(1R,2S)-2-(3,4-二氟苯基)环丙胺的合成

替卡格雷是一种口服选择性小分子抗凝血药,不需要通过代谢激活,自身具有抗血小板活性。(1R,2S)-2-(3,4-二氟苯基)环丙胺是合成替卡格雷的一个关键中间体。该文在文献报道的合成路线基础上对其中关键步骤——不对称Corey-Chaykovsky环丙烷化反应进行了研究,筛选出最优反应条件:以L-薄荷醇为手性辅剂,三甲基碘化锍盐为硫叶立德试剂,二甲亚砜和四氢呋喃为混合溶剂,温度为10～12℃,质量分数10%的碘化亚铜为催化剂时,反应收率为60.5%;合成(1R,2S)-2-(3,4-二氟苯基)环丙胺5步总收率为20.0%。

Synthesis of (1R,2S)-2-(3,4-difluorophenyl) Cyclopropanamine

Ticagrelor,which is a small molecule anti-clotting drug peros with high selectivity,has anti-platelet activity without metabolic activation.And(1R,2S)-2-(3,4-difluorophenyl) cyclopropanamine is an important intermediate of ticagrelor.The key-step of Corey-Chaykovsky asymmetric cyclopropanation reactions was studied based on the references and the optimum synthetic conditions were developed as follows:L-menthol as chiral auxiliary agents;trimethylsulfonium iodide as sulfur-ylide reagent;n(DMSO):n(THF)=4:1 as reaction solvent;reaction temperature 10-12 ℃;and 10% CuI as reaction catalyst.Under such optimum conditions,the yield was 60.5%.Based on the reaction,the total yield of the five steps was 20.0%.