A5056642872- interferon and immune responses
- Innovative Microfluidic and Catalytic Techniques Innovation
- Biochemical and Molecular Research
- RNA modifications and cancer
- Synthesis and Catalytic Reactions
- RNA and protein synthesis mechanisms
- Metal-Catalyzed Oxygenation Mechanisms
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Manufacturing Process and Optimization
- Catalysts for Methane Reforming
- Porphyrin and Phthalocyanine Chemistry
- Catalysis and Oxidation Reactions
- Carbon dioxide utilization in catalysis
- Chemistry and Chemical Engineering
- Carbohydrate Chemistry and Synthesis
- Pharmacogenetics and Drug Metabolism
- Monoclonal and Polyclonal Antibodies Research
- Chemical Reactions and Isotopes
- Catalytic Processes in Materials Science
- Organophosphorus compounds synthesis
- Enzyme Catalysis and Immobilization
Merck & Co., Inc., Rahway, NJ, USA (United States)
2019-2025
Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non-heme iron α-ketoglutarate-dependent dioxygenase direct stereo- regio-selective non-native fluoroindanone en route to oncology treatment belzutifan, replacing five-step...
The development of robust manufacturing processes for active pharmaceutical ingredients (APIs) is paramount to ensure a supply safe and effective medications. Implementation holistic control strategy, including quality incoming raw materials, key element in meeting this goal. This paper describes several examples from recent Merck API routes, which impurities materials affected the various ways, giving rise new process impurities, jeopardizing safety causing damage reaction vessels,...
As practitioners of organic chemistry strive to deliver efficient syntheses the most complex natural products and drug candidates, further innovations in synthetic strategies are required facilitate their construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions cost environmental impact. Enzyme-catalyzed reactions have become an impressive necessary tool that offers benefits such as increased selectivity waste limitation. amplified when enzymatic...
We report the development of a modified Kornblum oxidation mediated by 2-picoline N-oxide for synthesis belzutifan that circumvented safety and stench problems associated with original clinical supply route conditions. A robust quench crude bromination stream 1,3-dimethoxybenzene 2,6-lutidine enabled single-solvent through-process avoided isolation mutagenic intermediate resulted in significantly lower process mass intensity. ternary-solvent, constant-volume distillation was then used to...
A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity reduction reaction toward CO2 byproduct. Special effort was required to design scale-insensitive process removal with active nitrogen headspace sweeping, supported by modeling verification analytical technology data. Automated sampling facilitated data-rich experimentation via kinetic profiling, culminating in enhanced understanding...
We report the development of a one-pot synthesis 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in continuous fashion. Given sensitivity this transformation to temperature, we conducted critical experiments study exothermicity reaction and heat removal, which were for process. Our goal was improve yield purity pharmaceutical intermediate (2-fluoroadenine) develop more robust
An efficient synthesis of nucleoside 5′-monothiophosphates under mild reaction conditions using commercially available thiophosphoryl chloride was achieved with a cinchona alkaloid catalyst. A detailed mechanistic study the undertaken, employing combination kinetics, NMR spectroscopy, and computational modeling, to better understand observed reactivity. Taken collectively, results support an unprecedented mechanism for this class organocatalyst.
We describe the rapid end-game process development for first good manufacturing (GMP) delivery of 3C-like protease inhibitor MK-7845 (1), an experimental treatment SARS-CoV-2. Three operations, including amide-coupling, oxidation, and crystallization, were rapidly developed implemented on a kilogram scale to enable critical safety studies phase 1 clinical trials move forward highly accelerated timeline. Key success this undertaking was our focus purging key impurities formed in...
The process development for 2′F-thio-adenosine monophosphate, an intermediate MK-1454, immunooncology therapeutic, is described. Kinetic profiling, nuclear magnetic resonance monitoring, investigation of product decomposition pathways, and crystallization control identified important parameters efficient thiophosphorylation process. Among those are the use pivaloyl as protecting group nucleoside starting material well triethylphosphate a green reaction solvent, both which critical allowing...
Abstract Biocatalytic oxidations are an emerging technology for selective C−H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non‐heme iron α‐ketoglutarate‐dependent dioxygenase direct stereo‐ regio‐selective non‐native fluoroindanone en route to oncology treatment belzutifan, replacing...