摘要
目的对奈韦拉平的工业化生产工艺进行改进与优化。方法以2-氯-N-(2-氯-4-甲基吡啶-3-基)烟酰胺为起始原料,与环丙胺进行胺化反应得到N-(2-氯-4-甲基吡啶-3-基)-2-环丙胺基烟酰胺,再与氢化钠反应得到环合物,该环合物经重结晶后得到奈韦拉平。结果与结论奈韦拉平的结构经MS、~1H-NM R和^(13)C-NM R谱确证。本文首次报道工业生产中奈韦拉平成品中关键杂质的结构,并通过对杂质结构的分析,对反应条件和反应装置进行优化。改进后的生产工艺有效地减少了产品中杂质的含量,降低了生产成本,具有收率高、纯度高、减少三废排放量等特点,适用于工业化生产。
Nevirapine is a non-nucleoside reverse transcriptase inhibitor for the treatment of AIDS. The first synthetic route to nevirapine was developed by Bochringer Ingelheim Company. An improved production process was developed in this paper. The intermediate N-(2-chloro-4-methylpyridin-3-yl)-2-( cyclopropylamino )nicotinamide was synthesized by the nucleophilic substitution reaction of cyclopropylamine with the 2- chloro-N-(2-chloro-4-methylpyridin-3-yl) nicotinamide. Then was treated with sodium hydrogen to give the crude product. Finally, nevirapine was obtained by recrystallization. The structure of nevirapine was confirmed by MS, 1H-NMR, 13 C-NMR. The causes of the major impurities were analyzed in the product and improved the production process by optimizing the production equipment and reaction conditions. The improved route has practicality, high conversion rate, simple post-processing features, and is suitable for the large-scale production.
作者
董鹏
邢运哲
丁成荣
DONG Peng;XING Yun-zhe;DING Cheng-rong(Zhejiang Huahai Pharmaceutical Co.,Ltd.,Linhai 317016,China;Chemical Engineering College,Zhejiang University of Technology,Hangzhou 310014,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2018年第5期384-387,共4页
Chinese Journal of Medicinal Chemistry
关键词
奈韦拉平
杂质
合成
生产工艺
nevirapine
impurities
synthesis
production process