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INTERMEDIATES OF N-(2-(4-(N-(Hexyloxycarbonyl)amidino)phenylamino methyl)-1-methyl-1H-benzimidazol -5-ylcarbonyl) -N- (2-pyridyl)-beta-alanine ethyl ester

IP.com Disclosure Number: IPCOM000179673D
Publication Date: 2009-Feb-23
Document File: 3 page(s) / 35K

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INTERMEDIATES OF N-(2-(4-(N-(Hexyloxycarbonyl)amidino)phenylamino

methyl)-1-methyl-1H-benzimidazol -5-ylcarbonyl) -N-

(2-pyridyl)-beta-alanine ethyl ester

N-(2-(4-(N-(Hexyloxycarbonyl)amidino)phenylaminomethyl)-1-methyl-1H-benzimidazol -5-ylcarbonyl) -N-(2-pyridyl)-beta-alanine ethyl ester is an anticoagulant from the class of the direct thrombin inhibitors.

Provided is a process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride, an intermediate for the preparation of N-(2-(4-(N-(Hexyloxycarbonyl)amidino)phenylaminomethyl)-1-methyl-1H-benzimidazol -5-ylcarbonyl) -N-(2-pyridyl)-beta-alanine ethyl ester comprising combining acetyl chloride or any other chlorine donor, ethanol, ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, and organic solvents. The reaction mixture is stirred for about 48 hours and than combined with ammonia or a suspension of ammonium carbonate. The mixture is maintained for sufficient time to obtain ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride.

The above obtained ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride was analyzed by XRPD and its main peaks are: 6.6, 7.6, 7.9 ,11.7 ,15.1 ,15.7 ,16.2 ,17.9 ,18.6 ,19.8 ,20.5 ,21.1 ,22.1 ,22.4 ,23.0, 23.6 ,25.5 ,26.2 ,26.6 ,27.6 ,28.0 ,29.0 ,30.8, 31.8, 32.7 and 33.2± 0.2 degrees 2-theta.

Also provided is a process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate acetate comprising combining ethyl 3-(1-methyl-2-((4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenylamino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, acetic acid, organic solvent, water and a catalyst. The reaction mixture is stirred for about 48 hours at a temperature of about 40-50°C. The solvent is removed by vacuum and the crude product is suspended with organic solvent and heated again to reflux temperature with the addition of active carbon. The mixture is maintained for sufficient time to obtain ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate acetate.

 The above obtained ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate acetate was analyzed by XRPD and its main peaks are: 2.9, 4.3, 6.6, 7.2, 8.1, 8.5, 8.7, 9.3, 9.6, 10.4,11.0,11.5,12.0, 12.6, 12.8, 13.3, 13.6, 14.5, 15.2, 16.0, 16.5, 17.2, 17.5, 17.7, 18.2, 19.0, 19.5, 19.8, 20.4, 20.9, 21.1, 21.3, 21.9, 22.4, 22.6, 23.2, 23.9, 24.3, 2...