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Process for the preparation of Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl] (2-pyridinyl)-amino}propanoate mesylate and intermediate thereof

IP.com Disclosure Number: IPCOM000232582D
Publication Date: 2013-Nov-19
Document File: 3 page(s) / 78K

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              Process for the preparation of Ethyl 3-{[(2-{[(4-{N'- [(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5- yl)carbonyl] (2-pyridinyl)-amino}propanoate mesylate and intermediate thereof

    Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino] methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl] (2-pyridinyl)-amino}propanoate
is an anticoagulant from the class of the direct thrombin inhibitors and has the following chemical structure:

Provided is the single step process for the preparation of Ethyl N[(2-[(4-

cyanophenyl)amino]methyl)-1H-benzimidazole-5-carbonyl]-N-(pyridine-2-yl)-3-amino

propionate (compound II), comprising reacting ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- yl)benzamido)propanoate (compound III) with 2-( 4-cyanophenylamino )acetic acid (compound


IV) in presence of a organic solvent and a coupling reagent selected from 1,1 '- carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBT), polyphosphoric acid (PPA), mesylchloride, thionyl chloride and the like. The above reaction may
be carried out with or without cyclization reagent under heating, examples of which may be selected from the group comprising of p-toluene sulphonic acid (PTSA), phosphorous oxychloride (POCl3), acetic acid, oxalyl chloride and the like. The ratio of coupling agent and

2-(4-cyanophenylamino) acetic acid used in the reaction may be in the range of about 0.8-
1.3:1.4-1.9 to obtain compound II with desired purity (> 97%). The temperature during the above reaction may be in the range from about 15ÂșC to about reflux.

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    The organic solvents used in the above reaction may be selected from the group comprising of esters, halogenated solvents, cyclic hydrocarbons, 2-methyltetrahydrofuran, C1-C3

nitriles and mixture thereof. Examples of esters may include ethyl acetate, isopropyl acetate, butyl acetate and the like. Examples of halogenated solvents may include dichloromethane, ethylene chloride, chlorobenzene, chloroform and the like. Examples of cyclic hydrocarbons may include cyclopentane, cyclohexane, cycloheptane and the like. Examples of C1-C3 nitriles may include acetonitrile, propionitrile and the like. The purification and/or isolation of compound II may be c...