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Process for the preparation of 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid

IP.com Disclosure Number: IPCOM000244456D
Publication Date: 2015-Dec-13
Document File: 1 page(s) / 129K

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Process for the preparation of 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-

1H-benzo[d]imidazole-6-carboxylic acid

5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid, referred to herein as compound 1, may be an intermediate in the preparation of 5-((4- bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H- benzo[d]imidazole-6-carboxamide (referred to as compound A).

4,5-diamino-2-((4-bromo-2-fluorophenyl)amino)-3-fluorobenzoic acid (referred herein as compound 2) was prepared in three steps from 2,3,4-trifluoro-5-nitrobenzoic acid. In the first step 2,3,4-trifluoro-5-nitrobenzoic acid was coupled with 4-bromo-2-fluoroaniline in the presence of the base by employing the process discussed in the literature (for example WO2005009975) to form 2-((4-bromo-2-fluorophenyl)amino)-3,4-difluoro-5-nitrobenzoic acid which was reacted by NH4OH in the second step to form 4-amino-2-((4-bromo-2- fluorophenyl)amino)-3-fluoro-5-nitrobenzoic acid.

4-amino-2-((4-bromo-2-fluorophenyl)amino)-3-fluoro-5-nitrobenzoic acid is hydrogenated in the third step over metal catalyst to form compound 2.

Compound 1 was prepared by cyclization of compound 2 according to the process described in US8039637.

The compound 1 was obtained in high purity and yield which may be further adapted by process optimization.

The obtained compound 1 can be converted to compound A by process described in the literature, for example WO2014063024.