拉米地坦关键中间体合成工艺改进  

Process for the Synthesis of Key Intermediates of Lasmiditan

作　　者：张堃 张宽才 何登坤 李雯[2,3] ZHANG Kun;ZHANG Kuan-cail;HE Deng-kun;LIWen(Jiangsu Jiuxu Pharmaceutical Co.,Ltd.,Xuzhou 221200,China;School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China;Key Laboratory of Advanced Drug Preparation Technologies,Ministry of Education&Collaborative Innovation Center of New Drug Research and Safety Evaluation,Henan Province&Key Laboratory of Henan Province for Drug Quality and Evaluation,Zhengzhou 450000,China)

机构地区：[1]江苏九旭药业有限公司,江苏徐州221200 [2]郑州大学药学院,河南郑州450001 [3]药物关键制备技术教育部重点实验室、新药创制与药物安全性评价河南省协同创新中心和河南省药品质量控制与评价重点实验室,河南郑州450000

出　　处：《精细化工中间体》2022年第6期38-41,共4页Fine Chemical Intermediates

基　　金：河南省科技厅科技攻关项目(222102310279)。

摘　　要：以2-溴-6-(1-甲基哌啶-4-基羰基)吡啶为原料,微量氧化亚铜为催化剂,氨水为氨源,在常压和80~90℃条件下反应4 h,可制得2-氨基-6-(1-甲基哌啶-4-基羰基)吡啶,经与盐酸成盐后获得拉米地坦合成的关键中间体2-氨基-6-(1-甲基哌啶-4-基羰基)吡啶双盐酸盐。该方法采用氨水替代高危试剂液氨,规避了高压条件,收率可达70%,产品HPLC纯度可达98%以上。其合成工艺具有反应条件温和,操作简便易行,不需要高压设备,符合绿色化学理念,适合规模化制备的优点。The key intermediate for the synthesis of lamidirtan 2-amino-6-(1-methyl piperidine-4-ylcarbonyl)pyridine was prepared from the reaction between 2-bromo-6-(1-methyl piperidine-4-ylcarbonyl)pyridine and2-bromo-6-(1-methyl piperidine-4-ylcarbonyl)pyridine under normal pressure at a temperature of 80~90℃using trace of cuperous oxide as catalyst and ammonia water as ammonia source for 4 h.The target intermediate was obtained after salt formation with hydrochloric acid.In this method water solution of ammonia replaced high risk reagent liquid ammonia to avoid high pressure conditions with a yield of 70%and the HPLC purity of 98%.This method has the advantages including mild reaction conditions,simple operation,no need of high-pressure equipment,and suitable for large-scale preparation.

关 键 词：拉米地坦 中间体 2-氨基-6-(1-甲基哌啶-4-基羰基)吡啶 工艺优化 

分 类 号：R917[医药卫生—药物分析学]