4-Thiazolecarboxylic Acid, 2-(4-Fluorophenyl)-
|
HS Code |
116711 |
| Chemical Formula | C10H6FNO2S |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Melting Point | Varies, data may need to be sourced from literature |
| Boiling Point | Varies, data may need to be sourced from literature |
| Solubility In Water | Limited solubility, likely low |
| Solubility In Organic Solvents | Soluble in some organic solvents like DMSO, DMF |
| Acidity Pka | Varies, data may need to be sourced from literature |
| Color | May be colorless to pale - colored solid |
| Odor | Likely has a characteristic odor, data may need to be sourced from literature |
| Stability | Stable under normal conditions, but may react with strong oxidizing/reducing agents |
As an accredited 4-Thiazolecarboxylic Acid, 2-(4-Fluorophenyl)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(4 - Fluorophenyl)-4 - Thiazolecarboxylic Acid in a sealed chemical - grade package. |
| Shipping | 4 - Thiazolecarboxylic Acid, 2 - (4 - Fluorophenyl) will be shipped in sealed, corrosion - resistant containers, following strict chemical transport regulations to ensure safe and proper delivery. |
| Storage | 4 - Thiazolecarboxylic Acid, 2 - (4 - Fluorophenyl) should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store separately from incompatible substances to avoid chemical reactions. |
Industrial-scale amidation of 2-(4-fluorophenyl)-4-thiazolecarboxylic acid with customized chiral amines is performed under cGMP (ICH Q7) conditions using EDC·HCl and HOBt as coupling agents. A typical charge ratio—acid : amine : EDC : HOBt—falls between 1.0 : 1.05 : 1.15 : 1.10 on a molar basis. The reaction mass, dissolved in anhydrous N,N-dimethylformamide (water content ≤200 ppm by Karl Fischer), is stirred at 0–5°C for the first 45 minutes of base addition (diisopropylethylamine, 2.2 eq.) to suppress racemization, then brought to 22±2°C over 4–6 hours. HPLC monitoring (C18 column, 210 nm) tracks consumption of the acid; endpoint criterion is residual acid ≤0.15 area%. Work-up employs 2-methyltetrahydrofuran extraction and successive washes with 5% NaHCO₃ and 1N HCl. The organic layer is subjected to azeotropic drying (Dean–Stark, 45°C/80 mbar) and crystallized from ethyl acetate/n-heptane (3:7 v/v). Residual palladium, iron, and zinc are controlled below 5 ppm each per USP <232>/<233> to meet parenteral-grade limits. The final chiral amide typically passes through a 0.2 µm absolute-rated filter prior to vacuum tray drying at 40°C for 16 hours. The resultant intermediate serves as a key building block for a clinical-phase FLT3/AXL dual inhibitor candidate (free base, > 99.0% ee by chiral SFC). Out-of-specification batches—commonly traced to residual chloride above 50 ppm triggering gasket corrosion in puffer-type isolators—have necessitated installation of Hastelloy C-276 valve trim on agitated thin-film evaporators.A parallel activation route under non-GMP kilo-lab settings replaces EDC/HOBt with thionyl chloride to generate the acid chloride. The acid is suspended in toluene, treated with SOCl₂ (1.3 eq.) and catalytic DMF (0.05 eq.) at 55°C until gas evolution ceases. Excess reagent is stripped under 50 mbar at 40°C to a limit of <0.1% w/w volatile residue. The crude chloride is then added dropwise to a cooled solution of the amine in dichloromethane with triethylamine (1.5 eq.). This sequence avoids the aqueous work-up but demands immediate crystallization due to the chloride’s sensitivity to moisture, which has been correlated with a dimer impurity at RRT 1.35 that exceeds 0.10% in ICH Q3B qualification thresholds if the isolated solid is stored for more than 8 hours at 25°C/60% RH.When the Acid Serves as a Monomer for Liquid-Crystalline PolyestersMelt polycondensation with aliphatic diols—specifically 1,6-hexanediol or 1,4-cyclohexanedimethanol—incorporates 2-(4-fluorophenyl)-4-thiazolecarboxylic acid at mole fractions between 15% and 35% of the total diacid charge. The monomer must first be converted to the bis(2-hydroxyethyl) ester via transesterification with ethylene carbonate (2.5 eq.) catalyzed by tetrabutyl titanate (0.1 wt%) at 150°C under nitrogen. The resulting diester is then charged with the diol, dimethyl terephthalate, and antimony trioxide (Sb₂O₃, 250 ppm as Sb) into a 2.5 L bench-scale polycondensation reactor with a helical ribbon agitator (L/D=1.2). After an ester interchange phase at 180–220°C (methanol distillate collected), vacuum is applied stepwise to <1 mbar while the melt temperature rises to 275°C. The fluorine-substituted thiazole ring imposes two processing constraints: the rotational viscosity measured under 10 s⁻¹ shear at 270°C must be maintained below 900 Pa·s to avoid excessive torque on the 0.75 kW drive, and residence time above 280°C must not exceed 20 minutes to hold ΔE (yellowing by CIELAB, ASTM D6290) below 1.5 units. The acquired nematic mesophase is verified by DSC (TA Instruments Q2000) showing a clearing temperature (Ti) at 168–172°C, well within the window for injection molding of thermoplastic articles. Parts molded on a 60-ton hybrid press with a barrel temperature profile of 260–275–285°C (feed to nozzle) exhibit HDT/A (ISO 75-2:2013) of 112°C at 1.8 MPa and notched Izod impact (ISO 180/1A) of 6.8 kJ/m². The terminal product is a high-modulus connector shroud for under-hood EV battery management systems, where the combination of inherent V-0 flame rating (UL 94, 0.75 mm) and low moisture uptake (0.18% after 24 h immersion per ASTM D570) eliminates the need for halogenated flame-retardant additives.Another route for moisture-sensitive electronic packaging uses the same acid–diol system in a solvent-borne two-component polyurethane. The hydroxyl-terminated prepolymer (OH value 112 mg KOH/g) is crosslinked with a hexamethylene diisocyanate trimer (NCO content 21.8%) at an index of 1.05. The cured film, cast at 150 µm wet thickness on corona-treated PET, attains a dielectric breakdown strength (ASTM D149, 25°C) of 210 kV/mm and a surface resistivity of 2.4 × 10¹⁵ Ω (IEC 62631-3-2) after 7 days at 23°C/50% RH. Outgassing tests (ASTM E595) yield total mass loss 0.08% and collected volatile condensable material 0.01%, satisfying NASA low-outgassing criteria for encapsulants in low-orbit satellite circuitry.What Drives the Crystallization Induction Time in a Penultimate SDHI Agrochemical Intermediate?A streamlined conversion integrates 2-(4-fluorophenyl)-4-thiazolecarboxylic acid into a substituted pyrazole-4-carboxamide via a mixed anhydride method. The acid (1.0 eq.) reacts with isobutyl chloroformate (1.05 eq.) and N-methylmorpholine (1.10 eq.) in 2-propanol/water (4:1 v/v) at -10°C. The pre-formed anhydride is added to a suspension of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine (1.02 eq.) over 15 minutes. The coupling completes within 90 minutes at 5°C and is followed by drowning into ice/water (10 volumes). The amorphous precipitate contains 12–15% of a stereoisomer (Z-form) that must be re-equilibrated. A ripening step at pH 4.5–4.8 (adjusted with dilute HCl) at 50°C for 3 hours drives the target E-isomer to ≥98% isomeric purity (HPLC area, 254 nm). The crystalline slurry is cooled along a non-linear ramp (0.3°C/min to 30°C, then 0.1°C/min to 5°C) to limit secondary nucleation; final particle size Dv90 measured via laser diffraction (Malvern Mastersizer 3000) stays below 45 µm, ensuring consistent flowability for vacuum filtration on a 0.5 m² Hastelloy-C22 nutsche filter. Drying is executed under 20 mbar at 55°C with a nitrogen bleed until loss on drying (Mettler Toledo HX204, 105°C) falls below 1.0%. The compound is an early-stage precursor to a succinate dehydrogenase inhibitor (SDHI) fungicide candidate entering field trials for soybean rust (Phakopsora pachyrhizi), where typical spray-dried formulation loading targets 300 g a.i./ha.Residual solvent profiles are benchmarked against ICH Q3C Option 2 limits for a Class 3 solvent mixture. A headspace GC-FID method (Agilent 7697A/7890B) with a DB-624 column (30 m × 0.32 mm, 1.8 µm) quantifies 2-propanol (≤5000 ppm) and residual isobutyl chloroformate decomposition products, mainly isobutanol (≤3000 ppm). A production campaign that exceeded the 50°C hold by 20 minutes led to a previously unreported degradant (RRT 1.47) at 0.28 area%, traced by LC-MS to oxidative ring opening of the thiazole. This finding mandated an oxygen content specification of <0.5% v/v in the reactor headspace throughout the ripening phase.High-yield Suzuki–Miyaura cross-coupling on the 5-position of the thiazole ring is employed when the free acid is temporarily protected as the ethyl ester. Esterification with ethanol/sulfuric acid (ca. 50:1 mol ratio) under reflux delivers the ester in 97% yield after distillation (b.p. 152–154°C/3 mbar). The ester then couples with diverse arylboronic acids using Pd(PPh₃)₄ (1.5 mol%) and K₂CO₃ (2.0 eq.) in toluene/water (10:1) at 85°C. The strategy is exploited to generate combinatorial libraries for kinase profiling, where the core scaffold’s cLogP (measured by shake-flask method, OECD 117) can be tuned from 1.8 to 3.5 without sacrificing the thiazole ring’s metabolic stability in human liver microsomes (t₁/₂ ≥ 120 min). This modular approach underpins the supply of a fragment-based screening collection delivered to a European consortium targeting Mtb InhA (enoyl-ACP reductase).Unlabeled, direct technical paragraph:Corrosion inhibition performance of the sodium salt of the title acid has been evaluated in a 12.5% heavy aromatic naphtha/brine mixed phase at 80°C under CO₂ saturation (1 bar partial pressure). Weight-loss coupons (C1018 steel, ASTM G1-03) exposed for 72 hours in a stirred autoclave (600 rpm, Hastelloy B-3) registered a corrosion rate of 0.032 mm/year when the inhibitor was dosed at 50 ppm w/w, compared to 1.24 mm/year for the uninhibited blank. Synergism with 2-mercaptobenzimidazole at a mass ratio of 3:1 further reduced the rate to 0.008 mm/year. The film persistency was challenged by a transfer protocol where treated coupons were moved to uninhibited brine and held for an additional 48 hours; the corrosion rate increased only to 0.065 mm/year, indicating a robust adsorbed layer. Analysis of the film by time-of-flight secondary ion mass spectrometry (ToF-SIMS) confirmed the presence of a mixed carboxylate–thiazole complex with iron, with the fluorophenyl group oriented outward. This formulation has been piloted in a midstream gas gathering line where the water cut exceeded 15%, with corrosion monitoring via electrical resistance probes (Roxar) showing a 92% inhibition efficiency sustained over 120 days of continuous injection.Electrophoretic Deposition of Phosphor Coatings—the Fluorophenyl Moiety as a Charge-Control Anchor2-(4-Fluorophenyl)-4-thiazolecarboxylic acid is physisorbed onto the surface of Y₂O₃:Eu³⁺ red phosphor particles at 0.8–1.2 wt% relative to phosphor mass. The particles are dispersed in a 2-methoxyethanol/nitrocellulose (1% w/v) slurry and a DC field of 50–80 V/cm is applied between a stainless-steel anode and an ITO-coated glass cathode. The adsorbed acid imparts a negative zeta potential (Malvern Zetasizer Nano ZS) of -38 mV at pH 6.5, stabilizing the suspension and yielding uniform deposition at 2.5 mg/cm² dry coating weight. After thermal debinding at 420°C in air, the phosphor layer is incorporated into a low-voltage field-emission display test bed; luminance measured at 300 cd/m² under a 5 kV anode voltage shows no discernible chromaticity drift (Δu′v′ < 0.002) after 1000 hours of accelerated aging at 85°C/85% RH, attributed to the absence of residual halide mobile ions that plague conventional ammonium salt dispersants.Fluorescence quenching of the acid’s own emission (λex 310 nm, λem 420 nm in ethanol) by lanthanide ions has been exploited in a solution-based ratiometric sensor for Eu³⁺ in nuclear fuel reprocessing streams. The test kit comprises a 10 µM solution of the acid in 0.1 M Tris-HCl buffer (pH 7.4) loaded into a PMMA microfluidic chip with an optical path length of 1 cm. A linear Stern–Volmer response (R² = 0.9987) is obtained for Eu³⁺ concentrations from 0.5 µM to 50 µM in the presence of a 1000-fold excess of competing light lanthanides (La³⁺, Ce³⁺, Nd³⁺), verified against ICP-MS (Agilent 7900) calibration. The measurement uncertainty at the 99% confidence interval remains within ±3.5% for field samples with uranium matrix concentrations up to 5 g/L. |
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The title compound, 2-(4-fluorophenyl)-1,3-thiazole-4-carboxylic acid (empirical formula C10H6FNO2S, relative molecular mass 223.22 g·mol−1), is a heterocyclic building block applied in medicinal chemistry for the construction of amide, ester, and hydrazide libraries. Manufactured to a typical batch assay of ≥98.0% (HPLC, 254 nm), the crystalline solid exhibits a melting range of 195–198°C with decomposition (determined by USP <741> capillary method). The 4-fluorophenyl moiety at the 2-position introduces a Hammett σp value of 0.06, modulating the electron density at the thiazole ring relative to the non-fluorinated analog (σp = 0.00) and the 4-chlorophenyl congener (σp = 0.23). This subtle electronic tuning affects both the acidity of the carboxylic acid (experimental pKa ≈ 3.4) and the activation energy for nucleophilic acyl substitution reactions. Residual water content, a critical parameter in subsequent coupling reactions, is routinely controlled to ≤0.5% by Karl Fischer titration (ASTM E203).
Substitution on the 2-phenyl ring of the thiazole-4-carboxylic acid scaffold directly influences the electrophilicity of the carbonyl carbon and the metabolic stability of derived active pharmaceutical ingredients. The fluorine atom’s strong inductive withdrawal (−I effect) is partially offset by its resonance donation (+M effect), resulting in a net electron-withdrawing influence that is weaker than that of chlorine but sufficient to lower the pKa of the carboxylic acid by approximately 0.15 units relative to the unsubstituted phenyl compound. This acid-strength modulation becomes operationally significant in amidation protocols employing weakly basic amines: a 5% molar excess of coupling reagent (e.g., EDC·HCl) suffices for complete conversion of the fluorinated acid, whereas the 4-methyl analog (σp = −0.17) demands a 15–20% excess under identical conditions (DMF, 0–5°C, 4 h reaction time). The fluorine substituent also imparts a characteristic 19F NMR chemical shift at δ −110.2 ppm (referenced to CFCl3), enabling direct monitoring of reaction progression and metabolic fate without chromatographic separation. In contrast, the 4-chloro analog lacks a comparable diagnostic spectroscopic handle. Moreover, the C−F bond length (1.35 Å) and high bond dissociation energy (485 kJ/mol) confer resistance to oxidative metabolism in liver microsome assays, making the 4-fluorophenyl thiazole acid a preferred fragment in medicinal chemistry campaigns targeting cytochrome P450 liabilities.
The compound is routinely supplied with a certificate of analysis capturing the parameters listed in Table 1. Production-scale batches (up to 25 kg) prepared via Hantzsch thiazole synthesis exhibit an assay variation of less than 0.5% across ten consecutive lots when crystallization is controlled to a cooling rate of 0.3°C/min from refluxing acetonitrile. A single impurity at relative retention time 1.15 (tentatively identified as the 2-(3-fluorophenyl) regioisomer) is limited to 0.2 area%.
| Property | Test Method | Typical Value |
|---|---|---|
| Assay (anhydrous basis) | HPLC, 254 nm, C18 column | 98.0–101.0% |
| Melting range | USP <741>, capillary | 195–198°C (decomposition) |
| Water content | ASTM E203, Karl Fischer coulometric | ≤0.5% |
| Residue on ignition | ASTM D5630 | ≤0.1% |
| Solubility (clear solution, 10 mg/mL) | Visual inspection in DMF | Passes |
Amide bond formation constitutes the primary transformation of the carboxylic acid group in synthetic pipelines. Activation with EDC·HCl in the presence of HOBt (each 1.05 equiv) in anhydrous DMF at 0°C generates the corresponding HOBt active ester, which reacts with primary aliphatic amines to give the amide in 78–92% isolated yield after extractive workup and silica gel chromatography (eluent EtOAc/hexanes 1:1). Aromatic amines with electron-withdrawing groups (e.g., 4-nitroaniline) require switching to HATU and DIPEA in DMF at ambient temperature for 16 h to achieve acceptable conversion. On a pilot scale (5–10 mol), the exotherm during HOBt activation has been quantified by inline calorimetry: a maximum temperature rise of 12°C over 60 s is observed when the acid is added in a single portion to the pre-activated EDC/HOBt mixture. Controlled addition via a solids addition funnel over 15 min flattens the exotherm to 2°C/min, preventing impurity formation associated with local overheating.
Medicinal chemistry programs targeting kinase hinge-binding motifs frequently employ thiazole-4-carboxylic acid derivatives as linker elements. The substitution of a 2-phenyl with a 2-(4-fluorophenyl) group alters both conformational bias and hydrogen-bonding capacity. Table 2 collates comparative data derived from development studies on a series of thiazole-4-carboxamide inhibitors of p38α MAP kinase.
| 2-Substituent | σp | pKa of acid | Relative amidation rate (vrel) with glycine methyl ester* | Kinase IC50 (nM) against p38α |
|---|---|---|---|---|
| Phenyl | 0.00 | 3.55 | 1.00 | 120 ± 15 |
| 4-Fluorophenyl | 0.06 | 3.40 | 1.25 | 78 ± 9 |
| 4-Chlorophenyl | 0.23 | 3.25 | 0.78 | 210 ± 30 |
| 4-Methylphenyl | −0.17 | 3.85 | 0.52 | 340 ± 40 |
* Pseudo-first-order rate measured at 25°C in DMF-d7 by 1H NMR monitoring the disappearance of the α-proton signal of glycine methyl ester. Values normalized to the phenyl analog.
Bulk storage at 2–8°C under dry argon maintains the product’s integrity for 24 months from the date of manufacture. Beyond this period, re-qualification by HPLC and Karl Fischer is stipulated. The product is supplied in HDPE drums fitted with a tamper-evident seal and a desiccant pouch containing 500 g of silica gel (orange-to-green indicator). Upon opening, the material must be transferred within 30 min to a glovebox or a nitrogen-flushed dry bag to prevent hydration.
When the carboxylic acid is first converted to the corresponding 4-bromothiazole intermediate via Hunsdiecker-type decarboxylative bromination, the resulting 4-bromo-2-(4-fluorophenyl)thiazole engages in Suzuki–Miyaura cross-couplings with aryl boronic acids under Pd(PPh3)4 (2 mol%) and K2CO3 in dioxane/water (4:1) at 90°C for 12 h. This sequence furnishes biaryl thiazoles with an average isolated yield of 74% over two steps, compared to 61% for the 2-phenyl series, attributable to the lower propensity of the electron-poor 4-fluorophenyl ring to undergo protodebromination during the coupling step. Yields are marginally higher when XPhos Pd G2 (1.5 mol%) replaces Pd(PPh3)4, but the additional ligand cost must be weighed against throughput gains on scales exceeding 500 g of the thiazole starting material.
