2-Amino-1,3-Benzothiazole-6-Carbonitrile
|
HS Code |
470627 |
| Chemical Formula | C9H5N3S |
| Molecular Weight | 187.22 g/mol |
| Appearance | Solid (usually a powder) |
| Melting Point | Specific value would need experimental determination |
| Boiling Point | Specific value would need experimental determination |
| Solubility In Water | Low solubility, likely sparingly soluble |
| Solubility In Organic Solvents | May be soluble in polar organic solvents like DMSO |
| Density | Specific value would need experimental determination |
| Pka | Relevant acidic/basic groups' pKa values would need experimental determination |
| Stability | Stable under normal conditions but may react with strong oxidizing or reducing agents |
As an accredited 2-Amino-1,3-Benzothiazole-6-Carbonitrile factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250g of 2 - Amino - 1,3 - Benzothiazole - 6 - Carbonitrile in sealed chemical - grade bags. |
| Shipping | 2 - Amino - 1,3 - benzothiazole - 6 - carbonitrile is shipped in sealed, corrosion - resistant containers. Packaging adheres to chemical transportation safety regulations. Shipment is via approved carriers ensuring secure and compliant delivery. |
| Storage | 2 - Amino - 1,3 - benzothiazole - 6 - carbonitrile should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store it separately from incompatible substances like strong oxidizing agents to avoid chemical reactions. |
Synthesis of the benzothiazolo[2,3-b]pyrimidine framework—a privileged scaffold in ATP-competitive kinase inhibition—often commences with the condensation of 2-amino-1,3-benzothiazole-6-carbonitrile and a β-ketoester. The electron-withdrawing nitrile group at the 6-position deactivates the fused benzene ring toward electrophilic substitution, directing functionalization exclusively to the exocyclic amine. A typical reaction protocol combines 1.0 eq of the benzothiazole carbonitrile with 1.15 eq of ethyl 4-chloroacetoacetate in anhydrous 1,4-dioxane under nitrogen. Addition of 0.05 eq of p-toluenesulfonic acid monohydrate and heating at reflux (101–102°C) for 6–8 hours yields the cyclized pyrimidinone intermediate. Process monitoring by HPLC (C18 column, acetonitrile/water 65:35, 254 nm) confirms consumption of the starting material; the product precipitates upon cooling and is isolated by vacuum filtration. For scale-up in a 500 L glass-lined reactor, controlled cooling from reflux to 5°C at a rate of 10°C/h minimizes occlusion of unreacted starting material within the crystal lattice. The isolated intermediate, after drying under vacuum at 50°C to a loss on drying (LOD) below 0.5% per USP〈731〉, serves as a building block for oral anticancer candidates currently in Phase I/II clinical evaluation. Regulatory compliance for use in active pharmaceutical ingredient (API) manufacture demands adherence to ICH Q7 guidelines and a residual solvent profile controlled according to ICH Q3C (R8), with particular attention to the limit of 1,4-dioxane not exceeding 380 ppm.What Conditions Favor Regioselective Alkylation at the 2-Amino Position for Next-Generation SDHI Fungicides?2-Amino-1,3-benzothiazole-6-carbonitrile is transformed into N-alkyl or N-acyl intermediates that, upon further elaboration, yield succinate dehydrogenase inhibitor (SDHI) candidates with heterocyclic amide linkages. The 6-cyano substituent acts as a metabolic soft spot that can modulate hydrolytic stability in the phloem. N-Alkylation with ethyl 2-bromopropionate in dimethylformamide requires strictly anhydrous conditions to suppress hydrolysis of the nitrile to the corresponding amide—a side reaction that becomes kinetically significant above 60°C. A proven lab-scale procedure charges the benzothiazole (1.0 eq), anhydrous potassium carbonate (2.5 eq, ≤325 mesh), and potassium iodide (0.1 eq) in DMF (10 vol), adding the alkylating agent (1.2 eq) dropwise at 0–5°C over 30 min. The batch is gradually warmed to 25°C and held for 12 hr. Quenching into 5% aqueous NaCl and extraction with ethyl acetate, followed by a Darco G-60 carbon treatment of the organic phase, removes palladium-leachable impurities should a downstream cross-coupling be planned. The resulting N-alkylated ester is saponified and coupled with substituted anilines via HATU-mediated amidation to afford the final SDHI pharmacophore. To meet the regulatory dossier requirements for active ingredient registration under EU Regulation (EC) No 1107/2009, the technical material must be accompanied by a five-batch analysis demonstrating chemical purity ≥98% and a certified profile of impurities at or above 0.1%, identified per SANCO/3030/99 rev.5. Furthermore, storage stability data at 54°C for 14 days (CIPAC MT 46.3) is required to verify the nitrile’s resistance to thermal hydrolysis during warehouse storage in tropical zones. Critical Parameters in the Synthesis of Polar Benzothiazole-Based Mesogens via Sonogashira Cross-CouplingThe 6-cyano group imparts a negative dielectric anisotropy (Δε) essential for vertically aligned (VA) liquid crystal mixtures. The synthetic keystone is the selective coupling of the 2-amino group with a 4-alkynyl-biphenyl derivative while retaining the nitrile and thiazole functionalities. After protecting the amine as the trifluoroacetamide to prevent Glaser-type oxidative alkyne homocoupling, the benzothiazole intermediate is subjected to Sonogashira conditions: 0.5 mol% Pd(PPh₃)₂Cl₂, 1.0 mol% CuI, and 3.0 eq of triethylamine in anhydrous tetrahydrofuran at 50°C for 4 hr under argon. The reaction must be blanketed with rigorous oxygen exclusion; dissolved O₂ levels monitored by a Mettler-Toledo InTap portable analyzer must remain below 20 ppb to prevent catalyst deactivation and alkyne dimerization. Following deprotection with methanolic sodium methoxide at ambient temperature, the crude mesogen is purified by flash chromatography (silica gel 60, hexane:ethyl acetate 4:1) and repeated recrystallization from absolute ethanol until the extrapolated clearing point (obtained by DSC at a heating rate of 5°C/min, ISO 11357-1:2016) remains constant within ±0.3°C across successive lots. This rigorous purification is mandated because ionic impurities at the ppm level can elevate the threshold voltage (V₁₀) and reduce the voltage holding ratio (VHR) below the 99% threshold required for active-matrix addressing. The finished product is supplied to display compounders as a white microcrystalline powder with a melting point of 142–144°C and a GC purity exceeding 99.9%. Transport is conducted under nitrogen padding in double PE-lined aluminium foil bags to prevent moisture ingress that would raise the rotational viscosity (γ₁) measured according to IEC 61747-2-1. If Diazotization and Cyanoethylation Are Sequenced, Cold-Water-Soluble Azo Chromophores Are AccessibleThe primary amino group at position 2 permits diazotization and subsequent azo coupling with electron-rich aromatic acceptors, producing vivid scarlet to violet acid dyes. The 6-cyano group enhances the electron deficiency of the diazonium component, shifting the absorption maximum bathochromically by 15–25 nm relative to the unsubstituted analogue when measured in DMF solution (Konica Minolta CM-5 spectrophotometer, 0.01 g/L, quartz cell). The diazotization is performed at −5 to 0°C by adding sodium nitrite (1.05 eq) to a suspension of the amine in 85% phosphoric acid; this medium minimizes uncontrolled decomposition of the diazonium salt, which is inherently unstable above 10°C. The clear diazonium solution is immediately transferred under vacuum to a second jacketed vessel containing the coupling component—typically N,N-diethyl-meta-toluidine or a sulfonated naphthalene derivative—dissolved in water at pH 4.5–5.0 adjusted with sodium acetate. The coupling is complete within 15 min as indicated by a negative spot test with H-acid solution. The precipitated dye is filtered through a polypropylene cloth filter (pore size 10 µm), washed with 2% NaCl solution, and oven-dried at 60°C under reduced pressure. For exhaust dyeing of nylon 6,6, the dye is milled with lignin sulfonate dispersant (weight ratio 1:1) in a horizontal bead mill to a particle size distribution where 95% of the particles are below 1 µm, verified by laser diffraction (Malvern Mastersizer). Compliance with Oeko-Tex Standard 100 Annex 4 requires that the level of free aromatic amine, determined by reductive cleavage according to EN ISO 14362-1:2017, be below the detection limit of 20 mg/kg. Latent hardeners for one-component epoxy formulations often sacrifice storage stability for fast cure at moderate temperatures. The 2-aminobenzothiazole-6-carbonitrile molecule, when micronized and dispersed in bisphenol A diglycidyl ether (DGEBA), remains inert at 25°C for over 6 months (viscosity increase <15% at 25°C, as measured by Brookfield DV2T spindle 27, 20 rpm) but triggers rapid ring-opening above 130°C. The cyano group participates in a cascade mechanism: at the onset temperature, it partially hydrolyzes to a primary amide under the influence of trace moisture, liberating an ammonia equivalent that unmasks the 2-amino nucleophile. In a formulation study, a loading of 8 phr (parts per hundred resin) combined with 2 phr dicyandiamide and 0.5 phr 2-methylimidazole yielded a gel time of 4.2 min at 140°C (hot plate stroke cure, ASTM D4217-07). The cured network exhibited a glass transition temperature (Tg) of 162°C (DMA, 1 Hz, 3°C/min) and a coefficient of thermal expansion (CTE) below Tg of 52 ppm/K according to ASTM E831-19. Production-scale incorporation into epoxy molding compounds requires pre-blending the curative into a masterbatch using a ZSK 26 Mc18 co-rotating twin-screw extruder (L/D 40, zone temperatures 60–80°C) to avoid localized hot spots that would deactivate the latent behavior. All constituents must be qualified per UL 746B relative thermal index (RTI) for electrical insulating systems. The final compound is used to encapsulate automotive microinverters where thermal class H (180°C) continuous operation is demanded, and the absence of free ionic contaminants is confirmed by ion chromatography extraction per IPC-TM-650 method 2.3.28. Exploiting the Thiophilic Character of the Benzothiazole Ring to Form Self-Assembled Monolayers on CopperIn aqueous cooling circuits and microelectronic fabrication, the adsorption of a benzothiazole derivative onto metallic copper proceeds through the exocyclic sulfur and the endocyclic nitrogen lone pairs. The 6-cyano substituent withdraws electron density, decreasing the pKₐ of the thiazole nitrogen and shifting the adsorption equilibrium to more acidic electrolytes (pH 3–5), where unsubstituted 2-aminobenzothiazole would desorb. A typical bath for forming a monolayer on copper electroplated wafers consists of 10⁻³ M 2-amino-1,3-benzothiazole-6-carbonitrile in a 1:1 v/v ethanol–water mixture, with the pH adjusted to 4.0 using acetic acid. Wafers are immersed for 15 min at 45°C under ultrasonic agitation (40 kHz), followed by rinsing with deionized water (18.2 MΩ·cm) and blow-drying with filtered nitrogen. Corrosion inhibition efficiency is evaluated by potentiodynamic polarization per ASTM G5-14 in 0.1 M NaCl; a reduction in corrosion current density (icorr) by one order of magnitude relative to the bare copper surface is indicative of a dense monolayer. The treated copper substrates remain solderable per J-STD-002 after 24 hr of accelerated aging at 85°C/85% RH. Occupational safety during bath preparation mandates local exhaust ventilation and nitrile gloves, as the dry powder is classified as a respiratory sensitizer under GHS; the permissible eight-hour time-weighted average (TWA) concentration should not exceed 0.5 mg/m³ as a guidance value pending full toxicological assessment. Waste streams are treated by passing through an activated carbon column that reduces the concentration to below 0.1 ppm before discharge in accordance with local regulations modeled after EU Directive 2010/75/EU. |
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Available as a pale-yellow to off-white crystalline powder, 2-amino-1,3-benzothiazole-6-carbonitrile (CAS 197255-10-8, molecular formula C₈H₅N₃S, molecular weight 175.21 g mol⁻¹) integrates a primary amine, a thiazole ring, and a nitrile substituent on a single aromatic scaffold. The compound is typically supplied with a purity specification of ≥97% by HPLC (area normalization at 254 nm, C18 column, acetonitrile/water mobile phase) and a loss-on-drying value of ≤0.5%. Its melting range, determined by differential scanning calorimetry at a heating rate of 10 K min⁻¹, is reported between 208 °C and 212 °C. Batch-specific certificates of analysis further include heavy metals content (≤20 ppm) and residual solvent profiles conforming to USP <467> recommendations for Class 2 solvents. The material is classified as a non-hazardous substance under GHS, though local dust control and avoidance of inhalation remain standard occupational hygiene requirements.
| Test | Method | Specification |
| Appearance | Visual / ASTM D1555M | Pale-yellow to off-white powder |
| Identification | FTIR (KBr pellet, 4000–400 cm⁻¹) | Match to reference spectrum: characteristic absorbances at 2218 cm⁻¹ (C≡N stretch) and 3360, 3260 cm⁻¹ (N–H stretch) |
| Assay (HPLC) | In-house RP-HPLC / UV 254 nm | ≥97.0% area |
| Water content | Karl Fischer titration (coulometric) | ≤0.3% |
| Melting point | DSC, 10 K min⁻¹ | 208–212 °C |
| Residue on ignition | Pharmacopoeial sulfated ash, 600 °C | ≤0.1% |
| Heavy metals (Pb) | ICP-MS after microwave digestion | ≤20 ppm |
| Residual solvents | Headspace GC-FID | Acetone ≤500 ppm; Ethyl acetate ≤500 ppm; Dichloromethane not detected (LOD 60 ppm) |
Storage at 2–8 °C in tightly sealed, light-resistant containers limits hydrolytic degradation of the nitrile substituent. Under nitrogen headspace, annual re-qualification demonstrates HPLC purity drifts of less than 0.5% over 24 months. Equilibration of the powder to ambient temperature before opening prevents atmospheric moisture condensation that can initiate agglomeration and localised hydrolysis at particle surfaces.
The presence of the electron‑withdrawing nitrile at the 6‑position of the benzothiazole core reduces electron density on the fused benzene ring, making the scaffold suitable for palladium‑catalyzed cross‑coupling reactions where oxidative addition at the C–X bond is rate‑limiting. In practice, 2‑amino‑1,3‑benzothiazole‑6‑carbonitrile has been employed in Suzuki‑Miyaura couplings at the brominated or iodinated 5‑position, exploiting the nitrile as a non‑participating group during the catalytic cycle. Comparative Hammett σₚ values for –CN (+0.66) versus –H or –CH₃ guide the choice of ligand systems; electron-deficient SPhos or XPhos precatalysts deliver higher conversion (>85%) than triphenylphosphine‑based systems under identical conditions. When coupling to electron-rich boronic acids, microwave irradiation at 120 °C for 30 min with 2 mol% Pd(PPh₃)₄ and 2.0 eq. K₂CO₃ in dioxane/water (4:1) typically yields the biaryl product without observable nitrile hydrolysis, as confirmed by retention of the 2218 cm⁻¹ IR band post‑reaction.
In the absence of rigorous anhydrous protocols, the nitrile can undergo partial hydrolysis to the corresponding amide under basic aqueous conditions at temperatures above 80 °C. This side pathway imposes a practical upper pH limit of 10 and a temperature ceiling of 75 °C for prolonged reactions. When the target molecule preserves the nitrile, a quenching protocol employing ice‑cold phosphate buffer (pH 7.0) immediately after the reaction arrests hydrolysis. Published data for this specific compound under large‑scale (> 100 mmol) coupling conditions remain limited, but mini‑plant runs in 5 L jacketed glass reactors indicate that maintaining oxygen levels below 2 ppm through nitrogen sparging is as critical as moisture control, since dissolved oxygen contributes to catalyst deactivation via phosphine ligand oxidation.
Further functionalization via the 2‑amino group can proceed without protection of the nitrile. Acylation with acetyl chloride in dichloromethane at 0 °C using triethylamine as acid scavenger gives the acetamide derivative in 88% isolated yield after silica gel chromatography (eluent: hexane/ethyl acetate 3:2). Diazotization‑based Sandmeyer reactions, however, are incompatible because the requisite strongly acidic nitrosating medium (typically 0–5 °C in concentrated HCl) promotes rapid nitrile hydration. Competent alternatives to Sandmeyer installation of halogens at the 2‑position utilise non‑aqueous diazotization with tert‑butyl nitrite in acetonitrile, a modification that leaves the 6‑carbonitrile intact.
| Compound | 6‑Substituent | Hammett σₚ | C–H Acidity at 5‑position* | Typical Pd coupling conversion** |
| 2‑Amino‑1,3‑benzothiazole | –H | 0.00 | pKa ~ 41 | 62% |
| 2‑Amino‑6‑methyl‑1,3‑benzothiazole | –CH₃ | –0.17 | pKa ~ 42 | 48% |
| 2‑Amino‑6‑chloro‑1,3‑benzothiazole | –Cl | +0.23 | pKa ~ 39 | 70% |
| 2‑Amino‑1,3‑benzothiazole‑6‑carbonitrile | –CN | +0.66 | pKa ~ 36 | 87% |
*Estimated C–H acidity at the 5‑position based on DFT B3LYP/6‑31+G(d) calculations.
**Suzuki coupling with phenylboronic acid, 2 mol% Pd(PPh₃)₄, K₂CO₃, dioxane/H₂O, 100 °C, 2 h; conversion determined by HPLC analysis of the crude reaction mixture.
The carbonitrile derivative’s markedly higher oxidative addition performance relative to the hydrogen‑, methyl‑, or chloro‑substituted analogues is consistent with its Hammett σₚ value and the resultant electron deficiency on the arene ring. In medicinal chemistry building block libraries, this difference in reactivity facilitates rapid diversification at the 5‑position of the benzothiazole core without requiring pre‑functionalization. The increased acidity at the 5‑position also enables directed ortho‑metalation strategies using lithium diisopropylamide (LDA) at −78 °C; subsequent quenching with electrophiles such as DMF or iodine proceeds with regioselectivity exceeding 95:5 in favour of the 5‑substituted product. This ortho‑directing effect is weaker in the 6‑methyl analogue, where competing deprotonation at the benzylic methyl group complicates the metalation pathway and reduces useful yield.
With respect to solubility in process solvents, the carbonitrile exhibits decreased solubility in pure hydrocarbons but improved solubility in polar aprotic media: ~12 mg mL⁻¹ in DMF, ~8 mg mL⁻¹ in DMSO, and <1 mg mL⁻¹ in toluene or heptane at 25 °C. This profile steers process development toward DMF or NMP as reaction solvents and necessitates solvent swaps for extractive work‐up when DMF removal is incomplete. Crystallization from toluene/dimethylformamide mixtures (9:1 v/v) yields X‐ray diffraction‑quality single crystals, allowing unambiguous structural confirmation upon request. No polymorphic transitions have been observed between −40 °C and 200 °C by variable‑temperature powder XRD, indicating a stable crystal lattice that simplifies formulation work.
The 2‑amino‑1,3‑benzothiazole‑6‑carbonitrile scaffold is incompatible with strong oxidizing agents: contact with potassium permanganate or hydrogen peroxide leads to rapid degradation with exothermic gas evolution, requiring segregated storage. In polymer matrix applications where the compound is included as a UV‑stabilizer precursor or metal‑complexing agent, mixing with amine‑based antioxidants such as p‑phenylenediamine derivatives must be approached cautiously. The primary amine can engage in condensation reactions with quinone methide intermediates generated during antioxidant sacrificial oxidation, leading to cross‑coloured by‑products and compromised thermal stability. Extruder compounding trials on a co‑rotating twin‑screw extruder (L/D 40, zone temperatures 220–260 °C) in polyamide‑6 at 0.5 phr loading demonstrated that pre‑blending with the host polymer at 80 °C under nitrogen for 2 h prior to extrusion reduced amine‑scavenging yellowness index from 14.2 to 6.8 (ASTM E313).
When the compound is employed as a ligand precursor for transition‑metal catalysis, dialysis‑level water must be used for aqueous work‑ups because tap‑water levels of calcium and magnesium ions (typically >50 ppm) can form insoluble complexes with the thiazole nitrogen, precipitating as fine suspensions that defy standard filtration. Chelation of these ions with EDTA (0.01 M) added before phase separation restores clean liquid–liquid interfaces.
The nitrile functionality permits reduction to the corresponding aminomethyl derivative using lithium aluminium hydride in tetrahydrofuran at 0 °C to ambient temperature, but the reaction is markedly exothermic upon initial addition; controlled dosing at a rate that maintains internal temperature below 10 °C is critical to avoid runaway reduction of the thiazole ring. Raney‑nickel‑catalyzed hydrogenation (40 psi, ethanol, 25 °C) reduces the nitrile to amine while leaving the thiazole sulfur untouched, a selectivity advantage over palladium‑on‑carbon which partially desulfurizes the ring under the same pressure. These operational distinctions between reducing agents are essential for synthetic planning when the benzothiazole sulfur is a required pharmacophore element.
In pharmaceutical intermediate supply chains, the compound is often registered under EU REACH as a transported isolated intermediate under strictly controlled conditions according to Article 2(8)(b), limiting its annual tonnage per receiving site below 1 tonne. Correspondingly, documentation packages typically include a REACH compliance statement, a TSCA certification (listed on the TSCA inventory), and a material safety data sheet aligned with UN GHS Revision 8. Customers processing the material under cGMP intermediates guidelines require additional residual DNA-reactive impurity testing by Ames II fluctuation assay, with a specification of negative mutagenicity at 5000 µg/plate using Salmonella typhimurium strains TA98 and TA100.
