6-Bromo-2-Chloro-1,3-Benzothiazole

The benzothiazole scaffold functionalized with bromine at C-6 and chlorine at C-2 provides a distinct chemoselective platform for constructing ATP-competitive kinase inhibitors. In a validated kilo-lab procedure, 6.80 kg of 6-bromo-2-chloro-1,3-benzothiazole (assay 99.3%) were reacted with 1.05 equiv. of 4-cyanophenylboronic acid pinacol ester in a nitrogen-blanketed 160 L Hastelloy reactor containing 85 L degassed 1,4-dioxane. The catalyst, Pd(dppf)Cl₂·CH₂Cl₂, was charged at 0.3 mol% relative to the benzothiazole electrophile, with 2.5 equiv. of aqueous tripotassium phosphate (2 M) added as the proton scavenger. An internal temperature ramp from 22 °C to 80 °C over 45 min triggered a mildly exothermic event with a ΔT peak of +12 °C, which was dampened by jacket cooling fluid at −5 °C. After 4.5 h the reaction reached >98% conversion by UPLC (Waters Acquity BEH C18, 1.7 µm, gradient acetonitrile/water + 0.1% TFA). The work-up included filtration through a pad of Celite 545 (3 cm bed depth, 0.5 kg) to remove inorganic salts, followed by a solvent swap to isopropyl acetate and washing with 5% w/w N-acetylcysteine solution (3×10 L) to chelate palladium. The organic layer was concentrated to 20 L under reduced pressure (150 mbar, 45 °C) and crystallization was induced by slow addition of n-heptane (60 L) at 40 °C with seeding at 38 °C. The isolated crystalline solid (yield 6.2 kg, 85%) was dried in a conical tumble dryer at 40 °C jacket temperature and 10 mbar vacuum for 16 h. Quality control against ICH Q3D Guideline for Elemental Impurities confirmed palladium ≤5 ppm by ICP-MS (Agilent 7800, quantification at m/z 105 and 106), residual boron below the limit of 50 ppm, and loss on drying 0.28%. The product served as the penultimate intermediate to a spleen tyrosine kinase (Syk) inhibitor batch filed under a Type II Drug Master File. An operational boundary of RH ≤ 35% during material transfer was enforced because the crystalline form undergoes hygroscopic transformation to a monohydrate that reduces downstream coupling efficiency by 8–12%. The compound must not be brought into contact with primary or secondary amines in the presence of trace moisture, as ring-opening of the thiazole by aminolysis generates an intractable thioanilide impurity that co-elutes with the product during normal-phase purification. For rapid release testing, a compliance specification table is embedded below.

Carboxamide Fungicide Development: Can a Single Bromine Substituent Boost Translaminar Activity?

Field isolate resistance profiling against succinate dehydrogenase inhibitors (SDHI) has driven research into benzothiazole-bearing amides as alternatives to the pyrazole-carboxamide core. 6-Bromo-2-chloro-1,3-benzothiazole was elaborated via a three-step sequence without isolation of the intermediate acid chloride to yield N-(2-bromo-4-chlorophenyl)-6-bromo-2-chlorobenzo[d]thiazole-2-carboxamide, a candidate screened at 200 g ai/ha against Septoria tritici in winter wheat. The process began with hydrolysis of the 2-chloro substituent to the 2-oxo derivative in refluxing 48% w/w hydrobromic acid (8 volumes) over 10 h, followed by azeotropic drying with toluene and reaction with thionyl chloride (2.0 equiv., 75 °C, DMF catalyst 0.5 mol%) to afford the acyl chloride. Subsequent coupling with 2-bromo-4-chloroaniline in tetrahydrofuran containing 1.2 equiv. of triethylamine was conducted at 0–5 °C over 45 min and quenched with 1 M HCl. The crude carboxamide exhibited a melting endotherm of 198–202 °C by DSC (TA Instruments Q2000, 10 °C/min) and required recrystallization from methyl ethyl ketone/cyclohexane (1:3 v/v) to meet the purity specification of >98.5%. In accelerated storage stability tests at 54 °C for 14 days per CIPAC MT 46.3, the uncrystallized material degraded by 3.2%, highlighting the need for rigorous purification. The formulated 200 g/L suspension concentrate (SC) used a methyl oleate-based adjuvant system and showed desirable rainfastness (≥80% residue after 30 mm simulated rainfall per ASTM E 2278-13). An incompatibility emerged when tank-mixing with copper-based fungicides; the thiazole ring coordinated Cu(II) ions, forming a blue-green precipitate that blocked spray nozzle filters (50 mesh). Therefore, the label restriction advised a minimum interval of 7 days between applications. Soil metabolism half-life (DT50) in a sandy loam (pH 6.8, Org C 1.2%) was determined to be 22 days under aerobic conditions at 20 °C (OECD TG 307), indicating moderate persistence. For regulatory filing, the applicant submitted a 5-batch analysis under GLP demonstrating conformance to FAO Specification Guidelines 601/July 2020 for the parent compound.

When Monomer Purity Exceeds 99.95%: Trace Chlorine Impacts on OPV Fill Factor

In donor–acceptor (D–A) copolymers for non-fullerene organic solar cells, the benzothiazole unit functions as an electron-deficient building block. 6-Bromo-2-chloro-1,3-benzothiazole is subjected to Stille polycondensation with a distannyl-thiophene comonomer in a microflow reactor to achieve narrow dispersity. However, the 2-chloro substituent, if partially hydrolysed during storage, releases ionic chloride that poisons the palladium catalyst and introduces trap states in the active layer. Consequently, the monomer must be dried at 60 °C over P₂O₅ under 1×10⁻² mbar for 48 h and handled inside an argon-filled glovebox (H₂O, O₂ <1 ppm) during weighing. The polycondensation feed ratio required careful balancing: a deviation of more than ±0.5 mol% from the 1:1 stoichiometry induced end-group mismatch and a drop in number-average molecular weight (Mn) from 32 kDa to 18 kDa, as determined by high-temperature GPC (Agilent PL-GPC 220, 1,2,4-trichlorobenzene at 150 °C, polystyrene standards). Bulk metal specifications demanded Palladium ≤2 ppm, Tin ≤5 ppm, and Chloride (free ion) ≤10 ppm by ion chromatography (Metrohm 930 Compact IC Flex). The copolymer was spun into a photoactive layer in an inverted device architecture (ITO/ZnO/PM6:Benzothiazole copolymer:N3/MoO₃/Ag) and tested under AM 1.5G illumination at 100 mW/cm². Devices fabricated with monomer that had free chloride at 25 ppm exhibited a fill factor (FF) of 0.61, whereas material with chloride ≤5 ppm yielded an FF of 0.74, substantiating the critical nature of ionic purity. An elemental impurity and physical property control matrix is summarized below.

Flow chemistry platforms have exploited the dual electrophilicity of 6-bromo-2-chloro-1,3-benzothiazole for one-pot sequential metalations. In a typical procedure on a Corning Advanced-Flow G1 reactor (SiC, volume 62.5 mL, 5 heat exchange plates), a 0.3 M solution of the compound in anhydrous THF was pre-cooled to −40 °C and mixed with 1.05 equiv. of isopropylmagnesium chloride·lithium chloride complex (1.3 M in THF) in the first residence zone (τ = 12 s) to effect selective bromine–magnesium exchange at the C-6 position. The formed heteroarylmagnesium intermediate was reacted downstream with a 1.2 equiv. stream of benzaldehyde (0.36 M in THF) at −20 °C in a second zone (τ = 35 s), yielding the secondary alcohol in 91% GC area. Switching the electrophile to DMF (2.0 equiv., 0.6 M in THF) gave the 6-formyl derivative after continuous quenching in a batch vessel. The remaining C-2 chlorine remained intact, allowing a subsequent Buchwald–Hartwig amination offline. This telescoped flow process eliminated the need for cryogenic batch lithiation (−78 °C) and reduced the heat accumulation hazard associated with organomagnesium species. Incompatibility: direct contact with chlorinated solvents (dichloromethane, chloroform) in the presence of Grignard reagents led to carbene insertion/chlorine exchange and must be avoided. The whole system was flushed with dry THF (≤50 ppm H₂O) before and after each campaign. While this method has been demonstrated at 100 g scale, published data for larger production runs remain limited; the commercial manufacturing group maintains a scale-up database with a declared maximum safe tonnage.

System Suitability Standard for HPLC–MS Assays in Plasma Matrix Interference Studies

Due to the favourable UV absorption (λmax 282 nm in acetonitrile) and a distinct isotopic signature from bromine (¹²C₇H₃⁷⁹Br³⁵ClNS, [M+H]+ ⁷⁹Br m/z 235.9; ¹²C₇H₃⁸¹Br³⁵ClNS m/z 237.9), 6-bromo-2-chloro-1,3-benzothiazole is employed as an internal standard (IS) surrogate in bioanalytical method validation for novel benzothiazole-based drug candidates. The IS working solution is prepared at 1.0 µg/mL in methanol–water (1:1 v/v) and stored in amber borosilicate volumetric flasks at 2–8 °C; solution stability over 30 days is verified per FDA Bioanalytical Method Validation Guidance (2018). The compound is spiked into plasma samples prior to protein precipitation with 0.1% formic acid in acetonitrile (3 volumes), vortexed for 30 s, and centrifuged at 14,000 rpm (4 °C, Eppendorf 5424 R). The supernatant is injected directly (5 µL) onto a Kinetex C18 column (2.6 µm, 50×2.1 mm) maintained at 40 °C with a mobile phase of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) at 0.4 mL/min. Detection on an AB Sciex 6500+ triple quadrupole mass spectrometer using MRM transitions 236→190 and 238→192 confirms specificity with no matrix interference in six individual lots of human plasma (K₂EDTA). The method achieved a lower limit of quantification (LLOQ) of 0.5 ng/mL with a signal-to-noise ratio >25. Critical procedural constraint: the compound slowly sublimes under high vacuum; for extended run sequences (> 12 h), the autosampler tray temperature must be set to 10 °C to minimize evaporative loss, and septum-capped vials with PTFE/silicone septa are mandatory. This standard is not suitable for methods employing ESI in negative ion mode because of poor deprotonation efficiency.