NO158298B - (13E) - (8R, 11R, 12R) -11,15-DIHYDROXY-16,19-DIMETHYL-9-OXO-13,18-PROSTA-DIETIC ACID DERIVATIVES AND ANTICONCTIONS CONTAINING THESE. - Google Patents

Description

The present invention relates to (13E)-(8R,11R,12R,15S, 16RS)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadic acid and (13E)-(8R,11R, 12R,15R)-11,15-dihydroxy-16,16,19-dimethyl-9-oxo-13,18-prostadic acid, their physiologically acceptable salts and contraceptives containing these compounds.

German publication publication 26 35 985 describes prostanic acid derivatives of general formula I:

in which R1 denotes a or in which Rg denotes a hydroxyl group, a straight-chain or branched alkoxy group with 1-10 C atoms, a substituted or unsubstituted aryloxy group, an 0-CH2-U-V group, where U denotes a direct bond, a carbonyl - or carbonyloxy group and V denotes a phenyl ring which is substituted with one or more phenyl groups, alkoxy groups with 1-2 C atoms or halogen atoms, preferably bromine atom, or denotes a -NHR^Q group, in which R^Q denotes an alkyl or aryl group or an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms, R^ and Rg denote hydrogen or alkyl groups with 1-4 C atoms and Rg denotes either an acid residue of an organic carboxylic or sulfonic acid with 1-15 C atoms or an inorganic acid, or denotes a

in which R^0 has the above meaning,

A denotes a -CI^-CI^- or a cis- or trans-CH=CH-

group,

B denotes a -CH^-CI^-, a trans-CH=CH-, a -CafC group or in which the methylene group can stand in a- or

Island position,

W denotes a free or functionally modified hydroxymethylene group, a free or functionally modified carbonyl

in which denotes a hydrogen atom or an alkyl group with 1-5 C atoms and where the OH group may be in the a- or |3-position and may be functionally modified, Z denotes a carbonyl or hydroxymethylene group, which may be free or functionally modified, X^^^Y denotes or when Z denotes a free or functionally modified hydroxymethylene group, or

or -CH=CH- when Z denotes a free or func-

functionally modified carbonyl group, where the residue R^2 denotes a hydrogen atom, a methyl or cyanide group, or a free or functionally modified hydroxy group,

R2 denotes a hydrogen atom or an alkyl group,

R^ denotes a hydrogen atom or an alkyl group,

R^=R,- and denotes a methyl group, or

R 4 denotes a chlorine atom when R 4 denotes a methyl group or

R,, denotes a chlorine atom when R4 denotes a methyl group,

and if Rg denotes a hydroxy group, their physiologically acceptable salts with bases.

The compounds exhibit valuable therapeutic properties and are distinguished in particular by the fact that, after a single intrauterine administration, they induce menstruation or can terminate a pregnancy. They are also suitable for synchronizing the sexual cycle in female mammals such as monkeys, cattle, pigs, sheep etc. The prostaglandin derivatives known from DE-OS 26 35 985 are strongly uterine contracting as well as luteolytic; to trigger an abortion, smaller dosages are needed than of the corresponding natural prostaglandins. In the case of the prostaglandins, the desired main effect is most often accompanied by unwanted side effects, which significantly reduce the quality of the main effect.

Among the compounds described in DE-OS 26 35 985, the compounds (13E)-(8R,11R,12R,15S,16RS)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienic acid exhibit and (13E)-(8R,11R,12R,15R)-11,15-dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadic acid as an abortifacient outstanding properties, whereby the dosage in relation to commercial preparations such as "Sulprostone" can be reduced many times over, through which of course the unwanted side effects can also be greatly reduced. The compounds (13E)-(8R,11R,12R,15S,16RS)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadic acid and (13E)-(8R,11R,12R, 15R)-11,15,dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadienic acid is not named in DE-OS 26 35 985. The compounds in which A denotes a -CH^-CI^ group , in relation to the other compounds in which A denotes a cis-CH=CH group, was not emphasized.

The invention thus relates to (13E)-(8R,11R,12R)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadioic acids of formula:

wherein R represents hydrogen or methyl, or their physiologically acceptable salts with bases.

Preparation of the compounds 2-(1,4-dimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl ester and 2-(1,1,4-trimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl ester takes place according to procedures known per se, as as described in DE-OS 26 35 985.

For salt formation, all inorganic and organic bases that are known to the person skilled in the art to form physiologically acceptable salts come into consideration. Examples include alkali hydroxides such as sodium or potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)methyl, etc.

The reaction of (8R,9S,11R,12S)-9-benzoyloxy-13-oxo-11-(tetrahydropyran-2-yloxy)-14,15,16,17,18,19,20-heptanorprostanic acid methyl ester with 2- (1,4-dimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl ester and of (8R,9S,11R,12S)-9-benzoyloxy-13-oxo-11-(tetrahydropyran-2-yloxy)-14,15,16 ,17,18,19,20-heptanorprostanic acid methyl ester with 2-(1,1,4-trimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl ester is carried out in a manner known per se at temperatures of from 0 to 100° C, preferably at 20 to 80°C, in an aprotic solvent such as e.g. dimethylsulfoxide, dimethylformamide, benzene, toluene, xylene, diethylether, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethoxyethane, etc.

The oxidation of the 9-hydroxy group is carried out according to known methods with the usual oxidizing agents. For example, the oxidation can be carried out after intermediate protection of the 11- and 15-hydroxy groups, e.g. by silylation (Chem. Comm. 1972, 1120) with Jones reagent.

The functionally modified hydroxy groups are released according to known methods. For example, the cleavage of the hydroxy protecting group is carried out, such as e.g. the tetrahydropyranyl residue, in an aqueous solution of an organic acid, such as e.g. oxalic acid, acetic acid, propionic acid, or in an aqueous solution of an inorganic acid such as e.g. hydrochloric acid. In order to improve the solubility, a water-miscible inert organic solvent is suitably added. Suitable organic solvents are e.g. alcohols such as methanol and ethanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran and acetone. Tetrahydrofuran is preferably used. The separation is preferably carried out at temperatures between 20 and 80°C.

Saponification of the acyl group takes place, for example, with

alkali or alkaline earth carbonates or hydroxides in an alcohol or in an aqueous solution of an alcohol. As alcohols, aliphatic alcohols come into consideration, such as e.g. methanol, ethanol, butanol, etc., preferably methanol. As alkali carbonates and hydroxides, mention may be made of potassium and sodium salts, preferably the potassium salt. Examples of suitable alkaline earth carbonates and hydroxides are calcium carbonate, calcium hydroxide and barium carbonate. The reaction takes place at -10 to +70°C, preferably at +25°C.

(13E)-(8R,11R,12R,15S,16RS)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadic acid and (13E)-(8R,11R,12R,15R )-11,15-dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadienic acid can be transferred with suitable amounts of the corresponding inorganic bases to salts during neutralization. For example, the solid inorganic salt is obtained by dissolving the PG acid in water containing the stoichiometric amount of the base, after evaporation of the water or after the addition of a water-miscible solvent, for example alcohol or acetone.

For the preparation of an amine salt, which takes place in the usual way, the PG acid is dissolved, for example, in a suitable solvent, e.g. ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution. Thereby, the salt is usually precipitated in solid form or can be isolated in the usual way after evaporation of the solvent. The good dissociation of action of the new compounds is shown by examination of other smooth muscle organs such as e.g. on guinea pig ileum or isolated rabbit trachea, where significantly less stimulation is observed than with the natural prostaglandins.

o

The abortifacient activity of the compounds relative to the activity of PGE 2 =1 was measured as described in W. Elger, Animal Reproduction Science 2, 133-148 (1979).

PGE2 was used as a reference standard. The results obtained were as follows:

The new active substances are to be used in connection with the known and common excipients in galenic pharmacy, for example for the production of preparations for inducing abortion, for cycle disturbances or for inducing births. For this purpose, sterile, aqueous solutions containing 0.0001 - 10 µg/ml of the active compound can be used, such as intravenous infusion solutions. For the production of aqueous isotonic solutions, the acid and its salt are particularly suitable. To increase the solubility, alcohols such as ethanol and propylene glycol can be added. Furthermore, suppositories for intravaginal administration can be produced.

Depending on the application (vaginal, extra-amnial, intramuscular, intravenous), the unit dose is between 0.25 µg and 50 mg.

Example 1

(13E)-(8R,11R,12R,15S,16RS)-11,15-dihydroxy-16,19-dimethyl-9- OXO- 13, 18- prostadionic acid

a) 2- ethoxycarbonyl- 2, 5- dimethyl- 4- hexenoic acid ethyl ester

In a three-necked flask equipped with a reflux condenser, dropping funnel and stirrer, 36.1 g of sodium (divided into small pieces) was added. To this, 800 ml of absolute ethanol was added dropwise so quickly that the solution remained boiling. 269.6 g of freshly distilled methylmalonic acid diethyl ester was added dropwise to the hot alcoholate solution, after which the mixture was stirred for half an hour at 60°C and then 241.7 g of dimethylallyl bromide was added dropwise. After stirring for 1 hour while heating, the separated sodium bromide was filtered off, the precipitate was washed and the filtrate was evaporated. The residue was taken up in ether, washed neutrally with saturated sodium chloride solution, dried over magnesium sulfate and evaporated on a rotary evaporator. The evaporation residue was fractionated at the oil pump. 266 g of the title compound with Kp? = 97-112°C.

IR (film): 1735, 1245, 1025, 860/cm.

b) 2-carboxy-2,5-dimethyl-4-hexenoic acid

223.8 g of the diester obtained in a) was heated

together with 181 g of potassium hydroxide in 235 ml of water and 450 ml

ethanol 1 4 hours under reflux. The ethanol was then evaporated on the rotary evaporator, the residue was dissolved in 235 ml of water and, under ice-cooling, concentrated hydrochloric acid was added dropwise to pH = 1. The precipitate (m.p. 162-166°C) was collected, washed with water and used in the next step without further purification .

IR (KBr) 1700, 1230, 840/cm.

c) 2,5-dimethyl-4-hexenoic acid

Dicarboxylic acid obtained in the previous reaction step, was

kept in a distillation apparatus for 4 hours at normal pressure and then for 1 hour at 75 torr at 210°C. The product was then distilled in vacuo. 68 g of the title compound were obtained (Kp5 = 98 - 106°C; Kp1 = 67 - 70°C).

IR (film): 1705, 1220, 810/cm.

d) 2,5-dimethyl-4-hexenoic acid methyl ester

68 g of the carboxylic acid obtained in the previous step

so much ethereal diazomethane solution was added that no more nitrogen was evolved during the addition of a reagent, and the yellow color of the reaction solution remained constant. The solvent was then removed in vacuo and the residue fractionated. 62.3 g of product with Kp3 5_g = 32 - 35°C were obtained.

IR (film): 1735, 1160, 1050, 820/cm.

e) 2,5-dimethyl-4-hexenoic acid ethyl ester

85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester was dissolved in 645 ml of dimethylsulfoxide and then 29.7 g of lithium chloride and 6.3 ml of distilled water were added. The reaction mixture was then heated for 13 hours to 200°C and, after cooling, was poured into 1 liter of ice water.

The aqueous phase was extracted three times, each time with

500 ml methylene chloride. The combined organic extracts were then washed twice with water, dried over magnesium sulfate, evaporated on a rotary evaporator and distilled in vacuo. 53.1 g of product with Kp13 = 75 - 78°C was isolated. IR (film): 1735, 1160, 1050/cm.

f) 2-(1,4-dimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl ester

To a solution of 59 g of methanephosphonic acid dimethyl ester in 400 ml of absolute tetrahydrofuran was added dropwise under argon at -60°C 274.7 ml of eh 1.61 m butyl lithium solution in hexane. After 15 minutes of stirring, a solution of 34.05 g of 2,5-dimethyl-4-hexenoic acid ethyl ester in 100 ml of absolute tetrahydrofuran was added dropwise. The reaction mixture was warmed to room temperature in the course of 4 hours and was then stirred for a further 3 hours. The reaction mixture was added with 26.5 ml of glacial acetic acid and evaporated in vacuo. The residue was taken up in ether/water, solid sodium chloride was added to the aqueous phase and etherified. The combined organic phases were dried over magnesium sulfate and evaporated on a rotary evaporator. The evaporation residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as eluent. 32 g of the desired compound were obtained.

IR (film): 1710, 1260, 1030/cm.

g) (1S,5R,6S,7R)-6-[(t-butyl-dimethylsilyloxy)-methyl]-7-benzoyloxy- 2- oxabicyclo-[ 3. 3. 0]- octan- 3- one

A solution of 9 .9 g

dimethyl-t-butyl-chlorosilane in 40 ml of absolute dimethylformamide and 9.35 g of imidazole. After 2 hours of stirring at room temperature and under an argon atmosphere, the analytical thin layer chromatography showed complete conversion. The reaction mixture was diluted with 850 ml of ether, washed with 60 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The evaporation residue can optionally be purified by column chromatography on silica gel with ether as eluent. 17.8 g of the title compound were obtained (m.p. = 74-75°C after recrystallization from pentane/ether).

IR; 1775, 1715, 1600, 1580, 1275, 1255, 840, 790, 720/cm.

1U

h) (1S,5R,6S,7R)-6-[(t-butyl-dimethylsilyloxy)-methyl]- 7- hydroxy- 2- oxabicyclo-[ 3. 3. 0]- octan- 3- one

A solution of 17.3 g of the benzoate obtained in the preceding reaction step in 200 ml of absolute methanol was stirred at room temperature together with 6.5 g of dry potassium carbonate under argon. After 2 hours, thin layer chromatography showed complete conversion. The reaction mixture was then added dropwise at 0°C with 500 ml of 0.1 N hydrochloric acid, the mixture was stirred for 15 minutes at room temperature, after which it was evaporated in vacuo and extracted with acetic acid. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The evaporation residue was purified by column chromatography on silica gel with hexane/50-100% ether as eluent. 9.1 g of the desired compound were obtained (m.p. 57-58.5°C).

IR (film): 1775, 1255, 840, 790/cm.

i) (1S,5R,6S,7R)-6-[(t-butyl-dimethylsilyloxy)-methyl]-7-( tetrahydropyran-2- yloxy)- 2- oxabicyclo-[ 3. 3. 0]- octane- 3- on A solution of 15.8 g of the alcohol obtained in the previous section in 300 ml of distilled methylene chloride was stirred together with 7.5 ml of freshly distilled dihydropropane over potassium hydroxide and 1.38 g of pyridine-p-toluenesulfonate for 14 hours at room temperature . After evaporation of the reaction solution at room temperature, the residue was diluted with ether and washed with half-saturated sodium chloride solution. The organic solution was then dried over magnesium sulfate and then evaporated to dryness. If necessary, the product can be purified by column chromatography on silica gel with hexane/20-50% ether as eluent. The yield was 20 g.

IR (film): 1775, 1255, 1115, 1080, 1035, 835, 775/cm.

j) (IS,3RS,5R,6S,7R)-3-hydroxy-6-[(t-butyl-dimethylsilyloxy)-methyl]-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo-[ 3. 3 .3] - octane

To a solution cooled to -70°C of 5.4 g of the lactone obtained in the preceding reaction step in 200 ml of absolute toluene, 20 ml of a 20% DIBAH solution in toluene were added dropwise under argon and over the course of 15 minutes. After approx. After 5 minutes of stirring, 1.2 ml of isopropanol at the same temperature was added dropwise until no further foaming took place. The reaction solution was allowed to warm to 0°C, 16 ml of water was added and stirred for 10 minutes and filtered over a frit. The precipitate was washed out with vinegar. The organic phase was washed three times with saturated sodium chloride solution, was dried over magnesium sulfate and evaporated on a rotary evaporator. The product obtained (5.41 g) was used in the next reaction step without further purification.

k) (5Z)-(8R,9S,11R,12S)-9-hydroxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyldimethylsilyloxy)-14,15,16,17,18,19, 20-heptanor-5-prostenic acid

104.6 ml of a solution of methanesulfinylmethyl sodium

in absolute DMSO (prepared by dissolving 6 g of a 50% sodium hydride suspension in 120 ml of absolute dimethylsulfoxide at a maximum of 70°G) was added dropwise at 15°C to a solution of 25.67 g of 4-carboxybutyl-triphenylphosphonium bromide

(previously dried at 70-80°C on an oil pump) in 80 ml of absolute dimethylsulfoxide. This ylene solution was stirred for 30 minutes at room temperature and then, under water cooling, was added dropwise to a solution of 5.41 g of the lactol obtained in the previous step in 50 ml of absolute dimethyl sulfoxide over 15 minutes. The reaction mixture was then stirred for 4 hours at 35-40°C. (Optionally add 50-100 ml of absolute tetrahydrofuran to the reaction solution).

For work-up, the reaction mixture was added to ice/water, was extracted three times with ether, the aqueous phase was acidified with a 10% citric acid solution to pH = 4

and extracted three times with a 1:1 mixture of ether/hexane. The product was then extracted three times with methylene chloride. Due to the analytical thin-layer chromatography, the methylene chloride phase was discarded, the other two organic phases, on the other hand, were combined, dried over magnesium sulfate, filtered and evaporated on the rotary evaporator. The residue was purified by column chromatography on silica gel with hexane/70% ether as eluent. 4.32 g of the carboxylic acid was obtained.

IR (film): 3440 (wide), 3200-2500, 1725, 1700, 1250, 1100,

1020, 830, 770/cm.

1) (5Z)-(8R,9S,11R,12S)-9-hydroxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14,15,16,17,18, 19,20-heptanor-5-prostenic acid methyl ester

Preparation with diazomethane

4.32 g of carboxylic acid obtained in section k) was dissolved in

20 ml of methylene chloride and diazomethane solution was added in

until no further evolution of gas took place and the yellow coloring of the solution remained constant. After squeezing off the excess of diazomethane on a water jet vacuum, the reaction solution was evaporated to dryness on the rotary evaporator. 4.3 g of the desired carboxylic acid methyl ester were obtained.

Production with iodomethane

To a solution of 32.5 g of the carboxylic acid below

section k) in 4 50 ml acetonitrile was at room temperature drop-

show added 75 ml of N-ethyldiisopropylamine and 150 ml of iodomethane in 200 ml of acetonitrile over the course of 2 hours. The mixture was stirred for 1 hour, and - after DC control - the precipitate was separated, washed with ethyl acetate, after which the organic phase was extracted with sodium bisulphate, sodium bicarbonate

and sodium chloride solution. After drying over magnesium

sulfate, the residue was evaporated to dryness on a rotary evaporator whereupon the residue was purified by column chromatography on silica gel with hexane/50-100% ether as eluent. 32.3 g of the title compound were obtained.

IR (film): 3420 (wide), 1740, 1255, 1120, 1030, 840, 780/cm.

m) (5Z)-(8R,9S,11R,12S)-9-benzoyloxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14,15,16,17,18, 19,20-heptanor-5-prostenic acid methyl ester

To a solution of 4.7 g of the 9-hydroxy compound obtained according to 1) in 70 ml of pyridine, 2.32 ml of distilled benzoyl chloride was added dropwise with stirring and at room temperature.

After 2 hours of stirring under argon, 1.8 ml of water was added to the reaction solution, stirred for a further 1 hour and then evaporated on the oil pump at 30°C and at 1 torr. The residue was taken up in a two-phase mixture of ether/water, washed with sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. After column chromatography of the evaporation residue on silica gel with hexane/30-50% ethyl acetate as eluent, 5.11 g of the title compound was obtained as a colorless oil.

IR (film): 1745, 1720, 1605, 1590, 1280, 1260, 1120, 1030, 840, 780, 710/cm.

n) (8R,9S,11R,12S)-9-benzoyloxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14,15,16,17,18,19,20- heptanorprostanic acid methyl ester

A solution of 12.3 g of the unsaturated compound obtained according to m) in 160 ml of acetic acid was added to 1.23 g of 10% palladium-carbon and hydrogenated in a shaking apparatus at room temperature and a slight hydrogen overpressure. After absorption of 640 ml of hydrogen, the solvent was removed in vacuo, the residue was taken up in 40 ml of ether, the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness on a rotary evaporator. 12.1 g of the title compound were obtained.

IR (film): 1740, 1720, 1600, 1580, . 1275, 1255, 1115, 1070, 1025, 835, 780, 710/cm.

o) (8R,9S,11R,12S)-9-benzoyloxy-11-(tetrahydropyran-2-yloxy)-13-hydroxy-14,15,16,17,18,19,20-heptanor-prostanic acid methyl ester

To a solution of 6.94 g of the compound obtained in the previous reaction step in 110 ml of absolute tetrahydrofuran, 16.11 ml of a 2 m tetrabutyl-ammonium fluoride solution in tetrahydrofuran was added under ice-cooling. After 12 hours of stirring under argon, the reaction mixture was diluted with 1.3 1 ether, washed neutral with saturated sodium chloride solution, after which the washing solution was extracted twice with ether. The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by column

chromatography on silica gel with ethyl acetate as eluent.

5.54 g of the desired compound was obtained as a colorless oil.

IR (film): 3460 (wide), 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 710/cm.

p) (8R,9S,11R,12S)-9-benzoyloxy-13-oxo-11-(tetrahydropyran-2-yloxy)-14,15,16,17,18,19,20-heptanoprostanic acid methyl ester

A solution of 5.54 g of the alcohol obtained in the previous step in 56 ml of absolute methylene chloride was added dropwise at 5-10°C over 20 minutes to a slurry of 18.7 g of Collins reagent in 170 ml of absolute methylene chloride. After stirring for 1 hour under argon, 500 ml of a 1:1 mixture of ether and pentane was added to the reaction mixture and was decanted. The flask was washed twice, each time with 500 ml of the above mixture. The combined organic phases were then shaken three times, each time with 50 ml of a 5% sodium carbonate solution, three times, each time with 50 ml of a 5% sulfuric acid and were finally washed neutral with saturated sodium chloride solution. After drying over magnesium sulfate, the product was evaporated to dryness and the residue was filtered over a silica gel column

(50 g; eluent: ethyl acetate/hexane = 2/8). 4.6 g of the desired aldehyde were obtained.

IR (film): 2720, 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 715/cm.

q) (13E)-(8R,9S,11R,12R,16RS)-9-benzoyloxy-16,19-dimethyl-15-oxo-11-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

To a suspension of 0.48 g of 50% (suspended in oil) sodium hydride in 60 ml of dimethoxyethane distilled over lithium aluminum hydride, under argon and at room temperature 2.48 g of the phosphonate obtained in section f), and dissolved in 30 ml of absolute dimethoxyethane , added drop by drop. After addition of 0.43 g of lithium chloride (previously dried for 2 hours in vacuum at 50°C), the reaction mixture was stirred for 2 hours at

room temperature^ Then the suspension was cooled to -20°C

and added dropwise 4.61 g of the aldehyde obtained in section p), dissolved in 90 ml of absolute dimethoxyethane. The temperature was then allowed to rise over the course of 5 hours from -20 to 0°C <p>g over the course of 1.5 hours further to 5°C, after which the reaction solution was stirred for a further 3 hours at room temperature. At -10°C, 1 ml of glacial acetic acid and 100 ml of water were then added dropwise. The phases were separated, the aqueous phase was extracted 5 times with ether, the organic phases were combined and washed with 4% sodium bicarbonate and saturated sodium chloride solution. After drying over magnesium sulfate, the solution was evaporated

to dryness on a rotary evaporator. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane = 1/1 as eluent. 5.78 g of the title compound were obtained.

IR (film): 1740, 1720, 1695, 1670, 1625, 1600, 1580, 1270, 1105, 1060, 1025, 705/cm.

r) (13E)-(8R,9S,11R,12R,15R,16RS)-9-benzoyloxy-16,19-dimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

To a solution cooled to -40°C of 5.78 g of the ketone obtained in the previous reaction step in 115 ml of absolute methanol, 2.37 g of sodium borohydride was added in portions. After stirring for 1 hour at -40°C, 5.09 ml of glacial acetic acid was added dropwise to the reaction solution at this temperature.

After removal of the solvent on a rotary evaporator, methylene chloride/water was added to the residue, the separated water phase was added to solid sodium chloride and extracted twice with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The isomer separation took place by several days of column chromatography on silica gel with hexane/20-100% acetic acid as eluent. 2.11 g of the title compound were obtained as non-polar product.

IR (film): 3400 (wide), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1020, 710/cm.

s) (13E)-ØR,9S,11R,12R,15R,16RS)-9-benzoyloxy-16,19-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

To a solution of 2.11 g of the alcohol obtained in section r) in 60 ml of absolute methylene chloride was added at ice bath temperature 0.49 ml of dihydropyran (freshly distilled over potassium hydroxide) and 9.7 mg of p-toluenesulfonic acid, after which the mixture was stirred for 55 minutes at 0°C, after which the reaction mixture, diluted with saturated sodium bicarbonate solution and water, was extracted with methylene chloride.

The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane = 1/2 as eluent. 2.3 g of the desired compound were obtained.

IR. (film); 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1025, 715/cm.

t) (13E)-(8R,9S,11R,12R,15R,16RS)-9-hydroxy-16,19-dimethyl-11, 15- bis-(tetrahydropyran-2- yloxy)-13, 18- prostadionic acid En solution of 2.3 g of the benzoate obtained in section s)

in 70 ml of methanol was added 20.6 ml of 2 N potassium hydroxide solution and was stirred for 31 hours at room temperature. The reaction mixture was then evaporated on a rotary evaporator, the residue was taken up in a little water and extracted twice, each time with 150 ml of an ether/pentane mixture. The aqueous phase was acidified with citric acid to pH = 5, and was extracted three times, each time with 150 ml of acetic acid. The combined organic phases were washed neutral with saturated sodium chloride solution, were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as eluent. 1.62 g of the title compound was obtained.

IR (film); 3460, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1020, 810/cm.

u) (13E)-(8R,11R,12R,15R,16RS)-9-oxo-16,19-dimethyl-11,15-bis-(tetrahydropyran-2- yloxy)-13, 18-prostadioic acid

To a solution cooled to -20°C of 360 mg of the alcohol obtained in section t) in 7 ml of acetone was added 0.46 ml of Jones reagent, and the mixture was stirred for 45 minutes at this temperature. 0.6 ml of isopropanol was then added, and the mixture was further stirred for 10 minutes, diluted with cold ether, washed three times with cold, saturated sodium chloride solution, the organic phase was dried over magnesium sulfate and evaporated in vacuo. After filtration over a Sep-Pack finished column, 327 mg were obtained.

IR (film): 2730, 2660, 1740, 1710, 1110, 1075, 1025, 810/cm.

v) (13E)-(8R,11R,12R,15R,16RS)-9-oxo-11,15-dihydroxy-16,19-dlmethyl-13, 18-prostadic acid

327 mg of the compound obtained above was stirred

for 26 hours in 7 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10) at room temperature. The solution was then evaporated at room temperature several times with benzene using an oil pump vacuum. The residue was purified by column chromatography on silica gel with ethyl acetate/0-10% methanol as eluent. 68 mg of the title compound was obtained.

IR (film): 3420, 2730, 2670, 1735, 1710, 1075, 975/cm.

w) (13E)-(8R,9S,11R,12R,15S,16RS)-9-benzoyloxy-16,19-dimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)-13,18-prostadlenic acid methyl ester

During the sodium borohydride reduction of the ketone according to section r), 0.27 g of a/p mixture and 2.67 g of the title compound were eluted as a polar product in addition to 2.11 g of the Ø-alcohol.

IR (film): 3400 (wide), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1020, 710/cm.

x) (13E)-(8R,9S,11R,12R,15S,16RS)-9-benzoyloxy-16,19-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

Analogous to the preparation of the 15-|3-isomer in section s), by reaction of 2.67 g of the alcohol obtained in the previous reaction step and 0.6 2 ml of dihydropyran and 12.3 mg of p-toluenesulfonic acid (reaction time: 75 minutes) after column chromatography on silica gel with ethyl acetate/hexane = 1/3 as eluent, 2.96 g of the title compound were obtained as a colorless oil.

IR (film): 1740, 1720, 1600, 1585, 1275, 1115, 1075, 1025, 715/cm.

y) (13E)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-16,19-dimethyl-11, 15- bis-(tetrahydropyran-2- yloxy)- 13, 18- prostadic acid Analog with the preparation of the 153-isomer in section t) by reacting 2.96 g of the compound obtained in section x) with 2 6r5 ml of 2 N potassium hydroxide solution after column chromatography on silica gel with hexane/50-100% acetate as eluent obtained 2.22 g of the title compound.

IR (film): 3450, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1020, 810/cm.

z) (13E) - (8R, UR, 12R, 15S, 16RS) -9-oxo-16r 19-dimethyl-11, 15-bis-(tetrahydropyran-2-yloxy)-13, 18- prostadiic acid

360 mg of the alcohol obtained in the preceding reaction step was reacted analogously to the preparation of the corresponding 15£-isomer in u). 326 mg of the title compound were obtained.

IR (film): 2730, 2770, 1740, 1710, 1105, 1070, 1020, 810/cm.

(13E)-(8R,UR,12R,15S,16RS)-9-oxo-11,15-dihydroxy-16,19-dimethyl- 13, 18-prostadic acid

Analogous to the synthesis of the 150-isomer in v), by reacting 326 mg of the compound obtained in the preceding reaction step, the title compound according to example 1 (54 mg) was obtained.

IR (film): 3400, 2730, 2660, 1740, 1710, 1075, 975/cm.

Example 2

(13E)-(8R,11R,12R,15R)-11,15-dihydroxy-16,16,19-trimethyl- 9- oxo- 13, 18- prostadiic acid

a) 2, 2, 5-trimethyl-4-hexenesvre-ethvlester

A solution of 101.2 g of diisopropylamine in 125 ml

absolute tetrahydrofuran was added dropwise under argon at -20°C to 610 ml of a 1.64 N butyllithium solution in hexane. The temperature was briefly allowed to rise to 0°C, and then at -50 to -60°C 116 g of isobutyric acid ethyl ester was added dropwise to the lithium diisopropylamide solution. The reaction solution was stirred for 1 hour at 0°C, was then cooled again to -40°C and was then added to a solution of 200 g of 4-bromo-2-methyl-2-butene (dimethyl-allyl bromide) in 60 ml absolute dimethylsulfoxide cooled to -20°C. The temperature of the reaction mixture was allowed to rise to room temperature while the reaction mixture was stirred for 60 hours and then 250 ml of saturated sodium chloride solution was added. The organic phase was separated and the aqueous phase was extracted five times, each time with 200 ml of a 1/1 mixture of ether and hexane.

The combined organic phases were washed neutral with 0.5 N hydrochloric acid and saturated sodium chloride solution, were dried over magnesium sulfate and evaporated on a rotary evaporator. The residue was distilled in vacuo. 91.5 g of the desired ester KP^3 = 76 - 81°C were obtained.

IR (film): 1735, 1160, 1060, 820/cm.

b) 2.2. 5-trimethyl -4-hexeneHyrP-Tnpt.hyl ester

The preparation took place in the same way as for the preparation of the corresponding ethyl ester.

Kp13 = 72 - 74°C.

IR (film): 1735, 1160, 1050, 820/cm.

c) 2, 2, 5-trimethyl-4-hexenesvre

The preparation took place as above with iso-butyric acid as well as two equivalents of lithium diisopropylamide. Kp 0.2 - 0.4 = 94 - 100°C.

IR (film): 1705, 1220, 820/cm.

d) 2-(1,1,4-trimethyl-3-pentenyl)-2-oxoethane-phosphonic acid dimethyl ester

To a solution of 13 g of methanephosphonic acid dimethyl ester

in 160 ml of absolute tetrahydrofuran was added dropwise under argon at -60°C 49.5 ml of a 2.02 N butyllithium solution in hexane. After 15 minutes, a solution of 9.2 g of 2,2,5-trimethyl-4-hexenoic acid ethyl ester in 25 ml of absolute tetrahydrofuran was added dropwise. After 2 hours at -60°C, the reaction mixture was allowed to warm to room temperature over the course of 1 hour, 5.72 ml of glacial acetic acid was added and was then evaporated in vacuo. The residue, a white gel-like mass, was partitioned into a biphasic mixture of 35 ml of water and 165 ml of ether. The organic phase was dried over magnesium sulfate and evaporated on a rotary evaporator. After distilling off the volatile by-product at 60°C and 0.1 torr, the residue was purified by column chromatography on silica gel with hexane/50 - 100% acetate as eluent. 8.6 g of the title compound were obtained.

IR (film): 1705, 1260, 1030, 800/cm.

e) (IS,5R,6S,7R)-6-[(t-butyl-dimethylsilyloxy)-methyl]-7-benzoyloxy- 2- oxabicyclo-[ 3. 3. 0]- octan- 3- one

To a solution of 13.8 g of (IS,5R,6R,7R)-6-hydroxy-methyl'-7-benzoyloxy-2-oxabicyclo-[3.3.0]-octan-3-one in 30 ml of absolute dimethylformamide was added a solution of 9.9 g of dimethyl-t-butylchlorosilane in 40 ml of absolute dimethylformamide and 9.35 g of imidazole. After 2 hours of stirring at room temperature and under an argon atmosphere, an analytical thin layer chromatography showed complete conversion. The reaction mixture was diluted with 850 ml of ether, was washed with 60 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution and was then dried over magnesium sulfate. The evaporation residue can optionally be purified by column chromatography on silica gel with ether as eluent. 17.8 g of the title compound were obtained (m.p. = 74-75°C after crystallization from pentane/ether).

IR: 1775,. 1715, 1600, 1580, 1275, 1255, 840, 790, 720/cm.

f) (IS,5R,6S,7R)-6-[(t-butyl-dimethylsilyloxy)-methyl]-7- hydroxy- 2- oxabicyclo-[ 3. 3. 0]- octan- 3- one

A solution of 17.3 g of the benzoate obtained in the preceding reaction step in 200 ml of absolute methanol was stirred at room temperature together with 6.5 g of dry potassium carbonate. After 2 hours, analytical thin-layer chromatography showed complete conversion. At 0°C, 500 ml of 0.1 N hydrochloric acid was then added dropwise to the reaction mixture, which was stirred for 15 minutes at room temperature, evaporated in vacuo and extracted with acetic acid. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate.

The infiltration residue was purified by column chromatography

on silica gel with hexane/50-100% ether as eluent.

9.1 g of the desired compound were obtained (boiling point: 57-58.5°C),

IR (film): 1775, 1255, 840, 790/cm.

g) (IS,5R,6S,7R)-6-[(t-butyl-dimethylsilyloxy)-methyl]-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo-[3.3.0]-octan-3- Wed

A solution of 15.8 g of the alcohol obtained in the previous section in 300 ml of distilled methylene chloride was, together with 7.5 ml of dihydropropane, freshly distilled over potassium hydroxide, and 1.38 g of pyridine-p-toluenesulfonate stirred for 14 hours at room temperature. After evaporation of the reaction solution at room temperature, the residue was diluted with ether and washed with half-saturated sodium chloride solution. The organic solution was then dried over magnesium sulfate and evaporated to dryness. If necessary, the product can be purified by column chromatography on silica gel with hexane/20-50% ether as eluent. The yield was 20 g.

IR (film): 1775, 1255, 1115, 1080, 1035, 835, 775/cm.

h) (1S,3RS,5R,6S,7R)-3-hydroxy-6-[(t-butyl-dimethyl-silyloxy)-methyl]-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo- [ 3 .3.0] - octah

To a cooled to -70°C solution of 5.4 g of the lactone obtained in the preceding reaction step in 200 ml of absolute toluene, 20 ml of a 20% DIBAH solution in toluene was added dropwise under argon and over the course of 15 minutes. After 5 minutes of stirring, 1.2 ml of isopropanol was added dropwise at the same temperature until no further foaming took place. The reaction solution was allowed to warm to 0°C, 16 ml of water was added, stirred for 10 minutes and filtered over a frit. The precipitate was washed with vinegar. The organic phase was washed three times with saturated sodium chloride solution, dried over magnesium sulfate and evaporated on a rotary evaporator. The product obtained (5.41 g) was used without further purification in the subsequent reaction step.

i) (5Z) - (8R,9S,UR,12S)-9-hydroxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14,15,16,17,18, 19, 20-heptanor-5-prostenic acid

104.6 ml of a solution of methanesulfinylmethyl sodium

in absolute DMSO (prepared by dissolving 6 g of a 50% sodium hydride suspension in 120 ml of absolute dimethyl sulfoxide at a maximum of 70°C) was added dropwise at 15°C to a solution of 25.67 g of 4-carboxybutyl-triphenylphosphonium bromide

(previously dried at 70-80°C on an oil pump) in 80 ml of absolute dimethylsulfoxide. This ylene solution was stirred for 30 minutes at room temperature and was then added dropwise under water cooling to a solution of 5.41 g of the lactol obtained in the preceding reaction step in 50 ml of absolute dimethylsulfoxide over 15 minutes. The reaction mixture was then stirred for 4 hours at 35-40°C under argon. (If necessary, add 50-100 ml of absolute tetrahydrofuran to the reaction solution).

For work-up, the reaction mixture was poured onto ice/water, extracted three times with ether, the aqueous phase was acidified with a 10% citric acid solution to pH = 4 and extracted with a 1/1 mixture of ether/hexane. The reaction mixture was then shaken three times with methylene chloride. Due to the analytical thin layer chromatography, the methylene chloride phase was discarded, however, the other two organic phases were combined, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue was purified by column chromatography on silica gel with hexane/70-100% ether as eluent. 4.32 g of the carboxylic acid was obtained. IR (film): 3440 (broad), 3200-2500, 1725, 1700, 1250, 1100, 1020, 830, 770/cm.

j) (5Z)-(8R,9S,11R,12S)-9-hydroxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14,15,16,17,18, 19, 20- heptanor- 5-prostenic acid- methyl residues Production with diazomethane

The 4.32 g of carboxylic acid obtained according to i) was dissolved in 20 ml of methylene chloride and ethereal diazomethane solution was added until no further gas evolution took place and the yellow color of the solution remained constant. After driving off excess diazomethane under a water jet vacuum, the reaction solution was evaporated to dryness on a rotary evaporator. 4.3 g of the desired carboxylic acid methyl ester were obtained.

Production with iodomethane

To a solution of 32.5 g of the carboxylic acid obtained in

i) 75 ml of N-ethyldiisopropylamine and 150 ml of iodomethane in 200 ml of acetonitrile were added dropwise at room temperature to 450 ml of acetonitrile over the course of 2 hours. The mixture was stirred for 1 hour, and - after DC control - the precipitate was separated, washed with acetic acid, after which the organic phase was shaken out with sodium bisulphate, sodium hydrogencarbonate and sodium chloride solution. After drying over magnesium sulfate, the reaction mixture was evaporated to dryness on a rotary evaporator, and the residue was purified by column chromatography on silica gel with hexane/50-100% ether as eluent. 32.3 g of the title compound were obtained.

IR (film): 3420 (wide), 1740, 1255, 1120, 1030, 840, 780/cm.

k) (5Z)-(8R,9S,11R,12S)-9-benzoyloxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14, 15, 16, 17, 18, 19, 20-heptanor-5-prostenic acid methyl ester

To a solution of 4.7 g of the 9-hydroxy compound obtained in j) in 70 ml of pyridine, 2.32 ml of distilled benzoyl chloride was added dropwise while stirring at room temperature. After 2 hours of stirring under argon, 1.8 ml of water was added to the reaction solution, stirred for 1 hour and then evaporated at 30°C and 1 torr on an oil pump. The residue was taken up in a two-phase mixture of ether/water, was washed with sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. After column chromatography of the evaporation residue on silica gel with hexane/30-50% ethyl acetate as eluent, 5.11 g of the title compound was obtained as a colorless oil.

IR (film): 1745, 1720, 1605, 1590, 1280, 1260, 1120, 1030, 840, 780, 710/cm.

1) (8R, 9S,UR, 12S)-9-benzoyloxy-11-(tetrahydropyran-2-yloxy)-13-(t-butyl-dimethylsilyloxy)-14,15,16,17,18, 19, 20- heptanorprostanic acid methyl ester

A solution of 12.3 g of the unsaturated compound obtained in k) in 160 ml of acetic acid was added to 1.23 g of 10% palladium-carbon and was hydrogenated in a shaking apparatus at room temperature and at a slight hydrogen overpressure. After absorption of 640 ml of hydrogen, the solvent was removed in vacuo, the residue was taken up in 40 ml of ether, the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness on a rotary evaporator. 12.1 g of the title compound were obtained.

IR (film): 1740, 1720, 1600, 1580, 1275, 1255, 1115, 1070, 1025, 835, 780, 710/cm.

m) (8R,9S,11R,12S)-9-benzoyloxy-11-(tetrahydropyran-2-yloxy)-13-hydroxy-14,15,16,17,18,19,20-heptanor-prostanic acid nrethyl ester

To a solution of 6.94 g of the compound obtained in the preceding reaction step in 110 ml of absolute tetrahydrofuran, 16.11 ml of a 2 m tetrabutyl-ammonium fluoride solution in tetrahydrofuran was added under ice-cooling. After 12 hours of stirring under argon, the reaction mixture was diluted with 1.3 1 ether, washed neutral with saturated sodium chloride solution, after which the washing solution was extracted twice with ether.

The combined organic phases were dried over sodium sulfate

and evaporated in vacuo. The residue was purified by column chromatography on silica gel with acetic acid as eluent. 5.54 g of the desired compound were obtained as a colorless oil.

IR (film) in 3460 (wide), 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 710/cm.

n) (8R, 9S, UR, 12S) -9-benzoyloxy-13-oxo-U-(tetrahydro-pyran-2-yloxy)-14,15,16,17,18,19,20-heptanorprostanic acid eme t hy 1 e s ter

A solution of 5.54 g of the alcohol obtained in the previous step in 56 ml of absolute methylene chloride was added dropwise at 5-10°C over 20 minutes to a slurry of 18.7 g of Collins reagent in 170 ml of absolute methylene chloride. After stirring for 1 hour under argon, 500 ml of a 1/1 mixture of ether and pentane was added to the reaction mixture and was decanted. The flask was washed twice, each time with 500 ml of the above mixture. The combined organic phases were then shaken three times, each time with 50 ml of a 5% sodium carbonate solution, three times, each time with 50 ml of a 5% sulfuric acid solution and finally with saturated sodium chloride solution. After drying over magnesium sulfate, the product was evaporated to dryness and filtered over a silica gel column (50 g; eluent: ethyl acetate/hexane = 2/8). 4.6 g of the desired aldehyde were obtained.

IR (film): 2720, 1735, 1715, 1600, 1580, 1275, 1115, 1070, 1025, 715/cm.

o) (13E)-(8R,9S,11R,12R)-9-benzoyloxy-16,16,19-trimethyl-15-oxo-11-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

To a suspension of 0.74 g of 50% (suspended in oil) sodium hydride in 90 ral of dimethoxyethane freshly distilled over lithium aluminum hydride, under argon and at room temperature 4.05 g of the phosphonate obtained in example d) was dissolved in 45 ml of absolute dimethoxyethane added drop by drop. After adding 0.66 g of lithium chloride (previously dried for 2 hours at 50°C in a vacuum cabinet), the reaction mixture was stirred for 2 hours at room temperature. The suspension was then cooled to -20°C and 7.11 g of the aldehyde obtained in n), dissolved in 140 ml of absolute dimethoxyethane, was added dropwise. The temperature was then allowed to rise from -20 to 15°C over the course of 5 hours, after which the reaction solution was stirred for 19 hours at room temperature. At -10°C, 1.6 ml of glacial acetic acid as well as 100 ml of water were then added dropwise. The phases were separated, the aqueous phase was extracted five times with ether, the organic phases were combined and washed with 4% sodium bicarbonate and saturated sodium chloride solution. After drying over magnesium sulfate, the product was evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography on silica gel with hexane/150-100% acetate as eluent. 9.19 g of the title compound were obtained.

IR (film): 1740, 1720, 1695, 1670, 1625, 1600, 1580, 1270, 1105, 1060, 1030, 705/cm.

p) (13E)-(8Rr9S,11R,12R,15S)-9-benzoyloxy-16,16,19-trimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)-13,18-prostadlenic acid methyl ester

To a solution cooled to -40°C of 9.19 g of the ketone obtained in the previous step in 180 ml of absolute methanol, 3.68 g of sodium borohydride were added in portions. After 3.5 hours of stirring at -40°C, 7.9 ml of glacial acetic acid was added dropwise to the reaction solution at this temperature. After removal of the solvent on a rotary evaporator, the residue was added to methylene chloride/water, the separated water phase was added to solid sodium chloride and extracted twice with methylene chloride.

The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The isomer separation took place by several column chromatography on silica gel with hexane/20-40% acetate as eluent. 2.02 g of the title compound were obtained as non-polar product.

IR (film): 3400 (broad)., 1740, 1720, 1600, 1580., 1275, 1120, 1030, 1025, 710/cm.

q) (13E)-(8R,9S,UR, 12R,15S)-9-benzoyloxy-16,16,19-trimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

To a solution of 2 g of the alcohol obtained in p) in 60 ml of absolute methylene chloride was added 0.45 ml of dihydropyran at ice bath temperature (freshly distilled over potassium hydroxide) and 9 mg of p-toluenesulfonic acid, after which the mixture was stirred for 55 minutes at 0°C, whereupon the reaction solution, previously diluted with methylene chloride, was extracted with saturated sodium bicarbonate solution and water. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane = 1/2 as eluent. 2.12 g of the desired compound were obtained.

IR (film): 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1020, 715/cm.

r) (13E)-(8R,9S,11R,12R,15S)-9-hydroxy-16,16,19-trimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13,18-prostadioic acid

A solution of 2.12 g of the benzoate obtained in q) in 60 ml of methanol was added to 19 ml of 2 N potassium hydroxide solution and was stirred for 26 hours at room temperature. The reaction mixture was then evaporated on the rotary evaporator, the residue was taken up in a little water and extracted twice, each time with 150 ml of an ether/pentane mixture. The aqueous phase was acidified with citric acid to pH = 5, and extracted three times, each time with 150 ml of acetic acid. The combined organic phases were washed neutral with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as eluent. 1.43 g of the title compound were obtained.

IR (film)<*>. 3460, 2730, 2660, 1730, 1710, 1130, UIO, 1075, 1025, 810/cm.

s) (13E) — (8R,11R,12R,15S)-9-oxo-16,16,19-trlmethyl-11,15-bis-(tetrahydropyran-2- yloxy)-13, 18-prostadioic acid

To a solution cooled to -20°C of 500 mg of the alcohol obtained ir) in 10 ml of acetone was added 0.63 ml of Jones reagent, and the mixture was stirred for 45 minutes at this temperature. 0.8 ml isopropanol was then added, the reaction mixture was further stirred for 10 minutes, diluted with cold ether, washed three times with cold saturated sodium chloride solution, the organic phase was dried over magnesium sulfate and evaporated in vacuo. After filtration over a Sep-Pack finished column, 442 mg of product was obtained.

IR (film): 2730, 2660, 1740, 1710, 1105, 1070, 1025, 810/cm.

t) (13E)-(8R,11R,12R,15S)-11,15-dihydroxy-16,16,19-trimethyl- 9- oxo- T3, 18- prostadiic acid

442 mg of the product obtained above was stirred in

24 hours in 9 ml of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10) at room temperature. The reaction mixture was then evaporated at room temperature several times with benzene in oil pump vacuum. The residue was purified by column chromatography on silica gel with ethyl acetate/0-10% methanol as eluent. 124 mg of the title compound were obtained.

IR (film): 3420, 2730, 2670, 1740, 1710, 1075, 975/cm.

u) (13E)-(8R,9S,11R,12R,15R)-9-benzoyloxy-16,16,19-trimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

During sodium borohydride reduction of the ketone according to p), 2.02 g of Ø-alcohol and 0.7 g of a/p mixture and 4.28 g of the title compound were eluted as polar product.

IR (film): 3400 (wide), 1740, 1720, 1600, 1575, 1275,

1120, 1030, 1020, 710/cm.

v). (13E)-(8R,9S,UR,12R,15R)-9-benzoyloxy-16,16,19-trimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13,18-prostadic acid methyl ester

Analogously to the preparation of the 15-p-isomer in q), by reacting 4.28 g of the alcohol obtained in the previous reaction step with 0.96 ml of dihydropyran and 11 mg of p-toluenesulfonic acid (reaction time: 75 minutes) after column chromatography on silica gel with acetate/hexane = 1/3 as eluent, obtained 4.3 g of the title compound as a colorless oil,

IR (film): 1740, 1720, 1600, 1585, 1275, 1115, 1075, 1020, 715/cm.

w) (13E)-(8R,9S,UR,12R,15R)-9-hydroxy-16,16,19-trimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13,18-prostadioic acid

Analogous to the preparation of the 15|3-isomer in r), by reacting 4.3 g of the product from v) with 38.5 ml of 2 N potassium hydroxide solution after column chromatography on silica gel with hexane/50-100% acetate as eluent, 2 was obtained .8 g of the title compound.

IR (film): 3450, 2730, 2660, 1730, 1710, 1130, 1110, 1075, 1025, 810/cm.

x) (13E)-(8R,UR,12R,15R)-9-oxo-16,16,19-trimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-13, 18- prostadiic acid

500 mg of the alcohol obtained in the previous reaction step was reacted analogously to the preparation of the corresponding Ø-isomer in s). 410 mg of the title compound were obtained.

IR (film): 2730, 2770, 1740, 1710, 1110, 1075, 1020, 810/cm.

y) (13E) - (8R,UR,12R,15R) -11, IS-dihydroxy-ieuerig-tri-m^thylj^^ojco^l^U^proj^

Analogously to the synthesis of the 15fi-isomer in x), by reacting 410 mg of the compound obtained in the previous reaction step, 110 mg of the title compound was obtained.

IR (film): 3400, 2730, 2660, 1740, 1710, 1075, 975/cm.

Example 3

The tris-(hydroxymethyl)-aminomethane salt can be prepared analogously to example 40 in DE-OS 26 35 985: To a solution of 94.5 mg of the compound according to example 1 or 98 mg of the compound according to example 2 in 14 ml of acetonitrile at 60 oC added a solution of 32.9 mg of tris-(hydroxymethyl)-aminomethane in 0.1 ml of water, and the mixture was allowed to stand for 14 hours at room temperature. Dividend: 63.5 or 68.5 mg.

Example 4

An injection solution was prepared from:

0.5 mg (13E)-(8R,11R,12R,15S,16RS)-1^1S-dihydroxy-ie^-dimethyl^-oxo-1S, 18-prostadienic acid

8.9 mg NaCl

1.212 mg trometamol

0.01 ml of ethanol (96%) and

1 ml water for injection.

Claims (4)

1 • (13E) - (8R, UR, 12R) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienic acids, characterized by the formula wherein R represents hydrogen or methyl, or their physiologically acceptable salts with bases. 2. Prostadic acid according to claim 1, characterized in that this is (13E)-(8R,UR,12R,15S,16RS)-11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadic acid. 3. Prostadic acid according to claim 1, characterized in that this is (13E)-(8R,UR,12R,15R)-11,15-dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadic acid. 4. Contraceptives, characterized in that they contain as active ingredient a compound according to claims 1-3.