(558e) Green Process Development and Characterization of an Alkylation Reaction to Improve API Impurity Control

Authors: 
Yang, C., Merck & Co., Inc.
Ward, M., Merck & Co., Inc.
Humprey, G., Merck & Co., Inc.
Krishnamurthi, B., Merck & Co., Inc.
Dienemann, E., Merck & Co., Inc.
Wright, T., Merck & Co., Inc.
Rogus, N., Merck and Co. Inc.
Mohan, A. E., Merck & Co., Inc.
Maligres, P., Merck & Co., Inc.
Anacetrapib is a CETP inhibitor which was developed to prevent cardiovascular disease, via control of cholesterol levels, by Merck. Extensive efforts have been made to develop an alkylation reaction as the last synthesis step for this drug substance to deliver high conversion, robust impurity control, as well as green chemistry elements such as low Process Mass Intensity (PMI) and reduced waste. Compared to the previously developed NaHMDS-based chemistry, the use of catalytic tetrabutylammonium iodide (TBAI) and potassium carbonate, as a base, not only minimize the epimerization of the final API into the Trans impurity, but also eliminates two process unit operations that were in the previous version of this step. Thorough process characterization was executed with the end-game chemistry to better understand the alkylation reaction, extraction and crystallization procedures for good product quality control. The combination of Design of Experiments (DOE) with statistical analysis and one factor at a time (OFAT) type experiments surrounding multiple process performance-impacting parameters further confirmed the reaction pathway and mechanism. It was found that an undesired hydrolysis reaction and an epimerization of final API were competing against the target pathway. The by-product formation was largely impacted by reactant stoichiometry and TBAI charges, solvent volume and reaction temperature. During the extraction sequence using selected extractants, the hydrophobic nature of API resulted in the formation of a 3rd solution phase (an oily phase), which was found to have no impact on the downstream crystallization process. The risked posed by the oil phase formation in the crystallization process was well controlled by slowing down the batch transfer rate and the final cooldown rate. The optimized reaction, extraction and crystallization process which were performed within the proposed Proven Acceptable Ranges (PAR) for the regulatory filing, showed high conversion, robust impurity control, and improved operability and productivity of the entire process step, as well as decreasing the environmental impact of the step by decreasing the PMI and waste volumes.