A5089063563- Cyclopropane Reaction Mechanisms
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Catalytic C–H Functionalization Methods
- Chemical Synthesis and Analysis
- Asymmetric Hydrogenation and Catalysis
- Chemical Synthesis and Reactions
- Chemical synthesis and alkaloids
- Catalytic Cross-Coupling Reactions
- Synthesis and Catalytic Reactions
- Oxidative Organic Chemistry Reactions
- Chemical Reaction Mechanisms
- Synthesis and Biological Evaluation
- HIV/AIDS drug development and treatment
- Cell Adhesion Molecules Research
- Asymmetric Synthesis and Catalysis
- Fluorine in Organic Chemistry
- Synthesis of β-Lactam Compounds
- Chemical Reactions and Isotopes
- Chemical Reactions and Mechanisms
- Catalysis for Biomass Conversion
- Synthesis and Reactions of Organic Compounds
- Light effects on plants
- Cancer Immunotherapy and Biomarkers
- Coordination Chemistry and Organometallics
Bristol-Myers Squibb (United States)
2010-2024
Bristol-Myers Squibb (Germany)
2005
Texas A&M University
1997-1999
University of California, Los Angeles
1997
Scripps Research Institute
1997
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTExperimental and Theoretical Kinetic Isotope Effects for Asymmetric Dihydroxylation. Evidence Supporting a Rate-Limiting "(3 + 2)" CycloadditionAlbert J. DelMonte, Jan Haller, K. N. Houk, Barry Sharpless, Daniel A. Singleton, Thomas Strassner, Allen ThomasView Author Information Department of Chemistry, Texas A&M University College Station, 77843 The Scripps Research Institute La Jolla, California 92037 Chemistry Biochemistry Los Angeles,...
The process optimization of a key step in the synthesis NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. convergent three-stage telescope featuring four discrete chemical transformations: Pd-catalyzed Miyaura borylation, followed by Suzuki–Miyaura cross-coupling, then concurrent acid-mediated cyclization THP (tetrahydropyran) cleavage. Through targeted development focused on safety, sustainability, robustness, we developed safer...
The aliphatic Claisen rearrangement of allyl vinyl ether and the aromatic phenyl are investigated in a combined experimental calculational study. Theoretically predicted kinetic isotope effects (KIEs) at all levels disagree with about half literature heavy-atom effects. New 13C 2H were determined by multisite NMR methodology natural abundance, 17O novel methodology. These new inconsistent values agree well high-level KIEs, suggesting that prior theory/experiment disagreement results from...
The process development and kilogram-scale synthesis of beclabuvir (BMS-791325, 1) is described. convergent features the use asymmetric catalysis to generate a chiral cyclopropane fragment coupling with an indole via alkylation. Subsequent palladium-catalyzed intramolecular direct arylation efficiently builds central seven-membered ring. target was prepared in 12 linear steps five isolations overall yield 8%.
Despite recent advancements in metal-catalyzed borylations of aryl (pseudo)halides, there is a continuing need to develop robust methods access both early-stage and late-stage organoboron intermediates amendable for further functionalization. In particular, the development general catalytic systems that operate under mild reaction conditions across broad range electrophilic partners remains elusive. Herein, we report application three (two Pd-based one Ni-based) direct borylation...
The development of a safe, robust process for the preparation ravuconazole (1), an antifungal agent, is described. discovery and procedures enabling efficient synthesis multikilogram quantities 1 demonstration through plant scale preparations are presented. A controlled means to prepare Grignard reagent utilization Fourier Transform Infrared spectroscopy (FTIR) monitoring safely conduct reaction featured.
The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled unified protocol for the direct conversion enantioenriched N-acyloxazolidinones to corresponding chiral esters, amides, and carboxylic acids. This straightforward catalytic method shown remarkable chemoselectivity substitution at acyclic N-acyl carbonyl diverse array N-acyloxazolidinone substrates. ionic radius Lewis acid catalyst was demonstrated as key driver performance that led...
Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or αLβ2, belongs to the β2 integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, 3 (ICAM 3). interactions between ICAMs are critical for cell adhesion, preclinical animal studies clinical data from humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept an immunological target. This article will detail...
The process development and the kilogram-scale synthesis of linrodostat (BMS-986205, 1) are described. features several highly efficient telescoped processes use Evans auxiliary to install a methyl-bearing stereocenter. target was prepared in 12 steps with 7 isolations an overall yield 31%.
The use of LiOH/H2O2 for cleavage Evans oxazolidinones is an essential but often overlooked part using these ubiquitous chiral auxiliaries in synthetic routes. These conditions were disclosed the literature more than 30 years ago and have found widespread with little change. During studies focused on synthesis a drug candidate, we discovered evolution oxygen under auxiliary. We find this phenomenon to be general tied fact that initially formed peracid not stable reaction conditions. rapidly...
Process development of a selective serotonin reuptake inhibitor (1) is described. The synthesis features Nishiyama catalyst-mediated asymmetric cyclopropanation vinyl indole 2 with ethyldiazoacetate to install the trans-disubstituted cyclopropane. active pharmaceutical ingredient was prepared in 13 chemical steps 9 isolations and proceeded an overall yield 34%.
A combined experimental and theoretical investigation of the deuterium isotope effects on bacterial luciferase reaction is described. The studies focus determining if unusual aldehydic effect approximately 1.5 observed in these reactions an intrinsic resulting from a single rate-limiting step or composite multiple steps. not significantly affected by variation aldehyde chain length, changes pH over range 6-9, use alphaC106A alphaC106S site-directed mutants, chloride substitution at...
We have discovered and developed a highly chemoselective O-benzylation of ambident 2-quinolinone nucleophiles via Pd-catalysis. Detailed reaction analysis using direct-injection high resolution mass spectrometry (DI-HRMS) combined with in situ 31P NMR implicate phosphine mono-oxide Pd(II) η1-benzyl complex as key intermediate on the catalytic cycle. Extrapolation this method to selectively O-alkylate series substituted 2-quinolinones several benzylic electrophiles is demonstrated providing...
A simple metal-free method has been developed for the reductive N-alkylation of indoles employing aldehydes as alkylating agent and inexpensive Et3SiH reductant. wide range aromatic aliphatic are viable substrates along with a variety substituted indoles. In addition, was applied to one-pot sequential 1,3-alkylation indole successfully demonstrated on 100 mmol scale.
A practical synthesis of 3-((1S, 2S)-2-dimethylaminomethylcyclopropyl)-1H-indole-5-carbonitrile hydrochloride (1), a selective serotonin reuptake inhibitor (SSRI), is described. The process to prepare 1 was demonstrated on laboratory scale and highlights an enantioselective Simmons−Smith cyclopropanation allylic alcohol 3 using Charette's chiral dioxaborolane ligand. improved enabled production in 8 chemical steps (5 isolations) overall yield 38%.
The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. synthesis relies on key Miyaura borylation tandem Suzuki–Miyaura coupling between an iodoimidazole o-aminochloroarene, followed by acid-mediated cyclization afford aminoquinoline core. subsequent Boc cleavage regioselective acylation target compound. Two routes intermediate are presented, along with o-aminochloroarene via Negishi...
In the pharmaceutical industry, H2O2-mediated oxidation reactions are commonly used in chemical syntheses but they can also introduce unexpected safety hazards. Our labs recently reported on discovery of oxygen evolution during LiOH/H2O2-mediated cleavage Evans oxazolidinone. Faced with this previously hazard, authors, herein, report development and demonstration a methodology for safe scale-up O2-releasing reaction. It was found that O2 headspace could be controlled by combination N2...
The process development and the kilogram-scale synthesis of BMS-688521 (1) are described. features a highly efficient telescoped sequence which utilizes previously described spirocyclic hydantoin (4b) to produce final intermediate via an SNAR reaction. A deprotection step affords in high quality with overall yield 65% from key intermediate, (4b).
The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. features a [3 + 2] azomethine ylide cycloaddition to efficiently build spirocyclic core in diastereoselective fashion followed by classical resolution which affords desired enantiomer >98% enantiomeric excess. target was prepared four steps an overall yield 22%.
Several additives were screened for the stereoselective reduction of a 4-substituted cyclohexanone en route to linrodostat mesylate. It was found that addition sub-stoichiometric cerium(III) chloride in conjunction with sodium borohydride provided desired trans-cyclohexanol (arising out axial delivery hydride onto carbonyl) >16:1 selectivity and excellent conversion. The reaction initially scaled up 3.5 kg scale eventually >100 scale.
Mechanistic investigations on the intramolecular direct arylation of an indole-containing aryl bromide en route to HCV NS5B inhibitor beclabuvir are reported. A combination stoichiometric, kinetic, and computational studies revealed origin unique effectiveness tetramethylammonium acetate (TMAOAc) base uncovered unexpected dual role cation, as well unusual turnover-limiting step for this reaction. The arylpalladium oxidative addition complex is in equilibrium with key that undergoes C–H bond...
A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (1), a key intermediate in the an immuno-oncology asset, is described. Negishi cross-coupling between situ generated heteroaryl zinc reagent 4 and 5-bromo-2-chloroaniline (3) catalyzed by Pd(Xantphos)Cl2 enabled construction aryl–heteroaryl bond. first-generation process was developed that delivered 1 multikilogram quantities. Building upon knowledge from initial process, more efficient workup isolation...