(470b) Process Fingerprinting Tools in the Development of an Alkylation Reaction

Stone, K., Merck & Co., Inc.
Wyvratt, B. M., Merck & Co., Inc.
Adachi, E., Merck & Co., Inc.
McMullen, J. P., Merck & Co. Inc.
Mohan, M., Merck & Co., Inc.
The final chemical transformation in the synthesis of doravirine (an NNRTI drug intended for the treatment of HIV) is an alkylation reaction with several key process variables and interactions that had historically produced high sensitivities in reaction performance. In this work, high-throughput experimentation and data-intensive PAT tools are applied to characterize and optimize this reaction for greatly improved performance. With the use of automated reactors and sampling devices, large data sets are produced to measure reaction kinetics, build models, and define ideal operating parameters to reduce impurity generation and process variability. In-situ FTIR, FBRM, and PVM are also applied to characterize the multi-phase reaction mixture by measuring solubility and addressing scale-up effects. This case study highlights the ability of these tools to enable rapid, data-driven decision making in various phases of chemical process development.