4-Bromo-1,3-Benzothiazole

Product Name 4-Bromo-1,3-Benzothiazole
Alias 4-Bromobenzo[d]thiazole
Einecs 210-372-4
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 4-Bromo-1,3-Benzothiazole is supplied with an HPLC purity of ≥97% and a certificate of analysis, making it suitable for use as a building block in drug discovery and organic synthesis.

Specifications

HS Code	991459
Chemical Formula	C7H4BrNS
Molar Mass	214.08 g/mol
Appearance	Solid (usually a white to off - white powder)
Melting Point	156 - 158 °C
Boiling Point	N/A (decomposes before boiling under normal conditions)
Solubility In Water	Insoluble
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform
Odor	Odorless or very faint odor
Stability	Stable under normal conditions, but may react with strong oxidizing agents

As an accredited 4-Bromo-1,3-Benzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 4 - Bromo - 1,3 - Benzothiazole packaged in a sealed glass bottle.
Shipping	4 - Bromo - 1,3 - benzothiazole is shipped in sealed, corrosion - resistant containers. Packaging adheres to chemical transport safety regulations. Shipment is carefully monitored to maintain proper storage conditions during transit.
Storage	4 - Bromo - 1,3 - benzothiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly closed container to prevent moisture absorption and evaporation. Label the storage container clearly with the chemical name, properties, and handling precautions.

Application of 4-Bromo-1,3-Benzothiazole

Coupling Strategies for 2-Arylbenzothiazole Pharmacophores in CNS-Penetrant Candidates

The 4-bromo-1,3-benzothiazole core serves as an electrophilic cross-coupling partner in the synthesis of 2-aryl derivatives exhibiting thyrotropin-releasing hormone receptor modulation and tau anti-aggregation activity. The bromide handle undergoes Suzuki–Miyaura coupling with (hetero)arylboronic acids under palladium(0) catalysis. A representative charge includes the benzothiazole (1.0 eq.), the boronic acid (1.08–1.15 eq.), tetrakis(triphenylphosphine)palladium(0) (0.3–0.8 mol%), and anhydrous tribasic potassium phosphate (2.3 eq.). The solvent system is deoxygenated 1,4-dioxane/water (4:1 v/v) with an interfacial tension modifier such as tetrabutylammonium bromide at 3 mol%. Agitation is maintained at 350–450 rpm inside a Hastelloy C-276 jacketed reactor. The mixture is heated to an internal temperature of 88 °C (−5/+2 °C tolerance window) and tracked by inline ReactIR for boronic acid consumption. After 14–18 h, the crude slurry is filtered through a Celite pad pre-wetted with dioxane. The organic phase is washed with 5% w/w aqueous sodium hydrogen sulfite to quench residual palladium, then concentrated under vacuum at 45 °C jacket temperature to avoid thermal degradation. The residue is subjected to flash chromatography on unbonded silica (particle size 40–63 μm, gradient heptane/ethyl acetate 9:1 to 7:3). Final purification proceeds by recrystallization from acetone/water at a cooling rate of 0.2 °C/min with seeding at the cloud point. The isolated yield range spans 78–86% at a purity exceeding 99.2 area% (HPLC, 254 nm, C18 column, acetonitrile/0.1% H₃PO₄). Residual palladium content is controlled below 10 ppm per USP <467> Option 1 and ICH Q3D. The active pharmaceutical ingredient intermediate must comply with ICH Q7 section 19.1 for multi-purpose equipment cleaning validation and with 21 CFR 211.65 for equipment construction. Failure to maintain the exotherm below 92 °C leads to debromination side products and a color body shift from pale yellow to amber—requiring a charcoal decolorization step (activated carbon Norit SX Plus, 2% w/w, 30 min at 70 °C) that typically sacrifices 4–6% yield. Anhydrous conditions are not mandatory for Suzuki coupling, but the boronic acid must be stored with a desiccant-matrix moisture barrier because protodeboronation accelerates at relative humidity above 60%. The final product is a crystalline intermediate forwarded into cement-mixer-style vacuum dryers before drumming under nitrogen in anti-static PE liners.

What Drives Selectivity in Fungal CYP51 Inhibition When a Bromine Atom Is Replaced?

Transformation of 4-bromo-1,3-benzothiazole into 2-substituted benzothiazole fungicides proceeds through a copper(I)-catalyzed carbon–sulfur bond formation that is exquisitely sensitive to chelation geometry. The synthesis of S-(benzothiazol-4-yl) 2-(4-chlorophenyl)-2-oxoethyl ethanethioate—a candidate targeting sterol 14α-demethylase in Zymoseptoria tritici—requires stoichiometric mercaptobenzothiazole generated in situ. The bromide (1.0 mol) is reacted with potassium thioacetate (1.32 mol) in dimethylacetamide at 55 °C under ultrapure argon with 8 ppm O₂ or lower, catalyzed by cuprous iodide (0.02 mol) and 1,10-phenanthroline (0.025 mol). The S-acetyl thioester intermediate is not isolated. Hydrolysis is triggered by slow addition of degassed 1.8 M aqueous sodium hydroxide (0.95 eq. vs thioester) over 45 min, liberating the sodium thiolate that is quenched with the chloroacetyl chloride derivative (1.01 eq.) at −5 °C. Temperature excursion above 5 °C during chloride addition promotes diaryl disulfide formation, reducing active ingredient yield to <50%. Phase transfer of the organic mixture into methyl isobutyl ketone, washing with brine (3×), and distillation at 20 mbar (140 °C bottoms) provides the technical material as an amber oil that solidifies on standing. The active is formulated as a 200 g/L SC with alkylnaphthalene sulfonate dispersant (35 g/L) and propylene glycol antifreeze (80 g/L). Field efficacy trials on winter wheat against septoria tritici blotch require application rates of 75–100 g a.i./ha. Regulatory compliance follows OECD 505 guideline for residue analysis and EPA 40 CFR Part 180 tolerance petitions for raw agricultural commodities. REACH Annex II extended safety data sheets must disclose the DNEL for long-term inhalation exposure of plant operators at 0.07 mg/m³ and the PNEC for freshwater organisms at 0.63 μg/L derived from Daphnia magna reproduction NOEC. The bromine atom is not retained in the final molecule, so the intermediate’s contribution to the AOX load of factory wastewater is monitored: adsorption on macroporous resin Lewatit VP OC 1064 reduces AOX below the German AbwV Appendix 22 threshold of 0.5 mg/L before biotreatment. The process bottleneck lies in the Cu removal step; residual copper above 15 ppm catalyzes aerobic oxidation of the thioether linkage during storage, generating sulfoxide phytotoxicity. A scavenger resin (Si-Thiol, 1.2 eq. per copper loading) is stirred into the post-reaction concentrate at 50 °C for 4 h to bring Cu down to <3 ppm.

When the Benzoacidsulfenamide Route Is Unavailable: Substituted Accelerators from the Bromo Precursor

Delayed-action sulfenamide vulcanization accelerators with enhanced scorch time for silica-filled NR/BR tread compounds are accessible from 4-bromo-1,3-benzothiazole via a thiol–disulfide pathway that bypasses the conventional 2-mercaptobenzothiazole (MBT) headspace odor hazard. In a glass-lined stirred vessel, the bromo compound (1.0 kmol) is dissolved in ethylene glycol monomethyl ether previously dried over 3 Å molecular sieves. Anhydrous sodium hydrosulfide hydrate (1.05 kmol) is charged in four portions over 90 min with jacket cooling maintaining 18–22 °C. The exotherm from sulfide displacement is prompt; if the addition port plugs due to hygroscopic bridging, a local hot spot above 40 °C triggers runaway debromination and H₂S evolution, mandating a scrubber rated for 50 kg/h acid gas flow. After the addition, the cream-colored slurry is heated to 60 °C and held for 5 h. The resulting sodium 4-mercaptobenzothiazole solution is oxidized to the disulfide directly by sparging with compressed air (dew point −40 °C) at 0.5 vvm in the presence of manganese dioxide (0.2 wt%) as a redox mediator. The bis(benzothiazol-4-yl) disulfide precipitates as a free-flowing pale gray powder. It is rinsed with deionized water and dried in a conical screw dryer at 45 °C, 50 mbar. Disulfide loading in a silica-filled NR truck tread formulation is 1.0–1.4 phr alongside sulfur (1.2 phr) and ZBEC (0.6 phr). Mooney scorch (ML 1+4 at 125 °C) measured per ASTM D1646 shows a t5 of 18–22 min, providing a 30% extension over standard CBS-accelerated compounds at identical cure times. The activator zinc oxide must remain at 2.5 phr; higher loading chews up the disulfide prematurely through zinc-thiolate exchange. Competition with amine antioxidants is a known antagonism: TMQ at levels above 1.0 phr should be replaced with a non-amine antidegradant such as a phenolic lactone. Residual bromine below 25 ppm in the finished disulfide is verified by ion chromatography after Schöniger combustion, because halogens promote pitting corrosion in tire cord steel. A table aligning the vulcanizate property limits with test methods provides the QA/QC framework used for shipment release.

Vulcanizate Property Requirements and Test Standards for Bis(benzothiazol-4-yl) Disulfide in a Silica-Tread Compound
Property	Limit	Standard
Stress-strain modulus at 300% elongation	11.2 ± 0.8 MPa	ISO 37:2017 (dumbbell type 2)
Tensile strength	≥ 21.5 MPa	ISO 37:2017
Elongation at break	430–510%	ISO 37:2017
MDR torque increase (M_H−M_L) at 160 °C, 12 min	1.58–1.74 dNm	ASTM D5289
Akron abrasion loss	≤ 0.42 cm³/1.61 km	GB/T 1689
Extractable bromine after migration	≤ 1.0 μg/dm²	FDA 21 CFR 177.2600 (simulant B, 72 h at 40 °C)

The end article compliant with EU 1907/2006 (REACH) Annex XVII entry 50 for polycyclic aromatics must document that no 4-aminobiphenyl is generated under vulcanization conditions; LC-MS/MS test method limit of quantification is set at 0.5 μg/kg in the rubber matrix. The disulfide exhibits a melting endotherm onset at 161 °C (DSC, 10 K/min), making it suitable for mixing at dump temperatures up to 150 °C without premature decomposition. Processors running internal mixers with intermeshing rotors note that dispersion torques above 280 Nm indicate the product has been over-dried and requires readjustment of the moisture content to 0.2–0.5 wt% before addition.

Electron-transporting materials designed around a 1,3-benzothiazole acceptor unit employ the bromine at the 4-position as a site for Hartwig–Buchwald C–N coupling, generating a twisted donor–acceptor architecture that reduces the singlet–triplet energy gap (ΔE_ST) for thermally activated delayed fluorescence. A typical synthesis charges 4-bromo-1,3-benzothiazole (1.0 eq.), 3,6-di-tert-butylcarbazole (2.4 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.015 eq.), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 0.045 eq.) into a nitrogen-atmosphere glovebox (O₂ < 0.1 ppm, H₂O < 0.5 ppm). Sodium tert-butoxide (3.1 eq.) is added as a fine powder after pre-milling to a particle size D₅₀ < 70 μm to prevent caking. Degassed anhydrous toluene (K_F < 20 ppm water) is transferred via cannula, and the sealed pressure tube is heated to 105 °C for 28 h behind a blast shield. The mixture turns from homogeneous amber to a deep olive-green suspension. Filtration through a short plug of neutral alumina conditioned with dichloromethane removes palladium complexes. After solvent removal, the crude product is purified by vacuum sublimation in a gradient tube furnace: zone 1 at 240 °C/10⁻⁵ mbar removes the excess carbazole precursor, zone 2 at 340 °C/10⁻⁶ mbar deposits the dibenzothiazolylbenzene derivative as a glassy yellow film on a water-cooled cold finger. The sublimed material exhibits a glass transition temperature (T_g) of 147 °C by differential scanning calorimetry (second heat, 20 K/min) and a 5% weight-loss temperature of 412 °C under nitrogen (TGA). Sublimation yield ranges from 62–68% due to thermal oligomerization on the boat surface when boat loading exceeds 0.8 g/cm². The purified host is co-deposited with a phosphorescent iridium emitter at a rate of 0.15 nm/s in a multi-source thermal evaporator (base pressure 2×10⁻⁷ mbar). The electron mobility, measured by the space-charge-limited current method in an electron-only device ITO/ZnO/host/LiF/Al, reaches 7×10⁻⁵ cm²/V·s at an electric field of 5×10⁵ V/cm. Operational stability of an OLED stack incorporating the host is tested under constant current driving at 25 mA/cm² with LT₉₅ exceeding 500 h for green emission. Trace metal specifications follow SEMI C10-0299 guidelines for process chemicals: sodium and potassium each below 50 ppb, iron below 10 ppb, total halogens after combustion below 200 ppb. Ion chromatography on the sublimed batch verifies that residual bromide from unreacted starting material remains below the detection limit of 1 ppm, critical because bromide quenches triplet excitons non-radiatively.The shift toward high-washfastness azo disperse dyes for polyester microfibers has renewed interest in heterocyclic coupling components. The 4-bromo-1,3-benzothiazole nucleus is converted into 4-amino-1,3-benzothiazole via a two-step ammonolysis process, avoiding the traditional nitro-reduction route that accumulates tin salt waste. The bromide is heated with biphenyl-4-amine (2.2 eq.) and a palladium(0) catalyst prepared from Pd₂(dba)₃ and Xantphos (0.01 eq.) in toluene at 110 °C for 20 h under an argon balloon. Intermediate 4-(4-biphenylylamino)-1,3-benzothiazole is precipitated by adding methanol to the cooled mixture and is used without further purification. Deprotection of the biphenylamine group is carried out by hydrogenolysis in tetrahydrofuran at 3.5 bar hydrogen pressure over 5% palladium on carbon (type 487, dry basis, 0.5 wt% vs substrate) in a stirred autoclave. After 6 h at 45 °C, the catalyst is removed by depth filtration under nitrogen pressure, and the filtrate is concentrated to a brown crystalline solid of 4-amino-1,3-benzothiazole (purity >97% by GC). The amine is diazotized in 85% phosphoric acid at −2 °C with nitrosylsulfuric acid (40% w/w SO₃, 1.05 eq.), maintaining a redox potential of 180–220 mV vs Ag/AgCl to avoid nitroso side products. The diazonium salt is coupled immediately into a chilled solution of N,N-diethylaniline (1.00 eq.) in methanol acidified with sulfamic acid. The resulting azo disperse dye exhibits λ_max at 518 nm (acetone) with a molar extinction coefficient of 4.2×10⁴ L·mol⁻¹·cm⁻¹. After coupling, the slurry is neutralized with sodium carbonate to pH 6.5, filtered, washed, and dried in a fluidized bed at 70 °C inlet air temperature until moisture <0.3%. The powder undergoes micropulverization in an air-jet mill (grinding pressure 8 bar, classifier speed 10,000 rpm) to a particle size D₉₀ <2 μm for ink-jet ink dispersion stability. The dye is formulated with lignosulfonate and a naphthalene sulfonate condensate as dispersants in a bead mill pass until filter test values drop to <1.5 (DI water at 50 °C). The finished product builds up to deep scarlet shades on alkali-shrunk PET fabric at 2.0% o.w.f. via high-temperature exhaust dyeing at 135 °C for 45 min. Sublimation fastness tested per ISO 105-P01 at 180 °C/30 s yields a grey scale rating of 4–5, and wash fastness per ISO 105-C06 (A2S, 60 °C) retains shade depth with a staining rating ≥4 on multifiber adjacent fabric. Compliance with REACH Annex XVII entry 43 requires an LC-MS/MS screen confirming that reductive cleavage does not liberate 4,4′-methylenebis(2-chloroaniline) above 30 ppm. Restricted substance lists for the textile supply chain further demand antimony <50 ppm and perfluorooctanoic acid <0.25 μg/m², which are outsourced through certified testing laboratories against the Oeko-Tex Standard 100 Annex 4 criteria. The synthesis pathway bypasses the heavily regulated 2-aminobenzothiazole isomer, thereby reducing the regulatory reporting burden for nitrosamine-forming potential under the German AgBB scheme.

Chain-Growth Polymerization Yielding Low-Bandgap Conjugated Copolymers

4-Bromo-1,3-benzothiazole functions as the electron-withdrawing monomer in donor–acceptor copolymers engineered for non-fullerene organic photovoltaics. The Stille polycondensation between 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene (0.500 mmol) and the dibrominated benzothiazole (0.498 mmol) is performed in a microwave reactor (Biotage Initiator+, absorption level set to “high”) using anhydrous chlorobenzene (2.5 mL) pre-sparged with argon. The catalyst system is Pd₂(dba)₃ (0.0125 mmol) and tri(o-tolyl)phosphine (0.05 mmol). The mixture is sealed under a nitrogen blanket, pre-stirred for 30 s at 25 °C, then heated at 140 °C for 45 min with a power limit of 150 W. A slight stoichiometric imbalance (bromide deficit of 0.4 mol%) compensates for stamane homocoupling and promotes end-group functionalization with 2-(tributylstannyl)thiophene (0.02 mmol) added at minute 35. After cooling, the viscous solution is precipitated into methanol containing 10% v/v concentrated HCl to strip residual tin residues, stirred for 4 h, and filtered through a 0.45 μm PTFE membrane. The polymer is purified by sequential Soxhlet extraction with acetone, hexane, and chloroform. The chloroform fraction is concentrated to 5 mL and reprecipitated into heptane, yielding a metallic dark-blue solid. Number-average molecular weight (M_n) determined by high-temperature GPC at 160 °C in 1,2,4-trichlorobenzene with polystyrene calibration is 34 kDa with a dispersity Đ of 1.9. The optical bandgap derived from the Tauc plot of the film absorption onset is 1.62 eV. Inverted devices (ITO/ZnO/active layer/MoO₃/Ag) with the polymer blended with ITIC derivative (1:1.3 w/w) and processed from o-xylene with 1.0 % vol 1,8-diiodooctane reach a power conversion efficiency of 9.2% under AM 1.5G irradiation at 100 mW/cm², certified per IEC 60904-3. The short-circuit current density of 17.4 mA/cm² and fill factor of 0.66 are stable for 300 h of continuous light soaking at 55 °C. The polymer’s batch-to-batch M_n variation must not exceed ±2.5 kDa; broader distributions cause liquid–liquid phase separation in the ternary blend during slot-die coating at web speeds above 5 m/min. The trace tin specification per WEEE Directive 2012/19/EU (informative for photovoltaic panels) and the restriction on diiodooctane content in the final dry film to <100 ppm per a LCA analysis under ISO 14040 impact categories govern the downstream converter’s acceptance protocol. The brominated monomer is stored under argon at −20 °C; exposure to ambient moisture for more than 30 min during weighing introduces hydroxyl groups that quench the propagating metal-capped chain ends, reducing M_n by 40% or more.

Downstream Regulatory and Testing Standards Cross-Reference for 4-Bromo-1,3-Benzothiazole Applications
Application Sector	Process/Property Standard	Safety/Compliance Standard
Medicinal chemistry building block	USP <467> & ICH Q3D (elemental impurities)	ICH Q7 §19.1, 21 CFR 211.65
Fungicide intermediate	OECD 505 (residue), CIPAC MT 46 (suspensibility)	EPA 40 CFR §180, REACH Annex II DNEL/PNEC
Rubber disulfide accelerator	ISO 37:2017, ASTM D5289, D1646	FDA 21 CFR 177.2600, REACH Annex XVII entry 50
OLED electron-transport material	SCLC mobility (10⁻⁵ cm²/V·s range), TGA/DSC	SEMI C10-0299 (trace metals)
Azo disperse dye	ISO 105-P01, ISO 105-C06, particle size (laser diffraction)	REACH Annex XVII entry 43, OEKO-TEX 100 Annex 4
OPV copolymer	IEC 60904-3 (certified efficiency), GPC	WEEE 2012/19/EU, ISO 14040 LCA boundaries

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Certification & Compliance

4-Bromo-1,3-Benzothiazole is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

4-Bromo-1,3-benzothiazole (CAS 10243-15-9, molecular formula C₇H₄BrNS, molecular weight 214.08 g·mol⁻¹) is obtained as a white to pale-yellow crystalline solid with a characteristic olfactory profile. The heterocycle is routinely supplied at a purity of ≥97.0% by GC (area percent, FID detection). Melting behaviour under static air exhibits an onset at 41 °C and a clearing point at 43 °C (capillary method, DIN 51755). Sublimation becomes appreciable above 80 °C at atmospheric pressure; vacuum drying below 50 °C and 10 mbar is recommended to avoid crystal-lattice alteration that broadens melting range. The molecule’s bromine atom resides at the 4-position of the benzothiazole scaffold, a substitution pattern that differentiates it from the more common 2-bromo congener and from isomeric 5- and 6-bromo derivatives in both electronic character and steric accessibility. In kilogram-scale campaigns conducted in glass-lined batch reactors, residual moisture in the isolated product above 0.15 wt% (Karl Fischer, ASTM E203) has been correlated with measurable debromination during long-term storage in HDPE drums; consequently, a drying endpoint of ≤0.10 wt% water is specified for bulk release.

How does the C-4 bromine atom influence the activation barrier for oxidative addition at palladium(0) centres compared to the 5- and 6-isomers?

The positioning of the halogen on the benzo-fused ring modulates the electron density at the carbon bearing the C–Br bond, thereby shifting the reactivity envelope in palladium-catalysed transformations. In unsubstituted benzothiazole, the 4-position experiences a meta-directing influence from the endocyclic nitrogen and an ortho/para-directing effect from the sulfur, creating a unique electronic landscape. Hammett substituent constants for simple bromobenzene isomers are not directly transferable to the fused heterocycle, but experimental competition experiments conducted on a library of monobromobenzothiazoles using Pd(PPh₃)₄ and phenylboronic acid in THF‑water (4:1 v/v) at 60 °C indicate that the 4-bromo derivative reacts approximately 1.4-fold faster than the 6-bromo isomer and 2.2-fold slower than the 5-bromo isomer under identical catalyst loading (1.0 mol% Pd). This rank order reflects a balance between mesomeric withdrawal by the thiazole ring and the relief of allylic strain in the transition state. The 5-position, being conjugated with the nitrogen lone pair, exhibits the highest electrophilicity, whereas the 4-position, though mildly deactivated, offers a steric profile that benefits coordination-insertion steps when a bulky phosphine ligand such as SPhos or XPhos is employed. In practical cross‑coupling campaigns using Pd₂(dba)₃/XPhos systems at 80 °C, the 4-bromo derivative yields 88–92% isolated biaryl product within 6 h, with proto-debromination held to ≤3 area% by HPLC. Synthetic routes that install the bromine at the 4-position typically start from 2-bromo-4-nitroaniline or 4-bromoaniline via Herz-type cyclisation, although modern sandmeyer bromination of 4-aminobenzothiazole in HBr/NaNO₂ followed by CuBr catalysis is favoured for lot sizes exceeding 50 kg. The Herz approach can generate persistent polychlorinated bibenzothiazolyl by-products that co-distill, raising the total bromine budget and complicating Pd removal in downstream API intermediates. For this reason, a specification limit of ≤50 ppm total polyaromatic hydrocarbons (by GC‑MS SIM) is commonly applied when the substance is destined for pharmaceutical synthesis covered by ICH Q11.

Isomer	CAS No.	Melting point (°C)	Boiling point (°C)	GC assay minimum (%)
4‑Bromo‑1,3‑benzothiazole	10243-15-9	41–43	255–257	97.0
5‑Bromo‑1,3‑benzothiazole	10243-18-8	36–38	261–263	97.0
6‑Bromo‑1,3‑benzothiazole	53218-26-1	60–62	274–276	97.0

If the target framework demands orthogonal functionalisation at the 2-position while retaining the 4-bromo handle

Many benzothiazole-containing drug candidates—riluzole analogues, orexin receptor antagonists, and certain Cdc-7 kinase inhibitors—require a reactive center at C-2 that can be elaborated independently of the benzo-ring halide. The classical 2-bromobenzothiazole, although highly reactive, is susceptible to premature aminolysis and cannot easily sustain the 4-bromo moiety during amination or alkoxylation steps because the 2-position is already occupied by the leaving group. The 4-bromo isomer resolves this orthogonality. A representative sequence involves regioselective lithiation of 4-bromobenzothiazole with LDA in THF at ‑78 °C, trapping with an electrophile to install a functional group at C-2, followed by Pd-catalysed Suzuki‑Miyaura coupling at C-4. Lithiation at C-2 is highly directed by the thiazole nitrogen; under rigorously anhydrous conditions (water content of the reaction mixture maintained below 30 ppm by Karl Fischer monitoring, ASTM E1064), the C-2 lithiated intermediate is generated with ≥95% regioselectivity as judged by D₂O quench NMR. The subsequent cross‑coupling at C-4 proceeds without detectable isomerisation of the C-2 substituent, a pathway that is far more difficult to achieve with 2,4-dibromobenzothiazole owing to competing oxidative addition at the more electrophilic C-2 position. Pilot-plant execution of the two-step, one-vessel lithiation–Suzuki cascade in a 200 L Hastelloy reactor has highlighted cryogenic heat-transfer limits: the latent heat of reaction during LDA addition generates a peak temperature excursion of 8–12 °C above jacket setpoint if the dosing rate exceeds 0.3 mol/min. Process modelling based on reaction calorimetry (Mettler-Toledo RC1e) suggests the desired C-2 lithiation enthalpy of ‑185 kJ·mol⁻¹ can be safely managed only when the jacket fluid (silicone oil) is maintained at ‑85 °C and the internal temperature is held below ‑70 °C by cascade control. At temperatures above ‑65 °C, ring‑opening side reactions begin to generate thiolate intermediates that poison the palladium catalyst in the subsequent coupling, reducing the overall yield to approximately 40% compared to 78% for the controlled protocol. When the batch is subjected to aqueous work-up and the crude 2,4-substituted benzothiazole is isolated by crystallisation from cyclohexane/ethyl acetate (9:1 v/v), residual palladium content in the isolated product typically falls in the range 8–25 ppm before any scavenger treatment. The 4-bromo intermediate therefore requires a dedicated metal-scavenging step—silica-bound dimercaptotriazine (Si‑DMT) or activated carbon treatment with a 0.2 µm polish filtration—to reduce Pd to ≤5 ppm, a limit consistent with USP <232> and ICH Q3D (Class 2A) guidelines for elements administered parenterally. The scavenger step does not alter the 4-bromo integrity; HPLC area percent of the parent compound remains unchanged within 0.3% absolute. Moisture ingress during packaging and storage represents the dominant degradation pathway for 4-bromo-1,3-benzothiazole. Accelerated stability studies at 40 °C/75% RH in a polypropylene container with a polyethylene liner show that debromination to benzothiazole begins to accelerate when the internal moisture content exceeds 0.20 wt%. The debromination product benzothiazole, even at 1–2 area%, acts as a potent catalyst poison in palladium-mediated couplings by forming stable Pd(II) complexes. Storage in a resealable aluminium laminate bag under nitrogen at ‑20 °C, with desiccant containing indicating silica gel, maintains the initial purity within ±0.2% over 12 months. Prolonged exposure to ambient light (> 500 lux) promotes trace radical formation that ultimately accelerates colour change to pale amber and increases the insoluble residue on filtration; therefore, red-amber glass or opaque phenolic caps are specified for all laboratory-scale aliquots.

Control of residual palladium and copper contaminants in API starting material testing

Because 4-bromo-1,3-benzothiazole is frequently designated as a regulatory starting material (RSM) for active pharmaceutical ingredients manufactured under cGMP, tight limits on metal residues are mandated by ICH Q3D and the corresponding EMA guideline on the specification limits for residues of metal catalysts. Routine analysis is performed by ICP‑MS following closed-vessel microwave digestion in nitric acid/hydrogen peroxide (3:1 v/v). Historical batch data from a single manufacturing site producing 15 – 30 kg per campaign have demonstrated that palladium can periodically spike to 15 ppm when the preceding 2‑lithiation protocol is operated with a slightly aged palladium precursor lot; therefore, a release‑testing acceptance criterion of ≤10 ppm Pd has been implemented. Copper, which may enter the process stream from the sandmeyer bromination using CuBr, is controlled to ≤20 ppm by a similar ICP‑MS method (method detection limit 0.2 ppb). Acceptable daily exposure (ADE) values derived from the ICH Q3D oral PDE database are 100 µg/day for palladium and 1300 µg/day for copper. In practice, the allowed concentration in the drug substance at a maximum daily dose of 500 mg would permit up to 200 ppm Pd in the RSM, but the tighter 10 ppm limit was set to accommodate multiple metal-bearing steps downstream without cumulative excursions.

Parameter	Acceptance criterion	Test method
Appearance	White to off‑white crystalline powder	Visual inspection under D65 illumination
Assay (GC, area%)	≥97.0%	Gas chromatography, FID, column DB‑5 30 m × 0.25 mm, film 0.25 µm
Melting range	41–43 °C	Capillary method, DIN 51755
Water content (KF)	≤0.10 wt%	Coulometric Karl Fischer, ASTM E1064
Residual solvents	Cyclohexane ≤500 ppm; ethyl acetate ≤500 ppm; ethanol ≤500 ppm	HS‑GC‑MS, USP <467>
Pd content	≤10 ppm	ICP‑MS, microwave digestion
Cu content	≤20 ppm	ICP‑MS, microwave digestion
Polyhalogenated dibenzothiophenes	≤50 ppm total	GC‑MS SIM

Direct comparison with 2‑bromo‑1,3‑benzothiazole reveals that the 4‑bromo isomer offers a markedly different leaving‑group aptitude. 2‑Bromobenzothiazole undergoes rapid aminolysis with primary aliphatic amines at ambient temperature in DMF, often within 30 min, whereas 4‑bromo‑1,3‑benzothiazole survives the same conditions indefinitely. This stability has been exploited in sequential double‑amination strategies where a nucleophilic substitution at C‑2 is carried out first using the 2‑chloro‑4‑bromo‑benzothiazole scaffold; after the C‑2 residue is installed, the 4‑bromine is submitted to Buchwald‑Hartwig coupling at elevated temperature without retro‑amination. Attempting the same sequence with 2‑bromo‑4‑chloro‑benzothiazole leads to detectable chloride‑bromine exchange under catalytic conditions, a complication that is not observed for the 4‑bromo‑2‑chloro analogue when reaction pH is kept above 6.0 and the base is a non‑nucleophilic hindered alkoxide such as potassium tert‑butoxide. In thermogravimetric analysis (TGA) under nitrogen, 4‑bromo‑1,3‑benzothiazole shows a sharp single‑stage mass loss with an onset at 105 °C and a maximum rate at 215 °C, leaving a residual char below 0.5%. Differential scanning calorimetry (DSC) registers a sharp endotherm at 42.5 °C (ΔH_fus +138 J·g⁻¹) and no exothermic decomposition up to 300 °C, confirming that the bulk substance does not pose an auto‑catalytic thermal runaway risk under standard UN RTDG test conditions (DSC screening per the recommendations of the UN Manual of Tests and Criteria, Section 28.3.1). Shipment classification falls under non‑dangerous goods for land and sea transport, although the 49 °C flash point (closed cup, ASTM D93) warrants precaution against ignition sources during packaging. The acute oral LD₅₀ in rats is reported as > 2000 mg·kg⁻¹ (OECD 423), and a workplace exposure limit of 2 mg·m⁻³ (eight‑hour TWA) is advised pending formal OEL establishment. During bulk‑solid handling, the product has a tendency to build electrostatic charge when conveyed through PTFE‑lined chutes at relative humidities below 30%, a condition observed during winter production runs at facilities located in continental climates. An earth‑bonded 316L stainless‑steel hopper and ionisation bars have eliminated discharge events that previously caused localised thermal discolouration and an increase in insoluble foreign matter counts at the 5 µm filtration step prior to packaging. The minimum ignition energy of the dust cloud, measured in a MIKE‑3 apparatus, is >1000 mJ, placing the fine fraction outside the usual concerns for dust explosion classification, though nitrogen inerting remains mandatory for milling operations that generate particle sizes below 50 µm.