Design and synthesis of deuterium-labeled vorapaxar

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 ［D₈］ vorapaxar effectively for the first time. All intermediates and final products were confirmed by NMR and high resolution mass spectrometry(HRMS). Importantly, the prepared ［D₈］ vorapaxar could meet the requirements of sample analysis as the internal standard.