Taylor Behre

Merck & Co., Inc., Rahway, NJ, USA (United States)

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Clara Hartmanshenn

Merck & Co., Inc., Rahway, NJ, USA (United States)

Brittany M. Armstrong

Merck & Co., Inc., Rahway, NJ, USA (United States)

Nadine Kuhl

Merck & Co., Inc., Rahway, NJ, USA (United States)

Ben W. H. Turnbull

Merck & Co., Inc., Rahway, NJ, USA (United States)

Nastaran Salehi Marzijarani

Merck & Co., Inc., Rahway, NJ, USA (United States)

Erin McCarthy

Merck & Co., Inc., Rahway, NJ, USA (United States)

Rekha Gangam

Merck & Co., Inc., Rahway, NJ, USA (United States)

Gerard Capellades

Rowan University

Erik D. Guetschow

Merck & Co., Inc., Rahway, NJ, USA (United States)

Anna V. Jenks

Merck & Co., Inc., Rahway, NJ, USA (United States)

Cooperative Institutions

Merck & Co., Inc., Rahway, NJ, USA (United States)

Merck Institute for Science Education

Massachusetts Institute of Technology

United States Military Academy

Merck (Japan)

Boehringer Ingelheim (United States)

University of Michigan–Ann Arbor

Tianjin University

University of Oregon

Rowan University

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Integrating Process Development and Safety Analysis for Scale-Up of a Diborane-Generating Reduction Reaction

Organic Process Research & Development (2023)

Brittany M. Armstrong Taylor Behre Ben W. H. Turnbull Daniel Bishara Clara Hartmanshenn

Our company has developed a robust and scalable process to synthesize an amino alcohol tosylate salt, a penultimate intermediate in the synthesis of nemtabrutinib. A key reaction in this synthetic sequence is a reductive acetal ring opening using boron trifluoride diethyl etherate as a Lewis acid and triethylsilane as the reducing agent. Detailed mechanistic inquisition revealed that in the presence of sulfolane, boron trifluoride is reduced by triethylsilane to generate diborane as the active reductant. Diborane poses many process safety hazards; it is highly reactive, flammable, and acutely toxic. The reaction headspace was studied using infrared spectroscopy and gas chromatography, while the reaction stream was studied using heat flow and adiabatic calorimetry to ensure safe scale-up of the process. Process understanding demonstrated that containing diborane within the reactor was essential to control key impurities. Extensive development efforts were directed to design a process that could safely sequester the hazardous gas. Herein, we describe the process safety analysis, the optimization, and the scale-up of the reduction reaction and the isolation, producing two batches of the amino alcohol tosylate salt with high purity at a pilot scale.

Diborane

Boron trifluoride

Triethylsilane

Process development

Flow chemistry

Extractive distillation

10.1021/acs.oprd.3c00018

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Citations (6)

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5─Chemoenzymatic Diastereoselective Fluorination/DKR

Organic Process Research & Development (2024)

Scott D. McCann Sean Hyun Dubina Birgit Kosjek Embarek Alwedi Taylor Behre

A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced a precious metal catalyst with a ketoreductase (KRED) in the DKR. Achieving this one-pot reaction required several rounds of enzyme evolution that improved enzyme stability in the presence of acetonitrile and methanol. To maintain development progress and satisfy program timelines, process development around the reaction, workup, and isolation operations was performed in parallel with the enzyme evolution and required ongoing modification, as new variants were made available. Additionally, opportunities for improvements to product quality and process robustness were identified by resolving issues observed in piloting experiments.

Kinetic resolution

Process development

Time line

10.1021/acs.oprd.3c00421

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Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control

Organic Process Research & Development (2021)

Nastaran Salehi Marzijarani Adam J. Fine Stephen M. Dalby Rekha Gangam Samiksha Poudyal

A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO2 byproduct. Special effort was required to design a scale-insensitive process for the removal of CO2 with active nitrogen headspace sweeping, supported by process modeling and verification with process analytical technology data. Automated sampling facilitated data-rich experimentation via kinetic profiling, culminating in enhanced understanding and further robustness-based optimization for the reduction reaction. Herein we report the development of a one-pot through-process with direct isolation of 3 in high yield (>90%) and purity (>99 LCAP, >99 ee) at commercial scales. The newly developed process ensures process robustness and improves cycle times and process mass intensity.

Robustness

Process development

Flow chemistry

10.1021/acs.oprd.1c00231

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Citations (21)

Quality Control for Incoming Raw Materials Beyond Identity and Purity: Case Studies from Recent Merck API Manufacturing Processes

Organic Process Research & Development (2025)

Nelo R. Rivera Rekha Gangam Rebecca A. Arvary Taylor Behre Zhiwei Chen

The development of robust manufacturing processes for active pharmaceutical ingredients (APIs) is paramount to ensure a supply of safe and effective medications. Implementation of a holistic control strategy, including quality control of incoming raw materials, is a key element in meeting this goal. This paper describes several examples from recent Merck API manufacturing routes, in which impurities in raw materials affected the processes in various ways, including giving rise to new process impurities, jeopardizing process safety and causing damage to reaction vessels, and─sometimes unexpectedly and counterintuitively─suppressing formation of process impurities. In all of these examples, analytical characterization plays a critical role in identifying these impurities and enabling their control to ensure consistent process performance and product quality.

10.1021/acs.oprd.4c00423

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Prevalence of Impurity Retention Mechanisms in Pharmaceutical Crystallizations

Organic Process Research & Development (2023)

Fredrik L. Nordström E. B. Sirota Clara Hartmanshenn Thomas T. Kwok Mitchell Paolello

The rejection of process impurities from crystallizing products is an essential step for the purification of pharmaceutical drugs and for the isolation of active pharmaceutical ingredients with the right crystal quality attributes. While several impurity incorporation mechanisms have been reported in the literature, the frequency of those mechanisms in actual industrial processes is largely unknown. This work presents the outcome of a joint investigation by crystallization scientists from two pharmaceutical companies and an academic institution, on the prevalence of impurity retention mechanisms in cooling and antisolvent crystallizations. A total of 52 product-impurity pairs have been explored in detail using the so-called Solubility-Limited Impurity Purge (SLIP) test as the diagnostic tool to identify the underlying impurity retention mechanism of already crystallized materials with challenging impurities. The results show that formation of solid solutions is the most common mechanism, where the impurity and product are partially miscible in the solid state. In 73% of cases, only one solid solution phase was obtained in which the impurity became incorporated into the crystal lattice of the product (α phase). In 6% of the examples, two solid solution phases were obtained, where the second solid phase (β phase) comprised predominantly the impurity and the product was the minor component. The remaining impurity retention mechanisms (21%) are related to solid-state immiscible impurities that precipitated from solution resulting in a physical mixture between the product and the impurity. The reasons for the results are discussed through a comprehensive analysis of theoretical reported retention mechanisms, which includes physical constraints for the scale-up of isolation processes, thermodynamic assessments using ternary phase diagrams, and restrictions in the context of current pharmaceutical syntheses of small organic molecules. Three industrial case studies are presented that exemplify how knowledge of the retention mechanisms can be used to delineate appropriate strategies for process design and to effectively purge these impurities during crystallization or washing.

Lattice (music)

10.1021/acs.oprd.3c00009

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Citations (18)