维格列汀相关物质的合成工艺改进  

Process Improvement on Synthesis of Vildagliptin Related Substance

作　　者：张明[1] 张豪 王天宝 钟彩灵 向圆圆 林宏博 石忠波 胡湘南[1] ZHANG Ming;ZHANG Hao;WANG Tian-bao;ZHONG Cai-ling;XIANG Yuan-yuan;LIN Hong-bo;SHI Zhong-bo;HU Xiang-nan(Pharmacy School,Chongqing Medical University,Chongqing 400016,China)

机构地区：[1]重庆医科大学药学院,重庆400016

出　　处：《合成化学》2018年第1期46-50,54,共6页Chinese Journal of Synthetic Chemistry

基　　金：重庆市科委资助项目(cstc2015zdcy-ztzx120003);重庆医科大学大学生科学研究与创新实验(201726)

摘　　要：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.

关 键 词：盐酸金刚烷胺 L-脯氨酸 维格列汀 相关物质 药物合成 Box-Behnken响应面法 工艺优化 

分 类 号：R914.5[医药卫生—药物化学]