DE2310556A1 - NEW PROSTAGLAND-LIKE COMPOUNDS AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

J -.- ". -'- ' ¹ L-QiEM. WALTER BEIL -kiO HV PPc Ki R
DR. JUR. · ,,.: .- c :: - · \ -.Μ..j. WOLf * DA. JUR. HA. \ J C-.iii. Cifii.

FRANKFURT AM MAIN -HOCHSI AKtONSHMSSM »

F / Dl

March 1, 1973

Our no. 18 565

G.D. Searle & Co. Skokie, 111., V.St.A.

New prostaglandin-like compounds and processes for their preparation.

The present invention relates to a process for the preparation of prostaglandins, in particular a new process for the preparation of racemic PGE ₁ and its esters and "" homologues of the structural formula below

COOR

ÖH

ORIGINAL INSPECTED

_ ρ -

in which R and R ″ each represent a hydrogen atom or a Denote an alkyl group having 1 to 7 carbon atoms. It should be particularly noted that while the invention Process expediently for the preparation of racemic mixtures can be used, it in the same Manner applied to the preparation of the individual optically active, pharmacologically useful isomers of formula I. can be.

The particular prostaglandins represented by above formula are hypotensive in terms of their and the smooth ones Muscle stimulant effectiveness than pharmacological Active ingredients useful.

The alkyl groups represented by R and R ″ in Formula I. include methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl radicals and their branched-chain isomers.

The present method makes the surprising discovery take advantage of certain new intermediate products of the following structural formulas

OOR

(III)

GOOR

COOR

/ 1218

in which R and R "have the abovementioned meaning and R ^{1 is} a tetrahydropyran-2-yl, ^ -alkoxytetrahydropyran-M-yl or trialkylsilyl radical, are useful in the reaction according to the present process for the stereospecific preparation of the compounds of the formula I. So are compounds of the formula

COOR

CHO (VI)

OH

in which R has the above meaning; with dihydro-γ-pyran, a 4-alkoxy-2,3-dihydro- <x-pyran or a trialkylsilyl halide brought into contact, whereby compounds of the formula II are obtained. When considering compounds of the formula II with chromium-II-sulfate, chromium-II-acetate or chromium-II-perchlorate lets react, compounds of structural formula III are preferably formed. By condensation of this Compounds with a triaryl or trialkylalkanoylmethylene phosphorane the corresponding compounds of formula IV are obtained. Treating the connections of the Formula IV with a suitable reducing agent and then removing the protecting group from the resulting Compounds of the formula V, the corresponding compounds of the formula I are obtained. This reduction is under minimal formation of the 15-epimeric products is achieved.

Examples of aryl groups are phenyl and tolyl groups. The alkanoyl radicals contain 6 to 13 carbon atoms; Examples are hexanoyl, heptanoyl, octanoyl and Nonanoy! Groups. The alkoxy radicals contain 1 to 7 carbon

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stoffatomej Examples are K. -hoxy, ethoxy, prooxy, isopropoxy and butoxy radicals, examples of alkyl radicals which contain 1 to J Kühlensto-ffacen.e are methyl, ethyl, propyl, butyl, pentyl -, hexyl and heptyl radicals and their branched-chain isomers. The halogen ions derive them from bromine, chlorine, fluorine and iodine atoms.

The new intermediates that be. / succumbing; -Experienced usable are »show. · ... considerable r ^ ances compared to the 3-hydroxy compounds _s the previous syntheses ^ or: PGE. were used. For example, the use of compounds with a protected hydroxy group enables a process which is stereoselective both during the reduction of the compounds II to the compounds III and during the reduction of the compounds IV to the compounds V. The protected compounds are to be cleaned more carefully than the 3-hydroxy derivatives, which are more soluble in water than the protected hydroxy derivatives. In addition, the protected hydroxy compounds are more stable than the 3-hydroxy compounds and can therefore be stored and handled at room temperature. By using the present method, the chromatographic separation of the desired stereoisomers from the undesired products is also considerably facilitated. For example, the desired Her · (protected hydroxy) -9,15-diketone, which is derived from the Wittig condensation of the 2-formyl derivative, is the first fraction, which in the chromatography on silica by elution with a vol -igen Ethylace ^ tat solution in benzene is obtained. Its IL3 epimer and the by-product triphenylphosphine oxide follow one after the other. This separation process is simple and, as a result, has greater economic advantages.

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The present process is particularly useful because the bulk stereoisomers are those which are analogous _{in configuration to natural PGE 1.} Thus, the reduction of 2-formyl-3- (protected. Hydroxy) -5-oxo-l-cyclopentene-l-heptanoic acid preferably gives the corresponding 2ß-formyl-3a- (protected. Hydroxy) -5-oxo- cyclopentane-la-heptanoic acid. moreover provides (protected hydroxy.) reduction of the 15-Ketorestes in the Ha- preferably -9.15 dioxoprost-13-trans-acid, the corresponding Ha ^- (geschützt.-hydroxy) -15a-hydroxy-9-oxoprost-13 ~ trans -enic acid as the main product.

According to the first stage of the process according to the invention, the 2-formyl-3 ^{-hydroxy compounds of the formula VI with dihydro-γ-pyran, a 1} i-alkoxy-2,3-dihydro-a-pyran or are allowed to prepare the intermediates of the formula II react with a trialkylsilyl halide. These reactions are expediently carried out in solvents such as methylene chloride, tetrahydrofuran, pyridine and the like. A catalytic amount of p-toluenesulfonic acid is preferably added to the reaction mixture to promote the formation of the pyranyl ether. When the trialkylsilyl ethers are formed using tetrahydrofuran as the solvent, it is desirable to add the corresponding hexaalkyldisilazane to the solvent in order to increase the yield.

The compounds of formula II are then treated with chromium II sulfate, Chromium-II-acetate or chromium-II-perchlorate reduced, the compounds of the formula III being formed as the main products. The preferred reducing agent is chromium (II) sulfate. Examples of solvents that are suitable for this reduction are dimethyl sulfoxide, aqueous dimethyl

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formamide and aqueous dioxane. For example, 2-formyl-5-0x0-3- (tetrahydropyran-2-yl) -oxy-l-cyelopen.ten-l-heptanoic acid is reacted with chromium (II) sulfate in this reaction, with 2β-formyl-5 as the main product -oxo-3a- (tetrahydropyran-2-yl) "^i> oxycyclopentan-la-heptanoic acid, accompanied by the by-product 2ß-formyl-5-oxo-3ß- (tetrahydropyran-2-yl) -oxycyclopentan-ierheptanoic acid, obtained wii ^ d These compounds can be separated off by chromatography or they can be reacted further as crude products.The condensation of compounds of the formula III with a triaryl- or trialkylalkanoylmethylene phosphorane leads to the 11- (protected hydroxy) -9,15-diketo-prostanoic acid derivatives of formula IV, which are then reduced to give the 15a-hydroxy derivatives of structure V. The regeneration of the hydroxy radical by hydrolysis then leads to the desired compounds of formula I.

Examples of reducing agents which can be used in the present process for reducing the 9,15-diketones of the formula IV to the 15-hydroxy-9 ~ ketones of the formula V are metallic hydrides such as sodium borohydride, sodium cyanoborohydride, aluminum hydride, lithium perhydro-9b- boraphenalyl hydride, diisobutyl aluminum hydride, zinc borohydride, lithium tri (tert-butoxy) aluminum hydride, tris (sec-butyl) lithium borohydride and lithium tetrahydrolimonyl thexylborohydride {Lithiura-2,6-dimethy 1- ¹ I- (1, 1,2-trimethylpropyl) -lJ-borabicy clo- £ 3 · 3 · 1 lionyl hydride}. Suitable solvents are, for example, tetrahydrofuran, ethyl ether and 1,1-dimethoxyethane.

The hydrolysis of the 11-ethers of the formula V to give the compounds of the formula I is carried out by customary methods with such hydrolysing agents as hydroxylic organic or an-

organic acids. Typical of such means \ are mixtures of lower alkanols with acids, such as methanol;

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Acetic acid and aqueous acid mixtures, such as tetrahydrofuran-water-citric acid, Dimethoxyethane-water-phosphoric acid and acetic acid-water-tetrahydrofuran.

The reaction temperatures and times seem to be necessary for the stereoselective course of the process according to the invention not to be critical. Such temperatures and times can be found by the person skilled in the art from the following examples, and they can be selected by standard chemical methods. Accordingly, some reactions proceed at Reflux temperatures, others at room temperature and still others at lower temperatures.

Equivalent to the racemic intermediates of these Invention are the optically active enantiomers thereof. The racemic compounds corresponding to the formulas II, III, IV and V, can be converted into their optically active enantiomers by conventional methods in each process stage. be solved.

The starting compounds of the formula II can expediently be prepared from styrylglyoxal, which is prepared by oxidation of 4-phenyl-3-buten-2-one with selenous acid, and the dialkyl esters of 3-oxoundecane-l, ll-dicarboxylic acid. The dimethyl ester of the 3-0xoundecan-l, ll-dicarboxylic acid is then saponified with potassium hydroxide, _v, and the dicarboxylic acid obtained is interspersed with Styrylglyoxal order to give ll-hydroxy-9 ^{"12-dioxo-l-i} 4 phenyltetradec-13-enoic acid receives. The cyclization of the latter intermediate in the presence of potassium hydroxide leads to 3-hydroxy-5-oxo-2-styryl-1-cyclopentene-1-heptanoic acid. The 2- (α »ß-dihydroxyphenethyl) derivatives are then easily obtained by hydroxylation of the corresponding 2-styryl compounds. A convenient reagent is osmium tetroxide. The methyl ester of

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3-Hydroxy-5 ~ oxo-2-styryl-1-cyclopenten-1-heptanoic acid is brought into contact in this way at room temperature with osmium tetroxide in dioxane, the 3-hydroxy-2- (α, β-dihydroxyphenethyl) -5-oxo -1-cyclopentene-1-heptamic acid methyl ester is obtained. By cleaving the glycol structure of the corresponding 2- (<x, ß-dihydrö ^> yphenethyl) compounds, the 2-formyl compounds are expediently prepared. The methyl ester of 3-hyiroxy-2- (a, ß ~ dihydroxyphenäthyD-5-oxo-1-cyclopentene-1-hcptanoic acid in ethanol 'is brought into contact with an aqueous sodium pheate solution, the methyl ester of 2-formyl ~ 3 -hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid, but the 2-formyl compounds can also be prepared from the corresponding 2-styryl derivatives by combining the hydroxylation and cleavage processes. 5-oxo-2-styryl-1-cyclopentene-1-heptanoic acid reacted in aqueous dioxane with osmium tetroxide and sodium periodate, the methyl ester of 2-formyl-3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid being obtained.

The invention is explained in more detail with the aid of the following examples. In these examples the temperatures are in Degrees of Celsius, and the amounts of material are given in parts by weight, unless otherwise specified. The relationship between parts by weight and parts by volume is the same as it exists between grams and milliliters. The magnetic Nuclear magnetic resonance spectra were recorded on a 100 megahertz instrument using tetramethylsilane as the internal Standard determined. The infrared absorption maxima are in microns (μ), and the ultraviolet absorption maxima are in Millimicrons (mp) stated.

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1. Production of the starting materials preparation A

A mixture containing 44.3 parts of dl-3-hydroxy-5-oxo-2-styryl-1-cyclopentene-1-heptanoic acid, 11.3 parts of diazomethane and 700 parts of ether was kept at room temperature for 5 minutes, after which acetic acid was added to destroy the excess reagent. The resulting mixture was then washed with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography, first over silica gel using a mixture of Äthylacetot and benzene in a volume ratio of 1: 1 as eluent, followed by Trockenchromatographie over silica gel, the 8 weight - containing% water, there being obtained a mixture of ethyl acetate and. Benzene used in a volume ratio of 1: 1. In this way, the methyl ester of dr ^ -hydroxy-S-oxo ^ -styryl-1-cyclopentene-lheptanoic acid was obtained. This compound was characterized by infrared absorption maxima at about 2.75 »2.87, 5» 76 »5.88, and 6.17 W in chloroform.

ι
Preparation B

A mixture of 13 parts of dl-3-hydroxy-5-oxo-2-styryl-lcyclopenten-1-heptanoic acid, 17.8 parts of sodium periodate, 55 parts of water, 160 parts of dioxane and 2 parts of a solution of 2 % osmium tetroxide in dioxane ( W / V) was stirred under nitrogen for about 4 hours at room temperature. This reaction mixture was then extracted with ether, and the ether layer was separated off and extracted several times with a 0.5% strength by weight aqueous sodium chloride solution. The salt extracts were mixed with sodium

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saturated with chloride and then extracted with ether. The ether layer was separated, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure, where dl-2-formyl-3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid was obtained by an ultraviolet absorption maximum in methanol at about 228 mp with a Molecular extinction coefficients of about 10,100 has been characterized.

Preparation C

When replacing the diazomethane in preparation A with an equivalent Amount of diazoethane was the ethyl ester of the dl-3 " Hydroxy-5-oxo-2-styryl-1-cyclopentene-1-heptanoic acid was obtained.

Preparation D

Using an equivalent amount of the ethyl ester of dl-3-hydroxy-5-0x0-2-styryl-1-cyclopentene-1-heptanoic acid in the process according to preparation B, the ethyl ester of dl-2-formyl-3-hydroxy-5-oxo-l-cyclopentene-l-heptanoic acid obtain.

Preparations

To a stirred mixture of 500 parts by volume of a MO weight aqueous potassium hydroxide solution and a 200 parts of N-nitrosomethylurea were added in portions to the same volume of ether. The ether layer, which the diazomethane thus formed was decanted off and dried over potassium hydroxide. The dried ether layer was transferred to another vessel, and 81.3 parts of n-octanoyl chloride were added. This mixture was stirred for one hour at about -5 ° C, and then

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-U-

dry hydrogen chloride gas was bubbled in while the temperature was held almost constant until the previously yellow solution became colorless (approximately 30-5 minutes), ice water was added, the mixture was shaken, and the ether layer was separated and dried over anhydrous sodium sulfate. After removing the solvent, 2-oxo-n-nonyl chloride was obtained as an oil. This oil was dissolved in 745 parts of chloroform which contained an excess of triphenylphosphine (about 1.4 moles of triphenylphosphine to 1 mole of 2-oxo-n-nonyl chloride). The chloroform mixture was refluxed for 4 hours and then cooled. Removal of the solvent under reduced pressure gave an oil which was dissolved in a minimal amount of hot acetone with stirring. While the solution was stirred, so much ether was added that the solution became cloudy. With further stirring, white crystals of triphenyl-2-oxo-n-nonyl-phosphorus anylchlorid were obtained which had a melting point of about to 211 ⁰ C.

About 250 parts of the triphenyl-2-oxo-nnonyl-phosphoranyl chloride shown above were taken up in 3,000 parts of chloroform and then shaken with about 1,000 parts by volume of a 10% strength by weight aqueous potassium carbonate solution . The chloroform layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residual oil slowly crystallized to give pure triphenyl-n-octanoyl-methylenpho.sphoran .

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Preparation F

Using an equivalent amount of n-nonanoyl chloride in the process of preparation E gives triphenyln-nonanoyl methylenephosphorane. The triphenyl-2-oxo-n-decylphosphoranyl chloride, which is formed as an intermediate in the preparation of the Wittig reagent, melts at about 198 to 201 ^° C.

2. Process examples

example 1

A solution of 2 parts dl- ^
Cyclopenten-1-heptanoic acid and 1 volume part of dihydropyran in 6.7 parts of methylene chloride were admixed with a solution which contained 0.02 part of p-toluenesulfonic acid in 0.18 part of tetrahydrofuran. A very rapid exothermic reaction ensued. After the completion of the reaction, the mixture was diluted with 400 parts of methylene chloride, washed with aqueous sodium sulfate and dried over anhydrous sodium sulfate. Concentration of the dried mixture under reduced pressure gave dl-2-formyl-5-0x0-3- (tetrahydropyran-2-yl) -oxy-l-cyclopentene-l-heptanoic acid as a pale yellow oil.

The crude reaction mixture, which contained the dl-2-formyl-5-oxo-3- (tetrahydropyran-2-yl) -oxy-l-cyclope ^r ben-l-heptanoic acid described in the previous section, was with 32 parts by volume of chromium-II sulfate solution, which had been prepared from chromium III sulfate, as described in Organic Synthesis, Vol. 49, p. 98, was added. The resulting reaction mixture was stirred under nitrogen for about 30 minutes, after which there was added 3 parts of ammonium sulfate

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and 25 parts sucrose added. The mixture was then acidified by adding Im - aqueous citric acid, extracted with ether, and the ether extract was separated, washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution «dried over anhydrous sodium sulfate and concentrated under reduced pressure, the main product being dl-2ß-formyl-5-oxo-3cr (tetrahydropyran-2-yl) oxycyclopentanla-heptanoic acid was obtained. The corresponding 3ß- (tetrahydropyran-2-yl) ether was obtained as a by-product.

Example 2

A solution containing 2.2 parts of dl-2ß-formyl-5-oxo-3ar (tetrahydropyran-2-yl) -oxycyclopentane-lcrheptanoic acid and 5 parts of triphenyl-n-hexanoyl-methylenephosphorane in 101 Portions of benzene were heated at reflux temperature for about 4 hours, then cooled and added sequentially an aqueous citric acid solution and an aqueous sodium chloride solution, over anhydrous sodium sulfate dried and chromatographed on a silica column. By eluting the column with a 15 volume Jigen Ethyl acetate solution in benzene became dl-9 »15" dioxo-lla- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid obtain. The corresponding IIß isomer was obtained as a by-product, which on thin layer chromatography using a silica gel plate with a benzene: ethyl acetate: acetic acid (50: 50: 2 Volume) mixture is more polar than developer solution.

Example 3

A mixture of Ik parts of crude dl-2ß-formyl-5-oxo-3 <x- (tetrahydropyran-2-yl) -oxycylcopentan-la-heptanoic acid, 50

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- l4 ~

Share triphenyl-n-hexanoyl-methylenephosphorane and 264 Portions of benzene were heated at reflux temperature for 5 hours. After cooling the solution became the organic Layer with a cold 3% by weight aqueous citric acid solution / Determine 2% strength by weight aqueous sodium chloride solution washed, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. That Remaining material was chromatographed over silica and eluted with a 15 vol. solution of ethyl acetate in benzene, with fractions successively of dl-9 »15-dioxo-lla- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid, dl-9> 15-dioxo-11ß- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid and triphenylphosphine oxide. The ratio of the Ila epimer to the IIβ epimer was about 4: 1.

Example 4

44.0 parts of crude dl-2β-formyl-5-oxo-3a ~ (tetrahydropyran-2-yl) -oxycyclopentane-l & -heptanoic acid was treated in the same way as in Example 3. After chromatography, however, 2 fractions were obtained which consisted of dl-9,15-dioxolla- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid and a mixture of dl-9,15-dioxo-lla- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid and dl-9,15-dioxo-11ß- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid passed.

Example 5

A cooled solution of 0.208 parts of dl-9,15-dioxo-lla- (tetrahydropyran-2-yl) -oxoprost-13-trans-enoic acid in 17.4 parts of methanol was with 0.048 parts by volume of triethylamine, then treated with 0.94 parts of an aqueous sodium borohydride solution, which consists of 0.058 parts of sodium borohydride and 3> 0 parts of water had been made. One let

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this genii sh while chilled by an ice bath, React for 2 hours. Thereafter, the excess sodium borohydride was decomposed with acetone and the reaction mixture was diluted with ether. The essential solution was successively with a cold 2 percent by weight aqueous Citric acid solution and a 2% strength by weight aqueous sodium chloride solution washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed over silica, using a mixture of ethyl acetate and benzene by volume of 1: M was used as the eluent. This gave fractions which consist of dl-9,15-dioxo-II <x- (tetrrahydropyran-2-yl) -oxyprost-13-trans-enoic acid, dl-9a-hydroxy-15-oxo-llcr (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid and a mixture in the ratio of about 50:50 of dl-15a-hydroxy-9-οχο-ΙΙα- (tetrahydropyran-2-yl) -oxyprost-13- transenic acid and dl-9β-hydroxy-15-oxo-llcr (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid passed.

Which consists of the abovementioned mixture at a 50:50 ratio fraction was washed with one volume of a solution of acetic acid, water and tetrahydrofuran in a volume ratio of 20: 3 treated, heated for 3 hours at ¹ IO ⁰ C and chromatographed on a distribution column: 10th This distribution column was prepared by shaking together 15 parts by volume of benzene, 5 parts by volume of methanol and 2 parts of water. The 2 layers thus formed were separated, the upper layer being used for elution and the lower layer being used as the stationary phase. The column was made by adding 75 parts of silica

and carefully mix 75 volumes of the lower phase and transfer this mixture to a column containing the upper phase contained, brought. Before its use, the column was

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washed with 500 parts by volume of the upper phase. The crude product was placed on the column and, after elution with the upper phase, fractions of dl-lla, -15a-dihydroxy-9 * -oxoprost-13-trans-enoic acid and dl-9ß, llar dihydroxy-15-oxoprost- 13-trans-enoic acid obtained. The initial fraction, which consists of dl-PGE. was melted at about 112 to 113 ⁰ C and showed a nuclear magnetic resonance spectrum in Deuteromethanolsowie in deuterochloroform that were with denjenigern natural PGE s ^ identical. The latter fraction, which consisted of dl-9ß, lla-dihydroxy-15-oxoprost-13-transenoic acid, which was obtained as an oil, showed in the ultraviolet spectrum in methanol an absorption of about 232 μm with a molecular extinction coefficient of 13.IOO.

Example 6

A solution of 0.189 parts of dl-9,15-dioxo-lla- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid in 8.88 parts of tetrahydrofuran, which in a bath of solid carbon dioxide and acetone was cooled, was added with 0.254 parts of tri- (tert-butoxy) lithium aluminum hydride treated in 2.26 parts of tetrahydrofuran. After the addition was complete, the cold bath replaced by an ice bath. The reaction was allowed to continue for 2 hours and the products were after the in Example 5 method described separated and hydrolyzed. In this way dl-lla, 15a-dihydroxy-9 ~ oxoprost-13-trans-enoic acid, dl-9a, lla-dihydroxy-15-oxoprost-13-transenoic acid and dl-9β, Ha-dihydroxy-15-oxoprost-13-transenoic acid obtain.

Example 7

A solution of 2.0 parts of dl ^ -Formyl ^ -hydroxy-S-oxo-lcyclopenten-1-heptanoic acid in 8.9 parts of tetrahydrofuran was with 1.0 part of (tert-butyl) dimethylsilyl chloride

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and 1.0 part 1,3-di- (tert-butyl) -1, 1,3,3-tetramethylsilizane. The reaction mixture was heated to 35 ^° C. and allowed to react for 20 minutes. It was then concentrated under a stream of nitrogen and chromatographed over silica, the main product being dl-3a ~ (tert-butyl) -dimethylsilyloxy-2-formyl-5-oxo-1-cyclopentene-1-heptanoic acid.

If the crude reaction mixture with chromium-II-sulfate in reacts in the manner described in the second paragraph of Example 1, the main product obtained is dl-3a- (tert-butyl) -dimethylsilyloxy-2-formyl-5-oxQ-cyclopentane-laheptanoic acid. The corresponding 3β isomer was a by-product obtain.

Example 8

A solution of 7.5 parts of dl-3a- (tert-butyl) -dimethylsilyloxy-2ß-formyl-5-oxo-cyclopentan-la-heptanoic acid and 15 parts of triphenyl-n-hexanoyl-methylenephosphorane in 220 Parts of benzene were heated at reflux temperature for 5 hours. The solution was then cooled and after Treated procedures described in Example 3. The desired product, dl-lla- (tert-butyl) -dimethylsilyloxy-9,15-dioxoprost-13-trans-enoic acid, was chromatographed on a silica column and with a 10 vol Eluted solution of ethyl acetate in benzene. This isomer was followed by dl-11ß- (tert-butyl) -dimethylsilyloxy-9,15-dioxoprost-13-trans-enoic acid. The ratio of the IIIa epimer to the IL3 epimer was about 85:15.

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Example 9

A solution of 2.0 parts of dl ^ -Formyl ^ -hydroxy-lj-oxo-lcyclopenten-1-heptanoic acid and 1.0 part by volume of 4-methoxy-2,3-dihydro-he pyran in 7 parts of methylene chloride was with a solution of 0.02 part of p-toluenesulfonic acid in 0.2 part of tetrahydrofuran was added. After the completion of the reaction, the mixture was diluted with 400 parts of methylene chloride, washed with a cold aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, dl-2-pormyl-3- ( ⁱ * -methoxytetrahydropyran-i | -yl) -oxy-5-oxo-lcyclopenten-1-heptanoic acid was obtained as a pale yellow oil.

Example 10

A mixture of 14 parts of crude dl-2ß-formyl-5-oxo-3a- (tetraoydropyran-2-yD-oxycyclopentan-la-heptanoic acid, ¹ JO parts of tri- (n-butyl) -n-hexanoylmethylene phosphorane and 280 parts Xther was turned off for 18 hours. The reaction mixture was then washed successively with a cold 3% strength by weight aqueous citric acid solution and a 2% strength by weight aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was evaporated over silica chromatographed and eluted with a 15 volume solution of ethyl acetate in benzene, successively fractions of dl-9 »15 ~ dioxo-II <x- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid and dl- 9,15-dioxo-11ß- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid were obtained.

Example 11

100 parts by volume of a cold solution of Im Borane in Tetrahydrofuran, in an ice-salt bath under a nitrogen

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atmosphere was cooled, 8.4 parts of 2,3-dimethylr-2-butene were added, and the mixture was ^{stirred at 0} ° C. for 2 hours. Then each solution of 13 parts of d-liraones in 29 parts of tetrahydrofuran and the thexylborane solution prepared as indicated above were added simultaneously to 125 parts of cold tetrahydrofuran. The addition was carried out over a period of 40 minutes at a temperature of from ⁰ ° C. After the addition was complete, the reaction mixture ^{was stirred at 0 °} C. for 2 hours. The final solution, which was 285 parts by volume, contained 0.35 moles of tetrahydrolimonyl-thsxylborane per liter.

30 parts by volume of the tetrahydrolimonyl-thexylborane solution prepared as described above were 4.56 parts by volume 2.3m tert-butyllithium in n-pentane solution at room temperature treated under a nitrogen atmosphere. the The colorless solution thus obtained contained 0.304 millimoles of lithium tetrahydrolimonyl-thexylborohydride per milliliter.

A solution, cooled in a bath of solid carbon dioxide in acetone, of 0.483 parts of dl-9,15-dioxo-lla- (tetrahydropyran-2-yl) oxyprost-13-trans-enoic acid in 2 parts by volume of tetrahydrofuran was mixed with 8 parts by volume of the above Lithium tetrahydrolimonylthexylborohydride solution prepared as described. The reaction was allowed ■ at -78 ⁰ C for 30 minutes to run away long. The still cold reaction mixture was then treated with 50 parts of ether and 20 parts by volume of a 3% strength by weight aqueous citric acid solution. The ethereal solution was washed with a 2% strength by weight aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica, a mixture of

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-2G-

Ethyl acetate and benzene in a volume ratio of 1: 3 were used as eluants. In this chromatographic separation, 0.2 parts ¹ Il recovered starting material and 0.314 parts of crude reduction product were obtained which, dl-15a-hydroxy-9-oxo-LLA (tetrahydropyran-2-yl) -oxyprost-13 ~ trans-enoic acid.

The latter crude product was treated with 3 parts by volume of a solution of acetic acid, water and tetrahydrofuran in a volume ratio of 20: 10: 3 at room temperature and left to stand for about 18 hours. The solvent was then evaporated in a stream of nitrogen, and the residue was chromatographed on 10 parts of silica and eluted first with 5ΟΠΓ * ethyl acetate in benzene and then with 70 vol. 1 ethyl acetate in benzene. Pure crystalline dl-lla, 15a-dihydroxy-9-oxoprost-13-trans-enoic acid with a melting point of about 112 to 113 ° C. was obtained from the 70 vol .-% ethyl acetate fraction.

Example 12

When using an equivalent amount of dl-2-formyl-3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid methyl ester In the procedure of Example 1, crude methyl dl-2ß-formyl-5-oxo-3a- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoate was obtained obtain.

Example 13

When using an equivalent amount of crude methyl dl-2ß-pormyl-5-oxo-3a ~ (tetrahydropyran-2-yl) -oxycyclopentan-laheptanoate In the procedure of Example 3, the main product was methyl dl-9,15-dioxo-IIcr (tetrahydropyran-2-yl) oxyprost-13-trans-enoate and as a by-product, methyl dl-9,15-dioxo-11ß- (tetrahydropyran-2-yl) oxyprost-13-transenoate obtain.

309839/1218

example

When using an equivalent amount of dl-9> 15-dioxo-Ha- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid methyl ester in the process of paragraphs 3 and 4 of Example 11 dl-llailSa-dihydroxy-g-oxoprost-IS-trans-enoic acid methyl ester was obtained.

Example 15

By treating an equivalent amount of dl-2-formyl-3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid ethyl ester following the procedures of Examples 1 and 3 and paragraphs 3 and 4 of Example 11, ethyl dl-llajlSa-dihydroxy-iJ-oxoprost-13-trans-enoate was obtained.

Example 16

When using an equivalent amount of triphenyl-nheptanoyl-methylenephosphorane in the method of Example 3 dl-5-oxo-2ß- (3-oxonon-1-en-1-yl) -3a- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid was obtained. Subsequent Reduction of this compound according to the procedure of paragraph 3 of Example 11 gave dl -2β- (3a-hydroxynon-1-en-1-yl) -5-oxo-3a- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid , which then according to the procedure of paragraph 4 of Example 11 was hydrolyzed, wherein dl-3a-hydroxy-2ß- (3a-hydroxynon-l-en-yl) -5-oxocyclopentan-la-heptanoic acid was obtained. This compound is the to-methyl homologue der dl-llajlSa-dihydroxy-iJ-oxoprost - ^ - trans-enoic acid.

Example 17

When using an equivalent amount of dl-lla ~ (tert-butyl) -dimethylsilyloxy-9,15-dioxoprost-13-trans-enoic acid following the procedure of paragraphs 3 and 4 of Example 11

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dl-lla, 15a-dihydroxy-9-oxoprost-13-trans-enoic acid with a melting point of about 112-113 ° C.

Example 18

By treating an equivalent amount of dl-2-formyl-3- (4-methoxy-tetrahydropyran-4-yl) -oxy-5-oxo-1-cyclopentene-1-heptanoic acid with chromium-II-sulfate according to the method described in In the 2nd paragraph of Example 1 was described, dl-2ß-pormyl-3a- ( ^1- t-methoxy-tetrahydropyran- ⁱ l-yl) -oxy-5- oxo- cyclopentane-lcrheptanoic acid was obtained. In carrying out the method according to Example 3 using an equivalent amount of this product and subsequent to the procedure of Example 3 and the procedures described in paragraphs 3 and H of Example 11 application was dl-lla "15a-dihydroxy-9-oxoprost-13 -trans-enoic acid obtained.

Example 19

36 parts of dl ^ -Formyl ^ -hydroxy ^ -oxo-l-cyclopentene-lheptanoic acid were dissolved in 200 parts of methylene chloride, and 25 parts by volume of dihydropyran were added. This mixture was admixed with 2 parts by volume of a solution of 0.2 part of p-toluenesulfonic acid in 1.8 parts of tetrahydrofuran , which was followed by a very rapid exothermic reaction . The mixture was stirred for about 30 minutes, then cooled by the addition of solid carbon dioxide and diluted with 89 parts of tetrahydrofuran. This crude dl-2-pormyl-5-oxo-3- (tetrahydropyran-2-yl) -oxy-l-cyclopentene- 1-heptanoic acid- containing solution was under a nitrogen atmosphere at once with 600 parts by volume of a chromium ( II) sulfate solution (made from chromium III sulfate, as described in Organic Synthesis, Vol. * J9, p. 98).

309839/1218

The mixture thus obtained was stirred for one hour and added successively with 50 parts of ammonium sulfate and 400 parts Treated sucrose. This mixture was made with citric acid acidified to pH 3 »5, ethyl ether was added and the mixture was shaken vigorously. The organic layer was separated, extracted 3 times more in the same manner, and then over anhydrous Dried sodium sulfate. Removal of the solvent gave an oil which was dissolved in benzene. To' Filtering off the solids gave a solution which, as the main product, dl-2ß-formyl-5-oxo-3a- (tetrahydropyran-2-yl) -oxycyclopentan-1 <x-heptanoic acid and the corresponding 3ß- (tetrahydropyran-2-yl) ether as a by-product.

Benzene was additionally added to the aforementioned solution in order to increase the total volume to about 300 parts by volume. Then 250 parts by volume were im triphenyl-n-octanoylmethylene phosphorane added in benzene solution. The resulting solution was refluxed for 4 hours, then cooled, diluted with an approximately equal volume of ethyl ether and treated with a cold 2% strength by weight aqueous citric acid solution washed. The organic layer was separated off and first with water, then with a 1 wt aqueous sodium chloride solution and finally washed with a saturated aqueous sodium chloride solution. the organic solution was dried over anhydrous sodium sulfate and the solvent was reduced under reduced pressure Pressure removed. The residual oil was chromatographed on silica. After elution with a 15% by volume Ethyl acetate solution in benzene were successively dl-5-oxo-2ß- (3-oxodec-1-en-1-y1) -3cr (tetrahydropyran-2-y1) -oxycyclopentan-la-heptanoic acid and obtained a mixture of this compound and the 3β-tetrahydropyranyloxy epimer. '

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- 2k -

Example 20

A solution of 1 part dl-5-oxo-2ß- (3-oxodec-l-en-l-yl) -3a- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid in 36 parts of tetrahydrofuran, which in a Bad was cooled in solid carbon dioxide and acetone to -78 ⁰ C and was under a nitrogen atmosphere, was added dropwise over 15 minutes with an excess of Lithiumtetrahydr-olimonyl thexyl-borohydride was added, the solution turned dark. The volume of the solution was tripled by the addition of ethyl ether, and an aqueous citric acid solution was added with vigorous stirring, whereby ice formation occurred. The solution was then allowed to warm to 5 ° C. After the ice melted, the organic layer was separated, washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the yellow residual oil was chromatographed on silica. During the elution of a 35% by volume solution of ethyl acetate in benzene, dl-2ß- (3ß-Hydroxydec-l-enl-yl) -5-oxo-3a- (tetrahydropyran-2-yl) -oxycylcopentan-laheptanoic acid were successively used as By-product and dl-2ß- (3a-hydroxydec-l-enl-yl) -5-oxo-3a- (tetrahydropyran-2-yl) -oxycyclopentan-laheptanoic acid obtained as the main product.

Example 21

A mixture of 1 part dl-2ß- (3a-hydroxydec-l-en-l-yl) -5-oxo-3a ~ (tetrahydropyran-2-yl) -oxycyclopentan-la ~ heptanoic acid in 500 parts by volume of a mixture of acetic acid, Water and tetrahydrofuran in a volume ratio of 20: 10: 3 were left to stand for about 2k hours at room temperature.

309839/1218

Thereafter, the solvent was removed at a temperature below 35 ° C and under reduced pressure and the residue was taken up in benzene. Azeotropic distillation of this benzene solution gave an oil which was chromatographed on silica using a 70 volume solution of ethyl acetate in benzene as the eluent. After evaporation of the solvent from the fraction obtained in the column chromatography solid dl-3a-hydroxy-2ß- (3 <x-hydroxydec-l-en-l-yl) -5-oxocyclopentan-la-heptanoic acid with a melting point of about 80 , 5 ⁰ C obtained.

Example 22

When using an equivalent amount of triphenyl-n-nonanoylmethylene phosphorane instead of the triphenyl-n-octanoylmethylene phosphorane in Example 19, and if the procedure of this example is essentially repeated, succeeds one dl-5-oxo-2ß- (3 "-oxoundec-l-en-l-yl) -3a- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid. Reduction of this compound according to the procedure of Example 20 gives dl-2ß- (3a-hydroxyundec-l-en-l-yl) -5-oxo-3a- (tetrahydropyran-2-yl) -ox.ycyclopentan-la- heptanoic acid, after hydrolysis according to the method of Example 21 dl-3a-hydroxy-2ß- (3a-hydroxyundec-l-en-l-yl) -5-oxocyclopentan-laheptanoic acid with a melting point of about 91 - 92 ° C,

Example 23

If you have an equivalent amount of the dl-2-pormyl-3-hydroxy-5-oxo-l-cyclopentene-l-heptanoic acid methyl ester for example

19 instead of dl-2-formyl-3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid used and the procedures of Examples 19,

20 and 21 essentially repeated, one obtains dl-3a-hydroxy-2ß- (3a-hydroxydec-l-en-l-yl) -5-oxocyclopentan-la-

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heptanoic acid methyl ester. This compound is characterized by infrared absorption maxima in chloroform at around 2.8 and 5.7 μ.

309839/1218

Claims (1)

Patent claims: 1. Method "for making a compound of the general Formula. COOR (X) in which R and R "each represent a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, thereby characterized in that a) a compound of the general formula COOR CHO (VI) OH in which R has the meaning given above, with dihydro-γ-pyran, brings an i | -alkoxy-2,3-dihydro-a-pyran or a trialkylsilyl halide in contact, the corresponding Compound of the general formula 309839/1218 COOR CHO OR ¹ in the R has the aforementioned meaning and R 'is a tetra ^ hydropyran-2-yl-, a ^ -alkoxytetrahydropyran- ^ - yl- or is a Trxalkylsilylrest, is formed, b) the compound of formula II thus obtained with chromium-II-sulfate, Chromium-II-acetate or chromium-II-perchlorate in contact brings, with the appropriate compound of general formula COOR CHO (III) in which R and R ^{1 have the} abovementioned meaning, c) the compound of the formula III with a triaryl- or trialkyl-alkanoyl-methylenephosphorane of the general formula 309839/1218 in which X is a phenyl, tolyl or alkyl radical and R " has the aforementioned meaning, brings into contact, the corresponding compound of the general formula COOiI (HT) in which R, R ¹ and R "have the aforementioned meanings, is obtained, d) the compound of the formula IV thus obtained is brought into contact with a suitable reducing agent, wherein the corresponding compound of the general formula COOR (V) in which R, R ¹ and R ″ have the aforementioned meanings, is obtained, and e) the compound of the formula V is brought into contact with a suitable hydrolyzing agent. 309839/1218 2. The method according to claim I _5, characterized in that there is used as the reducing agent in step (b) chromium (II) sulfate, a metal hydride as the reducing agent in step (d) and a hydroxylic acid as the hydrolyzing agent in step (e). 3. The method according to claim 2, characterized in that the metal hydride is sodium cyanide, aluminum hydride, lithium perhydro-9b-boraphenalyl hydride, diisobutylaluminum hydride, zinc borohydride, lithium tri- (tert-butoxy) aluminum hydride or lithium tetrahydrolimonyl thexyl borohydride, and aqueous citric acid, acetic acid or phosphoric acid are used as the hydrolyzing agent. l \. Process according to one of Claims 1 to 3, characterized in that a compound is used in which R ^{1 is} a tetrahydropyran-2-yl radical, X is a phenyl radical and R "is a hydrogen atom. 5. The method according to any one of claims 1 to 3, characterized in that a compound is used in which R ^{1 is} a tetrahydropyran-2-yl radical, X is a phenyl radical and R "is an alkyl radical having 1 to 3 carbon atoms. 6. The method according to claim 4 or 5, characterized in that a compound is used in which R is a hydrogen atom, and lithium tetrahydrolimonylthexyl borohydride is used as the metal hydride and a mixture of water, acetic acid and tetrahydrofuran as the hydrolyzing agent. 7. Process for the preparation of prostaglandin-like compounds of the general formula 309839/1218 2310555 COOR CHO in which R and R ^{1 have the} following meanings, characterized in that a compound of the general formula COOR CHO Or ¹ in which R is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms and R ^{1 is} a tetrahydropyran-2-yl, ^ -alkoxytetrahydropyran - ^ - yl or a trialkylsilyl radical, with chromium (II) sulfate, chromium (II) acetate or Bringing chromium-II-perchlorate into contact. 8. The method according to claim 7 »characterized in that the reducing agent used is chromium (II) sulfate. 9. The method according to claim 7 or 8, characterized in that a compound is used in which R ^{1 is} a tetrahydropyran-2-yl radical. 10. The method according to any one of claims 7 to 9, characterized in that one uses a compound in which R represents a hydrogen atom. 309839/1218 11. Process for the preparation of prostaglandin-like compounds of the general formula COOR CHO in which R and R 'have the following meanings, characterized in that a compound of the general formula COOR CHO
OR ' in which R is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms and R 'is a tetrahydropyrane-2-yl-, ii-alkoxy-tetrahydropyran - ^ - yl or a trialkylsilyl radical mean, where, when R is a hydrogen atom, R 'does not mean a tetrahydropyran-2-yl radical, with chromium-II-sulfate, Chromium-II-acetate or chromium-II-perchlorate in contact brings. 12. The method according to claim 11, characterized in that the reducing agent used is chromium (II) sulfate. 13 · Process for the preparation of the prostaglandin-like compound of the formula 309839/1218 COOH CHO '"O characterized in that a compound of the formula COOH brings into contact with chromium-II-sulfate. 14. Process for the preparation of prostaglandin-like compounds of the general formula COOR OH in which R, R ¹ and R "have the following meanings, characterized in that a compound of the general formula 309839/1218 OOR in which R and R "are each a hydrogen atom or an alkyl group having 1 to 7 carbon atoms and R ^{1 is} a tetrahydropyran-2-yl, ¹ I-alkOXytetrahydropyran-4-yl or a trialkylsilyl radical, with a suitable reducing agent. 15. Process according to Claim 14, characterized in that a metal hydride is used as the reducing agent. 16. The method according to claim 15, characterized in that the metal hydride used is sodium cyanoborohydride, aluminum hydride, Lithium perhydro-9b-boraphenalyl hydride, diisobutyl aluminum hydride, Zinc borohydride, lithium tri- (tert-butoxy) aluminum hydride or lithium tetrahydrolimonyl thexyl borohydride used. 17. The method according to any one of claims 14 to 16, characterized in that a compound is used in which R ^{1 is} a tetrahydropyran-2-yl radical and R "is a hydrogen atom. 18. The method according to any one of claims lH to l6, characterized in that a compound is used in which R * is a tetrahydropyran-2-yl radical and R "is an alkyl radical having 1 to 3 carbon atoms. 309839/1218 19. The method according to claim 17 or 18, characterized in that a compound is used in which R is a hydrogen atom, and lithium tetrahydro-limonyl-thexyl-borohydride is used as the metal hydride. '. Compounds of the general formula COOR in which R is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, R ^{1 is} a tetrahydropyran-2-yl, 4-alkoxytetrahydropyran - ^ - yl or a trialkylsilyl radical, and Y is a formyl radical or a radical of the general formula -CH = CH-Z- (CH ₂ ) ₅ R " represents in which Z is a carbonyl or α-hydroxymethylene radical and R "is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms. 21. Compounds of the general formula 0OR 309839/1218 in which R is a hydrogen atom or an alkyl group with up to 7 carbon atoms and R ^{1 is} a tetrahydropyran-2-yl, iJ-alkoxytetrahydropyran - ^ - yl or a trialkylsxlyl radical. 22. Compounds of the general formula ⁰ -COOR CHO in which R is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms. 23. dl-2ß-Formyl-5-oxo-3a- (tetrabydropyran-2-yl) -oxycyclo pentane-IOL-heptanoic acid. 24. Compounds of the general formula COOR in which R and R "are each a hydrogen atom or an alkyl group having 1 to 7 carbon atoms and R ^{1 is} a tetrahydropyran-2-yl, ^ -alkoxytetrahydropyran-jj-yl or a trialkylsilyl radical. 309839/1218 25 · Compounds of the general formula O COOR in which R and R ″ each represent a hydrogen atom or a Denote an alkyl group having 1 to 7 carbon atoms. 26. Compounds of the general formula COOR in which R denotes a hydrogen atom or an alkyl group having up to 7 carbon atoms. 27. dl-9,15-Dioxo-lla- (tetrahydropyran-2-y1) -oxyprost-13-trans-enoic acid. 28. Compounds of the general formula 309839/1218 in which R is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms and R "is an alkyl group having 1 to 3 mean carbon atoms. 29. dl-5-Oxo-2ß- (3-oxonone-1-en-1-yI) -3 & - (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid. 30. dl-5 ~ Oxo-2ß- (3-oxodec-1-en-1-yl) -3d- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid. 31. dl-5-Oxo-2ß- (3-oxoundec-1-en-1-yl) -3a- (tetrahydropyran-2-yl) -oxycyclopentan-ia-heptanoic acid. 32. Compounds of the general formula 0OR in which R and R ″ each represent a hydrogen atom or a Alkyl group with 1 to 7 carbon atoms and R 'a tetrahydropyran-2-yl-, ^ -alkoxytetrahydropyran - ^ - yl- or mean a trialkylsilyl radical. 309839/1218 33 · Compounds of the general formula OOR in which R and R ″ each represent a hydrogen atom or a Denote an alkyl group with 1 to 7 carbon atoms. 3 * t. Compounds of the general formula COOR in which R has a hydrogen atom or an alkyl group Means 1 to 7 carbon atoms. 35. dl-15tt-Hydroxy-9-oxo-lla- (tetrahydropyran-2-yl) -oxyprost-13-trans-enoic acid. 36. Compounds of the general formula 309839/1218 COOR in which R is a hydrogen atom or an 'alkyl group with 1 to 7 carbon atoms and R "denotes an alkyl group having 1 to carbon atoms. 37. dl-2ß- (3tt-Hydroxynon-1-en-1-yl) -5-oxo-3a- (tetrahydropyran-2-yl) -oxycyclopentan-la-heptanoic acid. 38. dl -2β- (3a-Hydroxydec-1-en-1-yl) -5-oxo-3a- (tetrahydropyran-2-y1) -oxycyclopentane-1α-heptanoic acid. 39. dl -2β- (3a-Hydroxyundec-1-en-1-yl) -5-oxo-3a- (tetrahydropyran-2-y3) -oxycyclopentane-1α-heptanoic acid. For: G.D. Searle & Co, Dr HL J. Wolff Attorney at Law 309839/1218