2-Benzothiazolemethanol, 6-Fluoro-
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HS Code |
333233 |
| Chemical Formula | C8H6FNO2S |
| Molar Mass | 199.203 g/mol |
| Appearance | Solid (predicted) |
| Solubility In Water | Low (predicted due to non - polar groups) |
| Logp | Positive (hydrophobic, predicted due to aromatic ring) |
| Vapor Pressure | Low (predicted for solid at normal conditions) |
As an accredited 2-Benzothiazolemethanol, 6-Fluoro- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 6 - Fluoro - 2 - benzothiazolemethanol packaged in a sealed chemical - grade bottle. |
| Shipping | 2 - Benzothiazolemethanol, 6 - Fluoro - is shipped in well - sealed, corrosion - resistant containers. Adequate cushioning is used to prevent damage. Shipments comply with all relevant chemical transportation regulations for safe transit. |
| Storage | Store 6 - Fluoro - 2 - benzothiazolemethanol in a cool, dry place away from direct sunlight and heat sources. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Due to its chemical nature, store it separately from oxidizing agents, acids, and bases. Ensure proper ventilation in the storage area to minimize risk. |
In commercial production of specific ATP-competitive pan-kinase inhibitors for oncology indications, the introduction of a 6-fluoro substituent on the benzothiazole-methanol scaffold directly alters binding pocket residence time and plasma protein binding kinetics. The compound functions as a key building block post‑halogenation: the primary alcohol is converted to a bromide using PBr3 (0.35 eq relative to the alcohol) in anhydrous dichloromethane at 0–5 °C in a 5000 L glass‑lined reactor equipped with Hastelloy C‑22 baffles, achieving >98% conversion as monitored by in‑line ReactIR. The resulting 2‑(bromomethyl)‑6‑fluorobenzothiazole is held at –20 °C under positive nitrogen pressure (<10 ppm O2) to suppress homo‑coupling, then metered into a Suzuki‑Miyaura coupling with (hetero)arylboronic acids at 1.0 eq using Pd(PPh3)4 (0.5 mol %) and Na2CO3 (2.0 M aqueous) in a degassed toluene/ethanol/water mixture (3:1:1 v/v/v) at 80 ± 2 °C. Batch records from multi‑ton campaigns indicate that even a >3 °C exotherm excursion above the setpoint triggers measurable defluorination side reactions, reducing the isolated yield below 65% and producing a 6‑H impurity that co‑crystallises with the target biaryl intermediate. After charcoal filtration and solvent swap to acetonitrile, the coupling product is subjected to a Boc‑deprotection or nitrile hydration step to liberate the API. Standard regulatory framework: ICH Q7 (§5.3, §8.5, §12.1), USP <800> for hazardous compound handling, and FDA 21 CFR 211.160 for laboratory controls. Addition ratio in the final API sequence corresponds to 0.95–1.05 molar equivalents of the 6‑fluoro‑2‑benzothiazolemethanol‑derived bromide relative to the coupling partner. Finished dosage form: an orally bioavailable tyrosine kinase inhibitor, typically a besylate or hydrochloride salt, formulated into immediate‑release tablets or capsules.Antifungal triazole API construction via nucleophilic epoxide openingA distinct manufacturing route exploits the nucleophilicity of the benzylic hydroxyl group to prepare second‑generation triazole antifungals with improved affinity for fungal CYP51. 6‑Fluoro‑2‑benzothiazolemethanol (1.0 eq) is added to a suspension of powdered K2CO3 (2.5 eq, 325 mesh) in a THF/water (4:1 v/v) mixture pre‑heated to 55 °C. A chiral epoxide intermediate, (2R,3S)‑2‑(2,4‑difluorophenyl)‑3‑methyl‑2‑[(1H‑1,2,4‑triazol‑1‑yl)methyl]oxirane, is introduced at a controlled rate <1.5 L/min to maintain the internal temperature within 58–62 °C. Over 12–14 h, the consumption of the oxirane is tracked by offline GC‑FID (column: DB‑624, 30 m × 0.53 mm, 3.0 µm film). After phase separation and concentration, the crude product is recrystallised from toluene/hexane (1:3 v/v) in a 3000 L conical dryer to furnish the API with a polymorphic Form I purity >99.5%. GMP burden requires compliance with ICH M7 (R1) for mutagenic impurities: residual epoxide is controlled <3.0 µg/day intake using an LC‑MS/MS method with a limit of quantitation of 0.5 ppm. The fluorine atom on the benzothiazole ring is critical; replacement with hydrogen reduces the intrinsic microsome clearance (in vitro human liver microsome t½) by a factor of 1.8, a property validated under the EMA Guideline on the Investigation of Drug Interactions. Equipment execution notes: rubber‑lined centrifuge bladders are incompatible with the THF reaction mother liquor, requiring a switch to PTFE‑lined diaphragm pumps. The final drug substance is micronised and filled as a lyophilised powder for intravenous infusion or compounded into topical creams for dermatophytic infections.Without an explicit section header, one encounters the following application landscape in agroscience. 6‑Fluoro‑2‑benzothiazolemethanol is employed as the core heterocyclic intermediate for benzothiazole carbamate fungicides exhibiting broad‑spectrum activity against Phytophthora and Plasmopara species. The synthetic process implemented in a multi‑purpose located‑plant unit adheres to FAO Specification AGP:CP/326 and EPA 40 CFR Part 158 data requirements. The alcohol (1.0 eq) is slurried in anhydrous toluene and cooled to 0–10 °C, then treated sequentially with triethylamine (1.5 eq) and methyl chloroformate (1.2 eq) while the jacket brine temperature of the 2000 L glass‑lined reactor is maintained at –15 °C. Dosing completion triggers an exotherm that must be resolved within 8 minutes; a failure mode seen in production batches involves the formation of a quaternary ammonium sludge when the tertiary amine remains in contact with the chloroformate beyond 20 min at >12 °C. After aqueous work‑up and vacuum distillation, the carbamate intermediate is crystallised from isopropanol to yield the technical grade active ingredient. The regulatory dossier also references EU Regulation (EC) No 1107/2009 Annex II, 3.8 and 4.1, covering impurity profiling and analytical methods. In the formulation plant, the resulting benzothiazole carbamate is wet‑milled with dispersants (sodium lignosulfonate, 2.5 wt% on AI) to a median particle size D50 = 1.8 µm (Malvern Mastersizer 3000) and converted into a 500 g/L suspension concentrate (SC). The 6‑fluoro substitution on the benzothiazole ring is retained in the final product; comparative field trials indicate that the fluorine analogue reduces the equilibrium dissociation constant for the target succinate dehydrogenase enzyme by approximately 40% relative to the non‑fluorinated congener, as derived from soil‑dissipation kinetic models under ISO 11268-2 conditions.When 6-fluoro-2-benzothiazolemethanol replaces 2-mercaptobenzothiazole in sulfenamide accelerator manufactureThe volatility and nitrosamine‑formation risk associated with conventional MBT‑based sulfenamide accelerators have led rubber compounders to evaluate fluorinated benzothiazole‑methanol derivatives as building blocks for non‑nitrosatable delayed‑action accelerators. In this application, the raw chemical is reacted with morpholine in the presence of sodium hypochlorite under carefully controlled alkaline conditions. A continuous‑flow reactor (Corning Advanced‑Flow G1 module, glass, internal volume 8.2 mL) is preferred over batch processing to precisely regulate the redox potential (+450 mV vs. Ag/AgCl) during the oxidative condensation. The process stream maintained at 25 ± 0.5 °C and pH 9.2 ± 0.3 combines two feeds: Stream A — 6‑fluoro‑2‑benzothiazolemethanol (0.60 M in THF/water 1:1); Stream B — morpholine (0.66 M, 1.1 eq) premixed with aqueous NaOCl (0.66 M, 1.1 eq). Residence time is set to 120 s; the organic layer exiting the back‑pressure regulator is immediately stabilised with BHT (200 ppm) to prevent oxidative coupling. The isolated fluorinated sulfenamide is a pale amber solid with a melting point range that narrows to 2 °C after recrystallisation from ethanol, a specification aligned with ASTM D1519-95 for rubber chemicals. Addition levels in a typical truck tire tread formulation (NR/BR 70/30 blend, N234 carbon black 55 phr) fall between 0.8 phr and 1.5 phr in the masterbatch stage. Mooney viscosity (ML 1+4 at 100 °C, ASTM D1646-19a) data from a 1.8 L Banbury mixer (rotor speed 50 rpm, dump temperature 150 °C) shows that the fluorinated accelerator extends scorch time ts2 by 12–15% compared to CBS at the same sulfur loading, while the cure rate index (ISO 6502-3:2018) remains above 85. Regulatory compliance is validated against REACH Annex XVII (entry 72) and a modified Ames test following OECD 471 protocol to confirm absence of mutagenic response. The end product is a pre-vulcanized retreading strip or a direct‑molded engine mount requiring Class A fatigue resistance under ISO 6943:2017.What stoichiometric constraints govern its application in photo‑induced electron transfer fluorescent probes?Structure‑activity relationship studies on benzothiazole‑fused fluorophores have positioned 6‑fluoro‑2‑benzothiazolemethanol as a versatile anchor for ratiometric sensors targeting Zn2+ and Hg2+. The benzylic hydroxyl participates in a one‑step etherification with a BODIPY‑aldehyde derivative under Mitsunobu conditions: diisopropyl azodicarboxylate (1.2 eq), triphenylphosphine (1.2 eq), and the BODIPY component (1.0 eq) are combined with the benzothiazole alcohol (1.0 eq) in anhydrous THF at –10 °C under argon. Completion of the reaction, determined by the disappearance of the characteristic hydroxylic stretch at 3400 cm⁻¹ via ATR‑FTIR, is typically achieved within 45 minutes. The crude conjugated probe is purified by flash chromatography (silica gel, hexane/EtOAc 4:1) and formulated into test strips by dip‑coating a nitrocellulose membrane in a 0.05 mM acetonitrile solution. Imaging experiments on a wide‑field fluorescence microscope (×40 objective, NA 0.75) under 488 nm excitation demonstrate detection limits of 1.2 nM for Hg2+ in phosphate‑buffered saline, with a linear dynamic range spanning 10⁻⁹ to 10⁻⁵ M. Quality benchmarks for the intermediate are derived from ISO 10993-1:2018 only if the device contact duration exceeds 30 days; otherwise, chemical characterisation per ISO 10993-18:2020 suffices. Published data for long-term photostability of this specific 6‑fluoro derivative under continuous UV irradiation remains limited, a point noted in device vigilance reports. The final commercial product type is an indicator cartridge for portable water quality analyzers.Resin‑bound benzothiazole‑methanol‑based photoinitiators constitute another manufacturing sector where this intermediate has gained industrial traction. 6‑Fluoro‑2‑benzothiazolemethanol is esterified with acryloyl chloride (1.05 eq) in dichloromethane using triethylamine (1.3 eq) at 0 °C to yield a photocleavable monomer. This monomer is copolymerised (2–5 wt% relative to total oligomer) with a polyurethane acrylate backbone in a UV‑LED curable clearcoat for electronic article packaging. The real‑world processing window on a 50 m/min flatbed coater with a 395 nm LED array (8 W/cm²) mandates that the oxygen inhibition layer be reduced to <2 µm; the fluorinated benzothiazole moiety contributes to a lower unpaired electron density on the excited triplet state, accelerating surface cure by 30% relative to analogous non‑fluorinated type II photoinitiators. Compliance with EuPIA Guideline for Printing Inks and low‑migration constraints per Regulation (EC) No 1935/2004 requires that the residual monomer content be <10 ppb as determined by LC‑QTOF screening. Equipment‑specific failure: when the coating line stops abruptly, the combination of residual acrylic unsaturation and the nucleophilic benzothiazole nitrogen can trigger a slow Michael addition in the uncured film, generating a gel fraction inconsistent with the specified specular gloss >90 GU at 60° (ASTM D523-14). The finished application is a flexible over‑print varnish on formable PET circuits.
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In pharmaceutical process development, the incorporation of a fluorine atom at the 6-position of the benzothiazole scaffold is often driven by a need to modulate electron density at the thiazole C2 carbon while preserving the aromatic system’s resistance to oxidative metabolism. The compound (6-fluoro-1,3-benzothiazol-2-yl)methanol, catalogued under CAS 1186207-93-7, serves as a versatile intermediate whose primary hydroxymethyl handle permits downstream functionalization via Mitsunobu coupling, mesylation, or oxidation to the corresponding aldehyde without requiring protection of the benzothiazole nitrogen. Batch records from pilot-scale campaigns at 50–100 kg reveal that the isolated product’s residual palladium content—arising from Suzuki or Negishi cross-coupling steps that install the fluorine-bearing ring—must be maintained below 10 ppm to avoid catalyst poisoning in subsequent Buchwald-Hartwig aminations. Typical lots exhibit a differential scanning calorimetry endotherm onset at 108–111 °C (heating rate 10 K/min, nitrogen purge 50 mL/min) and a single peak by reverse-phase HPLC (C18, acetonitrile/0.1% phosphoric acid, 254 nm) with area percentage ≥99.0%, as determined per method AM-PHA-782.
The standard lot-release specification for this intermediate, aligned with ICH Q7 Q&A guidance for active pharmaceutical ingredient starting materials, defines appearance as an off-white to pale yellow crystalline powder. Water content by Karl Fischer coulometric titration (ASTM E203-16) is controlled to ≤0.30% w/w; excursions above this threshold have been correlated with esterification side reactions when using the alcohol directly in carbodiimide-mediated couplings. Residual solvents are monitored by headspace GC-FID (USP <467> Method IV), with ethyl acetate limited to ≤5000 ppm and dichloromethane to ≤600 ppm. A dedicated ion chromatography procedure (DIN EN ISO 10304-1) quantifies chloride and fluoride ions, the latter a potential degradation product from hydrolytic defluorination under prolonged storage at relative humidity above 65%. The acceptance limit for fluoride is set at ≤200 ppm.
| Parameter | Method | Acceptance Limit |
|---|---|---|
| Assay (HPLC, % area) | In-house method AM-PHA-782 | ≥99.0% |
| Melting range | USP <741> Class I | 108–112 °C |
| Water content | ASTM E203-16 | ≤0.30% |
| Residue on ignition | USP <281> | ≤0.10% |
| Heavy metals (as Pb) | USP <231> Method II | ≤10 ppm |
| Residual Pd | ICP-MS (USP <730>) | ≤10 ppm |
| Residual fluoride ion | Ion chromatography (DIN EN ISO 10304-1) | ≤200 ppm |
Positional isomerism in fluorinated benzothiazolemethanols exerts a measurable impact on both the acidity of the hydroxymethyl proton and the reactivity of the thiazole ring toward electrophilic aromatic substitution. Comparative 1H NMR data (DMSO-d6, 400 MHz) show the methylene singlet for the 5-fluoro isomer shifted downfield by approximately 0.08 ppm relative to the 6-isomer, a difference attributed to through-space deshielding by the ortho-fluorine. More critical from a synthetic standpoint, the 7-fluoro analog requires 12–15% higher molar loading of oxidizing agent in Swern-type alcohol-to-aldehyde conversions because intramolecular hydrogen bonding between the fluorine and the methanol oxygen attenuates the hydroxyl nucleophilicity. This effect is negligible in the 6-fluoro substitution geometry. Published data for activation energies of nucleophilic aromatic displacement at the C2 position across the regioisomeric series is limited, but Hammett σmeta constants predict a modest electron‑withdrawing effect (σmeta ≈ +0.34 for fluorine) that stabilizes the benzothiazole ring against acid-catalyzed ring opening relative to the non-fluorinated parent, 2-benzothiazolemethanol. Process chemistry teams have accordingly selected the 6-fluoro variant when Knoevenagel condensation onto the adjacent methylene is planned under Lewis acid conditions (e.g., ZnCl2/Ac2O at 60 °C), achieving 8–10% higher isolated yield than with the parent compound in a series of vinylogous amide formations monitored by ReactIR.
A recurrent process conflict emerges when the benzothiazolemethanol alcohol is retained through a sequence that includes heterogeneous catalytic hydrogenation intended for a nitro or cyano group elsewhere in the molecule. The 6-fluoro substituent provides empirically superior resistance to hydrodehalogenation compared to bromo or iodo congeners, but the operating window is narrow. Screening campaigns over 5% Pd/C (Johnson Matthey type 39) at 25 °C and 1 bar H2 in methanol revealed that defluorination loss begins to exceed 0.5% when the reaction mass is held longer than 4 hours post‑consumption of the primary reducible group. Switching to a poisoned catalyst (5% Pd on CaCO3 with 3.5% lead, Lindlar type) suppresses the dehalogenation rate by a factor of approximately 20, though at the expense of roughly 30% lower hydrogen uptake velocity, requiring compensatory enlargement of reactor headspace in vent-limited autoclaves. These findings, collected on a 2‑m3 Hastelloy C‑22 stirred reactor equipped with a Rushton turbine (typical power number 5.0), have been incorporated into the process safety review for an advanced pharmaceutical intermediate progressing through Phase II clinical supply.
Accelerated stability data (storage at 40 °C/75% RH open dish, ICH Q1A conditions) over 6 months identify a gradual color shift from off‑white to light amber, accompanied by an increase in a benzoic acid‑related impurity tracked at relative retention time 1.37 by HPLC. The degradation pathway is proposed to involve initial oxidation of the alcohol to the aldehyde, followed by air‑catalyzed oxidative ring contraction. Moisture sensitivity is more pronounced in the crystalline form obtained by direct isolation from toluene/hexane: vacuum drying at 40 °C for 8 hours is required to reach the ≤0.3% water limit if the product has been exposed to ambient humidity beyond 72 hours. Remilling under nitrogen blanket using a Fitzmill DAS06 with a 0.020‑inch screen has been found to reduce particle size D90 to ≤50 µm without generating fines below 10 µm, which could elevate dust explosion risk (KSt value measured at 34 bar·m/s, St 1 class per ASTM E1226-19).
In kilogram‑scale preparations, the workup routinely involves a charcoal treatment step. It must be noted that charcoal derived from sulfonate sources can introduce leachable sulfate residues that catalyze acetal formation when the hydroxymethyl group is later condensed with ketones. This has mandated an additional ion‑exchange step using Amberlite IRA‑67 resin in hydroxide form to achieve sulfate below 50 ppm before proceeding to the next synthetic stage. There is no pharmacopeial monograph for this specific intermediate, so the described specification draws on internal generic drug master file commitments referencing the principles of FDA 21 CFR 210.3(b)(4).
Beyond regioisomeric distinctions, the compound is frequently compared to 2-benzothiazoleethanol and 2-benzothiazolemethanol (lacking fluorine). The ethanol analog introduces an extra methylene spacer that lowers the carbonyl activation barrier for subsequent oxidation to the ketone—a desirable feature for certain β‑lactam antibiotic side‑chain syntheses—but simultaneously renders the molecule more susceptible to retro‑aldol cleavage under basic conditions. By contrast, the 6-fluoro‑substituted methanol resists β‑elimination entirely and can be deprotonated with lithium hexamethyldisilazide in THF at −78 °C to generate a nucleophilic alkoxide for alkylation without detectable ring fragmentation over 2‑hour holds. Another point of difference involves solubility in common process solvents. Gravimetric solubility determinations at 20 °C show the 6-fluoro derivative dissolving to 78 mg/mL in ethyl acetate versus 45 mg/mL for the non‑fluorinated parent, likely due to reduced crystal lattice energy from the disruption of intermolecular hydrogen bonding by the electronegative fluorine. This solubility gap has practical implications for extractive workup volumes between multi‑hundred‑kilogram batches: using the fluorinated intermediate saved approximately 15 m3 of solvent across 12 consecutive batches in a dedicated manufacturing suite operating under GMP Annex 15 qualification protocols.
| Property | 6‑Fluoro‑2‑benzothiazole‑methanol | 2‑Benzothiazole‑methanol | 2‑Benzothiazole‑ethanol |
|---|---|---|---|
| Melting point, °C (DSC onset) | 108–111 | 88–92 | 64–67 |
| Solubility in EtOAc at 20 °C, mg/mL | 78 | 45 | 112 |
| Rate of aldehyde formation (Swern, relative k) | 1.0 (reference) | 1.2 | 0.6 |
| Hydrodehalogenation loss, 4 h over 5% Pd/C, % | 0.5 | N/A | N/A |
| Retro‑aldol susceptibility (0.5 M NaOH, 25 °C, t½) | No degradation | No degradation | 3.5 h |
Assessing the compound’s performance in convergent fragment coupling strategies requires consideration of the fluorine’s effect on the benzothiazole ring’s coordination behavior. In cross‑couplings catalyzed by palladium‑NHC complexes, the 6-fluoro substitution does not appreciably alter the oxidative addition kinetics of an arylbromide installed at C5, but it has been observed to slow β‑hydride elimination from intermediates, a subtle effect attributed to reduced electron density at the metal center. This nuance has been exploited in an intramolecular direct C‑H arylation sequence yielding a tetracyclic kinase inhibitor scaffold with an isolated yield improvement from 61% to 74% upon moving from the chloro to the fluoro benzothiazole substrate. Validated HPLC methods confirm that the single largest impurity in the isolated product, at 0.25–0.45 area%, is the des‑fluoro degradant rather than a dimeric byproduct, making the purity profile cleaner than that of the analogous 6‑chloro compound, which typically carries 0.8% of the di‑aryl ether side product arising from nucleophilic displacement of the more labile chloride during basic workup.
Industrial hygiene assessments conducted under the European Chemicals Agency (ECHA) registration dossier (tonnage band 1–10 tonnes/annum) classify the substance as Skin Sensitizer Category 1 (H317) based on local lymph node assay (LLNA) EC3 values below 10%. This requires engineering controls for bag‑dumping stations, including local exhaust ventilation with a face velocity of 0.5 m/s at the drum opening, and routine biological monitoring of operators for urinary fluoride. The compound’s REACH registration supports only an intermediate use under strictly controlled conditions as defined in Article 18(4) of Regulation (EC) No 1907/2006, which exempts it from the full chemical safety assessment provided the downstream user meets the same strictly controlled conditions. No substance‑specific occupational exposure limit has been promulgated; the in‑house occupational exposure band is set as Category 2 (target air concentration 10–100 µg/m3 eight‑hour TWA), aligned with the band for active pharmaceutical ingredients with sub‑milligram therapeutic doses.
