VB Chemical Research LLC

An extraordinary advancement in the synthesis of primary α-tertiary amines via photoredox catalysis has been achieved through the collaborative efforts of #DanLehnherr's team at #Merck and #TomislavRovis's team at #ColumbiaUniversity! This breakthrough demonstrates how two bench-stable starting materials—benzylic O-benzoyl ketoximes and benzylic iminium chloride salts—can be efficiently coupled with 4-cyano-heteroarenes, showcasing a remarkable tolerance for diverse functional groups. Source: https://lnkd.in/gmbxgUJH. Why are Amines Important? Amines are essential in #drugdiscovery, valued for their versatility and their presence in biologically active molecules. Quaternary carbon-centered primary amines are particularly significant—they are rare, difficult to synthesize, and vital as core structures in #activepharmaceuticalingredients (APIs), intermediates, and ligand libraries. Their unique structural properties make them fundamental to advancing #medicinalchemistry and developing #innovativetherapeutics. Key Highlights: Photoredox Catalysis: A single-electron disconnection approach is employed to synthesize primary amines featuring a fully substituted α-carbon center (quaternary carbon) from readily available starting materials. This method provides a streamlined pathway for accessing these challenging structures. Dual Role of Photoredox Catalyst: This work identifies how the photoredox catalyst efficiently facilitates a net reductive coupling by functioning as both a reductant and a triplet sensitizer. This concurrent tandem catalysis significantly enhances the overall efficiency of the reaction. Library Synthesis of Hindered Primary Amines: This innovative approach enables the efficient synthesis of libraries of hindered primary amines through parallel photoredox processes, paving the way for high-throughput experimentation that is particularly advantageous for medicinal chemists. A versatile and practical approach: This method accommodates a broad range of functional groups—including aryl and heteroaryl compounds—bearing functional groups such as halides, trifluoromethyl, esters, ethers, heterocycles, as well as unprotected alcohols and alkynes. #vbchemicalresearch #photoredoxcatalysis #oncology #ProcessDevelopment #discoverychemistry #medicinalchemistry #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #DrugDevelopment #CMC #SmallMolecules #Intermediates #API #Manufacturing

We are thrilled to highlight a remarkable contribution from #Guodu Liu’s group at Inner Mongolia University highlights the innovative application of the Biaryl phosphine ligand (L1, 1-(tert-butyl)-7-(2,6-dimethoxyphenyl)-2,3-dihydro-1H-phosphindole) in Suzuki-Miyaura cross-coupling reactions between aryl halides or pseudohalide and #alkylboronicacids. This work opens new avenues in the field and exemplifies pioneering advancements in #TransitionMetalCatalysis. Source: https://lnkd.in/g834hMF6 Why is this reaction so special? § Due to its versatility and robustness, the Suzuki-Miyaura cross-coupling reaction stands among the top-ranked carbon-carbon bond-forming reactions widely utilized in #drugdiscovery. § However, the Suzuki-Miyaura cross-coupling reaction encounters a notable limitation: β-hydride elimination, a frequent side reaction associated with alkyl fragments (particularly those containing β-hydrogens) in transition metal catalysis. This side reaction often competes with and challenges the desired cross-coupling reaction. § The innovative approach developed here effectively addresses this challenge by preventing β-hydride elimination and enabling smooth cross-coupling with alkyl partners through the selection of a suitable phosphine ligand (L1). This advancement demonstrates significant utility for industrial applications. Key Advantages of This Method: ·       Water-Soluble Byproducts: The reaction byproducts (boric acid or borate) are water-soluble, allowing for easy removal through aqueous workup and simplifying the purification process. ·       Robust Process: This method accommodates a wide variety of coupling partners, including aryl, heteroaryl, and alkyl groups, even when they are sterically hindered. This versatility enhances its reliability and broadens its application across complex molecules. ·       Successful Application in Drug Synthesis: This approach contributed to the synthesis of lumacaftor, a critical component of the prescription medication #ORKAMBI® (lumacaftor/ivacaftor), used in the treatment of cystic fibrosis (CF). #vbchemicalresearch #crosscoupling #oncology #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #DrugDevelopment #CMC #SmallMolecules #Intermediates #API #Manufacturing

An impressive contribution from #AbigailDoyle’s group at #PrincetonUniversity showcases the innovative use of Machine Learning (ML) in the #Deoxyfluorination of Alcohols with Sulfonyl Fluorides, marking a significant advancement in synthetic chemistry. Source: https://lnkd.in/gweHYpTS. Why is Fluorine So Crucial in #DrugDiscovery? The role of fluorine in #drugdesign and #development is advancing rapidly due to its remarkable properties. Incorporating fluorine into a molecule can significantly improve its #conformation, #pKa, #intrinsicpotency, #membranepermeability, #metabolicstability, and #pharmacokineticproperties. This unique element is a game-changer, helping to unlock new therapeutic potential. (Source: Applications of Fluorine in Medicinal Chemistry by #EricGillis’s team at #BristolMyersSquibb [BMS], https://lnkd.in/grdHhZnp). Key Advantages of This Method: 1. Cost-effective and Stable Reagents: The fluorinating agent, Sulfonyl Fluorides, are affordable, commercially available, and exhibit higher stability compared to the traditionally used sulfur(IV) reagents, which often suffer from thermal instability. 2. Easy Accessibility: These fluorides are easily prepared from commonly found sulfonyl chlorides. 3. High-value Products: The resulting Aliphatic Fluorides are highly sought after in pharmaceutical development. 4. Machine Learning Integration: A cutting-edge ML algorithm is employed to successfully model and predict reaction outcomes, enhancing the efficiency of this process. #vbchemicalresearch #fluorination #machininelearning #oncology #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #DrugDevelopment #CMC #SmallMolecules #Intermediates #API #Manufacturing

Today's inspiring topic: PROTAC Targeted Protein Degraders Proteolysis-targeting chimeras (PROTACs) are innovative molecules that selectively eliminate unwanted proteins from cells. Unlike traditional enzyme inhibitors, PROTACs induce targeted intracellular proteolysis by harnessing the cell’s own ubiquitin-proteasome system (UPS). Targeted protein degradation (TPD) represents an emerging therapeutic strategy with the potential to address disease-causing proteins that have historically been difficult to target using conventional small molecules. Two PROTACs currently in clinical trials are ARV-110 and ARV-471 (Given below). Best Reads: PROTAC Targeted Protein Degraders https://lnkd.in/gX624nEf https://lnkd.in/g7Wzy-dq https://lnkd.in/gsT3ceAg https://lnkd.in/gHQpsMSq https://lnkd.in/geJwThPp https://lnkd.in/gEUFEpTZ https://lnkd.in/gvfGWUud https://lnkd.in/gVc95i6n #oncology #Targeting #Chimera #PROTAC #PROteolysisTargetingChimeraPROTACMarket #PROteolysis #ProcessDevelopment #DrugDevelopment #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #CMC #SmallMolecules #Intermediates #API #manufacturing

A fantastic contribution to the synthesis of fully substituted hindered primary amines by #DanLehnherr's team at #Merck and #TomislavRovis's team at #ColumbiaUniversity! #Amines are crucial structural motifs in active pharmaceutical ingredients (#APIs) and their intermediates, as well as key components in ligand libraries for both biological and catalytic applications. You can explore the full publication here: https://lnkd.in/g7_4yySd Key Highlights: 1. Electrochemical Method: A novel electrochemical approach is described to access hindered primary and secondary amines, utilizing benchtop-stable iminium salts and a cyanoarene as starting materials. 2. Mechanistic Insight: This process involves proton-coupled electron transfer (PCET) followed by heteroradical−radical coupling, with subsequent re-aromatization leading to the final products. 3. Substrate Scope: At least one aryl group is required to stabilize the α-amino radicals in the imine; alkyl iminium salts are incompatible due to lack of radical stabilization. 4. Critical Parameters: The choice of cathode material and the supporting electrolyte are crucial for the success of this reaction. Key Merits: 1. A versatile and practical approach: This method accommodates a broad range of substituted heterocycles—including pyridine, pyrimidine, pyrazine, purine, and azaindole—bearing functional groups such as halides, trifluoromethyl, esters, amides, ethers, heterocycles, as well as unprotected alcohols and alkynes. #ProcessDevelopment #DrugDevelopment #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #CMC #SmallMolecules #Intermediates #API #manufacturing