2-(4-Fluorophenyl)-1,3-Benzothiazole

Production of the amyloid PET imaging agent 18F-Flutemetamol (Vizamyl®) relies on a 2-(4-fluorophenyl)-1,3-benzothiazole structural core, where the fluorine-18 isotope is introduced via nucleophilic aromatic substitution on a suitable precursor. The non-radioactive 2-(4-fluorophenyl)-1,3-benzothiazole supplied serves as the reference standard (cold standard) for radiochemical purity validation by radio-HPLC according to USP <823> and as a key starting material for synthesizing the nitro- or trimethylammonium-substituted precursor used in automated radiosynthesis modules. Compliance with 21 CFR Part 212 (current good manufacturing practice for positron emission tomography drugs) and ICH Q7 for active pharmaceutical ingredient manufacture is mandatory; additionally, the reference standard must be qualified against a certified chemical reference with a purity assignment traceable to ISO 17034 and characterized by differential scanning calorimetry (ASTM E928) and quantitative NMR. Within a typical GE TRACERlab FXFN or IBA Synthera+ module, the precursor mass loading ranges from 1.0 mg to 2.5 mg per synthesis run, dissolved in anhydrous DMSO (water content ≤ 50 ppm by Karl Fischer). The downstream process involves azeotropic drying of 18Ffluoride with Kryptofix 2.2.2/K2CO3 at 100–110 °C, nucleophilic fluorination at 120–140 °C for 10–15 min, acid hydrolysis of protecting groups at 80–90 °C, and semipreparative HPLC purification on a C18 column with an ethanol/water mobile phase. The terminal finished product is a sterile injectable solution containing 18FFlutemetamol with a radiochemical yield of 15–25 % (decay-corrected), specific activity > 3.7 GBq/μmol, and total chemical impurities ≤ 0.5 % as determined by TLC and HPLC. Batch release documentation must include residual solvent levels per USP <467> (acceptance limits for DMSO 5000 ppm, acetone 5000 ppm, ethanol 5000 ppm) and endotoxin testing per USP <85> (≤ 17.5 EU/mL).

What governs the regioselectivity of fluorophenyl benzothiazole in kinase inhibitor scaffolds?

In the preparation of type II tyrosine kinase inhibitors targeting mutated EGFR or VEGFR-2, the 2-(4-fluorophenyl)-1,3-benzothiazole fragment serves as a hinge-binding heterocycle, where the electron-withdrawing para-fluorine enhances metabolic stability by reducing CYP450-mediated hydroxylation at the adjacent phenyl ring. The compound participates in palladium-catalyzed cross-coupling reactions—specifically Suzuki-Miyaura and Buchwald-Hartwig amination—requiring rigorous control of palladium residues. The typical addition ratio is 0.95—1.05 molar equivalents relative to the coupling partner, with a purity threshold ≥ 99.0 % by HPLC (215 nm) and individual impurities ≤ 0.10 %. Downstream manufacturing under ICH Q11 for starting material selection demands a complete impurity fate and purge study; any impurity carrying forward into the final API above the ICH Q3A reporting threshold (0.05 %) must be structurally identified by LC-MS and NMR. During the multistep synthesis, the molecule frequently undergoes a para-fluorine displacement with nitrogen nucleophiles, for which adiabatic reaction calorimetry (ASTM E1981) is recommended to assess the thermal hazard of the amine substitution step. Post-synthesis, the API is isolated as a hydrochloride or mesylate salt via pH-controlled crystallization in an isopropanol/water mixture, with residual palladium measured by ICP-MS according to USP <232>/<233> (limit ≤ 10 μg/g). The terminal finished product is a film-coated tablet or lyophilized powder for injection, with the benzothiazole moiety contributing between 40 % and 55 % of the molecular weight of the final active pharmaceutical ingredient. Material for preclinical GLP toxicology batches must be accompanied by a certificate of analysis referencing the column lot, gradient elution profile, and relative response factor for 0.10 % of the benzothiazole dimer impurity.

Within the analytical chemistry supply chain, 2-(4-fluorophenyl)-1,3-benzothiazole is deployed as a pre-column derivatization reagent for primary and secondary amino acids. The reaction exploits nucleophilic aromatic substitution at the para-fluorine position by the amino group under alkaline conditions, generating a fluorescent adduct with excitation/emission maxima at 340/450 nm. The addition ratio in the derivatization protocol establishes the reagent in 50 mM borate buffer (pH 9.0) at a concentration of 5.0 mM, blended with the amino acid sample to achieve a molar excess of reagent to analyte exceeding 50:1, ensuring pseudo-first-order kinetics and complete conversion within 20 min at 45 °C. The downstream process terminates the reaction with 0.1 % formic acid and injects the mixture directly onto a C18 reversed-phase column (150 × 4.6 mm, 3 μm) with a gradient of acetonitrile/water mobile phase at 0.8 mL/min. Detection limits for glycine routinely reach 0.5 fmol per injection, with linear calibration across 1–500 pmol (r² > 0.999). The terminal products are amino acid analysis kits regulated under ISO 17025 for testing laboratories and must pass method validation per AOAC Appendix K guidelines, including recovery rates between 95 % and 105 % and intermediate precision RSDr ≤ 2.0 %. Accelerated stability testing at 40 °C/75 % RH for 6 months is required to confirm that the reagent powder maintains purity ≥ 98.5 % by HPLC.

OLED Host Matrix Doping and Exciton Confinement

In phosphorescent organic light-emitting diodes, electron-transporting host materials based on a 2-(4-fluorophenyl)-1,3-benzothiazole core provide a low-lying LUMO (measured by cyclic voltammetry at −2.8 eV vs. Fc/Fc⁺) and a triplet energy exceeding 2.85 eV, sufficient to confine green and red phosphors. The compound is co-evaporated with the emissive dopant—typically fac-tris(2-phenylpyridine)iridium(III) or bis(2-phenylbenzothiazole)iridium(III)acetylacetonate—in a vacuum chamber at a base pressure ≤ 5 × 10⁻⁷ Torr. The addition ratio of the benzothiazole host relative to the guest ranges from 85:15 to 95:5 by weight, monitored in real time by quartz crystal microbalance with a deposition rate of 1.0–2.0 Å/s for the host and 0.1–0.3 Å/s for the dopant. The downstream fabrication sequence includes hole-injection layer deposition (HAT-CN, 10 nm), hole-transport layer (NPB, 40 nm), emissive layer (30 nm), electron-transport layer (Bphen or TPBi, 30 nm), and LiF/Al cathode encapsulation under nitrogen glovebox conditions (O₂ and H₂O each ≤ 0.1 ppm). Device characterization follows IEC 62341-1-1 for OLED display performance, measuring current efficiency (cd/A), external quantum efficiency (EQE), and CIE coordinates with a spectroradiometer. Published data on analogous 2-arylbenzothiazole host matrices indicate an EQE of 18–22 % at 1000 cd/m² and a LT95 lifetime (time to 95 % of initial luminance) under accelerated aging at 85 °C that is highly dependent on the purity of the benzothiazole precursor; sublimation-grade material with non-volatile residue ≤ 0.01 % is mandatory. The terminal finished product is an AMOLED display panel, which must comply with the RoHS 2011/65/EU directive and undergo substance screening for Substances of Very High Concern (SVHC) under REACH Article 33.

When a benzothiazole fungicide backbone demands fluorine at the para position

During development of contact fungicides targeting Botrytis cinerea and Uncinula necator on grapevines and ornamentals, the introduction of a para-fluorophenyl substituent at the 2-position of benzothiazole modulates the octanol/water partition coefficient and delays metabolic deactivation in the fungal cell. A representative synthetic route starts with 2-(4-fluorophenyl)-1,3-benzothiazole, which undergoes nitration at the 6-position followed by reduction to the amino derivative and subsequent acylation with a chloroformate, yielding a benzothiazole carbamate active ingredient. The addition proportion of the title intermediate accounts for 32–38 % of the molecular weight of the final technical material. The downstream production is carried out in a 2000 L glass-lined reactor, where the nitration step uses mixed acid (HNO₃/H₂SO₄ ratio 1:3) at 0–5 °C, followed by reduction with iron powder in aqueous acetic acid at 80 °C. After acylation, the crude active ingredient is purified by recrystallization from toluene/hexane and formulated as a 500 g/L suspension concentrate (SC) using a wet bead mill (zirconia beads 0.6–0.8 mm, agitator speed 3000 rpm) to achieve a particle size distribution D₉₀ ≤ 4 μm. The terminal product must conform to FAO Specification 406/SC (storage stability at 54 °C for 14 days, pourability residue ≤ 0.5 %, wet sieve retention on 75 μm ≤ 0.2 %). Analytical methods are validated by CIPAC MT 46 for suspensibility and OCSPP 830.1800 for accelerated storage. A 5-batch technical concentrate analysis report and the corresponding OECD 501 hydrolysis study data are prerequisites for joint registration under EU PPP Regulation 1107/2009. The effective application rate in the field is 250–400 g a.i./ha, and the pre-harvest interval must be established according to OECD 506 residue trials.

The table below aggregates compliance thresholds, test methodologies, and critical material attributes across the five application verticals. Each entry aligns with a specific international standard or pharmacopoeial chapter to provide auditable traceability for regulatory submissions.