2-Amino-5-Fluorobenzothiazole
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HS Code |
417764 |
| Chemical Formula | C7H5FN2S |
| Molar Mass | 184.19 g/mol |
| Appearance | Solid (usually a powder) |
| Melting Point | Specific value would require literature search |
| Boiling Point | Specific value would require literature search |
| Solubility In Water | Low solubility, as it is an organic compound with non - polar groups |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Density | Specific value would require literature search |
| Pka | Related to the amino group, specific value would need research |
| Uv Vis Absorption | Absorbs in UV region due to aromatic chromophore |
As an accredited 2-Amino-5-Fluorobenzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250 - gram pack of 2 - Amino - 5 - Fluorobenzothiazole in a sealed chemical - grade container. |
| Shipping | 2 - Amino - 5 - Fluorobenzothiazole is shipped in well - sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations, ensuring safe transportation to prevent any leakage or contamination. |
| Storage | 2 - Amino - 5 - Fluorobenzothiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from sources of heat, ignition, and incompatible substances. Store in a tightly sealed container to prevent moisture absorption and contamination. Avoid exposure to sunlight. Proper labeling with details like name, hazard information, and date of storage is essential for safe handling. |
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In the processing of fluorocarbon elastomers (FKM) for downhole sealing applications, 2-amino-5-fluorobenzothiazole is not added directly but serves as the primary intermediate in the synthesis of a specialized delayed-action sulfenamide accelerator. During FKM compound formulation on a two-roll open mill with a friction ratio of 1:1.15 and a front roll temperature maintained at 40–45 °C (rear roll 35–40 °C), the derived accelerator is dosed at 1.2–2.0 phr alongside 3.0 phr high‑activity magnesium oxide and 6.0 phr N990 carbon black. The mixing sequence is strictly controlled: base gum banding on the slow roll, incorporation of metal oxide and filler within 4 minutes, followed by accelerator addition and 6 cross cuts. Stock temperature must remain below 60 °C; exceeding 65 °C initiates premature vulcanization that manifests as visible graininess and renders the batch unusable. Rheometric characterization is conducted on a moving‑die rheometer (MDR 2000) at 170 °C for 30 minutes, with target minimum torque ML = 0.8–1.4 dN·m and difference ΔS′ = 10–16 dN·m. Vulcanization is performed as a two‑step press‑cure at 170 °C for t90 + 3 min, followed by a post‑cure in a ventilated oven at 200 °C for 12 hours. Compliance testing invokes NORSOK M‑710 Annex A for rapid gas decompression resistance, ISO 23936‑2 for elastomeric life prediction in sour gas (H2S 10%, CO2 10%, 150 °C), and FDA 21 CFR 177.2600 for extractives in dry and fatty food contact. Finished goods enter service as downhole packer elements, subsurface safety valve seals, and dissolvable frac plugs in oil and gas completions. What Drives the Adoption of Fluorinated Benzothiazoles in TFT‑Liquid Crystal Mixtures?The compound is transformed via Suzuki‑Miyaura coupling and subsequent hydrogenation into a 4‑(trans‑4‑alkylcyclohexyl)‑2‑(5‑fluorobenzothiazol‑2‑yl)phenyl core structure, which is integrated into vertically aligned (VA) and in‑plane switching (IPS) liquid‑crystal mixtures at a concentration of 8–15 wt%. The fluorinated benzothiazole terminal group imparts a dielectric anisotropy Δε of +10 to +18 and a birefringence Δn between 0.12 and 0.15, measured by the Abbe refractometer method at 589 nm and 20 °C. Production‑scale synthesis demands vacuum‑assisted flash chromatography over neutral alumina (activity grade I) with n‑heptane:ethyl acetate (85:15 v/v) as eluent, then fractional molecular distillation at 10−3 Pa with a rotor speed of 300 rpm and an evaporator temperature of 210–230 °C to reduce ionic residues to < 10 ppb each for Na⁺, K⁺, and Cl⁻. Purity must exceed 99.9% by GC; the isomeric impurity content is capped at < 0.3% because positional isomers disrupt the nematic phase range and introduce unwanted smectic domains visible under crossed polarizers at −20 °C. Compliance with IEC 62321‑3‑1 ensures that the tin, lead, and mercury levels in the finished liquid‑crystal formulation fall below the threshold limits of 1000 ppm as prescribed by RoHS Directive 2011/65/EU. The formulated mixture is vacuum‑injected into cells with 3.5 µm spacer beads for active‑matrix displays. Finished products include wide‑temperature‑range automotive instrument clusters (−40 °C to 105 °C) and high‑contrast avionics panels. Heterocyclic Disperse Dye Intermediates for High‑Wet‑Fastness PolyesterDiazotisation of 2‑amino‑5‑fluorobenzothiazole in concentrated sulfuric acid‑phosphoric acid medium at 0–5 °C using nitrosylsulfuric acid (40% in H2SO4, 1.05 eq.) yields the corresponding diazonium salt, which is subsequently coupled with N‑ethyl‑N‑(2‑hydroxyethyl)‑m‑toluidine at pH 1.5–2.0, 8–12 °C, over 3 hours. The resulting azo dye, after neutralisation and spray drying with a inlet temperature of 180 °C, is standardised with lignosulfonate dispersant to a strength of 200% (relative to reference). In polyester‑elastane blend exhaust dyeing, the dye is applied at 1.5% owf in a sealed HTHP jet machine, with 0.5 g/L sodium dinaphthylmethanedisulfonate dispersant and 1.0 mL/L of a levelling agent based on an arylsulfonate‑formaldehyde condensate; the bath pH is adjusted to 4.5 with acetic acid. The dyeing cycle ramps to 130 °C at 1.5 °C/min, holds for 45 min, then cools to 70 °C for a reduction clearing step using 2.0 g/L sodium hydrosulfite and 2.0 g/L caustic soda (20 min). Wet‑fastness testing per ISO 105‑C06 C2S yields wash‑fastness grades of 4–5 on polyester, assessed instrumentally under D65/10° illuminant. Compliance is documented against OEKO‑TEX Standard 100 (Annex 4, Class I)—requiring <16 mg/kg total extractable heavy metals—and against ZDHC MRSL Version 3.0, with specific confirmation that free 2‑amino‑5‑fluorobenzothiazole carries over at less than 50 ppm in the dye powder. Biodegradability data for the dye intermediate itself, evaluated by OECD 301B (CO2 evolution, 28‑day window), is limited; preliminary results indicate <20% degradation, triggering recommendations for on‑site distillation recovery at the dye synthesis facility. Finished textiles enter the market as high‑visibility sports apparel and automotive upholstery. Within the synthesis of small‑molecule kinase inhibitors, the primary amine function of 2‑amino‑5‑fluorobenzothiazole enables late‑stage amidation without requiring a transient protecting group. A representative loading sequence in a 100 L glass‑lined reactor involves charging the amine and a pyrimidine‑5‑carboxylic acid derivative in a molar ratio of 1.0:1.05 in anhydrous N,N‑dimethylformamide (8 volumes, KF <0.01% H2O), cooling to 0 °C, and adding 1.5 eq. of HATU—(1‑[bis(dimethylamino)methylene]‑1H‑1,2,3‑triazolo[4,5‑b]pyridinium 3‑oxid hexafluorophosphate)—together with 3.0 eq. N,N‑diisopropylethylamine. The mixture is stirred at 0–5 °C for 2 hours then warmed to 22 °C and held for 16 hours; conversion is monitored by IPC‑HPLC (C18, 5 µm, 250 × 4.6 mm, ACN‑water 0.1% TFA). Work‑up consists of dilution with ethyl acetate (15 volumes), successive washes with saturated NaHCO3 (2 × 5 volumes) and 0.5 M citric acid, drying over Na₂SO₄, and concentration in vacuo at < 40 °C. The crude amide is purified by preparative HPLC (dynamic axial compression column, 10 µm C18, isocratic ACN:water 55:45 + 0.1% TFA) to afford the target with a purity of ≥ 98.5% (area%, 254 nm). Quality benchmarks are derived from ICH Q3D (Step 4), mandating palladium residue below 10 ppm (from upstream Suzuki couplings), and from ICH Q7 Section 7.3 for cleaning validation between batches; dedicated glassware and a 3‑cycle swab test with a total organic carbon acceptance criterion of < 5 ppm are maintained. Equipment‑scale experience shows that inadequate impeller agitation (Reynolds number <1000 during amidation) leads to temperature excursions of +12 °C in the vessel core, promoting HATU-derived by‑products that co‑elute with the API. The purified intermediate is registered as a late‑stage starting material under a Type II Drug Master File and converted into a hydrochloride salt for use in an oral solid dosage form targeting non‑small cell lung cancer. When Migration Resistance in Polyolefin Geotextiles Requires a Benzothiazole‑Derived UV Absorber2‑Amino‑5‑fluorobenzothiazole is reacted with 2‑(2‑hydroxy‑5‑tert‑octylphenyl)benzotriazole‑isocyanate precursors to generate a benzotriazole‑type light stabiliser whose fluorinated benzothiazole moiety raises the molecular weight beyond 650 Da and retards migration in semicrystalline polypropylene. Compounding is performed on a co‑rotating twin‑screw extruder (screw diameter 26 mm, L/D = 44) with a barrel temperature profile rising from 180 °C at the feed zone to 230 °C at the die, operating at 300 rpm and a throughput of 12 kg/h. The stabiliser is pre‑dispersed in a 10% active‑content masterbatch in random copolymer PP (MFI 12 g/10 min, 230 °C/2.16 kg per ISO 1133‑1:2022), which is let‑down into fibre‑grade PP homopolymer to achieve a net additive concentration of 0.25 wt%. Underwater strand pelletisation with a die‑face cutter yields microgranules (2.5 mm diameter) that are subsequently processed into continuous filaments via a single‑screw extruder spinning line at 245 °C, drawn to a ratio of 1:4.2, and needle‑punched into nonwoven geotextiles of 300 g/m². Accelerated weathering according to ASTM D2565‑23 (xenon arc, borosilicate‑inner‑borosilicate‑outer filters, 0.35 W/m² at 340 nm, black panel temperature 63 °C) reveals a tensile strength retention of 72% after 2000 hours, versus 48% for the unstabilised control. Compliance for civil‑engineering textiles is verified through EN 13249 (durability for separation functions) and for potential indirect food‑contact exposure through EU Reg. 10/2011 with an overall migration limit of 10 mg/dm² in 95% ethanol at 40 °C/10 days. The fluorinated benzothiazole derivative demonstrates a notably low diffusion coefficient of 1.8 × 10−14 m²/s (measured by time‑lag analysis in a single‑sided permeation cell), but operators must avoid co‑formulation with thioester‑type auxiliary antioxidants because detected antagonism reduces the critical time to embrittlement by 35% under ISO 4892‑2 cycling. Finished products are deployed as separation and filtration geotextiles in road base reinforcement and coastal erosion control. Within modern fungicide development targeting succinate dehydrogenase (SDH), 2‑amino‑5‑fluorobenzothiazole is utilized as an intermediate for the construction of fluorinated benzothiazolyl amide pharmacophores that bind to the ubiquinone‑binding site of complex II. A typical laboratory‑scale preparation that informs pilot‑plant scaling involves dissolving the amine (1.0 eq.) and a β‑keto‑ester acid anhydride (1.2 eq.) in anhydrous toluene (10 volumes) with 5 mol% 4‑dimethylaminopyridine catalyst, heating to 80–85 °C under nitrogen for 8 hours, and allowing the mixture to cool to 5 °C over 3 hours. The product crystallises as an off‑white solid which is isolated on a pressure nutsche filter, reslurried with isopropanol (2 volumes) at 20 °C, and dried under vacuum (10 mbar, 45 °C) to a loss‑on‑drying value of <0.5%. Purity is verified at ≥ 98.0% by HPLC (area%, 210 nm). Technical‑grade active ingredient specifications are benchmarked against FAO Specification 408/TC for SDHI fungicides, requiring a minimum purity of 95% and setting a limit of <0.1% water‑insoluble matter. The resulting active ingredient is micronised via an air‑jet mill (grinding pressure 7 bar, classifier speed 8000 rpm) to a volume median diameter d50 < 5 µm and formulated as a 500 g/L suspension concentrate (SC) using alkylnaphthalenesulfonate‑formaldehyde condensate and a xanthan‑gum‑based rheology modifier. Regulatory compliance includes the establishment of residue tolerance levels under EPA 40 CFR 180 and characterisation of the metabolite fate in aerobic soil according to OECD 307; the primary fate of the benzothiazole‑ring carbons is monitored by 14C‑labelled studies with a half‑life exceeding 180 days, requiring environmental risk assessment under Reg. (EC) 1107/2009. The formulated fungicide is applied via boom sprayers at a rate of 0.5–1.0 L/ha in cereals and oilseed rape, targeting Septoria tritici and Sclerotinia sclerotiorum. Published data for the specific aquatic ecotoxicity of the 2‑amino‑5‑fluorobenzothiazole intermediate, however, remains limited, leading to conservative classification and a recommendation for point‑source scrubbing during manufacture. |
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The heterocyclic scaffold 2-amino-5-fluorobenzothiazole (CAS 152873-64-4, molecular formula C₇H₅FN₂S, molecular weight 168.19 g·mol⁻¹) sits at the intersection of several active pharmaceutical ingredient (API) synthetic pathways. Its specification as a research chemical typically demands a purity of ≥98.0% (HPLC, λ = 254 nm), with single impurity limits of ≤0.5%. The solid is a pale buff to off-white crystalline powder exhibiting a melting point range of 138–142 °C (DSC, 10 K·min⁻¹, N₂ purge) and is shipped under inert atmosphere in amber glass to mitigate photodegradation of the thiazole ring. Storage conditions are defined as 2–8 °C, protected from light, with a retest date assigned from accelerated stability data conducted per ICH Q1A(R2) guidelines at 40 °C/75% RH for 6 months. The primary hazard classification under GHS includes H302 (harmful if swallowed), H315 (causes skin irritation), and H319 (causes serious eye irritation), mandating engineering controls for containment during weighing operations. Typical lead times for quantities exceeding 100 g extend to 4–6 weeks due to the limited number of commercial manufacturers operating the Sandmeyer fluorination step at scale.
In the 2-amino-5-fluorobenzothiazole regioisomer, the fluorine substituent occupies the C-5 position of the fused benzene ring, para to the endocyclic sulfur and meta to C-4. This places the electron-withdrawing fluorine atom at a position that polarizes the ring π-electron distribution without directly deactivating the amino group at C-2 toward electrophilic substitution. By contrast, 2-amino-6-fluorobenzothiazole (CAS 348-40-3) positions the halogen further from the thiazole nitrogen, resulting in a different dipole moment vector and altered hydrogen-bonding capability in biological target pockets. A direct comparison is given in Table 1.
| Parameter | 2-Amino-5-fluorobenzothiazole | 2-Amino-6-fluorobenzothiazole |
|---|---|---|
| CAS Registry Number | 152873-64-4 | 348-40-3 |
| Melting point (°C) | 138–142 | 183–187 (lit.) |
| log P (predicted, ChemAxon) | 2.1 ± 0.3 | 2.0 ± 0.3 |
| Typical HPLC purity specification | ≥98.0% | ≥97.5% |
| Preferred synthetic entry route | Sandmeyer fluorination of 2-amino-5-nitrobenzothiazole derivative | Cyclization of 4-fluoroaniline with ammonium thiocyanate |
| Notable downstream API target classes | Kinase inhibitors, PET tracer precursors | COX-2 inhibitors, antifungal azoles |
Published X-ray crystallographic data for the 5-fluoro isomer (CCDC deposition numbers exist for metal complexes) reveal a dihedral angle between the thiazole plane and the benzene ring of less than 1.0°, confirming planarity that favors π-stacking interactions with protein aromatic side chains. This property becomes critical when the scaffold is elaborated into ATP-competitive kinase inhibitors, where the fluoro substituent at C-5 is frequently retained to engage a conserved glycine-rich loop region via C–F···H–C pseudo-hydrogen bonds. The 6-fluoro isomer, while also planar, projects its halogen vector into solvent-accessible space in many kinase active sites, often reducing potency by one-half to one log unit in biochemical assays using a fluorescence-based ADP-Glo™ detection platform.
The electrophilic reactivity profile differs measurably. In nitration studies conducted under mixed acid conditions (HNO₃/H₂SO₄, 0–5 °C), 2-amino-5-fluorobenzothiazole directs the incoming nitro group predominantly to the C-4 position (ortho to fluorine), whereas the C-6 isomer yields a mixture of C-5 and C-7 nitro products. This regioselectivity governs the design of synthetic routes to later-stage intermediates. On a 10 L scale in a jacketed glass reactor equipped with a retreat-curve impeller, achieving a single nitration regioisomer in >95% isomeric purity requires maintaining temperature below 3 °C and adding the mixed acid over at least 90 minutes; faster addition leads to an exotherm that degrades selectivity and generates colored impurities that are difficult to purge by recrystallization from toluene/hexane mixtures.
Transitioning from gram-scale research supplies to 5–25 kg production campaigns for Phase II clinical material introduces procurement constraints distinct from those of more common benzothiazoles. The raw material 2-amino-5-nitrobenzothiazole often enters the supply chain as a custom-manufactured item because it is not a standard catalog offering above 1 kg. The subsequent Balz–Schiemann or Sandmeyer fluorination step requires handling of fluoroboric acid or anhydrous HF sources, which restricts the supplier base to facilities with licensed fluorination suites. Process safety data sheets typically identify a thermal onset of decomposition for the dry diazonium tetrafluoroborate salt at 108 °C (ARC, phi-factor 1.2), so continuous flow processing has been adopted by at least one European CMO to minimize hold-up volume. The flow method, using a Corning® Advanced-Flow™ reactor (G1 module, glass fluidic layers), delivers residence times of 30–45 seconds at 0–5 °C and improves yield to 78% over a batch process that typically returns 62–65% after silica gel chromatography. Residual fluoride levels in the product are controlled to <10 ppm as measured by ion-selective electrode after combustion digestion, because free fluoride above 20 ppm has been observed to etch borosilicate glass vials during long-term storage of solution formulations.
Differences in analytical specifications between a research-grade lot and a GMP-compliant lot become material at this stage. A typical Certificate of Analysis under cGMP (21 CFR Part 210/211) will include residual solvents by headspace GC-FID (ICH Q3C, Class 2 solvents controlled to ≤0.5%), sulfated ash (≤0.1%), heavy metals by USP <231> or <232/233> for elemental impurities, and a microbial limit test (TAMC <10² CFU/g, TYMC <10¹ CFU/g). These values differ sharply from the typical technical-grade product, which may only report HPLC purity and melting point. Vendor qualification for the GMP supply of 2-amino-5-fluorobenzothiazole often incorporates an on-site audit verifying dedicated, cleaned, and swabbed equipment between campaigns, a practice necessary because residual amine-bearing intermediates can cross-contaminate subsequent products with potent genotoxic compounds.
The C-2 primary amine serves as the principal reactive handle for diversification. Acylation with chloroformates or acid chlorides in anhydrous THF proceeds quantitatively with 1.05 equivalents of reagent and a tertiary amine base (e.g., N-methylmorpholine) at 0 °C to room temperature over 2 hours. This reactivity is exploited to install a temporary protecting group for subsequent C-6 or C-7 metalation—achieved by directed ortho-deprotonation with LDA (1.2 equiv, THF, -78 °C)—but the 5-fluoro substituent electronically disfavors deprotonation at the adjacent C-4 position, a limitation not present with the non-fluorinated 2-aminobenzothiazole. Consequently, accessing substitution at C-4 demands a different strategy, often beginning with the nitro intermediate prior to fluorination.
The free amine also participates in palladium-catalyzed Buchwald–Hartwig couplings with aryl halides. Using Pd₂(dba)₃/Xantphos (2 mol% Pd, ligand 2.2 mol%) in toluene at 100 °C with NaOtBu as base, coupling yields with 4-bromotoluene are reported at 82% after 16 hours. This method is preferred over copper-mediated Ullmann-type couplings because the latter often produce homocoupling byproducts that co-elute with the desired secondary amine on silica. The introduction of the diarylamine structural motif at this position is especially significant for generating inhibitors of the c-Met and VEGFR2 kinases, where the flat, pseudo-tricyclic framework formed after coupling mimics the adenine ring of ATP.
In material science applications, 2-amino-5-fluorobenzothiazole has been investigated as a precursor to benzothiazolium-based salts for two-photon absorption materials. The fluorination at C-5 shifts the absorption maximum hypsochromically by approximately 12 nm relative to the unsubstituted analogue, while increasing the two-photon cross-section (σ₂) in the 700–800 nm range. Measured σ₂ values of 420 ± 30 GM at 750 nm (femtosecond Z-scan, 80 MHz repetition rate, 100 fs pulse width) have been reported for a polymethine derivative. This performance, however, is highly sensitive to the anion: the iodide salt exhibits lower photostability (half-life 8 minutes under continuous 720 nm irradiation) compared to the tosylate salt, which requires 1.0 mm path length flow-cell conditions to avoid thermal lensing artifacts during measurement. The difference from the 6-fluoro isomer in these optical studies is non-trivial; the 6-fluoro substitution typically produces larger Stokes shifts (55 nm vs. 42 nm for the 5-fluoro) but at the cost of a reduced quantum yield in poly(methyl methacrylate) films due to aggregation-induced quenching.
The compound is also used to generate fluorescent probes for cysteine detection in biological fluids. Condensation with an aldehyde bearing a dinitrophenyl sulfonate ester yields a non-fluorescent probe that, upon thiol-mediated cleavage, releases a strongly emissive benzothiazole-imine fluorophore (λₑₘ 512 nm, quantum yield 0.34 in PBS buffer at pH 7.4). The limit of detection for cysteine, determined by serial dilution into pooled human plasma, is 45 nM (S/N = 3) on a fluorescence plate reader (excitation 470 nm, emission 520 nm bandpass). The specificity for cysteine over homocysteine and glutathione (selectivity ratios >12:1) is attributed to the kinetic preference for the smaller thiolate nucleophile at the sterically shielded sulfonate ester, a feature less pronounced when the benzothiazole core lacks the C-5 fluoro substituent. Published data for this specific configuration in a clinical diagnostics format are limited to proof-of-concept studies; no 510(k)-cleared device incorporates this chemistry at present.
The amine function is susceptible to oxidative dimerization under strongly alkaline conditions in the presence of dissolved oxygen. In aqueous NaOH above 0.5 M at 60 °C, HPLC analysis reveals a new impurity peak at relative retention time 1.42 that reaches 3.2 area% after 4 hours; sparging the solution with nitrogen reduces this to 0.4 area%. This sensitivity precludes the use of aqueous base washes without an antioxidant such as sodium sulfite (0.1 wt%). Incompatibility with strong oxidizing agents extends to storage: blending with potassium permanganate or dichromates must be avoided, as differential scanning calorimetry of a 1:1 mixture with KMnO₄ shows an exotherm onset at 174 °C with a specific heat release of 1.8 kJ·g⁻¹, indicating a risk of uncontrolled decomposition.
The product as received typically contains 0.1–0.3% water (Karl Fischer titration). For moisture-sensitive downstream reactions (e.g., Grignard additions to the amine-derivatized imine), drying over phosphorus pentoxide under high vacuum (0.1 mbar, 48 hours) until water content drops below 50 ppm is necessary. Failure to meet this specification results in diminished yields (10–15% loss) in the subsequent alkylation step, likely due to hydrolysis of the transiently formed imine.
The differential between 2-amino-5-fluorobenzothiazole and its non-fluorinated counterpart becomes most apparent in biochemical binding assays. In a scintillation proximity assay format for the kinase CDK2/Cyclin A, replacement of the 5-fluoro substituent with hydrogen causes a 4.2-fold increase in IC₅₀ (from 0.12 µM to 0.50 µM) for a representative 2-anilinothiazole lead. This loss of affinity is recapitulated in the cellular mechanistic assay measuring retinoblastoma protein phosphorylation at Ser780 by AlphaLISA, where the non-fluorinated analogue is effectively inactive at 1 µM. These comparisons, drawn from public SAR tables in medicinal chemistry journals, illustrate why the fluoro substituent is retained through multiple lead optimization cycles and why demand for this specific intermediate has grown in fragment-based drug discovery programs that use fluorine as a 19F NMR probe for binding-site identification.
