Abstract
A new and efficient preparation of 2-aminothiazole-5-carbamides: applications to the synthesis of the anti-cancer drug dasatinib
Highlights
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4pyrimidinyl]-amino)]-1,3-thiazole-5-carboxamide (BMS-354825, dasatinib, SPRYCEL®) is a novel multi-targeted kinase inhibitor recently approved in several countries for the treatment of chronic myelogenous leukemia (CML) as well as Philadelphia chromosome-positive acute lymphocytic leukemia (ALL)
A new and efficient method has been developed for the synthesis of 2aminothiazole-5-carboxamide 13
The new method involved a chemoselective α-bromination of β-ethoxyacrylamides followed by a one-pot treatment with thiourea to give the desired 2aminothiazole-5-carboxylamide excellent yields
Summary
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4pyrimidinyl]-amino)]-1,3-thiazole-5-carboxamide (BMS-354825, dasatinib, SPRYCEL®) is a novel multi-targeted kinase inhibitor recently approved in several countries for the treatment of chronic myelogenous leukemia (CML) as well as Philadelphia chromosome-positive acute lymphocytic leukemia (ALL). Our initial focus was to use ethyl 2-aminothiazole-5-carboxylate 10 as core intermediate which could be readily prepared in large scale using a process that was previously developed by us via electrophilic α-bromination of ethyl β-ethoxyacrylate 9 followed by thiazole ring formation with thiourea.[8] N-Boc protection of ethyl 2-aminothiazole-5-carboxylate 10, ester hydrolysis and carboxylic acid group activation followed by coupling with anilines gave the desired 2-N-Bocaminothiazole-5-carboxamides 13 in fair to good overall yields with simple anilines, which were successfully used in our SAR studies.[7] coupling with 2-chloro-6-methylaniline 12 was unsatisfactory and not amenable for large scale synthesis of 1, presumably due to the steric hindrance of the aniline.
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