沙奎那韦中间体合成工艺改进

治疗艾滋病的沙奎那韦的中间体———(3S,4 aS,8 aS)-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(Ⅱ)是通过(2S,3S)-4氯--3羟-基-1苯-基丁烷-2氨-基甲酸苄酯(Ⅲ)和(3S,4 aS,8 aS)-N-叔丁基-十氢异喹啉-3-羧酰胺(Ⅴ)反应得到的。该文对工艺进行了如下改进:Ⅲ的环化和与Ⅴ的反应合并为“一锅煮”工艺,去除原有文献报道的柱层析过程,只需洗去氢氧化钾的分液操作,直接加入w(Pd)=10%的Pd/C催化剂,室温反应12 h即脱去保护基。反应完毕后,以乙腈重结晶即得到目标产物Ⅱ。改进后的工艺总产率达到87%,w(Ⅱ)=98.5%。该法原则上适用于多种H IV蛋白酶抑制剂的合成。

Improvement in the Synthetic Method of Intermediate of Saquinavir

(3S,4aS,8aS)-2-((2R,3S)-3-Amino2-hydroxy-4-phenybutyl)-N-tert-butyl-decahydroisoquinoline-3-carboxamide(Ⅱ),an important intermediate of saquinavir for anti-AIDS,was prepared starting from benzyl(2S,3S)-4-chloro-3-hydroxy-1-phenylbutane-2-ylcarbamate(Ⅲ) and(3S,4aS,8aS)-N-tert-butyl-decahydroisoquinoline-3-carboxamide(Ⅴ)."One pot" process was introduced into the cyclization of Ⅲ and the reaction with Ⅴ,and then potassium hydroxide was removed in the process of skimming.The crude benzyl(2S,3S)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)-octahydroisoquinoline-2(1H)-yl)-3-hydroxy-1-phenylbutan-2-yl carbamate was reduced by Pd/C(w(Pd)=10%) for 12 h at the room temperature without chromatographic separation.Pure Ⅱ was obtained through recrystallisation in acetonitrile.The improved process was easy to operate with high yield of 87% and purity w(Ⅱ)=98.5%.It is appropriate to the synthesis of lots of HIV protease inhibitors in principle.