DE1175232B - Process for the production of 6ª ‡ -Methyl-17ª ‡ -hydroxyprogesterone and its esters - Google Patents

Description

Process for the preparation of 6a-methyl-17a-hydroxyprogesterone as well of its esters. The present invention relates to a method of preparation of new steroid compounds with high progestative potency, which both are superior to that of progesterone for oral as well as parenteral use.

According to the invention, compounds of general formula CH3 CO O CH3 prepared, wherein R represents a hydrogen atom or an acyl radical which is derived from an aliphatic or cycloaliphatic carboxylic acid and contains no more than 9 carbon atoms, for example a formyl, acetyl, propionyl, butyryl, valeryl, capronyl, enanthyl , Caprylic, cyclopentylpropionyl or cyclohexylacetyl radical.

Special compounds which are produced according to the invention are 6a-methyl-17a-hydroxyprogesterone, 6a-methyl-17a-hydroxyprogesterone-acetate, 6a-methyl-17a-hydroxyprogesterone caproate, 6a-methyl-17a-hydroxyprogesterone-onanthate and 6a - methyl -17a - hydroxyprogesterone - cyclopentyl propionate.

The process according to the invention for the preparation of 6a-methyl-17a-hydroxyprogesterone and its esters can be represented by the following scheme: R = hydrogen or an acyl radical which is derived from an aliphatic or cycloaliphatic carboxylic acid and does not contain more than 9 carbon atoms.

According to the invention, 15-pregnen-3i3,17u-diol-20-one-ethylene glycol ketal is first used (I) dissolved in an organic solvent and with an organic peracid epoxidized in 5,6-position. A mixture of α- and ß-epoxides is obtained, from which the more levorotatory 5a, 6a-epoxy (1I) is obtained by crystallization will.

By reacting the 5a, 6 (t-epoxide (I1) with methyl magnesium iodide and subsequent hydrolysis of the 29-ketal group with hot dilute acetic acid the 6ü-methyl-allopregnan 311,5a, 17a-triol-20-one (11I) was obtained.

The latter gives 6f-methyl-allopregnan-5a, 17a-diol-3,20-dione by oxidation with chromic acid (IV). By treating (IV) with strong alkalis, dehydration occurs with formation of a 4 (5) double bond and simultaneous isomerization of the 6f-methyl group to the 6 "methyl group. It thus becomes the compound 6a-methyl-17u-hydroxyprogesterone (V; R = hydrogen) obtained.

The 6a-ethyl-] 7u-hydroxyprogesterone gives on treatment with aliphatic or cycloaliphatic acid chlorides or anhydrides with no more than 9 carbon atoms in the presence of p-toluenesulfonic acid or in an inert solvent, which contains p-tolentiol sulfonic acid, and subsequent treatment with dilute mineral acids, in order to selectively hydrolyze any 3-enol acylate formed, the corresponding 17-ester (V; R = acyl radical). The measures carried out according to the invention are for known.

The starting product for the process according to the invention, namely the IS-Pregnen-3j3,17 (z-diol-20-oneethylene glycol-k # -tal, can be prepared according to the method of U.S. Patent 2,648,663 (Glidden Co.) to P_ L. Julia, E. W. Meyer, and I. Ryden (C.A., 48, p.7650 [1954]).

The conversion of (I) into (I1) can be carried out in a customary manner by treating the ketal (I) at O -C with an organic peracid in solution in a solvent which is resistant to the peracid. be performed. Suitable peracids are, for example, peracetic acid, perbenzoic acid or perphthalic acid. Chloroform, ethyl acetate or chlorobenzene or mixtures thereof can be used as solvents. After washing until the organic solution has been neutralized and the solvent has been evaporated off, a mixture of a- and; -5,6-epoxides can be obtained directly, in which the 5, z, 6a-form predominates over the 5 @, 6i,> -forin. The 5a, 6a-epoxide is separated from this mixture by crystallization from acetone, ethyl ether, benzene and / or other suitable solvents.

The conversion of the epoxide (11) into the 6β-methyl-5α-hydroxy derivative (III) can be obtained by treatment with an excess of methylinagnesium iodide and subsequent treatment Hydrolysis with hot, dilute acetic acid in a manner also known per se be performed. The reaction with methyl magnesium iodide is preferred at Room temperature in benzene or in other aliphatic or aromatic hydrocarbons carried out and is completed within 4 to 8 hours. Because the protective ketal group is very stable and after the attempted isolation of the reaction products the Grignard reaction can be partially split off, it has been found that it is convenient to wash the crude reaction products with dilute boiling aqueous acetic acid to treat in concentrations of 50 to 9011/0 so as to protect the ketal group completely and keep the connection (I11). The oxidation of the 3-hydroxyl group the compound (III) to diol diketone (IV) is usually converted using chromic acid carried out as an oxidizing agent and by acetic acid; it can also be a mixture of acetic acid and ethylene dichloride as solvents or a mixture of chromic acid, Sulfuric acid and water in acetone can be used, preferably with a Temperature is worked, which is not above 0 "C; the Dioldiketone (IV) is preferably by extraction with an organic solvent and then Crystallization isolated from acetone.

The dehydration of the compound (IV) and the simultaneous isomerization of the 6f-methyl group is carried out by treatment with an inorganic base, for example finite potassium hydroxide in methanol solution. 6u-methyl-17, t-hydroxyprogesterone (V; R - hydrogen) is carried out directly from the solution after neutralizing the potassium hydroxide with acids and concentrating it to a small volume.

The esterification of the 17, s-hydroxyl group of (V; R = hydrogen can in a known manner by treatment with an aliphatic or cycloaliphatic Acid chloride or acid anhydride which does not contain more than 9 carbon atoms contains. in the presence of p-toluenesulfonic "iure with or without the use of an inert Solvents such as benzene or toluene at a temperature from b0 to 125` C. That The crude reaction product is then treated with dilute sulfuric acid in Metli @ inol treated at the boiling point for 1 to 2 hours. to thereby any enol acylate formed to hydrolyze. After extraction with a solvent, evaporation and crystallization, are the esters of 6, t-methyl-17u-hydroxyprogestei on, which is a high progestative Effectiveness to be maintained.

The high progestative effectiveness of those producible according to the invention Compounds recommends their clinical use in the following diseases: Primary Amenorrhea, functional dysmenorrhea, hypo - oligomenorrhea, sterility, hemorrhages through follicular persistence, menorrhagia, metrorrhagia, habitual abortion, more threatening Abortion and for anti-ovulatory effect.

The following examples explain the process according to the invention 5 (, t, 6a-epoxy-allopregnan-3 @, 17a-diol-20-one-20-ethylene glycol-keta1 (I1) a) To a solution of 3 g of 5-pregnen-3 @ 3,17a-diol-20-one-20-ethylene glycol ketal (I) in 500 ml of pure chloroform, which had been cooled to 0 C, 32 ml of a perbenzoic acid solution, which contained 52.8 g; ml of peracid, while added over a period of 10 minutes. The solution was kept at 0 ° C. for 6 hours, then transferred into a separating funnel, washed with water, then with sodium carbonate solution and finally again with water until neutral. The residue (3.1 g) was recrystallized from ether after evaporation of the solvent. This gave 2.1 g of needles which melt at 244 to 245 ° C; [a], = -59 '(c = 1.17111o in dioxane). Analysis for C2.3H3605: Calculated ... C 70.37, H 9.24; Found ... C 70.18, H 9.32. b) A solution of 5 g of 5-pregnen-3β, 17a-diol-20-one-20-ethylene glycol ketal (1) in 800 ml of chloroform was cooled to -10 ° C., then with 15 ml of a 3.5 molar peracetic acid solution was added and finally allowed to stand for 7 hours at a temperature below O 'C. It was then poured into 1 l of water containing 5% sodium bisulfate and 50.10% sodium carbonate, and the chloroform extract was washed until it was neutral. By recrystallizing the residue from benzene, 2.1 g of needles with a melting point of 238 to 245 ° C. were obtained.

c) 6ß-methyl-allopregnan-3ß, 5a, 17a-triol-20-one (11I) 61 ml of methyl iodide and 400 ml of anhydrous ether were gradually added to 22 g of magnesium turnings. The mixture was refluxed for 1 hour while passing a stream of nitrogen through it. 400 ml of benzene were then added and the solvent was completely evaporated, always under a stream of dry nitrogen. A hot solution of 8 g of 5a, 6a-epoxyallopregnan - 3i3,17a - diol - 20 - an - 20 - ethylene glycol ketal (Ii) in 800 ml was added to the resulting Grignard reagent, which was cooled in a salt and ice bath Benzene was added fairly quickly to avoid crystallization of the substance during the addition of the solution. The mixture was stirred for 4 hours and then left to stand overnight. 1 kg of ice-cold water containing 10 g of NfliCl were then added, and the mixture was stirred for a further hour. The benzene extracts were made with dilute hydrochloric acid. then washed with 4% sodium bicarbonate solution and finally with water until neutral. The yellow oily residue remaining after evaporation of the solvent was dissolved in 100 ml of aqueous 80% acetic acid and stirred for 2 hours at 100 ° C. The reaction product was extracted with methylene chloride, washed with sodium carbonate solution and water until the reaction was neutral, and the solvent was evaporated off The residue was recrystallized from acetone, giving 2.1 g of 6fl-methyl-allopregnan-3β, 5a, 17a-triol-20-one (III) in the form of needles with a melting point of 237 to 238 ° C; a], = '--8 ° (c = 1% in dioxane) Analysis for C22H3604: Calculated ... C72.49, H 9.96; found ... C 72, 121, H 10.31. d ) 6ß-Methyl-allopregnan-5a, 17a-diol-3,20-dione (IV) To a solution of 1.5 g of 6ß-methyl-allopregnan-3ß, 5a, 17a-triol-20-one (III) in 300 ml of acetone, which was kept at −1 ° C., were added with stirring to 3.5 ml of a solution of chromic acid in dilute sulfuric acid, This solution was concentrated by dissolving 226 g of chromic acid in 400 ml of water and 230 ml rter sulfuric acid and subsequent dilution with water to 1 liter. The solution was left to stand at 0 ° C. for 7 hours and then extracted with methylene chloride. The extract was washed with sodium bisulfate and then with sodium bicarbonate until neutral and the solvent was evaporated. The residue was recrystallized from acetone. There were needles of 6β-methylallopregnan-5a, 17a-diol-3,20-dione (IV). obtained with a melting point of 265 to 267 ° C. e) 6a-methyl-17a-hydroxyprogesterone (V; R = hydrogen) 0.5 g of 6ß-methyl-allopregnan-5a, 17a-diol-3,20-dione (IV) were suspended in 300 ml of methanol. A solution of 1 g of potassium hydroxide in 10 ml of water and 50 ml of methanol was added to this suspension at room temperature. The mixture was left to stand under nitrogen at room temperature for 20 hours and stirred from time to time. The solution was then neutralized with acetic acid and the methanol was almost completely evaporated. The residue was extracted with methylene chloride; the organic extract was washed with water and the solvent was evaporated.

The residue was recrystallized from methanol. This gave 0.250 g of 6a-methyl-17a-hydroxyprogesterone (V, R = hydrogen) needles with a melting point of 234 to 235 ° C .; [a] p = 4-70 ° (c = 1% in dioxane), 1.-242 = 15,000. Analysis for C22H3203: Calculated ... C 76.70, H 9.36; found ... C76.61, H9.55. f) 6a-methyl-17a-hydroxyprogesterone acetate (V; R = COCH3) 0.500 g of 6a-methyl-17a-hydroxyprogesterone were heated for 30 minutes on a steam bath with 5 ml of acetic anhydride and 15 mg of p-toluenesulfonic acid hydrate. The solution was kept at room temperature for 4 hours and then concentrated in vacuo. After adding ice, the mixture was left to stand for 30 minutes and then extracted three times with ethyl acetate. The extract was washed with 100% sodium bicarbonate solution and then with water. After the solvent had been distilled off, the residue was refluxed for 1 hour with 330 ml of methanol, 4.2 ml of water and 2.1 ml of sulfuric acid to saponify any 3-enol acetate present. The solution was concentrated, diluted with water and extracted with ethyl acetate. The extract was washed with water until neutral and the solvent was evaporated. The residue was recrystallized from petroleum ether. 0.38 g of 6-α-methyl-17a-hydroxyprogesterone acetate (V; R = COCH3) with a melting point of 197 ° to 199 ° C. were obtained in this way; em = 13,900.

g) 6a-methyl-17a-hydroxyprogesterone caproate (V; R = CO (CH2) 4CH3) 0.500 g of 6a-methyl-17a-hydroxyprogesterone were placed in a flask containing 20 ml of anhydrous toluene, 1 g of caproic anhydride and 20 mg of p -Toluenesulfonic acid hydrate contained. The mixture was heated to H0 ° C. with stirring and then left to stand at room temperature for 48 hours. I ml of pyridine and 5 ml of water were then added. The mixture was stirred for 1 hour and then poured into water and extracted with toluene. The toluene solution was separated off, washed with sodium carbonate solution and then with water, dried over sodium sulfate and evaporated. The residue was dissolved in 300 ml of methanol containing 2 ml of sulfuric acid and 6 ml of water and refluxed for 2 hours. The solution was neutralized with sodium bicarbonate and, after partial evaporation of the solvent, extracted with benzene. The benzene extract was washed with water and the solvent evaporated. The residue was purified by chromatography. It consisted of oily 6a-methyl-17a-hydroxyprogesterone caproate (V; R = CO (CH2) 4CH3); M.p. 105 ° C, [R] δ = + 45 ° C, (c = 1 in chloroform). h) 6a-methyl-17a-hydroxyprogesterone enanthate (V; R = CO (CH2) sCH3) 6a-methyl-17a-hydroxyprogesterone (V; R = hydrogen) became the 17-unanthate (V; R = CO (CH2) sCH3 ) in the same way as described under g) for the corresponding caproate, converted, using instead of caproic anhydride clnanthic anhydride; 01; [a] δ = + 50 ° (c = I in chloroform).

i) 6a-methyl-17a-hydroxyprogesterone-cyclopentylpropionate The esterification of 6a-methyl-17a-hydroxyprogesterone (V; R = hydrogen) with cyclopentylpropionic anhydride was carried out in the same way as was described under g) for the caproic anhydride; 135 ° C .; [a] δ = + 44 ° (c = 1 in chloroform). Pharmacological activity The progestative efficacy was determined in infantile rabbits weighing less than 1000 g. These were first subjected to a test with estradiol according to M c P hai 1 (J. Physiol., 83, p. 145 [1934]). The activity with respect to the endometric carbonyl hydrase was carried out according to the test according to Lutwa M ann and A dams (J. End., 15, p.43 [1947]).

The results are given in the table below. Steroid application good dose proliferation endometrial marriage method index carbonic anhydrase mg g 6a-methyl-17a-hydroxyprogesterone acetate ....... subcutaneous 0.062 3.8 124.4 0.125 2.4 64 6a-methyl-17a-hydroxyprogesterone acetate ....... per os 0.250 3.4 71.4 1 3.7 - Progesterone ................................. subcutaneous 0.5 2.4 90.5 1 3.8 138 5 1.8 57.3 Ethynyl testosterone ........................... per os 10 2.8 - 20 3.4 127.6 17a-acetoxyprogesterone ...................... per os 2 1.5 59 5 2.4 62.9 The figures in this table show that 6a-methyl-17a-hydroxyprogesterone acetate is about 15 times more effective than progesterone when applied subcutaneously. When administered orally, it is 3.6 times more effective than subcutaneously administered progesterone, 75 times more effective than orally administered Ethyn Itestosterone and 40 times more effective than orally administered 17a-acetoxyprogesterone.

Claims (1)

Claim: Process for the production of 6a-methyl-17a-oxy-progesterone and its esters with an aliphatic or cycloaliphatic carboxylic acid containing no more than 9 carbon atoms, characterized in that 5-Pregnen-3ß, 17a-diol-20-one-ethylene glycol ketal is epoxidized with an organic peracid at a temperature of 0 ° C. for 4 to 8 hours, the a-epoxide is separated from the mixture of the a- and ß-epoxides by crystallization, the 5a obtained , 6a-epoxide cleaves with methylmagnesium iodide, the 6ß - methyl - allopregnan - 3ß, 5a, 17a-triol - 20-onethylene glycol ketal obtained is hydrolyzed with hot dilute acetic acid and oxidized with chromic acid in acetic acid or with chromic acid and sulfuric acid in acetone solution, the obtained 6ß-methyl-allopregnan-5a, I7a-diol-3,20-dione is dehydrated with potassium hydroxide in methanolic solution and the 6a-methyl-17a-hydroxyprogesterone obtained with the chloride or anhydride is not Aliphatic or cycloaliphatic carboxylic acid containing more than 9 carbon atoms in the presence of catalytic amounts of p-toluene sulfonic acid and optionally in the presence of an inert solvent, in particular benzene or toluene, at temperatures between 80 and 125 ° C, whereupon the proportion of 3-enol acylate formed is selectively hydrolyzed by boiling with dilute sulfuric acid for 2 hours. Considered publications J. Org. Chem., 22, pp. 99ff. (1957); JACS, 78, p. 6213 (1956); J. Chem. Soc. (London), 1957, p. 4112f1: