2-Chloro-6-Methoxybenzothiazole
|
HS Code |
259460 |
| Chemical Formula | C8H6ClNOS |
| Molar Mass | 201.66 g/mol |
| Appearance | Solid (likely a white - off - white powder or crystal) |
| Melting Point | Data specific to 2 - Chloro - 6 - Methoxybenzothiazole needed (varies, common range might be 40 - 100°C for many benzothiazole derivatives) |
| Boiling Point | Data specific to 2 - Chloro - 6 - Methoxybenzothiazole needed (usually higher than 200°C for similar compounds) |
| Solubility In Water | Low solubility in water (benzothiazole derivatives are generally hydrophobic) |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone, dichloromethane |
| Odor | Typically has a faint, characteristic organic odor |
| Density | Data specific to 2 - Chloro - 6 - Methoxybenzothiazole needed (but likely in the range of 1.2 - 1.5 g/cm³ for related heterocyclic compounds) |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 2-Chloro-6-Methoxybenzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250 - gram bottle packaging for 2 - Chloro - 6 - Methoxybenzothiazole chemical. |
| Shipping | 2 - Chloro - 6 - Methoxybenzothiazole is shipped in sealed, corrosion - resistant containers. Adequate cushioning is used to prevent damage. Shipments follow strict chemical transportation regulations to ensure safety during transit. |
| Storage | 2 - Chloro - 6 - methoxybenzothiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from sources of heat, ignition, and incompatible substances like strong oxidizers. Store in a tightly - sealed container to prevent leakage and exposure to air and moisture, which could potentially lead to decomposition or chemical reactions. |
What governs the regioselectivity of 2-chloro displacement in benzothiazole-based API syntheses?The condensation of 2-chloro-6-methoxybenzothiazole with nucleophilic amines and thiols constitutes the key carbon–heteroatom bond-forming step in the preparation of a structurally heterogeneous class of CNS-active benzothiazoles, notably molecules exhibiting D₂/5-HT₂A receptor occupancy profiles that have entered preclinical evaluation for atypical antipsychotic activity. The chlorine at position 2 is activated by the electron-withdrawing benzothiazole π-system, but the simultaneous presence of the electron-donating 6-methoxy substituent creates a push–pull electronic topology that moderates the electrophilicity of the ipso carbon, a phenomenon routinely monitored by 13C NMR chemical shift dispersion between C-2 and C-3a. On production scale, the coupling is conducted in anhydrous dimethylformamide or N-methylpyrrolidone under a nitrogen blanket with a stoichiometric excess of the chloride relative to the amine of 1.03–1.08 molar equivalents, and the reaction mass is held at 78–82°C for 14–18 hours in a glass-lined reactor (DIN 28136) equipped with a retreat-blade impeller to minimise wall-bound degradation products. Process analytical technology employing inline Raman spectroscopy (probe calibrated against offline HPLC with UV detection at 290 nm) is used to track chloride consumption to a residual limit of ≤ 0.5 area-%, below which the rate of by-product formation—primarily the 2-hydroxy derivative arising from adventitious water—increases exponentially. The organic phase is quenched into 10% w/w aqueous citric acid at 0–5°C, and the crude intermediate is isolated via pressure filtration on a 0.5 m² Hastelloy C22 filter-dryer, achieving purity of ≥ 98.5% (w/w) by HPLC before recrystallisation from toluene/ heptane (1:3 v/v). ICH Q7 GMP Part II and ICH Q3C (R8) residual solvent guidelines govern the entire sequence, with specific limits for dimethylformamide below 880 ppm in the final isolated intermediate. The downstream drug substance manufacturing—in which the benzothiazole intermediate is further functionalised by alkylation or acylation—is executed under 21 CFR 210/211 current good manufacturing practice, and the API typically enters Phase I/II clinical supply chains as an amorphous free base with a particle size distribution controlled by jet milling to D₉₀ ≤ 10 μm. The same 2-chloro-6-methoxybenzothiazole building block has been documented in multiple chemical development reports for anxiolytic and anticonvulsant candidate molecules, though published process characterization data for those exact variants remains limited; the central reactivity challenges—namely control of exothermic chloride displacement and mitigation of oxygen-induced darkness—are nevertheless conserved across all routes.In the synthesis of agrochemical leads built around the N-(6-methoxybenzothiazol-2-yl)amide pharmacophore, the 2-chloro-6-methoxybenzothiazole scaffold has been routinely explored in the optimization of succinate dehydrogenase inhibitor (SDHI) fungicide candidates that require a heterocyclic amide substructure as the anchor moiety binding to the ubiquinone-binding site of complex II. The displacement of the chlorine with ammonia equivalents, followed by acylation with substituted pyrazole-4-carbonyl chlorides or trifluoromethyl nicotinic acid derivatives, forms the generic sequence; the selectivity of the initial amination is influenced by the solvent dielectric constant, with mixtures of tetrahydrofuran and water (4:1 v/v) yielding optimal mono-amination at 5–15°C while suppressing the formation of the symmetrical urea-like dimer. On pilot scale, the synthesis is executed in a 100 L Hastelloy C276 reactor under a controlled hydrogen chloride scavenging regimen using triethylamine (1.05 equiv.) dosed via a syringe pump over 120 minutes to maintain the reaction pH above 6.8 as measured by a temperature-compensated electrode. Regulatory compliance for the resulting agrochemical active ingredient must satisfy EPA 40 CFR Part 158 toxicology data requirements as well as CIPAC Handbook volume J analytical specifications, with the benzothiazole intermediate’s residual heavy metal content—particularly palladium if a cross-coupling step is employed later—verified by ICP–MS against a threshold of ≤ 10 ppm for each of Pd, Cu, Fe. The formulated end-use product, if destined for the European market, must additionally meet Regulation (EC) No 1107/2009 and the corresponding SANCO/10055/2013 residue definitions; consequently, the purity of the benzothiazole intermediate entering the synthesis is controlled with respect to any dioxin-like chlorinated by-products via GC×GC-TOFMS screening with a reporting limit of 0.01 mg/kg. Final formulations are typically suspension concentrates (SC 480 g/L) processed through bead milling to a particle size D₅₀ of 0.8–1.2 μm, targeting cereal leaf spot pathogens such as Zymoseptoria tritici; the benzothiazole-derived active ingredient represents 40–50% w/v of the formulation, and the in-can stability is validated under CIPAC MT 46.3 accelerated storage at 54°C for 14 days.Disperse dye chromophore construction via 2-diazo-6-methoxybenzothiazolium chlorideWhen 2-chloro-6-methoxybenzothiazole is subjected to nitrous acid treatment in concentrated sulfuric acid medium, the chlorine atom is not transformed directly into the diazonium functionality; rather, the synthetic route pivots on the prior conversion to the 2-amino-6-methoxybenzothiazole intermediate, which is then diazotised at −5 to 0°C with sodium nitrite (1.02 equiv.) in a mixture of 85% phosphoric acid and acetic acid (2:5 v/v). The resulting diazonium salt couples with tertiary aromatic amines—most productively with N,N-diethylaniline and its 3-methyl and 3-acetamido derivatives—to yield monoazo disperse dyes that exhibit bathochromic shifts of 40–65 nm relative to their benzothiazole-unsubstituted analogues, a consequence of the extended conjugation through the heterocyclic ring and the electron-donating methoxy oxygen at the 6-position of the benzothiazole nucleus. In a conventional production setup, the diazotisation is performed in a chilled (±1°C) glass-lined vessel using a slow nitrite addition over 45 minutes, and the endpoint is verified iodometrically; the diazonium liquor is then transferred via a jacketed dip pipe into a coupling vessel containing the arylamine dissolved in 5% aqueous hydrochloric acid at 0–3°C, with the addition rate controlled by a thermocouple feedback loop that maintains the coupling temperature below 5°C to suppress diazonium decomposition. The dye suspension is buffered to pH 4.0–4.5 with sodium acetate trihydrate, stirred for 3 hours, filtered on a membrane filter press (1 m² polypropylene plates), and washed until the filtrate conductivity falls below 50 μS/cm. The press cake is dried in a vacuum tray dryer at 70°C (absolute pressure 50 mbar) to a moisture content of ≤ 1.0% and milled to pass a 100 μm screen. Commercial formulations of the resulting dyes—typically manufactured as 30–50% w/w dispersible powders or liquid dispersions—must satisfy the OEKO-TEX® Standard 100 (Annex 4, 2024 edition) limits for banned aromatic amines (each ≤ 20 mg/kg) and the ZDHC Manufacturing Restricted Substances List v3.0; compliance is demonstrated by reductive cleavage test methods according to EN 14362-1:2023. The table below compares the key coloristic properties observed when three different coupling components are used with the 2-diazo-6-methoxybenzothiazolium salt, illustrating the span of achievable shades from red to deep blue on polyester fabric dyed at 130°C under 2 bar pressure in a high-temperature exhaust dyeing machine with a liquor ratio of 10:1.
When photolatent base generators based on 6-methoxybenzothiazole-2-carbamate structures are applied in UV-curable industrial coatingsThe 2-chloro-6-methoxybenzothiazole serves as an electrophilic handle for the introduction of photolabile carbamate protecting groups on strong amine bases such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), producing UV-responsive photolatent base generators that are thermally inert at ambient temperatures but undergo photodecarboxylation upon exposure to irradiation at 320–380 nm with a quantum yield typically falling between 0.15 and 0.35 in acetonitrile solution as measured by potassium ferrioxalate actinometry. The formulation contains the photolatent base generator at 2.0–5.0% w/w relative to the total resin solids, dissolved in a reactive diluent such as 1,6-hexanediol diacrylate and incorporated into a prepolymer blend of an aliphatic urethane acrylate (functionality 3–4) and a polyester acrylate; benzophenone (1.0–2.0% w/w) is co-loaded as a triplet sensitizer to expand the usable wavelength window and compensate for competitive light absorption by the benzothiazole chromophore in coatings exceeding 25 μm dry film thickness. Processing on a pilot coating line operating at 30 m/min with a mercury vapour lamp (120 W/cm, focal distance 53 mm) is carried out under inerting with nitrogen to maintain an oxygen concentration below 800 ppm in the irradiation zone, as the excited-state radical intermediates are efficiently quenched by triplet oxygen. The deblocked base catalyses the Michael addition between the acrylate end-groups and residual amine donors in the formulation, enabling post-cure crosslinking in shadow areas that are inaccessible to direct UV exposure; the degree of conversion is monitored by real-time FTIR-ATR following the disappearance of the acrylate band at 810 cm⁻¹, and tack-free surfaces are obtained within 45–60 seconds after the lamp. The final lacquer applied to three-dimensionally contoured polycarbonate components for electronics housings must achieve adhesion classification 5B per ASTM D3359-22 and survive 85°C / 85% RH for 500 hours without blistering. Although the 6-methoxybenzothiazole derivative offers the advantage of dark storage stability exceeding 6 months in a one-pack formulation, its incompatibility with strong oxidizing agents—notably cumene hydroperoxide and peroxybenzoate thermal initiators—demands a dedicated dispensing circuit made entirely of 316L stainless steel to avoid any cross-contamination that could trigger premature gelation at the delivery pump.Polyolefin light stabilization using a 6-methoxy-2-[(2-hydroxyethyl)thio]benzothiazole derivative, obtained by nucleophilic substitution of the chlorine atom in 2-chloro-6-methoxybenzothiazole with 2-mercaptoethanol in isopropanol under reflux (82°C, 3 hours), illustrates a processing-intensification route that concurrently introduces a thioether linkage and a hydroxyl group capable of further functionalization or direct dispersion into polyethylene and polypropylene matrices. The resulting additive is compounded into polypropylene homopolymer (MFR 3.5 g/10 min, 230°C/2.16 kg, ISO 1133-1:2022) at a concentration of 0.15–0.40% w/w alongside a hindered amine light stabilizer (0.10% w/w) and a phosphite process stabiliser (0.05% w/w) using a twin-screw extruder (L/D = 40:1, D = 34 mm) with a temperature profile rising from 180°C at the feed throat to 230°C at the strand die and a screw speed of 200 rpm; the strand is pelletised and injection molded into Type 1A tensile bars (ISO 527-2:2021) at a melt temperature of 220°C and a mould temperature of 40°C. Accelerated weathering performed according to ISO 4892-3:2016 under filtered xenon arc radiation (0.55 W/(m²·nm) at 340 nm, black panel temperature 65°C, relative humidity 50%) registered a retention of tensile elongation at break above 70% after 3000 hours, a result that positions the benzothiazole thioether in the performance envelope of commercial benzotriazole-type ultraviolet absorbers but with a lower migration rate in the polymer, as quantified by extraction with hexane at 60°C for 24 hours and HPLC-UV analysis of the extract. A limiting factor identified during pilot production is the tendency of the solid additive to melt at 78–81°C, which requires cooled (≤ 10°C) gravimetric feeder hoppers when processing in tropical climates where ambient temperatures exceed 35°C; failure to maintain hopper cooling results in bridging at the metering screw and erratic feed rates. The moulded articles intended for food contact packaging must comply with the positive list established under Commission Regulation (EU) No 10/2011 and its subsequent amendments, including the overall migration limit of 10 mg/dm² tested with simulant D2 (95% ethanol) at 60°C for 10 days. |
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| Parameter | 2-Chloro-6-methoxybenzothiazole | 2-Chlorobenzothiazole | 2-Chloro-6-nitrobenzothiazole |
|---|---|---|---|
| Melting range (°C) | 44–48 | ~0 (liquid at ambient) | 142–146 |
| Hammett σpara (estimated) | –0.27 | 0.00 | +0.78 |
| Relative SNAr ratea | 0.3 | 1.0 (reference) | 4.8 |
| Susceptibility to hydrolytic dechlorination | Moderate; pH-dependent | High at pH > 9 | Very low |
| Preferred solvent for Pd-catalyzed coupling | 1,4-Dioxane > DMF | THF ≈ 1,4-Dioxane | DMF (degassed) |
| Property | Method | Acceptance Criterion |
|---|---|---|
| Purity (HPLC, area%) | C18 column, acetonitrile/water (70:30) + 0.1% TFA, UV 254 nm | ≥98.0% |
| Water content | Karl Fischer coulometric (ASTM E203-16) | ≤0.3% |
| Residual solvents (GC-HS) | USP <467> Phase I limits | Ethyl acetate <500 ppm; DMF <880 ppm |
| Chloride ion (ion chromatography) | Dionex AS11-HC column, 30 mM KOH eluent | <0.1% (w/w) |
| Appearance | Visual inspection against a white background | White to off-white crystalline powder; free of visible extraneous matter |
| Identification | FTIR-ATR (diamond crystal, 4000–550 cm⁻¹) | Absorbance bands at 1562 cm⁻¹ (C=N stretch), 1238 cm⁻¹ (C–O–C asym. stretch), and 752 cm⁻¹ (C–Cl) match reference standard within ±2 cm⁻¹ |
