Patent ID: 8309712
Filing Date: 2012-11-13
Classification: A61P,C07J

Abstract:
1. Industrial process for the preparation of 17-hydroxy-6β,7β; 15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid y-lactone of the formula (I) from the known 15α-hydroxy-androst-4-ene-3,17-dione of the formula (III) characterized in that the 15α-hydroxy-androst-4-ene-dione of the formula (III) is esterified on the hydroxy in position 15 with a reactive derivate of a C wherein R stands for hydrogen atom or an alkyl group having 1-5 carbon atoms, said compound of the general formula (IV) is reacted in the presence of an acidic catalyst with a trialkyl orthoformiate having 1-4 carbon atoms in the alkyl moieties to give 15α-acyloxy-3-alkoxy-androsta-3,5-diene-17-one of the general formula (V), wherein R has the same meaning as defined above and R 1 stands for an alkyl group having 1-4carbon atoms, said compound of the general formula (V) is reacted with trimethylsulfoxonium methylide prepared in situ in dimethyl sulfoxide from a trimethylsulfoxonium salt and an alkali metal hydroxide to yield 15β,16β-methylene-3-alkoxyandrosta-3,5-diene-17-one of the general formula (VI), wherein R 1 has the same meaning as defined above, said compound of the general formula (VI) is reacted in the presence of lithium metal with 2-(2-bromoethyl)-1,3-dioxolane or 2-(2-bromoethyl)-dialkoxy-acetal having 1-4carbon atoms in the alkoxy moieties, to give 17-hydroxy-15β,16β-methylene-3-alkoxy-17α-pregna-3,5-diene-21-carboxaldehyde-cyclic 1,2-ethanediyl acetal or the 17-hydroxy-15β,16β-methylene-3-alkoxy-17α-pregna-3,5-diene-21-carboxaldehyde dialkoxyacetal of general formula (VII) wherein R 1 has the same meaning as defined above and R 2 and R 3 stand for an alkyl group having 1-4carbon atoms or form together a 1,2-ethylene group, said compound of the general formula (VII) is oxidized with chloranil (2,3,5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione) to form 17-hydroxy-15β,16β-methylene-3-oxo-17α-pregna-4,6-diene-21-carboxaldehyde cyclic 1,2-ethanediyl-acetal or 17α-hydroxy-15β,16β-methylene-3-oxo-17α-pregna-4,6-diene-21-carboxaldehyde dialkoxy-acetal of the general formula (VIII) wherein R 2 and R 3 have the same meaning as defined above, said compound of the general formula (VIII) a) is cyclized in acidic medium to form 15β,16β-methylene-3-oxo-androsta-4,6-diene-[17(β-1)spiro5′]-perhydrofuran-2′ξ-ol-alkyl ether of the general formula (IX) wherein R b) is reacted with trimethylsulfoxonium methylide prepared in situ in dimethyl sulfoxide from a trimethylsulfoxonium salt and alkali metal hydroxide; to give a bismethylene derivative of the general formula (IXa) wherein R then from the 6ξ,7ξ;15β,16β-bismethylene-3-oxo-androst-4-ene-[17(β-1)spiro5′]-perhydrofuran-2′ξ-ol-alkyl ether mixture of the general formula (X) obtained at the end in any of the above alternative step sequences wherein R 4 stands for methyl, ethyl or propyl group and the ˜ bond represents α and β configuration, the 6β;7β-isomer is separated by chromatography and oxidized with the Jones-reagent to give the drospirenone, or the 6ξ,7ξ;15β,16β-bismethylene-3-oxo-androst-4-ene-[17(β-1)spiro5′]-perhydrofuran-2′ξ-ol-alkyl ether mixture of the general formula (X) obtained at the end in any of the above alternative step sequences, wherein R 4 stands, for methyl, ethyl or propyl group and the ˜ bond represents α and β configuration, is oxidized with Jones reagent to give 6ξ,7ξ; 15β,16β-bismethylene-3-oxo-androst-4-ene-[17(β-1)spiro5′]-perhydrofuran-2 ′-one (17-hydroxy-6ξ,7ξ; 15β,16β-bismethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone) of the general formula (XI) wherein the ˜ bond represents α and β configuration, and from this isomeric mixture the 6β,7β-isomer is isolated and if desired the drospirenone of the formula (I) obtained by any of the above synthesis routes is purified by crystallization.