地依麦迪的合成工艺研究

Study on the synthesis of delamanid

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。

An optimized synthetic process to delamanid was developed. （R） -4-Nitrobenzene sulfonic acid 2-rneth- ylglycidyl （15） was prepared from 2-methallyl alcohol through Sharpless asymmetric epoxidation followed by the hydroxyl group activation with p-nitrobenzenesulfonyl chloride. 4-[ 4-（4-Trifluoromethoxyphenoxy ）-piperidin-1- yll phenol（3） was synthesized from N-Boc-4-hydroxyl piperidine and p-trifluoromethoxy phenol via Mitsunobu reaction,Boc deprotection,Buchwald-Hartwig amination and benzyl deprotection. The nucleophilic substitution of 15 with 3 gave （ R ）-1-（4-（ （ 2-methyloxiran-2-yl ） methoxy ） phenyl ）-4-（4-（ trifluoromethoxy ） phenoxy ） piperi- dine,which reacted with 2-bromo-4-nitroimidazole to form the desired product（delamanid）. The total yield of the process was 27.6% （based on 2-methallyl alcohol） and 33.4% （ based on N-Boc-4-hydroxyl piperidine） respectively,and the HPLC purity and ee value both reached 100%. The optimized synthetic route to delamanid was characterized with improved yield,easier operations,suitable for industrial production.