A5091279948- Asymmetric Synthesis and Catalysis
- Catalytic C–H Functionalization Methods
- Asymmetric Hydrogenation and Catalysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Biochemical and Molecular Research
- Synthetic Organic Chemistry Methods
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Synthesis and Catalytic Reactions
- Axial and Atropisomeric Chirality Synthesis
- Monoclonal and Polyclonal Antibodies Research
- Alzheimer's disease research and treatments
- Biosimilars and Bioanalytical Methods
- Cholinesterase and Neurodegenerative Diseases
- Tuberculosis Research and Epidemiology
- Chemical Synthesis and Reactions
- Carbohydrate Chemistry and Synthesis
- Lipoproteins and Cardiovascular Health
- Analytical Chemistry and Chromatography
- Advanced Synthetic Organic Chemistry
- Coordination Chemistry and Organometallics
- Cyclopropane Reaction Mechanisms
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2025
Harvard University
2022
Stanford University
2008-2015
Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low lipoprotein-cholesterol, but despite nearly 2 decades effort, an oral inhibitor is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable small-molecule drug design. Methods: Novel mRNA display screening technology was used...
We report the total synthesis of enlicitide decanoate, an orally bioavailable inhibitor proprotein convertase subtilisin/kexin type 9 that is being developed for treatment atherosclerotic cardiovascular disease. It a highly complex macrocyclic peptide with significant number nonpeptide structural elements presents daunting synthetic chemistry challenge. describe development convergent, efficient, and robust manufacturing process enables large-scale production enlicitide.
We report a strategy for the employment of highly unstabilized anions in palladium-catalyzed asymmetric allylic alkylations (AAA). The "hard" 2-methylpyridyl nucleophiles studied are first reacted situ with BF3.OEt2; subsequent deprotonation resulting complexes LiHMDS affords "soft" that competent AAA reactions. reaction is selective 2-position methylpyridines and tolerates bulky aryl alkyl substitution at 3-, 4-, 5-positions. Investigations into mechanism demonstrate configuration...
We report a new method for the highly regio-, diastereo-, and enantioselective palladium-catalyzed allylic alkylation of 2-substituted pyridines that allows formation homoallylic stereocenters containing alkyl, aryl, heteroaryl, nitrogen substituents. When reaction is conducted with asymmetric acyclic electrophiles, both linear branched products may be obtained exclusively by selecting appropriate regioisomeric starting material ligand, an example "memory effect." Deuterium-labeling studies...
A new ligand class: The title reaction was made possible by the discovery of a class phosphoramidite ligands. variety sterically and electronically diverse allylarenes undergo with 2-acetyl-1-tetralones to form quaternary carbon stereocenters. This is conceptually mechanistically distinct strategy from traditional methods for synthesis enantioenriched allylic substitution products. 2,6-DMBQ=2,6-dimethylbenzoquinone. As service our authors readers, this journal provides supporting information...
We report the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction of a variety nitrogen-containing aromatic heterocycles, including pyrazine, pyrimidine, pyridazine, quinoxaline, and benzoimidazole derivatives. The mesityl ester, whose steric bulk prevents competitive deacylation electrophile from "hard" nucleophiles, is introduced as new leaving group in chemistry. In contrast to our previous studies AAA reactions with pyridine-based substrates, no precomplexation Lewis acid...
Activated: The title reaction proceeds with a broad range of nucleophiles and variously substituted 1,4-dienes under mild conditions, provides direct access to the corresponding 1,3-diene-containing products high regio- stereocontrol (see scheme; 2,6-DMBQ=2,6-dimethylbenzoquinone, EWG=electron-withdrawing group). This is first catalytic allylic CH alkylation that in absence sulfoxide ligands.
We report the discovery, synthesis, and application of a new class non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative redox-neutral palladium-catalyzed asymmetric allylic alkylations 1,3-diketones. The resulting chiral products are typically obtained high yield with good to excellent levels enantioselectivity.
The first GMP synthesis of MK-2118, a small molecule agonist the stimulator interferon genes (STING) is described. represents dramatic change in chemical matter from more complex cyclic dinucleotides previously disclosed. In this article, we detail route-scouting, decision-making, and development details campaign typical for delivery on an accelerated timeline. route chosen involves key copper-mediated Negishi coupling using chiral organozinc reagent subsequent direct isolation. Several...
Neue Liganden: Die Titelreaktion wurde durch eine neue Klasse von Phosphoramiditliganden ermöglicht. Sterisch und elektronisch unterschiedliche Allylarene reagieren mit 2-Acetyl-1-tetralonen unter Bildung quartärer Kohlenstoffstereozentren. Diese Strategie unterscheidet sich konzeptuell mechanistisch der traditionellen Methode zur Synthese enantiomerenangereicherten allylisch substituierten Produkten. 2,6-DMBQ=2,6-Dimethylbenzochinon.
We report the development of an organolithium addition to a chiral ketimine at pilot-plant scale using flow chemistry. Given mixing sensitivity this process, established previously both lab and kilogram scale, we conducted critical experiments understand impact rate, temperature, on performance reaction in factory-sized static mixer. Online process analytical technology was used collect real-time data batches demonstrate steady-state operation over multiple hours also confirm robustness...
Verubecestat is an inhibitor of β-secretase being evaluated for the treatment Alzheimer's disease. The first-generation route relies on amide coupling with a functionalized aniline, preparation which introduces synthetic inefficiencies. second-generation replaces this copper-catalyzed C–N coupling, allowing more direct access to target. Other features new include diastereoselective Mannich-type addition into Ellman sulfinyl ketimine and late-stage guanidinylation.
Enzymes are capable of unique and selective transformations that can enable efficient chemical production. While many industrial processes have been developed using free enzymes in aqueous solutions, immobilizing on a solid support offer considerable advantages, including improved reaction efficiency, enzyme stability, the ability to perform reactions non-aqueous media, simplified separation product from enzyme. Herein, we describe development biocatalytic transaminase Cyrene (2) utilizing...
We report that an organolithium addition to a chiral ketimine, which because of competitive proton transfer proceeds with only modest yield in batch, can be significantly improved flow. The transformation was discovered highly mixing-sensitive but remarkably temperature-independent flow, enabling the continuous process performed under noncryogenic conditions. Experiments at kilogram scale provided robust operating conditions are amenable implementing this chemistry for manufacture...
We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis the product distribution. As result these studies, we have designed, 3D-printed, characterized stainless steel mixer. This approach enabled evaluation different configurations ensured scale-up across development commercial facilities that should allow for enhanced...
The development of a protecting group-free, 2-step synthesis 5-amino-2-hydroxymethyltetrahydropyran 1a from biorenewable Cyrene™ is described which renders access to BTK-inhibitor nemtabrutinib (2) more efficient and sustainable.
We report the process development for active pharmaceutical ingredient (API) step of commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation treatment several hematological malignancies. Significant improvements on efficiency were achieved by direct isolation leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness impurity...
Aktiviert: Die Titelreaktion verläuft mit einer hohen Bandbreite an Nucleophilen und 1,4-Dienen unter milden Bedingungen bietet direkten Zugang zu 1,3-Dien-Produkten hoher Regio- Stereokontrolle (siehe Schema; 2,6-DMBQ=2,6-Dimethylbenzochinon). Dies ist die erste katalytische allylische Alkylierung, in Abwesenheit von Sulfoxidliganden stattfindet.
The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights which include the application continuous processing step outcompete fast proton transfer in Mannich-type ketimine addition, copper-catalyzed amidation reaction, and an optimized guanidinylation procedure form key iminothiadiazine dioxide core.
The solution-based gram-scale synthesis of complex and highly potent proprotein convertase subtilisin-like/kexin type 9 (PCSK9) inhibitor 1 is presented. Construction Northern fragment 2, followed by stepwise installation Eastern 3, Southern 4, Western 5 fragments, provided macrocyclic precursor 19. This intermediate was cross-linked via an intramolecular azide-alkyne click reaction, which preceded macrolactamization to afford the core framework compound 1. Finally, coupling with...
Nemtabrutinib (MK-1026) is a novel oral Bruton's tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation highly reactive transient intermediate and use n-butyllithium. Cryogenic temperatures (−60 °C) were also required achieve modest 61% yield, with one major impurity, resulting from dehalogenation, accounting majority mass balance. alternative process was developed increase yield decrease dependence...
In one of the two penultimate steps in commercial route to nemtabrutinib, a ketone intermediate is formed from 7-bromo-6-chloro-7-deazapurine and methyl 2-chloro-4-phenoxybenzoate series reactions mediated by methyllithium n-butyllithium. Flow chemistry was identified development as useful tool for safe efficient scale-up these while minimizing formation unwanted impurities. Here, we present first pilot-scale implementation process where tubular flow reactor employed produce multiple...
Mal so, mal so: Eine Tandemkatalyse bewirkt sequenzielle Pd0-katalysierte allylische Alkylierungen unter Abspaltung einer ionischen Abgangsgruppe und PdII-katalysierte über C-H-Aktivierung. Oxidation überführt die katalytische Spezies vom Pd0- in den PdII-Zustand, sodass beide Transformationen einem Reaktionsgefäß mit demselben Präkatalysator ausgeführt werden können. So gelingt selektive Einführung ansonsten nicht unterscheidbarer Allylgruppen. Detailed facts of importance to specialist...