Synthesis of ABT-116, a TRPV1 receptor antagonist

ORGN 770

Su Yu, su.yu@abbott.com, Anthony Haight, Lei Wang, and Brian Kotecki. Global Pharmaceutical Research and Development, Abbott Laboratories, 1401 N. Sheridan Road, North Chicago, IL 60044
A five-step synthesis of ABT-116, a TRPV1 receptor antagonist is described. The key step of the synthesis involves a novel palladium catalyzed amidation reaction of 4-chloro-1-methylindazole 1 with the benzyl urea 2 to form unsymmetrically substituted urea ABT-116. 4-chloro-1-methylindazole 1 is prepared from readily available 2-chloro-6-fluoro-benzaldehyde by reacting it with excess methyl hydrazine to afford the desire indazole in good yield. Benzyl urea is prepared via a three-step sequence from 3-chloro-4-cyano-benzotrifluoride. Sonogashira coupling of 3-chloro-4-cyano-benzotrifluoride with 3,3-dimethylbut-1-yne is accomplished using Davephos ligand in triethylamine at 65oC with 95% yield. Hydrogenation of the Sonogashira product reduces the nitrile and alkyne group at same time. The resulting amine reacts with phenyl carbamate to form the desired benzyl urea 2 in excellent yield.