Patent DE-102009031908-A1 (DE)
Title: Producing drospirenone, useful as hormonal contraceptives, by oxidatively converting hydroxy-dimethylenandrostane-one to hydroxy-dimethylenandrostan-dione, eliminating hydroxy group, followed by reacting with 1-halopropan-3-oxy
Inventor: DOEHLER THOMAS
IPC: C07J71/00
Filed: 2009-07-01
Abstract: Producing drospirenone from 3,5-hydroxy-6,7,15,16-dimethylenandrostan-17-one (DHDH) comprises oxidative conversion of DHDH to 5-hydroxy-6,7,15,16-dimethylenandrostan-3,17-dione (DMHD), eliminating 5-hydroxy group in an acid/base medium to obtain 6,7,15,16-dimethylen-androst-4-en-3,17-dione (DMED), reacting DMED with a 1-halopropan-3-oxy compound (I) to obtain 6,7,15,16-dimethylen-17beta -hydroxy-17alpha -(3'-alkoxypropyl)-androst-4-en-3-one (DMPP) (II), convting DMPP to 6,7,15,16-dimethylen-17beta -hydroxy-17alpha -(3'-hydroxypropyl)-androst-4-en-3-one (DMHP) and converting DMHP under oxidative conditions. Producing drospirenone: either from 3,5-hydroxy-6,7,15,16-dimethylenandrostan-17-one (DHDH) comprises oxidative conversion of DHDH to 5-hydroxy-6,7,15,16-dimethylenandrostan-3,17-dione (DMHD); eliminating 5-hydroxy group in an acid or base medium to obtain 6,7,15,16-dimethylen-androst-4-en-3,17-dione (DMED), reacting DMED with a 1-halopropan-3-oxy compound X(CH 2) 3OR (I) to obtain 6,7,15,16-dimethylen-17beta -hydroxy-17alpha -(3'-alkoxypropyl)-androst-4-en-3-one (DMPP) of formula (II), followed by conversion to 6,7,15,16-dimethylen-17beta -hydroxy-17alpha -(3'-hydroxypropyl)-androst-4-en-3-one (DMHP) and converting DMHP under oxidative conditions; or from DMED comprises converting (I) to (II), converting DMPP to DMHP, followed by reacting under oxidative conditions; or reacting DMED with a halopropionaldehydeacetal XCH 2CH 2CH(O2a) 2(III) to 6,7,15,16-dimethylen-17beta -hydroxy-17alpha -(3,3-dialkoxypropyl)-androst-4-en-3-one (DMEK), converting DMEK to 6,7,15,16-dimethylen-androst-4 en-3-on-17-spirol (SPIR) and subsequently converting SPIR under oxidative conditions; or converting DMED with an ortho-(3-halopropionicacid)-trialkylester XCH 2CH 2C(OR3a) 3(IV) to 17alpha -(3,3,3-trialkoxypropyl)-17beta -hydroxy-6,7,15,16-dimethylen-androst-4-en-3-one (DMOE), and converting DMOE; or reacting DMED with 2-(1-ethoxyethoxy)-but-3-ene nitrile in the presence of a strong base to obtain 6,7,15,16-dimethylen-17beta -hydroxy-17alpha -prop-2-en-3-cyano-(1-ethoxyethoxy)-androst-4-en-3-one (DMCE) and converting DMCE. X : Cl, Br (preferred), I, mesylate, tosylate or triflate; R : alkyl, benzyl, acyl or organosilyl, preferably 1-tetrahydropyranyl or trialkylsilyl; R2a : alkyl, aryl or benzyl; and R3a : 1-3C alkyl. Independent claims are included for: (1) preparation of DMED by reacting prasterone with strong base and phenylsulfonic acid methyl ester to prasterone-16-sulfoxide (PSO), isolating the reaction product and subsequently heating in an aprotic solvent to prasteron-15-ene (PREN), further reacting with trimethylsulfoxonium iodide to 15,16-methylprogesterone (MEP), oxidizing MEP, preferably by Oppenauer oxidation or through reacting with sodium hypochlorite in presence of a catalytic quantity of tetramethylpiperidinoxyl (TEMPO) and potassium bromide to 5,16-methylenandrost-4-en-3,17-dione (MADO), reacting MADO with trimethyl orthoformate to 3-methoxy-15,16-methylenandrostan-3,5(6)-dien-17-one (MOMA), converting MOMA with a mild oxidative agent to obntain 15beta ,16beta -methylen-androst-4,6-dien-3,17-dione (15,16-MDD) and subsequently cyclopropanation between double bonds in the position 6th and 7th position of the steroid nucleus of 15,16-MDD, or reacting androstenedione with trimethyl orthoformate to 3-methoxyandrost-3,5(6)-en-17-one (MAD), further reacting with potassium tert-butylate and phenylsulfonic acid methyl ester to 3-methoxy-16-phenylsulfonylandrostan-3,5(6)-dien-17-one (MPSA), reacing MPSA with a mild oxidative agent to obtain 16- phenylsulfonylandrosta-4,6-dien-3,17-dione (PSAD), methyl addition at the 6,7-double bonds of PSAD to obtain 16-phenylsulfonyl-6,7-methylenandrost-4-en-3,17-dione (SMAD), removing the phenylsulfonyl group to obtain 6beta ,7beta -methylenandrost-4,15(16)-dien-3,17-dione (6,7-MDD) and subsequently cyclopropanation between the double bonds in the position 15 and 16 of the steroide nucleous of 6,7-MDD, or reacting 15-hydroxyandrost-4-en-3, 17-dione with pivaloyl chloride to obtain 15-pivaloylandrost-4-en-3,17-dione (PAD), further reacting with trimethyl orthoformate in the presence of catalytic quantity of an acid to obtain 15-pivaloyl-3-methoxyandrost-4,6-dien-17-one (PIMA), reacting PIMA with a mild oxidative agent to obtain 15-pivaloyl-androstan-4,6-dien-3,17-dione (PIDD) and subsequently cyclopropanation between the double bonds in the 6 and 7 positions of the steroide nucleus of PIDD or eliminating the pivaloyl group with following methyl addition at the positions 15/16 of the steroid nucleus without reconditioning the intermediate products, or converting 3,5-hydroxy-6,7,15,16-dimethylenandrostan-17-one (DHDH) through oxidative reaction to 5-hydroxy-6,7,15.16 dimethylenandrostan-3,17-dione (DMHD) and subsequently eliminating 5-hydroxy group in an acid or base medium; and (2) intermediate compounds comprising DMPP, 6beta ,7beta ,15beta ,16beta -dimethylen-17beta -hydroxy-17alpha -(3'-trimethylsilyloxypropyl)-androst-4-en-3-one, DMHP, 6,7-MDD and PIDD for preparing drospirenone. [Image] ACTIVITY : Antiandrogenic; Contraceptive. MECHANISM OF ACTION : None given.