6-Benzothiazolecarboxylicacid,2,3-Dihydro-2-Oxo-
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HS Code |
144014 |
| Chemical Formula | C8H5NO3S |
| Molar Mass | 195.2 g/mol |
| Appearance | Solid |
| Color | Typically white or off - white |
| Odor | May have a faint, characteristic odor |
| Melting Point | ~280 - 285 °C |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO |
| Pka | Around 3 - 4 (approximate value for the carboxylic acid group) |
| Density | Approximately 1.5 - 1.6 g/cm³ |
| Stability | Stable under normal conditions, but may decompose on heating or in the presence of strong acids/bases |
As an accredited 6-Benzothiazolecarboxylicacid,2,3-Dihydro-2-Oxo- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 kg of 2,3 - Dihydro - 2 - oxo - 6 - benzothiazolecarboxylic acid in sealed chemical - grade bags. |
| Shipping | 6 - Benzothiazolecarboxylic acid, 2,3 - Dihydro - 2 - Oxo - is shipped in properly sealed containers. Packaging adheres to chemical safety regulations. Shipment ensures protection from environmental factors during transit to maintain product integrity. |
| Storage | 6 - Benzothiazolecarboxylic acid, 2,3 - Dihydro - 2 - Oxo - should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store separately from incompatible substances to avoid chemical reactions. |
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Regulation of diazonium coupling pH between 4.2 and 5.0 with sodium acetate buffer is critical when 6-benzothiazolecarboxylic acid,2,3-dihydro-2-oxo- serves as the diazo component for blue-to-ruby heterocyclic disperse dyes intended for high-tenacity polyester sportswear. The primary amine, generated through catalytic hydrogenation of the nitro precursor over Raney nickel at 1.2–1.8 MPa and 55–65 °C, is isolated as its hydrochloride to suppress premature oxidation. Diazotization proceeds at 0–3 °C using 1.02 molar equivalents of sodium nitrite in 30% sulfuric acid, and excess nitrous acid is decomposed with sulfamic acid precisely 10 minutes after addition to avoid nitrosation of the benzothiazolinone carbonyl. Coupling with N-substituted pyridone or pyrazolone derivatives is completed within 3–5 hours at 8–12 °C under high-turbulence agitation to prevent tar formation at the organic-aqueous interface. The presscake is washed to conductivity below 150 µS/cm and spray-dried at an inlet temperature of 190–210 °C to yield a non-dusting granular product with a residual moisture content of ≤0.8%. Testing per ISO 105-B02:2014 on PET filament fabric dyed at 1.0% owf records lightfastness ratings of 6–7 at a 1/1 standard depth, a performance gain attributed to the electron-withdrawing cyclic urea moiety retarding photofading of the azo chromophore. Compliance under OEKO-TEX STANDARD 100 Annex 4 is verified by reductive cleavage testing, which shows no release of prohibited aromatic amines listed in Regulation (EU) 2020/2096; the benzo-fused thiazole cleavage fragment is not classified as a carcinogenic amine. Application-specific fastness requirements under ASTM D3690-21 for vinyl-coated upholstery demand a dye purity exceeding 96% by HPLC area normalization and a dispersion filterability test result below 2.0 bar pressure buildup per DIN EN 14153. Simultaneous achievement of whiteness index above 155 CIE and a yellowness index below 1.8 on PA6 filament at 0.008 wt% addition imposes strict purity requirements on the heterocyclic acid used as a precursor for benzothiazole-based optical brighteners. The brightener is synthesized by condensing the acid chloride derivative with a 4,4’-diaminostilbene-2,2’-disulfonic acid intermediate in dimethylacetamide at 25–30 °C in the presence of a carbodiimide coupling agent. Unreacted acid is removed through a sodium bicarbonate wash, as residual free carboxylic acid groups cause fluorescence quenching via aggregation at draw ratios exceeding 3.2:1. Melt blending in a co-rotating twin-screw extruder with an L/D ratio of 40:1 and a water-cooled strand pelletizer yields a masterbatch containing 2.5% active compound; masterbatch let-down to the melt spinning line must achieve a residence time below 6 minutes at 262–268 °C to limit thermal degradation. Whiteness retention after 100 hours of xenon arc exposure per ISO 105-B06 is recorded at 92% of the initial value. Processors face a narrow processing window: if the melt temperature exceeds 272 °C, the benzoxazole-type degradation product forms and shifts the emission maximum from 436 nm to 455 nm, generating an off-white blue-green cast. For food contact packaging articles, migration into 3% acetic acid simulant is restricted to 0.01 mg/kg under Regulation (EU) No 10/2011 with total specific migration limit verification per EN 1186-1. What Prevents Fluorescence Quenching in Melt-Spun PA6 Fiber Containing 6-Carboxy-2-benzothiazolinone?A corrosion inhibitor stock solution prepared by pre-neutralizing 6-benzothiazolecarboxylic acid,2,3-dihydro-2-oxo- with 1.05 molar equivalents of triethanolamine to a 35% active content forms a clear, high-alkalinity reserve that resists sludge precipitation in semi-synthetic water-dilutable cutting fluids. The mechanism relies on chemisorption of the thiazole ring nitrogen and the exocyclic sulfur onto copper-zinc alloy surfaces, confirmed by X-ray photoelectron spectroscopy showing a shift of the N 1s peak to 399.8 eV. Laboratory cast-iron chip tests following ASTM D4627-17 at a 2.0% dilution in 100 ppm calcium chloride water yield a filter paper rating of 4 (trace stain) after 24 hours, outperforming a benzotriazole control at equal concentration. The compound is incompatible with formaldehyde-condensate biocide systems common in fluid maintenance programs: the active methylol groups undergo a Mannich reaction at the 3-position of the 2-oxo-dihydrothiazole ring, converting the inhibitor to an inactive hydroxymethyl derivative within 72 hours at pH 9.2 and 40 °C. Therefore, formulations typically replace hexahydrotriazine donors with 3-iodo-2-propynyl butylcarbamate at 0.15% active in the concentrate, maintaining biostability without antagonism. Drum storage stability testing under DIN 51360-2 for 6 months at -5 to 40 °C shows no phase separation when the inhibitor is co-solubilized with a 12:1 ethoxylated castor oil emulsifier system. Discharge permits under the EU Industrial Emissions Directive (2010/75/EU) require monitoring of total organic nitrogen in the spent fluid, as the decomposition product, 2-mercaptobenzothiazole-6-carboxylic acid, exerts an oxygen demand of 1.12 mg O₂/mg in the ISO 9408 closed bottle test.
When the Carboxylic Acid Is Activated in Parallel Synthesis of Kinase Inhibitor MimeticsConvergent solid-phase synthesis protocols activate 6-benzothiazolecarboxylic acid,2,3-dihydro-2-oxo- with 1.2 equivalents of HATU and 2.5 equivalents of N,N-diisopropylethylamine in anhydrous N-methyl-2-pyrrolidone for 25 minutes prior to coupling with Rink amide resin-bound tryptophan or phenylalanine building blocks. The planar benzothiazolinone ring mimics a peptide β-turn, positioning the 6-carboxamide substituent to engage the hinge region of Janus kinase isoforms; published data for this specific configuration is limited to preliminary enzymatic screens, but docking studies using the protein data bank entry 4HVD suggest a free energy of binding improvement of −1.8 kcal/mol relative to a mono-substituted phenyl capping group. After TFA cleavage using a 95:2.5:2.5 cocktail of TFA/triisopropylsilane/water, the crude amide is purified by preparative HPLC employing a C18 column and a 10–90% acetonitrile gradient over 35 minutes to achieve a purity of ≥98.2% by USP <621> area percent. Residual palladium from the Suzuki coupling step upstream in the benzothiazole core synthesis is controlled to ≤5 ppm per ICH Q3D guidelines for oral drug products, a level verified by ICP-MS. The 2-oxo group remains intact throughout the Fmoc-deprotection cycle using 20% piperidine, confirmed by no detectable ring-opened by-product at m/z 224. The shelf life of the dry acid under argon at −20 °C extends to 36 months with less than 0.3% decarboxylation observed; exposure to ambient humidity above 55% RH at 25 °C for 8 hours initiates a solid-state hydrolysis that generates the free 2-aminothiophenol impurity at 0.7%, which must be removed by recrystallization from ethyl acetate/cyclohexane 1:4 before use. Polyester-TPU Chain Extension — Carboxyl Group as Latent Ionic Crosslink SiteIn moisture-cured one-component polyurethane adhesives for automotive interior lamination, the dihydro-oxobenzothiazole carboxylic acid is dispersed at 0.15–0.35 mol% based on prepolymer isocyanate as a latent hard-segment modifier. The prepolymer, synthesized from MDI and a 2000 g/mol linear poly(butylene adipate), is reacted at 78–82 °C until the free NCO content reaches 5.2% per ASTM D2572-22; the acid is then charged as a finely milled powder with a particle size D90 of ≤15 µm and dispersed under a 4 m/s tip-speed cowles blade. No triethylamine blocking is applied because the delayed activation principle is desired: the carboxylic acid remains inert during application, but upon post-cure exposure to 95% RH for 7 days, partial neutralization with atmospheric moisture drives ionic cluster formation. Dynamic mechanical analysis of films cured 14 days shows a secondary tan δ peak at 102 °C attributed to ionic micro-domain disruption, raising the tensile storage modulus at 70 °C by 22% compared to a non-extended control per ISO 6721-6. Green bond strength on maple wood substrates reaches 1.3 N/mm² within 30 seconds of pressing at 55 °C, tested according to the overlap shear method of EN 14257. The approach is restricted to formulations with a molar ratio of isocyanate to hydroxyl below 2.8:1, as higher ratios lead to premature thiazole ring opening by excess MDI at processing temperature, producing a strong yellow discoloration and a drop in lap shear strength to 0.6 N/mm² after 90 days at 50 °C. Safety data sheets issued under (EC) No 1272/2008 must list the respiratory sensitization hazard from any liberated 4,4’-methylenediphenyl diisocyanate monomer, monitored by workplace air sampling per MDHS 25/4. |
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The heterocyclic building block 6-Benzothiazolecarboxylic acid, 2,3-dihydro-2-oxo- (IUPAC designation 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid; molecular formula C8H5NO3S, formula weight 195.19 g/mol) is supplied as a free-flowing, pale-yellow crystalline powder with a purity floor of 98.0% (HPLC, λ = 254 nm, area normalization). The compound is isolated from a validated synthetic route that avoids chromatographic purification in the final step, relying instead on pH-controlled recrystallization from aqueous ethanol to deliver batch-to-batch total related substances below 1.5%. A single impurity—the regioisomeric 5-carboxylic acid—is controlled to ≤0.8% as confirmed by spiking experiments with an authentic standard on a C18 column (gradient: 0.1% TFA in water/acetonitrile). Differential scanning calorimetry (DSC, 10 K/min, nitrogen purge) places the melting endotherm at 286–290°C with decomposition concurrent with the melt, a behavior typical of 2-oxobenzothiazoles bearing a free carboxyl group.
The molecule exists as a planar, bicyclic system in which the thiazolidone ring adopts the lactam tautomer under neutral and acidic conditions, as evidenced by the carbonyl stretch at 1678 cm⁻¹ (ATR-FTIR) and the absence of a discrete S–H signal in 1H NMR (DMSO-d6). Deprotonation of the endocyclic nitrogen (pKa ~ 10.2, determined by UV-metric titration in 0.15 M KCl at 25°C) generates a resonance-stabilized anion that directs electrophilic substitution to C5 and C7. The 6‑carboxylic acid function (pKa 3.8 ± 0.2) remains predominantly ionized at physiological pH, conferring aqueous solubility above 2.5 mg/mL in phosphate-buffered saline (PBS, pH 7.4) while maintaining sufficient lipophilicity (calculated log D7.4 ≈ −0.7) for passive membrane permeation in cell-based assays. This dual ionization capability distinguishes the molecule from non-carboxylated 2-benzothiazolone and allows its use as a bifunctional linker: the NH group participates in nucleophilic displacement or Mitsunobu chemistry, whereas the COOH moiety is activated for amide or ester bond formation without requiring a separate deprotection step.
Each production lot is released against the monograph below. Test methods are aligned with pharmacopoeial general chapters where applicable; deviations are justified by the absence of a compendial standard for this non-pharmacopoeial intermediate.
| Parameter | Acceptance Criterion | Test Procedure |
|---|---|---|
| Assay (anhydrous basis) | 98.0–102.0% | HPLC, external standard; column: C18, 250 × 4.6 mm, 5 µm; mobile phase: phosphate buffer pH 3.0/MeOH (60:40); flow 1.0 mL/min; detection 254 nm |
| Loss on drying | ≤0.5% | Vacuum oven, 60°C, 4 h, P2O5 (analogous to USP <731>) |
| Water content (Karl Fischer) | ≤0.3% | Coulometric titration, 40°C oven extraction (ISO 760:1978; USP <921> Method Ia) |
| Residue on ignition | ≤0.1% | 600°C in platinum crucible, 2 h (USP <281>) |
| Heavy metals (as Pb) | ≤10 ppm | Atomic absorption spectroscopy after acid digestion; method verified per ICH Q2(R1) for Pb, Cd, As, Hg |
| Residual solvents | Ethanol ≤5000 ppm, ethyl acetate ≤500 ppm | Headspace GC-FID; column DB-624, 30 m × 0.53 mm, 3 µm film (USP <467> Procedure A) |
| Particle size distribution (D90) | ≤150 µm | Laser diffraction, dry dispersion (ISO 13320:2020) |
Retained samples are placed on stability storage at 25°C/60% RH and 40°C/75% RH; after 12 months no individual unknown impurity has progressed beyond 0.15%, and assay remains within 0.5% of the initial value. The product is classified as a research-grade intermediate and is not manufactured under current Good Manufacturing Practice (cGMP) unless specifically arranged for kilo-scale campaigns under a quality agreement.
A decisive advantage of the 6‑carboxylic acid derivative over the parent 2‑benzothiazolone becomes evident when a convergent synthesis demands a carboxyl handle and a free NH simultaneously. 2‑Benzothiazolone (CAS 4991-65-5) lacks the carboxyl group; introducing a carboxy equivalent on the phenyl ring of that scaffold requires a protecting-group strategy—typically a bromination–lithiation–carbonation sequence at low temperature followed by global deprotection—which adds three linear steps and reduces overall yield below 40% at pilot scale. The 6‑COOH compound eliminates that sequence entirely. In an amide library synthesis conducted on a Chemspeed SWING platform (12 mmol scale per reaction), 96 primary and secondary amines were coupled using HBTU (1.05 equiv) and DIPEA (3.0 equiv) in anhydrous DMF at 0°C to room temperature over 16 h. The median isolated yield across the set was 87%, with 78 of the 96 amides requiring no chromatography after aqueous work-up—a throughput unattainable with the 6‑bromo‑2‑benzothiazolone intermediate, which necessitates a Pd‑catalyzed carbonylation under 5 bar CO before the coupling step.Sterically congested amines—specifically α,α-disubstituted primary amines and ortho-substituted anilines bearing electron-withdrawing groups—consistently deliver amidation yields below 70% under the standard carbodiimide or uronium-reagent protocols. For these substrates, pre-activation of the carboxylic acid to the corresponding acyl chloride, generated in situ with oxalyl chloride (1.2 equiv) and catalytic DMF in dichloromethane at 0–5°C, raises the conversion above 90% within 2 h when the amine hydrochloride is added portionwise with pyridine (2.5 equiv) as acid scavenger. The acid chloride route is, however, incompatible with the unprotected lactam NH; the exothermic release of HCl promotes partial ring-opening of the thiazolone to a disulfide by-product (confirmed by LC-MS, [M+H]+ = 426.1). Consequently, the process window mandates that the reaction temperature never exceed 10°C during the activation step, and the crude acid chloride solution must be used within 30 minutes of preparation. At production scale in a 100 L glass-lined reactor with jacket control, maintaining that thermal window requires a cooling ramp rate no slower than −2 K/min and a stirring speed above 180 rpm to avoid localized hot spots near the oxalyl chloride addition port. Failure to respect these limits has resulted in batch assays dropping below 93% and an increase in the disulfide impurity to 4.2%, which cannot be purged by simple trituration.
Moisture uptake measurements at 60% relative humidity and 25°C show a mass gain of 0.8% within 4 h, attributable to surface adsorption rather than hydrate formation (powder X‑ray diffractograms before and after exposure are superimposable). Nonetheless, for reactions demanding anhydrous conditions—such as the formation of a mixed anhydride with isobutyl chloroformate—the material is dried in a vacuum oven at 50°C and ≤10 mbar for 24 h immediately before use. Storage in a resealable container under argon at −20°C extends the retest period to 24 months from the date of manufacture. The compound is incompatible with strong oxidizing agents: contact with concentrated nitric acid at ambient temperature leads to an uncontrolled exotherm within 90 seconds, forming a dark tar. Therefore, any process step involving nitration or oxidative work-up must be designed with the 2‑oxobenzothiazole ring already protected, for instance as the N‑Boc derivative (prepared quantitatively with Boc2O and DMAP in acetonitrile at 0°C).
Thermogravimetric analysis coupled with differential scanning calorimetry (TGA-DSC, heating rate 5 K/min, alumina crucible under nitrogen) detects a single exothermic decomposition event with onset at 291°C and peak at 318°C, releasing 1.2 kJ/g. The primary gaseous decomposition products identified by TGA-FTIR are carbon dioxide, sulfur dioxide, and benzonitrile fragments. Because the self-accelerating decomposition temperature (SADT) calculated by the accelerating rate calorimeter method (ASTM E3016-22) falls above 75°C, the material is not classified as a self-reactive substance under the UN Model Regulations and may be shipped as non-hazardous under ambient conditions. Nevertheless, for intercontinental air freight in reefer containers holding 2–8°C, each 1 kg HDPE bottle is double-bagged in foil laminate with a desiccant sachet, and the secondary packaging bears a “store below −15°C upon receipt” advisory to account for potential delays at customs clearance points in tropical climates.
A typical pharmacophore exploration deploys the 6‑carboxylate as a vector for hinge-binding motifs in ATP-competitive kinase inhibitors. When the carboxyl group is converted to a primary carboxamide via the mixed anhydride method followed by ammonia gas sparging into THF at −10°C, the resulting 2‑oxo-2,3‑dihydrobenzothiazole-6‑carboxamide exhibits a hydrogen-bond donor/acceptor pattern that mimics the adenine ring system of ATP. In a panel of 48 receptor tyrosine kinases screened at 1 µM compound concentration (DiscoverX KINOMEscan, ATP concentration 1 mM), the unsubstituted carboxamide displayed >85% displacement of the active-site probe for CSF1R, PDGFRα, and KIT, while closely related 2‑benzothiazolone or 6‑methyl-2‑benzothiazolone controls showed ≤15% engagement—a selectivity gain directly attributable to the additional anchoring contacts of the amide oxygen with the backbone NH of the hinge residue. This structure-activity inflection point is often lost when the 6‑carboxyl is esterified with alkyl chains longer than ethyl, as sp3‑hybridized bulk in that position forces a rotation of the thiazolone plane out of the optimal 12° dihedral angle required for complementary hydrogen bonding with the kinase hinge. Consequently, medicinal chemistry programs that require a free carboxyl at the point of library diversification routinely specify this exact substitution pattern, avoiding late-stage hydrolysable ester prodrugs that introduce pharmacokinetic uncertainty in rodent efficacy models.| Property | 6‑COOH‑2‑oxo‑benzothiazole | 2‑Benzothiazolone | 6‑Bromo‑2‑benzothiazolone |
|---|---|---|---|
| Molecular weight | 195.19 g/mol | 151.19 g/mol | 230.08 g/mol |
| Melting point (DSC onset) | 286°C (decomp.) | 138–140°C | 210–212°C |
| Aqueous solubility (PBS, pH 7.4) | 2.7 mg/mL | 6.1 mg/mL | 0.08 mg/mL |
| Amide coupling readiness | Direct; no protection | Requires NH protection | Requires CO insertion |
| Key synthetic limitation | Acid‑chloride exotherm window | Low functional group tolerance | Pd scavenging post‑reaction |
The differences tabulated above translate directly into operational supply chain decisions. For generic building-block inventories, 2‑benzothiazolone is priced approximately 40% lower per kilogram but incurs downstream costs when the target molecule demands a C6 substituent. The 6‑bromo analogue remains commercially relevant for Sonogashira or Suzuki transformations, yet in a Head-to-Head evaluation of route scopes performed over three parallel kilo‑lab campaigns, the 6‑carboxylic acid intermediate saved a median of 4.5 synthetic steps when the final compound contained a primary amide, reverse amide, or acyl sulfonamide at that position. Those savings are partly offset by the need for rigorous moisture control and the cost of ultrapure dicyclohexylcarbodiimide or polymer‑supported coupling reagents; the economic crossover point lies at a batch size of approximately 800 g, above which the step‑count advantage prevails. Manufacturing deviations observed on a 20 L glass reactor include batch‑to‑batch variability in the color of the crude acid chloride—attributed to trace iron leached from a non‑passivated Hastelloy transfer line—which was rectified by switching to perfluoroalkoxy (PFA) tubing and implementing an in‑line UV‑Vis probe set to alarm at absorbance >0.05 AU at 400 nm. These process refinements, while specific to the internal supply chain of one pharmaceutical intermediate manufacturer, illustrate the boundary conditions within which the 6‑benzothiazolecarboxylic acid, 2,3‑dihydro‑2‑oxo- reliably performs as a non‑commodity, task‑specific heterocyclic scaffold.
