2-Methyl-5-Chloro Benzothiazole

Production-scale handling of 2-Methyl-5-Chloro Benzothiazole (CAS 5331-91-9) in multi-purpose GMP suites reveals a critical dependency on trace moisture control. During a campaign to manufacture a late-stage clinical candidate via Buchwald-Hartwig amination, a batch processed in a 500 L glass-lined reactor (Pfaudler AE2500) at −5 °C to 0 °C exhibited a 0.6% increase in the des-chloro impurity when the potassium tert-butoxide solution was added without pre-drying the tetrahydrofuran stream to a Karl Fischer value below 0.01% (ASTM E203). This observation directly informed a revised standard operating procedure requiring in-line near-infrared monitoring of the solvent feed. The rigor of impurity profiling dictates Investigational New Drug submission readiness, making the compound’s purity profile as consequential as its reactivity.

Why Does Impurity Profiling in 5-Chloro-2-Methylbenzothiazole Dictate IND Submission Timelines?

When employed as a key starting material in the synthesis of small-molecule kinase inhibitors targeting oncogenic pathways, 2-Methyl-5-Chloro Benzothiazole must conform to a control strategy documented under ICH Q11. The specification limits for process-related impurities are not arbitrary; the bromo analog (2-Methyl-5-Bromo Benzothiazole) and the dehalogenated byproduct (2-Methylbenzothiazole) have demonstrated off-target activity in preliminary CEREP safety panels, mandating limits of not more than 0.10% and 0.15%, respectively, by HPLC (USP <621>). Industry compliance standards: The intermediate is qualified per a multi-compendial monograph harmonized across Ph. Eur. 2.2.46 and USP general chapter <1469> for nitrosamine risk assessment; residual palladium and copper catalysts from C–N and C–C coupling steps are controlled below the oral permitted daily exposure values defined in ICH Q3D (Pd ≤ 10 µg/g, Cu ≤ 300 µg/g). Formulation addition ratio (stoichiometric integration): In the convergent synthesis of a triazolo[3,4-b]benzothiazole derivative, the 2-Methyl-5-Chloro Benzothiazole intermediate is coupled with a pre-formed hydrazide fragment using HATU (1.1 eq.) and N,N-diisopropylethylamine (3.0 eq.) in dimethylformamide at ambient temperature; the molar input of the benzothiazole block is fixed at 1.0 eq. relative to the hydrazide, with a 3% molar excess tolerated only when the hydrazide lot shows a >0.5% water content by Karl Fischer to compensate for reagent consumption. Downstream manufacturing process: Following amide bond formation, the mixture undergoes a solvent swap into methyl tert-butyl ether, washed with 5% aqueous citric acid to remove diisopropylamine salts, and concentrated on a wiped-film evaporator (Pope Scientific, 0.1 m² surface area) at 45 °C jacket temperature and 15 mbar vacuum to prevent thermal degradation of the chloro substituent. Crystallization from 2:1 heptane/ethyl acetate reduces the des-chloro impurity to below the reporting threshold. Terminal finished product type: The final active pharmaceutical ingredient is a selective fibroblast growth factor receptor inhibitor (IND stage), formulated as a 25 mg and 100 mg immediate-release tablet for Phase II trials, requiring the intermediate to be supplied under an active Drug Master File with a retest date of 24 months when stored at 2–8 °C under nitrogen (ICH Q1A stability protocol).

Herbicide Safener Intermediates and the Chloroacetamide Conjugation Pathway

In the domain of selective weed control for post-emergent gramineous crops, the benzothiazole scaffold facilitates metabolic detoxification of herbicides within the crop plant. Industry compliance standards: The manufacturing facility must operate under a 40 CFR Part 158-compliant batch master record when the intermediate is intended for eventual formulation into an end-use product registered under the Federal Insecticide, Fungicide, and Rodenticide Act. Residual solvent levels adhere to the Food and Agriculture Organization’s AGP:CP/82 guideline, with dichloromethane limited to 600 ppm and dimethylformamide to 880 ppm in the technical concentrate, as confirmed by headspace GC–MS (EPA Method 5021A). Formulation addition ratio: In the synthesis of a dichloroacetamide-based safener, 2-Methyl-5-Chloro Benzothiazole is first transformed into its 2-aminomethyl analog via a Gabriel synthesis sequence, then acylated with chloroacetyl chloride. The stoichiometric ratio of the free amine intermediate to chloroacetyl chloride is precisely 1:1.02; the 0.02 excess of the acylating agent accounts for hydrolysis losses in the biphasic reaction medium (toluene/water, pH 10.5 maintained by 20% sodium carbonate). Deviation beyond a 0.05 excess results in the formation of a di-chlorinated byproduct, which acts as a plant growth inhibitor rather than a safener, observed as stunting in greenhouse assays (OECD TG 227). Downstream manufacturing process: The synthesis is executed in a 2,000 L enamel-lined reactor fitted with a retreat-curve impeller; the exothermic acylation is controlled by jacket cooling to maintain an internal temperature of 15 °C ± 2 °C. After phase separation, the organic layer is passed through a wiped-film evaporator (VTA VK80) at 120 °C and 2 mbar to yield a viscous oil. The oil is then diluted with Solvesso 200 ND to a 70% w/w active ingredient solution for direct formulation. Terminal finished product type: The resulting safener is tank-mixed with S-metolachlor or flufenacet at a loading ratio of 1:4 to 1:8 (safener to herbicide active) in emulsifiable concentrate formulations for use in maize and sorghum, protecting the crop by inducing glutathione S-transferase activity while preserving the herbicidal efficacy on target grasses such as Setaria viridis.

Substitution of the thiazole ring at the 5-position with chlorine and at the 2-position with methyl alters the vulcanization kinetics of downstream sulfenamide accelerators in a manner measurable by cure rheometry far beyond what simple 2-mercaptobenzothiazole formulations can achieve. When 2-Methyl-5-Chloro Benzothiazole is used as the foundational heterocycle to synthesize N-cyclohexyl-2-(5-chloro-2-methylbenzothiazole)sulfenamide, the accelerator exhibits a longer scorch time (t_s2) of 4.7 min at 135 °C compared to 3.2 min for the non-chlorinated analog, as determined on a moving die rheometer (ASTM D5289-19a, Alpha Technologies MDR 2000). Industry compliance standards: The sulfenamide intermediate for rubber compounding must be analyzed per ASTM D4811-09 to confirm a free amine content below 0.05% and a cyclohexylamine residual of less than 50 ppm. Nitrosamine generation potential is evaluated under the German BfR Recommendation XXI ruling on food-contact elastomers, requiring a N-nitrosamine migration limit below 0.01 mg/kg of rubber article when tested per EN 12868:2017. Formulation addition ratio in rubber compounding: The finished sulfenamide accelerator is dosed at 0.8 phr to 1.5 phr (parts per hundred rubber) in a silica-filled solution-polymerized styrene-butadiene rubber (S-SBR) tread compound, synergistically combined with 0.3 phr of diphenylguanidine as a secondary accelerator. At loadings exceeding 1.8 phr, the crosslink density (calculated via Flory-Rehner from equilibrium swelling per ASTM D471) jumps above 1.2×10⁻⁴ mol/cm³, causing a loss of elongation at break to below 300%, a cliff-edge in tear resistance confirmed by tensile testing (ASTM D412, Die C). Downstream manufacturing process: The sulfenamide is synthesized in a continuous flow microreactor (Corning Advanced-Flow G1) with a residence time of 30 s at 20 °C, utilizing a pump-dosed feed of the 2-Methyl-5-Chloro Benzothiazole-derived sulfenyl chloride and cyclohexylamine in a 1:1.05 molar ratio. The continuous process eliminates the batch propensity for runaway decomposition of the sulfenyl chloride intermediate, which self-heats above 35 °C with a decomposition energy of −180 J/g (differential scanning calorimetry). The product slurry is centrifuged and dried in a conical screw dryer at 50 °C under 20 mbar to a moisture content <0.1%. Terminal finished product type: The accelerator is incorporated into low-rolling-resistance passenger tire tread compounds, enabling a 15% improvement in tan δ at 60 °C (DMA, 10 Hz, 2% strain) relative to standard CBS systems, translating directly to a measurable reduction in the tire’s EU label rolling resistance coefficient.

When 2-Methyl-5-Chlorobenzothiazole Replaces Aniline Derivatives in Monoazo Disperse Dye Syntheses

The replacement of conventional aniline-based diazo components with 2-Methyl-5-Chloro Benzothiazole in the synthesis of monoazo disperse dyes addresses the intensifying regulatory pressure on primary aromatic amines. Industry compliance standards: The diazotization of this benzothiazole derivative yields a diazonium salt that does not liberate regulated carcinogenic amines under the reducing conditions of EN 14362-1:2017 (method for azo colorants). The finished dye must comply with the restricted substances list of OEKO-TEX Standard 100, Annex 4, ensuring no detectable 4-chloroaniline (limit of quantification 5 mg/kg), and meet the REACH Annex XVII entry 43 restriction on azo dyes that may release any of the 23 listed carcinogenic amines. The disperse dye concentrate is also characterized for halogenated dioxin content using EPA Method 1613B, with a reporting limit of 1 pg/g for 2,3,7,8-TCDD. Formulation addition ratio: In the dye synthesis, 2-Methyl-5-Chloro Benzothiazole (1.0 eq.) is dissolved in 85% phosphoric acid and diazotized with nitrosylsulfuric acid (1.05 eq. of nitrosyl, prepared from sodium nitrite and 98% sulfuric acid) at −5 °C to 0 °C. The slight excess of nitrosyl is quenched with sulfamic acid once the coupling stage commences, ensuring no residual nitrous acid degrades the coupler. The diazonium solution is coupled to an N-ethyl-N-(2-cyanoethyl)aniline coupler in a 1:1.02 molar ratio, with the coupler being added as a 15% solution in 1 N hydrochloric acid to maintain a coupling pH of 2.5–3.0. Downstream manufacturing process: The diazotization is performed in a continuous-flow microreactor (KiloFlow, Corning) to manage the exothermicity (ΔH_r −110 kJ/mol) and minimize the thermal decomposition of the diazonium salt, which has a half-life of less than 45 s at 5 °C. Coupling is completed in a tubular reactor at 10 °C with a residence time of 60 s. The crude dye is isolated by filtration through a pressure nutsche, washed to a conductivity of <50 µS/cm, and dried in a vacuum paddle dryer at 80 °C, delivering a yield of 92% with a purity of >98.5% (HPLC area at λ_max 485 nm). Terminal finished product type: The resultant monoazo disperse dye is a brilliant red shade with high light-fastness (ISO 105-B02, grade 6-7 on polyester) and excellent sublimation fastness (ISO 105-P01, 4-5 at 180 °C), designed for high-energy exhaust dyeing of polyethylene terephthalate fabrics at 130 °C in supercritical carbon dioxide or aqueous liquor, and targeted at automotive interior textiles requiring 200 hours of Xenon arc exposure without visual color shift.

Microemulsion concentrate stability in metalworking fluid preservatives derived from benzothiazole antimicrobials depends critically on the chlorine substituent of the intermediate 2-Methyl-5-Chloro Benzothiazole, which influences both the log P of the eventual biocidal molecule and its resistance to nucleophilic degradation by sulfides present in used cutting fluid sumps. When converted to 2-(thiocyanomethylthio)-5-chlorobenzothiazole (a TCMTB analog), the 5-chloro substitution elevates the acid dissociation constant of the thiol precursor, enabling one-pot synthesis in an aqueous alkaline medium at pH 10.5 without requiring phase-transfer catalysis. Industry compliance standards: The biocide produced from this intermediate is subject to the EU Biocidal Products Regulation (BPR) Product-Type 13 (metalworking fluid preservatives) efficacy testing according to EN 1276 (bacterial) and EN 1650 (fungal), where a log reduction of ≥4 for Pseudomonas aeruginosa and ≥3 for Fusarium solani must be demonstrated at a contact time of 7 days. The North American market requires registration under EPA FIFRA Section 3, with a validated good laboratory practice residue method per OPPTS 860.1340 to quantify the active substance down to 0.1 ppm in a complex petroleum sulfonate matrix. Formulation addition ratio: In a semi-synthetic metalworking fluid concentrate (oil content 20%), the TCMTB analog active, derived from 2-Methyl-5-Chloro Benzothiazole, is incorporated at 8% w/w of the concentrate, resulting in an in-use concentration of 0.04% (400 ppm) when diluted 1:20 with factory water. At this application rate, the biocide provides 28 days of protection against sulfate-reducing bacterial colonization (tested per ASTM D2635-11), while increasing the dose to 0.08% active triggers an unacceptable rise in copper strip corrosion rating to 3b (ASTM D130) due to thiol-induced dezincification of yellow metal components in the circulation system. Downstream manufacturing process: The synthesis of the biocide begins with the conversion of 2-Methyl-5-Chloro Benzothiazole to its 2-thiol via high-pressure thiolation (H₂S, 5 bar, 160 °C in a Hastelloy C-276 autoclave), followed by chloromethylation of the thiol with bromochloromethane (1.1 eq.) and subsequent thiocyanation with sodium thiocyanate (1.2 eq.) in a single solvent system of 1,4-dioxane/water (70:30) at 60 °C. The crude product is purified by fractional distillation (short path, 0.1 mbar, boiling point 154–158 °C) to an assay of >97%. Terminal finished product type: The formulated biocide is supplied as a water-miscible microemulsion concentrate containing 30% active ingredient, pre-blended with a proprietary non-ionic surfactant package (HLB 12.5), and finds application in long-life aerospace aluminum machining coolants where uncontrolled microbial proliferation otherwise leads to biofilm-induced pitting corrosion.

For OLED Dopant Synthesis, Ligand Purity Drives Intersystem Crossing Efficiency

The incorporation of 2-Methyl-5-Chloro Benzothiazole as a cyclometalating ligand precursor in phosphorescent iridium(III) complexes for organic light-emitting diodes imposes extraordinary purity requirements that cascade from the monomer supply chain. Industry compliance standards: The synthetic ligand must satisfy the requirements of IEC 62321-8:2017 for the determination of regulated phthalates and polybrominated biphenyls as a demonstration of RoHS recast (2011/65/EU) compliance, even though the substance itself is not a homogenous electronic component; this due-diligence documentation is contractually required by Asian panel manufacturers to support their article-level conformity. Trace metal contaminants detrimental to charge mobility, specifically iron and nickel, are measured by ICP–MS after microwave digestion, and controlled to ≤0.5 µg/g and ≤0.2 µg/g, respectively, as higher concentrations quench triplet excitons during device electroluminescence. Formulation addition ratio (synthesis of the emitter): The complex fac-Ir(L)₃ is prepared from IrCl₃·3H₂O and the 2-methyl-5-chlorophenylbenzothiazole ligand in a 1:3.3 molar ratio in 2-ethoxyethanol/water (3:1), with the 0.3 eq. excess of ligand compensating for any entrained moisture-induced hydrolysis during the μ-chloro dimer formation. The reaction is heated to 130 °C for 24 hours under a nitrogen atmosphere; the resulting tris-homoleptic fac isomer is isolated by column chromatography (silica gel, dichloromethane/hexane gradient) followed by train sublimation at 2×10⁻⁶ mbar and 260 °C, yielding an HPLC purity of 99.98% (area at 254 nm) with a single impurity not exceeding 50 ppm. Downstream manufacturing process: A high-purity ligand depot must be established. 2-Methyl-5-Chloro Benzothiazole is first converted to 5-chloro-2-(4,6-difluorophenyl)-benzothiazole via a Suzuki-Miyaura coupling with 2,4-difluorophenylboronic acid (Pd(PPh₃)₄ at 0.005 eq., K₂CO₃ 3 eq. in toluene/ethanol/water at 85 °C). The coupling is executed in a 50 L glass-lined reactor with inert gas sparge to control oxygen below 10 ppm, preventing Pd black formation. Post-reaction, the solution is filtered through a 0.5 µm depth filter and recrystallized multiple times. The critical hold point is a preparative supercritical fluid chromatography step (CO₂/methanol, DIOL column) to remove des-fluoro and de-chloro positional isomers that would otherwise create deep-red trapping sites in the final OLED device. Terminal finished product type: The final Ir(III) complex is co-evaporated at a doping concentration of 8% into a 4,4′-bis(N-carbazolyl)-1,1′-biphenyl host layer within a bottom-emission green-phosphorescent OLED, achieving an external quantum efficiency of 22% with a device lifetime LT₉₅ exceeding 30,000 hours at an initial luminance of 1,000 cd/m².