甲磺酸雷沙吉兰的合成工艺改进  

Improved Synthesis of Rasagiline Mesylate

作　　者：李杰 潘辛梅 赖永莉 钟辉云 LI Jie;PAN Xinmei;LAI Yongli;ZHONG Huiyun(Dept.of Pharmacy,Sichuan Vocational College of Health and Rehabilitation,Zigong 643000;Dept.of Pharmacy,the First Affiliated Hospital of Army Medical University,Chongqing 400038)

机构地区：[1]四川卫生康复职业学院药学系,四川自贡643000 [2]陆军军医大学第一附属医院药学部,重庆400038

出　　处：《中国医药工业杂志》2021年第5期639-641,660,共4页Chinese Journal of Pharmaceuticals

基　　金：四川卫生康复职业学院培育基金项目(CWKY-2018Y-02)给予资助。

摘　　要：本研究改进了甲磺酸雷沙吉兰(1)的合成工艺。用对甲苯磺酰氯(2)与炔丙醇(3)在二氯甲烷中反应得到对甲苯磺酸炔丙酯(4)。另用1-茚酮(5)与甲酸铵、10%钯炭在常温常压下反应得到1-氨基茚满(6),与4反应得到N-炔丙基-1-氨基茚满(7),再经L-酒石酸拆分得到二[(R)-(+)-N-炔丙基-1-氨基茚]-L-酒石酸盐(8),最后与甲磺酸成盐得到目标产物1,总收率约12%(以5计)。制备6时,采用甲酸铵、钯炭体系"一锅法"完成5的还原胺化,缩短了反应步骤,收率由37%提高至70%;制备7时,以空间位阻较大的4代替3-氯丙炔,有效减少氨基二取代副反应,收率由68%提高至78%。改进后的方法操作简单,试剂价廉易得,反应条件温和可控,收率高,具备工业化生产潜力。The synthetic method of rasagiline mesylate was improved.Propargyl alcohol(3)was reacted with tosyl chloride(2)in dichloromethane to get propargyl p-toluenesulfonate(4).1-Indanone(5)was reacted with ammonium formate under the catalysis of 10%Pd/C to give 1-indanamine(6),which was then treated with 4 to afford N-propargyl-1-indanamine(7),then through enantioseparation by L-tartaric acid to get(R)-(+)-N-propargyl-1-indanamine tartrate(8).Finally,the target product was prepared by reacting with methanesulfonic acid.The overall yield was 12%(based on 5).During preparation of 6,the reductive amination was accomplished by ammonium formate and Pd/C with one pot method,which reduced the steps and substantially increased the yield from 37%to 70%.In the preparation of 7,3-chloropropyne was replaced by 4 with large steric hindrance,which effectively reduced the side reaction of amino disubstitution,and increased the yield from 68%to 78%.This improved synthetic method has several advantages,such as simple operation,inexpensive materials,mild conditions and high yield,which offers great potential for industrial application.

关 键 词：雷沙吉兰 帕金森病 1-氨基茚满 工艺改进 

分 类 号：R971.5[医药卫生—药品]