2-Amino-4-Fluorobenzothiazole

In sulfur-accelerated vulcanization of EPDM compounds processed on intermeshing twin-screw extruders with L/D ≥ 48:1, the partial replacement of conventional sulfenamide accelerators (CBS or TBBS) by 2-Amino-4-Fluorobenzothiazole displaces the scorch time plateau by 2.5–3.0 minutes at 135 °C as recorded on a MDR 2000 rheometer per ASTM D5289-19a. In a standard formulation comprising 100 phr EPDM (ethylene content 55%, ENB 5.5%), 50 phr N550 carbon black, 5 phr ZnO, 1 phr stearic acid, and 2 phr rhombic sulfur, the introduction of AFBT at 0.8–1.5 phr in place of 0.4–0.7 phr CBS extends Mooney scorch (MS-t5, 125 °C, ISO 289-1:2015) from a baseline of 18 min to 24–28 min, simultaneously shifting the activation energy of crosslink formation (calculated by the Kissinger method from DSC non-isothermal curing exotherms) upward by approximately 8–12 kJ/mol. Production-scale experience on a Ø 70 mm co-rotating twin-screw line—operated at screw speed 220 rpm, barrel zones 80/90/100/110 °C, and equipped with a gear pump and 200-mesh screen pack—reveals that AFBT-loaded compounds exhibit a 15–20% increase in head pressure relative to CBS-only loads when the fluoro content exceeds 1.2 phr, attributable to transient melt-state association of the aromatic amine with filler-bound silanol groups. This rheological signature requires recalibration of the auto-thermal regulation loop. After strip-fed cold-feed extrusion and underwater pelletizing, injection molding into automotive turbocharger charge-air cooler hoses demands a clamp force margin ≥ 15% above the calculated projected area requirement to accommodate the delayed viscosity rise. The finished hose meets the ASTM D2000 M2BG710 classification, with tensile strength ≥ 10 MPa (ISO 37:2017), elongation at break ≥ 300%, and compression set (22 h/125 °C) below 25% (ISO 815-1:2019). Regulatory conformance integrates Regulation (EC) No 1907/2006 (REACH) Annex XVII restrictions on PAH content, FDA 21 CFR §177.2600 for repeated-use rubber articles in dry food contact, and the limits for 2-aminobenzothiazole migration of ≤ 0.15 mg/kg food simulant in EU 10/2011 (Annex II, specific migration limit for non-listed substances). Process boundary: AFBT should not be combined with peroxide-coagent cure systems because the primary aromatic amine quenches alkoxy radicals, yielding a severe undercure (Δ torque < 2 dNm on MDR). Outdoor storage of uncured AFBT-containing compounds requires wrapping in aluminum-laminated barrier film at RH > 60% to prevent pre-crosslinking catalyzed by ammonia released from slow ambient hydrolysis of the fluorinated heterocycle.

What Limits the Regio-selectivity in Fungicidal Benzothiazole Carboxamide Synthesis?

During the preparation of benzothiazole carboxamide fungicides structurally related to benthiavalicarb, the coupling of 2-Amino-4-Fluorobenzothiazole with isopropoxycarbonyl-protected L-valine acid chloride in anhydrous tetrahydrofuran (≤ 50 ppm water by Karl Fischer titration) proceeds with a regio-selectivity exceeding 98:2 when the reaction temperature is maintained at −10 to −5 °C and diisopropylethylamine is dosed at 1.05 molar equivalents over 40–50 minutes. The molar input ratio of AFBT to acyl chloride is precisely controlled at 1.00:1.02 to suppress bis-acylation; excess AFBT (> 1.05 eq) leads to a difficult-to-purge impurity co-eluting with the product on silica gel (Rf difference ≤ 0.03 in n-hexane/ethyl acetate 3:1). The downstream manufacturing campaign in a glass-lined 2,000 L reactor equipped with a retreat-curve impeller (tip speed 1.8 m/s) and a −20 °C jacket charged with Syltherm XLT includes a subsequent aqueous work-up at pH 8.5 ± 0.3 to hydrolyze unreacted anhydride residues, followed by vacuum distillation of THF at ≤ 45 °C jacket temperature to avoid the formation of dehydrative dimers. Crystallization from 2:1 methylcyclohexane/ethyl acetate yields the protected amide intermediate with 99.5% (AUC at 254 nm) purity. The terminal fungicide active ingredient, obtained after a second deprotection step with 4 M HCl/dioxane and coupling with methyl (S)-2-isocyanato-3-methylbutyrate, is formulated as a 150 g/L suspension concentrate meeting FAO Specification 590/SC (2022) and registered under Regulation (EC) No 1107/2009. Field performance against Phytophthora infestans in processing tomato cultivation (per EPPO PP1/213(4)) at a rate of 1.2–1.5 kg a.i./ha demonstrates curative activity only when the benzothiazole moiety carries a 4-fluoro substituent; the 5-fluoro isomer fails to translocate beyond the treated leaflet (acropetal petiole uptake < 5% vs. 22% for the 4-fluoro derivative in 14C-radiolabel tracing). Impurity management adheres to ICH Q3C(R8) residual solvent limits for THF (≤ 720 ppm) and 1,4-dioxane (≤ 380 ppm), while the absence of N-nitrosamine admixtures is verified by LC-MS/MS with a limit of quantification of 0.03 ppm per USP <1469>.

Veterinary Anthelmintic Intermediate Purity and Mutagenic Impurity Monitoring

Synthesis of benzothiazole-based fasciolicide drug substances targeting immature Fasciola hepatica begins with 2-Amino-4-Fluorobenzothiazole as the eastern fragment building block, representing 42–48 weight% of the final active pharmaceutical ingredient (API). In a validated GMP sequence conducted per ICH Q7 and VICH GL1, AFBT is N-acylated with 5-chloro-2-nitrobenzoyl chloride (1.03 molar equivalents) in dimethylacetamide at 0–5 °C over 2 hours in a 500 L hastelloy C-22 reactor, producing the ortho-nitro amide intermediate. Stannous chloride dihydrate in concentrated HCl (12 mol equivalents) reduces the nitro group at 70 °C with exotherm control via jacket ramp to 85 °C, forming the aniline that cyclises in situ to the benzimidazole core—the desired benzimidazo[2,1-b]benzothiazole scaffold crystallizes upon neutralisation with 20% aqueous NaOH to pH 7.2 and is recrystallized from isopropanol/water (7:3 v/v) to achieve polymorphic Form I (monohydrate) with D[v,0.9] < 80 µm suitable for a direct-compression oral bolus. The finished veterinary medicinal product, a 900 mg tablet for sheep, must comply with VICH GL18(R2) residue depletion analysis showing edible tissue concentrations below 10 µg/kg muscle and 20 µg/kg liver 14 days post-treatment. Because AFBT carries a structural alert for mutagenicity under ICH M7(R2) (primary aromatic amine), the API specification sets a limit of ≤ 1.5 mg/day based on a threshold of toxicological concern of 1.5 µg/day applied to a 1000 kg bovine. Control is achieved by a dedicated HPLC-UV method (column: C18, 150 x 4.6 mm, 3 µm; mobile phase: phosphate buffer pH 2.5/acetonitrile gradient; quantification at 254 nm) with an LOQ of 5 ppm for residual AFBT in the API. Process limitation: stannous chloride reduction yields a tin residual level of 800–1,200 ppm in crude intermediate, requiring a second recrystallization to reach ≤ 10 ppm Sn per Ph. Eur. 2.4.24—the rejection rate for first-crop crystallizer product averages 15–18% across 25 consecutive commercial batches.

When 2-Amino-4-Fluorobenzothiazole is diazotized with sodium nitrite (1.02 mol eq) in 85% phosphoric acid at 0 to 5 °C and coupled to N-ethyl-N-(2-chloroethyl)aniline in a buffered medium (pH 4.5, acetic acid/sodium acetate), the resulting monoazo disperse dye exhibits a bathochromic shift of 23 nm (λ_max in DMF: 518 nm) compared to the 6-chloro analogue, attributable to the electron-withdrawing effect of the 4-fluoro substituent on the benzothiazole-chromophoric system. Exhaustion dyeing on knitted polyester (PET, 1.5 denier) is carried out in a Thies jet-dyeing machine at a 10:1 liquor ratio, ramping from 70 °C to 130 °C at 1.5 °C/min and holding for 60 minutes; dyebath uptake reaches 92–94% at a 1.0% o.w.f. shade without carrier. The molar coupling ratio of diazonium salt to coupling component is held at 1.00:1.00 to avoid residual aromatic amine in the finished dye powder, which is standardised to 200% colour strength with lignin sulfonate dispersant and milled to a particle size D90 ≤ 2 µm (laser diffraction, ISO 13320:2020). The dyed fabric, intended for automotive upholstery, must pass ISO 105-B02:2014 lightfastness at rating ≥ 6 (Xenon arc, 42 W/m² at 300–400 nm, 100 hours) and the build-up curve is linear up to 2.5% o.w.f. before the wash fastness (ISO 105-C06:2010, test C2S) drops below grade 4–5. Compliance with the ZDHC Manufacturing Restricted Substances List (MRSL) v3.1 and OEKO-TEX Standard 100 Annex 4 (limit for 4-aminoazobenzene-derived amines: 20 mg/kg) requires certification that the dyestuff contains no detectable primary aromatic amine from incomplete coupling—routinely verified by reductive cleavage and GC-MS with a reporting limit of 5 mg/kg. During scale-up to a 5,000 L coupling vessel, the exotherm of the diazotization—−28 kJ/mol AFBT—must be managed by jacket brine circulation at −10 °C and a controlled nitrite addition profile spanning 45 minutes; a temperature excursion above 8 °C triggers decomposition of the diazonium salt, drop in coupling conversion to < 85%, and a hue shift toward brown that cannot be corrected by post-precipitation blending.

When 5-Chloro-2-aminobenzothiazole is Replaced by 2-Amino-4-Fluorobenzothiazole in Antitubercular Hydrazone Lead Optimization

In a structure-activity relationship campaign targeting InhA enoyl-ACP reductase from Mycobacterium tuberculosis, replacement of the 5-chloro substituent on the benzothiazole hydrazone core with a 4-fluoro group resulted in a 4- to 8-fold improvement in whole-cell potency against drug-sensitive H37Rv (MIC reducing from 0.5 µg/mL to 0.0625 µg/mL in 7H9/ADC/Tween 0.05% medium) as determined by the microplate Alamar Blue assay per CLSI M24-A2. Synthesis of the pivotal hydrazone utilises AFBT condensed with 4-(trifluoromethyl)benzaldehyde in refluxing absolute ethanol containing 0.5% v/v glacial acetic acid, employing a 1.0:1.2 molar ratio of aminobenzothiazole to aldehyde to ensure complete consumption of the amine and facile removal of excess aldehyde by trituration with cyclohexane. Downstream kilogram-scale production in a 100 L glass reactor fitted with a Dean-Stark trap and operated under nitrogen sweep produces the hydrazone in 85% yield after cooling to −5 °C and filtration; residual ethanol and acetic acid are stripped to ≤ 500 ppm and ≤ 100 ppm respectively by vacuum oven drying at 40 °C/10 mbar for 18 hours. The compound serves as an early-development phase intermediate for a benzothiazole hydrazone antitubercular agent now undergoing preclinical pharmacokinetic profiling, where the 4-fluoro motif raises logD_7.4 by 0.6 units (1.8 to 2.4) without increasing hERG liability (IC₅₀ > 30 µM on CHO-hERG automated patch clamp). All processing steps adhere to ICH Q11 for starting material specification and the development report includes a genotoxic impurity evaluation per ICH M7(R2), with AFBT being treated as a Class 3 primary aromatic amine requiring purge factor calculations (predicted purge factor ≥ 3,000 in the final recrystallized API). Operational boundary: the condensation must be run in ethanol of water content ≤ 0.5%; higher water levels promote hydrazone hydrolysis and yield loss exceeding 25%.

Thermoplastic polybenzothiazole dielectric films for high-frequency flexible printed circuits have been prepared by polycondensation of 2-Amino-4-Fluorobenzothiazole with 1,2,4,5-benzenetetramine tetrahydrochloride in polyphosphoric acid at 180 °C under a nitrogen sweep for 24 hours. The molar ratio of AFBT to tetraamine is maintained at 2.00:1.00 to obtain bis(benzothiazole) telechelic oligomers with controlled molecular weight (M_n 8,000–12,000 GPC vs. polystyrene standards in NMP/0.05 M LiBr). Film casting from N-methylpyrrolidone solution on a polished glass plate and subsequent stepwise annealing to 350 °C under nitrogen yields a 25 µm transparent film exhibiting a dielectric constant (D_k) of 2.6 at 10 GHz (split-post dielectric resonator, IEC 61189-2-721:2015) and a dissipation factor below 0.004. The material meets RoHS Directive 2011/65/EU (Annex II, restricted substances) and the fluorinated character guarantees an oxygen index of 38% (ISO 4589-2:2017) without flame retardant additives. Commercial viability is constrained by the polyphosphoric acid work-up, which requires massive aqueous quench volumes (50:1 v/v water:PPA) and generates phosphate waste streams that necessitate on-site neutralization and precipitation before discharge.