【摘要】 以"一锅煮"方法合成了奈非那韦中间体-(3S,4aS,8aS)-2-((2R,3R)-3-氨基-2-羟基-4-(苯硫)丁基)-N-tert-丁基-十氢异喹啉-3-羧酰胺(Ⅶ),并以活泼酯新方法连接中间体Ⅶ得到了奈非那韦(Ⅸ)。在不同浓度和温度氢氧化钾的催化下,环合氯醇化合物(2R,3S)-4-氯-3-羟基-1-苯基硫丁基-2-氨基甲酸苄酯(Ⅲ),然后与(3S,4aS,8aS)-N-叔丁基-十氢异喹啉-3-羧酰胺(Ⅴ)反应,再脱去苄氧羰基保护基得中间体Ⅶ,收率89.0%。以2-甲基-3-乙酰氧基苯甲酸琥珀酰亚胺酯(Ⅱ)连接Ⅶ,再以浓氨水脱去乙酰基得奈非那韦(Ⅸ),收率86.0%。讨论了奈非那韦的红外光谱特征吸收峰所对应的官能团的振动形式,以MALDI-TOFMS(基质辅助激光解吸电离飞行时间质谱)得到了其分子离子及准分子离子峰,利用一维(1HNMR,13CNMR)和DEPT(不失真极化转移增强谱)及HMBC(1H检测的异核多键相关谱)、HSQC(1H检测的异核单量子相干谱)、DQF-COSY(双量子过滤相干谱)等二维核磁共振波谱手段对奈非那韦的分子结构进行了表征,并对其核磁谱线进行了归属分析。这对奈非那韦的结构鉴定及质量控制均有重要的参考价值。更多还原

【Abstract】 An efficient and environmentally friendly procedure for the one-pot synthesis of (3S,4aS,8aS)-2-((2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyl)-N-tert-butyl-decahydroisoquinoline-3-carboxamide(Ⅶ), the intermediate of nelfinavir, was described, and activating ester was applied to getting nelfinavir(Ⅸ). Under the catalysis of potassium hydroxide, benzyl (R)-1-((S)-oxiran--yl)-2-(phenylthio) ethyl carbamate was obtained(Ⅳ) in methanol. Then Ⅳ and (3S,4aS,8aS)-N-tert-butyl-decahydroisoquinoline-3-carboxamide(Ⅴ) were refluxed in methanol until the reaction was finished. Potassium hydroxide(w(KOH)=40%) in water was added to remove benzyloxycarbonyl group in water bath with a yield of 89.0%. 3-acetoxy-2-methylbenzoic acid-succinimide ester(Ⅱ) reacted with Ⅶ and acetyl group was removed by dense aqueous ammonia, giving nelfinavir(Ⅸ). The vibrations of functional groups of this compound corresponding to the main infrared absorption peaks were discussed. The molecular ion and quasi molecular ion peaks were obtained via MALDI-TOF MS, and 1H NMR and 13CNMR shifts of this compound were assigned by means of DEPT(distortionless enhancement by polarization transfer spectrum), HMBC(1H detected heteronuclearmultiple bond correlation spectrum), HSQC(1H detected heteronuclear single-quantum coherence spectrum) and DQF-COSY(double-quantum filtered-correlated spectroscopy). The results provided useful information for structure characterization and quality control of nelfinavir.更多还原