抗丙肝新药盐酸氘代达卡他韦的合成  

Synthesis of the New Anti-HCV Drug Deudaclatasvir Dihydrochloride

作　　者：丰巍伟 刘飞 徐云根[2] 张寅生 FENG Weiwei;LIU Fei;XU Yungen;ZHANG Yinsheng(Chia Tai Tianqing Pharmaceutical Group Co.,Ltd.,Nanjing 211122;School of Pharmacy,China Pharmaceutical University,Nanjing 211198)

机构地区：[1]正大天晴药业集团股份有限公司,南京211122 [2]中国药科大学药学院,南京211198

出　　处：《中国医药工业杂志》2020年第5期586-590,共5页Chinese Journal of Pharmaceuticals

基　　金：国家“重大新药创制”科技重大专项(2017ZX09201006010);江苏省博士后科研资助计划(2018K044A)。

摘　　要：盐酸氘代达卡他韦(1b)是我们自主研发的HCV NS5A抑制剂,拥有较高的成药性。本研究以4,4’-二(2-溴乙酰基)-1,1’-联苯(2)和N-叔丁氧羰基-L-脯氨酸(3)为起始原料,经酯化反应得到4,4’-二[N-叔丁氧羰基-(2S)-吡咯烷-2-羰基氧甲基甲酰基]-1,1’-联苯(4),4再氨解环合得到4,4’-二[2-[N-叔丁氧羰基-(2S)-吡咯烷-2-基]-1H-咪唑-5-基]-1,1’-联苯(5),盐酸脱Boc保护基得到4,4’-二[2-[(2S)-吡咯烷-2-基]-1H-咪唑-5-基]-1,1’-联苯四盐酸盐(6),6与N-(三氘代甲氧羰基)-L-缬氨酸(8)经缩合反应和氯化氢成盐得到1b,纯度99.66%,总收率45%(以2计)。该工艺条件温和、操作简便,适合工业化生产。Deudaclatasvir dihydrochloride(1 b) is a HCV NS5 A inhibitor developed independently by us, which has a better druggability. 4,4’-Bis[N-tert-butoxycarbonyl-(2 S)-pyrrolidine-2-carbonyloxymethylformyl]-1,1’-biphenyl(4) was synthesized via esterification between 4,4’-bis(2-bromoacetyl)-1,1’-biphenyl(2) and N-tert-butoxycarbonyl-Lproline(3). Then 4,4’-bis[2-[N-tert-butoxycarbonyl-(2 S)-pyrrolidine-2-yl]-1 H-imidazol-5-yl]-1,1’-biphenyl(5) was prepared by ammonolysis and cyclization of 4. Compound 5 was deprotected by hydrochloric acid to give 4,4’-bis[2-[(2 S)-pyrrolidine-2-yl]-1 H-imidazol-5-yl]-1,1’-biphenyl tetrahydrochloride(6), which was followed by condensation with N-[(methoxy-d3)carbonyl]-L-valine(8) and salt formation with HCl(g) to provide 1 b with a purity of 99.66% and a total yield of 45%(based on 2). This process had the advantages of mild reaction conditions and simple operation, which was suitable for industrial production.

关 键 词：氘代达卡他韦 抗丙型肝炎病毒 NS5A抑制剂 合成 

分 类 号：R914[医药卫生—药物化学] R978.7[医药卫生—药学]