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目的改进抗结核药地依麦迪的合成工艺。方法 2-甲基烯丙醇经Sharpless环氧化后与对硝基苯磺酰氯反应得到中间体(R)-2-甲基环氧丙醇-4-硝基苯甲磺酸酯;N-Boc-4-羟基哌啶与对三氟甲氧基苯酚经Mitsunobu反应、脱保护、Buchwald-Hartwig反应、脱苄基得到中间体4-[4-(4-三氟甲氧基-苯氧基)哌啶基]苯酚,这两个中间体经亲核取代反应得到(R)-1-[4-(2,3-环氧-2-甲基丙氧基)苯基]-4-(4-三氟甲氧基苯氧基)哌啶,该化合物与2-溴-4-硝基咪唑经亲核取代、环合得到终产物地依麦迪。结果与结论工艺优化后,以2-甲基烯丙醇计,总收率为27.6%(优化前为17.8%),以N-Boc-4-羟基哌啶计,总收率为33.4%(优化前为11.0%),产物的HPLC化学纯度为100%,ee值也达到了100%,新工艺路线操作简单,适合工业化生产。
Objective To improve the synthesis of anti-tuberculosis drugs according to McGrady’s technology. Method 2-Methylallyl alcohol was reacted with p-nitrobenzenesulfonyl chloride by Sharpless epoxidation to obtain intermediate (R) -2-methyloxypropanol-4-nitrophenyl methanesulfonate. N- Boc-4-hydroxypiperidine and p-trifluoromethoxyphenol were Mitsunobu reaction, deprotection, Buchwald-Hartwig reaction, debenzylation to obtain the intermediate 4- [4- (4- trifluoromethoxy-phenoxy ) Piperidinyl] phenol, both of which were subjected to nucleophilic substitution to give (R) -1- [4- (2,3-epoxy-2-methylpropoxy) phenyl] -4- 4-trifluoromethoxyphenoxy) piperidine, which is nucleophilic substitution with 2-bromo-4-nitroimidazole to give the final product of epimedium. Results and Conclusions After optimization of the process, the total yield was 27.6% (pre-optimization 17.8%) based on 2-methylallyl alcohol and 33.4% for N-Boc-4-hydroxypiperidine 11.0% before optimization), the HPLC chemical purity of the product was 100%, ee value reached 100%, the new route easy to operate, suitable for industrial production.