抗HIV药物硫酸阿扎那韦的合成工艺改进

Improved synthesis of anti-HIV drug atazanavir sulfate

目的改进抗HIV药物硫酸阿扎那韦的合成工艺。方法对已报道的硫酸阿扎那韦及其关键中间体(2R,3S)-1,2-环氧-3-叔丁氧羰基氨基-4-苯基丁烷(6)的合成路线进行分析,以其中一条路线为基础对其合成工艺进行改进和优化。以L-苯丙氨酸为起始原料,经Boc保护、偶合、Arndt-Eistert反应、还原、环合得到硫酸阿扎那韦的关键中间体6,该中间体与市售化合物2-[4-(2-吡啶基)苄基]-肼羧酸叔丁酯经环氧环开环胺解、脱Boc基、成盐、经碱液游离得到另一中间体1-[4-(吡啶-2-基)-苯基]-4(S)-羟基-5(S)-2,5-二氨基-6-苯基-2-氮杂己烷,其与市售的N-甲氧羰基-L-叔亮氨酸缩合并经离子交换反应制得硫酸阿扎那韦。结果与结论优化了硫酸阿扎那韦的合成工艺,目标化合物的结构经~1H-NM R、^(13)C-NM R和M S谱确证,总收率为53.8%(以L-苯丙氨酸计),HPLC法测定纯度达99.8%。与文献报道的工艺相比,该路线所用原料价廉易得、操作简便、收率较高、成品质量好,为中试放大实验奠定了一定基础。

Atazanavir sulfate, an oral azapeptide HIV-1 protease inhibitor, was developed and launched by Bristol-Myers Squibb（BMS） under license from Novartis AG and used in combination with other antiretroviral drugs in treatment-naive or treatment-experienced HIV-lpatients. Synthetic routes to atazanavir sulfate and its key intermediate （ 2R, 3 S） -3- （ N-Boc -amino ） - 1 -oxirane-4-phenylbutane were summarized in this article. During the course of analyzing the reported synthetic routes, some disadvantages were found in some synthetic steps. To get the product and improve the synthetic methods, an efficient and practical synthesis of （2R ,3S）-3-（N-Boc-amino）-1-oxirane-4-phenylbutane was developed by optimizing the synthetic steps from L-phenylalamine as the starting material by Boc-protection, coupled with ethyl chloroformate, Arndt-Eistert reacted, reduction, cyclization. Then reacted with commercially available 2- [ 14- （2-pyridinyl） phenyl ] methyl ] - hydrazinecarboxylic acid 1,1-dimethylethyl ester through incorporated reaction of epoxide ring aminolysis, Boc-deprotection, followed by salifying, basic free, getting intermediate （ 2S, 3 S ） -3 -amino-4-phenyl- 1 - （ 1 - （ 4- （ pyridin-2-yl ） benzyl ） hydrazinyl ） butan-2-ol, and ultimately reacted with commercially available （S） -2- （（methoxycarbonyl） amino）-3,3-dimethylbutanoic acid through condensation and employing ion exchange resin reaction to give atazanavir sulfate. The structure of atazanavir sulfate was confirmed by 1H-NMR, 13C-NMR and MS, with an overall yield of 53.8% and a purity of 99.8% by HPLC determination. The process has several advantages over those reported procedures, such as simplifying the reaction conditions and following treatments ,reducing the use of reagents and reactants, improved yield, high purity and industrial production.