A5024594099- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Chemical synthesis and alkaloids
- Catalytic Cross-Coupling Reactions
- Marine Sponges and Natural Products
- Chemical Synthesis and Analysis
- Microbial Natural Products and Biosynthesis
- Monoclonal and Polyclonal Antibodies Research
- Asymmetric Hydrogenation and Catalysis
- HER2/EGFR in Cancer Research
- Catalytic C–H Functionalization Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Synthesis and Catalytic Reactions
- Biosimilars and Bioanalytical Methods
- Cyclopropane Reaction Mechanisms
- Click Chemistry and Applications
- Oxidative Organic Chemistry Reactions
- Carbohydrate Chemistry and Synthesis
- Synthesis and Characterization of Heterocyclic Compounds
- Enzyme Catalysis and Immobilization
- Biochemical and Molecular Research
- Traditional and Medicinal Uses of Annonaceae
- Synthesis and Biological Evaluation
- Axial and Atropisomeric Chirality Synthesis
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2025
Merck Institute for Science Education
2016
Scripps Research Institute
2005-2010
University of California, San Diego
2005-2006
University of Oxford
2001-2003
MSD (UK) Limited (United Kingdom)
2000-2001
Columbia University
1950
In studying the evolution of organic chemistry and grasping its essence, one comes quickly to conclusion that no other type reaction plays as large a role in shaping this domain science than carbon-carbon bond-forming reactions. The Grignard, Diels-Alder, Wittig reactions are but three prominent examples such processes, among those which have undeniably exercised decisive roles last century emergence chemical synthesis we know it today. quarter 20th century, new family based on...
Abstract With the exception of palladium‐catalyzed cross‐couplings, no other group reactions has had such a profound impact on formation carbon–carbon bonds and art total synthesis in last quarter century than metathesis olefins, enynes, alkynes. Herein, we highlight number selected examples syntheses which processes played crucial role imparted to these endeavors certain elements novelty, elegance, efficiency. Judging from their short but impressive history, influence chemical is destined increase.
Abstract Wenn man die Entwicklung der organischen Chemie betrachtet, kommt schnell zu dem Schluss, dass kein Reaktionstyp dieses Gebiet in vergleichbarer Weise geprägt hat wie Kohlenstoff‐Kohlenstoff‐Kupplungen. Grignard‐, Diels‐Alder‐ und Wittig‐Reaktionen sind nur drei herausragende Beispiele für solche Prozesse, im vergangenen Jahrhundert zweifellos entscheidend am Aufstieg chemischen Synthese beteiligt waren. Im letzten Viertel des 20. Jahrhunderts bereicherte eine neue Familie von...
Abstract Die Entwicklung und Umsetzung von Kaskadenreaktionen hat zu beachtlichen neuartigen, eleganten effizienten Synthesestrategien geführt. Als besonders anspruchsvoll erwies sich die Anwendung in der Naturstoffsynthese, doch gerade hier winken verblüffende zugleich aufschlussreiche Ergebnisse als Belohnung. In diesem Aufsatz werden ausgewählte Totalsynthese erläutert, wobei neuere Anwendungen hervorgehoben werden. erörterten Beispiele sollen Leistungsfähigkeit dieser Prozesse beim...
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.
Abstract Mit Ausnahme der palladiumkatalysierten Kreuzkupplungsreaktionen hatte im vergangenen Vierteljahrhundert keine Reaktionsklasse einen derart weitreichenden Einfluss auf die Kohlenstoff‐Kohlenstoff‐Verknüpfung und Totalsynthese wie Metathesereaktionen von Olefinen, Eninen, Alkinen. In diesem Aufsatz präsentieren wir Glanzlichter aus einer Reihe ausgewählter Totalsynthesen, in denen diese eleganten effizienten Reaktionen entscheidend zum Erfolg beigetragen haben. Schon an ihrer kurzen,...
Process development of the synthesis orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N-arylation an indazole derivative as late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions racemic aldehyde surrogates provided enantioselective syntheses 3-aryl-piperidine partner. Conversion C–N cross-coupling product to final API was...
In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by Process Chemistry group. The syntheses were initially as an enabling tool for Medicinal colleagues in order rapidly explore structure–activity relationships (SAR) and procure first milligrams diverse target molecules vitro evaluation. initial aziridine opening/cyclodehydration strategy was also directly amenable GMP deliveries (1), streamlining transition from milligram kilogram-scale production...
The development of a convergent, chromatography-free synthesis an allosteric Akt kinase inhibitor is described. route comprised 17 total steps and was used to produce kilogram quantities the target molecule. A key early transformation, for which both batch flow protocols were developed, formylation dianion derived by deprotonation subsequent lithium-halogen exchange from 2-bromo-3-aminopyridine precursor. Improved reaction yield practicality achieved in continuous processing mode. Further...
A general and highly convergent synthetic route to the macrocyclic core structures of antitumour agents amphidinolide N (1) caribenolide I (2) has been developed, total synthesis iso-epoxy-amphidinolide des-epoxy-caribenolide is described. Central revised strategy was use a Horner–Wadsworth–Emmons olefination between β-ketophosphonate 51 aldehyde 14 construct C1–C13 sector common both 1 2. Stereoselective alkylation hydrazone 11 with iodide 65 then bromide 56 allowed for rapid assembly...
A concise asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester, a key intermediate in the preparation many hepatitis C virus inhibitors, is described. Stereoselective cyclopropanation (E)-N-phenylmethyleneglycine ester was effected by treatment with trans-1,4-dibromo-2-butene presence catalytic amount chiral phase-transfer catalyst. Microscale high-throughput experimentation techniques were successfully used to identify cinchonidine-derived catalyst that...
Antibody–drug conjugates (ADCs) are becoming increasingly established as a mainstream therapeutic modality for oncology, with more than dozen compounds already approved marketing and hundreds of clinical trials ongoing. ADCs hybrid construct combining, via chemical conjugation, biologic (monoclonal antibody) small-molecule (drug-linker) moieties into single drug substance. They also present significant technical strategic challenges chemistry, manufacturing, controls (CMC). Within the IQ...
Two strategies for the projected total synthesis of phenomenally potent antitumour macrolides amphidinolide N (1) and caribenolide I (2) are described. The title compounds introduced as challenging unique targets chemical synthesis, their retrosynthetic analysis is presented. four defined key building blocks (10, 39, 67 72), required construction (1), in enantiomerically pure forms, described, followed by coupling 10, 39 72 through hydrazone alkylation processes to generate complete C6-C29...
Antibody–drug conjugates (ADCs) are increasingly prevalent as investigational and marketed treatments for a variety of cancers other diseases. The structures most ADCs comprise small-molecule component (the drug-linker) chemically conjugated to monoclonal antibody, this hybrid construct presents number challenges Chemistry, Manufacturing, Controls (CMC) development. A Small Molecule Considerations ADC Development Working Group (WG) has been established within the IQ Consortium serve forum...
The double ring closing metathesis reaction of α-hydroxyester derived tetraenes 4 proceed to give spirocyclic dihydropyrans in excellent yield and with good selectivity. first examples diastereoselective RCM reactions medium spirocycles are also reported.
Concise and versatile routes suitable for the synthesis of three geometric isomers an analogue left hand triene sub-unit oxazolomycin are reported. A strategy based upon a key Heck reaction was unsuccessful, this traced to combination steric encumbrance electronic deactivation alkene substrate. An alternative Stille coupling strategy, however, proved be both high yielding, is potentially applicable analogues with variation in side-chain geometry identity terminal aromatic or heteroaromatic residue.
This position study provides a science-based, holistic approach to evaluating the risks of nitrosamine presence in drug-linkers as intermediates toward antibody–drug conjugate (ADC) drug substances. The evaluation 47 different ADC substances, which have recommended dose available public domain, supports conclusion that chemically synthesized fragments ADCs are unlikely lead final product. Hence, it can be concluded for most there few introduced by and their impurities. An abbreviated...
Antibody–drug conjugates (ADCs) and N-nitrosamines are two topics that have seen a surge of interest in recent years. ADCs increasingly prevalent as oncology therapeutics clinical development on the market. Concerns about potential presence pharmaceutical products led to increased regulatory scrutiny implementation robust control strategies by industry. This article, first two-part series, provides visibility into current industry practices for risk assessment with results analysis from...