Process for preparing drospirenone and intermediate thereof
OwnerAlessandro Pontiroli, Nicola Diulgheroff +4inventors
InventorsAlessandro Pontiroli, Nicola Diulgheroff, Francesca Scarpitta, Roberto Arosio, Andrea Poggiali, Marco Villa
Life of this patent
Estimating the term…
Abstract
The present invention encompasses processes for preparing drospirenone and intermediates thereof.
Claims33
A process for preparing 17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol of Formula X:
- comprising reacting 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one of Formula VIII:
- with about 1.8 to about 3 moles of propargyl alcohol per mole equivalent of 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one and about 4 to about 6 moles of a base per mole equivalent of 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one to provide a reaction mixture;
- and quenching the reaction mixture to obtain 17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol, wherein the base is selected from the group consisting of:
- a base derived from a tertiary alcohol, an alkali metal hydride, an alkali metal amide, a C4-C8 alkyl lithium and mixtures thereof.
A process for preparing 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of Formula XIa:
- comprising reacting 17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol of Formula X with at least one hydrogen source and a hydrogenation catalyst, wherein if the hydrogen source is hydrogen gas then the process further comprises a base that is not pyridine.
A process for preparing drospirenone comprising (a) reacting 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of Formula XIa with an alkali metal permanganate to provide a reaction mixture containing an intermediate of Formula XII:
- and (b) reacting the intermediate of Formula XII with an acid to provide drospirenone.
A process for preparing drospirenone comprising:
- a) reacting 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one with about 1.8 to about 3 moles of propargyl alcohol per mole equivalent of 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one and about 4 to about 6 moles of base per mole equivalent of 3β,5-dihydroxy-6β,7β;15β,16β-dimethylene-5β-androst-17-one to provide a reaction mixture, wherein the base is selected from the group consisting of:
- a base derived from a tertiary alcohol, an alkali metal hydride, an alkali metal amide, a C4-C8 alkyl lithium and mixtures thereof;
- b) quenching the reaction mixture to provide 17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol of Formula X;
- c) reacting 17α-(3-hydroxy-1-propynyl)-6β,7β;15β,16β-dimethylene-5β-androstane-3β,5,17β-triol of Formula X with a hydrogen source selected from the group consisting of:
- hydrogen gas, sodium hypophosphite, ammonium formate, benzyl alcohol, allyl alcohol, cyclohexene, N-benzylaniline, formic acid, triethylammonium formate and mixtures thereof, and a hydrogenation catalyst providing 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of Formula XIa, wherein if the hydrogen source is hydrogen gas then the process further comprises a base that is not pyridine;
- d) reacting 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-5β-androstan-3β,5,17β-triol of Formula XIa with an alkali metal permanganate to provide a reaction mixture containing an intermediate of Formula XII;
- and
- e) reacting the intermediate of Formula XII with an acid to provide drospirenone.
Dependencies are inferred from the claim text.