Patent ID: 8450476
Filing Date: 2013-05-28
Classification: A61P,C07J

Abstract:
1. A process for the preparation of 17-hydroxy-6β,7β;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone of the formula (I), from 15α-hydroxy-androst-4-ene-3,17-dione of the formula (II) characterized in that the 15α-hydroxy-androst-4-ene-3,17-dione of the formula (II) is acetylated with acetic anhydride in dry tetrahydrofuran in the presence of 4-dimethylaminopyridine catalyst at room temperature to give the 15α-acetoxyandrost-4-ene-13,17-dione of the formula (III), said compound of the formula (III) in dry tetrahydrofuran is reacted with a trialkoxy orthoformiate containing alkyl groups having from 1 to 5 carbon atoms, in the presence of sulfuric acid catalyst at 0-10° C. temperature to yield 15α-acetoxy-3-alkoxy-androsta-3,5-diene-17-one of the general formula (IV), wherein R 1 stands for an alkyl group having 1-4 carbon atoms, said compound of the general formula (IV) is reacted with a trimethylsulfoxonium methylide in situ prepared in dimethyl sulfoxide from a trimethylsulfoxonium salt with an alkali metal hydroxide, to give the 15β,16β-methylene-3-alkoxy-androsta-3,5-diene-17-one of the general formula (V), said compound of the general formula (V)—wherein R 1 stands for an alkyl group having 1-4 carbon atoms—in dimethyl sulfoxide is reacted with trimethysulfonium iodide in the presence of potassium tert-butylate at a temperature of 15-25° C. to give the 15β,16β-methylene-3-alkoxy-spiro[androsta-3,5-diene-17β2′-oxirane] of the general formula (VI), wherein R 1 stands for an alkyl group having 1-4 carbon atoms, said compound of the of the general formula (VI) in ethanol is reacted with a di (C wherein R 1 and R 2 stand for an alkyl group having 1-4 carbon atoms, and the ˜ bond represents α and β configuration, said compound of the general formula (VII) is dehydrogenated with tetrachlorobenzoquinone in acetone to give 17-hydroxy-15β,16β-methylene-3-oxo-17α-pregna-4,6-diene-21,21-dicarboxylic acid alkyl ester γ-lactone of the general formula (VIII), wherein R 2 stands for an alkyl group having 1-4 carbon atoms and the ˜ bond represents α and β configuration, said compound of the formula (VIII) is reacted with trimethylsulfoxonium methylide in situ prepared in dimethyl sulfoxide from a trimethylsulfoxonium salt and an alkali metal hydroxide to give 17-hydroxy-6ξ,7ξ;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21,21-dicarboxylic acid alkyl ester γ-lactone of the general formula (IX), wherein R 2 is an alkyl group having 1-4 carbon atoms and the ˜ bond represents α and β configuration, and either from said compound of the general formula (IX) the 17-hydroxy-6β,7β;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21,21-dicarboxylic acid alkyl ester γ-lactone (an isomer of the general formula (IXa)) is isolated by chromatography and recrystallization—in general formula (IXa) R and said isomer of the general formula (IXa) in dimethylformamide is decarboxylated at a temperature around the boiling point of the reaction mixture to give the 17-hydroxy-6β,7β;15β;16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone of the formula (I) which is isolated, or the 17-hydroxy-6ξ,7ξ;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21,21-dicarboxylic acid alkylester γ-lactone of the general formula (IX), wherein R 2 stands for an alkyl group having 1-4 carbon atoms and the ˜ bond represents α and β configuration, in dimethylformamide is decarboxylated at a temperature around the boiling point of the reaction mixture to give 17-hydroxy-6ξ,7ξ;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone of the formula (X), wherein the ˜ bond represents α and β configuration, from which the 17-hydroxy-6β,7β;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone of the formula (I) is separated by chromatography and recrystallization; or the 17-hydroxy-15β,16β-methylene-3-oxo-17α-pregna-4,6-diene-21,21-dicarboxylic acid alkyl ester γ-lactone of the general formula (VIII) wherein R 2 stands for an alkyl group having 1-4 carbon atoms and the ˜ bond represents α and β configuration, in dimethylformamide is decarboxylated at a temperature around the boiling point of the reaction mixture, to give the 17-hydroxy-15β,16β-methylene-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone of the formula (VIIIa) which is isolated, said compound of the formula (VIIIa) is reacted with trimethylsulfoxonium methylide prepared in situ in dimethyl sulfoxide from a trimethylsulfoxonium salt and an alkali metal hydroxide to yield 17-hydroxy-6ξ;7ξ;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone of the formula (X), wherein the ˜ bond represents α and β configuration, and from said compound of the formula (X) the 17-hydroxy-6ξ,7ξ;15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21carboxylic acid γ-lactone of the formula (I) is separated by chromatography and recrystallization.