洛匹那韦的合成工艺优化  

Improved Synthetic Process of Lopinavir

作　　者：何茶生 翟自然 周阳 王冠[1,2] HE Chasheng;ZHAI Ziran;ZHOU Yang;WANG Guan(Novel Technology Center of Pharmaceutical Chemistry,Shanghai Institute of Pharmaceutical Industry,China State Institute of Pharmaceutical Industry,Shanghai 201203;Shanghai Engineering Research Center of Pharmaceutical Process,Shanghai 201203;School of Engineering,China Pharmaceutical University,Nanjing 211198)

机构地区：[1]中国医药工业研究总院上海医药工业研究院化学制药新技术中心,上海201203 [2]上海药物合成工艺过程工程技术研究中心,上海201203 [3]中国药科大学工学院,江苏南京211198

出　　处：《中国医药工业杂志》2021年第2期198-202,共5页Chinese Journal of Pharmaceuticals

摘　　要：本研究改进了洛匹那韦(1)的合成工艺。以[(1S,3S,4S)-4-氨基-3-羟基-5-苯基-1-(苯甲基)戊基]氨基甲酸叔丁酯(2)为起始原料,在苯并三唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)和三乙胺作用下,与2,6-二甲基苯氧乙酸(3)反应制得(2S,3S,5S)-2-(2,6-二甲基苯氧乙酰基)氨基-3-羟基-5-(叔丁氧羰基)氨基-1,6-二苯基己烷(4),再经三氟乙酸脱除Boc保护基制得N-[(1S,2S,4S)-4-氨基-2-羟基-5-苯基-1-(苯甲基)戊基]-2-(2,6-二甲基苯氧基)乙酰胺(5),最后与(2S)-(1-四氢嘧啶-2-酮)-3-甲基丁酸(6)缩合、精制得1。优化后的工艺操作简便,产品质量稳定可控,总收率63%(以2计)。同时还制备了价格昂贵且国内无商业供应的原料3和6,可为低成本制备1提供参考。The synthetic process of lopinavir(1)was improved in this reported.Tert-butyl[(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]carbamate(2)reacted with 2,6-dimethylphenoxyacetic acid(3)in the presence of O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate(HBTU)and trimethylamine to give(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(tert-butoxycarbonyl)amino-1,6-diphenylhexane(4).And then N-[(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide(5)was prepared by deprotecting N-Boc from 4 with trifluoroacetic acid.Compound 5 was condensed with(2S)-(1-tetrahydropyrimidine-2-one)-3-methylbutyric acid(6)to obtain 1 in a total yield of 63%(based on 2).This improved process was easy to operate and the product quality was stable and controllable.The expensive raw materials 3 and 6,which had no commercial supply in China,were also prepared,and it could provide a reference for lowcost preparation of 1.

关 键 词：洛匹那韦 合成 工艺改进 

分 类 号：R978.7[医药卫生—药品] R914.5[医药卫生—药学]