Process Development of Tryptophan Hydroxylase Inhibitor LX1031, a Drug Candidate for the Treatment of Irritable Bowel Syndrome

Two process routes for LX1031, a tryptophan hydroxylase inhibitor for the treatment of irritable bowel syndrome, were developed. They shared the same left-hand and right-hand starting materials as well as the penultimate intermediate. The chiral center in the left-hand moiety was established via a Noyori asymmetric hydrogenation of a trifluoromethyl aryl ketone. The right-hand boronate was prepared via a palladium-catalyzed borylation of l-tyrosine-derived aryl triflate. Union of these two fragments to the pyrimidine core, from the right- or left-hand side, constituted the first- and second-generation routes, respectively. Removal of the Boc-protecting group from the penultimate intermediate gave LX1031. The challenges overcome in purification and isolation of the LX1031 zwitterion are also discussed. Both process routes were successfully performed on multikilogram scales to supply LX1031 API for the preclinical and clinical studies.