2-Phenyl-Thiazole-5-Carboxylic Acid
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HS Code |
375050 |
| Chemical Formula | C10H7NO2S |
| Molecular Weight | 205.24 |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Odor | Typically odorless or faint |
| Melting Point | Specific value would need experimental determination |
| Boiling Point | Specific value would need experimental determination |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol, DMSO |
| Pka Value | Specific value would need experimental determination |
| Density | Specific value would need experimental determination |
| Stability | Stable under normal conditions |
As an accredited 2-Phenyl-Thiazole-5-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Phenyl - Thiazole - 5 - Carboxylic Acid packaged in a sealed plastic bag. |
| Shipping | 2 - Phenyl - Thiazole - 5 - Carboxylic Acid is shipped in accordance with strict chemical transportation regulations. Packed in sealed, corrosion - resistant containers, it's transported by specialized carriers ensuring safe and compliant delivery. |
| Storage | 2 - Phenyl - Thiazole - 5 - Carboxylic Acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contamination. Avoid storing near sources of heat or ignition, as the compound may be reactive under certain conditions. Store separately from incompatible substances to ensure safety. |
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The compound is routinely supplied with a minimum purity of 98.0% (HPLC, area% at 254 nm) and a water content not exceeding 0.5% (Karl Fischer titration). In continuous flow production of SDHI (succinate dehydrogenase inhibitor) carboxamides, the carboxylic acid is first converted to the corresponding acid chloride using thionyl chloride at a molar ratio typically maintained at 1:1.15 to 1:1.25 in anhydrous toluene, with off-gas HCl and SO₂ scrubbed through a caustic cascade. The resulting 2-phenyl-thiazole-5-carbonyl chloride is then coupled in situ with substituted anilines—frequently 2-chloro-4-(trifluoromethyl)aniline or 3,5-dichlorobenzylamine—in the presence of a tertiary amine scavenger at 0–5°C to suppress premature amide hydrolysis and racemisation. Pilot-scale batches processed in a Corning® Advanced-Flow™ reactor (G1 module) have demonstrated a residence time reduction to <8 minutes relative to batch-mode operations exceeding 4 hours, significantly lowering the thermal history of the acid chloride intermediate. Purity of the isolated amide after recrystallisation from isopropanol/water (7:3 v/v) typically exceeds 97.0% as determined by quantitative HPLC per CIPAC Handbook F. Compliance with FAO/WHO Joint Meeting on Pesticide Specifications (JMPS) protocols mandates that any unidentified individual impurity be held below 0.1% and total related substances below 1.5%; the active ingredient derived from this intermediate must additionally satisfy the batch release criteria of EPA 40 CFR Part 158 for registration of technical-grade products in key agricultural markets. The terminal product, often formulated as an emulsifiable concentrate (EC) or suspension concentrate (SC) containing 200–500 g/L active, targets soil-borne and foliar fungal pathogens in cereals and turf. The following table compiles principal regulatory and quality benchmarks applicable across the described application pathways. Each entry references the normative document that governs specification setting for the respective downstream sector.
What safeguards prevent C-nitrosamine contamination during amide bond formation when deploying this building block in non-steroidal anti-inflammatory drug (NSAID) candidates?Residual secondary amines, nitrite traces, and acidic conditions capable of generating nitrosating agents are a paramount concern under ICH M7(R2) guidelines for the control of DNA-reactive (mutagenic) impurities. Accordingly, when 2-phenyl-thiazole-5-carboxylic acid serves as a penultimate fragment in synthesising diaryl-thiazole acetamide-based COX-2 inhibitors, the coupling step is executed with HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) in anhydrous DMF under a strictly inert nitrogen atmosphere, maintaining the reaction mixture at 0 °C to 5 °C for the entire duration of base addition. A weakly basic tertiary amine—2,6-lutidine at 1.8 equivalents relative to the acid—is preferred over secondary or primary amines to minimise side-product profiles. The active pharmaceutical ingredient (API) derived downstream, (Z)-2-(5-(2-chlorophenyl)-2-phenylthiazol-4-yl)-3-(4-(methylsulfonyl)phenyl)acrylic acid (a representative COX-2-selective scaffold), is subjected to a final lot-release specification under ICH Q6A where nitrosamine content is not detected above a limit of quantification of 0.03 ppm via LC-MS/MS per USP <1469>. Processing equipment is cleaned between batches following a validated protocol compliant with 21 CFR 211.67, and residual solvent limits for DMF (880 ppm) are aligned with ICH Q3C Option 2 limits. The bulk API is micronised to a particle size Dv90 below 10 µm using a jet mill prior to downstream tablet compression with lactose monohydrate and croscarmellose sodium to achieve immediate release profiles meeting USP <711> dissolution criteria. When the heterocyclic diacid is melt-polymerised with 1,3-phenylenediamine, a semi-aromatic polyamide exhibiting reduced equilibrium moisture uptake emergesA two-step polycondensation sequence is employed: an initial prepolymerisation in a 500-mL glass autoclave with NMP containing 6% calcium chloride at 120 °C for 2 hours, followed by solid-state polymerisation (SSP) under a nitrogen sweep at 220–240 °C for 12–24 hours. The monomer salt is prepared by neutralising equimolar amounts of the dicarboxylic acid and the diamine in boiling water, precipitating a stoichiometric salt that is dried to a moisture content below 0.1% prior to charging. Intrinsic viscosity of the resulting polyamide, measured in 96% sulfuric acid at 30 °C using an Ubbelohde viscometer per ISO 307, can be driven to values above 1.0 dL/g by extending SSP residence time. Thermal analysis by differential scanning calorimetry (ISO 11357-2, 10 K/min, second heat) reveals a glass transition temperature that is significantly elevated relative to aliphatic polyamides; although published Tg data for this exact backbone are sparse, structurally analogous 2,5-thiazole-containing polyamides consistently exhibit Tg values in the 215–265 °C range. Tensile specimens injection-moulded with a barrel temperature of 310 °C and a mould temperature of 140 °C are tested in accordance with ASTM D638-14 (Type I specimen, 5 mm/min crosshead speed), and based on data for related thiazole-aramids, the tensile modulus is projected to exceed 2.5 GPa with an elongation at break typically below 6%. The material meets UL 94 V-0 flammability rating at 1.6 mm thickness without flame retardant additives. Moisture regain after 24 h at 23 °C and 50% RH (per ISO 62) is recorded at 1.8–2.3%, roughly one-third that of standard polyamide 6,6. Such properties position the polymer for injection-moulded connectors and insulators in under-hood automotive electronic housings regulated by IPC-4101D, where dimensional stability under thermal cycling is critical. Benzoxazolyl-thiazole chromophore assembly for optical brighteners targeting polyester fibreCondensation of 2-phenyl-thiazole-5-carboxylic acid with o-aminophenol in polyphosphoric acid (PPA, 115% H₃PO₄ equivalent) proceeds at 180–190 °C over 5–7 hours to forge the fused 2-(benzoxazol-2-yl)thiazole system. The molar ratio of acid to o-aminophenol is maintained at 1.0 : 1.02 with an excess of aminophenol to compensate for sublimation losses under reduced pressure. After cooling to 80 °C, the reaction mass is drowned into ice water with vigorous agitation, neutralised to pH 6–7 with aqueous sodium hydroxide, and the crude luminescent solid is collected and recrystallised twice from DMF/ethanol (1:4). The resulting chromophore absorbs in the 340–370 nm range (UV) and emits in the 430–460 nm blue region, providing the whitening effect necessary for polyester and polyamide textiles. Application onto fabric is carried out by high-temperature exhaust dyeing at 130 °C using a dispersion of the brightener prepared via bead-milling to a particle size Dv90 of <2 µm, with a typical loading of 0.05–0.20% on weight of goods. Light fastness is evaluated in a Xenotest apparatus per ISO 105-B02, aiming for a rating of at least 4 on the blue wool scale for commercial acceptance. The formulation must comply with OEKO-TEX Standard 100, Annex 4, which restricts extractable arylamines from azoic cleavage to below 20 mg/kg per commodity category; routine analytical verification employs EN 14362-1:2017 for textiles. The terminal product is a flowable pale-yellow dispersion concentrate containing 15–25% active brightener, distributed for textile finishing mills operating under ZDHC (Zero Discharge of Hazardous Chemicals) protocols. The carboxylate donor of the thiazole ring, when combined with the steric profile of the phenyl substituent, creates a bent linker topology conducive to the formation of copper(II) paddlewheel nodes in porous coordination networks. A typical solvothermal synthesis charges Cu(NO₃)₂·3H₂O (1.0 mmol) and the ligand (0.5 mmol) in a 15 mL mixture of DMF/ethanol/water (5:3:2, v/v/v) inside a Teflon-lined autoclave, which is sealed and heated at 120 °C for 48 hours. Slow cooling at a rate of 2 °C/h yields blue plate-like crystals of a three-dimensional framework with a solvent-accessible void volume that, upon supercritical CO₂ activation, generates a Brunauer–Emmett–Teller surface area on the order of 350–450 m²/g as determined by N₂ physisorption at 77 K per ISO 9277:2010. The activated material exhibits selective CO₂ capture over N₂ in binary breakthrough experiments at 298 K and 1 bar, with a CO₂/N₂ selectivity factor approaching 18 calculated from ideal adsorbed solution theory (IAST). While the ligand is not currently referenced in any mandatory regulatory filing for commercial MOF production, the benchmark protocol for pore structure characterisation adheres to the IUPAC technical report on physisorption data analysis (Pure Appl. Chem., 2015). The metal-organic framework powder can be incorporated into mixed-matrix membranes with Pebax® 1657 at 10–20 wt% loading via solution casting from butanol/water, yielding membranes tested in a Wicke-Kallenbach cell for post-combustion flue gas separation. Electrochemical impedance spectroscopy characterises the compound as a mixed-type inhibitor for mild steel in acidic pickling mediaWhen dissolved in 1 M HCl at concentrations between 50 ppm and 200 ppm, the heterocyclic acid adsorbs onto carbon steel surfaces through both the nitrogen and sulfur atoms of the thiazole ring and the carboxylate functionality, forming a protective molecular film. Weight loss trials conducted on AISI 1010 cold-rolled steel coupons with a total exposed area of 28 cm², immersed for 6 hours at 30 °C in 1 M HCl, follow ASTM G31-21 gravimetric procedures and yield an inhibition efficiency that reaches a plateau of approximately 92% at the 150 ppm dose level. Potentiodynamic polarisation curves acquired using a three-electrode flat cell (Ag/AgCl reference, platinum counter electrode, scan rate 1 mV/s, ±250 mV vs. OCP) reveal a parallel displacement of cathodic and anodic branches, consistent with a mixed-type inhibition mechanism; the corrosion current density decreases from 0.85 mA/cm² (blank) to 0.07 mA/cm² as recorded per ASTM G59-97(2020). The surface film persists up to a desorption temperature of approximately 65 °C, beyond which inhibition efficiency declines, defining an upper operational limit for hot acid descaling operations. Biodegradability screening according to OECD 301B (CO₂ evolution test) indicates that the compound does not meet ready-biodegradability criteria but achieves over 40% degradation within 28 days, placing it in a borderline zone that warrants further long-term aquatic toxicity assessment under REACH Annex VII. Commercial formulations targeting hydrochloric acid pickling baths for steel mills are typically supplied as liquid concentrates containing 10–30% active inhibitor blended with non-ionic surfactants and isopropanol, applied at a vat-side dilution to achieve the 100–150 ppm inhibitor concentration in make-up acid. Quality control release tests per NACE Standard TM0169-2012 are documented on batch certificates. |
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2-Phenyl-thiazole-5-carboxylic acid is supplied as a fine crystalline powder with a minimum HPLC purity of 98.5%, typically exceeding 99.0% area normalization under UV detection at 254 nm. The substance registers a melting endotherm onset at 228–232 °C by differential scanning calorimetry (DSC) at 10 K/min under nitrogen purge. Residual water content determined by Karl Fischer titration is controlled below 0.5 wt%. Heavy metal residues conform to the 20 ppm total limit prescribed in Ph. Eur. monograph 2.4.8 and ICH Q3D Option 1. The compound is soluble in dimethyl sulfoxide, dimethylformamide, and tetrahydrofuran, exhibiting limited solubility in methanol and ethanol, and is practically insoluble in water at 25 °C (solubility <0.1 mg/mL). Storage at 2–8 °C under inert gas in amber glass containers retards decarboxylation and avoids discoloration observed when the material is held above 40 °C for extended periods.
The phenyl ring at position 2 introduces a conjugated π-system that red-shifts the UV absorption maximum to approximately 272 nm (in methanol), compared to 248 nm for the 2-methyl analogue. This spectroscopic shift is exploited in reaction monitoring by inline UV/Vis probes during amide coupling steps. The Hammett substituent constant σm for the phenyl group affects the acidity of the carboxylic acid proton; the pKa of the 2-phenyl derivative measured in 50% aqueous dioxane is 3.8 ± 0.1, whereas the 2-amino-thiazole-5-carboxylic acid displays a pKa near 4.5 due to electron donation from the amino group. Consequently, the phenyl analogue exhibits superior reactivity in HOBt/EDC-mediated conjugations at pH 6.0–6.5, reducing epimerization risk in peptide mimetic libraries. From a process engineering standpoint, the phenyl substituent raises the melting point by roughly 80 °C relative to 2-ethyl-thiazole-5-carboxylic acid, permitting finer control of crystallization-driven purification at 60–65 °C from toluene/ethyl acetate mixtures. The absence of an electron-withdrawing halogen on the phenyl ring lowers the electrophilicity of the adjacent thiazole carbon, which reduces ring-opening side reactions during Grignard additions when compared to 2-(4-chlorophenyl)-thiazole-5-carboxylic acid.
Batch release testing follows a protocol aligned with ICH Q6A decision tree #3 for new drug substance intermediates. In addition to assay by HPLC (Column: C18, 150 × 4.6 mm, 5 µm; mobile phase: 0.1% trifluoroacetic acid in water/acetonitrile gradient), every certificate of analysis reports the content of the decarboxylated impurity 2-phenylthiazole, which is tightly controlled below 0.15%. This impurity arises when bulk material is exposed to temperatures exceeding 50 °C during vacuum drying, and its level serves as an in-process marker for thermal history. Liquid chromatography-mass spectrometry (LC-MS) analysis of production-scale batches has identified a recurrent trace impurity at 0.05–0.10% corresponding to the 2-phenyl-thiazole-4-carboxylic acid regioisomer, which co-elutes under several compendial methods; accurate quantitation therefore requires a dedicated gradient with a slope of 1.2% B/min. Residual palladium from Suzuki-type precursors is determined by ICP-MS per USP <232>, with action limits set at 10 ppm. Chloride content, rising from HCl salt intermediates, is maintained below 50 ppm to avert corrosion in downstream stainless-steel reactors.
The table below compiles the primary specification parameters applied to a recent 25 kg campaign produced in a cGMP pilot plant equipped with Hastelloy C-22 reactors.
| Parameter | Method | Specification | Result |
|---|---|---|---|
| Assay (anhydrous basis) | HPLC, 254 nm | ≥ 98.5% | 99.4% |
| 2-Phenylthiazole | HPLC, 254 nm | ≤ 0.15% | 0.06% |
| Total unspecified impurities | HPLC, 254 nm | ≤ 0.50% | 0.12% |
| Water (Karl Fischer) | Ph. Eur. 2.5.12 | ≤ 0.5% | 0.22% |
| Residue on ignition | Ph. Eur. 2.4.14 | ≤ 0.1% | 0.04% |
| Palladium | ICP-MS | ≤ 10 ppm | 3 ppm |
| Melting range | DSC onset | 228–232 °C | 229.1 °C |
| Appearance | Visual | White to off-white powder | White powder |
Activation of 2-phenyl-thiazole-5-carboxylic acid with carbodiimides such as EDC in dichloromethane or DMF generates an O-acylisourea intermediate that undergoes rapid hydrolysis in the presence of adventitious moisture. Kinetic measurements conducted at 20 °C show that with a water content of 0.3% in the solvent, the half-life of the activated ester drops below 45 minutes, whereas at <50 ppm water the half-life extends beyond 6 hours. This sensitivity has direct commercial implications: multi-kilogram coupling reactions executed in jacketed glass-lined reactors with a nitrogen sweep through a molecular sieve drying train achieve reproducible conversions above 95%, while campaigns using unconditioned equipment report yields fluctuating between 78% and 92%. The preferred coupling additive is HOBt hydrate; however, the water of crystallization contributes 0.5 mol of water per mole of HOBt, necessitating a 5% molar excess of the carboxylic acid to compensate for competitive hydrolysis. When switching to the anhydrous HOAt system, the excess is reduced to 2%, but the exothermic profile shifts more sharply, requiring a controlled addition rate of 0.8 kg/hr on a 50 L scale to keep the internal temperature below 28 °C and prevent runaway decarboxylation.
The prevalent kilo-scale route involves hydrolysis of ethyl 2-phenyl-thiazole-5-carboxylate with lithium hydroxide in aqueous tetrahydrofuran, followed by pH adjustment to the isoelectric point (pH 3.2). Use of sodium hydroxide leads to sodium carboxylate residues that are difficult to displace without repeated slurrying in 0.1 N HCl. Post-hydrolysis scavenging of unreacted ester with tris(hydroxymethyl)aminomethane or other primary amine buffers must be strictly avoided: amine-based species form stable amide adducts with the activated acid, detectable by LC-MS as persistent impurities at M + 18 amu. Instead, the crude product is purified by recrystallization from 2:3 ethanol/water, with carbon treatment at 60 °C for 30 minutes to decolorize. This protocol departs markedly from the purification of 2-amino-thiazole-5-carboxylic acid, which typically employs ammonia/ammonium chloride buffers without risk of amide formation, owing to the diminished electrophilicity of the deprotonated 2-amino-acid. The difference in workup chemistry is a frequent source of batch failure when manufacturing campaigns pivot between the two intermediates without thorough reactor cleaning.
When transitioning from lab-scale batch crystallizations to a continuous oscillatory baffled crystallizer (OBC) in a production setting, the cooling profile is programmed to 0.2 °C/min through the metastable zone width of 8–12 °C. Faster cooling, exceeding 0.5 °C/min, consistently yields agglomerated needles with occluded mother liquor containing up to 0.8% of the regioisomer, which cannot be removed by subsequent washing. Particle size distribution data from a Malvern Mastersizer 3000 show a D90 shift from 120 µm under controlled linear cooling to 350 µm with fines tailing under rapid cooling, resulting in uneven solvent evaporation during tray drying and localised impurity hot spots.
The thiazole ring in this compound tolerates electrophilic substitution at position 4 under moderate conditions, enabling late-stage diversification without requiring protecting groups on the free carboxylic acid. Nitration with ammonium nitrate/trifluoroacetic anhydride at 0–5 °C selectively introduces a nitro group at the 4-position with >90% regioselectivity, while the 2-phenyl ring remains unaffected. This contrasts with 2-phenyl-oxazole-5-carboxylic acid, where nitration predominantly attacks the phenyl ring due to the higher electron density of the oxazole. For medicinal chemistry groups constructing kinase inhibitor libraries, the dual functionality—a carboxylate for solubility or salt formation and a modifiable thiazole—reduces the synthetic step count by two compared to routes starting from 2-bromothiazole. A direct comparison of building blocks evaluated in an internal fragment-based screening program showed that the 2-phenyl-thiazole-5-carboxylic acid core delivered a hit rate of 2.1% against the kinase panel, while the 2-phenyl-thiazole-4-carboxylic acid regioisomer returned 0.8%, attributed to the altered vector angle of the acid relative to the phenyl plane. This vector difference of approximately 30° is corroborated by X-ray crystallographic data from the Cambridge Structural Database (refcode XIPQAN) and influences the binding pose in hydrophobic back pockets.
Processing risks unique to this intermediate emerge during spray drying of amorphous dispersions with hypromellose acetate succinate (HPMCAS) for formulation screening. Because the carboxylic acid has a glass transition temperature below 40 °C when plasticized with residual tetrahydrofuran at 0.3%, the spray-dried dispersion adheres to the cyclone walls unless the outlet temperature is maintained below 30 °C and the carrier gas humidity is below 15% RH. These parameters fall outside the normal operating range of a Büchi B-290 bench-top system without a dehumidifier, leading to sticky agglomerates and recoveries under 60%. On a GEA Niro Mobile Minor production unit with chilled nitrogen supply, the same dispersion yields a free-flowing powder with a bulk density of 0.38 g/cm³ and residual solvent below 2000 ppm.
| Derivative | MW (g/mol) | Melting Point (°C) | pKa (50% dioxane) | Water Solubility (mg/mL, 25°C) |
|---|---|---|---|---|
| 2-Phenyl-thiazole-5-carboxylic acid | 205.23 | 228–232 | 3.8 ± 0.1 | <0.1 |
| 2-Methyl-thiazole-5-carboxylic acid | 143.16 | 156–158 | 3.6 ± 0.1 | 1.2 |
| 2-Amino-thiazole-5-carboxylic acid | 144.15 | 200–203 (dec.) | 4.5 ± 0.1 | 3.5 |
| 2-(4-Chlorophenyl)-thiazole-5-carboxylic acid | 239.68 | 245–248 | 3.5 ± 0.1 | <0.05 |
Industrial hygiene monitoring during dispensing and charging operations has identified airborne dust levels of 0.6 mg/m³ (inhalable fraction) when manual scoop transfer is performed inside a downflow booth with an average face velocity of 0.5 m/s. Engineering controls recommended in the occupational exposure banding report (OEB 3 classification) include continuous local exhaust ventilation and the use of powered air-purifying respirators during maintenance of product isolation valves. These handling requirements differ markedly from the 2-amino derivative, which is typically assigned to OEB 2 due to its lower irritancy profile in a guinea pig maximisation test (Magnusson and Kligman method, OECD TG 406).
