利培酮关键中间体的合成工艺改进

Improved Synthetic Process of Key Intermediate of Risperidone

本研究改进了利培酮关键中间体3-(2-氯乙基)-2-甲基-6,7,8,9-四氢-4H-吡啶并[1,2-a]嘧啶-4-酮(1)的合成工艺。以2-氨基吡啶(3)、2-乙酰基-γ-丁内酯(4)和三氯氧磷为原料,经环合氯化反应得到环合物3-(2-氯乙基)-2-甲基吡啶并[1,2-a]嘧啶-4-酮(2),再经氢化得到目标产物1,纯度大于99.5%,总收率72%(以3计)。在环合氯化反应中,投料方式对反应收率有着显著影响,将3和4的甲苯溶液滴加到三氯氧磷中,产率可由52%提高到80%;氢化反应中以水为溶剂,盐酸用量为反应体系的9%(约2的4倍摩尔质量)时可抑制脱氯杂质的产生。本工艺适合工业化生产。

The improved synthetic process of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin-4-one(1),a key intermediate of risperidone,was reported.2-Aminopyridine(3) reacted with 2-acetyl-γ-butyrolactone(4) in POCl3 to give 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(2),followed by the hydrogenation catalyzed by Pd/C to obtain the target compound with a total yield of 72%(based on 3),and the purity was more than 99.5%.Feeding orders had a significant effect on the yield of intermediate 2.The toluene solution of 3 and 4 was added dropwise to POCl3,and the yield by the above feeding method could be increased from 52% to 80%.In the hydrogenation reaction,9% hydrochloric acid aqueous solution as the solvent(about 4 eq HCl of 2) could help to inhibit the formation of dechlorination impurity.This process reported herein was suitable for industrial production.