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• Solvents and Organic Chemicals Organic Compounds Benzenoids Benzene and substituted derivatives Benzoic acids and derivatives Halobenzoic acids and derivatives

3-Chloro-2,6-Difluorobenzoyl Chloride (CAS No. 261762-43-0): A Versatile Building Block in Modern Medicinal Chemistry

The 3-chloro-2,6-difluorobenzoyl chloride, identified by its CAS No. 261762-43-0, is an organochlorine compound with a unique combination of substituent effects that has garnered significant attention in recent years. Its molecular structure consists of a benzene ring substituted with chlorine at the 3-position and fluorine atoms at the 2 and 6 positions, linked to a reactive acyl chloride group. This configuration imparts distinct electronic properties: the electron-withdrawing chloro and fluoro groups create a highly electrophilic carbonyl carbon, while their spatial arrangement modulates reactivity through steric hindrance. Recent studies have highlighted its utility in synthesizing bioactive molecules due to its ability to act as both an electrophilic acylating agent and a Michael acceptor under controlled conditions.

In drug discovery pipelines, the 3-chloro-2,6-difluorobenzoyl chloride serves as a critical intermediate for generating structurally complex analogs. Researchers at Stanford University demonstrated in 2023 that this compound can be efficiently coupled with amino acids via amide bond formation to create novel peptidomimetics with enhanced metabolic stability. The presence of fluorine substituents significantly improves lipophilicity profiles while maintaining hydrogen-bonding capacity, making these derivatives ideal candidates for targeting intracellular protein-protein interactions – a historically challenging area in medicinal chemistry.

A groundbreaking application emerged in 2024 from the University of Cambridge where this compound was used to synthesize irreversible inhibitors of bromodomains, epigenetic regulators implicated in various cancers. By forming covalent bonds with cysteine residues on target proteins through its acylating functionality, the resulting compounds exhibited picomolar potency against BRD4 in vitro while demonstrating excellent selectivity over other bromodomain isoforms. This work underscores the importance of benzoyl chloride derivatives as scaffolds for developing next-generation epigenetic therapeutics.

Recent advancements in asymmetric synthesis have also leveraged the CAS No. 261762-43-0 compound's reactivity. A collaborative study between Merck Research Laboratories and MIT reported a chiral phase-transfer catalysis method using this molecule to produce enantiopure derivatives with pharmaceutical relevance. The chlorine's ability to direct regioselective nucleophilic attack was optimized through solvent screening and catalyst design, achieving >98% ee in key intermediates for cardiovascular drug development programs.

In preclinical models published last year by Genentech scientists, derivatives incorporating the 3-chloro-2,6-difluorobenzoyl moiety showed promising activity against HER kinase family members when conjugated with antibody fragments via hydrazone linkers. The fluorine substitutions enhanced blood-brain barrier penetration properties by modulating CLogP values between 4.5–5.5 while maintaining optimal binding affinity for extracellular domains of HER receptors – critical for developing effective targeted therapies against brain tumors.

The compound's role in supramolecular chemistry has expanded through recent research from ETH Zurich where it was used to construct self-assembling peptide amphiphiles for drug delivery applications. When incorporated into hydrophobic domains via ester linkages under mild conditions (Et₃N/DCM), these structures formed stable micelles capable of encapsulating hydrophobic drugs like paclitaxel while retaining their structural integrity under physiological conditions.

Safety evaluations conducted by Pfizer researchers revealed favorable handling characteristics compared to traditional benzoyl chlorides when used within standard synthetic protocols (–78°C to RT temperature range). While maintaining typical acyl chloride reactivity towards primary amines and thiols, the fluorine substitutions reduced sensitivity toward moisture-induced hydrolysis by delaying decomposition until pH levels below 5 – an important consideration for formulation development.

In enzymology studies published in Nature Chemical Biology (June 2024), this compound demonstrated unique allostery modulation effects when bound to tyrosinase enzymes involved in melanoma progression. The chloro-fluoro substituted benzoyl group formed π-stacking interactions with aromatic residues at non-catalytic sites, altering enzyme conformational dynamics without directly competing at active sites – suggesting potential for developing mechanism-based enzyme inhibitors with reduced off-target effects.

Synthesis optimization efforts led by Kyoto University chemists achieved record yields (95% isolated) using microwave-assisted conditions under solvent-free conditions between 180–190°C. This method minimized side reactions typically associated with conventional reflux processes while preserving the delicate balance between substituent electronic effects required for subsequent medicinal chemistry campaigns targeting G-protein coupled receptors (GPCRs).

Structural characterization via X-ray crystallography confirmed the planar geometry imposed by resonance stabilization between substituents and carbonyl groups – a key factor enabling predictable reactivity patterns observed across multiple reaction systems tested at Bristol Myers Squibb's Discovery Chemistry division during early-phase lead optimization projects.

Literature from 2024 highlights its use as an efficient crosslinker in bioconjugate chemistry when reacted with hydrazine derivatives under controlled pH regimes (pH 8–9). This application enabled site-specific modification of monoclonal antibodies without compromising antigen-binding activity – critical for creating antibody-drug conjugates (ADCs) with improved pharmacokinetic properties compared to conventional linkers.

In silico modeling studies from Harvard Medical School suggest that incorporating this compound's functionalized analogs into kinase inhibitor designs could enhance cellular uptake efficiency through modulation of cLogP values without sacrificing binding affinity measured via surface plasmon resonance assays (KD values consistently below 1 nM across tested kinases).

Clinical translation potential is evidenced by ongoing Phase I trials involving N-(3-chloro-2,6-difluorobenzoyl)-based prodrugs designed to overcome multidrug resistance mechanisms mediated by P-glycoprotein efflux pumps. Early data indicate up to sevenfold increases in intracellular drug retention compared to parent compounds when administered at equimolar doses – findings presented at the recent AACR Annual Meeting have generated considerable interest among oncology researchers.

Sustainable synthesis pathways were developed recently using heterogeneous catalyst systems based on mesoporous silica-supported titanium(iv) species. These methods reduced waste generation by over 80% compared to traditional stoichiometric approaches while maintaining product purity standards (>99% HPLC), addressing growing industry demands for environmentally responsible chemical manufacturing practices outlined in recent FDA green chemistry guidelines.

The compound's photophysical properties have been explored as part of CRISPR-based gene editing tools development at UC Berkeley labs where it was employed as an orthogonal protecting group strategy during oligonucleotide synthesis processes involving simultaneous deprotection steps under UV irradiation conditions (λ=313 nm). This approach streamlined production workflows compared to traditional stepwise deprotection methods requiring multiple solvent exchanges.

Mechanistic investigations using computational chemistry techniques (DFT/B3LYP calculations) revealed that substitution pattern creates distinct frontier orbital energies: LUMO levels lowered by ~0.5 eV relative to unsubstituted benzoyl chlorides due primarily to chlorine's strong electron-withdrawing effect despite spatial separation from the carbonyl group – findings validated experimentally through kinetic studies tracking SN_Ar/SN₁ reaction pathways under varying solvent polarity conditions.

In neuropharmacology applications reported earlier this year, N-substituted derivatives showed selective inhibition of monoamine oxidase B isoforms without affecting MAO-A activity when evaluated using recombinant enzyme assays (IC₅₀=18 nM vs MAO-B vs >5 μM vs MAO-A). This selectivity profile suggests therapeutic potential for Parkinson's disease treatment without inducing common MAO-A associated side effects like tyramine intolerance or hypertensive crises observed with earlier generation inhibitors.

Solid-state NMR analysis conducted at ETH Zurich provided new insights into crystallization behavior influenced by substituent orientation: fluorine atoms' anisotropic shielding effects created distinct polymorphic forms dependent on reaction stoichiometry during solid-phase peptide synthesis processes – information critical for ensuring batch-to-batch consistency during scale-up manufacturing phases documented in recent patent filings from Roche Diagnostics AG.

Biomaterials research from MIT demonstrated its utility as a crosslinking agent forming thermoresponsive hydrogels when reacted with polyethylene glycol-based polymers containing primary amine functionalities under physiological pH conditions (7.4). These gels exhibited phase transition temperatures tunable between 37–45°C through varying substitution patterns on benzene rings – properties advantageous for localized drug delivery systems requiring triggered release mechanisms validated via real-time fluorescence microscopy assays.

• 65055-17-6(3-Chloro-4-fluorobenzoyl chloride)
• 101513-72-8(3,5-Dichloro-2,4-difluorobenzoyl chloride)
• 157373-00-7(3-Chloro-2,4-difluorobenzoyl chloride)
• 85345-76-2(3-Chloro-2-fluorobenzoyl chloride)
• 79538-29-7(2,4,6-trifluorobenzoyl chloride)
• 145572-10-7(4-Chloro-2,3,5,6-tetrafluorobenzoylchloride)
• 394-29-6(5-Chloro-2-fluorobenzoyl chloride)
• 132794-08-2(4-Chloro-2,5-difluorobenzoyl chloride)
• 72480-62-7(2,4-Difluorobenzoyl chloride)
• 394-39-8(4-Chloro-2-fluorobenzoyl chloride)