FI71308C - ANALOGIFICATION OF THERAPEUTIC FREQUENCY OF THERAPEUTIC ANALYSIS (13E) - (8R, 11R, 12R) -11,15-DIHYDROXI-16,19-DIMETHYL-9-OXO-13,18-PROSTADIENSYRADERIVAT OCH AV DERAS - Google Patents

Description

71308

Analogous process for the preparation of therapeutically useful (13E) - (8R, 11R, 12R) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid derivatives and their salts

The invention relates to an analogous process for the preparation of therapeutically useful (13E) - (8R, HR, 12R) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid derivatives of formula 10.

O

<? 3 R CH

3, 3 OH OH CH 3 wherein R is hydrogen or methyl, and their physiologically acceptable base salts.

German application 26 35 985 sets out requirements for prostanoic acid derivatives of general formula I

25 s <XIi R (1) 4> B— - ^ <30 x \ R3 Xr5 where R ^ is -CR ^ or -C-OR „, wherein R ^ is„ 6 / '' p 9 6 35 O R7 8 a hydroxyl group, a straight or branched C 1-4 alkoxy group, a substituted or unsubstituted aryloxy group, a 2 71308 OC 1 -UV group in which U is a direct bond or a carbonyl or carbonyloxy group and V represents one or more phenyl groups, C 1-4 A 2-alkoxy group or a halogen atom, preferably a bromine atom, a substituted phenyl-5 ring or an -NHR 4 g group denoting an alkyl or aryl group or an organic carbon or sulfonic acid having 1 to 15 carbon atoms / acid residues, R 1 and R 8 represents hydrogen atoms or C 1-6 alkyl groups, and R 8 is either an acidic residue of an organic carbonic or sulfonic acid having 1 to 15 carbon atoms or an inorganic acid, or it is

-C-NHR ^ q group, wherein Re has the meaning given above, O

A represents either a cis- or trans-CH = CH group, B represents a trans-CH = CH- group, a -C = C group or a -CH-CH group, wherein the methylene group may be «- <- or \ : h2 at the f * position, W represents a free or functionally positioned hydroxymethylene group, a free or functionally located carbonyl or R 1 -C-

OH

a group in which R 1 represents a hydrogen atom or an alkyl group having 1 to 5 C atoms, and the OH group may be in the 25 o <or / '' position or may be functionally substituted, Z represents a carbonyl or a hydroxymethylene group which may be placed freely or functionally, Χ.Λ.Υ is -CH -CH- or -CH -C-,

“I“ M

R102 when Z is a free or functionally located hydroxymethylene group, or -CH -CH- or -CH = CH- when Z is Z | R12 is a free or functionally located carbonyl group, wherein R12 represents a hydrogen atom or a methyl or cyanide group or a free or functionally placed hydroxy group, 3 71 308 represents a hydrogen atom or an alkyl group, represents a hydrogen atom or an alkyl group, R 1 = R 2. represents a methyl group or R1 represents a chlorine atom, while R1 represents a methyl group or R1. represents a chlorine atom when it represents a methyl group, and in the case where R 1 represents a hydroxy group, the physiologically acceptable salts formed with their bases.

These known compounds have valuable therapeutic properties, which are manifested in particular by the fact that, when administered once in utero, they can cause menstruation or terminate pregnancy. Furthermore, they are suitable for synchronizing the pedigree in female mammals, such as monkeys, cattle, pigs and sheep. The prostaglandin derivatives according to DE-A-2635985 have a strong astringent effect on the uterus as well as a luteolytic effect, i. lower doses are required to induce abortion than with similar natural prostaglandins.

20 In the case of prostaglandins, the desired main effects are usually followed by undesirable side effects that substantially reduce the quality of the main effect.

It has now surprisingly been found that of the compounds covered by the requirements of DE-A-26 35 985, the compounds (13E) - (8R, 11R, 12R, 15S, 16RS) -11.15-dihydroxy-16,19-dimethyl-9- oxo-13,18-prostadienoic acid and (13E) - (8R, 11R, 12R, 15R) -11,15-dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadienoic acid as drugs that can be used to reduce the dosage many times over commercial preparations ("Sulproston") (the compounds according to the invention have 10-100 times the potency compared to the compounds known from DE application 26 35 985), in which case, of course, undesired side effects are even more strongly reduced. (13E) - (18R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid and (13E) - (8R, HR, 12R, 15R) ) -11,15-dihydroxy-16,16,19-71308 trimethyl-9-oxo-13,18-prostadienoic acid is not mentioned by name in DE-A-26 35 985. Compounds in which A is -CK the preparation is not described in In DE, only the preparation of compounds where A is cis-CH = CH- is described.

The process according to the invention is characterized in that (8R, 9S, 11R, 12S) -9-benzoyloxy-13-oxo-11- (tetrahydropyran-2-yloxy) -14,15,16,17,18,19,20 -heptanor-prostanoic acid methyl ester is reacted with 2- (1,4-10 dimethyl-3-pentenyl) -2-oxoethanephosphonic acid dimethyl ester or 2- (1,1,4-trimethyl-3-pentenyl) -2-oxoethanephosphonic acid dimethyl ester, and then 1-5 keto groups are reduced and protected with dihydropyran, after release the 9-hydroxy group is oxidized, the existing protecting groups are removed and the compound is optionally converted into a physiologically acceptable salt.

The preparation of 2- (1,4-dimethyl-3-pentenyl) -2-oxoethanephosphonic acid dimethyl ester and 2- (1,1,4-trimethyl-3-pentenyl) -2-oxoethanephosphonic acid dimethyl ester is carried out according to methods known per se, such as DE- is described in application publication 26 35 985.

Salt formation includes all inorganic and organic bases known in the art for the preparation of physiologically acceptable salts.

For example, alkali hydroxides such as e.g.

sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia and amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine and tris- (hydroxymethyl) methylamine.

Reaction of (8R, 9S, 11R, 12S) -9-benzoyloxy-13-oxo-11- (tetrahydropyran-2-yloxy) -14,15,16,17,18,19,20-heptanor-prostanoic acid methyl ester 2 With - (1,4-dimethyl-3-pentenyl) -2-oxoethanephosphonic acid dimethyl ester or 2- (1,1,4-trimethyl-3-pentynyl) -2-oxoethanephosphonic acid dimethyl ester can be carried out in a manner known per se at 0-100 ° C , preferably at 20-80 ° C, in an aprotic solvent such as dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, chloroform, methylene chloride or dimethoxyethane.

The oxidation of the 5-hydroxy group is carried out by methods known per se using conventional oxidizing agents. For example, oxidation can be performed, e.g., with Jones reagent by silylation / Chem. Comm. (1972) 11207 / while the 11- and 15-hydroxy groups are intermediate protected.

The release of the functionally located hydroxy groups is carried out by known methods. The cleavage of the hydroxy-protecting groups, such as, for example, tetrahydropyranyl groups, is carried out in an aqueous solution of an organic acid, such as, for example, oxalic, acetic or propionic acid, or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid. To improve solubility, some water-miscible organic solvent is added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, ethers, such as dimethoxyethane, dioxane and tetrahydrofuran, and acetone. Tetrahydrofuran is mainly used. The cleavage is preferably performed at a temperature of 20-80 ° C.

The saponification of the acyl groups is carried out, for example, with alkali or alkaline earth metal carbonates or hydroxides in an alcohol or in an aqueous solution of an alcohol. Suitable alcohols are aliphatic alcohols, such as, for example, methanol, ethanol and butanol, preferably methanol. As the alkali metal carbonates and hydroxides, mention may be made of the potassium and sodium salts, with potassium salts being preferred. Suitable alkaline earth metal lycarbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is carried out at -10 to + 70 ° C, preferably at + 25 ° C.

(13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-35 dimethyl-9-oxo-13,18-prostadienoic acid and (13E) - (8R, 11R, 12R, 15R) -11,15-Dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadienoic acid can be converted to salts by neutralizing 6 71308 with appropriate amounts of the corresponding inorganic bases. For example, a solid inorganic salt is obtained by dissolving the PG acid in water containing a stoichiometric amount of the base, evaporating the water or adding a water-miscible solvent, e.g. alcohol or acetone.

To prepare the amine salt, which is carried out in a conventional manner, the PG acid is dissolved in e.g. a suitable solvent, e.g. ethanol, acetone, diethyl ether or benzene, and at least a stoichiometric amount of amine is added to this solution. In this case, the salt usually precipitates in solid form, or is isolated after evaporation of the solvent in a conventional manner.

The good dissociation of the substance according to the invention is evident when studying its effect on other smooth muscle organs, such as, for example, the guinea pig's ileum or the isolated trachea of a rabbit, where substantially less stimulation is observed than through natural prostaglandins.

The active ingredient according to the invention shows an bronchodilator effect in vitro in an isolated rabbit trachea and strongly inhibits gastric acid secretion and has a protective effect on cells in the stomach and regulates cardiac arrhythmias. The new compound further lowers blood pressure and has a diuretic effect.

The effect of the compounds according to the invention (compounds 1 and 2) on the pregnancy of the guinea pigs was compared with the corresponding effect of the compounds (compounds 3-6) known from DE-A-26 35 985. In the experiment, guinea pigs were administered the test compound subcutaneously on days 43 and 44 of gestation, and on day 50 of gestation, the animals were sacrificed and their uteri examined. The results obtained are shown in the following table.

7 71 308

Table

Compound Dose Miscarriage ___ (mg / d) _

Compounds of the invention: 1) (13E) - (8R, HR, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid 0.01 3/3 2) ( 13E) - (8R, HR, 12R, 15R) -11,15-dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadienoic acid_0.01_3 / 3_ Reference compounds according to DE application 26 35 985: 3 ) (5Z, 13E) -8R, 11R, 12R, 15R) -9-oxo-11,15-dihydroxy-19-methyl-5,13,18-prostatrienoic acid methyl ester (Example 4) 10/3 15 4) (5Z, 13E) - (8R, 11R, 12R, 15S) -9-oxo-11,15-dihydroxy-16,16,19-trimethyl-5,13,18-prostatrienoic acid ethylsulfamide (Example 32) 1 1/3; 3/3 + 0.1 2/3; 3/3 + 0.03 1/3; 1/3 +

20 0.01 0/3 A

5) (5Z, 10Z, 13E) - (8R, 12R, 15S) -15-hydroxy-9-oxo-19-roethyl-5,10,13,18-prostatetraenoic acid (Example 5) 1 0/3 6) (5Z, 10Z, 13E) - (8R, 12R, 15S) -15-Hydroxy-9-oxo-16,16-19-trimethyl-5,10,13,18-25 prostatetraenoic acid methylsulfamide (methylsulfamide of Example 31) ) _1_0 / 3_

As can be seen from the table, the compounds of the invention are still effective at a dose of 0.01 mg, with all three guinea pigs in the experimental group having a miscarriage. In control compounds 3, 5 and 6, none of the guinea pigs in the experimental group had a miscarriage at 100 times the dose (1 mg). Compound 4 is very toxic; at a dose of 0.1 mg, all three experimental animals died, but only two of them had a miscarriage.

For medical use, the active agent may be formulated for inhalation, oral or parenteral administration.

For inhalation, aerosol or spray solutions are conveniently prepared.

71308

Tablets, granules or capsules are suitable, for example, for oral administration.

For parenteral administration, sterile injectable aqueous or oleaginous solutions are employed.

The active compounds according to the invention are to be used with galenical, known and conventional excipients, for example in preparations used for induction of abortion, regulation of circulation or preparation for childbirth.

For this purpose, sterile aqueous solutions containing 0.0001 to 10 .mu.g / ml of active compound can be used as an intravenous injection solution. Acids and their salts are particularly suitable for the preparation of isotonic aqueous solutions. Alcohols such as ethanol and propylene glycol may be added to control solubility. Furthermore, läa-15 swabs can be easily prepared for intravaginal administration.

Example 1 (13E) - (8R, 11R, 12R, 15S, 16RS) -11,15-Dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadienoic acid

20 C00H

/ ί CIS

ÖH i. CH3

OH

25 a) 2-Ethoxycarbonyl-2,5-dimethyl-4-hexene-acid ethyl ester

A three-necked flask equipped with a reflux condenser, dropping funnel and stirrer was charged with 36.16 g of sodium (broken into small pieces). To this was added dropwise 800 ml of absolute ethanol so rapidly that the solution was left to boil vigorously. 269.6 g of freshly distilled methyl malonic acid diethyl ester were added dropwise to the hot alcoholate solution, stirred | hours at 60 ° C, 35 and then 241.7 g of dimethyl allyl bromide were added dropwise in the same manner. After stirring under heating for 1 hour, the precipitated sodium 71308 bromide was removed by filtration, the precipitate was washed and the filtrate was concentrated by evaporation. The residue was taken up in ether, washed neutral with saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The evaporation residue was fractionated with an oil lamp.

266 g of the title compound of 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) were refluxed for 4 hours with 181 g of potassium hydroxide in 235 ml of water in 450 ml. ethanol. The ethanol was then evaporated on a rotary evaporator, the residue was dissolved in 235 ml of water, and the pH was adjusted to 1 with concentrated hydrochloric acid under ice-cooling. The precipitate-15 nucleus (m.p. 162-166 ° C) was collected, washed with water and air for further purification was used for the next step.

IR (KBr) 1700, 1230, 340 / cm.

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

The dicarboxylic acid obtained in the previous reaction step was kept in a distillation apparatus for 4 hours at normal pressure, then for one hour at 75 torr at 210 ° C. The product was then vacuum distilled. 68 g of the title compound were obtained (b.p. = 98-106 ° C; bp = 67-70 ° C).

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

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

The carboxylic acid (68 g) obtained according to the above procedure was treated by adding ethereal diazomethane solution until no more nitrogen evolved upon addition of the reagent and the reaction mixture was removed.

the yellow color of the solution remained. The solvent was then removed in vacuo and the residue was fractionated. 62.3 g of material with a mp = 32-35 ° C were obtained

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

10 71 308 e) 2,5-Dimethyl-4-hexenoic acid ethyl ester 85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester were dissolved in 645 ml of dimethyl sulfoxide and successively added 29.7 g of g of lithium-5 chloride and 6.3 ml of distilled water. The reaction mixture was then heated for a total of 13 hours at 200 ° C, and then, after being allowed to cool, poured into 1 liter of ice water. The aqueous fraction was extracted three times with 500 ml portions of methylene chloride. The combined organic fractions were then washed twice with water, dried over magnesium sulfate, concentrated by rotary evaporation and distilled in vacuo. 53.1 g of material with mp = 3 = 75-78 ° C were 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 a 1.61 M solution of butyllithium in hexane. After stirring for 15 minutes, 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 allowed to warm to room temperature over 4 hours and then stirred for an additional 3 hours. 26.5 ml of glacial acetic acid were then added and the mixture was concentrated by evaporation in vacuo. The residue was taken up in ether / water, the aqueous fraction treated with solid sodium chloride and the ether removed. The combined organic fractions were dried over magnesium sulfate and concentrated by rotary evaporation. The evaporation residue was purified by column chromatography on silica gel using hexane / 50-100% ethyl acetate as the solvent. 32 g of the desired compound were obtained.

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

11 7130 8 g) (1S, 5R, 6S, 7R) -6 - [(tert-butyl-dimethyl-silyloxy) -methyl] -7-benzoyloxy-2-oxabicyclo [3.3.1] [7 octane-3- one

To a solution of 13.8 g of (1S, 5R, 6R, 7R) -6-5 hydroxymethyl-7-benzoyloxy-2-oxabicyclo [3.3.3] octan-3-one in 30 ml of absolute dimethylformamide was added a solution. , containing 9.9 g of dimethyl-tert-butyl-chlorosilane in 40 ml of absolute dimethylformamide, and 9.35 g of imidazole. After stirring for 2 hours at room temperature under argon, analytical thin layer chromatography indicated that the reaction was complete. The reaction mixture was diluted with 850 ml of ether, washed with about 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 using ether as solvent. (Crystallization from pentane / ether gives a substance with a melting point = 74-75 ° C.

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

h) (1S, 5R, 6S, 7R) -6-Z (tert-butyldimethylsilyloxy) -methyl 1 ± 7, 7-hydroxy-2-oxabicyclo [3.3.0] octane 3-one 25 A solution of 17.3 g of the benzoate obtained in the previous reaction step in 200 ml of absolute methanol was stirred at room temperature under argon together with 6.5 g of dry potassium carbonate.

After 2 hours, analytical thin layer chromatography indicated that the reaction was complete. At about 0 ° C, 500 ml of 0.1 N hydrochloric acid was added dropwise to the reaction mixture, stirred for 15 minutes at room temperature, concentrated by evaporation in vacuo and extracted with ethyl acetate. The organic fraction was washed with saturated sodium chloride-35 solution and dried over magnesium sulfate.

71308

The evaporation residue was purified by column chromatography on silica gel using hexane / 50-100% ether as solvent. 9.1 g of the desired compound were obtained (melting point: 57-58.5 ° C).

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

i) (15,5R, 6S, 7R) -6-Z] Tert-butyl-dimethylsilyloxy) methyl-7- [7- (tetrahydropyran-2-yloxy) -2-osabicyclo [3.3.3] octane -3-one

A solution of 15.8 g of the alcohol obtained according to step 10 above in 300 ml of distilled methylene chloride was mixed with 7.5 ml of freshly distilled dihydropropane over potassium hydroxide and 1.38 g of pyridine p-toluenesulfonate for 14 hours. time at room temperature. After concentration by evaporation at room temperature, the mixture was diluted with ether and washed with half-saturated sodium chloride solution. The organic solution was then dried over magnesium sulfate, and then concentrated to dryness by evaporation. Optionally, the product can be purified by column chromatography on silica gel using hexane / 20-50% ether as solvent. The yield increased to 20 g.

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

j) (1S, 3RS, 5R, 6S, 7R) -3-Hydroxy-6 - [(tert-butyl-dimethylsilyloxy) -methyl] -7- (tetrahydropyran-2-yloxy) -2- ok sa1i cyclo / 3.3.07 octane to a solution cooled to -70 ° C of 5.4 g of lactone-30 obtained in the previous reaction step and 200 ml of absolute toluene was added dropwise under argon over 15 minutes. ml of a 20% DIBAH solution prepared in toluene. After stirring for about five minutes, 1.2 ml of isopropanol was added dropwise at the same temperature until no more foaming occurred. The reaction solution 71308 was allowed to warm to 0 ° C, 16 ml of water was added, stirred for 10 minutes and filtered through a sinter. The precipitate was washed with ethyl acetate. The organic fraction was washed three times with saturated sodium chloride-5 solution, dried over magnesium sulfate and concentrated by rotary evaporation. The obtained product (5.41 g) was used without further purification in the next reaction step.

k) (5Z) - (8R, 9S, 11R, 12S) -9-hydroxy-11- (tetra-10-hydropyran-2-yloxy) -13- (tert-butyl-dimethyl-silyloxy) -14, 15,16,17,18,19,20-heptanor-5-prostenoic acid 104.6 ml of a solution of methanesulfinylmethyl sodium in absolute DMSO (prepared by dissolving 6 g of a 50% suspension of sodium hydride in 120 ml of absolute dimethyl sulphoxide up to At 70 ° C) was added dropwise at 15 ° C to a solution of 25.67 g of 4-carboxybutyl-triphenylphosphonium bromide (pre-dried at 70-80 ° C by means of an oil pump) in 80 ml of absolute dimethyl sulfoxide. This "generalized" solution (Ylenlösung) was stirred for 30 minutes at room temperature and then added dropwise over one minute using water-cooling to a solution of 5.41 g of the lactols obtained in the previous reaction step in 50 ml of absolute dimethyl sulfoxide. The reaction mixture was then stirred for 4 hours at 35-40 ° C under argon. (Optionally add 50-100 ml of absolute tetrahydrofuran to the reaction solution). To complete the work, the reaction mixture was poured onto ice / water, extracted three times with ether, partitioned with water with 10% citric acid solution, and extracted three times with 1/1 ether / hexane. It was then shaken three more times with methylene chloride. Based on analytical thin layer chromatography, the methylene chloride fraction was discarded, the other two organic fractions were purified, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by column chromatography on silica gel using hexane / 70-100% ether as solvent.

4.32 g of carboxylic acid were obtained.

IR (film): 3440 (broad), 3200-2500, 1725, 1700, 1250, 1100, 1020, S30, 770 / cm.

1) (5Z) -18R, 9S, HR, 12S) -9-hydroxy-11-tetrahydropyran-2-yloxy) -13- (tert-butyldimethylsilyloxy) -14,15,16, 17,18,19,20-Heptanor-5-prostenoic acid methyl ester Preparation with diazomethane: 4.32 g of the carboxylic acid obtained in k) were dissolved in 20 ml of methylene chloride and treated with ethereal diazomethane solution until no more gas formation and solution occurred. the color remained. After the excess diazo-20 methane was removed by water jet vacuum, the reaction solution was concentrated to dryness on a rotary evaporator. 4.3 g of the desired carboxylic acid methyl esters were obtained.

Preparation with iodomethane:

To a solution of 32.5 g of the carboxylic acid obtained in k) in 450 ml of acetonitrile were added dropwise at room temperature 75 ml of N-ethyl-diisopropylamine and 150 ml of iodomethane in 200 ml of acetonitrile over two hours. The solution was stirred for 1 hour, then after TLC control, the precipitate was filtered off with suction, washed with ethyl acetate, and the organic fraction was shaken successively with sodium bisulfate, sodium hydrogen carbonate and sodium chloride solutions. After drying over magnesium sulfate, it was concentrated to dryness on a rotary evaporator, and the residue was purified by column chromatography on silica gel using hexane / 50-100% ether as solvent. 32.3 g of the title compound were obtained.

IR (film): 3420 (broad), 1740, 1255, 1120, 1030, 840, 5780 / cm.

m) (5Z) - (8R, 9S, HR, 12S) -9-benzoyloxy-11- (tetrahydropyran-2-yloxy) -13- (tert-butyldimethylsilyloxy) -14,15,16,17 , 18,19,20-heptanor-5-prostenoic acid methyl ester To a solution of 4.7 g of the 9-hydroxy compound obtained in 1) in 70 ml of pyridine was added dropwise at room temperature, with stirring, 2.32 ml. distilled benzoyl chloride. After stirring for 2 hours under an argon atmosphere, 1.8 ml of water was added to the reaction solution, stirred for a further hour, and then concentrated with an oil pump at 30 ° C and 1 torr. The residue was taken up in binary ether / water, washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. After column chromatography of the evaporation residue on silica gel with hexane / 30-50% ethyl acetate as solvent, 5.11 g of the title compound were obtained as a colorless oil.

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

n) (8R, 9S, HR, 12S) -9-benzoyloxy-11- (tetrahydropyran-2-yloxy) -13- (tert-butyldimethylsilyloxy) -14,15,16,17, 18,19,20-Heptanorprostanoic acid methyl ester To a solution of 12.3 g of the unsaturated compound obtained in m) in 160 ml of ethyl acetate was added 1.23 g of 10% palladium on carbon and hydrogenated on a shaker at room temperature. at low hydrogen overpressure. After 640 ml of hydrogen were removed, the solvent was removed in vacuo, the residue was taken up in 40 ml of ether, the organic fraction was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness on a rotary evaporator to give 12.1 g of the title compound. IR (film): 1740, 1720, 1600, 1580, 1275, 1255, 1115, 1070, 1025, 835, 780, 710 / cm.

o) (8R, 9S, HR, 12S) -9-benzoyloxy-11- (tetrahydropyran-2-yloxy) -13-hydroxy-14,15,16,10,17,18,19,20-heptanorprostanoic 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 was added 16.11 ml of a 2 molar solution of tetrabutylammonium fluoride in tetrahydrofuran under ice-cooling. After stirring under argon for 12 hours, the reaction mixture was diluted with 1.3 L of ether, washed neutral with saturated sodium chloride-20 solution, and the washings were extracted twice with ether. The combined organic fractions were dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate as solvent. 5.54 g of the desired compound were obtained as a colorless oil.

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

p) (8R, 9S, HR, 12S) -9-benzoyloxy-13-oxo-11- (tetrahydropyran-2-yloxy) -14,15,16,17,18,30,19,20-heptanorprostanoic acid methyl ester

A solution of 5.54 g of the alcohol obtained as described above in 56 ml of absolute methylene chloride was added dropwise at 5-10 ° C over 20 minutes to a suspension of 18.7 g of Collins reagent in 35,170 ml. absolute methylene chloride. After stirring for 1 hour under an argon atmosphere, the reaction mixture was diluted with 500 ml of a 1/1 mixture of ether and pentane. The flasks were washed twice more with 500 ml of the above mixture. The combined organic fractions were then shaken three times with 50 ml of 5% sodium carbonate solution, three times with 50 ml of 5% sulfuric acid, and then washed neutral with saturated sodium chloride solution. After drying over magnesium sulphate, they were concentrated to dryness and the residue was filtered through silica gel (50 g; solvent: ethyl acetate / hexane = 2/8). 4.6 g of the desired aldehyde were obtained.

IR (film): 2720, 1735, 1715, 1600, 1580, 1275, 1115, 1570, 1025, 715 / cm.

q) (13E) - (8R, 9S, HR, 12R, 16RS) -9-benzoyloxy-16,19-dimethyl-15-oxo-11- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid methyl ester 20 To a solution of 0.48 g of 50% sodium hydride (suspended in oil) in 60 ml of fresh dimethoxyethane distilled over lithium aluminum hydride was added dropwise under argon at room temperature 2.48 g of the phosphonate obtained according to Example f), which was dissolved in 25 tu in 30 ml of absolute dimethoxyethane. After adding 0.43 g of lithium chloride (previously dried in a vacuum oven at 50 ° C for 2 hours), the reaction mixture was stirred for 2 hours at room temperature. The suspension was then cooled to -20 ° C, and 4.61 g of the aldehyde obtained in p) dissolved in 90 ml of absolute dimethoxyethane were added dropwise. The temperature was then allowed to rise from -20 ° C to 0 ° C within 5 hours and further to 5 ° C within 1.5 hours to stir the reaction solution at room temperature for a further three hours. At -10 ° C, 1 ml of glacial acetic acid and about 100 ml of water were then added dropwise. The fractions were separated, the aqueous fraction was extracted five times with ether, the organic fractions were combined and washed with 4% sodium bicarbonate and saturated sodium chloride solution. After drying over magnesium sulfate, it was concentrated to dryness on a rotary evaporator. The residue was purified by column chromatography on silica gel 10 using ethyl acetate / hexane = 1/1 as the solvent. 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, HR, 12R, 15R, 16RS) -9-benzoyl-15-oxy-16,19-dimethyl-15-hydroxy-11- (tetrahydropyran-2-yloxy) -13 , 18-prostadienoic acid methyl ester A solution of 5.78 g of the ketone obtained in the previous reaction in 115 ml of 20% absolute methanol, cooled to -40 ° C, was added portionwise to 2.37 g of sodium borohydride. After stirring at -40 ° C for 1 hour, 5.09 ml of glacial acetic acid was added to the reaction solution, also at this temperature. After the solvent was removed on a rotary evaporator, methylene chloride / water was added to the residue, solid sodium chloride was added to the separated aqueous fraction, and it was extracted twice with methylene chloride. The combined organic fractions were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. Separation of the isomers was performed by repeating the column chromatography several times using silica gel and hexane / 20-100% ethyl acetate as solvent. 2.11 g of the title compound were isolated as a non-polar product.

13 71 308 IR (film): 3400 (broad), 1740, 1720, 1600, 1580, 1275, 1120, 1030, 1020, 710 / cm.

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

To a solution of 2.11 g of the alcohol obtained in r) in 60 ml of absolute methylene chloride was added 0.49 ml of dihydropyran (fresh, distilled over 10 potassium hydroxide) and 9.7 mg of p-toluenesulfonic acid, stirred 55 ml. for 1 minute at 0 ° C, and then the reaction solution previously diluted with methylene chloride was extracted with saturated sodium hydrogencarbonate solution and water. The organic fraction was dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue was purified by column chromatography over silica gel using ethyl acetate / hexane = 1/2 as the solvent. 2.3 g of the desired compound were obtained. IR (film); 1740, 1720, 1605, 1585, 1275, 1115, 1080, 2025, 715 / cm.

t) (13E) - (8R, 9S, 11R, 12R, 15R, 16RS) -9-hydroxy-16,19-dimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid

To a solution of 2.3 g of the benzoate obtained in s) in 70 ml of methanol was added 20.6 ml of 2N potassium hydroxide solution, and it was stirred at room temperature for 31 hours. The reaction mixture was then concentrated on a rotary evaporator, the residue taken up in a small amount of water and extracted twice with 150 ml of ether / pentane. The aqueous fraction was adjusted to pH 5 with citric acid and extracted three times with 150 ml of ethyl acetate. The combined organic fractions were washed neutral with brine, dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel using hexane / 50-100% ethyl acetate as solvent. 1.62 g of the title compound were obtained.

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

u) (13E) - (18R, HR, 12R, 15R, 16RS) -9-oxo-16,19-dimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid - To a solution of 360 mg of the alcohol obtained in 10 (t) in 7 ml of acetone cooled to 20 ° C was added 0.46 ml of Jones reagent and stirred at this temperature for 45 minutes. 0.6 ml of isopropanol were then added, the mixture was further stirred for 10 minutes, diluted with cold ether, washed three times with cold, saturated sodium chloride solution, the organic fraction was washed with magnesium sulphate and concentrated by evaporation in vacuo. Filtration through a "Sep-Pack-Fertig" column gave 327 mg of material.

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

v) (13E) - (8R, HR, 12R, 15R, 16RS) -9-oxo-11,15-dihydroxy-16,19-dimethyl-13,18-prostadienoic acid 25 327 mg obtained according to the instructions above , was stirred for 26 hours at room temperature in 7 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10). It was then concentrated by evaporation several times with benzene in a vacuum provided by an oil pump. The residue was purified by column chromatography over silica gel using ethyl acetate / 0-10% methanol as solvent. 68 mg of the title compound were obtained.

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

35 71308 21 w) (13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -9-benzoyloxy-16,19-dimethyl-15-hydroxy-11- (tetrahydropyran-2-yloxy) -13,18-Prostadienoic acid methyl ester By reduction of the ketone obtained in r) with sodium borohydride, 2.11 g of β-alcohol and 2.27 g of <* / A mixture were eluted from the column along with 0.27 g of the title compound. as a polar product.

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

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

In accordance with the description of the 15 ~ A isomer given in the instruction according to s); 2.96 g of the title compound were obtained as a colorless oil by reacting 2.67 g of the alcohol prepared in the previous reaction step with 0.62 ml of dihydropyran and 12.3 mg of p-toluenesulfonic acid (reaction time: 75 minutes, followed by column chromatography on silica gel using ethyl acetate / hexane = 1/3 as solvent.

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-prostadienoic acid 30 Consistent with the description of the 15/9 isomer given in step t), 2.22 g of the title compound were obtained by reacting 2.96 g of the compound of Example x) with 26.5 ml of 2N potassium hydroxide solution, which followed by column chromatography on silica gel using 71308 hexane / 50-100% ethyl acetate as solvent.

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

z) (13E) - (8R, HR, 12R, 15S, 16RS) -9-oxo-16,19-5 dimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid 360 mg of the alcohol obtained in the previous reaction step reacted in accordance with the description of the corresponding 15β-isomers given in the instructions described in u) -10. 326 mg of the title compound were obtained.

IR (film): 2730, 2670, 1740, 1710, 1105, 1070, 1020, 810 / cm.

y) (13E) - (8R, 11R, 12R, 15S, 16RS) -9-oxo-11,15-di-15-hydroxy-16,19-dimethyl-13,18-prostadienoic acid

Consistent with the synthesis of the 15 is-isomer shown in step v), the title compound of Example 1) (54 mg) was prepared by reacting 326 mg of the compound obtained in the previous reaction step.

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

Example 2 (13E) - (8R, HR, 12R, 15R) -11,15-dihydroxy-16,16,19-25 trimethyl-9-oxo-13,18-prostadienoic acid o 71308 23 cooh OH OH 3 5 a) 2,2,5-trimethyl-4-hekseenihappoetyyliesteri

To a solution of diisopropylamine (101.2 g) in 125 ml of abs. tetrahydrofuran was added dropwise under argon at -20 ° C 610 ml of a 1.64 N solution of butyllithium in hexane.

The temperature was allowed to rise for some time to about 0 ° C, then 116 g of isobutyric acid ethyl ester was added dropwise to the lithium diisopropylamide solution at -50 ° to -60 ° C. The reaction solution was stirred for 1 hour at 0 ° C, then the solution was cooled to -40 ° C and added to a solution of 4-bromo-2-methyl-2-butene (dimethylallyl] bromide, 200 g) in 60 ml of abs. dimethyl sulfoxide, keeping the temperature of the solution at -20 ° C during the addition. The temperature was allowed to rise to room temperature, and the reaction mixture was stirred for 60 hours, then 250 ml of saturated sodium chloride solution was added to the mixture. The organic phase was separated and the aqueous phase was extracted with a 1: 1 mixture of ether and hexane (5 x 200 mL). The combined organic phases were washed with 0.5N hydrochloric acid and neutral saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness on a rotary evaporator. The residue was distilled in vacuo to give 91.5 g of the desired ester, b.p. = 76-81 ° C / 13 torr.

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

b) 2,2,5-Trimethyl-4-hexenoic acid methyl ester The compound was synthesized in the same manner as the corresponding ethyl ester above. Kp. = 72-74 ° C / 13 torr.

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

71 308 24 c) 2,2,5-trimethyl-4-hexenoic acid

The preparation was carried out as described above using isobutyric acid and 2 equivalents of lithium diisopropylamide as starting materials. Kp. = 94-100 ° C / 0.2-0.4 torr.

Δ IR (film): 1705, 1220, 820 / cm.

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

To a solution of methanephosphonic acid dimethyl ester (13 g) in 160 ml of abs. tetrahydrofuran was added dropwise under argon at -60 ° C to 49.5 ml of a 2.02-n-butyllithium hexane solution. After 15 minutes, 9.2 g of 2,2,5-trimethyl-4-hexenoic acid ethyl ester in 25 ml of abs. tetrahydrofuran. After standing for 2 hours at -60 ° C, the reaction mixture was allowed to warm to room temperature over 15 hours, 5.72 ml of glacial acetic acid were added and the mixture was evaporated to dryness in vacuo. The residual white gelatinous mass was treated with a two-phase mixture of water (35 ml) and ether (165 ml). The organic phase was dried over magnesium sulfate and evaporated on a rotary evaporator.

The volatile by-products were distilled off at 60 ° C / 0.1 torr, and the residue was purified by silica gel column chromatography eluting with hexane / ethyl acetate (50-100%). 8.6 g of the title compound were obtained.

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

e) (1S, 5R, 6S, 7R) -6- (tert-butyldimethylsilyloxy) methyl] -7-benzoyloxy-2-oxa-bicyclo [3.3.1] octan-3-one (IS, 5R, To a solution of 6R, 7R) -6-hydroxymethyl-7-benzoyloxy-3S-2-oxabicyclo [3.3.3.1 3, CT / octan-3-one (13.8 g) in 30 ml of abs. dimethylformamide was added to a solution of dimethyl tert-butylchlorosilane (9.9 g) in 40 ml of abs. dimethylformamide and 9.35 g of imidazole.

After stirring for 2 hours at room temperature under 35 argon, thin layer chromatography analysis indicated that the reaction was complete. The reaction mixture was diluted with 850 ml of ether, washed with about 60 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. The evaporation residue can be purified by chromatography on a silica gel column eluting with ether. 17.8 g of the title compound were obtained (m.p. 84-75 ° C, crystallization from pentane / ether).

IR: 1775, 1715, 1600, 1580, 1275, 1255, 840, 790, 720 / cm. 10 f) (IS, 5R, 6S, 7R) -6- / J! tert-butyldimethylsilyloxy) methyl / -7-hydroxy-2-oxabicyclo [3.3.1] octan-3-one

A solution of the benzoate (17.3 g) obtained in the previous reaction step in 200 ml of abs. methanol was stirred at room temperature under argon with anhydrous potassium carbonate (6.5 g). After 2 hours, thin layer chromatography indicated that the reaction was complete. 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 20 room temperature, the mixture was evaporated to dryness in vacuo, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The evaporation residue was purified by chromatography on a silica gel column 25 eluting with hexane / ether (50-100%). 9.1 g of the expected compound are obtained, m.p. 57 to 58.5 ° C.

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

g) (1S, 5R, 6S, 7R) -6- (tert-Butyldimethylsilyloxy) methyl-7- [7- (tetrahydropyran-2-yloxy) -30 2-oxabicyclo [1,3,3] octan-3-one

A solution of the alcohol obtained in the previous reaction step (15.8 g) in 300 ml of distilled methylene chloride was stirred for 14 hours at room temperature with freshly distilled (distillation Κ0Η) dihydropropane (7.5 ml) and pyrrolidine-p-toluenesulfonate (1.38 g). The reaction solution 26 71 308 was evaporated at room temperature, diluted with ether and washed with brine The organic solution was dried over magnesium sulphate and evaporated to dryness. The yield was 20 g.

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

h) (1S, 3RS, 5R, 6S, 7R) -3-Hydroxy-6-7 "(tert-butyl-dimethylsilyloxy) methyl-7- 7- (tetrahydropyran-2-yloxy) -2-oxabicyclo] -3 .3, <3 / octane To a cooled solution of the lactone (5.4 g) obtained in the previous reaction step in -70 ° C in 200 ml of absolute toluene was added dropwise, under argon, 15 ml of 20% DIBAH solution over 15 minutes. Stirring was continued for about 5 minutes, then 1.2 ml of isopropanol was added dropwise at the same temperature until foaming ceased, the reaction solution was allowed to warm to 0 [deg.] C., 16 ml of water were added, the mixture was stirred for 10 minutes and filtered through sintered glass. The precipitate was washed with ethyl acetate The organic phase was washed three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated on a rotary evaporator to give the product (5.41 g) which was used without further purification in the next reaction step.

i) (5Z) - (8R, 9S, 11R, 12S) -9-hydroxy-11- (tetrahydropyran-2-yloxy) -13- (tert-butyldimethylsilyloxy) -14,15,16,17, 18,19,20-hepta-nor-5-prostenic acid

Methanesulfinylmethyl sodium solution (104.6 ml) abs. In 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), 4-35 carboxybutyltriphenylphosphonium bromide (25.67 g) (pre-dried at 70-80 ° C in an oil pump vacuum) was added dropwise - 27 71 308 sa) in a solution in 80 ml of dimethyl sulfoxide. This general solution was stirred for 30 minutes at room temperature, then added dropwise over 15 minutes to a solution of the lacto-5 (5.41 g) obtained in the previous reaction step in 50 ml of abs. dimethyl sulfoxide while cooling with water. The reaction mixture was then stirred at 35-40 ° C under argon for 4 hours (optionally 50-100 ml of abs. Tetrahydrofuran is added to the reaction mixture). The reaction mixture was poured into ice water, extracted 3 times with ether, the aqueous phase was acidified to pH 4 with 10% citric acid and extracted with ether / hexane 1: 1. The aqueous phase was then shaken 3 more times with methylene chloride. Based on TLC analysis, the methylene chloride phase was discarded, the other 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 eluting with hexane / ether-20 (70-100%). 4.32 g of carboxylic acid were obtained. IR (film): 3440 (broad), 3200-2500, 1725, 1700, 1250, 1100, 1020, 830, 770 / cm.

j) (5Z) - (8R, 9S, HR, 12S) -9-hydroxy-11- (tetrahydropyran-2-yloxy) -13- (tert-butyldimethyl-25yloxy) -14,15,16,17 , 18,19,20-heptanor-5-pro Steen Acid Methyl Preparation Using diazomethane:

The carboxylic acid obtained in step i) (4.32 g) was dissolved in 20 ml of methylene chloride, and an ethereal solution of diazomethane was added to the solution 30 until gas evolution ceased and the solution was permanently yellow. Excess diazomethane was evaporated in a water pump vacuum and the reaction solution was evaporated to dryness on a rotary evaporator. 4.3 g of the desired carboxylic acid-35-style ester were obtained.

20 71308

Manufacture from iodomethane:

To a solution of the carboxylic acid obtained in step i) (32.5 g) in 450 ml of acetonitrile was added dropwise over 2 hours at room temperature 75 ml of N-ethyldiisopropylamine and 150 ml of iodomethane in 200 ml of acetonitrile. After stirring for 1 hour and control by thin layer chromatography, the precipitate was filtered, washed with ethyl acetate, and the organic phase was shaken successively with sodium bisulfate solution, sodium hydrogen carbonate solution and sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated to dryness on a rotary evaporator, the residue was purified by column chromatography on silica gel eluting with hexane / ether (50-100%). 32.3 g of the title compound were obtained.

IR (film): 3240 (broad), 1740, 1255, 1120, 1030, 840, 780 / cm.

k) (5Z) - (8R, 9S, 11R, 12S) -9-benzoyloxy-11- (tetrahydropyran-2-yloxy) -13- (tert-butyl-20-dimethylsilyloxy) -14,15,16,17,18 , 19,20-heptanor-5-prostenoic acid methyl ester To a solution of the 9-hydroxy compound obtained in step j) (4.7 g) in 70 ml of pyridine was added dropwise at room temperature 2.32 ml of freshly distilled benzoyl chloride.

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

29 71 30 8 IR (film): 1745, 1720, 1605, 1590, 1280, 1260, 1120, 1030, 840, 780, 710 / cm.

l) (8R, 9S, HR, 12S) -9-benzoyloxy-11- (tetrahydropyran-2-yloxy) -13- (tert-butyldimethylsilyloxy) -14,15,16,17,18,19 , 20-heptanostrostanoic acid methyl ester To a solution of the unsaturated compound obtained in step k) (12.3 g) in 160 ml of ethyl acetate was added 1.23 g of 10% Pd / C catalyst, and the mixture was hydrogenated on a shaker at room temperature under low pressure. under hydrogen overpressure. After uptake of 640 ml of hydrogen, the solvent was evaporated in vacuo, 40 ml of ether were added to the residue, the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate 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, HR, 12S) -9-benzoyloxy-11- (tetrahydropyran-2-yloxy) -13-hydroxy-14,15,16,17,18,19,20-heptanorprostanoic acid methyl ester to a solution of the compound obtained in the reaction step (6.94 g) in 110 ml of abs. tetrahydrofuran was added under ice-cooling to 16.11 ml of a tetrahydrofuran solution of 2-m tetrabutyl-ammonium fluoride. After stirring for 12 hours under argon, the reaction mixture was diluted with 1.3 liters of ether, washed neutral with saturated sodium chloride solution, and the washings were extracted with ether. The combined organic phases were dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate. 5.54 g of the desired compound were obtained as a colorless oil.

IR (film): 3460 (broad), 1735, 1715, 1600, 1580, 35 1275, 1115, 1070, 1025, 710 / cm.

30 7 1 3 0 8 n) (8R, 9S, HR, 12S) -9-benzoyloxy-13-oxo-11- (tetrahydropyran-2-yloxy) -14,15,16,17,18,19,20 -heptanorprostaanihappometyyliesteri

A solution of the alcohol (5.54 g) obtained in the previous step in 56 ml of abs. methylene chloride was added dropwise at 5-10 ° C over 20 minutes to a suspension of Collins reagent (18.7 g) in 170 ml of abs. of methylene chloride. After stirring for 1 hour under argon, 500 ml of a 1: 1 ether / pentane mixture was added to the reaction mixture, and the reaction mixture was decanted. The reaction vessel was washed twice more with 500 ml of the same solvent mixture. The combined organic phases were then shaken with 5% sodium carbonate solution (3 x 50 ml) and 5% sulfuric acid (3 x 50 ml) and the solution was finally washed with neutral saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. . The residue was filtered through a silica gel column (50 g, solvent: 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-prostadienoic acid methyl ester 25 A suspension of a 50% sodium hydride oil suspension (0.74 g) in 90 ml of dimethoxyethane (freshly distilled with lithium aluminum hydride) was added dropwise under argon at room temperature a solution of the phosphonate (4.05 g) obtained in step 45) in 45 ml of abs. dimethoxyethane. Then, 0.66 g of lithium chloride (pre-dried for 2 hours under vacuum at 50 ° C) was added and the reaction mixture was stirred at room temperature for 2 hours. The suspension was cooled to -20 ° C and 7.11 g of the aldehyde obtained in step n) dissolved in 140 ml of 35 abs were added dropwise. dimethoxyethane. The temperature was allowed to rise from -20 ° C to 15 ° C over 5 hours, and the reaction mixture was stirred for a further 19 hours at room temperature. At -10 ° C, 1.6 ml of glacial acetic acid and about 100 ml of water were then added dropwise. The phases were separated and the aqueous phase was extracted 5 times with ether, the combined organic phases were washed with 4% sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography eluting with hexane / ethyl ester 10 (150-100%). 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) - (8R, 9S, HR, 12R, 15S) -9-benzoyloxy-16,16,19-trimethyl-15-hydroxy-11- (tetra-15 hydropyran-2-yloxy) -13.18 -prostadienoic acid methyl ester

To a solution of the ketone (9.19 g) obtained in the previous reaction step cooled to -4 ° C in 180 ml of abs. methanol was added portionwise to 3.68 g of sodium borohydride. After stirring for 3.5 hours at -40 ° C, 7.9 ml of glacial acetic acid were added dropwise to the mixture at the same temperature. The solvent was evaporated on a rotary evaporator, methylene chloride and water were added to the residue, solid sodium chloride was added to the separated aqueous phase, and the aqueous phase was extracted twice with methylene chloride. The combined methylene chloride extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. Separation of the isomers was performed by multiple chromatography on a silica gel column eluting with hexane / ethyl acetate (20-40%). The title compound (2.02 g) was isolated as a non-polar product.

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

(71E) - (8R, 9S, HR, 12R, 15S) -9-benzoyloxy-16β-16,19-trimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid methyl ester

To a solution of the alcohol (2 g) obtained in p) in 60 ml of abs. methylene chloride was added in an ice bath temperature to 0.45 ml of dihydropyran (freshly distilled with KOH) and 9 mg of p-toluenesulfonic acid, the mixture was stirred for 55 minutes at 0 ° C, then the mixture was diluted with methylene chloride and extracted with saturated sodium hydrogen carbonate and water. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / hexane (1: 2). 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, HR, 12R, 15S) -9-hydroxy-16,16,19-trimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18-prostadienoic acid 20 To a solution of the benzoate obtained in step q) (2.12 g) in 60 ml of methanol was added 19 ml of 2N KOH solution, and the mixture was stirred for 26 hours at room temperature. The reaction mixture was evaporated to dryness on a rotary evaporator, a small amount of water was added to the residue, and the mixture was extracted with ether / pentane (2 x 150 ml). The aqueous phase was acidified (pH = 5) with citric acid and extracted with ethyl acetate (3 x 150 mL). 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 chromatography on a silica gel column eluting with hexane / ethyl acetate (50-100%). 1.43 g of the title compound were obtained.

IR (film): 3460, 2730, 2660, 1730, 1710, 1130, 1110, 35 1075, 1025, 810 / cm.

33 71 308 s) (13E) - (8R, HR, 12R, 15S) -9-oxo-16,16,19-trimethyl-11,15-bis- (tetrahydropyran-2-yloxy) - 13.18 -prostadieenihappo

To a cooled solution of the alcohol obtained in r) (500 mg) at -20 ° C in 10 ml of acetone was added 0.63 ml of Jones reagent, and the mixture was stirred at the same temperature for 45 minutes. 0.8 ml of isopropanol was then added to the mixture, stirring was continued for a further 10 minutes, the mixture was diluted with cold ether, washed 3 times with cold saturated sodium chloride solution, the organic phase was dried over magnesium sulphate and filtered on a Sep-Pack column to give 442 mg the title compound.

IR (film): 2730, 2660, 1740, 1710, 1105, 1070, 1025, 1510 / cm.

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

The compound obtained above (442 mg) was stirred in glacial acetic acid / water / tetrahydrofuran (66:35:10) -20 (9 ml) for 24 hours at room temperature. The mixture was then evaporated to dryness with benzene several times at room temperature under oil pump vacuum. The residue was chromatographed on a silica gel column eluting with ethyl acetate / methanol (0-10%). 124 mg of the title compound were obtained.

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

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

After reduction of the ketone with sodium borohydride in step p), 4.28 g of the title compound eluted from the column along with a mixture of N-alcohol (2.02 g) and 4.

IR (film): 3400 (broad), 1740, 1720, 1600, 17575, 1275, 1120, 1030, 1020, 710 / cm.

34 71308 v) (13E) - (8R, 9S, 11R, 12R, 15R) -9-benzoyloxy-16,16,19-trimethyl-11,15-bis- (tetrahydropyran-2-yloxy) -13,18- prostadienoic acid methyl ester 5 In analogy to the preparation of the 15β-isomer in step q), the reaction obtained in the previous step between the alcohol (4.28 g) and dihydropyran (0.96 ml) and p-toluenesulfonic acid (11 mg) was obtained (reaction time 75 minutes). ) the title compound. Purification by column chromatography on silica gel eluting with ethyl acetate / hexane 1: 3 gave 4.3 g of the title compound as a colorless oil.

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

15 w) (13E) - (8R, 9S, 11R, 12R, 15R) -9-hydroxy-16,16,19-trimethyl-11,15-bis (tetrahydropyran-2-yloxy) -13,18- prostadienoic acid In analogy to the preparation of the 15/3 isomer in step r), the compound obtained in step v) (4.3 g) was reacted with 2N KOH solution (38.5 ml) and chromatographed on a silica gel column eluting with hexane / ethyl acetate ( 50-100%) mixtures of 2.8 g of the title compound.

IR (film): 3450, 2730, 2660, 1730, 1710, 1130, 1110, 2575, 1025, 810 / cm.

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

The alcohol (30 mg) obtained in the above reaction step (500 mg) was reacted analogously to the reaction of the corresponding 15β-isomer shown in s). 410 mg of the title compound were obtained.

IR (film): 2730, 2670, 1740, 1710, 1110, 1075, 1020, 810 / cm.

35 35 71 308 y) (13E) - (8R, 11R, 12R, 15R) -11,15-dihydroxy-16,16,19-trimethyl-9-oxo-13,18-prostadienoic acid

In analogy to the synthesis of the 15β-isomer 5 described in x), the title compound (110 mg) was obtained from the compound obtained in the previous reaction step.

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

Preparation of Trls (hydroxymethyl) aminomethane salt 10 a) To a solution of the compound of Example 1 (94.5 mg) in 14 ml of acetonitrile at 60 ° C was added a solution of tris (hydroxymethylmethane (32.9 mg) in 0.1 ml of water. After standing for 14 hours at room temperature, 63.5 mg of the tris (hydroxymethyl) aminomethane-15 salt of the compound of Example 1 were obtained.

b) To a solution of the compound of Example 2 (98 mg) in 14 ml of acetonitrile at 60 ° C was added a solution of tris (hydroxymethyl) aminomethane (32.9 mg) in 0.1 ml of water.

After standing for 14 hours at room temperature, 68.5 mg of the tris (hydroxymethyl) aminomethane salt of Example 2 were obtained.

Preparation Example (Solution for Injection) (13E) - (8R, HR, 12R, 15S, 16RS) -11,15-dihydroxy-16,19-dimethyl-9-oxo-13,18-prostadiene-25 acid 0.5 mg sodium chloride 8.9 mg

Trometamol 1.212 mg

Ethanol (96%) 0.01 ml

Water (for injection) ad 1 ml 30

Claims (1)

An analogous process for the preparation of therapeutically useful (13E) - (8R, 11R, 12R) -11,15-dihydroxy-16,19-dimethyl-9-5 oxo-13,18-prostadienoic acid derivatives of formula O 10. ch3 r ch3 - £ XCH. ° H OH 3 wherein R is hydrogen or methyl, and for the preparation of their physiologically acceptable base salts, characterized in that (8R, 9S, 11R, 12S) -9-benzoyloxy-13-oxo-11- (tetrahydropyran-2-yloxy) ) -14,15,16,17,18,19,20-heptanor-prostanoic acid methyl ester is reacted with 2- (1,4-dimethyl-3-pentenyl) -2-oxoethanephosphonic acid 20-dimethyl ester or 2- (1,1,4 with trimethyl-3-pentenyl) -2-oxoethanephosphonic acid dimethyl ester and then the 15-keto group is reduced and protected with dihydropyran, after release the 9-hydroxy group is oxidized, the existing straight groups are removed and the compound is optionally converted into a physiologically acceptable salt.