Jonathan P. McMullen

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

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Klavs F. Jensen

Massachusetts Institute of Technology

François Lévesque

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

Brian M. Wyvratt

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

Daniel A. DiRocco

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

John A. Porco

Boston University

Chuan-Xing Ho

Karthik Narsimhan

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

Aaron B. Beeler

Boston University

John R. Naber

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

Nikolay Zaborenko

Eli Lilly (United States)

Cooperative Institutions

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

139

Merck Institute for Science Education

Massachusetts Institute of Technology

Merck (Japan)

United States Military Academy

IIT@MIT

California Institute of Technology

Rutgers, The State University of New Jersey

University of Illinois Urbana-Champaign

Princeton University

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An Integrated Microreactor System for Self-Optimization of a Heck Reaction: From Micro- to Mesoscale Flow Systems

Angewandte Chemie (2010)

Jonathan P. McMullen Matthew T. Stone Stephen L. Buchwald Klavs F. Jensen

Aufbauen, anschalten, fertig: Die Kombination einer Rückkopplungssteuerung mit Durchflussoperationen in Mikroreaktoren (siehe Bild) ermöglicht eine vollautomatische Online-Reaktionsoptimierung. An einer Heck-Reaktion wird das Potenzial für eine schnelle Vielvariablen-Optimierung demonstriert, die mit minimalen Materialmengen auskommt. Die optimalen Bedingungen lassen sich schnell in einen 50-mal größeren Maßstab übertragen.

Microreactor

10.1002/ange.201002590

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Citations (54)

Development and Simulation of Annular Flow Photoreactors: Integration of Light-Diffusing Fibers as optical diffusers with Laser Diodes

Reaction Chemistry & Engineering (2024)

Sergio Carrillo De Hert Rafael Lopez-Rodriguez Michael J. Di Maso Jonathan P. McMullen Steven Ferguson

Laser driven platform for photochemical reactions. Modelling: predictability and optimization.

10.1039/d4re00400k

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Citations (0)

Palladium-catalyzed amination reactions in flow: overcoming the challenges of clogging via acoustic irradiation

Chemical Science (2010)

Timothy Noël John R. Naber Ryan L. Hartman Jonathan P. McMullen Klavs F. Jensen

A continuous-flow palladium-catalyzed amination reaction was made possible through efficient handling of solids via acoustic irradiation. Various diarylamines were obtained with reaction times ranging from 20 s to 10 min.

Clogging

10.1039/c0sc00524j

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Citations (218)

Automated Optimization under Dynamic Flow Conditions

Jonathan P. McMullen Brian M. Wyvratt

Automated optimization in flow reactors is a technology that continues to gain interest in academic and industrial research. For drug substance applications, where limited material is available for extensive studies, it is imperative that the automated optimization procedure identify ideal conditions for manufacturing in a resource sparing manner. It is equally as important that these investigations provide data-rich results so that the information can be used for process understanding. Achieving these two objectives in parallel is challenging with traditional automated optimization systems that rely on steady-state data. Dynamic flow systems, which adjust process inputs in a controlled manner to collect transient reaction results, maximize reaction information content. In this work, the gains in reaction knowledge by performing the automated optimization in a dynamic flow system are demonstrated using a nucleophilic aromatic substitution as a case study. A gradient-based search algorithm is used to optimize a multi-faceted objective function that accounts for yield, material input, and productivity. The immense dataset from the automated dynamic optimization was used to establish a reaction model to provide greater insight to the reaction kinetics and selectivity.

Transient (computer programming)

10.26434/chemrxiv-2022-5b8rk

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Amination of a Green Solvent via Immobilized Biocatalysis for the Synthesis of Nemtabrutinib

Christopher K. Prier Karla Camacho Soto Jacob H. Forstater Nadine Kuhl Jeffrey T. Kuethe

Enzymes are capable of unique and selective transformations that can enable sustainable chemical production. While many industrial processes have been developed using free enzymes in aqueous solutions, immobilizing enzymes on a solid support can offer considerable advantages, including improved reaction efficiency, enzyme stability, the ability to perform reactions in non-aqueous media, and simplified separation of product from enzyme. Herein, we describe the development of a biocatalytic transaminase reaction of CyreneTM (2) utilizing an immobilized, evolved transaminase enzyme in an organic solvent to provide amine intermediate 3a en route to the Brutons tyrosine kinase (BTK) inhibitor nemtabrutinib. Enzyme immobilization is critical to facile isolation of the water-soluble product. Improved reaction kinetics and diastereoselectivity were achieved by bridging directed enzyme evolution with the selection of an optimal reaction solvent and solid support for immobilization, enabling a unified solvent system and direct isolation of 3a as a crystalline salt with dr > 50:1.

Biocatalysis

Transaminase

Enzyme Catalysis

Reductive amination

10.26434/chemrxiv-2023-cbfs1

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Citations (1)

Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development

Organic Process Research & Development (2021)

Jon A. Jurica Jonathan P. McMullen

Automated reactor and sampling technologies were used in process characterization studies of a cyclization reaction using gaseous ammonia. These data-rich experiments were structured according to a 24 full factorial design of experiment, with each experiment having 12 reaction samples at equal time intervals. Data-driven models were established for key reaction responses to create a process fingerprint, to identify the optimal operating conditions under various constraints, and to evaluate the stability of the process. Leveraging these technologies in late-stage reaction characterization enabled significant improvements in efficiency and experimental reproducibility compared to conventional methods.

Design of experiments

Advanced process control

10.1021/acs.oprd.0c00496

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Citations (17)

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 3─Development of a Scalable Enzymatic Oxidation Process

Organic Process Research & Development (2024)

Jungchul Kim Victoria Zhang Kotoe Abe Yangzhong Qin Daniel A. DiRocco

Belzutifan (MK-6482) is an FDA-approved hypoxia inducible factor 2α inhibitor for the treatment of Von Hippel–Lindau disease-associated renal cell carcinoma. One of the key synthetic steps is an enzymatic benzylic hydroxylation of an indanone. Prior to optimization, hydroxylation reactions required dilute conditions (100 volumes of water) and high enzyme loading (50 wt %) to achieve the target conversion, which was unsuitable for a long-term manufacturing process. Reduction of reaction volumes introduced additional complexity for large-scale operations due to the low solubility of the reaction components. In addition to reaction development, it was also necessary to find an optimal method of protein residue removal from the reaction mixture to isolate a high-quality product. We present here our efforts to overcome these challenges and ultimately successfully developed, optimized, and demonstrated at a multikilogram scale a process with improved process mass intensity using only a 7.5 wt % enzyme, 25 volumes of water, and 1-octanol as a unique additive.

Hydroxylation

10.1021/acs.oprd.3c00420

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Citations (10)

Benzylic Photobromination for the Synthesis of Belzutifan: Elucidation of Reaction Mechanisms Using In Situ LED-NMR

The Journal of Organic Chemistry (2021)

Yining Ji Cecilia Bottecchia François Lévesque Karthik Narsimhan Dan Lehnherr

A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two distinct mechanisms of overbromination, namely, the ionic and radical pathways, have been revealed by this study. The behavior of the major reaction species, including reactants, intermediates, products, and side products, has been elucidated. Comprehensive understanding of both pathways informed and enabled mitigation of a major process risk: a sudden product decomposition. Detailed knowledge of the processes occurring during the reaction and their potential liabilities enabled the development of a robust photochemical continuous flow process implemented for commercial manufacturing.

10.1021/acs.joc.1c01465

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Citations (23)

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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Citations (5)

Effective Control of Crystal Size via an Integrated Crystallization, Wet Milling, and Annealing Recirculation System

Organic Process Research & Development (2020)

Wei Meng E. B. Sirota Hanzhou Feng Jonathan P. McMullen Lorenzo Codan

For drug substance manufacturing, it is necessary to have a robust crystallization process that can isolate quality active pharmaceutical ingredients with the desired crystal size distribution (CSD). This study presents a novel integrated crystallizer that combines cooling and antisolvent crystallization with wet milling and annealing operations to produce crystals with narrow size distributions. The incorporation of a wet mill and subsequent annealing vessel were carried out for size reduction and fines dissolution, respectively. The influential process parameters on CSD were identified by investigating the crystallization of verubecestat with the integrated system. Data-rich experimentation and enhanced process understanding were achieved by implementing process analytical technologies, such as attenuated total reflectance-Fourier transform infrared and focused beam reflectance measurement. Results show that the CSD can be tightly tuned through mill configuration, mill speed, and annealing temperature. Increasing mill rotational speed and using a denser rotor–stator teeth arrangement reduced crystal size, while a higher dissolution temperature was conducive to tightening CSD by dissolving fines and creating additional supersaturation for crystal growth. Results from the complete integrated system were compared to configurations without annealing vessel, which revealed that breakage, attrition, and secondary nucleation induced by milling led to wider CSD.

Supersaturation

Crystal (programming language)

10.1021/acs.oprd.0c00307

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Citations (23)