(497c) Experimental and Model Aided Approach for Development of High Pressure Direct Asymmetric Reductive Amination Reaction

Direct Asymmetric Reductive Amination (DARA) reactions are useful in pharmaceutical routes for converting carbonyl groups into amines. Typically, these reactions involve a catalyst system to promote the hydrogenation. A high pressure DARA reaction was used to synthesize an amine as an intermediate for one of the synthetic routes for a high volume drug. Given the water sensitivity of the reaction, ketone reagent was converted to ketal prior to carrying out the DARA reaction. Effects of key reaction variables â?? temperature, catalyst type, catalyst concentration, reaction volume, and pressures were explored to understand their effect on yield and impurity formation. It was found that there were a number of undesired side reactions that took place leading to impurity levels that needed to be controlled to achieve the final product specifications downstream. A mechanistic kinetics model was developed with some empirical relationships to capture the effect of certain reaction variables on the selectivity of desired to the undesired reactions. A combination of the experiments and simulations helped provide an understanding of the complicated chemistry. Together the approach was useful for: 1) mapping out and optimizing the design space, 2) determining the critical process parameters for the process, 3) developing impurity control strategies, and 4) designing experiments for risk assessment package for regulatory agencies. Thus, fundamental understanding was gained using these tools of an otherwise challenging and complicated chemistry.