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SYNTHESIS AND PURIFICATION OF FINASTERIDE [N-TERT-BUTYL-3-OXO-4-AZA-5ALPHA-ANDROST-1-ENE-17BETA-CARBOXAMIDE]

IP.com Disclosure Number: IPCOM000207988D
Publication Date: 2011-Jun-17
Document File: 6 page(s) / 1M

Publishing Venue

The IP.com Prior Art Database

Abstract

A process to obtain pure Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] is disclosed

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This is the abbreviated version, containing approximately 52% of the total text.

Page 01 of 6

SYNTHESIS AND PURIFICATION OF FINASTERIDE [N-TERT-BUTYL-3- OXO-4-AZA-5ALPHA-ANDROST-1-ENE-17BETA-CARBOXAMIDE]

ABSTRACT

A process to obtain pure Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] is disclosed.

DESCRIPTION

A process for the synthesis of Finasteride [N-tert-butyl-3-oxo-4-aza-5alpha-androst-1-ene-17beta- carboxamide] is disclosed.

The reaction is carried out in one step, consisting in the dehydrogenation of 17β-(t- Butylcarbamoyl)-4-aza-5α-androstan-3-one by using DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) as dehydrogenating agent in the presence of BSTFA (bis trimethylsilyl trifluoroacetamide) as silylating agent in toluene as solvent.

The crude product is then purified by reaction with perchloric acid and 1,3-dibromo-5,5- dimethylhydantoin and by successive crystallizations with DMF/water and acetonitrile.

REACTION PATHWAY

N

H

O CH3

C

H3

C

H3

O CH3

C

H3

C

H3

NH

NH

CH3

DDQ, BSTFA, toluene

CH3

CH3

CH3

O

O

N

H

1 2

Synthesis of Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] (2):

17β-(t-Butylcarbamoyl)-4-aza-5α-androstan-3-one (1), toluene, BSTFA and DDQ are mixed, under stirring, at 95 ± 1 °C; the reaction is checked by HPLC or TLC. At the end of the reaction, the mixture is cooled to room temperature and added to an aqueous solution of sodium bisulfite. The reaction product is extracted with ethyl acetate and the organic layers are washed with a solution of sodium carbonate in water, and then with brine and distilled under vacuum. Tert-butyl methyl ether is dropped in the mass and the precipitate thus obtained is separated by filtration.

Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] (2) is obtained and dried under vacuum.


Page 02 of 6

First purification of Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] (2)::

A suspension of crude Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] (2) in acetone and purified water is stirred at room temperature; 70% perchloric acid and 1,3- dibromo-5,5-dimethylhydantoin are added to the mass and after 1 hour a solution of sodium sulfite in water is added. The mixture is then added to potable water and, after stirring at 0 ÷ 5 °C for almost 1h 30', the precipitate is separated by centrifugation and dried under vacuum.

Second purification of Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] (2):

A solution of Finasteride [N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide] (2) first purified in DMF is heated to about 70 °C and purified water is the dropped in the solution. The mass is cooled to about 20 °C and, after stirring...