Patent ID: 7585971

Claim:
Process for the preparation of drospirenone comprising the following steps: a) bromination of 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one of formula (II), in position 7α, to obtain 7α-bromo-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one of formula (III) b) opening the epoxy ring of, and removing bromine from, 7α-bromo-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one of formula (III) to obtain 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one of formula (IV) c) hydrolysis of the pivaloyl group of 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one of formula (IV) to obtain 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one of formula (V) d) methylenation of 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one of formula (V), at the Δ 6 double bond, to obtain 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one of formula (VI) e) reacting 3β,5-dihydroxy-6β,7β; 15β,16β-dimethylene-5β-androst-17-one of formula (VI) with propargyl alcohol to obtain 17α-(3-hydroxy-1-propinyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of formula (VII) f) hydrogenating 17α-(3-hydroxy-1-propinyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of formula (VII) to obtain 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of formula (VII) g) oxidizing 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of formula (VIII) to obtain drospirenone of formula (I) said process being characterised in that: i) the 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one of formula (II) in step a) is reacted with mesyl chloride to obtain the corresponding mesylate of formula (II-Ms), which is not isolated and from which 7α-bromo-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one of formula (III) is obtained by adding lithium bromide and ii) said oxidation in step g) is carried out under such conditions that drospirenone forms under non-acidic pH conditions.