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 (TPH) inhibitor for the treatment of irritable bowel syndrome (IBS), 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 multi-kilogram scales to supply LX1031 API for the preclinical and clinical studies.