Synthesis of deuterium‐labeled CCR2 antagonist JNJ‐26131300, [4‐(1H‐indol‐ 3‐yl)‐piperidin‐1‐yl]‐{1‐[3‐(3,4,5‐trifluoro‐phenyl)‐acryloyl]‐piperidin‐4‐yl}‐acetic acid

Abstract

Synthesis of multiple deuterium‐labeled CCR2 antagonist JNJ‐26131300, that is, [4‐(1H‐indol‐3‐yl)‐piperidin‐1‐yl]‐{1‐[3‐(3,4,5‐trifluoro‐phenyl)‐acryloyl]‐piperidin‐4‐yl}‐acetic acid, is described. First, condensation of indole‐D7 with 4‐piperidone produced 3‐(1,2,3,6‐tetrahydropyridin‐4‐yl)‐1H‐indole‐D5, which subsequently underwent catalytic hydrogenation to give 3‐piperidin‐4‐yl‐1H‐indole‐D5. Next, bromo‐{1‐[3‐(3,4,5‐trifluoro‐phenyl)‐acryloyl]‐piperidin‐4‐yl}‐acetic acid was prepared through multiple steps from 3‐(3,4,5‐trifluoro‐phenyl)‐acrylic acid and bromo‐piperidin‐4‐yl‐acetic acid ethyl ester. Nucleophilic coupling of 3‐piperidin‐4‐yl‐1H‐indole‐D5 with bromo‐{1‐[3‐(3,4,5‐trifluoro‐phenyl)‐acryloyl]‐piperidin‐4‐yl}‐acetic acid afforded the desired compound [4‐(1H‐indol‐3‐yl)‐piperidin‐1‐yl]‐{1‐[3‐(3,4,5‐trifluoro‐phenyl)‐acryloyl]‐piperidin‐4‐yl}‐acetic acid‐D5.