艾氟康唑合成工艺改进

Process Improvement on the Synthesis of Efinaconazole

为了探索艾氟康唑合成的新路线,以R-乳酸甲酯为原料,经吗啉胺化成4-[(R)-2-羟基丙酮基]吗啉(Ⅱ),在羟基保护后与格氏试剂2,4-二氟苯基溴化镁反应得到(2R)-2',4'-二氟-2-(3,4,5,6-四氢-2H-吡喃-2-氧)丙基苯基酮(Ⅳ),之后采用"一锅法"完成科里-柴可夫斯基环氧化、三氮唑烷基化以及脱保护反应得到中间体(2R,3R)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三氮唑-1-基)-2,3-丁二醇(Ⅶ),经甲磺酰化、成环氧、与4-亚甲基哌啶缩合,得产物艾氟康唑(Ⅰ),总收率由17%提高到24%,产物经高效液相色谱测定纯度达99%以上;产物经核磁、质谱和旋光表征。

To explore a new route for the synthesis of efinaconazole,intermediate 4-[（R）-2-hydroxypropiony]morpholine（Ⅱ） was prepared from starting materials R-methyl lactate by amination with morpholine,（2R）-2＇,4＇-difluoro-2-（3,4,5,6-tetrahydro-2H-pyran-2-lyoxy） propiophenone（Ⅳ）was synthesized by reacting with 2,4-difluorophenyl magnesium bromide after hydroxy group was protected.Precursor（2R,3R）-2-（2,4-difluorophenyl）-1-（1H-1,2,4-triazol-1-yl）-2,3-butanediol（Ⅶ）was obtained via Corey-Chaykovsky epoxidation,trizole alkylation and deprotection in one pot reation.After reacting with methanesulfonyl chloride,epoxidation and subsequent alkylation with 4-methylenepiperidine,the product efinaconazole（Ⅰ） was acquired.The total yield of efinaconazole（Ⅰ）was increased to 24% from 17% with purity of more than 99% determined by HPLC.The stucture of product was characterized by means of1 HNMR,ESI-MS and polarimetry.