5-Fluoro-2-Methyl-1,3-Benzothiazole
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HS Code |
338377 |
| Chemical Formula | C9H6FN2S |
| Molecular Weight | 194.22 g/mol |
| Appearance | Solid (usually a white to off - white powder) |
| Melting Point | Typically in a certain temperature range (exact value needs more specific data) |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like dichloromethane, chloroform |
| Odor | Odorless or very faint odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
| Purity | Can be obtained in high purity grades (e.g., 95%+, depending on manufacturing process) |
As an accredited 5-Fluoro-2-Methyl-1,3-Benzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5 - Fluoro - 2 - Methyl - 1,3 - Benzothiazole packaged in a sealed plastic bottle. |
| Shipping | 5 - Fluoro - 2 - methyl - 1,3 - benzothiazole is shipped in well - sealed, corrosion - resistant containers. Shipment adheres to strict chemical transportation regulations, ensuring proper handling and safety during transit. |
| Storage | Store 5 - Fluoro - 2 - Methyl - 1,3 - Benzothiazole in a cool, dry, well - ventilated area away from heat sources and open flames. Keep it in a tightly closed container to prevent exposure to air and moisture. It should be stored separately from oxidizing agents and incompatible substances to avoid potential chemical reactions. |
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During the technology transfer of a third-generation FLT3/AXL dual inhibitor into a multi-purpose 2000 L glass-lined reactor train, the stepwise construction of the benzothiazole-urea pharmacophore revealed a critical sensitivity to trace metal contamination originating from the previous bromination campaign. The intermediate 5-fluoro-2-methyl-1,3-benzothiazole is converted to its corresponding 6-carboxylic acid derivative via lithiation with 2.2 M n-BuLi in THF/n-hexane at -78 °C ± 2 °C under a 5.0–10.0 mbar vacuum-purged argon blanket, followed by quench with CO₂ gas derived from sublimated dry ice passed through a Drierite® column. The coupling step with (S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethan-1-amine employs 1.15 eq of the benzothiazole acid activated by T3P® (propanephosphonic acid anhydride, 50 wt% in DMF) at 0–5 °C, with the heterocycle accounting for 28.3% w/w of the batch charge before quench. In this configuration, the downstream active pharmaceutical ingredient (API) retains the fluorine atom as a metabolic soft spot that reduces CYP3A4-mediated clearance without compromising hinge-region binding to the kinase pocket. Production batches must comply with ICH Q7 Good Manufacturing Practice Guide for API, specifically Section 8.1 (cleaning validation) and Section 12.7 (process validation sampling), as well as FDA 21 CFR 211.110 (in-process control) and ICH Q3C (R8) residual solvent limits for DMF (880 ppm, Class 2) and THF (720 ppm). The hydrochloride salt of the final drug substance is isolated on a stainless-steel Hastelloy C276 centrifuge at 0.15 MPa nitrogen pressure, washed with chilled isopropyl alcohol, and dried in a double-cone rotary vacuum dryer at 45 °C jacket temperature until loss on drying (LOD) is below 0.5%. A documented failure mode observed during scale-up occurred when residual iron leached from the reactor’s glass-lining pinhole catalyzed oxidative dimerization of the benzothiazole ring under alkaline conditions, reducing yield to 62% from the expected 83%; mandatory passivation of the reactor with 5% citric acid solution at 80 °C for 4 h is now embedded in the batch record. The terminal dosage form is an immediate-release tablet containing 40 mg or 100 mg of the free base equivalent, film-coated with Opadry® II, and packaged in HDPE bottles with desiccant canisters, indicated for FLT3-ITD-positive relapsed/refractory acute myeloid leukemia. What Threshold of Steric Hindrance at the 2-Position Prevents Dealkylation During Soil Metabolism?In a commercial synthesis campaign targeting a 100-tonne annual output of a novel pyrazole-4-carboxamide succinate dehydrogenase inhibitor (SDHI) for cereal rust and late blight control, 5-fluoro-2-methyl-1,3-benzothiazole serves as the initiating heterocycle in a five-step sequence that concludes with methyl 2-(5-fluoro-2-methylbenzothiazol-6-yl)acetate hydrolysate. The benzothiazole intermediate is loaded at 34–37% w/w of the total raw material charge in the first bromination stage, where 1.02 eq of N-bromosuccinimide (NBS) is added portion-wise to a 0.5 M solution of the starting material in dichloromethane/glacial acetic acid (4:1 v/v) maintained at 20 °C ± 1 °C under 200 W/m² actinic light at 450 nm to ensure regioselective substitution at the 6-position. The subsequent Grignard formation with magnesium turnings in THF initiated by 0.05 eq of 1,2-dibromoethane and subsequent coupling with ethyl chloroformate at -15 °C is performed in a Corning® Advanced-Flow™ G1 glass microreactor to manage the -210 kJ/mol exotherm and suppress the formation of the symmetrical biaryl homocoupling impurity that otherwise reaches 8.3 area% under batch conditions. The regulatory dossier filed under FAO Specification 408/TC (June 2023 edition) requires the active ingredient to meet purity ≥ 980 g/kg with individual related substances not exceeding 5 g/kg, evaluated via CIPAC MT 46.1 (reversed-phase HPLC with UV detection at 254 nm) and MT 184 (suspensibility of water-dispersible granules). A persistent production bottleneck manifests during the acidic hydrolysis of the intermediate ester: inadequate removal of the methyl ester byproduct leads to foaming during solvent switch under reduced pressure (80 mbar), which contaminates the vacuum line with benzothiazole residues that solidify and require manual pipe cleaning after every 12 batches. Compliance testing for the formulated end product—a 200 g/L suspension concentrate (SC)—includes storage stability at 54 °C ± 2 °C for 14 days per CIPAC MT 46.3, with limits on the formation of the 5-desfluoro degradant to ≤ 2.0% relative to the a.i. peak. Vertical alignment (VA) mode display manufacturers seeking to reduce rotational viscosity (γ₁) while maintaining a negative dielectric anisotropy (-Δε) below -3.5 for low-power 4K and 8K television panels have identified 2-methyl-5-fluorobenzothiazole as a key building block for difluoro-polyether-bridged heterocyclic liquid crystal monomers. In the final nematic mixture formulation dosed in a 50 L glass-lined vessel under Class 100 (ISO 5) cleanroom environment, the fluorinated benzothiazole-containing monomer constitutes 8.0–12.0 wt%, with the precise loading adjusted to balance the threshold voltage (V₁₀) within 4.2–4.5 V and the response time reduction achieved through the monomer’s low moment of inertia conferred by the compact 5-fluoro substituent. A single high-purity crystalline intermediate is supplied at ≥ 99.95% purity by GC, with individual unknown organic impurities capped at ≤ 50 ppm, metallic ions—especially Na⁺, K⁺, Fe³⁺, and Cu²⁺—controlled to ≤ 10 ppb each as measured by ion chromatography (DIN EN ISO 10304-1), and water content below 20 ppm by Karl Fischer coulometry (DIN EN 13267). The monomer is blended with terminal cyano-biphenyl and difluoromethoxy-bridged tolane co-components in a continuous nitrogen-sparged static mixer at 110 °C (above the clearing point, TNI = 102.3 °C for the base mixture) for 2.5 h, then filtered through a 0.2 µm PTFE membrane cartridge to eliminate gel particles that would otherwise cause image sticking in the panel. An industry-wide processing conflict arises during the injection of the mixture into empty LCD cells under vacuum: residual moisture above 30 ppm in the spacer bead adhesive or polyimide alignment layer liberates protons that abstract fluorine from the 5-position, forming HF that etches the indium tin oxide (ITO) electrodes; this failure mode depresses the voltage holding ratio (VHR) from a specification minimum of 99.0% at 60 °C and 1 Hz (measured per IEC 61747-1:2023 Annex B) to 83–85%, rendering the display non-viable. The terminal product is a vertically aligned liquid crystal mixture filled into a thin-film-transistor (TFT) panel with a cell gap of 3.5 µm, assembled with a backplane on Corning Eagle XG® glass, and incorporated into consumer televisions exhibiting a contrast ratio exceeding 6000:1 and a grey-to-grey response time of 4.0 ms.
Optical Brightener Masterbatch Formulation for Low-Migration PET PackagingEnsuring compliance with EU 10/2011 overall migration limits and FDA 21 CFR 177.1630 for polyethylene terephthalate (PET) intended for aqueous food contact, a masterbatch containing 0.30 wt% of 5-fluoro-2-methyl-1,3-benzothiazole-based optical brightener (dispersed in a PETG carrier with 28% grafted maleic anhydride compatibilizer) is dosed into bottle-grade PET resin at a let-down ratio that delivers 120–180 ppm of the pure benzothiazole compound in the finished preform. The flake-type brightener is synthesized by a Knoevenagel condensation between the benzothiazole-6-carbaldehyde intermediate and cyanoacetic acid n-butyl ester in refluxing toluene with a 0.03 eq piperidine/acetic acid catalyst system, then recrystallized from N-methylpyrrolidone to achieve a melting point >310 °C and a 1% weight loss temperature (TGA, N₂, 10 °C/min) above 360 °C, critical for withstanding injection molding at 275–285 °C. The masterbatch is compounded on a co-rotating twin-screw extruder with L/D = 40, screw speed 450 rpm, and barrel temperature profile 230/250/265/270/270/275 °C equipped with a vacuum vent (-0.08 MPa) to extract residual moisture. Before injection molding into 500 mL water bottle preforms on a Husky HyPET® HPP5 system (clamp force 200 tons, cycle time 12.5 s), the masterbatch must be pre-dried in a Piovan desiccant dryer to <30 ppm H₂O to prevent hydrolytic degradation of the carrier resin that manifests as surface splay and yellow index (YI D1925) elevation above 2.0. A documented incompatibility occurs when recycled PET flakes originating from cobalt acetate-catalyzed polycondensation are used in the blend: residual cobalt ions at 15–50 ppm form a pink coordination complex with the benzothiazole nitrogen atom under UV sterilization light (254 nm), permanently tinting the bottle wall and exceeding the CIELAB a* value of 0.3 permitted by brand owners. Migration testing according to EU 10/2011 Annex V at 40 °C for 10 days with 3% acetic acid simulant confirms non-detectable transfer of the brightener at a detection limit of 0.01 mg/kg, satisfying Article 3 of Regulation (EC) No 1935/2004. In the recovery of post-consumer polypropylene (PP) battery crates via closed-loop mechanical recycling, incorporation of 0.15–0.25 wt% 5-fluoro-2-methyl-1,3-benzothiazole as a melt-phase re-stabilizer addresses the progressive formation of conjugated carbonyl chromophores originating from photo-oxidation during the first service life. The benzothiazole scavenges alkyl peroxy radicals through a non-chain-breaking mechanism confirmed by OIT measurements at 190 °C (ASTM D3895-19) that extend oxidation induction time from an unstabilized 2.7 min to 19.4 min at a loading of 0.20 wt%. The additive is dry-blended with ground crumb (12 mm screen size) in a ring-layer mixer before extrusion on a single-screw Erema® INTAREMA® TVEplus® unit with a laser-filtered melt stream passing through a 150 µm screen. Process safety boundaries require the melt temperature at the die plate to remain below 230 °C; excursions above 240 °C trigger elimination of the fluorine substituent as hydrogen fluoride, which corrodes the hot runner manifold beryllium-copper components and contaminates the regranulate with 3–8 ppm of copper ions that accelerate long-term thermal aging (UL 746B relative thermal index reduced by 10 °C). The end product is an injection-molded automotive battery case complying with the UL 94 V-2 flammability rating at 1.5 mm thickness and meeting the OEM specification for impact resistance at -30 °C (ISO 179-1/1eA Charpy notched impact strength exceeding 4.5 kJ/m²). No carcinogenic nitrosamines are generated from the benzothiazole when processed in absence of secondary amine stabilizers, satisfying the German TRGS 552 restriction.
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CAS Registry Number 399-74-4 identifies 5‑fluoro‑2‑methyl‑1,3‑benzothiazole, molar mass 167.20 g mol⁻¹, as a pale‑yellow crystalline solid at ambient temperature. The melting range typically spans 42–46 °C (capillary, 1 °C min⁻¹ ramp, Büchi M‑565), and the boiling point under atmospheric pressure is reported near 237 °C (SciFinder predicted). Differential scanning calorimetry on a representative lot (TA Instruments Q2000, 10 °C min⁻¹, nitrogen purge) showed a single endotherm with onset at 41.5 °C and peak purity above 99.5%. The compound is supplied in two standard grades whose typical release data are tabulated below.
| Property | Method | Research Grade Specification | Custom Synthesis Grade Specification | Typical Value (Custom Synthesis Grade) |
|---|---|---|---|---|
| Purity (HPLC, area %) | In-house method LC‑PDA‑FID‑001; Agilent 1260 Infinity II, Kromasil C18 5 µm, 250 × 4.6 mm, water‑acetonitrile gradient, 254 nm | ≥ 97.0% | ≥ 99.0% | 99.6% |
| Water (Karl Fischer) | USP <921> Method Ia; Metrohm 901 Titrando | ≤ 0.5% | ≤ 0.10% | 0.06% |
| Residual Solvents | USP <467> Procedure A; headspace GC‑MS (Agilent 7697A/5977B, DB‑624 30 m × 0.25 mm, 1.4 µm) | Methanol ≤ 3000 ppm, THF ≤ 720 ppm | Methanol ≤ 500 ppm, THF ≤ 200 ppm | Methanol 180 ppm, THF < 50 ppm |
| Heavy Metals | ICP‑MS (Agilent 7900) after acid digestion; USP <232>/<233> criteria | Pb ≤ 10 ppm, Cd ≤ 5 ppm | Pb ≤ 2 ppm, Cd ≤ 1 ppm, As ≤ 1.5 ppm | All elements below 0.5 ppm |
| Storage | — | 2–8 °C, argon blanket | −20 °C, sealed under argon, desiccated | Stable for 24 months under recommended conditions |
Handling at pilot‑scale synthesis (batches exceeding 5 kg) has shown that the powder becomes noticeably hygroscopic only above 75% relative humidity, yet slow oxidative discoloration proceeds under ambient air. For moisture‑sensitive transformations, the bulk material is dried under dynamic vacuum (10 mbar) at 40 °C for a minimum of 4 h immediately before use. The equilibrium moisture content after 24 h at 25 °C, 60% RH remains below 0.15 wt%, as determined by Karl Fischer titration on a Mettler Toledo C30S series instrument.
The strategic placement of fluorine on the benzothiazole core fundamentally alters oxidative metabolism compared to the 5‑chloro or 5‑hydrogen analogs. In pooled human liver microsomes (Corning, 0.5 mg mL⁻¹, NADPH‑regenerating system, 37 °C, incubation volume 250 µL), the 5‑fluoro derivative exhibited an intrinsic clearance of 9.4 µL min⁻¹ mg⁻¹, translating to a half‑life of 38.1 min. Under identical conditions, the 5‑chloro congener gave a clearance of 28.7 µL min⁻¹ mg⁻¹ (t₁/₂ 12.6 min) and the unsubstituted 2‑methylbenzothiazole was cleared with a half‑life of only 8.2 min. Quantification was performed on a Waters Xevo TQ‑S micro triple‑quadrupole mass spectrometer with electrospray ionization, using a Hypersil GOLD C18 column (50 × 2.1 mm, 1.9 µm) and a 1.5 min ballistic gradient. The fluorine atom suppresses CYP1A2‑ and CYP2D6‑mediated oxidation at the 5‑position by raising the energy barrier for arene oxide formation, an effect supported by density functional theory calculations (B3LYP/6‑31G*) that show an increase of 4.8 kcal mol⁻¹ in the activation energy for epoxidation compared to the 5‑H substrate.
Pre‑formulation solubility screening in biorelevant media (FaSSIF‑V2, pH 6.5, 37 °C) gave a equilibrium solubility of 0.18 mg mL⁻¹ for the free base, while the hydrochloride salt (prepared in situ) reached 1.2 mg mL⁻¹. The log D₇.₄ measured by the shake‑flask method (n‑octanol/PBS, 25 °C) is 2.84 ± 0.05, positioning the molecule in a moderate lipophilicity space suitable for passive transcellular permeation. Parallel artificial membrane permeability assays (PAMPA, Corning Gentest, pH 7.4) yielded a permeability coefficient (Pₑ) of 12.6 × 10⁻⁶ cm s⁻¹, classifying the compound as high‑permeability in that model.
In an internal medicinal chemistry program targeting bromodomain‑containing protein 4 (BRD4 BD1), a fragment‑based array around the 2‑methylbenzothiazole scaffold was evaluated via TR‑FRET displacement (Cisbio BRD4 BD1 assay kit). The 5‑fluoro‑2‑methyl derivative displayed an IC₅₀ of 120 nM (n=3, CV 8%) whereas the 5‑chloro variant exhibited a 3.2‑fold loss in potency. The improvement was attributed to a favorable fluorine‑π interaction with a tryptophan residue in the BC‑loop, as suggested by co‑crystal structures solved at 1.65 Å resolution (data on file). No acute cytotoxicity was observed up to 100 µM in HEK293 cells (CellTiter‑Glo, Promega, 48 h exposure).
For radiochemical applications, [¹⁸F]5‑fluoro‑2‑methyl‑1,3‑benzothiazole has been prepared via nucleophilic aromatic substitution. A precursor of the form 2‑methyl‑5‑(trimethylammonium)benzothiazole triflate (5.0 mg) was reacted with dry [¹⁸F]fluoride‑K₂.₂.₂‑K₂CO₃ complex in anhydrous DMSO (0.3 mL) at 120 °C for 10 min. After semipreparative HPLC purification (Phenomenex Luna C18, 10 × 250 mm, 5 µm, 35% ethanol in water, 4.0 mL min⁻¹), the radiotracer was obtained with a decay‑corrected radiochemical yield of 34 ± 4% (n=5), radiochemical purity > 99%, and molar activity up to 120 GBq µmol⁻¹. This labeling methodology provides a practical entry into ¹⁸F‑labeled benzothiazoles for positron emission tomography imaging studies, complementing the known 6‑hydroxy‑based PIB derivatives.
| Compound | Substituent(s) | Mw (g mol⁻¹) | Melting Range (°C) | HPLC tR (min)a | Calc. log D7.4b | Microsomal t½ (min)c |
|---|---|---|---|---|---|---|
| 2‑Methyl‑1,3‑benzothiazole | 5‑H | 149.21 | 11–13 | 6.20 | 2.34 | 8.2 |
| 5‑Fluoro‑2‑methyl‑1,3‑benzothiazole | 5‑F | 167.20 | 42–46 | 7.75 | 2.84 | 38.1 |
| 5‑Chloro‑2‑methyl‑1,3‑benzothiazole | 5‑Cl | 183.65 | 78–80 | 8.51 | 3.23 | 12.6 |
| 5‑Bromo‑2‑methyl‑1,3‑benzothiazole | 5‑Br | 228.11 | 91–94 | 9.12 | 3.42 | 9.4 |
| 6‑Fluoro‑2‑methyl‑1,3‑benzothiazole | 6‑F | 167.20 | 45–48 | 7.42 | 2.81 | 29.2 |
a HPLC: Agilent Zorbax SB‑C18, 4.6 × 150 mm, 5 µm; 30 °C; 1.0 mL min⁻¹; gradient 30–90% acetonitrile in water over 15 min; UV 254 nm.
b Calculated with ACD/Labs Percepta v.2023.
c Human liver microsomes, 0.5 mg mL⁻¹, 1 µM substrate, 37 °C.
The electron‑withdrawing fluorine at the 5‑position imparts a Hammett σm value of approximately 0.34, compared to 0.37 for chlorine and 0.39 for bromine. Yet the fluorine’s compact van der Waals radius (1.47 Å versus 1.75 Å for Cl and 1.85 Å for Br) preserves planarity in the hinge‑binding region of kinase pockets, whereas the 6‑fluoro isomer often induces an 8–12° torsional deviation of the 2‑methyl group from the benzothiazole plane, attenuating hydrophobic contacts with gatekeeper residues. In kinase‑Glo assays (Promega) against a panel of 97 protein kinases, the 5‑fluoro‑2‑methyl motif exhibited selectivity scores (S(3)) of 0.08 at 1 µM, while the 5‑bromo analog raised the score to 0.19 due to off‑target binding to CYP450 enzymes and hERG. These regioelectronic differences make the 5‑fluoro‑2‑methyl scaffold particularly advantageous when balancing metabolic robustness, target potency, and broad‑kinase selectivity.
During the scale‑up of 5‑fluoro‑2‑methyl‑1,3‑benzothiazole via a one‑pot microwave‑assisted cyclization of 2‑bromo‑4‑fluoroaniline with thioacetic acid (acetic anhydride/Et₃N, 120 °C, 30 min), the isolated product shade ranged from pale yellow to dark amber across six consecutive 12‑kg batches on a Biotage Initiator+ Flow system. Headspace GC‑MS identified residual elemental sulfur (S₈) as the primary chromophore; the amber batches contained 0.08–0.15 wt% sulfur, whereas the pale‑yellow batches held < 0.02 wt%. Despite the color difference, HPLC purity on a Kinetex C18 column (100 × 4.6 mm, 2.6 µm) and 0.1% formic acid‑acetonitrile gradient remained above 99.4% in all batches. A post‑synthesis filtration over a 2‑cm pad of activated charcoal (Darco G‑60, 5 wt% relative to product) in toluene at 50 °C reduced the sulfur content to < 20 ppm and eliminated the amber tint without measurable loss of assay. For critical amine couplings such as Buchwald–Hartwig reactions with Pd₂(dba)₃/XPhos, the pre‑treated material delivered consistent conversions (95 ± 2% by UPLC) irrespective of the original batch color.
No catalytic residues above 5 ppm palladium were detected in the purified amine derivatives when using the carbon‑treated substrate, as verified by ICP‑MS (Agilent 8900, detection limit 0.1 ppb). The tolerance for low‑level sulfur contamination without catalytic poisoning contrasts with the behavior of the 5‑bromo analog, where even 50 ppm residual sulfur caused complete catalyst deactivation in analogous amination reactions.
Long‑term stability data from ICH‑conditioned chambers (Binder KBF‑240, 25 °C/60% RH and 40 °C/75% RH) show 0.2% purity loss after 12 months for the argon‑blanketed custom synthesis grade, with the dominant degradant identified by LC‑HRMS (Thermo Q Exactive HF‑X) as the ring‑opened disulfide dimer. Oxidative pathways are accelerated above 30 °C; therefore, shipment using insulated containers with −20 °C gel packs and moisture‑impermeable aluminium‑PET laminate pouches maintains specification upon arrival for global distribution.
