吡仑帕奈合成工艺的改进

Improved Synthetic Process of Perampanel

本研究优化了吡仑帕奈(1)的合成工艺,以2-甲氧基吡啶(2)为起始原料,经溴代制得5-溴-2-甲氧基吡啶(3),再与2-溴吡啶发生Kumada偶联制得6’-甲氧基-2,3’-联吡啶(4),经盐酸水解得到[2,3’-联吡啶]-6’(1’H)-酮(6),再与苯硼酸酐发生Chan-Evans-Lam偶联反应得1’-苯基-[2,3’-联吡啶]-6’(1’H)-酮(7),7与N-溴代琥珀酰亚胺发生溴代得5’-溴-1’-苯基-[2,3’-联吡啶]-6’(1’H)-酮(8),最后与2-(1,3,2-二氧硼己环-2-基)苄腈(9)在醋酸钯/三苯基膦催化下发生Suzuki偶联、精制得1。该路线反应条件温和,操作简便,成本低,产品质量可控,总收率约34%(以2计)。

This study improved the synthesis process of perampanel(1).5-Bromo-2-methoxypyridine(3) was prepared by bromination of 2-methoxypyridine(2),and then Kumada coupling of 3 with 2-bromopyridine was carried out to prepare 6’-methoxy-2,3’-bipyridine(4),followed by the hydrolysis with hydrochloric acid to obtain[2,3’-bipyridyl]-6’(1’H)-one(6),the latter underwent the Chan-Evans-Lam coupling reaction with phenylboronic anhydride to give 1’-phenyl-[2,3’-bipyridyl]-6’(1’H)-one(7),which was then brominated with NBS to give 5’-bromo-1’-phenyl-[2’,3-dipyridyl]-6(1’H)one(8),finally the Suzuki coupling of 8 with 2-(1,3,2-dioxaborexan-2-yl)benzonitrile(9) in palladium acetate/occurred under the catalysis of triphenylphosphine to give 1 with a total yield of 34%(based on 2).