DE1085155B - Process for the production of steroid alkyl ethers - Google Patents

Description

Process for the production of steroid alkyl ethers The main patent 1062 698 describes the production of preferably lower alkyl ethers of tertiary steroid alcohols of the androstane, estran and pregnane series, which carry an ethynyl group on the same carbon atom which is the seat of the tertiary hydroxyl group. This preparation is characterized in that the steroid alcohols mentioned - if necessary with intermediate protection of other reactive groups present in the molecule by modification known per se into less reactive functional derivatives - are reacted in a known procedure with alkylating agents and the intermediately protected groups then subsequently in the usual way sets free again and, if necessary, introduces the desired reactive groups into the end product only after the alkylation, namely by converting other groups present in the starting material into the ultimately desired ones.

The process products of the main patent are therapeutically valuable, since it has been shown that the characteristic effects of the steroid alcohols on which the ethers according to the invention are based are considerably increased by the etherification. It has now been found that the above-mentioned effect of increasing the effectiveness is retained if the ethynyl group characteristic of the starting materials of the main patent is used at any stage in the course of the process according to the main patent by partial or total hydrogenation to the vinyl or ethyl group by methods known per se subject. However, it is advisable to carry out the hydrogenation only after the alkylation, since the hydrogenation of the ethynyl group increases the tendency of the tertiary hydroxyl group to split off water. Example 1 17a-ethynyl-17-methoxy-45-androsten-3.beta.-ol (prepared according to the main patent 1 062 698, Example 1) is shaken in pyridine in the presence of palladium on calcium carbonate with hydrogen until the uptake of 1 mol per mol of substance. The catalyst is filtered off and the filtrate is evaporated in vacuo. The crude 17a-vinyl-17-methoxy-4 5-androsten-3ß-ol remaining as residue is purified by recrystallization from ethyl acetate or via the benzoate ( mp 170-171 ° C.) which crystallizes well. The pure 17a-vinyl-17-methoxy-d 5-androsten-3ß-ol melts at 150 to 150.5 ° C.

For the oxidation, the abovementioned compound is heated to boiling with toluene and cyclohexanone and a few cc of solvent is distilled off until the distillate passes over clear. Then aluminum isopropoxide (20% solution in toluene) is added in excess and the reaction mixture is subjected to slow distillation for a further 30 minutes. The reaction mixture, which has cooled to room temperature, is then mixed with water and the organic solvents are blown off with steam. After cooling to room temperature, it is acidified with dilute sulfuric acid and the crude oxidation product is taken up in ether. The ether solution, washed neutral and dried over sodium sulfate, is evaporated. The oily crystalline residue is recrystallized from methanol. 17a-vinyl testosterone methyl ether is obtained with a temperature of 119 to 120.5 ° C. Absorption in ultraviolet light: e "o = 16 860 infrared spectrum 3-keto band at 6.00 @. 44-keto band at 6.21 #t ether band at 9.21 #t vinyl bands at 9.95 and 10.70 Example 2 17a- Ethynyl testosterone methyl ether (manufactured according to main patent 1062 698, example 1 or 2) is hydrogenated in pyridine in the presence of palladium on calcium carbonate until 1 mol of hydrogen per mol of substance is absorbed The flocculent precipitated hydrogenation product is filtered off and washed with water. For purification, it is recrystallized from methanol. 17α-vinyl testosterone methyl ether is obtained with a melting point of 119.5 to 122 ° C. With the substance obtained according to Example 1, there is no depression of the melting point .

Example 3 17a-ethynyl-17-methoxy-45-androsten-3.beta.-ol (prepared according to the main patent 1 062 698, Example 1) is hydrogenated in methanol in the presence of PT02 to recording of 2 moles of hydrogen per mole of substance. The hydrogenation solution filtered off from the catalyst is mixed with water, and the precipitated product is filtered off and dried. After recrystallization from ethyl acetate, the pure 17α-ethyl-17-methoxy-45-androsten-3β-ol melts at 185.5 to 187.degree.

In the hydrogenation in methanol in the presence of palladium on charcoal in addition to the 17-ethyl-17-methoxy-androstenol described above, this is already obtained known pregnen-3ß-ol, which occurs in the hydrogenation under these conditions formed as a by-product through partial hydrogenolysis. The substance mixture is separated on the benzoates by chromatography. The 17α-ethyl-17-methoxy-45-androsten-3β-ol-benzoate obtained in this way (M.p. 184 to 185.5 ° C) provides the free 3-OH compound on alkaline saponification of the same melting point as above.

The same compound is also obtained in catalytic hydrogenation of the 17a-vinyl-17-methoxy-4 5-androsten-3ß-ol obtained according to Example 1 in methanol in the presence of Pt 02.

In the oxidation of 17a-ethyl-17-methoxy-45-androsten-3ß-ol under conditions analogous to those given in Example 1, 17a-ethyl testosterone methyl ether is obtained, which, after recrystallization from ethyl acetate, melts at 127 to 128.5 ° C. absorption in ultraviolet light: a240 = 16 160 infrared spectrum 3-keto band at 5.96 44-keto band at 6.18 ether band at 9.35 Example 4 17a-ethynyl-17-methoxy-4 5-androsten-3ß-ol is in glacial acetic acid in the presence of Pt02 up to the absorption of 3 mol of hydrogen each Mole of substance hydrogenated. The catalyst is filtered off and copious amounts are added Water. The precipitated hydrogenation product is filtered off and washed neutral. Pure 17α-ethyl-17-methoxyandrostan-3β-ol is obtained therefrom by recrystallization from methanol from 188 to 190 ° C.

The same compound is also obtained if in place of the ethynyl compound the corresponding vinyl or. Ethyl compound used in the above hydrogenation will. The 17-ethyl-17-methoxy-androstanol can be mixed with Cr03 (in 90% acetic acid) in 17a-ethyl-17-methoxy-androstan-3-one. After recrystallization from ethyl acetate, the pure ketone melts at 156 to 157 ° C. It forms with dinitrophenylhydrazine a sparingly soluble dinitrophenylhydrazone in hydrochloric acid-containing methanol.

Example 5 17a-ethynyl-19-nor-testosterone-17-methyl ether (prepared according to main patent 1062698, example 3) is hydrogenated in pyridine in the presence of palladium on calcium carbonate until 1 mol of hydrogen per mol of substance is absorbed. The catalyst is filtered off and water is added. 17α-vinyl-19-nortestosterone-17-methyl ether is obtained which, after recrystallization from methanol, melts at 178 to 179.5 ° C. Absorption in ultraviolet light: 8141 = 17,330 infrared spectrum 3-keto band at 6.0 #t 44-keto band at 6.17 ether band at 9.2 p. Vinyl bands at 5.33 and 10.7

Claims (1)

PATENT CLAIM: Modification of the process for the preparation of preferably lower alkyl ethers of tertiary steroid alcohols of the androstane, estran and pregnane series, which carry an ethynyl group on the same carbon atom, which is the seat of the tertiary hydroxyl group, by reacting the steroid alcohols mentioned with alkylating agents, known per se other reactive groups present in the molecule, if necessary during the alkylation, are intermediately protected by known modification into less reactive functional derivatives and then set free again, or reactive groups whose presence in the end product is desired only after the alkylation, namely by converting others in the Starting material groups present are introduced into the end product, characterized in that the abovementioned ethynyl group is known in the course of the process according to main patent 1062 698 of a partial or total hydrogenation annten methods for vinyl or ethyl group.