DE921753C - Process for the preparation of compounds of the pregnane series - Google Patents

Description

Process for the preparation of compounds of the Pregnan series Patent 657 017 describes a process for the preparation of cyanohydrins of compounds of the Etiocholan series, wherein saturated or unsaturated Etiocholanones or Etioallocholanones are made to react with hydrocyanic acid or hydrocyanic acid-releasing agents. Here z. B. from dehydroandrosterone or its derivatives, in which the hydroxyl group is modified into a group that can be converted back into this group, a compound of the formula obtained, in which R denotes hydroxyl or a substituent which can be converted into the hydroxyl group and which also contains a hydroxyl group in the 17-position in addition to the cyano group. According to the invention it is possible to prepare compounds of the pregnane series from compounds containing the cyanohydrin group in the z7-position, if such saturated or unsaturated compounds of the androstane series are treated with dehydrating agents, then the unsaturated compounds obtained are organometallic compounds of the type Lets CH.- Me-Halg act and, after cleavage of the ketimine, hydrogenates the resulting unsaturated pregnane compounds in the cyclopentano ring and, if necessary, oxidizes them in a manner known per se.

The elimination of water from the cyanohydrins is carried out in the usual way Effects of water-releasing agents. In particular, the Application of phosphorus oxyhalide in a suitable hydrogen halide binding agent Solvents such as pyridine, proven.

From the unsaturated nitriles it is possible to react with organometallic Compounds of the formula CH, # Me # Halg, Me being those which can be used for Grignard reactions Metals, especially magnesium and halogen, a halogen, e.g. B. bromine or iodine, means to replace the cyano group with an acetyl group.

During the reaction with the organometallic compounds arise primarily the corresponding ketimines, which in the usual way, for. B. by heating with alcoholic acids, e.g. B. alcoholic sulfuric acid, saponified to the ketones will.

When using the cyanohydrin of dehydroandrosterone acetate as a starting material the free d5 # 16-Pregnadien 01-3-on-2o is obtained because when performing the Reaction occurs at the same time saponification of the ester. The said connection is then partially hydrogenated in a known manner and optionally under protection of the existing ring double bond converted into the pregnendione-3.2o by oxidation. The oxidation can, for. B. with the help of chromic acid, metal alcoholates and ketones in excess or by biochemical methods.

EXAMPLE I 400 mg of dehydroandrosterone cyanohydrin acetate (3) are heated in a mixture of 10 cc of pyridine and 0.15 cc of phosphorus oxychloride (about twice the theoretical amount) in the containment tube to 15 ° for 11/2 hours. The dark brown but still transparent solution is poured into a mixture of ice and 40 cc of concentrated hydrochloric acid and the precipitate formed is filtered off. It is dissolved in acetone and separated from insoluble, dark colored flakes by filtration. After concentrating the solution and spraying it with water, 300 mg of 17-cyano-3-acetoxy-d5 # rs_androstadien from F. 2o6 '; the yield is 79 % of theory.

To 5 g of magnesium shavings under 20 ccm of absolute ether, those for activation A few grains of iodine are added, under ice-cooling gradually (by cold mixture chilled) methyl bromide was added until the dissolution started after some time of the metal is almost finished. A few more will be needed to complete the reaction Heated to the boil for minutes. The boiling Grignard solution is then with a Solution of 1.8 g of 17-cyano-3-acetoxy-dfi, 16-androstadiene added and 46 hours preserved in boiling. The Grignard product is decomposed by refluxing and external cooling, slowly 6o cc of glacial acetic acid and after the violent reaction has ended another 40 cc of water was added. The ether is distilled off from the mixture and enough water is added to the aqueous glacial acetic acid solution that the initially formed Cloudiness in the warmth just disappears again. To split about not yet hydrated ketinrins are heated to the boil for another 15 minutes. After this Cooling is poured into water; the resulting precipitate delivers by dissolving from acetone 1.26 g of crude product in leaves with a melting point of 212 '(75% of theory). This is recrystallized from ethyl acetate, with the 45-16-Pregnadienol-3-one-2o in small prismatic needles which melt at 216 'with a yellow coloration.

The ultraviolet absorption curve shows that for α, β-unsaturated ketones characteristic maximum at 237 with.

500 mg of pregnadienolone are dissolved in 5 cc of dry cyclohexanone, a solution of 700 mg of freshly distilled aluminum isopropoxide in 30 cc of toluene is added and the mixture is heated to the boil for 45 minutes. After the addition of water, the cyclohexanone and the toluene are blown over with steam. The aqueous solution is extracted with ether regardless of the precipitated aluminum hydroxide. The crystalline residue remaining after evaporation of the ether gives, redissolved in acetone, 38o mg of crude product with a melting point of 175 '; it still contains unchanged raw material. To remove it, it is dissolved in 15 cc of dry chloroform, 5 cc of pyridine and, while cooling with ice, a cooled mixture of 1.5 cc of chlorosulfonic acid and 6 cc of chloroform. Regardless of a crystalline precipitate which has separated out, the reaction mixture is heated to boiling for 15 minutes. A solution of 8 g of soda in 2o ccm of water is then added and the mixture is shaken out with ether. After the insoluble salts have been filtered off, the ethereal solution is washed with dilute sulfuric acid and water. After the solvent has been distilled off, 235 mg of 16-dehydroprogesterone are obtained in flakes from F. z86 'from aqueous acetone. After recrystallization from ethyl acetate it shows an F. from 186 to 188 '. Since the crystals hold onto water of crystallization very stubbornly, the pure substance is sublimated in a water jet vacuum at 21o to 220 '.

The ultraviolet absorption spectrum of 16-dehydroprogesterone shows a maximum of 234 mu-30o mg of pregnadienolone are dissolved in. 2o ccm of alcohol and with the addition of 0.15 g of sodium hydroxide solution in 3 ccm H20 with Raney nickel until saturation hydrogenated. After filtering off the catalyst, the solution is poured into water. The deposited precipitate is filtered off and yields after recrystallization from aqueous acetone 26o mg A'-pregnenolone as a crude product from F. i81 °. Pure ds-pregnen-ol- (3) -one (2o) is obtained by recrystallization from aqueous alcohol preserved in leaflets with a temperature of 188 to 19o °, the one made with stigmasterine Pregnenolone did not result in depression in the mixed sample.

Example 2 5049g obtained by the method of patent 657017 Androsterone cyanohydrin acetate are dried with 5o ccm of dry pyridine and 12 cc of phosphorus oxychloride so cooked minutes. The dark colored solution will cooled and poured drop by drop into ice water, which is used to bind the pyridine necessary amount of hydrochloric acid has been added. The dehydration product of Androsterone acetate cyanohydrins precipitates in light brown flakes, which after some Let time suck out. The pure substance crystallizes from ethyl acetate in colorless : Censures that melt at 198 to 200 ° (observation in the micro-melting point apparatus according to Kofler).

To 2.5 g of magnesium and 15 cc of absolute ether, to which a small iodine crystal has been added, methyl bromide is gradually added with external cooling. To complete the dissolution of the metal, the reaction mixture is heated to boiling for 15 minutes on a water bath at the end of the reaction, then treated with goo mg of nitrile dissolved in 50 ccm of absolute ether and refluxed for 30 hours. Then 40 ccm of glacial acetic acid and 25 ccm of water are added dropwise with external cooling. After the ether has evaporated, the warm solution is carefully diluted with water until it becomes slightly cloudy, boiled for another 1/4 hour and poured into water. The precipitated reaction product is filtered off and recrystallized from dilute glacial acetic acid: 450 mg of crude product with a melting point of 223 ° which, when dissolved from dilute dioxane, shows a constant melting point of 226 ° (uncorr.). [a] D = -f-54 '(in chloroform); Absorption in the ultraviolet: max. = 234 m / ', e = 9 soo (in ether).

50 mg of 418-epi-allo-pregnenol- (3) -one- (2o) are dissolved in 7 cc of glacial acetic acid and 32 mg of chromium trioxide in 3 cc of glacial acetic acid are added in the cold. After standing for five hours, it is precipitated with water and filtered off. After dissolving from dilute alcohol, 65 mg of d 18-allo-pregnendione are obtained in flakes with a melting point of 2o5 to 2o8 ° (uncorr.), Which slowly decompose when standing in the air, browning [a] D = + 72 ° (in Chloroform).

The residue left on the filter is made from dilute alcohol redissolved: 40 mg from the decomposition point 198 to 2o2 °.

Claims (4)

PATENT CLAIMS: 1. Process for the preparation of compounds of the Pregnan series, characterized in that the 17-position contains the cyanohydrin group Compounds of the androstane series are treated with water-releasing agents, whereupon the resulting unsaturated compounds are organometallic compounds of the type CH, -Mg-Halg can act and after cleavage of the ketimine the resulting unsaturated pregnane compounds in the cyclopentano ring hydrogenated and optionally oxidized in a manner known per se. 2. The method according to claim i, characterized in that that the cyanohydrin of dehydroandrosterone or its 3-acyl compounds is used will. 3. The method according to claim 1 and 2, characterized in that the elimination of water from the cyanohydrins by heating with phosphorus oxyhalide, especially phosphorus oxychloride, in a suitable, hydrogen halide binding solvent, such as pyridine will. 4. The method according to claim 1 and 2, characterized in that the reaction of the unsaturated nitriles obtained by dehydration with methyl magnesium halides, such as methyl magnesium iodide, takes place. Attracted publications Hoppe-Seyler's magazine for physiological chemistry, Vol. 252, 1938, pp.49 to 52; French Patent Specification No. 820,537. Journ. pharmac. Soc. Japan, Vol. 57, pp. 96/97.