维格列汀相关物质的合成工艺改进

Process Improvement on Synthesis of Vildagliptin Related Substance

以盐酸金刚烷胺和L-脯氨酸为原料,经羟基化、氯乙酰化及氨基化反应合成了维格列汀相关物质(S)-1-[2-(3-羟基-金刚烷-1-氨基)-乙酰基]吡咯烷-2-羧酸(3),其结构经~1H NMR,^(13)C NMR和MS(ESI)确证。采用Box-Behnken响应面法优化3的合成工艺。结果表明最优反应条件为:1-(2-氯乙酰基)吡咯烷-2-甲酸与3-氨基-1-金刚烷醇的摩尔比为2∶1、三乙胺0.006 mol,于65℃反应4 h,3的平均收率为82.84%,纯度98.8%,可作为维格列汀相关物质检测的对照品。

The related substances of vildagliptin,(S)-1-[2-(3-hydroxy-adamantan-1-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid(3),was synthesized from L-proline and amantadine hydrochloride through hydroxylation,chloroacetylation and amantadine amination.The structure was confirmed by 1H NMR,13 C NMR and MS(ESI).The synthetic process was optimized by Box-Behnken-response surface methodology.The results demonstrated that under the optimum conditions:the mass ratio of 1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid to 3-amino-1-adamantanol was 2∶1,the amount of triethylamine was 0.006 mol,reaction at 65℃for 4 h,the average yield of 3 was 82.5%and the purity was 98.8%,and 3 could be used as a reference substance for the detection of related substance.