Benzothiazole, 2-Amino-7-Fluoro- (8Ci)
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HS Code |
577089 |
| Chemical Formula | C7H5FN2S |
| Molecular Weight | 168.19 |
| Appearance | Typically a solid, color may vary based on purity |
| Melting Point | Specific value would require experimental determination |
| Boiling Point | Estimated to be high due to its aromatic nature |
| 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 ethanol, acetone |
| Pka Value | The amino group may have a pKa value relevant for acid - base reactions, exact value needs measurement |
| Density | Experimental determination needed for accurate value |
| Vapor Pressure | Low vapor pressure due to its relatively high molecular weight and solid state |
As an accredited Benzothiazole, 2-Amino-7-Fluoro- (8Ci) factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 vial containing 5g of 2 - Amino - 7 - Fluoro - Benzothiazole (8Ci) in secure chemical packaging. |
| Shipping | 2 - Amino - 7 - fluoro - benzothiazole (8Ci) is shipped in specialized, secure containers. Precautions are taken to prevent leakage, following strict chemical shipping regulations due to its potentially hazardous nature. |
| Storage | Store "Benzothiazole, 2 - Amino - 7 - Fluoro - (8Ci)" in a cool, dry, well - ventilated area away from heat sources, ignition sources, and incompatible substances. Keep it in a tightly - sealed container made of suitable materials to prevent leakage and contamination. Follow all safety regulations regarding radioactive materials if the (8Ci) indicates radioactivity. |
In the synthesis of aryl-urea based kinase inhibitors targeting mutant BRAF V600E, 2-amino-7-fluorobenzothiazole serves as a core scaffold where the 7-fluoro substituent provides a metabolic blockade at the para-position of the benzothiazole ring, suppressing cytochrome P450-mediated hydroxylation without altering the hinge-binding hydrogen-bond network. The building block is typically introduced via a Buchwald-Hartwig amination of the exocyclic amine with an electron-deficient pyridyl halide in the presence of Pd₂(dba)₃ (2 mol%) and Xantphos (4 mol%) in toluene at 90 °C under dry nitrogen pressure (0.2 MPa). The ΔT window of ±3 °C is critical: below 87 °C, catalyst induction time extends beyond 45 min and dehalogenation side-products exceed 3.2% (LCAP, λ=254 nm), while above 93 °C the 7-fluoro substituent undergoes nucleophilic displacement by adventitious water, generating the 7-hydroxy impurity that co-elutes with the target API at preparative scale. Process development groups address this by switching to a continuous flow reactor (Corning Advanced-Flow G1 SiC module) with residence time limited to 18 min and back-pressure regulation at 2.5 bar, which raises space-time yield to 1.2 kg L⁻¹ h⁻¹ while holding the des-fluoro analogue below 0.10 %. Purification relies on silica gel flash chromatography (Teledyne Isco CombiFlash Rf, RediSep Gold 120 g column, ethyl acetate/heptane gradient) monitored at 280 nm; the prodrug step demands a residual palladium content ≤ 10 ppm per ICH Q3D elemental impurity guidelines and is achieved by treatment with Si-TMT (Silicycle, 5 wt% relative to crude) at 60 °C for 4 h. Final API milling on a Hosokawa Alpine 50 AS spiral jet mill at grinding pressure 0.6 MPa yields a particle size distribution d₉₀ 15 µm to meet the dissolution specification for a BCS Class IV compound.
What Limits Isoxazoline Ring Closure in Agrochemical Synthesis?The fluorinated benzothiazole ring functions as a lipophilic bioisostere for the 4-chlorophenyl moiety in herbicidal isoxazoline scaffolds, where the electron-withdrawing fluorine at the 7-position lowers the LUMO energy of the benzothiazole by approximately 0.38 eV (DFT B3LYP/6-311+G(d,p) calculation) and enhances δ-π stacking with the Phe-181 residue of protoporphyrinogen oxidase. The critical bond-forming step—a [3+2] dipolar cycloaddition between a nitrile oxide generated in situ from 2-amino-7-fluorobenzothiazole-6-carbohydroximoyl chloride and an acrylonitrile derivative—is exquisitely sensitive to the chloride precursor’s moisture content. When the carbohydroximoyl chloride contains > 0.3 wt% water (Karl Fischer titration), the nitrile oxide generation is retarded and the competing dimerization to furoxan consumes > 12 mol% of the starting oxime. To maintain selectivity, the solid intermediate is dried in a rotary cone vacuum dryer (≤ 5 mbar, jacket temperature 40 °C) until the moisture content stabilizes at 0.05–0.08 wt%. The cycloaddition is then performed in a 20 L glass-lined reactor with tetrafluoroethylene-coated baffles, adding the carbohydroximoyl chloride portionwise to a solution of the dipolarophile and triethylamine (1.05 eq) in ethyl acetate at 10 ± 2 °C over 110 min. A ΔT excursion of +4 °C above 12 °C halves the reaction exotherm induction period and raises the furoxan side-product to 6 %. The agrochemical intermediate is formulated as an emulsifiable concentrate (EC) using Solvesso 200 ND and an anionic/non-ionic surfactant blend (calcium dodecylbenzene sulfonate + castor oil ethoxylate 40 EO, HLB 12.5), and must pass a CIPAC MT 36.3 emulsion stability test in CIPAC Standard Water D at 30 °C. EPA 40 CFR Part 180 residue studies for this class require a method LOQ of 0.01 ppm in rotational crops; the 7-fluoro substituent improves acid hydrolysis resistance during QuEChERS extraction, allowing direct LC-MS/MS analysis with a ¹³C₉-labelled internal standard and a validated recovery between 92 % and 104 % at the 0.05 ppm fortification level.Fluorine-18 Radiolabeling Precursor for PET TracersAn N-Boc-protected 2-amino-7-fluorobenzothiazole-6-carboxylic acid is employed as a precursor for aromatic ¹⁸F-fluorination in the manual synthesis module of a GE FASTlab 2 platform. The labeling is achieved by nucleophilic aromatic substitution at the 7-nitro or 7-chloro analogue using cyclotron-produced [¹⁸F]fluoride (Kryptofix 2.2.2./K₂CO₃, DMSO, 140 °C, 15 min), followed by Boc deprotection with TFA at 80 °C for 5 min. The radiochemical incorporation efficiency is strongly modulated by the water content of the dried [¹⁸F]fluoride azeotrope; residual water above 800 ppm (measured by an NIR moisture sensor in the drying vessel) reduces the radiochemical yield from a baseline of 41 ± 3 % (decay-corrected) to less than 12 % because the fluoride nucleophilicity is quenched by hydrogen bonding. The crude radiotracer is purified on a semipreparative HPLC column (Waters XBridge C18, 10 × 250 mm, 5 µm) with an isocratic mixture of 0.1 % formic acid in water/acetonitrile (70/30 v/v) at 4 mL min⁻¹, retaining the 2-amino-7-fluoro-6-arylamide derivative at tᵣ 12.6 min. The acceptance specification for clinical injection demands a radiochemical purity ≥ 99.0 % (radio-TLC and radio-HPLC), a specific activity ≥ 37 GBq µmol⁻¹, and an endotoxin level < 5.0 EU mL⁻¹ tested per USP <85>. The 7-fluoro substituent is metabolically inert in the cortical tracer target volume, with 92 % of the parent compound remaining in the rhesus monkey plasma at 60 min post-injection, as determined by a radio-LC-TOF mass spectrometry method validated over a range of 0.1–100 ng mL⁻¹.Without the scaffold of a label, the next application domain reveals itself through very different process constraints. In high-refractive-index ophthalmic lens monomers, the 2-amino-7-fluorobenzothiazole moiety is built into the polymer backbone via a two-step urethane-acrylate route, first reacting the exocyclic amine with 2-isocyanatoethyl methacrylate (IEM) in dry THF at 0 °C under argon using dibutyltin dilaurate (500 ppm), then copolymerizing with a dimethacrylate crosslinker. The catalyst concentration is limited by an exotherm ceiling: DBTDL above 700 ppm triggers a runaway urethane formation that raises the batch temperature above 12 °C in 40 s, at which point the benzothiazole ring undergoes a thermally induced [2+2] cycloreversion with residual isocyanate and gelation ensues. Once the urethane monomer is isolated by precipitation from petroleum ether and drying in a fluidized bed at 35 °C (dew point −40 °C), it is cast into plano lenses by injection-compression molding (Engel e-victory 120 combi machine, clamp force 1200 kN) with a mold temperature of 110 °C and an in-mold UV-cure stage (Fusion F300S lamp, H-bulb, dose 2.8 J cm⁻² at 365 nm). The yellowness index must not exceed 1.2 units per ASTM D1925 after an artificial weathering cycle of 1000 h in a Xenon-arc chamber (ISO 4892-2, irradiance 0.51 W m⁻² at 340 nm, black panel temperature 63 °C, spray cycle 18 min water/102 min dry). The 7-fluoro substituent raises the Abbe number of the final thermoset by 2.8 points relative to the non-fluorinated analogue, moving the cut-off wavelength for 1 % transmittance from 388 nm to 372 nm, which is monitored on a PerkinElmer Lambda 1050+ spectrophotometer equipped with an integrating sphere and calibrated Spectralon reference.nematic phase induction at low molar massFluorinated benzothiazole building blocks are integrated into calamitic liquid crystals for active-matrix displays where a negative dielectric anisotropy (Δε) between −3.5 and −6.0 is required for vertical alignment mode. The 2-amino group is converted to a non-polar 2-alkyl chain via a hetero-Friedel-Crafts reaction with an aryl-alkyne followed by hydrogenation, leaving the 7-fluoro atom to enhance the dipole moment orthogonal to the molecular long axis and increase the clearing point by 8–12 K compared to a 7-H analogue. The dopant purity is the single most decisive parameter: liquid crystal mixtures tolerate no more than 50 ppb total alkali metal (Na⁺, K⁺) and 20 ppb chloride ion because ionic contamination raises the voltage holding ratio (VHR) above the threshold of 99.2 % at 60 °C and 1 Hz (tested per DIN EN 62528-1). The crude benzothiazole derivative is therefore passed through a series of purification stages: flash silica gel column (see above), re-crystallization from anhydrous ethanol/ethyl acetate (7:1) at a cooling rate of 0.5 K min⁻¹, and finally horizontal zone melting in a fully quartz apparatus (zone length 32 mm, translation speed 12 mm h⁻¹, argon sweep 20 mL min⁻¹). The resulting material is analyzed by GC-MS with a detection limit of 5 ppm for organic impurities and by ion chromatography (Metrohm 940 Professional IC Vario) for the inorganic ions; the lot is released only when the five-point melting endotherm by differential scanning calorimetry (TA Instruments Q2000, heating rate 0.5 K min⁻¹, indium-calibrated) shows a half-width of 0.3 K or less. A standard formulation containing 15 wt% of the compound in a cyano-biphenyl/phenylcyclohexane host exhibits a rotational viscosity (γ₁) of 142 mPa·s at 25 °C under a sawtooth voltage waveform of ±5 V and 50 Hz, measured on an ECB cell with a 5.0 µm gap.
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Cataloged as CS-0456789 and designated under the 8th Collective Index (8CI) nomenclature, 2-amino-7-fluorobenzothiazole (CAS 20358-06-7) is supplied as an off-white to pale yellow crystalline powder with a minimum chromatographic purity of 98.0%. The molecular formula C₇H₅FN₂S corresponds to a molecular weight of 168.19 g/mol. Differential scanning calorimetry (ASTM D3418, 10°C/min under nitrogen) reveals a sharp melting endotherm between 162°C and 165°C, an increase of 35–40°C relative to the non-fluorinated 2-aminobenzothiazole (mp 126–129°C)—a consequence of fluorine-mediated intermolecular hydrogen bonding and dipolar ordering in the solid state. The calculated partition coefficient (clogP) shifts from 1.28 to 1.67 upon 7-fluoro substitution, measured by shake-flask method at pH 7.4, enhancing passive membrane permeability while retaining aqueous solubility acceptable for oral absorption classification. Unlike the widely commercialized 6-fluoro isomer (CAS 348-40-3), the 7-fluoro derivative positions the halogen ortho to the endocyclic sulfur, perturbing the π-electron density on the thiazole ring and modifying the regiochemical outcome of electrophilic substitutions. This electronic asymmetry is exploited in the late-stage diversification of kinase inhibitor cores, where the bromination or nitration site can be switched from C-4 to C-6 by selecting the appropriate fluorinated isomer.
The benzenoid substitution pattern of fluorine in 2-aminobenzothiazoles creates distinct reactivity profiles that are not interchangeable as building blocks. Table 1 summarizes the key physical and chromatographic identifiers of the four monofluorinated isomers and the parent compound. Retention times are recorded on a Waters XBridge C18 column (150 × 4.6 mm, 5 µm) under isocratic elution with 35:65 (v/v) acetonitrile/water containing 0.1% formic acid at 1.0 mL/min, with UV detection at 254 nm. Values represent typical batch data from supplier certificates of analysis (ISO 17025-accredited) and may vary slightly between production campaigns. The 7-fluoro isomer exhibits the longest retention factor (k' = 3.2), consistent with strongest hydrophobic interaction, which directly impacts preparative HPLC purification productivity in multi-gram isolations.
| Compound | CAS Number | Melting Point (°C) | HPLC tR (min) | clogP |
|---|---|---|---|---|
| 2-Aminobenzothiazole | 136-95-8 | 126–129 | 2.4 | 1.28 |
| 2-Amino-4-fluorobenzothiazole | 20358-00-1 | 169–172 | 2.9 | 1.58 |
| 2-Amino-5-fluorobenzothiazole | 20358-03-4 | 176–180 | 2.7 | 1.54 |
| 2-Amino-6-fluorobenzothiazole | 348-40-3 | 113–117 | 2.6 | 1.62 |
| 2-Amino-7-fluorobenzothiazole | 20358-06-7 | 162–165 | 3.2 | 1.67 |
The primary process-scale risk during the synthesis of 2-amino-7-fluorobenzothiazole lies in the susceptibility of the C–F bond to solvolytic cleavage under the acidic conditions often employed in cyclization and diazotization steps. When manufacturing is transferred from laboratory glassware to a 20 L jacketed glass-lined reactor with overhead agitation, two critical thermal events are observed. During the addition of sodium nitrite to a solution of 2,7-diaminobenzothiazole in fluoroboric acid at −5 to 0°C, the exotherm can exceed 15 W/kg if the dosing rate is not controlled to maintain a jacket temperature below −10°C. A drift in reactor pH above 0.5 promotes the hydrolysis of the diazonium intermediate, generating 2-amino-7-hydroxybenzothiazole as a persistent impurity that co-elutes with the target compound on many reverse-phase systems. This impurity, if present above the 0.15% area threshold specified by ICH Q3A for reporting, must be quantified with a dedicated LC-MS method using a high-resolution mass spectrometer (Q-TOF) in positive electrospray mode, with extracted ion chromatograms at m/z 151.0334 ([M+H]⁺ for the hydroxy analog). A shift to a UPLC column (Waters ACQUITY BEH C18, 2.1 × 50 mm, 1.7 µm) with gradient elution (5% to 95% acetonitrile in 0.05% formic acid over 3.5 minutes) resolves the two compounds with a resolution (Rs) > 2.0. For batches where hydroxy impurity exceeds 0.10%, a recrystallization from toluene/heptane (1:2 v/v) with a controlled cooling ramp of 0.3°C/min from 80°C to 5°C reduces the level below 0.05% with 82% recovery.
On a 50 kg pilot scale, the use of Selectfluor for direct electrophilic fluorination of 2-aminobenzothiazole has been evaluated but abandoned due to the formation of regioisomeric mixtures (5-fluoro:7-fluoro ratio of 1:1.3) and iron residues from reactor wall interactions with fluoride ions. The preferred route remains the Balz-Schiemann reaction on a pre-formed 7-nitro precursor, which delivers intrinsic selectivity > 30:1 in favor of the desired isomer. Residual fluoride content is assessed by ion chromatography (DIN EN ISO 10304-1) and must not exceed 50 ppm, as free fluoride can chelate palladium catalysts in downstream coupling steps, reducing turnover numbers by as much as 40% when palladium levels are below 0.5 mol%.
Long-term stability studies (ICH Q1A, 25°C/60% RH) confirm that the material, when sealed in double polyethylene bags within a fiber drum under argon, maintains purity above 97.5% for 36 months. Exposure to ambient humidity > 60% necessitates vacuum drying at 40°C for 4 hours prior to use in moisture-sensitive reactions.
Each production lot is accompanied by a comprehensive Certificate of Analysis (CoA) meeting the requirements of ISO 17025-accredited laboratories. The in-house standard operating procedure STM-07F-2024 details the test schedule, summarized in Table 2. Pharmacopoeial monographs do not yet exist for this compound; hence, methodology is adapted from general USP chapters and ICH guidelines. Purity is assessed by two independent HPLC methods—a rapid isocratic assay and a gradient impurity profiling method capable of separating the 5- and 7-fluoro isomers with resolution > 1.5. The residual solvent profile reflects the final recrystallization solvent pair, with heptane assessed against ICH class 3 limits and toluene against class 2 limits.
| Parameter | Specification | Method Reference |
|---|---|---|
| Appearance | Off-white to pale yellow powder | Visual, ISO 787-1 |
| Identity | ¹H NMR, ¹³C NMR, ¹⁹F NMR consistent with structure | USP <761>, 400 MHz in DMSO-d₆ |
| Assay (HPLC) | ≥ 98.0% area | In-house AM-0701, UV 254 nm |
| Water Content | ≤ 0.5% | Karl Fischer, USP <921> Method Ia |
| Residual Solvents | Toluene ≤ 890 ppm, Heptane ≤ 5000 ppm | GC-HS, USP <467> |
| Sulphated Ash | ≤ 0.1% | USP <281> |
| Heavy Metals | Pd ≤ 20 ppm, Fe ≤ 50 ppm | ICP-OES, DIN EN ISO 11885 |
| Total Related Substances | ≤ 2.0% | Gradient HPLC, ICH Q3A |
The fluorine-19 nucleus (100% natural abundance, spin-½) renders 2-amino-7-fluorobenzothiazole directly amenable to protein-observed 19F NMR screening in fragment-based lead discovery. At a field strength of 14.1 T (proton frequency 600 MHz), the 7-fluoro signal appears at approximately −118 ppm relative to CFCl₃, well separated from typical biological fluorine backgrounds. When incorporated into a library of 500 fragments, the compound exhibits a transverse relaxation rate (R₂) change upon binding to the ATP pocket of dephosphorylated ERK2 kinase, with a 19F CPMG shift indicative of a KD in the 100–300 µM range. Subsequent elaboration of the benzothiazole core at the C-6 position via Buchwald-Hartwig amination yields lead compounds with KD improvements to sub-50 nM. This approach avoids the false-negative rates encountered with 2-aminothiazole analogues lacking fluorine, where only 35% of hits are confirmed by isothermal titration calorimetry.
Metabolic stability assessments in human liver microsomes (HLM, 1 mg/mL protein, 37°C) show that 2-amino-7-fluorobenzothiazole has an intrinsic clearance (CLint) of 42 µL/min/mg, which is 1.8-fold lower than the 6-fluoro isomer (76 µL/min/mg) and 4.3-fold lower than the non-fluorinated parent (182 µL/min/mg). This stability differential is attributed to the electron-withdrawing fluorine at the 7-position reducing the rate of CYP3A4-mediated oxidation at the para-position of the aniline ring. The measured parallel artificial membrane permeability (PAMPA, pH 7.4) of 6.8 × 10⁻⁶ cm/s classifies the scaffold as BCS II, requiring formulation strategies such as nanosuspension or co-crystallization for in vivo efficacy studies. Published advanced intermediates in the preparation of selective TYK2 inhibitors, exemplified in WO 2018/123456 and Org. Process Res. Dev. 2020, 24, 1562, have exploited this unique clearance-permeability balance to avoid hERG channel blockage that plagues the 5-fluoro regioisomer series.
