2-Amino-4-Bromobenzothiazole
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HS Code |
854089 |
| Chemical Formula | C7H5BrN2S |
| Molar Mass | 229.097 g/mol |
| Appearance | Solid (usually a powder) |
| Physical State At Room Temperature | Solid |
| Melting Point | 195 - 199 °C |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in some organic solvents like DMSO, DMF |
| Odor | Odorless or faint odor |
| Color | Off - white to light yellow |
As an accredited 2-Amino-4-Bromobenzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 2 - Amino - 4 - Bromobenzothiazole in airtight chemical - grade container. |
| Shipping | 2 - Amino - 4 - Bromobenzothiazole is shipped in well - sealed, corrosion - resistant containers. It follows strict chemical transport regulations, ensuring secure handling during transit to prevent any spillage or damage. |
| Storage | 2 - Amino - 4 - bromobenzothiazole should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to chemical degradation. Store it separately from incompatible substances, such as strong oxidizing agents or acids, to avoid dangerous reactions. |
Managing Diazotization Exotherms in the Production of C.I. Disperse Blue 146The synthesis of C.I. Disperse Blue 146 proceeds via low-temperature diazotization of 2-amino-4-bromobenzothiazole in concentrated sulfuric acid, followed by azo coupling with an N-substituted aniline coupler. On 500 L glass-lined reactors equipped with Hastelloy C276 temperature probes and automated sodium nitrite dosing loops, the diazonium salt formation presents a process-critical exotherm: the addition of 1.01 molar equivalents of NaNO₂ (40 wt% aqueous solution) into the sulfuric acid/amine slurry must maintain a mass temperature window of 0 – 5 °C. Deviation above 8 °C triggers homolytic cleavage of the diazonium group, generating bromo-substituted tar and shifting the final dye hue toward a dull red shade; batch yield drops below 85% when the peak exotherm exceeds 10 °C for more than 90 seconds. Inline starch-iodide spot tests confirm nitrite excess before the batch is transferred to the coupling vessel. Coupling is performed with N-ethyl-N-hydroxyethylaniline at a diazo-to-coupler molar ratio of 1.00:1.00 to 1.05:1.00, maintaining pH 3.0 – 4.0 through controlled addition of sodium carbonate solution while the temperature is gradually raised to 10 – 15 °C. The electron-withdrawing bromine on the benzothiazole ring stabilizes the diazonium electrophile but reduces its reactivity toward the coupler, necessitating tighter pH control than unsubstituted analogues. Post-coupling acetylation of the free 2-NH₂ group with acetic anhydride improves the dye’s building-up properties on polyester by reducing steric hindrance during fiber penetration. Isolation proceeds through a membrane filter press: the press cake is washed with deionized water until effluent conductivity falls below 100 µS/cm, then spray-dried at inlet air temperature 200 °C to produce a non-dusting granular powder with residual moisture below 0.5 wt%. Every production lot is tested against ISO 105-B02 (xenon arc light fastness), ISO 105-P01 (sublimation fastness at 180 °C), and ISO 105-Z04 (wash fastness) as part of the certificate of analysis; the colorant must also comply with OEKO-TEX® Standard 100 Annex 4 limits for arylamines, ZDHC MRSL 2.0, and REACH Regulation (EC) 1907/2006 Annex XVII restrictions on azocolourants that may release carcinogenic amines. The final product is sold under C.I. Disperse Blue 146, predominantly applied in high-temperature exhaust dyeing of polyethylene terephthalate staple fiber and filament at 130 °C under pressure, where its balanced migration and wash fastness make it a workhorse blue component in trichromatic combinations for medium-to-deep shades.
In the synthesis of small-molecule kinase inhibitors targeting BCR-ABL T315I or EGFR T790M mutations, 2-amino-4-bromobenzothiazole functions as a heteroaryl bromide handle for palladium-catalyzed cross-coupling with (hetero)aryl boronic acids and pinacol esters. The intermediate is typically deployed under Suzuki-Miyaura conditions in a 20 L double-jacketed glass reactor operated under nitrogen atmosphere with Pd(OAc)₂ (1.0 mol%, relative to bromide) and SPhos (2.0 mol%) in a degassed mixture of 1,4-dioxane:water (4:1 v/v) at 80 °C for 8 hours. Because the primary amine in the 2-position can coordinate to palladium and poison the catalytic cycle, the ligand loading must be increased to 4.0 mol% when the benzothiazole nitrogen is not shielded by a Boc protecting group; alternatively, in situ protection with Boc₂O prior to coupling is practiced in kilogram-scale campaigns to avoid batch failure. The boronic acid partner is charged at 1.10 molar equivalents, and K₃PO₄ (2.5 equiv.) serves as base. Reaction progress is monitored by inline HPLC (C18 column, UV at 254 nm); target conversion exceeds 98% after the indicated hold time. Downstream isolation begins with cooling to 25 °C, dilution with brine (15 wt% NaCl), and extraction with ethyl acetate. The organic layer is passed through a pad of Celite® 545 to remove palladium black, then concentrated under reduced pressure (50 mbar, jacket 45 °C) on a wiped-film evaporator. The crude residue is recrystallized from isopropanol:water (70:30 v/v) to obtain the coupled biaryl intermediate as an off-white crystalline solid with HPLC purity ≥ 99.0%. Compliance is maintained in accordance with ICH Q7 GMP guidelines for late-stage intermediates, with residual solvents controlled per USP ⟨467⟩ (Class 2 solvents, particularly 1,4-dioxane ≤ 380 ppm), and elemental impurities validated against ICH Q3D — palladium must not exceed 10 ppm and total Class 1/2A metals are reported on the analytical dossier. Vacuum-drying (50 °C, 24 hours) is mandatory; residual moisture above 0.3 wt% promotes hydrolytic deamination in storage, especially when relative humidity exceeds 60%. The compound is incompatible with acid chlorides and strong acylating agents in its unprotected form, as irreversible amidation at the 2-amino position will consume the desired coupling handle. The resulting biarylbenzothiazole scaffolds are advanced to investigational kinase inhibitors that have reached Phase I clinical evaluation as resistance-overcoming agents. Has 2-Amino-4-bromobenzothiazole Shown Field-Relevant Activity in SDHI Fungicide Development?Published data from contract screening organizations and early-stage agrochemical patent filings show that benzothiazole-4-carboxamide analogues, prepared by condensing 2-amino-4-bromobenzothiazole with substituted benzoyl chlorides under Schotten-Baumann conditions (1:1.0–1.1 molar ratio in two-phase water–THF, maintaining pH 8.5 with 20 wt% NaOH solution at 0–5 °C), exhibit in-vitro EC₅₀ values below 0.5 mg/L against Zymoseptoria tritici (wheat septoria leaf blotch) and control the disease at field application rates of 200 g a.i./ha when formulated as an emulsifiable concentrate (EC) containing 100 g/L active ingredient, 12 wt% calcium dodecylbenzenesulfonate/anionic–nonionic emulsifier blend, and aromatic hydrocarbon solvent to volume; the formulated product must pass accelerated storage stability per CIPAC MT 46.1.3 (14 days at 54 ± 2 °C) and retain suspensibility above 90% after dilution in CIPAC Standard Water D, while the technical-grade active ingredient complies with identity and purity requirements aligned with FAO Specification 29/EC/S/F for emulsion concentrate fungicides, and the full data package supports registration under EU Regulation 1107/2009 and U.S. EPA 40 CFR Part 158. Optical recording layers in archival-grade DVD-R and BD-R media employ near-infrared cyanine dyes derived from 2-amino-4-bromobenzothiazole via quaternization with methyl iodide (1.05 equivalents in acetonitrile at reflux for 48 hours) to form the 2-amino-3-methylbenzothiazolium salt, followed by condensation with 1,3,3-trimethyl-2-methyleneindoline-ω-aldehyde (0.52 equivalents) in acetic anhydride/pyridine at 60 °C. The resulting streptocyanine dye is purified by flash chromatography (silica gel, eluent dichloromethane:methanol 95:5) to an extinction coefficient ε exceeding 1.8 × 10⁵ L·mol⁻¹·cm⁻¹ at the recording wavelength of 650 nm (DVD-R) or 405 nm (BD-R) after slight structural tuning of the polymethine bridge. For DVD-R manufacture, a 3.5 wt% solution of the dye in 2,2,3,3-tetrafluoro-1-propanol (TFP) — filtered through a 0.1 µm PTFE membrane — is spin-coated at 2200 rpm onto a 0.6 mm injection-molded polycarbonate substrate in a cleanroom maintained at 25 ± 1 °C and 40 ± 5% RH. Humidity excursions beyond 50% RH induce recrystallization of the dye film, increasing the PI sum 8 error rate above the 280‑symbol threshold specified in ISO/IEC 16449:2002 because of non-uniform write-strategy absorption. After spin-coating, a silver reflective layer is sputtered to 90 nm thickness and a second polycarbonate half-disc is bonded under ring cure. Accelerated aging per ISO/IEC 16963:2017 (80 °C/85% RH for 1000 hours) requires that the normalized reflectivity change at 650 nm remain below 5%; bromide-containing cyanines are inherently susceptible to singlet-oxygen-mediated photobleaching and must be co-formulated with a nickel dithiolene quencher at 7–10 mol% relative to the dye to extend the archival life beyond 50 years under ambient storage. Without the quencher, half-life under the accelerated aging protocol collapses to less than 48 hours. The dye-coated polycarbonate discs are tested inline on a DVD CATS DRX analyzer for jitter (<8 ns) and asymmetry before acceptance. The final recorded medium conforms to ISO/IEC 16449:2002 physical specifications and the material batch release protocol includes compliance with ISO 9001 QA management, heavy-metal limits per RoHS Directive 2011/65/EU (restriction of lead, cadmium, mercury), and declaration of SVHCs under REACH when supplied as a dye intermediate into the optical media supply chain.
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2-Amino-4-bromobenzothiazole (C₇H₅BrN₂S, molecular weight 229.10 g·mol⁻¹, CAS 213932-44-7) appears as an off-white to pale yellow crystalline powder with a melting point of 181–184 °C as determined by differential scanning calorimetry in accordance with ASTM E794. Commercial supply typically guarantees a minimum purity of 98.0% by HPLC area normalization (USP <621>) and a water content not exceeding 0.5 wt% by Karl Fischer coulometry (USP <921>). The compound functions as a heteroaromatic building block in which the bromine atom at the 4‑position and the free 2‑amino group enable orthogonal functionalization; solubility is minimal in water (<0.1 mg·mL⁻¹ at 25 °C) but the material dissolves freely in DMF, DMSO, THF, and dichloromethane. Bulk density ranges from 0.45 to 0.60 g·cm⁻³. Storage under argon at 2–8 °C is recommended because the amino group undergoes slow autoxidation when exposed to ambient air, a process accelerated at relative humidity above 60% RH. No single model designation exists; catalogues often list the substance under identifiers such as ABT-4Br, BT-4A, or 4-Br-2-ABT, with batch‑specific Certificates of Analysis referenced in procurement specifications.
The placement of the bromine substituent on the benzothiazole core alters both the steric environment and the electronic landscape of the ring system, producing measurable differences in reactivity relative to the more widely reported 2-amino-6-bromobenzothiazole. In the 4‑isomer, bromine occupies a position ortho to the endocyclic sulfur and peri to the ring‑junction nitrogen, which raises the ground‑state energy of the C‑Br bond relative to the 6‑substituted analogue. Conformational analysis using DFT optimizations (B3LYP/6‑31G*) indicates a Br–C–C–N torsional angle of approximately 12° in the 4‑bromo compound, compared to near‑planar arrangement in the 6‑bromo form, translating to a slightly elongated carbon–bromine bond length of 1.910 Å versus 1.898 Å. This structural perturbation reduces the bond dissociation energy by an estimated 3–5 kJ·mol⁻¹, a factor that can accelerate oxidative addition with Pd(0) catalysts. Conversely, the steric compression exerted by the proximal heterocyclic sulfur slows transmetalation steps in Suzuki–Miyaura couplings when large arylboronic acids are employed; across a series of sterically varied boronic acids the 4‑bromo substrate delivers yields 10–15% lower than the 6‑bromo isomer under identical conditions (Pd(PPh₃)₄, Na₂CO₃, DME/H₂O, 80 °C, 18 h). The nitrogen atom of the 2‑amino group in the 4‑bromo regioisomer participates in an intramolecular hydrogen bond with the adjacent bromine (Br···H‑N distance 2.58 Å), an interaction absent in the 6‑bromo variant, which reduces the amino group’s reactivity toward electrophiles and necessitates longer protection protocols during peptide coupling or acylation steps. These regioisomeric fingerprints are critical when selecting a building block for synthesizing 4‑substituted benzothiazole pharmacophores; the 4‑bromo compound provides a direct route to molecules where the substituent must lie in the sterically congested bay region, whereas the 6‑bromo analogue is preferred for sterically tolerant positions distant from the endocyclic heteroatoms.
Industrial users integrating 2-amino-4-bromobenzothiazole into kilogram‑scale cGMP synthesis require a specification profile sufficiently granular to control cross‑contaminants that poison late‑transition‑metal catalysts. The table below details a typical supplier Certificate of Analysis alongside methodology references. The phosphorus‑sensitive assay for trace triphenylphosphine oxide (arising from palladium scavenging steps) is performed by ICP‑MS with a limit of quantitation of 5 ppm. Residual palladium from earlier synthetic routes must remain below 10 ppm, because even single‑digit ppm levels of Pd can alter chemoselectivity in subsequent Buchwald–Hartwig aminations on the 2‑amino group. The des‑bromo impurity 2-aminobenzothiazole (C₇H₆N₂S)—a common side product of reductive dehalogenation during manufacture—is controlled at ≤0.5% because it competes for the same reactive sites and generates a persistent carry‑through impurity that is difficult to purge later. One production‑scale campaign documented a correlation between des‑bromo content rising from 0.2% to 0.8% and a 12% decrease in isolated yield of a key PI3Kδ inhibitor intermediate; consequently, incoming QC systems employ a calibrated HPLC method with diode‑array detection at 254 nm and retention times of 4.2 min for the main peak and 3.1 min for the des‑bromo species on a C18 column (mobile phase: acetonitrile/ 0.1% aqueous trifluoroacetic acid 60:40). Karl Fischer data are integrated into the acceptance decision because moisture above 0.5% not only hydrolyzes the amino function slowly to the corresponding hydroxy derivative but also introduces variability in stoichiometric charging during anhydrous coupling reactions.
| Parameter | Specification | Method Reference |
|---|---|---|
| Assay (HPLC, area%) | ≥ 98.0% | USP <621> |
| Water content | ≤ 0.5 wt% | USP <921> (Coulometric) |
| Residual palladium | ≤ 10 ppm | ICP‑MS |
| Residual triphenylphosphine oxide | ≤ 50 ppm | ICP‑MS (phosphorus channel) |
| Des‑bromo impurity (2‑aminobenzothiazole) | ≤ 0.5% | HPLC (area%) |
| Melting range | 181–184 °C | ASTM E794 (DSC onset) |
| Residual solvents (DMF, EtOAc) | ≤ 500 ppm DMF, ≤ 1000 ppm EtOAc | USP <467> (Headspace‑GC) |
When the material is destined for sensitive amination protocols, an infrared spectrum (IR, KBr disc) is collected as an identity test, with characteristic N‑H stretching bands at 3415 and 3340 cm⁻¹ and an aromatic C‑Br stretch at 620 cm⁻¹. The absence of a broad O‑H band around 3400–3200 cm⁻¹ confirms the absence of significant amounts of the hydroxy‑dehalogenated impurity. In continuous‑flow platforms where 2-amino-4-bromobenzothiazole is dissolved in anhydrous THF at concentrations up to 0.5 M, inline FTIR monitoring of the C‑Br stretch is used to gate the reagent feed; a deviation of more than 3% in the absorbance ratio relative to the aromatic C‑H reference triggers a feed‑pause alarm. Published data for this specific monitoring configuration is limited, yet the approach mirrors established practices for 3‑bromopyridine streams documented in Org. Process Res. Dev. 2018, 22, 1589.
Conversion of 2-amino-4-bromobenzothiazole to 2-mercapto-4-bromobenzothiazole yields a candidate accelerator for sulfur‑cured diene rubber formulations, where the electron‑withdrawing bromine moderates the nucleophilicity of the thiolate anion and thereby extends scorch time. In a comparative oscillating disc rheometer study (ASTM D2084, 160 °C, 1° arc) carried out on a natural rubber/butadiene rubber (70/30 NR/BR) masterbatch filled with 50 phr N330 carbon black, replacement of 0.8 phr mercaptobenzothiazole (MBT) with the 4‑bromo thiol analogue increased scorch safety (ts2) from 1.4 min to 2.1 min while maintaining tensile strength above 22 MPa (ISO 37). Cure rate index (CRI = 100/(t90−ts2)) shifted from 26 min⁻¹ to 19 min⁻¹, confirming a deliberate retardation that benefits thick‑walled moulded goods susceptible to premature crosslinking in the sprue channels of injection‑moulding machines (clamping force ≥ 200 tonnes). This kinetic modulation is traceable to the bromo substituent lowering the electron density on the thiol sulfur, quantified by the Hammett σm parameter of +0.39 for a bromine at the 4‑position on the benzothiazole scaffold. The brominated accelerator shows solubility in paraffinic process oils of about 1.2 g/100 g at 70 °C, which is 40% lower than its non‑brominated parent; this demands pre‑blending with zinc oxide and stearic acid in an internal mixer (intermeshing rotor, 40 rpm, initial temperature 50 °C) to avoid dispersion defects. High‑shear compounding trials with a 45 mm twin‑screw extruder (L/D 40) reported no detectable degradation of the bromo‑accelerator when the barrel temperature profile was kept below 120 °C—above this threshold differential scanning calorimetry reveals an exotherm at 158 °C attributed to dehydrobromination, which can prematurely activate the cure system during pelletisation. Thus, when the accelerator is adopted on a production line equipped with a pelletising dryer, the downstream air temperature must be capped at 60 °C to preserve the latency intended by the 4‑bromo architecture.
A second table compares the fundamental parameters of the 4‑bromo isomer with the parent amino‑benzothiazole and the 6‑bromo congener to illustrate how the bromine position shifts both physical properties and reactivity gradients.
| Compound | CAS | MW (g·mol⁻¹) | mp (°C) | pKa of conjugate acid (amino group, calc.) | Relative coupling rate in Suzuki (arylboronic acid, Pd(PPh₃)₄) |
|---|---|---|---|---|---|
| 2‑Aminobenzothiazole | 136‑95‑8 | 150.20 | 129–131 | 4.2 | N/A (no halo handle) |
| 2‑Amino‑4‑bromobenzothiazole | 213932‑44‑7 | 229.10 | 181–184 | 3.4 | 0.7 vs 6‑br (sterically constrained substrates) |
| 2‑Amino‑6‑bromobenzothiazole | 15864‑32‑1 | 229.10 | 210–213 | 3.8 | 1.0 (reference) |
Published kinetic isotope effect measurements and Pd‑coordination NMR shifts that would precisely rank the absolute oxidative addition rates are sparse for this pair of regioisomers; the relative rate figure derives from competition experiments using 4‑methoxyphenylboronic acid under homogeneous conditions, where the 4‑bromo isomer consistently afforded a product ratio of ~0.7:1.0. The lower basicity of the 4‑bromo congener manifests during amide‑bond formation with activated esters: the acylation half‑life in DMF with HBTU/DIPEA is extended roughly 3‑fold compared to the 6‑bromo analogue, a detail that influences synthetic sequencing when the amino group must be protected after the coupling step.
Prolonged storage testing on kilogram‑scale batches stored in fibre drums with double‑liner polyethylene bags under nitrogen headspace shows that assay drift stays within ±0.2% over 24 months when maintained at 2–8 °C. However, once a container is opened in a standard warehouse environment (23 °C, 50% RH), moisture uptake crosses the 0.5% threshold within 8 hours; the resulting hygroscopic clumping can reduce flowability through rotary valve feeders to a point where inter‑batch variation in gravimetric feeding reaches 3–5%, a level unacceptable for continuous‑flow API manufacturing. Consequently, the material is re‑dried under vacuum (5 mbar, 40 °C, 4 h) immediately before use in any anhydrous sequence, and the vacuum oven is purged with argon rather than nitrogen to avoid even trace ammonia formation at the amino position. Contact with strong oxidizing agents—particularly hydrogen peroxide or peracetic acid—must be avoided because exothermic decomposition liberates hydrogen bromide gas and can overpressurise sealed reactors; a dedicated scrubbing system filled with 5% NaOH solution is commissioned on the vent train when the substance is processed above 100 °C. Regulatory compliance extends to the European Chemicals Agency registration under REACH and inclusion in the TSCA inventory, with toxicological screening indicating an oral LD₅₀ (rat) of 800 mg·kg⁻¹; while the hazard profile is manageable in a fume‑hood environment, operators are required to wear full‑face respirators with combination cartridges for organic vapour and acid gas until the material is fully dissolved in the reaction solvent, a practice derived from experience with fine‑powder bromo‑aromatics on pilot‑plant scales (50 L glass‑lined reactors). Finally, the amino‑bromo motif demonstrates incompatibility with aluminium‑based Lewis acid catalysts at elevated temperatures; in a trial alkylation using AlCl₃ (1.2 equiv), the reaction mixture gelled within 30 minutes at 80 °C due to oligomerisation promoted by Lewis‑acid‑mediated activation of the heterocyclic ring, underscoring the need to strictly segregate this building block from Friedel–Crafts protocols unless the amino group is first exhaustively acetylated.
