Benzothiazole, 2-Methyl-5-(Trifluoromethyl)-

Introduction of a 2-methyl-5-trifluoromethyl-benzothiazole moiety into the core scaffold of Type II receptor tyrosine kinase inhibitors has been demonstrated to simultaneously improve selectivity for the DFG-out inactive conformation and reduce human ether-à-go-go (hERG) channel blockade, a critical optimization step during lead candidate development. The intermediate is typically deployed as a carboxylic acid functionalized at the 6-position or as the corresponding acyl chloride, prepared in situ via treatment with thionyl chloride (1.3–1.5 eq) in toluene containing catalytic N,N-dimethylformamide under nitrogen purge at 65–70°C until evolution of sulfur dioxide ceases, typically 4–6 h. The resulting acid chloride is coupled to an amine-bearing heterocycle under Schotten-Baumann conditions; the preferred protocol charges 1.02–1.10 eq of the acid chloride to a chilled biphasic mixture of tetrahydrofuran and saturated aqueous sodium bicarbonate at 0–5°C over 45–60 min with vigorous mechanical stirring, maintaining pH 7.5–8.0 monitored via in-line probe. Amide bond formation exotherms by approximately 12–15 kJ·mol⁻¹, and the jacket temperature is ramped to 20°C after complete addition. Stripping of tetrahydrofuran under reduced pressure (≤150 mbar, internal temperature <40°C) precipitates the crude benzothiazole-carboxamide, which is collected by centrifuge filtration, washed with deionized water until conductivity falls below 50 μS·cm⁻¹, and dried in a vacuum tray dryer at 45°C with <1% residual moisture before purification. Chromatographic purification employs silica gel 60 (230–400 mesh, Merck Grade 9385) and isocratic elution with dichloromethane:ethyl acetate (9:1 v/v); fractions are monitored at 254 nm, pooled when HPLC area% exceeds 99.2%, concentrated on a wiped-film evaporator at jacket temperature 38°C, and crystallized from ethyl acetate/n-heptane (1:3 v/v) by controlled cooling from 60°C to 2°C at a linear rate of 0.15°C·min⁻¹ to ensure consistent particle size distribution (d₅₀ 12–18 μm). Residual palladium is removed via treatment with SiliaMetS® Thiol resin (0.015 eq relative to Pd content) at 50°C for 4 h in the concentrated mother liquor prior to crystallization; the final active pharmaceutical ingredient intermediate must meet Pd <10 ppm, Ni <5 ppm, and Cu <15 ppm by inductively coupled plasma mass spectrometry, conforming to ICH Q3D elemental impurity guidelines for parenteral administration. The residual solvent specification per USP <467> is set at ethyl acetate <4000 ppm, n-heptane <5000 ppm, and dichloromethane <600 ppm, verified by headspace GC-FID using a DB-624 column (30 m × 0.32 mm, 1.8 μm film). The benzothiazole compound is sensitive to prolonged exposure to visible light under humid conditions; amber double-laminated polyethylene bags inside UN-approved fiber drums, with silica gel dessicant packets inserted, constitute the standard container closure system. Batch size variability on a kilo-lab scale occurs primarily during the acylation step where unreacted starting acid carried into the coupling phase by incomplete stripping can produce dimer impurity at relative retention time 1.43; this is controlled by endpoint analysis of the thionyl chloride reaction via GPC titration, terminating when chloride content reaches ≥98% of theoretical.

Fungicidal activity against Zymoseptoria tritici field isolates bearing the G143A mutation of cytochrome b is retained when the benzothiazole-2-methyl-5-CF₃ substructure replaces the traditional pyrazole-4-carboxamide in second-generation succinate dehydrogenase inhibitors (SDHI). The benzoheterocycle moiety acts as the amine component in the final amide linkage, anchoring into the lipophilic tunnel formed by residues Trp173, Phe129, and Leu239 of the ubiquinone binding site. Manufacturing at ton scale deploys a convergent route wherein 2-methyl-5-(trifluoromethyl)-1,3-benzothiazole-6-carboxylic acid is generated via potassium permanganate oxidation of the corresponding methyl derivative in water/tert-butanol 1:1 at 70°C, followed by quenching with sodium metabisulfite and hot filtration to remove manganese dioxide. The acid is converted to its acid chloride with phosgene in toluene (1.1 eq, bubbled at 0°C) to avoid sulfur-containing byproducts, with excess phosgene destroyed by aqueous ammonia scrubbers downstream; critical process parameters mandate a reactor partial pressure of COCl₂ maintained below 0.2 bar and reaction residence time not exceeding 90 min to minimize isocyanate formation. Condensation with 2-(1,2,4-triazol-1-yl)-3-difluoromethyl-1H-pyrazole-5-carboxamide in the presence of 1.5 eq of triethylamine in anhydrous acetone at reflux for 6 h yields the technical-grade active ingredient after drowning in ice-cold water and filtration; purity by GC-FID is typically 94–96%, with major impurities consisting of unreacted amine and symmetrical anhydride. A reslurry operation in toluene at 60°C for 2 h elevates purity to ≥98.5% (w/w) and reduces the water content below 0.3%. Quality control for registration under Regulation (EC) No. 1107/2009 includes compliance with FAO Specification 483/TC (octanol/water partition coefficient log P 3.8 ± 0.2), and the material must exhibit acute oral LD₅₀ in rats >2000 mg·kg⁻¹ with no skin sensitization in the local lymph node assay. The formulated suspension concentrate (SC 250 g·L⁻¹) integrates the active ingredient with a sodium lignosulfonate dispersant and a xanthan gum thickener, wet-milled in a horizontal bead mill (0.6–0.8 mm yttria-stabilized zirconia beads) to a volume median diameter d₅₀ of 1.5 μm. During bead milling, the product temperature must not exceed 35°C; Ostwald ripening is suppressed by the addition of 0.05% (w/w) of a non-ionic ethylene oxide-propylene oxide block copolymer, maintaining suspension stability for 14 days at 54°C accelerated storage test per CIPAC MT 46.3.

Sublimation-grade 2-methyl-5-(trifluoromethyl)-1,3-benzothiazole functions as a precursor for heteroleptic iridium(III) phosphorescent emitters in red organic light-emitting diodes (OLEDs), wherein the benzothiazole cyclometalating ligand raises the HOMO energy level to approximately −5.2 eV and shifts the emission maximum to 620–630 nm when coupled with a 2,4-pentanedionato ancillary ligand. The initial raw material, typically 98% GC purity, undergoes train sublimation in a three-zone horizontal quartz tube furnace under dynamic vacuum 1 × 10⁻⁶ mbar. Zone 1 is held at 85°C to evaporate low-mass organic fragments; zone 2, the primary deposition region, is maintained at 55°C; zone 3 at 25°C collects purified crystals as transparent pale-amber needles. A sublimation rate of 0.15–0.25 g·h⁻¹ is achieved with a carrier gas of ultra-high-purity argon flowing at 2 sccm; after a single pass, the product assay determined by non-aqueous titration with perchloric acid exceeds 99.9%, and metallic impurities by ICP-OES are specified at Na <0.5 ppm, K <0.2 ppm, Fe <0.3 ppm, and Zn <0.1 ppm. Halide residue from upstream Suzuki coupling must be reduced below 5 ppm chloride to prevent exciplex quenching in the emissive layer. Storage and packaging are executed inside a glovebox with O₂ and H₂O levels each regulated to <0.1 ppm; borosilicate glass bottles fitted with PTFE-lined caps are double-sealed in polyethylene-aluminum laminate barrier bags. For device fabrication, the host:dopant system (e.g., 4,4′-bis(N-carbazolyl)-1,1′-biphenyl doped at 6–8 wt%) is co-evaporated in a Kurt J. Lesker high-vacuum cluster tool at a base pressure of 5 × 10⁻⁷ mbar using a crucible temperature of 190–210°C for the dopant. The resulting OLED stack delivers an external quantum efficiency roll-off of less than 5% at a luminance of 1000 cd·m⁻² when the dopant’s sublimation-derived purity is maintained; any deviation above 0.3% non-luminescent impurity triggers measurable exciton-polaron annihilation that degrades the LT95 lifetime by ≥40% at constant current density of 10 mA·cm⁻² per JIS C 8153-2.

When a Copper CMP Slurry Operates Beyond the Passivation Threshold at pH 10.2

At pH 9.8–10.4, 2-methyl-5-(trifluoromethyl)-benzothiazole chemisorbs onto cupric oxide/hydroxide passivation layers via N–Cu and S–Cu coordination, forming a dense monomolecular film that suppresses etch rate in recessed features without retarding material removal on protruded copper surfaces during chemical mechanical planarization of 14-nm back-end-of-line interconnects. The compound is introduced into the slurry as a dilute solution in dipropylene glycol methyl ether (DPM, 0.5 wt% stock) following filtration through a 0.1 μm nylon membrane, yielding a working concentration window of 30–150 ppm relative to the total slurry weight. The silica-abrasive-based slurry (calcined fumed silica, 3.5 wt%, average primary particle size 40 nm, aggregate d₅₀ 120 nm) is oxidizer-augmented with hydrogen peroxide at 1.5%, and the interaction with the benzothiazole additive modulates the copper removal rate dynamically—excessive concentration above 200 ppm causes catastrophic pad glazing and a 60% drop in average removal rate as measured by sheet resistance mapping on a ResMap four-point probe system (Creative Design Engineering, model 178). Corrosion inhibition behavior is characterized potentiodynamically in an electrochemical flat cell (ASTM G5-14 reference) with a Cu rotating disk electrode at 1000 rpm; the attached table summarizes key parameters for different loading levels.

A stability index (ratio of η after 48 h to initial η) below 0.80 correlates with formation of insoluble Cu(I)-benzothiazole aggregates that adhere to the polishing pad asperities. Special attention is given to the initial ramping of the slurry flow rate on the platen: the slurry must be delivered at 250 mL·min⁻¹ through a single-point dispense arm to avoid localized enrichment. In advanced manufacturing fabs, endpoint detection uses an optical reflectance signal at 630 nm normalized to a replica wafer; the benzothiazole additive does not interfere with the spectral endpoint window when its absorbance at that wavelength remains below 0.08 AU in 1 cm path length. The material is mandated to comply with SEMI F57-0301 ultrapure chemicals guidelines, and peroxide compatibility testing under accelerated 60°C conditions for 72 h must confirm less than 2% decomposition of the active azole, measured by reverse-phase HPLC on a C18 column with 70/30 acetonitrile/water mobile phase. Incompatibility is documented with strong oxidizing acids; the additive blend should be segregated from nitric acid > 5% to avoid exothermic nitration at the 6-position of the benzothiazole ring.

Sulfur-vulcanized copolymers of tetrafluoroethylene and propylene (FEPM, AFLAS® type) exhibit delayed scorch and low crosslink density when accelerated solely with 2-mercaptobenzothiazole (MBT) due to the electron-withdrawing fluorocarbon backbone reducing mercaptide nucleophilicity. Substitution with 2-methyl-5-trifluoromethyl-benzothiazole, which lacks a thiol group, repositions the compound as a secondary accelerator that synergizes with sulfenamide accelerators such as N-cyclohexyl-2-benzothiazolesulfenamide (CBS) in a mixed cure package. In a standard FEPM 100H compound (100 phr polymer, 30 phr N990 carbon black, 5 phr zinc oxide, 1 phr stearic acid, 1 phr sulfur, 1.5 phr CBS), the addition of 2.0 phr of 2-methyl-5-trifluoromethyl-benzothiazole shifts the onset of vulcanization (tₛ₂ by moving die rheometer, ISO 6502-3:2018) from 1.8 min to 2.6 min at 177°C, while the maximum torque (M_H) elevates from 18.4 dNm to 23.8 dNm, indicating a substantially higher crosslink density attributable to accelerated sulfur intercalation. The compound is incorporated into the batch during the second stage of mixing on a two-roll mill (roll temperature 50 ± 5°C, friction ratio 1.2:1) after the carbon black masterbatch has cooled to room temperature, to prevent premature crosslinking. A distinct processing requirement is that the silica gel desiccation of the neat accelerator to moisture content below 400 ppm (Karl Fischer) is essential; hydrated material induces micro-voids visible by SEM at the filler-polymer interface after press-curing at 15 MPa for T₉₀ + 2 min. The table below contrasts scorch safety and state of cure for a model FEPM formulation adapted with different benzothiazole-derived secondary accelerators.

The formulation containing the trifluoromethyl-benzothiazole shows a 29% increase in M_H over the CBS-only control, without the detrimental bloom observed with MBTS after 72 h storage at ambient conditions. During prolonged service in oilfield seal applications (>200°C, H₂S partial pressure 0.5 bar), the retention of tensile strength after 168 h immersion in ASTM IRM 903 oil is 89%, while compression set (25%, 70 h at 200°C per ASTM D395 method B) measures 26%. It must be noted that the accelerator requires passivation of the mixing chamber with a dilute ammonia gas flush if production is paused to avoid hydrolysis of the CF₃ group under acidic sweep.

Does a 5-CF₃ Substituent Confer Adequate Positive Dielectric Anisotropy in Nematic Hosts?

Achieving a positive dielectric anisotropy Δε greater than +8 in fluorinated liquid crystal mixtures for thin-film transistor (TFT)-addressed TN and IPS displays requires terminal polarizable moieties that do not broaden the smectic phase range beyond −20°C. The benzothiazole heterocycle with a 5-CF₃ group functions as a core unit in three-ring phenylacetylene mesogens, where the lone-pair electrons of sulfur contribute to lateral polarizability and the trifluoromethyl group reinforces longitudinal dipole moment. The synthetic sequence operational at production scale begins with 2-methyl-5-trifluoromethyl-benzothiazole, which is regioselectively brominated at the 6-position in acetic acid with N-bromosuccinimide (1.02 eq) at 25°C in the dark, yielding >85% monobromo derivative after recrystallization from ethanol. Suzuki-Miyaura cross-coupling with 4-ethynylphenylboronic acid pinacol ester (Pd(PPh₃)₄, 0.008 eq; K₂CO₃ 2 M aq; ethanol/toluene 1:2) at 78°C for 10 h under argon constructs the teraryl scaffold, which is subjected to a final hydrogenolysis of acetyl-protecting groups over Lindlar catalyst (Pd/CaCO₃ poisoned with Pb) to generate the ethynyl linkage. Purification on preparative HPLC (C18, acetonitrile/water, 80:20 v/v) followed by single-zone vacuum sublimation at 120°C/10⁻⁴ mbar reduces alkali metal ion content below 0.2 ppm by atomic absorption spectroscopy; these residual ions directly dictate the voltage holding ratio (VHR) of the aligned liquid crystal cell. A VHR of 99.5% measured at 60°C under 1 V, 60 Hz square wave per IEC 61747-1:2015 is mandatory for gate line charging retention. The bulk resistivity is recorded at 1.8 × 10¹³ Ω·cm, with a birefringence Δn near 0.18 and a clearing point T_NI of 138°C. Thermo-oxidative stability under dry air at 150°C with 0.5% radical inhibitor 2,6-di-tert-butyl-4-methylphenol (BHT) is required to sustain VHR above 99% for 500 h. The material must conform to the EU Restriction of Hazardous Substances (RoHS) directive 2011/65/EU, as well as IEC 62321 halogen-free specifications with a total chlorine + bromine limit of 900 ppm; this is assured by the sublimation protocol, which expels halogenated homologs below the reporting threshold.