NO743960L - - Google Patents

Description

3_hydroxy-2-(4-hydroxy-1-alkynyl)-5_oxocyclopent-1-enalkanoic acids and derivatives thereof.

The present invention relates to new cyclopentane derivatives with the general formula:

where R is hydrogen or an alkyl radical of 1-7 carbon atoms;

R-^ is hydrogen or an alkanoyl radical of 1-7 carbon atoms;

R 2 is hydrogen or an alkanoyl radical containing 1-7 carbon atoms; R^ is hydrogen or an alkyl radical containing 1-7 carbon atoms; R^ ~er-et—aiky^^tHi^ 1-7 carbon atoms;

m is 6 or 7; and where the wavy lines indicate the alternative R and S absolute stereochemical configuration or the epimeric mixture.

The alkyl radicals in the above formula can be exemplified by methyl, ethyl, propyl, butyl, hexyl, heptyl and isomers thereof with a branched chain.

The alkanoyl radicals can be exemplified by formyl, acetyl, propionyl, butyryl, valeryl, caproyl, heptanoyl and the corresponding isomers with a branched chain.

The new compounds are prepared by condensing a compound of the general formula: where R, m and the wavy line have the meaning given above, the alkyl group contains 1-4 carbon atoms,<p>g R' is hydrogen or methoxymethyl, with an organometallic compound with the general formula:

where R^ and the wavy lines have the above meaning, and R" is hydrogen, tetrahydropyran-2-yl, or trialkylsilyl, where the alkyl group contains 1-4 carbon atoms. The reaction is carried out in an inert organic solvent, preferably an ether such as

tetrahydrofuran. Although the reactants may be mixed at room temperature, it is useful to heat the reaction mixture to the reflux temperature of the solvent to ensure complete reaction. The final reaction mixture is treated with acid in the usual manner to hydrolyze the organometallic adduct and remove any protecting groups.

The tertiary alcohols used as defined in the preceding structural formula where R 1 is an alkyl radical, are preferably prepared by reacting the appropriate Grignard reagent with a 4-methoxymethoxycyclopentane derivative of the type described in US Patent No. 3-558,682. 2-Methoxy-4-methoxymethoxy-4-oxocyclopent-1-enheptanoic acid, for example, can thus be reacted with 4(RS)-tetrahydropyran-2-yloxy-4(RS)-methyl-1-octynyl-magnesium bromide and the resulting product is treated with hydrochloric acid in methanol to effect cleavage of the tetrahydropyran-2-yl and methoxymethoxy groups thus giving 3-hydroxy-2-(4(RS)-hydroxy-4(RS)-methyl-1-octynyl) -5~oxocyclopent-1-enheptanoic acid.

The optically active R and S derivatives are obtained by using, as starting materials, the appropriate optically active acetylenic alcohols. 1-octyn-4(RS)-ol, for example, is converted to the phthalic acid half-ester by reaction with phthalic anhydride and the half-ester is reacted with (-) α-methylbenzylamine to give the diastereoisomeric salts, which are separated by fractional crystallization followed by hydrolysis to give the individual R and S acetylenic alcohols.

The carboxylic acid esters can be easily obtained by esterification of the corresponding acids. E.g. 3-hydroxy-2-(4(RS)-hydroxy-1-octynyl)-5-oxocyclpent-1-enheptanoic acid can be reacted with ethereal diazomethane to give methyl 3-hydroxy-2-(4(RS)-hydroxy-1-octynyl )-5-oxocyclopent-1-enheptanoate.

The alkanoyl derivatives according to the invention are obtained by reacting the corresponding hydroxy compounds with an alkanoic acid anhydride or halide, preferably in the presence of a suitable acid acceptor such as pyridine or triethylamine. Thus, 3-hydroxy-2-(4(RS)-hydroxy -1-octynyl)-5-oxocyclopent-1-enheptanoic acid with acetic anhydride and pyridine to obtain 3-acetoxy-2-(4(RS)-acetoxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid.

The starting compounds used in the present invention are suitably prepared by using oxoalkane acids and oxalic acid esters as starting substances. As a particular example, 9~oxodecanoic acid can be condensed with dimethyl oxalate in the presence of potassium tert-butoxide to obtain 2,3,5~trioxo-4-methoxyalylcyclopentaneheptanoic acid. Heating this ester with hydrochloric acid results in the loss of the methoxyallyl side chain and 2,3>5-trioxocyclopentaneheptanoic acid is thus obtained. This triketo acid is selectively reduced by catalytic ,-hydrogenation, suitably with a 5% palladium-on-carbon catalyst, to 2,5-dioxo-3-hydroxycyclopentaneheptanoic acid. Enol ether formation with simultaneous esterification of the carboxyl group is effected e.g. by reaction with a lower alkanol in the presence of an acid catalyst. The reaction of 2,5-dioxo-3-hydroxycyclopentaneheptanoic acid with methanol and sulfuric acid in benzene thus gives methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoate. Conversion of the free carboxyl

acid is conveniently effected by saponification at room temperature with dilute aqueous sodium hydroxide in methanol to 2-methoxy-4-hydroxy-5-oxocyclopent-1-enheptanoic acid. Condensation of this acid with 4(RS)-tetrahydropyran-2-yloxy-1-octynylmagnesium bromide or lithium tetra(4(RS)-triethylsilyloxy-1-octynyl)aluminate results in 3"hydroxy-2-(4(RS)-tetrahydropyran- 2-yloxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid and 3-hydroxy-2-(4(RS)-triethylsilyloxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid, respectively. Removal of the protective tetra-hydropyran-2-yl and triethylsilyl groups are effected by acid cleavage, suitably with hydrochloric acid in methanol, which thus gives 3-hydroxy-2-4(RS)-hydroxy-1-octynyl)-5~oxocyclopent-1-enheptanoic acid .

The compound according to the invention exhibits valuable pharmacological properties. They have e.g. anti-ulcerogenic and anti-secretory effect. In addition to this, they have anti-microbial activity which is shown by their ability to inhibit the microbial growth of bacteria such as Erwinia sp., protozoa such as Tetrahymena pyriformis and fungi such as Trichophyton ment.agrophytes and Verticillium albo-atrum.

The anti-secretory activity of the compound according to the invention is determined by means of the following test method:

Adult female beagle dogs with a weight of 4.5_733

kg is fitted with a Teflon-stainless steel gastric cannula and implanted in the most dependent part of the stomach near the antrum. After a recovery period of 1 month after the surgical intervention, the animals undergo a phase for about 20 hours and are then placed in a leather strap that allows only limited movement. The gastric cannula is opened and cleaned with warm (37°C) saline solution. The dogs are injected with one of two secretagogues, histamine or pentagastrin,

in a dose of about 2/3 of that which will cause maximum stimulation.

Immediately thereafter, the test compound is dissolved in an iso-osmotic buffer solution administered subcutaneously. The gastric juice is collected during 2 hours followed by administration of the secretagogue compound and the total volume is measured. These results are compared with those obtained from control animals treated with the secretagogue compound alone. The compound is judged to be active if statistically significant inhibition of secretory parameters occurs after treatment.

The compounds' anti-ulcerogenic properties are shown by their activity in the test described in detail in US patent no. 3,479•357• The tests used to demonstrate the anti-bacterial and anti-protozoan activity of the compounds according to the invention are described in US -patent no. 3 • 692,799, while the methods for the detection of their anti-fungal activity" are indicated in US patent 3-682, 951.

The following examples illustrate the invention, and the indicated amounts of substances are given as parts by weight unless parts by volume are specified.

Example 1

To a solution of 56.5 parts of potassium metal in 936 parts of tertiary butyl alcohol, 105 parts of dimethyl oxalate and a solution of 54 parts of 9-oxodecanoic acid in 156 parts of tertiary butyl alcohol were successively added. This addition was made over a period of about 40 minutes while the mixture was heated at reflux temperature in a nitrogen atmosphere. At the end of the addition period, heating was continued for about 90 minutes and the reaction mixture was cooled and filtered under nitrogen. The filter cake was added to a solution of dilute hydrochloric acid and this mixture was extracted with chloroform. The chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Recrystallization of the resulting residue from ether gave 2,3-trioxo-4-methoxyal-1-cyclopentaneheptanoic acid, m.p. about. 127-129°C.

Example 2

A mixture containing 50 parts of 2,3,5_trioxo-4-methoxyalylcyclopentaneheptanoic acid and 2,880 parts by volume of 2N hydrochloric acid was slowly distilled in a nitrogen atmosphere for about 2 hours, after which the whole was cooled and decolorized with activated carbon. The filtrate thus obtained was concentrated to dryness under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic solution was washed several times with saturated aqueous sodium chloride, then with water and finally dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. Recrystallization of the resulting residue from water gave pure 2,3,5-trioxocyclopentane-heptanoic acid, m.p. about. 102-104°C.

Example 3

To a solution of 2 parts of 2,3,5-trioxocyclopentane-heptanoic acid in 50 parts of 70% aqueous isopropyl alcohol, 0.2 parts of 5% palladium-on-carbon catalyst was added and the resulting reaction mixture was shaken with hydrogen at atmospheric pressure and room temperature until 1 molecular equivalent of hydrogen had been absorbed-. The catalyst was removed by filtration and the solvent was distilled under reduced pressure to give the impure product as a solid residue. Purification by recrystallization from water gave pure 2,5-dioxo-3-hydroxycyclopentaneheptanoic acid, m.p. about. 127-129.5°C.

Example 4

A solution containing 10 parts of 2,5-dioxo-3-hydroxycyclopentaneheptanoic acid in 1000 parts by volume of 1% methanolic hydrogen chloride was stored at room temperature for approx. 60 hours, and was then concentrated to dryness under reduced pressure. The resulting residue was dissolved in 280 parts of methanol and 10 parts of diazomethane dissolved in ether were added. Concentration of this reaction mixture to dryness gave a residue containing methyl 2-methoxy-3-hydroxy-5-oxocyclopent-1-eneheptanoate and methyl 2-methoxy-4-hydroxy-5-oxacyclopent-1-eneheptanoate. Recrystallization from ether gave the latter compound.

The material obtained from said ether filtrate was dissolved in 42 parts of ether and 4 parts of methanol containing 0.8 parts of hydrogen chloride were added. The resulting mixture was left at room temperature for about 5 days and the crystalline material that separated was additional methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-enhaptanoate. The filtrate was concentrated to dryness and the residue recrystallized first from acetone-hexane, then from water to give methyl 2,5-dioxo-3-hydroxycyclopentaneheptane-oate m.p. about. 98-90°C.

Example 5

To a solution of 5 parts of methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoate in 120 parts of methanol, 185 parts of 0.1N aqueous sodium hydroxide were added and the resulting reaction mixture was kept, at room temperature for about 24 hours, and the organic solvent was then removed by distillation under reduced pressure. The remaining mixture was extracted with benzene and the aqueous layer was separated, acidified with dilute hydrochloric acid and then extracted with chloroform. The remaining aqueous layer was separated and then extracted with ethyl acetate. The ethyl acetate solution thus obtained was dried over anhydrous sodium sulfate, then concentrated to dryness and the resulting residue was purified by recrystallization from acetone to give 2-methoxy-4-hydroxy-5-oxocyclopent-1-enheptanoic acid, m.p. about. 113.5-117°C.

Example 6

To a solution of 2.5 parts of 1-octyn-4(RS)-ol in 10 parts of benzene, 1.6 parts of dihydropyran and 0.15 parts of p-toluenesulfonic acid were added. The exothermic reaction was initially regulated by cooling in an ice bath and the temperature was thus kept at approx. 25°C. The resulting reaction mixture was left at room temperature for about 5 hours, and was then diluted with benzene, washed successively with dilute aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to give 1-octyne-4 (RS)-ol 4-tetrahydropyran-2-yl ether.

Example 7

To a solution of 12.6 parts of 1-octyn-4(RS)-ol 4-tetrahydropyran-2-yl ether in 112 parts of tetrahydrofuran was added 15.25 parts by volume of 3.3 M ethereal ethylmagnesium bromide and the resulting reaction mixture was set aside at room temperature for approx. 2 hours. The solution contained 4(RS)-tetrahydropyran-2-yloxy-1-octynylmagnesium bromide.

Example 8

Method A

A solution containing 0.882 parts of l-octyne-4(RS)-

ol 4-tetrahydropyran-2-yl ether in 20 parts by volume of tetrahydrofuran,

was cooled under nitrogen to about -5°C and 2 parts by volume of 3N ethereal ethylmagnesium bromide was added dropwise with stirring. The reaction mixture was stirred in reverse for 2.5 hours at room temperature, and after this time 0.256 parts of 4-hydroxy-2-methoxy-5-oxocyclopent-1-enheptanoic acid dissolved in 30 parts by volume of tetrahydrofuran was added. This mixture was heated at reflux with stirring for about 16 hours, then cooled and quenched with dilute hydrochloric acid. Stirring was continued for approx. 10 minutes after which the tetrahydrofuran was evaporated and ether added. The ether layer was separated and extracted with aqueous potassium carbonate.

The alkaline extract was then acidified and extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure.

The resulting crude product was purified on a chromatographic column to give 3-hydroxy-3-(4(RS)-hydroxy-1-octynyl-5-oxocyclopent-1-enheptanoic acid, mp ca. 77-80°C .

Method B

To a solution of 3553 parts of l-octyn-4(RS)-ol i

150 parts by volume of tetrahydrofuran at about 0°C, 16 parts by volume of 3M ethereal ethylmagnesium bromide were added dropwise. The resulting reaction mixture was stirred at room temperature for about 5 hours, after which 1 part of 4-hydroxy-2-methoxy-5-oxocyclopent-1-enheptanoic acid dissolved in 50 parts by volume of tetrahydrofuran was added dropwise in

during approx. 30 minutes. The resulting reaction mixture was heated at reflux temperature for approx. 5 hours and was then cooled to about 0°C and 5 parts by volume of 3M ethereal ethylmagnesium bromide was added dropwise. The mixture was stirred for about 2 hours at approx. 0°C, then for a further 2 hours at room temperature and was finally heated at reflux temperature for approx. 3 hours. The reaction mixture was quenched by addition of dilute hydrochloric acid and the solvent was removed by distillation under reduced pressure. The resulting aqueous mixture was extracted

with ethyl acetate and this organic extract was extracted with

dilute aqueous potassium carbonate. The alkaline extract was washed with ethyl acetate, then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain the crude product, which was purified by absorption on a silica gel chromatographic column and eluted with 10% ether in benzene to give 3-hydroxy-2- (4(RS)-hydroxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid, m.p. about. 77-80°C.

Example 9

Method A

To a stirred solution of 150 parts of 4(RS)-methyl-1-octyn-4(RS)-ol 4-tetrahydropyran-2-yl ether in approx. 1954 parts of dry tetrahydrofuran, 283 parts by volume of 3N were added dropwise

ethereal ethylmagnesium bromide while the temperature of the solution was kept below 30°C. Stirring was continued for approx. 1.5 hours, after which 31.5 parts of 2-methoxy-4-methoxymethoxy-4-oxocyclopent-1-enheptanoic acid dissolved in approx. 710 parts of tetrahydrofuran were added during approx. 10 minutes. The reaction mixture was set aside for approx. 16 hours after which it was quenched by adding dilute hydrochloric acid. The solvent was removed by distillation under reduced pressure and the residue was diluted with benzene. The organic layer was separated and washed with water and then distilled to dryness to 5"(4(RS)-methyl-4(RS)-tetrahydropyran-2-yloxy-1-octynyl)-4-methylacid-ethoxy-2-methoxycyclopent-1 -enheptanoic acid.

The latter product was dissolved in 4400 parts of acetone, 1600 parts of water and 71 parts of concentrated hydrochloric acid and the resulting mixture was heated at reflux temperature for about 20 hours. Removal of acetone under reduced pressure gave an aqueous solution

which was extracted with 1:.1 benzene ether. The benzene ether solution was extracted with <5% aqueous potassium carbonate and this extract was acidified with hydrochloric acid and then extracted with benzene ether. The latter extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to an oily residue, which was purified by chromatography on a silicic acid column. The crude product was further purified by recrystallization from ether, which gave 3-hydroxy-2-(4(RS)-methyl-

4(RS)-hydroxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid, which is characterized by the IR absorption maximum at approx. 1715 cm ^ and UV absorption maxima at approx. 270 nm (e23000).

Method B

The mixture containing 2.4 parts of 4(RS)-methyl-loctyn-4-(RS)-ol, 3.3 parts of triethylsilyl chloride, 10 parts by volume of N,N-dimethylformamide and 3 parts of triethylamine was refluxed with stirring overnight, after which 1 part triethylsilyl chloride was added and reflux continued for approx. 2 hours. The reaction mixture was then cooled to room temperature and poured into the mixture consisting of ether and water. The organic layer was separated and washed with 1N hydrochloric acid and then washed with water. Removal of the solvent by distillation under reduced pressure gave 4(RS)-methyl-octyn-4(RS)-ol triethylsilyl ether.

A solution consisting of 2 parts of 4(RS>-methyl-1-octyn-4(RS)-ol triethylsilyl ether in 25 parts of tetrahydrofuran was cooled to about -40°C with a dry ice bath and 353 parts by volume of 2.42 molar butyllithium in hexane was added and the resulting mixture was allowed to reach room temperature and then the mixture was stirred for about 30 minutes. The mixture was then cooled to -40°C in a dry ice bath and 0.268 parts of aluminum chloride was added. This mixture was allowed to reach room temperature. was obtained and 0.48 parts of methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoate dissolved in tetrahydrofuran was added. The mixture was stirred at room temperature for about 2 hours after which the mixture was diluted with ether and acidified with dilute hydrochloric acid. The solvent was removed by evaporation at room temperature and the residue was dissolved in a mixture of methanol and dilute hydrochloric acid.This mixture was kept at room temperature for about 2 hours and then treated with dilute aqueous potassium carbonate and set at room temperature overnight. The alkaline extract was washed with ethyl acetate, then acidified with hydrochloric acid and extracted with ethyl acetate.

The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to a viscous yellow oil. This resulting crude product was purified on a chromatographic column to give 3-hydroxy-2-(4(RS)-methyl-4(RS)-hydroxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid, which is characterized at the IR maximum at approx. 1715 cm 1 and UV absorption maxima at approx. 270 nm (e23000).

Example 10v

To a mixture consisting of 7 parts of potassium hydroxide dissolved in 13 parts of water and 100 parts by volume of ether, 6 parts of N-nitroso-methylurea were added. The resulting mixture was stirred until most of the solid had dissolved and the yellow ethereal solution was decanted into a solution consisting of 1 part of 3-hydroxy-2-(4(RS)-hydroxy-1-octynyl)-5~oxocyclopent- 1-enheptanoic acid dissolved in 50 parts by volume of cold ether. The reaction mixture was then allowed to stand at its temperature for a few minutes, after which excess reagent was destroyed by the dropwise addition of glacial acetic acid. When the ether solution became colorless, it was washed successively with cold water, cold dilute aqueous sodium bicarbonate and cold water, and then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The product thus obtained was further purified by absorption on a silica chromatographic column followed by elution with ethyl acetate-benzene mixtures, which gave methyl 3-hydroxy-2-(4(RS)-hydroxy-1-octynyl)-5-oxocyclopent-1 -enheptanoate.

Example 11 ■

A mixture consisting of 25 parts of 3-hydroxy-2-(4(RS)-hydroxy-1-octynyl)-5~oxocyclopent-1-enheptanoic acid, 10 parts of acetic anhydride and 10 parts of pyridine was left at room temperature for approx. 16 hours and was then thoroughly immersed in an excess of cold aqueous citric acid. The resulting aqueous mixture was left at room temperature for approx. 1 hour and was then extracted several times with ether. The combined ether extracts were washed with cold water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by absorption on a silica chromatographic column followed by elution with benzene-ethyl acetate mixtures to give 3-acetoxy-2-(4(RS)-acetoxy-1-octynyl)-5-oxocyclopent-1-anheptanoic acid.

Example 12

A mixture consisting of 6.3 parts of 1-octyn-4-(RS)-ol, 7.4 parts of di-phthalic anhydride and 10 parts of pyridine was heated at reflux temperature for approx. 3 hours, then it was cooled to room temperature, diluted with ether and washed with dilute hydrochloric acid. Extraction with dilute aqueous sodium hydroxide followed by acidification of the alkaline extract and extraction of the acidified mixture with ether gave an organic solution, which was dried over anhydrous sodium sulfate, decolorized with activated charcoal and then the solvent was removed to give l-octyne-4( RS)-ol phthalate.

A mixture containing 2.24 parts of the latter ester, 0.99 parts of L(-) α-methylbenzylamine and 125 parts by volume of dichloromethane was stirred for approx. 10 minutes, then the solvent was removed under reduced pressure and diluted with ether. The product was purified by recrystallization from cyclohexane which gave 1-octyn-4(S)-ol phthalate IL(-) α-methylbenzylamine salt, m.p. about. 109-112°C.

A mixture comprising 1.07 parts of the latter salt,

10 parts by volume IN sodium hydroxide and 10 parts by volume methanol were heated at approx. 60°C for about 90 minutes, and was then cooled and diluted with hexane. The hexane layer was separated, washed with water", dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1-octyn-4(S)-ol, which is characterized by an optical rotation in ether of -46.5° •

Example 13

By repeating the method in example 12 using D(+) α-methylbenzylamine instead of L(-) α-methylbenzylamine, 1-octyn-4(R)-ol was obtained.

Example 14

When an equivalent amount of either 1-octyn-4-(R)-ol 4-tetrahydropyran-2-yl ether or 1-octyn-4(S)-ol-4-tetrahydro-pyran-2-yl ether was used in the method of example 8, method A,

became 3-hydroxy-2-(4(R)-hydroxy-1-octynyl)-5-oxocyclopent-1-enhaptanoic acid and 3-hydroxy-2-(4(S)-hydroxy-1-octynyl)-5-oxocyclopent -1-enheptanoic acid.

Example 15

When an equivalent amount of either 1-octyne-4(R)-o1

or 1-octyn-4(S)-ol was used in example 8, method B, 3-hydroxy-2-(4(R)-hydroxy-1-octynyl)-5-oxocyclopent-1-enheptanoic acid and 3- hydroxy-2-(4(S)-hydroxy-1-octynyl)-5-

oxocyclopent-1-enheptanoic acid.

Claims (7)

1. Method of making a compound therewith general formula: where R is hydrogen or an alkyl radical of 1-7 carbon atoms; R 1 is hydrogen or an alkanoyl radical with 1-7 carbon atoms; R 2 is hydrogen or an alkanoyl radical of 1-7 carbon atoms; R 2 is hydrogen or an alkyl radical of 1-7 carbon atoms; m is 6 or 7, and where the wavy lines indicate the alternative R and S absolute stereochemical configuration or the epimeric mixture, characterized in that a compound with the general formula where R is hydrogen or an alkyl radical with 1-7 carbon atoms; R' is hydrogen or methoxymethyl; the alkyl group contains 1-4 carbon atoms; m is 6 or 7; and the wavy line indicates the alternative R and S absolute stereochemical configuration or the epimeric mixture, condensed with an organometallic compound of the general formula: where R-j is hydrogen or an alkyl radical with 1-7 carbon atoms; R" is hydrogen, tetrahydropyran-2-yl, or trialkylsily1, where the alkyl group contains 1-4 carbon atoms; and the wavy lines indicate the alternative R and S absolute stereochemical configuration or the epimeric mixture; provided that R is only hydrogen when the Grignard reagent is used; optionally followed by esterification. 2. Method according to claim 1, characterized in that R is hydrogen; R" is hydrogen, tetrahydropyran-2-yl or trialkylsilyl, where the alkyl group contains 1-4 carbon atoms, and m is 6. 3. Method according to claim 1, for the preparation of 2-(4(RS)-hydroxy-1-octynyl)-3-hydroxy-5-oxocyclopent-1-enheptanoic acid, characterized in that 4-hydroxy-2-methoxy-5~ oxocyclopent-1-enheptanoic acid is reacted with an organometallic derivative of l-octyn-4(RS)-ol. 4. Process according to claim 1 for the production of 2-(4(R)-hydroxy-1-octynyl)~3-hydroxy-5-oxocyclopent-1-enheptanoic acid, characterized in that 4-hydroxy-2-methoxy-5~ oxocyclopent -1-enheptanoic acid is reacted with an organometallic derivative of l-octyn-4(R)-ol. 5. Process according to claim 1, for the preparation of 2-(4(S)-hydroxy-1-octynyl)-3-hydroxy-5-oxocyclopent-1-enheptanoic acid, characterized in that 4-hydroxy-2-methoxy-5~ oxocyclopent-.1-enheptanoic acid is reacted with an organometallic derivative of i-octyne-4(S)-1. 6. Process according to claim 1, for the preparation of methyl 2-(4 (RS)-hydroxy-1-octynyl)-3r\hydroxy-5-oxocyclopent-1-enheptanoa-t, characterized in that 4-hydroxy-2- methoxy-5-oxocyclopent-1-enheptanoic acid is reacted with an organometallic derivative of l-octyn-4(RS)-ol followed by hydrolysis and subsequent methylation. 7. Process according to claim 1, for the preparation of 2-(4(RS)-acetoxy-1-octynyl)-3-acetoxy-5-oxocyclopent-1-enheptanoic acid, characterized in that 4-hydroxy-2-methoxy-5- oxocyclopent-1-enheptanoic acid is reacted with an organometallic derivative of l-octyn-4-(RS)-ol, followed by hydrolysis and subsequent acetylation. 8.. Process according to claim 1, for the production of 2-(4(RS)-hydroxy-4 (RS')-methyl-1-octynyl)-3-hydroxy-5-oxocyclopent-1-enheptanoic acid, characterized by that 4-hydroxy-2-methoxy-5-oxocyclopent-1-enheptanoic acid is reacted with an organometallic derivative of 4(RS)-methyl-1-octyn-4(RS)-ol.