福沙匹坦二甲葡胺的合成工艺改进研究

Improved Synthesis of Fosapitant Dimeglumine

报道了合成标题化合物的新工艺。以(2R,3S)-2-((1R)-1-(3,5-双(三氟甲基)苯基)乙氧基)-3-(4-氟苯基)吗啉盐酸盐为起始物料,与5-氯甲基-2,4-二氢[1,2,4]三唑-3-酮反应得到5-[[(2R,3S)-2-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)-4-吗啉]甲基]-1,2-二氢-3H-1,2,4-三氮唑-3-酮,即阿瑞匹坦。将得到的阿瑞匹坦在碱性条件下与焦磷酸四苄酯反应得到二-O-苄基磷酸酯。然后于高压釜中采用钯碳氢化还原后与N-甲基-D-葡糖胺成盐,最终通过精制得到合格的标题化合物,产率为61.8%。标题化合物经1HNMR、13CNMR和HR-MS确认结构,本路线切实可行、条件温和、产品质量可控,具有一定的工业应用价值。

A new process for the synthetic of Fosapitant dimeglumine was reported.(2R,3S)-2-((1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine hydrochloride as the starting material,it was reacted with 5-chloromethyl-2,4-dihydro[1,2,4]triazol-3-one to give 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholine]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.It was Aprepitant.Aprepitant was reacted with tetrabenzyl pyrophosphate under alkaline conditions to obtain di-O-benzyl phosphate.Phosphate was reduced by palladium hydrocarbonization in autoclaves,then reacted with N-methyl-D-glucosamine to form a salt.The final sample was refined to obtain a qualified title compound,and the yield was 61.8%.The titile compound was confirmed by 1HNMR,13CNMR and HR-MS.This route is feasible,with mild conditions,controllable product quality and certain industrial value.