ABSTRACT
Process Research and Development, Bristol-Myers Squibb Company,
One Squibb Drive, New Brunswick, NJ 08903-0191 steve.y.wang@bms.com
Abstract In situ reduction of Schiff’s bases is a common reaction used in the preparation of pharmaceutical intermediates. Muraglitazar (PPAR α/γ dual agonist) is being evaluated for the treatment of type II diabetes. We have recently carried out a large scale hydrogenation of an imine, prepared through the condensation of an aromatic aldehyde with an amine, to produce the final intermediate in the muraglitazar synthesis. Studies were carried out for better process understanding. We present a kinetic analysis using the Langmuir-Hinshelwood approach to model the complex reaction network. This knowledge has led to process conditions that minimize the formation of potential impurities, resulting in a more robust process. Introduction Intermediate C is prepared by a two-step telescoped reductive amination as depicted in the reaction scheme below. A solution of glycine methyl ester free base in methanol 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 using 5%Pd/C and a hydrogen pressure of 45psig. With these process conditions, numerous impurities were identified. The impurity profile strongly depends on hydrogenation performance parameters related to the type of reactor, operating conditions, catalyst loading and reaction time. It is essential to limit impurity formation in order to maximize the yield and to minimize isolation and purification complexity.
