氘代沃拉帕沙的设计与合成

Design and synthesis of deuterium-labeled vorapaxar

沃拉帕沙(vorapaxar)是一种新型蛋白酶激活受体1(PAR-1)拮抗剂,可抑制凝血过程。氘代沃拉帕沙作为内标可满足临床样品分析检测的需要。本文以未标记的沃拉帕沙为起始原料,经过水解、缩合、酯交换和氢氘交换4步反应首次高效地合成以D_8为主的氘代沃拉帕沙。所有中间体和终产物均经过核磁和高分辨质谱确证,所制备氘代化合物[D_8]沃拉帕沙满足内标化合物的使用要求。

Vorapaxar,a novel antagonist of the protease-activated receptor 1（ PAR-1）,can inhibit the clotting process. Deuterium-labeled vorapaxar was required for the analysis of clinical sample as an internal standard. Starting for unlabeled vorapaxar,four-step reactions including hydrolysis,condensation,transesterification and hydrogen-deuterium exchange were carried out to synthesize [D_8] vorapaxar effectively for the first time. All intermediates and final products were confirmed by NMR and high resolution mass spectrometry（ HRMS）. Importantly,the prepared [D_8] vorapaxar could meet the requirements of sample analysis as the internal standard.