Catalysis of Organic..

Wang et al. 233. Catalytic Hydrogenation of a Schiff’s Baseover Pd/Carbon Catalysts: Kinetic Prediction ofImpurity Fate and Byproduct FormationAbstractSteve S.Y.Wang, William F. Merkl, Hyei-Jha Chung, Wendel Doubledayand San KiangProcess Research and Development, Bristol-Myers Squibb Company,One Squibb Drive, New Brunswick, NJ 08903-0191steve.y.wang@bms.comIn situ reduction of Schiff’s bases is a common reaction used in the preparation ofpharmaceutical intermediates. Muraglitazar (PPAR α/γ dual agonist) is beingevaluated for the treatment of type II diabetes. We have recently carried out a largescale hydrogenation of an imine, prepared through the condensation of an aromaticaldehyde with an amine, to produce the final intermediate in the muraglitazarsynthesis. Studies were carried out for better process understanding. We present akinetic analysis using the Langmuir-Hinshelwood approach to model the complexreaction network. This knowledge has led to process conditions that minimize theformation of potential impurities, resulting in a more robust process.IntroductionIntermediate C is prepared by a two-step telescoped reductive amination as depictedin the reaction scheme below. A solution of glycine methyl ester free base inmethanol is generated from the corresponding hydrochloride and triethylamine.Schiff’s base B is formed by condensation of the free base with the aldehyde A.Catalytic hydrogenation of Schiff’s base is subsequently carried out at 40°C using5%Pd/C and a hydrogen pressure of 45psig. With these process conditions,numerous impurities were identified. The impurity profile strongly depends onhydrogenation performance parameters related to the type of reactor, operatingconditions, catalyst loading and reaction time. It is essential to limit impurityformation in order to maximize the yield and to minimize isolation and purificationcomplexity.