyl, Means dicyanomethyl or carbanioylcyanomethyl, 2 ~ '■ R represents hydroxy, tetrahydropyranyloxy or acetoxy, R ^{5 is} hydrogen or (lower) alkyl and R is hydrogen or (ii) X is ethylenedioxy, Y stands for a cis double bond, - 55 A 09 8 1 0/1175 . ■ AHP-? 811 Z stands for a trans double bond, 1
R cyano, carboxy, carbamoyl, formyl, hydroxymethyl, acetyl, Means 1-hydroxyethyl or nitromethyl, 2
R is hydroxy or acetoxy, R is hydrogen or lower alkyl and R is hydrogen or (iii) X is oxo, Y stands for a cis double bond, Z stands for a trans double bond, R carboxy, acetyl, carbamoyl, hydroxymethyl or 1-hydroxy ethyl means ρ
R means hydroxy χ a
R and R are hydrogen or (iv) X stands for ethylenedioxy, Y stands for a cis double bond, Z stands for a trans double bond, Ί
R represents nitromethyl or cyano, 2 4-R and R together represent oxo and R means hydrogen or (ν) Χ stands for ethylenedioxy, Y stands for a cis double bond, Z is a trans double bond, R is nitromethyl or cyano, R is methyl or phenyl, R is hydrogen and R is hydroxy or (vi) X is oxo, Y stands for a cis double bond, Z is a trans double bond, R is nitromethyl or cyano, 2
R is methyl or phenyl, - 56 409 8 10 / 117S ΑΗΡ-5811 3 23A2004 R is hydrogen and R is hydroxy or (vii) X represents Oxo, Y and Z stand for single bonds, R denotes nitromethyl or cyano, ρ R is methyl or phenyl, R is hydrogen and 4 R represents hydroxy or (viii) X is Oxo, Y and Z stand for single bonds, Ί R carbamoyl, methyl, carboxy, benzyl, nitromethyl, phenyl, Cyano, carb (low) alkoxycyanomethyl, carboxyeyanomethyl, Dicarb (lower) alkoxymethyl, dicarboxymethyl, hydroxymethyl, Means acetyl or 1-hydroxyethyl, 2 R is hydroxy, tetrahydropyranyloxy or acetoxy, R is hydrogen or (lower) alkyl and R is hydrogen or (ix) X is C ^ _0H , Y stands for a cis double bond, Z stands for a trans double bond, Ί R Mercapto, nitromethyl, vinyl, phenyl, methyl, benzyl, cyano, (Lower) alkylthio, phenylthio, carboxycyanoraethyl ,. Dicarboxymethyl, Means dicyanomethyl or carbamoylcyanomethyl, ρ R is hydroxy or tetrahydropyranyloxy, R is hydrogen or (lower) alkyl and R ^{4 is} hydrogen. 2. Compounds according to claim 1 of the general formula: O , 3 COOR- - 57 40981 0/1175 where R is nitromethyl, vinyl, phenyl, kethyl, benzyl, cyano, Mercapto, (lower) alkylthiο, phenylthio, - carboxycyanomethyl, Garb (low) alkoxycyanomethyl, dicarboxymethyl, dicarb (low) alkoxymethyl, Means dicyanomethyl or carbamoylcyanomethyl; ρ
R is hydroxy, tetrahydropyranyloxy or acetoxy and R * is hydrogen or (lower) alkyl. 3. Compound according to claim 2, nänilioh 7- / 5-cyano-2- (3-hydroxy-1-octenyl) -5-oxoeyclopentyl7-5-heptenoic acid. Compounds according to claim 1 of the general formula: COOR ^ where R is cyano, carboxy, carbamoyl, formyl, hydroxymethyl, Is acetyl, 1-hydroxyethyl or nitromethyl; 2
R is hydroxy or acetoxy and R. Represents hydrogen or methyl. Compounds according to claim 1 of the general formula: R ¹ OH wherein R ^{1 represents} carboxy, acetyl, carbainoyl, hydroxymethyl or 1-hydroxyethyl. 6. A compound according to claim 5, namely 7- / 3-hydroxy methyl 2- (3-hydroxy-1-octenyl) -5-oxocyclopentyl7-5-heptenoic acid. - 58 -409810/1175 Compounds of the formula: O O COOK wherein R is nitromethyl or cyano. Compounds of the formula: 0 0 COOH HO R ' 1 2 wherein R denotes nitromethyl or cyano and R denotes methyl or Represents phenyl. Compounds of the formula: O COOH HO R ' 1 wherein R is nitromethyl or cyano and R is methyl or phenyl. 10. Compounds of the formula: ⁰ COOH - 59 - 409810/1175 -Co- v / orin R nitroiriethyl or cyano and R methyl or phenyl ■ mean. 11. A compound according to claim 10, namely 3oc-cyano-2- (3-hyaroxy-3-methyloctyl) -5-oxocyclopentanheptanoic acid. 12. Connections of the. Formula: wherein R is carbamoyl, methyl, carboxy, benzyl, nitromethyl, Phenyl, cyano, carb (lower) alkoxycyanoiiiethyl, carboxycyanomethyl, Dicarb (lower) alkoxymethyl, dicarboxymethyl, hydroxymethyl, Is acetyl or 1-hydroxyethyl; 2
R is hydroxy, letrahydropyranyloxy or acetoxy and R represents hydrogen or (lower) alkyl. 13. Compounds of the formula:
OH COOR ³ where R is mercapto, nitromethyl, vinyl, phenyl, methyl, benzyl, Cyano, (lower) alkylthio, phenylthio, carboxycyanomethyl, dicarboxymethyl, Means dicyanomethyl or carbamoylcyanomethyl; 2
R is hydroxy or tetrahydropyranyloxy and R ⁵ denotes hydrogen or (lower) alkyl. H. Compound according to claim 9, namely 7- / * 3oC-cyano-2- (3-hydroxy-3-methyl-1-octenyl) -5-oxocyclopentyl / -5-heptenoic acid. - 60 409810/1175