Synthesis of 2, 4-dimethyl-8-[2 ́-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-5, 8-dihydro-6H-pyrido [2, 3-D] pyrimidin-7-one (tasosartan) and application of microwave assisted organic synthesis

摘要: Introduction: The improved synthesis of 2, 4-Dimethyl-8-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-5, 8-dihydro-6H-pyrido [2, 3-d] pyrimidin-7-one (tasosartan) 1 on multigramscale is described. Tasosartan is an angiotensin II antagonist for potential treatment of hypertension. Due to unresolved safety issues its NDA application was withdrawn in 1998. However, Tasosartan and its metabolites are still of interest in genomic and pharmaceutical studies [1]. Here the synthesis was developed in context of the DrugMatrix [2] genomics project.Chemistry: 1 was synthesized according to literature known procedures [3, 4] starting from 4-bromobenzylamine hydrochloride 2 and benzonitrile 3 in a convergent strategy, and the eight step synthesis was optimized using different reagents and applying microwave assisted organic synthesis (MAOS)[5] in several steps. The key step of the synthesis is the palladium catalysed coupling …