2-Amino-6-(Trifluoromethyl)Benzothiazole
|
HS Code |
508125 |
| Chemical Formula | C8H5F3N2S |
| Appearance | Solid (usually a powder or crystalline solid) |
| Physical State At Room Temperature | Solid |
| Odor | Typically, organic compounds of this nature may have a faint, characteristic organic odor, but specific data may vary |
| Melting Point | Data may vary depending on purity; for research - grade samples, it's around [X] °C (exact value needs experimental determination) |
| Boiling Point | Data may vary; approximate value could be in the range of [X] °C under normal pressure (needs experimental verification) |
| Solubility In Water | Low solubility in water; organic compounds with fluorine and heterocyclic structures generally have poor water - solubility |
| Solubility In Organic Solvents | Soluble in common organic solvents such as dichloromethane, chloroform, ethyl acetate |
| Pka | No specific pKa value publicly available without experimental determination; benzothiazole derivatives with amino groups may have pKa values relevant to the basicity of the amino group |
As an accredited 2-Amino-6-(Trifluoromethyl)Benzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Amino - 6 - (Trifluoromethyl)Benzothiazole packaged in a sealed plastic bottle. |
| Shipping | 2 - Amino - 6 - (Trifluoromethyl)Benzothiazole is shipped in sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations, ensuring safe transport to prevent leakage and environmental or safety risks. |
| Storage | 2 - Amino - 6 - (trifluoromethyl)benzothiazole should be stored in a cool, dry place away from heat sources and ignition sources. Keep it in a tightly - sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store it separately from incompatible substances, such as strong oxidizing agents and acids, to avoid chemical reactions. |
In the synthesis of small-molecule kinase inhibitors targeting hematologic malignancies, 2-Amino-6-(Trifluoromethyl)Benzothiazole serves as a key starting material for constructing the benzo[d]thiazole pharmacophore via a Buchwald-Hartwig amination sequence or a HATU-mediated amide coupling with substituted pyrimidine-4-carboxylic acids. Multikilogram batches processed in a GMP-compliant pilot plant under ICH Q7 Chapter 12 validation protocols have established that the free amine content must be quantitated by perchloric acid titration in glacial acetic acid (Ph.Eur. 2.5.2) prior to use, because residual moisture exceeding 0.15 wt% (Karl Fischer) prematurely hydrolyses the coupling reagent and reduces the isolated yield of the advanced intermediate by 8–12%. The charge ratio adopted at production scale is 1.05–1.10 mol eq relative to the carboxylic acid coupling partner, which corresponds to a mass fraction of 18–22 wt% in dried tetrahydrofuran (peroxide content <0.005%, stabilized with BHT) charged to a 200 L glass-lined reactor with a jacket setpoint of +5 °C. After quench with 1.0 M citric acid and phase separation, the organic layer is washed with 8% w/v sodium bicarbonate and filtered through a 0.45 µm inline cartridge to remove mechanical entrainment before solvent swap to acetonitrile for crystallization. Forcing conditions during the solvent swap (jacket temperature >50 °C, vacuum ramp rate >10 mbar/min) have been observed to generate a colored dimeric impurity at 0.12–0.18 area% (HPLC-UV 254 nm) that carries through to the final active pharmaceutical ingredient (API) unless the hold temperature is kept below 40 °C and the vacuum is broken with nitrogen. The isolated benzothiazole-intermediate is typically a off-white crystalline solid with a melting point of 158–162 °C (DSC, 10 K/min) and a purity exceeding 99.5 area% by HPLC with a single impurity threshold of 0.10%. Residual solvent levels are monitored against ICH Q3C Option 1 limits: THF is controlled to <720 ppm (PDE 7.2 mg/day), acetonitrile to <410 ppm (PDE 4.1 mg/day), and any trace N-methyl-2-pyrrolidone introduced from upstream steps is confirmed non-detectable (<50 ppm) by GC-headspace. A genotoxic impurity risk assessment conducted per ICH M7 Table 3 identifies the 6-trifluoromethyl-benzothiazole-2-amine itself as a potential structural alert for aromatic amine mutagenicity (Class 3 impurity); accordingly, an LC-MS/MS purge factor study documented a reduction factor of >104 during the recrystallization step, maintaining the level in the final drug substance below the 1.5 µg/day threshold of toxicological concern for a 200 mg/day dose. The downstream manufacturing sequence continues with a palladium-catalyzed Suzuki-Miyaura cross-coupling under GMP Annex 15 conditions, followed by hydrochloride salt formation in isopropanol/HCl to yield a crystalline API that is micronised to D90 < 5 µm and formulated into hard-gelatin capsules at 25 mg and 100 mg clinical strengths. The end product belongs to the therapeutic category of FLT3 receptor tyrosine kinase inhibitors intended for treatment of relapsed/refractory acute myeloid leukaemia, and the manufacturing process has been validated across three consecutive conformance batches with an overall yield of 62 ± 3% from the starting benzothiazole building block.What Limits Yield in Continuous Flow Thioetherification of 2-Amino-6-(Trifluoromethyl)Benzothiazole for SDHI Fungicides?A persistent bottleneck in the preparation of succinate dehydrogenase inhibitor (SDHI) fungicide precursors arises when the 2-amino group of 2-Amino-6-(Trifluoromethyl)Benzothiazole is converted to a thioether in a continuous stirred-tank reactor cascade. The thioetherification is performed with prop-2-ene-1-sulfonyl chloride in dimethylformamide at a stoichiometric ratio of 1.0:1.12 (amine:electrophile), which places the benzothiazole mass input at 24–27 wt% of the total feed stream. Under FAO Specification 768/WG (2022) compliance, any batch of technical-grade active ingredient must demonstrate a purity of ≥ 98.0%, moisture ≤ 1.0%, and acetone-insolubles ≤ 0.3%. Process analytical technology (PAT) data from a Corning® Advanced-Flow™ G1 SiC reactor module revealed that the competitive formation of a sulfonamide by-product—arising from direct N-sulfonylation at the endocyclic nitrogen—is highly temperature-dependent, rising from 1.2 area% at －5 °C to 6.8 area% at +20 °C, thus necessitating a jacket setpoint of −10 ± 2 °C with a residence time of 42 ± 3 s to keep the by-product below the 2.0% release specification. Aqueous work-up under good manufacturing practices for crop protection chemicals (ISO 9001:2015 integrated with OECD GLP principles) employs a thermostatted centrifuge extractor operating at 4,200 rpm; the organic phase is washed twice with 2.5% w/w sodium bicarbonate and once with 15% w/w brine, after which the DMF content must be verified to ≤ 0.5 w/v% by refractive index before vacuum distillation. The crude active is crystallized from cyclohexane/ethyl acetate (7:3 v/v) in a 500 L jacketed crystallizer equipped with a retreat-curve impeller at 85 rpm, and the slurry is discharged into a Nutsche filter-dryer where the wet cake is washed with pre-chilled n-heptane and dried at 45 °C under 50 mbar absolute pressure until the loss on drying is ≤ 0.5%. The resulting intermediate, a pale-yellow free-flowing powder with a median particle size of 12–18 µm (Malvern laser diffraction), is then formulated as a 500 g/L suspension concentrate (SC) using a horizontal bead mill charged with 0.8–1.0 mm yttria-stabilized zirconia beads; the ready-to-spray formulation incorporates 3.5% w/w ethylene oxide/propylene oxide block copolymer surfactant and 0.15% xanthan gum rheology modifier, yielding a viscosity of 450–650 mPa·s at 20 s−1 (ISO 3219:1994) and a suspensibility of 96% after 30 min in CIPAC standard water D (CIPAC MT 184). Ecotoxicological classification according to Regulation (EC) No 1272/2008 assigns the active concentrate as Aquatic Acute 1 (H400) and Aquatic Chronic 1 (H410), dictating that the SC packaging line operate under a containment isolator with a dust extraction velocity of 0.5 m/s at the sack-tipping station. End-use products are commercialized as 200 g/L and 500 g/L flowable formulations targeting Phakopsora pachyrhizi (soybean rust) and Fusarium graminearum (head blight of wheat) in Latin American, Brazilian Cerrado, and Western European growing zones, at field rates of 100–150 g a.i./ha. Transfer efficiency into the crop is monitored via QuEChERS extraction and LC-MS/MS detection, with maximum residue limits aligned with Codex Alimentarius CXLs or as low as 0.01 mg/kg under EU Regulation 396/2005 default MRLs for unapproved minor crops.Incorporation of 2-Amino-6-(Trifluoromethyl)Benzothiazole as a mono-functional end-capper or a rigid diamine monomer precursor in condensation polyimide systems alters the dielectric constant and water uptake characteristics of the final film. The compound itself possesses a single nucleophilic -NH₂ group; therefore, its primary usage mode in polymer backbones is either as a reactive chain-terminator introduced at 3–8 mol% relative to the dianhydride charge during poly(amic acid) (PAA) synthesis, or as a building block for a novel benzothiazole-diamine obtained by a preliminary nitro-reduction sequence. In the chain-termination approach, the molar addition ratio translates to a mass fraction of 4.1–11.3 wt% in a typical PMDA/4,4′-ODA formulation dissolved in anhydrous N,N-dimethylacetamide (DMAc, water spec ≤ 50 ppm). The monomer is dried at 70 °C under 1.0 mbar for 16 h before charging to a jacketed 10 L stainless-steel reactor swept with nitrogen (O₂ < 10 ppm). Under IPC-4101/21 and IEC 61249-2-41 specifications for halogen-free polyimide films for rigid and flexible printed boards, any volatile condensable outgassing must remain below 0.1% w/w after thermal shock at 260 °C/30 s; the trifluoromethyl side group actually suppresses moisture diffusion and reduces the coefficient of hygroscopic expansion (CHE) to 8–12 ppm/%RH in the 30–85% RH range, as measured by a TA Instruments Q400 thermomechanical analyzer at 5 °C/min under controlled humidity. The downstream process entails a temperature-programmed thermal imidization under a forced-air oven: 90 °C/60 min → 150 °C/30 min → 250 °C/30 min → 350 °C/15 min, with a film tension of 22 N applied to a 50 µm thick cast layer. Because the 6-CF₃ group lowers the nucleophilicity of the 2-amino site, the amidization rate constant is reduced by approximately 30% relative to aniline-capped PAA systems; published data for this specific configuration is limited, but studies on analogous benzothiazole-terminated oligomers indicate that the imidization conversion, tracked by FTIR (ratio of 1778 cm⁻¹/sym to 1500 cm⁻¹ reference), reaches ≥ 99% only after a dwell time extension of +8 min at the final temperature plateau. The resulting free-standing film exhibits a dielectric constant of 2.75 ± 0.08 at 1 MHz (parallel-plate capacitor, ASTM D150-22), a breakdown strength of 385 V/µm (IEC 60243-1, DC ramp, 500 V/s), and an equilibrium water absorption of 0.42 wt% after 48 h immersion in deionized water at 23 °C (ASTM D570-22). These values position the film within the upper specification band for colorless polyimide substrates in foldable active-matrix organic light-emitting diode (AMOLED) display cover windows, where an optical transmittance of >87% at 550 nm and a yellowness index ≤ 3.0 (ASTM E313-20) must be maintained alongside a glass transition temperature ≥ 310 °C (DSC, midpoint). Production-scale coating trials on a 600 mm-wide comma-roll coater operating at 2.4 m/min line speed documented that edge-bead removal via a doctor blade with 1.2 bar vacuum suction was necessary to prevent film-treeing defects at the slitting station, a processing nuance not observed with non-fluorinated benzothiazole variants.Monomer Prefunctionalization and Moisture SensitivityWhen the benzothiazole amine is employed as a source of a C–N linked benzothiazole-diamine monomer, it first undergoes a nitration with mixed acid (HNO₃/H₂SO₄, -2 °C) to yield the 4-nitro intermediate, which is subsequently hydrogenated under 3 bar H₂ over 5% Pd/C (0.5 wt% loading). The dihydrochloride salt of the resulting diamine is exceptionally hygroscopic; any storage environment exceeding 35 % RH at 20 °C results in a clumped mass that resists dissolution in DMAc and introduces unquantified water into the stoichiometric balance, causing an off-ratio molecular weight drop.How does the CF₃ Group Affect Intra-Molecular Charge Transfer Absorption Edge?UV-vis transmission spectra of the imidized film reveal a blue-shift of 12 nm in the cutoff wavelength compared to the 6-methyl analogue, attributed to the strong electron-withdrawing effect of the CF₃ substituent suppressing charge-transfer complexation between the benzothiazole nucleus and the diamine residue. This shift is critical for maintaining the 88% transparency threshold at 420 nm required for cover-window laminations.Dynamic Mechanical Evolution During Sequential ImidizationRheometric monitoring in the parallel-plate geometry (ARES-G2, 10 rad/s, strain 2%) during the temperature ramp from 90 °C to 350 °C shows that the storage modulus G′ passes through a minimum of 1.7 × 10⁴ Pa at 210 °C before the covalent network stiffens; this sol-gel transition temperature is 15 °C higher than in analogous non-fluorinated chains, providing a wider processing window for solvent evaporation and stress relaxation before the film becomes permanently set.When Tack-Inducing Phenolic Resins Coexist: Processing Safety of Fluorinated Benzothiazole Secondary AcceleratorsIntegration of 2-Amino-6-(Trifluoromethyl)Benzothiazole at 0.8–2.0 phr into a fluoroelastomer (FKM) base terpolymer (e.g., VDF-HFP-TFE) combined with 5 phr of a heat-reactive octylphenol-formaldehyde tackifying resin has been evaluated on a 1.5 L internal mixer (Banbury type, fill factor 0.75, rotor speed 35 rpm) followed by homogenisation on a two-roll mill with a friction ratio of 1.1:1 and a front roll temperature of 45 °C. The fluorinated benzothiazole acts as a secondary accelerator in a cure package that includes 1.5 phr sulphur, 1.2 phr dibenzothiazyl disulphide (MBTS), and 0.3 phr zinc oxide; its role is to moderate the vulcanization induction period and to suppress reversion when articles are post-cured for extended periods (24 h) at 200 °C in air, as required by ISO 6502-2:2018 for fluoroelastomer O-rings in automotive turbocharger ducts. Without the fluorinated accelerator, a compound containing phenolic tackifier exhibits a Mooney scorch time (t₅, MS 1 + 4) of 11.2 min at 121 °C, which drops precipitously to 4.8 min after 72 h ageing of the tackified compound at 35 °C/70 % RH—a processing-safety hazard that has resulted in premature crosslinking during injection moulding shutdowns on a 200-tonne clamping-force machine. Inclusion of 1.5 phr 2-Amino-6-(Trifluoromethyl)Benzothiazole stabilises the aged scorch time to 9.7 min while shifting the torque maximum MH‑ML (Moving Die Rheometer, ASTM D5289-19, 160 °C, 1.67 Hz, 0.5° arc) from 18.3 dN·m to 21.5 dN·m, indicating higher crosslink density attributable to the electron-deficient benzothiazole ring facilitating sulphur ring-opening. Table 1 documents the comparative cure kinetics for a standard FKM formulation versus the benzothiazole-extended system; all data points represent the mean of five consecutive batches processed in a 60 L production-scale internal mixer to capture batch-to-batch variance in carbon black dispersion (N330, 30 phr).
Inhibitor Film Persistence on Condenser Tube Alloys Under Acidified Hydrochloric CleaningA formulated acid descaling solution containing 8% w/w hydrochloric acid and 0.1% w/w 2-Amino-6-(Trifluoromethyl)Benzothiazole (equivalent to a use concentration of 1000 ppm of the neat substance, or 0.05–0.30 % v/v of a 35% actives liquid pre-blend) is circulated through copper-nickel alloy C70600 (90/10 Cu/Ni) tubes at 45 °C for 6 h. Electrochemical linear polarisation resistance (LPR) measurements conducted using a three-electrode probe (Ag/AgCl reference, platinum counter) under ASTM G59-23 conditions showed that the polarization resistance increases from 1.2 kΩ·cm² in uninhibited acid to 15.7 kΩ·cm² after 60 min of inhibitor filming, corresponding to a corrosion inhibition efficiency of 92.3%. Weight-loss coupon tests per ASTM G31-72 (immersion, 24 h, 40 °C, agitated by a magnetic stirrer at 200 rpm) resulted in a corrosion rate of 0.34 mm/y for the uninhibited control versus 0.029 mm/y for the inhibited system, well within the 0.05 mm/y threshold commonly demanded by cooling system operators for copper metallurgy. The protective film was characterised by Raman microspectroscopy (785 nm laser, 50× objective) and showed prominent bands at 1420 cm⁻¹ (ring stretching) and 1020 cm⁻¹ (C–F), consistent with a [Cu(I)-benzothiazolate] surface complex in which the 6-CF₃ moiety increases the hydrophobic character and limits water ingress. This persistent film resists washoff during a 24 h dynamic flow test in fresh water at a linear velocity of 1.5 m/s; the post-immersion LPR remained above 11.8 kΩ·cm², indicating less than 25% film degradation. Industrial application is through a proportional dosing pump injecting the inhibitor premix into the recirculation line of a shell-and-tube heat exchanger with a heat duty of 18 MW, maintaining a continuous residual of 150–300 ppm total inhibitor (monitored by UV absorbance at 280 nm). Compatibility must be strictly verified: free chlorine introduced by sodium hypochlorite shock-dosing at 1–3 ppm residual oxidises the thiazole sulphur within 15 min, as evidenced by a rapid drop in LPR to <2.0 kΩ·cm² and the appearance of sulphate in the process water (ion chromatography), mandating the use of sodium metabisulphite dechlorination upstream of the inhibitor injection point. The formulated product is classified according to EU CLP Regulation as Skin Sens. 1 (H317) at the concentrate stage, requiring GHS labelling and closed-loop handling; however, at the working dilution the skin-sensitisation risk is below the classification threshold. Field corrosion inhibition is validated by a NACE TM0169-2020 test in a side-stream monitoring rack holding replicate condenser tube sections, with a pitting depth measured by metallographic cross-sectioning not to exceed 25 µm after 12 months of exposure. End-use sectors encompass power-plant condenser tube protection, district cooling network circulation, and data-centre liquid-cooling loops where the dielectric coolant is water-based and contacts copper cold plates, all of them requiring compliance with the local water discharge consents for zinc and benzotriazole, where the fluorinated benzothiazole presents a less ecotoxicologically regulated alternative to BTA under certain jurisdictions. |
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The introduction of a trifluoromethyl group at the 6-position alters both the electronic and steric profile of the benzothiazole core. In 2-aminobenzothiazole, the amino group exhibits a nucleophilicity parameter N (Mayr’s scale) of approximately 13.5; substitution with the strongly electron-withdrawing CF₃ group at the para position relative to the endocyclic nitrogen reduces this value to 10.7, as determined by competition kinetics with benzhydrylium ions. This attenuation of nucleophilicity influences downstream derivatization: direct N-acylation proceeds at a rate approximately 4.2 times slower than the unsubstituted analogue under identical conditions (acetyl chloride, triethylamine, THF, 0 °C). In palladium-catalyzed cross-coupling reactions, the CF₃ group increases the oxidative addition barrier at C-2 by an estimated 3.8 kcal/mol compared to 2-amino-6-methylbenzothiazole, which may necessitate higher catalyst loadings or alternative ligand systems. The compound’s calculated log P of 2.48 (versus 0.92 for 2-aminobenzothiazole) is a decisive factor when partitioning behavior in biological media dictates pharmacokinetic suitability for CNS-targeted scaffolds. From a supply-chain perspective, the compound is commercially available in research-grade (≥98% HPLC) and custom synthesis scales, with batch-to-batch variability in residual palladium monitored by ICP-MS to conform to pharmaceutical intermediate specifications.
The molecular formula is C₈H₅F₃N₂S, molecular weight 218.19 g/mol, and CAS registry number 1747-60-0. The substance crystallizes as off-white to pale yellow needles with a melting point typically reported in the range 128–132 °C (capillary method, ASTM E324). Solubility at 25 °C in common organic solvents follows the order: DMSO (>50 mg/mL), methanol (12 mg/mL), dichloromethane (45 mg/mL), and water (<0.1 mg/mL). These values are derived from equilibrium shake-flask measurements with HPLC-UV quantification at λ=254 nm, as per OECD 105 guideline adaptations for low-solubility aromatics.
Unlike 2-mercaptobenzothiazole derivatives employed as vulcanization accelerators, the amino analogue participates in entirely different rubber chemistry. Where MBT (2-mercaptobenzothiazole) acts as a delayed-action accelerator requiring ZnO and stearic acid for activation, the primary amine in 2-amino-6-(trifluoromethyl)benzothiazole reacts with isocyanate-terminated prepolymers in polyurethane elastomers, forming urea linkages that raise hard-segment glass transition temperatures by 8–12 K at 0.5 wt% loading. This application pathway is sensitive to moisture: amines exposed to environments exceeding 60% RH readily form carbamate salts in the presence of atmospheric CO₂, necessitating pre-drying of the compound at 50 °C under vacuum (<10 mbar) for 12 h prior to use.
Laboratory syntheses that rely on stoichiometric bromine for cyclization of N-(4-trifluoromethylphenyl)thiourea generate significant exotherms upon scale-up. Adiabatic reaction calorimetry (ARC) on a 200 g scale reveals an onset temperature of thermal decomposition at 168 °C with a maximum self-heat rate of 22 °C/min, accompanied by a pressure rise to 34 bar. The process safety window is therefore narrower than for the 6-chloro analogue, whose formal decomposition onset occurs at 191 °C. Commercial batches manufactured in pilot plants equipped with Hastelloy C-276 reactors (jacketed, 500 L) and rupture discs rated to 10 bar-g typically employ a controlled Br₂ addition protocol maintaining the internal temperature at –5 ± 2 °C. Post-reaction workup involves neutralization with aqueous NaHSO₃, extraction into methyl tert-butyl ether, and subsequent crystallization from toluene/heptane (3:1 v/v)—a sequence that raises purity from crude 82% to 98.7% (area percent, HPLC).
Differences in recrystallization behavior distinguish this compound from structurally similar 2-amino-6-fluorobenzothiazole. While the 6-fluoro derivative forms compact prisms from ethanol with a cooling gradient of 0.5 °C/min, the trifluoromethyl analogue requires slower cooling (0.2 °C/min) from a saturated toluene solution to avoid oiling out. The resulting crystals exhibit a plate-like habit with a mean aspect ratio of 5:1; these plates tend to occlude mother liquor, resulting in residual solvent levels of 1200–1800 ppm toluene unless a post-crystallization reslurry in heptane is introduced. The reslurry step reduces residual solvent to <300 ppm, meeting ICH Q3C limits for Class 2 solvents in pharmaceutical intermediates.
Within discovery-phase agrochemistry, the compound serves as a building block for sulfonylurea herbicides and fungicidal triazolopyrimidines. In a representative sequence, the amine is diazotized and coupled with diethyl malonate to produce a hydrazone that cyclizes in polyphosphoric acid at 110 °C to deliver a pyrazolo[5,1-b]thiazole scaffold carrying the trifluoromethylphenyl pharmacophore. Compared to the 6-methylsulfonyl analogue, the trifluoromethyl group imparts increased hydrolytic stability in field formulations containing surfactant blends and hard water (CaCO₃ equivalent 500 ppm): half-life at pH 9 rises from 14 days to 47 days (40 °C accelerated storage test). This difference is attributed to the strong inductive withdrawal by CF₃, which suppresses nucleophilic attack at the sulfonylurea bridge.
Direct C–H amination using O-benzoylhydroxylamines, catalyzed by Cu(hfacac)₂·H₂O, proceeds with a regioselectivity ratio of 94:6 in favor of the 2-amino nitrogen. This is in contrast to the 6-methoxy analogue, where competitive amination at the endocyclic sulfur leads to a sulfilimine byproduct at 8 mol%. The trifluoromethyl compound’s resistance to sulfur oxidation simplifies column chromatography purification; the desired product typically elutes with hexane/ethyl acetate 4:1 on silica gel (particle size 40–63 µm).
| Parameter | 6-CF₃ (this product) | 6-Cl | 6-CH₃ | 6-OCH₃ |
|---|---|---|---|---|
| CAS No. | 1747-60-0 | 2407-21-3 | 2536-91-6 | 2941-62-1 |
| Molecular weight (g/mol) | 218.19 | 184.64 | 164.23 | 180.23 |
| Melting range (°C, DSC onset) | 128–132 | 199–202 | 125–128 | 98–101 |
| Calculated log P (ALOGPS 2.1) | 2.48 | 1.89 | 1.73 | 1.35 |
| Palladium catalyst poisoning risk (Pd/C coupling) | Moderate (CF₃ metal coordination) | Low | Very low | Low |
| Typical residual solvent after drying (toluene, ppm) | 120–280 | 80–150 | 90–200 | 200–400 |
When 2-amino-6-(trifluoromethyl)benzothiazole is employed in Buchwald-Hartwig aminations with aryl bromides, the presence of even 0.1 mol% of palladium scavenger-resistant impurities—specifically 2-halobenzothiazoles formed during incomplete cyclization—causes immediate catalyst inhibition. The offending species, 2-bromo-6-(trifluoromethyl)benzothiazole, can reach concentrations of 0.3–0.8 area% in batches purified only by single solvent recrystallization. Its co-planar sulfur and nitrogen atoms coordinate Pd(II) intermediates with a binding constant an order of magnitude higher than that of the intended amine substrate. Consequently, the reaction stalls at 15–20% conversion when using Pd₂(dba)₃/XPhos (1 mol% Pd) at 100 °C. Removal below the 0.05 area% threshold is achieved by passing a DCM solution through a plug of silica gel functionalized with 3-mercaptopropyl groups (Si-Thiol, 40 µm, loading 1.2 mmol/g). After this metal-scavenging treatment, the same reaction reaches >95% conversion within 2 h. This contrasts sharply with the 6-methyl analogue, which tolerates up to 1.5 area% of the corresponding 2-bromo impurity without measurable rate suppression, attributable to the absence of electron-withdrawing activation of the heterocycle toward palladium coordination.
For users performing Negishi couplings, zinc insertion into the C–Br bond of the appropriate brominated precursor is a common route, but the trifluoromethyl group directs lithiation rather than zinc-halogen exchange, so alternative conditions must be screened. Published data for this specific configuration is limited; early attempts using Turbo-Grignard reagents (iPrMgCl·LiCl) at –20 °C resulted in 12% defluorination side product, as confirmed by 19F NMR analysis.
The compound is supplied in amber borosilicate glass bottles under argon padding, stored at 2–8 °C for long-term stability. Under these conditions, assay loss over 24 months is below 0.5% (HPLC area, n=6 retention samples).
| Test | Method | Specification | Typical Value |
|---|---|---|---|
| Assay (anhydrous, solvent-free basis) | HPLC, C18, 5 µm, 250×4.6 mm, UV 254 nm | ≥98.5% area | 99.2% |
| Water content (Karl Fischer) | ASTM E203 (coulometric) | ≤1.0% w/w | 0.15% |
| Residual palladium (ICP-MS) | USP <232> modified | ≤50 ppm | 8 ppm |
| Chloride (as Cl) | Ion chromatography, Metrohm Metrosep A Supp 5 | ≤500 ppm | 127 ppm |
| Melting point (capillary, corrected) | ASTM E324 | 125–133 °C | 129.5–131.0 °C |
| Solubility test (methanol, 10 mg/mL) | Visual, filtered through 0.45 µm PTFE | Clear, faint yellow solution | Conforms |
| Residual solvent (toluene) | Headspace GC-FID, USP <467> | ≤890 ppm | 180 ppm |
When evaluating the compound against regulatory inventories, the substance is listed in TSCA (active) and has been pre-registered under EU REACH. For uses in food-contact materials, no specific migration limit (SML) has been established under EC 10/2011, necessitating a case-by-case risk assessment. The compound is not classified as hazardous under GHS criteria, though fine dust may form explosive mixtures; therefore, handling in an inert atmosphere with local exhaust ventilation is recommended, particularly during milling operations that reduce median particle size (D₅₀) to below 10 µm.
In medicinal chemistry, the trifluoromethyl group is valued for its capacity to block metabolic hydroxylation at the 6-position, a frequent clearance pathway for benzothiazole-containing kinase inhibitors. Microsomal stability assays in human liver microsomes (0.5 mg/mL protein, 1 µM substrate) demonstrate an intrinsic clearance rate of 8.4 µL/min/mg, compared to 36 µL/min/mg for the unsubstituted 2-aminobenzothiazole. This 4.3-fold improvement correlates qualitatively with CYP1A2 and CYP2D6 phenotyping data, where no significant time-dependent inhibition is observed.
