HIV蛋白酶抑制剂利托那韦的制备  

Preparation of HIV protease inhibitors ritonavir

作　　者：白跃飞 黄丽荣 皮昌桥 吴晓璟 崔振强 胡铁军 周凯 BAI Yue-fei;HUANG Ll-rong;PI Chang-qiao;WU Xiao-jing;CUI Zhen-qiang;HU Tie-jun;ZHOU Kai(Northeast Pharmaceutical Group Co.,Ltd.,Shenyang 110027,China;Shenyang Mental Health Center,Department of Pharmacy,Shenyang 110168,China)

机构地区：[1]东北制药集团股份有限公司,沈阳110027 [2]沈阳市精神卫生中心药剂科,沈阳110168

出　　处：《中国新药杂志》2018年第20期2412-2416,共5页Chinese Journal of New Drugs

基　　金：辽宁百千万人才工程基金资助项目(2015-2);辽宁省博士启动基金资助项目(201501139);沈阳市科学技术计划基金资助项目(F16-179-9-00)

摘　　要：目的:对利托那韦的制备工艺进行研究。方法:以2-甲基丙酰胺为原料,经硫代、环合与缩合反应得到中间体N-(2-异丙基噻唑基-4-甲基)-N-甲胺(5);以(S)-2-氨基-3-甲基丁酸甲酯为原料,经酰胺化反应得到中间体(S)-3-甲基-2-[(4-硝基苯基)羰基氨基]丁酸甲酯(8);中间体5与中间体8经偶联、水解得到中间体N-[[2-异丙基-1,3-噻唑基-4)甲基](甲基)氨基甲酰基]-L-缬氨酸(10);以(2S,3S,5S)-2-氨基-3-羟基-5-叔丁氧基甲酰氨基-1,6-二苯基己烷(11)为原料,经缩合、脱Boc再与中间体10缩合反应制得利托那韦。结果:目标化合物的结构经1H NMR,13C NMR,MS和X射线衍射确证,总收率为28. 9%(以2-甲基丙酰胺计),HPLC测定纯度达99. 8%。结论:该制备方法所用原料易得,操作简便,收率较高,成品质量好,适合工业化生产。Objective： To study the preparation method of ritonavir. Methods： Using 2-methylacrylamide as raw material,N-（ 2-isopropylthiazol-4-ylmethyl）-N-methylamine（ 5） was prepared by sulfur treatment,cyclization and condensation. Using（ S）-methyl 2-amino-3-methylbutanoate as raw material,（ S）-methyl 3-methyl-2-（ methyl（（ 4-nitrophenoxy） carbonyl） amino） butanoate（ 8） was prepared by amidization. The intermediate 5 was coupled with intermediate 8,followed by hydrolysis reaction to give N-[[（ 2-isopropyl-1,3-thiazol-4-yl） methyl]（ methyl）carbamoyl]-L-valine（ 10）. Taking tert-butyl（ 2 S,3 S,5 S）-2-amino-3-hydroxy-5-tert-butyloxy carbonylamino-1,6-diphenylhexane（ 11） as the material,ritonavir was prepared by condensation,deprotection Boc as well as recondensation with 10. Results： The structure of ritonavir was confirmed by1 H-NMR,13 C-NMR,MS and X-ray diffraction,with an overall yield of 28. 9%（ from 2-methylpropionamide）. The purity was 99. 8% determined by HPLC. Conclusion： This synthetic method has advantages of easy operation,good quality,high product yield,and is more suitable for industrial production.

关 键 词：利托那韦 人类免疫缺陷病毒蛋白酶抑制剂 制备 

分 类 号：R913.5[医药卫生—药学]