INDUSTRIAL PROCEDURE FOR THE PREPARATION OF GAMMA-LACTONE ACID 17-HIDROXI-6-BETA, 7-BETA, 15-BETA, 16-BETA-BISMETILEN-3-OXO-17-ALFA-PREGN-4-ENO-21-CARBOXILICO AND KEY INTERMEDIATES FOR THIS PROCEDURE.

摘要

Industrial process for the preparation of 17-hydroxy-6β, 7β; 15β, 16β-bismethylene-3-oxo-17α-pregn-4-eno-21-carboxylic acid γ-lactone of formula (I), ** (See formula) ** obtained from the known 15α-hydroxyandrost-4-ene-3,17-dione of formula (III), characterized in that the 15α-hydroxyandrost-4-eno-3,17-dione of formula (III ) ** (See formula) ** is esterified on hydroxy at position 15 with a reactive derivative of an alkanoic acid (C1-6) to produce a 15α-acyloxyandrost-4-ene-3,17-dione of general formula (IV), ** (See formula) ** in which R represents a hydrogen atom or an alkyl group of 1-5 carbon atoms, and said compound of general formula (IV) is reacted, in the presence of an acid catalyst, with a trialkyl orthoformate having 1-4 carbon atoms in the alkyl parts, to produce the 15α-acyloxy-3-alkoxyandrosta-3,5-diene-17-one of general formula (V), * * (See formula) ** in which R has the mi As defined above and R1 represents an alkyl group of 1-4 carbon atoms, said compound of general formula (V) is reacted with trimethylsulfoxonium methylide prepared in situ in dimethyl sulfoxide from a trimethylsulfoxonium salt and a alkali metal hydroxide, to produce the 15β, 16β-methylene-3-alkoxyandrosta-3,5-diene-17-one of general formula (VI), ** (See formula) ** in which R1 has the same meaning defined above, said compound of general formula (VI) is reacted, in the presence of lithium metal, with 2- (2-bromoethyl) -1,3-dioxolane or with a 2- (2-bromoethyl) -dialkoxy-acetal having 1-4 carbon atoms in the alkoxy parts, to produce cyclic 1,2-ethanediyl-acetal of 17-hydroxy-15β, 16β-methylene-3-alkoxy-17α-pregna-3,5-diene-21- carboxaldehyde or dialkoxyacetal of 17-hydroxy-15β, 16β-methylene-3-alkoxy-17α-pregna-3,5-diene-21-carboxaldehyde of general formula (VII), ** (See formula) ** in which R1 has the same meaning defined above and R2 and R3 represent an alkyl group of 1-4 carbon atoms or together form a 1,2-ethylene group, and said compound of general formula (VII) is oxidized with chloranil (2,3 , 5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione) to form cyclic 1,2-ethanediyl-acetal of 17-hydroxy-15β, 16β-methylene-3-oxo-17α-pregna-4, 6-diene-21-carboxaldehyde or dialkoxyacetal of 17α-hydroxy-15β, 16β-methylene-3-oxo-17α-pregna-4,6-diene-21-carboxaldehyde of general formula (VIII), ** (See formula) ** wherein R2 and R3 have the same meaning defined above, said compound of general formula (VIII) a) is cycled in an acidic medium to form 15β, 16β-methylene-3-oxoandrosta-4,6-diene- [ 17 (β-1) spiro5 '] - perhydrofuran-2'ξ-ol alkyl ether of general formula (IX), ** (See formula) ** in which R4 represents a methyl, ethyl or propyl group and the ∼ bond represents the α or β configuration, and said compound of formula (IX) is reacted n with trimethylsulfoxonium methylide prepared in situ in dimethyl sulfoxide from a trimethylsulfoxonium salt and an alkali metal hydroxide, or b) reacted with trimethylsulfoxonium methylide prepared in situ in dimethyl sulfoxide from a trimethylsulfoxonium salt and an alkali metal hydroxide to produce a bismethylene derivative of the general formula (IXa) ** (See formula) ** in which R2 and R3 have the same meaning defined above and the bond ∼ represents the α or β configuration, and said Compound of formula (IXa) is cycled in an acidic medium, and then, from the mixture of 6ξ, 7ξ; 15β, 16β-bismethylene-3-oxo-androst-4-eno- [17 (β-1) spiro5 '] -perhydrofuran-2'ξ-ol alkyl ether of general formula (X) obtained at the end in any one of the sequences of the previous alternative step, ** (See formula) ** in which R4 represents a methyl group, ethyl or propyl and the bond ∼ represents the α or β configuration, the iso mere 6β, 7β is separated by chromatography and oxidized with Jones reagent to produce drospirenone, or the mixture of 6ξ, 7ξ; 15β, 16β-bismethylene-3-oxoandrost-4-eno- [17 (β-1) spiro5 '] -perhydrofuran-2'ξ-ol alkyl ether of general formula (X) obtained at the end in any one of the sequences of the previous alternative step, in which R4 represents a methyl, ethyl or propyl group and the bond ∼ represents the α or β configuration is oxidized with Jones reagent to produce 6ξ, 7ξ; 15β, 16β-bismethylene-3-oxoandrost-4-eno- [17 (β-1) spiro5 '] - perhydrofuran-2'-one (γ-17-hydroxy-6ξ, 7 15; 15β, 16β-bismethylene-3-oxo-17α-pregn-4-eno-21-carboxylic acid) of general formula (XI), ** (See formula) * * in which the ∼ link represents the α or β configuration, and from this isomeric mixture the 6β, 7β isomer is isolated, and if so desired, the drospirenone of formula (I) obtained by any one of the synthetic routes above is purified by cri stalization. ** (See formula) **