A5017221568- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- HIV/AIDS drug development and treatment
- Carbohydrate Chemistry and Synthesis
- Protein purification and stability
- Synthetic Organic Chemistry Methods
- Coordination Chemistry and Organometallics
- Chemical Synthesis and Reactions
- Cancer Treatment and Pharmacology
- Synthesis and Reactions of Organic Compounds
- Metabolomics and Mass Spectrometry Studies
- Asymmetric Synthesis and Catalysis
- Molecular spectroscopy and chirality
- Cyclopropane Reaction Mechanisms
- Fluorine in Organic Chemistry
- Synthesis and Reactivity of Heterocycles
- Phenothiazines and Benzothiazines Synthesis and Activities
- Process Optimization and Integration
- Chemistry and Chemical Engineering
- Signaling Pathways in Disease
- Enzyme Structure and Function
Bristol-Myers Squibb (United States)
2006-2023
Bristol-Myers Squibb (Germany)
2003-2019
The Bristol-Myers Squibb Children's Hospital
2006
Mettler-Toledo (United States)
2005
Wallace Laboratories
1993
In an effort to remove residual palladium from a drug candidate prepared by palladium-catalyzed indolization, many treatments were examined. The most effective treatment was precipitate solution using 2,4,6-trimercapto-s-triazine (TMT), which reduced levels 600−650 ppm 20−60 in isolated indole intermediate. Subsequent crystallizations routinely afforded active pharmaceutical ingredient with <1 of palladium. TMT should prove useful reduce the concentration other reactions.
Many workflows in Pharmaceutical R&D involve the manipulation of defined amounts powders. Automated powder dispensing platforms are currently available; however, these existing technologies do not meet requirements for every high-throughput experimentation application. A Working Group (WG) composed pharmaceutical researchers within Enabling Technologies Consortium (ETC) evaluated automated commercially available from three manufacturers using an objective, systematic testing protocol. This...
The ability to quickly generate and identify crystalline solids for organic compounds in a parallel fashion requires rapid, adaptable crystallization screening strategy that delivers reliable, valuable, consistent results. key the system is standard platform small-scale (0.5–2 mg) crystallizer array reproducibly crystallizes facilitates presentation of samples both an automated polarized light microscope instrument capable PXRD analysis. Data science technologies were leveraged streamline...
A practical synthesis of the SGLT-2 inhibitor β-C-aryl-d-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-d-glucano-1,5-lactone as key chiral building block, prepared efficiently from commercially available, inexpensive raw materials, d-gluconolactone and trimethylsilyl chloride. salient step in is Lewis acid-mediated stereoselective reduction a methyl C-aryl peracetylated glycoside using silyl hydride to set stereochemistry crucial anomeric center. Several...
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%.
Rapid knowledge building of chemical processes with highly automated DoE (HAD) and statistical analyses modeling.
The development of a diastereoselective nucleoside phosphorylation is described, which produces single isomer complex monophosphate pro-drug. A stable phosphoramidic acid derivative coupled to the nucleoside, in process mediated by HATU and quinine, deliver product high chemical yield good diastereoselectivity. This unusual was shown proceed through dynamic kinetic resolution 1:1 mixture activated phosphonate ester diastereoisomers. optimized conditions afforded with combined [S,S(P)]...
A concise bulk synthesis of stereochemically complex CCR2 antagonist BMS-741672 is reported. distinct structural feature the chiral all-cis 1,2,4-triaminocyclohexane (TACH) core, which was assembled through consecutive stereocontrolled heterogeneous hydrogenations: efficient Pt-catalyzed reduction a β-enaminoester, directed by (S)-α-methylbenzylamine as low-cost template, and reductive amination 3,4-cis-disubstituted cyclohexanone over sulfided Pt/C introduced tert-amine, setting third...
A critical component of defining the feasible design space for an active pharmaceutical ingredient (API) crystallization is isolating preferred polymorph or crystal form compound, which defines many compound's performance-defining attributes such as solubility and bioavailability. While automated platforms workflows exist to support facets process development, few aim systematically investigate polymorphism its kinetics a function conditions, thus providing measure risk associated with...
Herein we present a novel route to enantiomerically enriched chiral alpha-substituted carboxylic acids by crystallization-induced dynamic resolution (CIDR) of their diastereomeric salts with amines. Thus, the racemic alpha-bromo acid 3 is converted reliably (1R,2S)-2-amino-1,2-diphenylethanol in presence catalytic amount tetrabutylammonium bromide into its R-enantiomer 4 90% yield 88% ee. Similarly, alpha-thiobenzoyl 5 could be resolved ee 74% yield. Further enrichment enantiomeric...
Preparative chiral supercritical fluid chromatography (SFC) employing an enantioenriched feedstock obtained via partial classical resolution enabled rapid access to kilogram quantities of a key intermediate common two glucocorticoid (GC) receptor modulator candidates for which neither chemical nor enzymatic resolutions provided the desired purity (>99.0 HPLC area percent). We developed racemate that afforded 85:15 mixtures with 90% recovery enantiomer and reduced SFC processing time by 54%....
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...
The final step of the semisynthetic route to paclitaxel involves cleavage triethylsilyl (TES) protecting group from C-7 hydroxyl group. Paclitaxel is an extremely complex molecule, and standard deprotection conditions led formation several impurities. Trifluoroacetic acid in aqueous acetic was found be very effective TES without compromising quality product.
A novel crystallization-induced chiral inversion of (S)-2-bromo-3-phenylpropanoic acid to its (R)-enantiomer with excellent enantiomeric excess (96−99%) is achieved. Optically pure (S)-2-acetylthio-3-phenylpropanoic can be prepared in good yield from inexpensive and commercially available l-phenylalanine via diazotization/bromination, inversion, thioacetate substitution reactions.
We report research focused on the preparation of an advanced intermediate in synthesis a novel antiretroviral. This manuscript describes development efficient oxidation 6-azaindole derivative, bromination resulting N-oxide using PyBroP, removal protecting group, and isolation brominated azaindole product. The work reported herein has been successfully implemented multikilogram scale to fund clinical activities BMS-663068.
We describe the synthesis, chromatographic purification, and isolation of epothilone–folic acid conjugate BMS-753493, an investigational new drug candidate for treatment cancer. The main challenges process development were instability BMS-753493 in aqueous solution, design optimization preparative chromatography, removal phosphate salts water from purified material. operating conditions batch purification optimized using a column adsorption model. free-salt active pharmaceutical ingredient...
The development of a telescoped process for the API step in route to reversible inhibitor BTK is reported. Although robust and effective reaction crystallization was previously implemented, concerns around storage stability penultimate material led investigating process. Utilizing design experiments (DoE) understand impacts high-throughput extractions (HTEx) optimize workup, rapidly developed achieve same quality with an overall 13% improvement yield 41% mass intensity (PMI).
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).
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...
An internal development project at Bristol-Myers Squibb (BMS) led to invention of a family organic chemistry synthesis blocks for both parallel in drug discovery and reaction optimization pharmaceutical development. The demand these became so great that the original team was challenged by burden ongoing manufacture, support, supply chain management. As result, BMS entered into unique industry partnership with Mettler-Toledo AutoChem (MT), Newark, DE, formerly Bohdan Automation, commercialize...
Our efforts are focused on the application of automation to Process R&D. This article will describe high throughput methods rapidly investigate a development challenge. In this case we needed study deprotection N'-trifluoroacetyl-S-tert-leucine-N-methylamide which afforded lower than expected yield when subjected standard reaction conditions. chemistry was systematically investigated by sequential series high-throughput experiments using various automated and semi-automated systems. The...