拉科酰胺的合成工艺改进

Process Optimization for the Synthesis of Lacosamide

以丙烯酸为起始原料与苄胺缩合得到N-苄基丙烯酰胺(4),收率由70%提高至83%,4与NBS通过烯烃双键双官能团化用二氯甲烷和甲醇混合溶剂得到N-苄基-3-甲氧基-2-溴丙酰胺(5)收率由70%提高至76%,5与叠氮钠反应得到N-苄基-2-叠氮基-3-甲氧基丙酰胺(6),6经钯碳加氢得到2-氨基-N-苄基-3-甲氧基丙酰胺(7)两步收率达到83.6%,7经乙酰化得到2-乙酰胺基-3-甲氧基-N-苄基丙酰胺(8),8经SFC色谱柱手性拆分得到拉科酰胺(1)(拆分收率47.6%),总收率22.8%(以2计)。拉科酰胺结构经~1CNMR、~1HNMR及MS确证。

N-beuzyl -acrylamide （4） was prepared by acrylic acid and benzylamine, with a yield of 83 %. After a difunctionalization of C-C double Bond, N-Benzyl-3-methoxy-2-bromopropanamide （5） was obtained in DCM and MeOH with a yield of 76 %. Then 5 was reacted with sodium azide to give N-benzyl-2-azido-3-methoxypropanamide （6）, 6 was reduced with Pd/C to give 2 -Amino-N-benzyl-3-methoxypropionamide （7） with two steps yield of 83 %. 2-acetamido-3-methoxy-N-benzylpropanamide （8） was obtained by 7 with acetic anhydride. Then the target compound Lacosamide （1） was prepared by SFC to chiral separate 8, （separation yield 47.6 %）.The total yield was 22.7 % （calculated as 2）. The target structure was confirmed by IHNMR, ICNMR and MS （ESI）.