A5085621143- Sulfur-Based Synthesis Techniques
- Catalytic C–H Functionalization Methods
- Lipid Membrane Structure and Behavior
- Innovative Microfluidic and Catalytic Techniques Innovation
- Biochemical and Molecular Research
- Chemistry and Chemical Engineering
- Chemical Synthesis and Reactions
- Catalytic Cross-Coupling Reactions
- Chemical Synthesis and Analysis
- Protein purification and stability
- Enzyme Catalysis and Immobilization
- Chemical synthesis and alkaloids
- Monoclonal and Polyclonal Antibodies Research
- Asymmetric Hydrogenation and Catalysis
- Crystallization and Solubility Studies
- Polymer Surface Interaction Studies
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Biotin and Related Studies
- Synthetic Organic Chemistry Methods
- Molecular Junctions and Nanostructures
- HIV/AIDS drug development and treatment
- X-ray Diffraction in Crystallography
- Chronic Lymphocytic Leukemia Research
- Microfluidic and Capillary Electrophoresis Applications
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015-2024
Biogen (United States)
2008-2018
Merck (Japan)
2017
Merck Institute for Science Education
2016-2017
The Ohio State University
2007-2010
Stetson University
2008
Amgen (United States)
1998-2005
IIT@MIT
2005
Massachusetts Institute of Technology
2005
Oregon Museum of Science and Industry
1995-2002
Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification intermediates. They also allow be linked together overcome an unfavorable equilibrium or accumulation unstable inhibitory We report in vitro cascade synthesis investigational HIV...
Molnupiravir (MK-4482) is an investigational antiviral agent that under development for the treatment of COVID-19. Given potential high demand and urgency this compound, it was critical to develop a short sustainable synthesis from simple raw materials would minimize time needed manufacture supply molnupiravir. The route reported here enabled through invention novel biocatalytic cascade featuring engineered ribosyl-1-kinase uridine phosphorylase. These enzymes were deployed with...
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...
Screening for pharmaceutically viable stability from measurements of thermally induced protein unfolding and short-term accelerated stress underpins much molecule design, selection, formulation in the pharmaceutical biotechnology industry. However, interrelationships among intrinsic conformational stability, thermal denaturation, are complex. There few publications which predictions unfolding-based screening methods examined together with relevant long-term storage performance. We have...
A concise and efficient one-pot synthesis of functionalized sulfonylated pyridines via an S(N)Ar reaction readily available sodium sulfinate salts in the presence tetrabutylammonium chloride is presented.
Herein we describe the development and application of a method for mild, late-stage conversion primary sulfonamides to several other functional groups. These reactions occur via initial reductive deamination sulfinates an NHC-catalyzed reaction transiently formed N-sulfonylimines. The described here is tolerant nearly all common groups, as exemplified by derivatization complex pharmaceutical compounds. On basis prevalence sulfonamide-containing drugs building blocks, have developed enable be...
Organic electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in organic synthesis. Concerns around the scalability electrochemical remain biggest reason behind their scarce implementation manufacturing routes for pharmaceutical industry. To fill this gap, we report workflow describing key reaction parameters toward successful scale-up an electrosynthetic method from milligram kilogram scale. The used demonstrate our and flow setting was...
The conversion of aryl halides to phenols under mild reaction conditions is a longstanding and formidable challenge in organic chemistry. Herein, we report the rational design broadly applicable Pd-catalyzed method prepare with benzaldehyde oxime as hydroxide surrogate. These reactions occur mildly basic enable late-stage hydroxylation several functionally-dense drug-like halides.
Parallel synthesis and mass-directed purification of a modular ligand library, high-throughput experimentation, rational evolution have led to novel copper catalyst for the phenols with traceless hydroxide surrogate. The mild reaction conditions reported here enable late-stage numerous complex, druglike phenols.
Aggregation of partially folded intermediates populated during protein folding processes has been described for many proteins. Likewise, unfolded chains, generated by perturbation numerous proteins heat or chemical denaturants, have also shown to aggregate readily. However, the process aggregation from native-state conditions is less well understood. Granulocyte-colony stimulating factor (G-CSF), a member four-helix bundle class cytokines, therapeutically relevant involved in growth and...
A high-yielding and practical method for the synthesis of phenols from electron-deficient haloarenes heteroarenes has been developed. The products are formed acetohydroxamic acid as hydroxide source via a novel SNAr reaction/Lossen rearrangement sequence. Notably, these reactions employ inexpensive air-stable reagents, require no special handling, occur under mildly basic conditions, form in high yields presence electrophilic protic functionality. utility this methodology is demonstrated by...
Sulfonamides are pervasive in pharmaceuticals and agrochemicals, yet they typically considered as terminal functional groups rather than synthetic handles. To enable the general late-stage functionalization of secondary sulfonamides, we have developed a mild method to reductively cleave N–S bonds sulfonamides generate sulfinates amines, components which can further react situ access variety other medicinally relevant groups. The utility this platform is highlighted by selective manipulation...
Cadmium is a toxic heavy metal ranked seventh on the Priority List of Hazardous Substances. As byproduct smelters, cadmium prevalent environmental contaminant. It also major component cigarette smoke, and its inhalation associated with decreased pulmonary function, lung cancer, chronic obstructive disease. Ion channels, including cystic fibrosis transmembrane conductance regulator (CFTR), play central role in maintaining fluid homeostasis functions. CFTR mostly expressed epithelial cells,...
A mild, high-yielding procedure for the preparation of beta-ketophosphonates is described. The condensation general with respect to ester and phosphonate, products are obtained in high yields within minutes at 0 degrees C. reaction operationally simple amenable large-scale preparations.
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application an enzymatic DKR reduction a keto ester, which easily accessed through novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation cyclic imine affords the cis-pyrrolidine high diastereoselectivity. By integrating biotechnology into organic isolating only three intermediates over 11 steps, core scaffold β3-AR agonists...
We have shown previously that lateral compression of pulmonary surfactant monolayers initially induces separation two phases but these remix when the films become more dense (1). In studies reported here, we used fluorescence microscopy to examine role different constituents in remixing separated phases. Subfractions containing only purified phospholipids (PPL), proteins and (SP&PL), neutral (N&PL) were obtained by chromatographic components extracted calf (calf lung extract, CLSE)....
Bruton's tyrosine kinase (BTK) is a Tec family with well-defined role in the B cell receptor (BCR) pathway. It has become an attractive target for selective inhibition and treatment of related diseases. We report series compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors excellent selectivity. Selectivity achieved through specific interactions ligand hinge driven by aminopyridine hydrogen bondings Ser538 Asp539, hydrophobic interaction...
A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation treatment refractory unexplained chronic cough. The newly commercial features low mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, significantly reduced API costs. key innovations are implementation highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine in...
Molnupiravir (MK-4482) is an investigational direct-acting antiviral agent that under development for the treatment of COVID-19. Given potential high demand this compound, it was critical to develop a sustainable and efficient synthesis from commodity raw materials. The three-step route we report here embodies shortest possible molnupiravir, enabled through invention novel biocatalytic cascade final condensation step. Each step occurs in over 95% yield only utilizes widely available reagents...