2-Benzothiazolecarboxylic Acid, 6-Methoxy-
|
HS Code |
602188 |
| Chemical Formula | C8H7NO3S |
| Molar Mass | 195.21 g/mol |
| Appearance | Solid (Appearance may vary based on purity and preparation) |
| Melting Point | Data may vary, needs experimental determination |
| Boiling Point | Data may vary, needs experimental determination |
| Solubility In Water | Limited solubility (depends on conditions) |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol, DMSO |
| Pka Value | Data may vary, needs experimental determination |
| Density | Data may vary, needs experimental determination |
| Flash Point | Data may vary, needs experimental determination |
As an accredited 2-Benzothiazolecarboxylic Acid, 6-Methoxy- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 6 - Methoxy - 2 - benzothiazolecarboxylic acid packaged in a sealed plastic bag. |
| Shipping | 2 - Benzothiazolecarboxylic Acid, 6 - Methoxy - will be carefully packaged to prevent breakage. Shipped in containers suitable for chemical transport, following all safety regulations, ensuring secure delivery. |
| Storage | Store 6 - Methoxy - 2 - benzothiazolecarboxylic acid in a cool, dry place away from direct sunlight and heat sources. Keep it in a tightly - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store separately from incompatible substances such as strong oxidizing agents or bases to avoid chemical reactions. |
In live-cell fluorescence microscopy protocols requiring ratiometric Zn²⁺ detection at nanomolar concentrations, the activated N-hydroxysuccinimidyl (NHS) ester derived from 6-methoxy-2-benzothiazolecarboxylic acid is conjugated to a poly(ethylene glycol) spacer arm terminated with a primary amine. The acid is first dried over P₂O₅ under vacuum (1 mbar, 24 h) and then dissolved in anhydrous DMF at 0 °C. Sequential addition of 1.05 eq N,N′-dicyclohexylcarbodiimide (DCC) and 1.1 eq NHS generates the 6-MBTCA-NHS ester, which is isolated by precipitation from ice-cold diethyl ether and recrystallized from EtOAc/hexane (1:3 v/v) to yield 92 % white crystals (m.p. 134–136 °C). The active ester is then coupled to amino-PEG-amine (Mn 2000 Da) in 50 mM sodium bicarbonate buffer (pH 8.5) containing 10 % DMF at 4 °C for 12 h. After dialysis (MWCO 1000 Da) against deionized water and lyophilization, the resulting 6-MBTCA-PEG conjugate exhibits an excitation maximum at 345 nm and an emission maximum at 425 nm in HEPES buffer (pH 7.4). Upon addition of ZnCl₂, a 12-fold fluorescence enhancement is observed, attributed to chelation-enhanced fluorescence (CHEF) with a dissociation constant Kd of 0.9 nM determined by nonlinear curve fitting. The limit of detection calculated from 3σ/slope is 0.8 nM, which rivals the widely used Zinquin ester. For use in diagnostic imaging kits, the manufacturing process must conform to ISO 13485:2016 design controls, and the final reagent is supplied as a sterile-filtered 1 mM stock in DMSO stored under argon at −20 °C. Cellular uptake studies in SH-SY5Y neuroblastoma cells show mitochondrial localization with minimal cytotoxicity (IC₅₀ > 100 µM) as per ISO 10993-5 extraction-dilution assay. The critical quality attribute is residual NHS ester content, which must remain below 0.05 % by 1H NMR to avoid nonspecific protein labeling in flow cytometry applications.What Drives Hydrolytic Stability of Sulfonamide Bridge in Pro-herbicides Based on This Acid?The acid serves as a versatile precursor for benzothiazole-containing sulfonylurea herbicides, a class that targets acetolactate synthase (ALS) in broadleaf weeds. The synthetic route to bensulfuron-methyl analogues proceeds via activation of 6-methoxy-2-benzothiazolecarboxylic acid to the corresponding acyl chloride using thionyl chloride (1.3 eq) and catalytic DMF in toluene under reflux until gas evolution ceases. The acid chloride is isolated by vacuum distillation (b.p. 168–172 °C at 0.5 mmHg) and used immediately to acylate methyl 2-(aminosulfonyl)benzoate in anhydrous THF at −10 °C with triethylamine as acid scavenger. A molar ratio of acid chloride to sulfonamide of 1:1.02 is maintained to minimize bis-acylation. The resulting sulfonamide intermediate is then phosgenated with 1.05 eq phenyl chloroformate, followed by condensation with 1.0 eq 2-amino-4-methoxypyrimidine to forge the sulfonylurea bridge. Overall yield from the carboxylic acid is 61–68 % after column chromatography (silica gel, hexane/EtOAc 3:2) and recrystallization from acetone/water. The benchmark specification for the technical active ingredient is ≥98.0 % HPLC purity, with sulfamide dimer content below 0.5 % as per FAO Specification 447/TC (bensulfuron-methyl). Stability of the sulfonylurea linkage is profoundly influenced by the methoxy substituent on the benzothiazole ring: electron-donating groups slow hydrolytic cleavage at pH 7–9, which is critical for paddy rice formulations. Accelerated storage stability testing at 54 °C for 14 days according to CIPAC MT 46.1 shows less than 3 % degradation. The technical material must be handled under controlled humidity (RH <30 %) because the acyl chloride intermediate reacts violently with moisture, generating corrosive HCl fumes. The final formulation is typically a 10 % WG (water-dispersible granule) containing lignosulfonate dispersant and kaolin filler, applied at a rate of 25–50 g a.i./ha. A MedChem team progressing a type II kinase inhibitor program for VEGFR-2 encountered solubility-limited dissolution of the free acid in the amide coupling step. The solution adopted involved pre-activation of 6-methoxy-2-benzothiazolecarboxylic acid with HATU (1.2 eq) and DIPEA (3.0 eq) in anhydrous DMF at 0 °C for 15 min, followed by addition of 0.9 eq of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline. The reaction mixture was stirred for 18 h at ambient temperature, quenched with 5 % NaHCO₃, and extracted with EtOAc. The crude amide was purified by flash chromatography (silica gel, DCM/MeOH 20:1) to yield 78 % of the target compound (97.2 % purity by UPLC-QTOF). Residual solvent analysis by headspace GC-MS showed DMF levels of 180 ppm and MeOH 240 ppm, well within ICH Q3C Option 2 limits (DMF 880 ppm, MeOH 3000 ppm). The benzothiazole amide demonstrated IC₅₀ of 14 nM against VEGFR-2 in a TR-FRET kinase assay (Eurofins KinaseProfiler™). Critical process parameters identified during scale-up to 100 g batch size included strict control of water content in DMF (<50 ppm by Karl Fischer) and nitrogen atmosphere to prevent formation of the decarboxylation impurity, which arises from thermal lability of the carboxylic acid above 60 °C. Differential scanning calorimetry confirmed an exothermic decomposition onset at 210 °C, mandating storage at 2–8 °C under argon. The synthetic intermediate is classified as a GMP starting material per ICH Q7 and must be accompanied by a Certificate of Analysis showing heavy metals (<20 ppm as per USP <231>) and sulfated ash (<0.1 %). The terminal drug candidate incorporating this scaffold entered IND-enabling toxicology studies, where no genotoxicity was observed in an Ames test (OECD 471) and hERG IC₅₀ > 30 µM assured cardiac safety margin. Processing Window Analysis: Melt Grafting onto PA66 with TSE6-Methoxy-2-benzothiazolecarboxylic acid has been valorized as a covalently bound UV-absorbing moiety for hindered amine light stabilizer (HALS) constructs tailored for polyamide 66 under-hood automotive components. The synthetic path first converts the acid into the acid chloride, which is then condensed with 4-amino-2,2,6,6-tetramethylpiperidine in dry DCM using pyridine as HCl trap, producing the 6-MBTCA-HALS adduct at 95 % yield after washing with dilute HCl and brine. This adduct is melt-blended into polyamide 66 (relative viscosity 3.0, Zytel® 101L type) via reactive extrusion on a co-rotating twin-screw extruder (Leistritz ZSE 27 MAXX, screw diameter 27 mm, L/D 40:1). The stabilizer powder is pre-dried at 80 °C for 4 h and side-fed at zone 5 at a loading of 0.5 wt% using a gravimetric feeder (Brabender MiniTwin). The barrel temperature profile from feed to die is: zone 1 260 °C, zone 2 270 °C, zones 3–8 280–290 °C, die 290 °C. Screw speed is maintained at 300 rpm with a specific mechanical energy input of 0.19 kWh/kg. A vacuum vent at zone 7 (−0.08 MPa) strips residual volatiles. Residence time distribution is approximately 45 s. The molten strands are water-quenched and pelletized. Injection molding of ASTM type I tensile bars is performed on an Engel Victory 500 press at melt temperature 290 °C, mold temperature 80 °C. Accelerated weathering according to PV 3929 (dry phase 38 min, 70 °C black standard temperature, 0.55 W/m² at 340 nm) for 2000 h yields a color shift Δb* of 1.3 versus 4.8 for unstabilized control, measured with a spectrophotometer under D65/10° conditions. Tensile strength retention after weathering is 92 % of initial value (ISO 527-2, specimen type 1A). A tight processing window is observed: extrusion above 295 °C triggers decarboxylation of residual free acid, generating CO₂ micro-voids and silver streaks in molded parts; temperatures below 270 °C drop grafting efficiency below 60 %, allowing the stabilizer to migrate and deposit on mold surfaces. Extractable stabilizer content is quantified via hexane extraction (ASTM D5227, 70 °C, 24 h) and must not exceed 0.1 mg/dm² to meet OEM fogging specifications (VDA 278). The terminal part is an air-intake duct operating continuously at 130 °C peak, and the benzothiazole HALS chain-extenders do not interfere with the PA66 glass fiber sizing, used at 30 % reinforcement. Co-adsorption onto 12-µm-thick TiO₂ photoanodes using a dilute bath of 6-methoxy-2-benzothiazolecarboxylic acid alongside N719 ruthenium sensitizer has been evaluated to suppress interfacial recombination in dye-sensitized solar cells. The acid (H₂L) possesses a carboxyl anchor that binds to the anatase surface. A stock solution of 0.2 mM H₂L and 0.3 mM N719 in acetonitrile/tert-butanol (1:1 v/v) is prepared and heated to 40 °C. TiO₂-coated FTO glass (Solaronix Ti-Nanoxide T/SP) is immersed for 24 h in the dark. After rinsing with acetonitrile and drying, cells are assembled with an iodide/triiodide electrolyte (Iodolyte AN-50) and a platinum counter electrode. The co-adsorbent coverage, determined by desorption in 0.1 M NaOH, is approximately 1.2 × 10⁻⁷ mol/cm², filling defect sites that otherwise catalyze recombination. Electrochemical impedance spectroscopy under illumination (100 mW/cm², AM 1.5G, IEC 60904-9) reveals a recombination resistance increase from 18 Ω to 42 Ω, translating to an open-circuit voltage gain of +45 mV. The short-circuit current density remains essentially unchanged at 14.2 mA/cm². The optical band gap of the co-adsorbent monolayer measured by UV-Vis diffuse reflectance is 2.10 eV, ensuring negligible parasitic absorption. Extended thermal stress at 85 °C for 500 h (IEC 61215 damp-heat pre-test) leads to a 5 % drop in efficiency, attributed to slow desorption of the monocarboxyl linker; a comparative pentaerythritol tetrakis anchor analogue showed 2 % loss, indicating that the single-carboxyl strategy relies heavily on the methoxy-induced electron density of the benzothiazole to strengthen binding. The completed modules are targeted for indoor low-light energy harvesting (office light 200 lux) where persistent dye regeneration is essential. Standard ISO 9060 radiometry verifies operation at 5–10 µW/cm². No health or environmental labeling above 0.1 % SVHC is required under REACH for the co-adsorbent because the acid is consumed in the device. Under autogenous pressure at 80 °C, a DMF/water solvothermal charge comprising 6-methoxy-2-benzothiazolecarboxylic acid (1.0 mmol) and Tb(NO₃)₃·5H₂O (0.5 mmol) in 3 mL DMF and 1 mL deionized water, with 40 µL of 2 M HNO₃ as modulator, yields needle-shaped crystals of a terbium-organic framework after 48 h of heating in a PTFE-lined stainless-steel autoclave (Parr 4745, 15 mL). The as-synthesized MOF is washed with DMF and exchanged with methanol over 3 days, then activated at 120 °C under vacuum for 12 h to provide a surface area of 580 m²/g (BET, N₂ 77 K). Single-crystal XRD analysis reveals that the ligand bridges terbium centers in a μ₂-η¹:η¹ mode, forming a 3D network with 1D channels (6.4 Å diameter). Photoluminescence measurements on the activated material at 320 nm excitation display the characteristic ⁵D₄→⁷F₅ transition at 545 nm, which is strongly quenched by molecular oxygen. Stern-Volmer analysis of the luminescence intensity yields a constant KSV of 5.2 bar⁻¹, and the ⁵D₄ lifetime measured by time-correlated single-photon counting decreases from 1.42 ms under nitrogen to 0.18 ms in pure oxygen, fitting a two-site quenching model. The detection limit for gaseous O₂ is 0.5 mbar, defined as the point at which 3σ of the luminescence baseline equals the quenching signal. This performance is evaluated against ASTM F2714-08 (Standard Test Method for Oxygen Headspace Analysis) using a film cast from the MOF dispersed in ethyl cellulose (5 wt% loading). Exposure to 75 % RH at 23 °C for 24 h causes 15 % loss of emission intensity due to framework hydrolysis at the carboxylate-Tb bond, imposing a strict operational humidity ceiling. The sensing film is intended for non-invasive continuous monitoring in modified-atmosphere packaging of fresh-cut produce, where oxygen levels must be maintained below 2 %. No regulatory issues arise for food contact because the MOF is embedded behind a gas-permeable PTFE barrier film conforming to EU 10/2011 overall migration limits. |
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2-Benzothiazolecarboxylic Acid, 6-Methoxy- (6-MBCA), a heterocyclic building block with molecular formula C₉H₇NO₃S and molecular weight 209.22 g·mol⁻¹, is manufactured as a crystalline powder under cGMP conditions for use in early-phase pharmaceutical R&D and agrochemical discovery. The 6-methoxy substitution imparts a unique electronic profile that differentiates this compound from the unsubstituted 2-benzothiazolecarboxylic acid and from 6-halogenated analogs commonly employed in Suzuki-Miyaura or Buchwald-Hartwig couplings. Unlike the 6-chloro derivative, which exhibits moderate solubility in tetrahydrofuran (< 20 mg·mL⁻¹ at 25 °C), 6-MBCA dissolves to at least 65 mg·mL⁻¹ in DMF and 48 mg·mL⁻¹ in DMSO, facilitating homogeneous catalytic reactions without co-solvent addition. The material is supplied in two grades: a research-grade batch with HPLC purity ≥ 98.0% (area%) and a high-purity custom synthesis grade with HPLC purity ≥ 99.5% (area%), individual organic impurities ≤ 0.15%, and residual water ≤ 0.2% (Karl Fischer, ASTM E203).
Electronic perturbation of the benzothiazole nucleus by the 6-methoxy group manifests in several measurable parameters. The Hammett σₚ value for methoxy (−0.27) indicates a net electron-donating resonance effect, in contrast to the electron-withdrawing character of chlorine (σₚ +0.23) or nitro (σₚ +0.78) substituents. In practice, this donation raises the energy of the highest occupied molecular orbital (HOMO), accelerating electrophilic aromatic substitution on the benzene ring and altering the rate of oxidative addition in Pd(0)-mediated couplings. Differential scanning calorimetry (ASTM D3418) reveals a melting endotherm with an onset temperature shifted by approximately 19 °C relative to 6-chloro-2-benzothiazolecarboxylic acid, attributable to altered crystal packing forces. The methoxy derivative demonstrates a pKa of the carboxylic acid proton (determined by potentiometric titration in 0.1 M KCl) of 2.84, versus 2.41 for the 6-nitro analog, consistent with reduced acidity due to electron donation. These differences become critical when the acid is subjected to in situ activation with carbodiimide coupling reagents; 6-MBCA consistently forms the O-acylisourea intermediate at a slower rate, requiring a pre-activation time of 15–20 minutes at 0 °C before amine addition to avoid racemization in chiral amine couplings.
| Parameter | 6-MBCA | 6-H-BTA (Parent) | 6-Cl-BTA | 6-NO₂-BTA |
|---|---|---|---|---|
| Melting onset (°C, ASTM D3418) | 165–168 | 108–112 | 190–193 | 215 (dec.) |
| pKa (0.1 M KCl, 20 °C) | 2.84 | 2.45 | 2.30 | 1.95 |
| Solubility in DMF (25 °C, mg·mL⁻¹) | 65 | 35 | 15 | 8 |
| Relative rate of oxidative addition krel (Pd(PPh₃)₄) | 1.0 (ref.) | 0.41 | 0.22 | < 0.05 |
krel determined by in-situ ReactIR monitoring of decarboxylative coupling with 4-bromoanisole; Pd(PPh₃)₄ 2 mol%, Cs₂CO₃, DMF, 110 °C.
In the synthesis of 2-arylbenzothiazole pharmacophores via decarboxylative C–H arylation, 6-MBCA has been employed as a substrate under Pd(II)/Ag(I) co-catalytic conditions. Utilizing Pd(OAc)₂ (5 mol%), Ag₂CO₃ (2.0 equiv), and 1,10-phenanthroline (10 mol%) in NMP at 130 °C, coupling with 4-iodoanisole proceeds to give the corresponding 2-(4-methoxyphenyl)-6-methoxybenzothiazole with isolated yields of 78–84% after 18 h. The methoxy substituent at the 6-position does not interfere with regiochemical control; 1H NMR (DMSO-d₆, 400 MHz) of the crude product consistently shows less than 2% of regioisomeric impurities. This contrasts with the 6-hydroxy analog, where competitive O-arylation under the same conditions produces detectable dibenzofuran by-products. During a pilot-scale batch (reactor volume 50 L) employing a retreat-curve impeller at 250 rpm, a previously unobserved precipitate of palladium black formed when the reaction mixture was cooled below 25 °C prior to filtration, resulting in a yield drop of 11% relative to the laboratory-scale protocol. Subsequent root-cause analysis indicated that the palladium scavenger (Si-thiol functionalized silica) loading must be maintained at 1.5 wt% relative to crude product to achieve residual Pd < 50 ppm per USP <232>, and that the filtration temperature must remain above 35 °C to prevent product co-precipitation with the scavenger. Mean isolated yield across three production demonstrator runs (reactor volume 20 L) was 81% with relative standard deviation 3.4%.| Test | Acceptance Criterion | Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual; photometric reflectance L* ≥ 92 |
| Identification (IR) | Conforms to reference spectrum; ν(C=O) 1685 ± 10 cm⁻¹ | Ph. Eur. 2.2.24 / ASTM E1252 |
| Identification (HPLC) | Retention time matches RS within ±2% | In-house validated method |
| Assay (HPLC, area%) | ≥ 99.5% | Ph. Eur. 2.2.29, λ = 280 nm |
| Water content | ≤ 0.2% w/w | ASTM E203 (Karl Fischer) |
| Residue on ignition | ≤ 0.1% | Ph. Eur. 2.4.14, 600 °C |
| Heavy metals | ≤ 20 ppm | USP <233> (ICP-MS) |
| Residual solvents | Meets ICH Q3C Class 2 & 3 limits | USP <467> (GC-HS, Method A) |
| Purity by DSC | Single endotherm, onset 165–168 °C | ASTM D3418, 10 K·min⁻¹ |
| Particle size distribution | d₉₀ ≤ 150 µm (laser diffraction) | ISO 13320:2020 |
| Microbial limits | TAMC ≤ 10² CFU/g, TYMC ≤ 10¹ CFU/g | Ph. Eur. 2.6.12/2.6.13 |
Purity and impurity profiling of 6-MBCA is conducted on an Agilent 1260 Infinity II Quaternary LC system equipped with a diode array detector set at 280 nm (bandwidth 4 nm). Separation is achieved on a Waters XBridge C18 column (150 mm × 4.6 mm, 3.5 µm particle size) thermostatted at 30 °C. Mobile phase A: 0.1% (v/v) phosphoric acid in water; mobile phase B: acetonitrile; gradient: 10% B to 90% B over 20 min, hold 5 min. Flow rate: 1.0 mL·min⁻¹. Injection volume 5 µL. Under these conditions, 6-MBCA elutes at 11.2 min with a tailing factor (USP) of 1.05–1.12. System suitability requires resolution ≥ 2.0 between 6-MBCA and the nearest specified impurity (6-hydroxy-2-benzothiazolecarboxylic acid), and signal-to-noise ratio ≥ 10 for the 0.05% level standard. This method has been validated per ICH Q2(R1) for specificity, linearity (0.05–120% of target concentration, R² ≥ 0.9999), accuracy (recovery 98.5–101.2%), and intermediate precision (RSD 0.4%, n=6).
Conversion of 6-MBCA to the corresponding acid chloride with thionyl chloride (1.5 equiv, SOCl₂) in toluene is exothermic and requires strict exclusion of moisture to prevent hydrolysis of both the reagent and the product. The substrate must be pre-dried under vacuum (≤ 10 mbar) at 40 °C for 4 h; Karl Fischer analysis should confirm water ≤ 0.05% before charging. The reaction is performed in a glass-lined vessel under dry nitrogen (−40 °C dew point) with a condenser vented to a caustic scrubber. Addition of a catalytic amount of DMF (0.1 equiv) accelerates the formation of the Vilsmeier intermediate, reducing the induction period from 90 min to 15 min at 65 °C. In-process monitoring by sampling and quenching into anhydrous methanol followed by GC analysis shows complete conversion (> 99%) within 3 h. The resulting acid chloride is unstable in ambient atmosphere: its half-life in air at 50% relative humidity and 25 °C is approximately 4 minutes, necessitating immediate use in the subsequent amidation or esterification step. Compatibility with downstream processes is limited; combination with amine-based additives or polyol solvents must be avoided due to rapid exothermic reaction that can elevate the pot temperature by 18–22 °C within 30 seconds of mixing.
Long-term storage of 6-MBCA in airtight containers under argon, with desiccant packs, preserves the anhydrous form. Once opened, the material should be used within 48 hours when stored at ambient temperature and relative humidity < 40%. For operations exceeding this window, a nitrogen-purged glovebox (O₂ < 10 ppm, H₂O < 1 ppm) is recommended. Exposure to light for extended periods promotes an oxidative demethylation side reaction, visible as a gradual pink discoloration; light-sensitive handling under yellow lighting (cut-off < 530 nm) is specified for campaigns lasting beyond 72 h.
The 6-MBCA ligand reacts with CuCl₂·2H₂O in ethanol to form a green complex [Cu(6-MBC)₂(H₂O)₂] with a magnetic moment (Gouy balance, 298 K) of 1.78 μ_B, consistent with a distorted octahedral geometry. IR spectroscopy (KBr pellet, ASTM E1252) shows a shift of the ν(COO⁻) asymmetric stretch from 1685 cm⁻¹ in the free acid to 1620 cm⁻¹ in the complex, indicating bidentate coordination via the carboxylate and thiazole nitrogen. Such complexes have been evaluated as catalysts for the oxidation of benzyl alcohol to benzaldehyde using H₂O₂ as terminal oxidant, achieving TONs up to 450 under optimized conditions (acetonitrile, 60 °C, 6 h). The 6-methoxy group reduces the redox potential (E₁/₂, vs. Ag/AgCl in CH₃CN) by 0.12 V relative to the unsubstituted analog, enhancing catalytic activity. In contrast, reaction with FeCl₃·6H₂O in methanol at 50 °C yields a tris-chelate [Fe(6-MBC)₃] that exhibits a λₘₐₓ at 510 nm (ε = 2.4 × 10³ M⁻¹·cm⁻¹) and does not catalyze epoxidation of styrene under PhIO-driven conditions, likely due to the stability of the low-spin d⁵ configuration preventing oxo-transfer.
