摘要
目的 对小分子布鲁顿酪氨酸蛋白激酶(BTK)抑制剂泽布替尼的合成工艺进行优化。方法 以4-苯氧基苯甲酸为原料,依次经酰化、甲基化、环合反应制得中间体3-氨基-4-氰基-5-(4-苯氧基苯基)吡唑(4);以1-叔丁氧羰基-4-哌啶甲酸为原料,依次经酰胺化、亲核加成、缩合反应制得中间体4-[3-(二甲基氨基)丙烯酰基]哌啶-1-羧酸叔丁酯(8);中间体4和8经环合、还原、脱Boc保护、水解、手性拆分、酰胺化反应制得泽布替尼。结果与结论泽布替尼的结构经1H-NMR、13C-NMR和MS谱确证,泽布替尼总收率为11.9%(以4-苯氧基苯甲酸计),纯度为99.60%(HPLC法),手性纯度为98.65%。与原研路线相比,该路线仅通过一次化学拆分即制得高手性纯度的泽布替尼,合成路线得以简化,收率得到提高。
Taking 4⁃phenoxybenzoic acid as the starting material,the key intermediate 3⁃amino⁃4⁃cyano⁃5⁃(4⁃phenoxyphenyl)pyrazole(4)was synthesized by acylation,methylation and cyclization.Another key intermediate tert⁃butyl⁃4⁃[3⁃(dimethylamino)acryloyl]piperidine⁃1⁃carboxylate(8)was prepared starting from 1⁃[(tert⁃butyl)oxycarbonyl]piperidine⁃4⁃carboxylic acid,followed by amidation,nucleophilic addition and condensation.Then intermediate 4 was condensated with intermediate 8,followed by cyclization,reduction,deprotection,hydrolysis,chiral resolution and amidation to obtain the target product zanubrutinib.The synthetic route was simplified and the yield was good.The total yield of zanubrutinib was 11.9%(calculated by 4⁃phenoxybenzoic acid),the purity was 99.60%,and the chiral purity(HPLC)was 98.65%.The chemical structure of zanubrutinib was confirmed by MS,IR,1H⁃NMR and 13C⁃NMR,and the chemical structures of some intermediates were confirmed by MS and 1H⁃NMR.
作者
吴秀静
张雅婷
周辉
黄敬璇
刘玖玉
宫平
WU Xiu-jing;ZHANG Ya-ting;ZHOU Hui;HUANG Jing-xuan;LIU Jiu-yu;GONG Ping(Shanghai High Standard Pharm&Med Co.,Ltd.,Shanghai 201112,China;Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)
出处
《中国药物化学杂志》
CAS
2023年第7期516-522,共7页
Chinese Journal of Medicinal Chemistry
关键词
泽布替尼
BTK抑制剂
合成
工艺改进
zanubrutinib
BTK inhibitor
synthesis
process improvement
