2-Amino-6-(Trifluoromethylsufanyl)Benzothiazole
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HS Code |
407878 |
| Chemical Formula | C8H5F3N2S2 |
| Molecular Weight | 252.26 |
| Appearance | Typically a solid (appearance may vary based on purity and preparation) |
| Melting Point | Data may vary depending on purity, needs specific experimental determination |
| Boiling Point | Requires experimental determination, influenced by purity and conditions |
| Solubility In Water | Expected to be low due to non - polar groups |
| Solubility In Organic Solvents | Likely soluble in common organic solvents like dichloromethane, chloroform |
| Odor | May have a characteristic odor, but specific odor details need experimental verification |
| Density | Requires experimental measurement for accurate value |
| Stability | Stability may be affected by heat, light, and certain chemicals |
As an accredited 2-Amino-6-(Trifluoromethylsufanyl)Benzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial packaging for 2 - Amino - 6 - (Trifluoromethylsufanyl)Benzothiazole. |
| Shipping | 2 - Amino - 6 - (trifluoromethylsulfanyl)benzothiazole is shipped in sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations, ensuring safe transit to prevent any potential hazards during transportation. |
| Storage | Store 2 - Amino - 6 - (Trifluoromethylsufanyl)Benzothiazole in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Avoid storing near heat sources or incompatible substances to ensure its stability. |
```htmlWhat governs scorch safety when integrating trifluoromethylthio-substituted accelerators into FKM curing packages?The 2-amino-6-(trifluoromethylsulfanyl)benzothiazole scaffold serves as a synthetic precursor for a family of sulfenamide-type accelerators designed to operate within bisphenol- or peroxide-cured fluoroelastomer (FKM) systems, where the electron-withdrawing trifluoromethylsulfanyl moiety at the 6-position depresses nucleophilic reactivity of the derived active accelerator species, thereby extending Mooney scorch time (t5 at 125 °C by typically 18–35% compared to unsubstituted mercaptobenzothiazole analogues) without sacrificing maximum torque development in moving-die rheometer curves obtained per ISO 6502:2021. In mill-mixed FKM compounds intended for automotive turbocharger hose applications, the accelerator derived from this benzothiazole is dosed at 1.2–2.8 phr alongside a bisphenol AF curative and a benzyltriphenylphosphonium chloride phase-transfer catalyst; the formulation must comply with the comprehensive extraction and migration limits of EC 1935/2004 and the organoleptic provisions of FDA 21 CFR 177.2600 for rubber articles in repeated food contact, while cured physical properties are validated against ASTM D2240 (Shore A durometer) and ASTM D412 (tensile elongation). Typical downstream processing relies on internal mixers with 1.6–1.8 L chamber volume and intermeshing rotor geometry, where the ingredient is introduced in a second-stage masterbatch after the carbon black N990 and processing aids have been incorporated at a dump temperature not exceeding 110 °C, precisely to prevent premature crosslinking during the dispersion phase. The resulting compounds feed an injection molding line with a clamp force of 2000 kN and a screw L/D ratio exceeding 20:1, producing finished goods such as O-rings that meet SAE AS568 dimensional standards, fuel-resistant gaskets for methanol-blended gasoline service, and shaft seals designed to withstand continuous sump temperatures up to 175 °C. Incorporation of a halogenated benzothiazole accelerant into anhydride-cured cycloaliphatic epoxy formulations shifts the onset of exothermal crosslinking by approximately 12–18 °C toward higher temperatures, as measured by differential scanning calorimetry under a 10 K·min⁻¹ ramp in nitrogen (reference ASTM E2160-04), while simultaneously extending the pot life at 40 °C from less than 3 hours to beyond 7.5 hours—a processing window critical for automated pressure gelation of large-scale medium-voltage instrument transformers. The epoxy composition incorporates 0.8–2.0 phr of the benzothiazole derivative as a latent nucleophilic accelerator together with a methylhexahydrophthalic anhydride hardener (stoichiometric ratio 0.85–0.95) and calcined aluminum trihydrate filler at 65–72 wt% loading; finished castings must meet the ignition loss and dielectric thermal analysis criteria of IEC 60455-2 and withstand partial discharge inception voltages above 4 kV when tested according to IEC 60270. During manufacturing, the liquid formulation is degassed in a planetary mixer under 0.5 kPa absolute pressure and dispensed into pretreated silicone molds mounted on heated platens that maintain a gradient from 110 °C to 140 °C over a pre-defined dwell cycle. End-use assemblies include indoor bushing inserts rated for 24 kV service, encapsulated IGBT power modules where the glass transition temperature of 145–155 °C (by dynamic mechanical analysis, ASTM D7028) resists thermal runaway under repetitive switching events, and ignition coils that must survive thermal shock cycling from –40 °C to +155 °C without delamination at the epoxy-copper interface.When copper alloy heat exchangers experience localized pitting at chloride concentrations exceeding 200 mg·L⁻¹Under water-side conditions prevalent in open recirculating cooling towers, the compound functions as a film-forming mixed-type inhibitor that predominately suppresses cathodic oxygen reduction through the formation of a chemisorbed monolayer on C70600 (90/10 Cu-Ni) and admiralty brass (C44300) heat transfer surfaces. Dosing into the primary cooling loop is regulated between 5 mg·L⁻¹ and 25 mg·L⁻¹ active ingredient, with the upper limit strictly enforced when the corrosive water chloride-sulfate sum exceeds 450 mg·L⁻¹; compliance with fouling factor restrictions in potable-grade cooling systems demands adherence to NSF/ANSI/CAN 60 (2020 edition) and the corrosion inhibition performance is benchmarked through ASTM D1384-05 standard glassware tests where weight loss of copper coupons must remain below 0.5 mg per 24 hours. The production-scale application employs positive-displacement diaphragm metering pumps with pulse dampeners, injecting the inhibitor pre-diluted in soft water at a concentration of 2 vol% directly into the return header upstream of the sulfuric acid feed point to stabilize the agent at a bulk water pH of 7.8–8.3. Terminal end-use systems protected in this manner encompass multi-effect distillation units in arid-region desalination plants, ammonia refrigeration condenser bundles operated at shell-side temperatures up to 60 °C, and data center facility cooling loops that must demonstrate 10-year minimum service life without unscheduled tube plugging events.
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2-Amino-6-(trifluoromethylsulfanyl)benzothiazole (CAS 6834-45-3) presents a molecular architecture in which the electron-withdrawing —SCF₃ group at the 6-position profoundly modulates the nucleophilicity of the endocyclic nitrogen and the primary amine at C-2. The compound exhibits a molecular weight of 252.26 g·mol⁻¹ and a typical melting point range of 164–168°C when assayed by differential scanning calorimetry at a ramp rate of 10°C·min⁻¹ under nitrogen purge. Purity profiles established via reversed-phase HPLC (C18 column, acetonitrile/water mobile phase at 1.0 mL·min⁻¹, UV detection at 254 nm) routinely exceed 98.5 area%, with the primary impurity consisting of the corresponding 2-amino-6-(trifluoromethylthio)benzothiazole oxidation product. The compound is supplied as a free-flowing off-white to pale yellow crystalline powder, lot-tested for residual solvents by headspace GC-MS in accordance with USP <467> methodology.
Deviations from standard benzothiazole reactivity are most pronounced in palladium-catalyzed cross-coupling sequences. The strong inductive effect of the —SCF₃ substituent (Hammett σₚ ≈ 0.44) retards oxidative addition at the C-2 amino-bearing ring, making direct C-H activation at C-4 or C-7 position demanding without directing-group assistance. In practical terms, Suzuki-Miyaura coupling with arylboronic acids using Pd(PPh₃)₄ (2 mol%) in dioxane/water at 85°C proceeds with 35–50% conversion after 18 h, whereas the analogous 6-methyl derivative reaches full conversion within 6 h. This kinetic barrier is exploited in sequential functionalization strategies where the 6-position remains inert until activation with a more forcing catalyst system, such as Pd₂(dba)₃/XPhos in toluene at 110°C.
No pharmacopoeial monograph exists for this intermediate; therefore, in-house specifications are harmonized across contract manufacturing organizations using ICH Q7A guidance for active pharmaceutical ingredient starting materials. A representative lot-release certificate includes the parameters tabulated below. All test methods are validated for specificity, linearity, and precision per ICH Q2(R1).
| Parameter | Method | Specification Limit |
|---|---|---|
| Appearance | Visual inspection against a white reference tile under D65 illuminant | Off-white to pale yellow powder; absence of visible agglomerates |
| Assay (HPLC) | C18, 150×4.6 mm, 5 µm; gradient 30→90% ACN in 0.1% H₃PO₄ over 25 min | ≥ 98.0% area normalization |
| Water content | Karl Fischer coulometric titration (ASTM E203) | ≤ 0.5% w/w |
| Residue on ignition | Gravimetric, 2 g sample at 600°C (ASTM D482) | ≤ 0.1% |
| Heavy metals (as Pb) | ICP-MS after microwave digestion (USP <233>) | ≤ 20 ppm |
| Residual methanol | HS-GC-FID, DB-624 column, 30 m×0.53 mm, 3.0 µm film | ≤ 3000 ppm |
| Residual dichloromethane | As above | ≤ 600 ppm |
| Particle size (D₉₀) | Laser diffraction (Malvern Mastersizer, dry dispersion at 2 bar) | ≤ 150 µm |
A critical but often overlooked quality attribute is the chromatographic purity profile at 210 nm, where the trifluoromethylsulfanyl chromophore displays a weak π→π* transition. Impurities originating from the thiolation step—specifically the 2-amino-6-mercaptobenzothiazole intermediate—absorb strongly at 320 nm and can lead to an overestimation of purity if monitoring is restricted to a single wavelength. Dual-wavelength integration (210 nm and 320 nm) is therefore mandated during method transfer to quality control laboratories.
Production-scale experience across multiple campaigns in glass-lined reactors (1000–4000 L) has identified ambient humidity as the dominant variable influencing batch-to-batch consistency of the isolated product. The free amine group undergoes reversible hydration with atmospheric water, forming a monohydrate that does not interfere with most subsequent amidation or urea-forming reactions but alters the effective molar mass charged by up to 6.7%. In campaigns conducted in coastal manufacturing sites where uncontrolled indoor relative humidity exceeded 75%, Karl Fischer titration of powder stored in open containers for 4 h showed an increase from 0.18% to 0.94% water. This led to a 2.1% undercharge of the active intermediate in a cGMP amide coupling step, detected only after in-process HPLC revealed a residual acyl chloride peak deviating from the validated control range.
The recommended handling protocol requires pre-drying of the crystalline solid under vacuum (≤10 mbar) at 40–45°C for not less than 12 h immediately before use in anhydrous reactions. When process logistics preclude vacuum drying of the full batch, the material should be dispensed in a nitrogen-purged glovebox with a dew point of ≤ –40°C. Compatible desiccants for storage containers include molecular sieve 4A, but not silica gel, as trace silanol-mediated degradation has been observed at headspace temperatures above 30°C during extended warehousing in tropical climates. Conditioning with phosphorous pentoxide is categorically prohibited due to the risk of localized exotherms and charring at the powder-desiccant interface.
An additional stability concern is the slow formation of the corresponding disulfide via aerobic oxidation of the trifluoromethylsulfanyl group to the sulfinyl (—S(O)CF₃) and sulfonyl (—SO₂CF₃) derivatives at elevated temperatures. Accelerated stability testing per ICH Q1A guidelines (storage at 40°C/75% RH in open petri dishes) demonstrated 1.8% sulfoxide formation over 6 months as quantified by HPLC-ESI-MS. At 25°C/60% RH in double polyethylene bags within a high-density polyethylene drum, the same degradant remained below the 0.3% reporting threshold for 24 months. These data support a retest date of 24 months from the date of manufacture when stored in the original unopened packaging at 2–8°C.
Substitution of the 6-trifluoromethylsulfanyl group with a 6-methylthio (—SCH₃) moiety in 2-amino-6-(methylthio)benzothiazole (CAS 7783-45-9) results in a marked shift in both lipophilicity and metabolic stability when these building blocks are incorporated into kinase inhibitor scaffolds. The experimentally determined log D₇.₄ (octanol/water, shake-flask method per OECD 107) for the —SCF₃ analog is 2.9, compared to 1.6 for the —SCH₃ variant. This increase of over one log unit translates into a measurable difference in passive membrane permeability in Caco-2 monolayers, where the apparent permeability (Papp) A→B at 10 µM donor concentration rises from 8.2 × 10⁻⁶ cm·s⁻¹ to 14.1 × 10⁻⁶ cm·s⁻¹. For medicinal chemistry programs targeting central nervous system indications, this property must be balanced against the elevated risk of P-glycoprotein-mediated efflux, as the trifluoromethylsulfanyl group is recognized by the transporter ATP-binding pocket.
Relative to the 5-trifluoromethylsulfanyl positional isomer (CAS 1208079-38-0), the 6-substituted derivative exhibits superior regioselectivity in electrophilic aromatic substitution. Nitration with HNO₃/H₂SO₄ at 0–5°C preferentially occurs at the 4-position with a 9:1 regiomeric ratio for the 6-SCF₃ compound, while the 5-isomer gives a 1:1.2 mixture of 4- and 6-substituted products. This electronic directionality originates from the meta-orienting effect of the thiazole nitrogen in conjunction with the strong —I effect of the —SCF₃ group at the 6-position, which deactivates the 5- and 7-positions toward electrophilic attack. In large-scale nitration (>10 kg), the higher regioselectivity reduces the burden of fractional crystallization required to achieve >99% isomer purity, directly lowering solvent consumption by an estimated 40% per kilogram of isolated product.
| Derivative | Buchwald-Hartwig amination conversion(a) | Sandmeyer bromination yield(b) | Acetylation half-life(c) |
|---|---|---|---|
| 6-SCF₃ (title compound) | 72% (24 h) | 61% | 42 min |
| 6-SCH₃ | 91% (18 h) | 78% | 28 min |
| 6-CF₃ | 58% (30 h) | 45% | 115 min |
| 6-Cl | 88% (16 h) | 82% | 35 min |
| 6-H (unsubstituted) | 95% (14 h) | 86% | 20 min |
(a) Reaction with morpholine (1.2 eq.), Pd₂(dba)₃ (1.5 mol%), BrettPhos (3 mol%), NaOtBu (1.4 eq.), dioxane, 100°C; conversion by HPLC. (b) tBuONO (1.3 eq.), CuBr₂ (1.1 eq.), MeCN, 0°C→rt; isolated yield after column chromatography. (c) AcCl (1.5 eq.), Et₃N (2.0 eq.), THF, 0°C; time to reach 50% consumption of starting amine by TLC.
The acetyl-protected variant, 2-acetamido-6-(trifluoromethylsulfanyl)benzothiazole, is sometimes preferred when the free amine interferes with organometallic reagent compatibility. Direct comparison of the unprotected title compound with its acetylated form in iron-catalyzed Kumada coupling with 4-tolylmagnesium bromide revealed that the acetyl group must be cleaved prior to coupling to avoid catalyst poisoning by the amidic carbonyl; in situ deprotection with K₂CO₃ in methanol at 50°C restored catalytic activity to the same level as the parent amine, but introduced an additional 3 h to the process cycle time. This operational trade-off favors direct use of 2-amino-6-(trifluoromethylsulfanyl)benzothiazole when the synthetic sequence can tolerate a nucleophilic amine in subsequent steps, as in one-pot reductive amination sequences where the amine is consumed by a ketone or aldehyde partner without isolation.
For users transitioning from 2-amino-6-chlorobenzothiazole in existing process chemistry, the —SCF₃ moiety introduces a substantially different thermal and solvolytic profile that must be accounted for in work-up unit operations. The title compound partitions preferentially into ethyl acetate over water (distribution coefficient 8.5 at pH 7) versus a value of 3.2 for the 6-chloro analog, necessitating a reduction in the organic-to-aqueous phase ratio during liquid-liquid extraction from 1:1 to 1:3 to avoid product loss to the aqueous layer via inefficient mass transfer. Conversely, precipitation from dichloromethane/n-heptane mixtures requires a higher antisolvent fraction (≥70% v/v n-heptane) to achieve the same recovery as the chloro derivative, owing to the enhanced solubility imparted by the trifluoromethylsulfanyl group in chlorinated solvents. Pilot-plant trials in a 200 L Hastelloy C-22 vessel confirmed that cooling the crystallization slurry to –10°C with a linear cooling rate of 0.3°C·min⁻¹ yields an acceptable filtration performance on a 0.5 m² agitated Nutsche filter, with specific cake resistance α ≈ 4.2 × 10¹⁰ m·kg⁻¹ at a pressure differential of 0.5 bar.
