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A scalable and facile synthetic process for N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride, a novel Rho kinase inhibitor with an unsymmetrical urea structure currently under investigation for the treatment of central nervous system disorders, was established. After optimisation of the reaction conditions, N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride was synthesised from 4-aminopyridine and N,N'-carbonyldiimidazole through acylation, deprotection and salt formation. This new procedure affords the product in 53% overall yield with high purity and it can be easily scaled up for production. [ABSTRACT FROM AUTHOR]

A facile method for the synthesis of N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide (Betrixaban) from 5-methoxy-2-nitrobenzoic acid is achieved by reduction, acylation, chlorination, acylation and the formation of the amidine. A dechlorinated impurity is avoided in this method. Using tetrahydrofuran as the solvent in the four steps makes its recovery easier. The total yield of the target compound is about 40% and this method is suitable for large-scale production. [ABSTRACT FROM AUTHOR]

A simple synthetic method has been developed for the synthesis of 3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl) benzamide (an impurity in crude roflumilast) from 3,4-dihydroxybenzaldehyde via alkylation, oxidation, chlorination and acylation reactions. Acetonitrile was used as the solvent in all the three steps for convenient recovery. The oxidation of 3,4-bis(cyclopropylmethoxy)benzaldehyde (purity, 86.2%) by sodium chlorite afforded the corresponding acid with purity of 99.2%. Finally, N-acylation of 3,5-dichloropyridin-4-amine yielded 3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl) benzamide. Without column chromatography, the overall yield of the target compound was about 70%. [ABSTRACT FROM AUTHOR]