平行-连续法合成沙奎那韦

采用平行-连续法合成了H IV蛋白酶抑制剂沙奎那韦。在中间体(S)-4-氨基-4-氧代-2-(喹啉-2-羧酰胺基)丁酸的合成中,由喹哪啶-2-羧酸与亚硫酰氯反应得其酰氯作为活化剂,最佳反应条件为:回流8 h,收率95.0%;采用水介质合成了(S)-4-氨基-4-氧代-2-(喹啉-2-羧酰胺基)丁酸,收率82.0%。在硅胶存在下,(S)-1-〔(S)-2-环氧乙烷〕-2-苯基乙基氨基甲酸苄酯和(3S,4aS,8aS〕-N-叔丁基-十氢异喹啉-3-羧酰胺室温反应72 h,得(2S,3R)-4-〔(3S,4aS,8aS)-3-(叔丁氨甲酰基)-十氢异喹啉〕-3-羟基-1-苯基丁基-2-氨基甲酸苄酯,不经提纯,加入Pd/C〔w(Pd)=10%〕催化剂室温下与H2反应12 h脱去保护基,反应完毕后以乙腈重结晶即得另一中间体(3S,4aS,8aS)-2-〔(2R,3S)-3-氨基-2-羟基-4-苯基丁基〕-N-叔丁基-十氢异喹啉-3-羧酰胺,收率87.0%;两个中间体连接时,使用便宜、常见的N-羟基琥珀酰亚胺,收率82.0%。

Synthesis of Saquinavir via Convergence Method

Synthesis of saquinavir,an HIV protease inhibitor,was researched via convergence method.In the process of synthesis of one intermediate(S)-4-amino-4-oxo-2-(quinoline-2-carboxamido)butanoic acid,quinaldine-2-carboxylic acid reacted with thionyl chloride under reflux for 8 h to give its acyl chloride as an activating reagent in 95.0% yield.The intermediate was prepared in the water with a yield of 82.0%.Benzyl(S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate reacted with(3S,4aS,8aS)N-tert-butyl-decahydroisoquinoline-3-carboxamide in the presence of silica gel at room temperature for 72 h,giving benzyl(2S,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)-decahydroisoquinoline-2((1H)-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate,which,without purification,was mixed with Pd/C(w(Pd)=10%) and stirred in hydrogen atmosphere at room temperature for 12 h to remove the benzyloxycarbonyl group,and recrystallized in acetontrile to get(3S,4aS,8aS)-2-((2R,3S)-3amino-2-hydroxy-4-phenylbutyl)-N-tert-butyl-decahydroisoquinoline3-carboxamide,another intermediate,with a yield of 87.0%.N-Hydroxysuccinimide was applied to the reaction of two intermediates to get the target product in 82.0% yield.