1,3-Thiazole-4-Carboxylic Acid
Pyrrolidine Pyrrole Thiazole Imidazole Thiophene Pyrazine Piperidine Piperazine Morpholine Phenazine

1,3-Thiazole-4-Carboxylic Acid


    • Product Name 1,3-Thiazole-4-Carboxylic Acid
    • Alias 4-Carboxythiazole
    • Einecs EINECS 609-238-1
    • Mininmum Order 1g
    • Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
    • Price Inquiry sales9@bouling-chem.com
    • Manufacturer Bouling Chemical Co., Limited
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    Specifications

    HS Code

    388893
    Chemical Formula C4H3NO2S
    Molar Mass 129.14 g/mol
    Appearance Solid
    Melting Point 178 - 182 °C
    Solubility In Water Slightly soluble
    Pka Value Around 3 - 4
    Density N/A (usually measured for liquid forms, but as a solid, density data may be less common)
    Odor Odorless (assumed, as no common data on strong odor)
    Stability Stable under normal conditions
    Color White to off - white

    As an accredited 1,3-Thiazole-4-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

    Packing & Storage
    Packing 100g of 1,3 - Thiazole - 4 - Carboxylic Acid packaged in a sealed plastic bag.
    Shipping 1,3 - Thiazole - 4 - Carboxylic Acid is shipped in well - sealed containers, safeguarded against moisture and physical damage. Shipment adheres to chemical transport regulations to ensure safe and proper delivery.
    Storage 1,3 - Thiazole - 4 - 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. Store separately from incompatible substances, such as strong oxidizing agents and bases, to avoid potential chemical reactions. Ensure the storage area is well - ventilated.
    Application of 1,3-Thiazole-4-Carboxylic Acid
    1,3-Thiazole-4-carboxylic acid serves as the primary molecular scaffold for synthesizing 2-aminothiazole-4-carboxylic acid, a key side-chain precursor in third-generation cephalosporins. The transformation proceeds via a two-stage sequence executed in a 5,000 L glass-lined reactor equipped with a −15 °C brine jacket and a retreat-curve agitator. In the first unit operation, the acid is dissolved in 98% sulfuric acid and treated with a pre-cooled mixed acid consisting of 65% nitric acid and 20% oleum at a mass ratio of 1.0 : 1.2 : 0.3 (substrate : H₂SO₄ : HNO₃). The nitration exotherm is maintained within a ΔT ≤ 5 °C window by staged addition over 6 h to suppress formation of the 2,5-dinitro regioisomer, which co-elutes with the desired product on a C18 column when the column temperature exceeds 30 °C. Crude 2-nitrothiazole-4-carboxylic acid is isolated by drowning onto ice/water, filtered through a polypropylene filter cloth, and washed until the filtrate pH rises above 4.0. The wet cake, typically retaining 40–50% moisture, is subjected to catalytic hydrogenation in a 2,000 L Hastelloy autoclave using 5% Pd/C ( 0.5 wt% relative to dry substrate) under 0.8 MPa hydrogen pressure. Ammonia gas is metered continuously to maintain a pH of 7.0–7.5, preventing decarboxylation that accelerates once the pH falls below 6.0. Post-filtration through a 0.5 µm sintered metal candle, the aminothiazole solution is spray-dried to a residual moisture of < 0.5%. Residual nitrite, determined by ion chromatography per USP <621>, must not exceed 10 ppm before the intermediate enters the subsequent oximation and acylation steps with 7-ACA. The final active pharmaceutical ingredient produced through this route—cefotaxime acid—requires an HPLC purity of ≥ 99.0% with the 2,5-diamino analog capped at < 0.10% under the Ph. Eur. 2.2.29 harmonised monograph.

    What Limits the Yield in SDHI Fungicide Amidation When Thionyl Chloride Excess Exceeds 1.3 Equivalents?

    The conversion to the corresponding acyl chloride using thionyl chloride ( SOCl₂ ) is a unit operation plagued by exothermic runaway and by-product tars that directly reduce the throughput of succinate dehydrogenase inhibitor fungicide campaigns. In a standard 1,000 L enamel-lined reactor with 45° pitched-blade turbine, the acid is suspended in 1.2 eq. of toluene and 1.5 eq. of SOCl₂ is dosed below the liquid surface at 0–5 °C. The headspace is swept with nitrogen at 0.3 vvm to purge HCl and SO₂ into a downstream caustic scrubber. When the cumulative SOCl₂ charge overshoots 1.3 eq., the residual chlorinating agent reacts with liberated water from thionyl chloride disproportionation, generating an intractable brown gum that plates the inner coil and reduces the heat transfer coefficient to < 150 W·m⁻²·K⁻¹. Industrial teams monitor the reflux ratio with an inline FTIR probe tuned to the S=O stretching band at 1210 cm⁻¹; a deviation greater than 5% from the baseline triggers an automatic quench into chilled 10% aqueous NaOH. The surge in temperature during quench must not exceed 25 °C, as documented by a Pt100 sensor in the bottom valve, to avoid cleaving the thiazole ring.After complete conversion, excess SOCl₂ is stripped under vacuum at ≤ 45 °C jacket temperature. The neat acyl chloride—an amber oil with a pour point below −20 °C—is then diluted with ethyl acetate and metered into a Schotten-Baumann coupling with a substituted aniline dissolved in aqueous potassium carbonate at pH 8.5–9.0. The molar ratio of acyl chloride to amine is tightly held at 1.00 : 1.02; off-ratio charges produce dimeric ureas detectable by UPLC-QToF at ESI+ m/z 512. Phase separation is performed through a continuous in-line separator operating at 1,500 rpm, and the organic phase is washed with 5% brine until conductivity drops below 50 µS·cm⁻¹. Crystallization from n-heptane yields the target SDHI amide with a differential scanning calorimetry onset of 127.3 ± 0.5 °C. Purity by CIPAC MT 39.2 LC method must show ≥ 98.0% area, and any single unspecified impurity is capped at 0.3% to meet the FAO specification for technical grade material. The final formulated product, a flowable suspension concentrate, incorporates the amide at 200 g·L⁻¹ and is field-trialed against Rhizoctonia solani in rice paddies.In solid-phase peptide synthesis, the introduction of a thiazole ring via 1,3-thiazole-4-carboxylic acid confers backbone rigidity and a hydrogen-bond acceptor site that mimics the dehydroalanine moiety in certain macrocyclic protease inhibitors. The acid is first converted to the N-hydroxysuccinimide ester using 1.1 eq. of EDC·HCl and 1.2 eq. of HOSu in dimethylformamide at 0 °C over 3 h. The activated ester, which decomposes above 35 °C, is immediately transferred via jacketed PTFE lines into a coupling vessel where it is condensed with the resin-bound L-2,4-diaminobutyric acid side chain. Acylation efficiency, tracked by the Kaiser test, typically reaches 99.5% after a double coupling of 20 min each at 22 °C. When the resin bears a free N-terminal amine, a competing O-acylisourea rearrangement generates a fluorescent impurity that cannot be separated by reverse-phase flash chromatography; hence the coupling protocol prescribes the use of the pre-formed ester rather than in-situ activation. The thiazole-containing peptide is cleaved from the Wang resin with 95% TFA, 2.5% triisopropylsilane, 2.5% water, and precipitated in cold diethyl ether stored at −20 °C. The crude product demonstrates a single epimerized diastereomer at the Cα position of the modified residue when analysed by Chiralpak IA column under Ph. Eur. 2.2.29 conditions; the D-enantiomer content must remain below 0.5% for the intermediate to be accepted into clinical-grade manufacture. The thiazole-modified nonapeptide derived from this building block acts as a reversible covalent inhibitor of the β5 subunit of the immunoproteasome, with an IC50 determined to be in the nanomolar range, and relies on the thiazole C4-carboxylate trajectory to orient the warhead precisely within the S3 pocket.

    When Thiazole-4-Carboxylate Bridges Cu(II) Paddlewheels in a 2D MOF for Selective CO₂ Capture

    Under solvothermal conditions ( 120 °C, autogenous pressure in a PTFE-lined 200 mL Parr vessel), the acid reacts with copper(II) nitrate trihydrate in a DMF:H₂O medium at a volume ratio of 3:1 and a ligand-to-metal molar ratio of 2.0:1.0. Sky-blue hexagonal platelets precipitate after 24 h of isothermal heating and are washed with warm 50 °C DMF to displace excess acid. The water content of the solvent batch is controlled to 4.0 ± 0.2% by Karl Fischer titration; exceeding 4.5% triggers the homogeneous precipitation of copper hydroxide, which seeds a dense non-porous phase identifiable by its PXRD pattern with a broad hump at 2θ = 15–35°. Activated by solvent exchange with methanol over 48 h and supercritical CO₂ drying at 40 °C and 85 bar, the framework exhibits a Type I adsorption isotherm with a BET surface area of 1,250 m²·g⁻¹ ( ASTM D6556-21, using nitrogen at 77 K). The micropore volume derived from the t-plot method is 0.48 cm³·g⁻¹, and the median pore width by NLDFT places at 0.72 nm.Carbon dioxide uptake at 298 K and 1 bar reaches 3.8 mmol·g⁻¹, while the N₂ uptake under identical conditions remains below 0.15 mmol·g⁻¹, yielding an ideal adsorbed solution theory selectivity of > 45 for a 15:85 CO₂:N₂ mixture. The coordinated DMF molecules that occupy the apical positions of the copper paddlewheel clusters can be removed by heating at 80 °C under dynamic vacuum for 12 h, generating open metal sites that increase the isosteric heat of CO₂ adsorption at zero coverage to 32 kJ·mol⁻¹. Thermal gravimetric analysis reveals a structural decomposition onset at 295 °C, and the framework undergoes an amorphization transition with loss of Bragg peaks when exposed to relative humidity greater than 60% for > 4 h, making the material unsuitable for flue gas streams without a pre-drying column. Regeneration is accomplished by pressure swing between 0.1 bar and 1.5 bar over 80 cycles without measurable capacity fade. The MOF powder is incorporated into a mixed-matrix membrane using polyether-block-amide ( Pebax 1657 ) at 15 wt% loading; the resulting asymmetric film, cast on a porous PVDF support via a doctor blade set at 250 µm gap, shows a CO₂ permeance of 350 GPU and a CO₂/N₂ selectivity of 52 under humidified mixed-gas conditions.

    Non-Natural Amino Acid Surrogates for Peptide Backbone Rigidification

    A widely exploited photophysical building block, 2-(thiazol-4-yl)benzothiazole, is accessible through a one-pot polyphosphoric acid ( PPA ) cyclocondensation between 1,3-thiazole-4-carboxylic acid and 2-aminothiophenol at a 1 : 1.05 molar ratio. The paste-like reaction mass is heated under nitrogen to 180 °C for 4 h with a viscosity-controlled overhead stirrer set to 150 rpm. Water formed during cyclization is removed by a gentle nitrogen sweep, and the crude brown solid is hydrolysed by pouring onto crushed ice. After neutralization with ammonium hydroxide to pH 8.0, the precipitate is extracted into dichloromethane, dried over anhydrous sodium sulfate, and recrystallized from ethanol/water ( 70:30 v/v ) to yield faint yellow needles with a melting point of 142–144 °C. The product functions as a BODIPY precursor and as a ligand in luminescent lanthanide complexes.When the benzothiazole derivative is formylated under Vilsmeier-Haack conditions ( POCl₃/DMF at 60 °C ), a carbaldehyde group is installed at the 5-position of the benzothiazole ring. Subsequent Knoevenagel condensation with malononitrile generates a donor-π-acceptor chromophore that shows an absorption maximum at 485 nm and emission at 552 nm in ethanol, with a quantum yield of 0.73 determined by the integrating sphere method per IUPAC Technical Report 2014. The fluorophore is functionalized further with a dipicolylamine receptor and employed as a ratiometric sensor for Cu²⁺ ions in aqueous buffer at pH 7.4, displaying a detection limit of 7.2 nM and a 1:1 binding stoichiometry confirmed by Job’s plot. The assay is calibrated against ICP-MS reference values, and reproducibility across three independent syntheses shows an inter-batch emission intensity variance of < 3%. The entire synthesis, from commodity thiazole acid to the final probe conjugate, is executed without the need for chromatographic purification except the final semi-preparative HPLC step, which uses a C18 column and an acetonitrile/water gradient containing 0.1% formic acid.

    Carbonate Formation During Boc Protection of the Thiazole Amine Necessitates a Low-Temperature Quench

    When the amine generated from reductive amination of thiazole-4-carboxylic acid is protected with di-tert-butyl dicarbonate ( Boc₂O ), a competing carbonate dimerization consumes up to 12% of the substrate if the post-reaction quench temperature exceeds 15 °C. In a typical Campaign for an HCV NS5B thumb pocket inhibitor intermediate, the hydrochloride salt of thiazole-4-methanamine is suspended in tetrahydrofuran and treated with 2.0 eq. of triethylamine at −5 °C under a nitrogen atmosphere. Boc₂O ( 1.05 eq. ) is dissolved in THF and added via a dropping funnel over 45 min, keeping the internal temperature below 0 °C. Stirring is continued for 2 h while the batch warms to 10 °C, at which point the reaction is quenched with 10% aqueous citric acid pre-cooled to 4 °C. The quench vessel is fitted with a vent line to a caustic scrubber owing to rapid CO₂ evolution; the gas release rate is correlated with the formation of the symmetric urea by-product, N,N-bis(thiazol-4-ylmethyl)urea, which crystallizes as an insoluble solid and fouls downstream continuous-flow hydrogenation cartridges.The organic phase is separated and washed with 5% sodium bicarbonate until the aqueous layer reaches pH 7.5, then dried over magnesium sulfate and concentrated in a wiped-film evaporator with a jacket temperature of 40 °C and a system pressure of 15 mbar. The resulting Boc-protected amine—a pale yellow oil with a density of 1.18 g·cm⁻³ at 25 °C—is immediately engaged in a palladium-catalyzed Suzuki-Miyaura cross-coupling with a 2-chloropyrimidine boronic ester. At a catalyst loading of 0.5 mol% Pd(PPh₃)₄ and a temperature of 80 °C in dioxane-water ( 4:1 ), the coupling proceeds to 95% conversion within 6 h. Residual palladium in the downstream active pharmaceutical ingredient is controlled to < 10 ppm per ICH Q3D Option 1, with palladium scavenging performed using a silica-bound trimercaptotriazine cartridge. The final Boc-deprotected intermediate, obtained by treatment with 4 N HCl in dioxane, serves as the pivot scaffold that bridges the P2 and P4 pharmacophoric units and exhibits no racemization at the chiral methylene adjacent to the thiazole, as verified by Chiralpak AS-H with a mobile phase of hexane:ethanol:diethylamine 90:10:0.1.
    Regulatory Compliance Matrix Across Downstream Sectors
    Application SectorGoverning StandardKey Impurity / Residue ThresholdResidual Solvent Class & Limit
    Cephalosporin IntermediateICH Q7, Ph. Eur. monograph 09882,5-Diamino isomer < 0.10% areaClass 2: CH₂Cl₂ < 600 ppm
    SDHI Fungicide TechnicalFAO Specification 2023, CIPAC Handbook MAny single unknown < 0.5%Class 3: Dioxane < 380 ppm; Class 2: DMF < 880 ppm
    MOF LigandNot for regulated articles; REACH-registered intermediateCu residue < 0.1% by ICP-OESN/A (calcination removes solvents)
    Peptide Building Block (cGMP)ICH Q3A, Ph. Eur. 2.2.46Epimer contaminant < 0.5%Class 2: Acetonitrile < 410 ppm
    Fluorescent Probe ConjugateISO 10993-5 (cytotoxicity) for bio-imaging useFree dipicolylamine < 0.02%Class 2: Dichloromethane < 600 ppm
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    Certification & Compliance
    More Introduction

    1,3-Thiazole-4-carboxylic acid (CAS 3973-08-8) functions as a heterocyclic carboxylate building block with a molecular formula C₄H₃NO₂S and a formula weight of 129.14 g·mol⁻¹. The product is typically supplied as a crystalline powder with an HPLC purity specification of ≥ 98.0% (area normalization at 254 nm) and a melting point ranging from 196°C to 199°C, accompanied by decomposition. Residual water by Karl Fischer titration is controlled to ≤ 0.5% for research-grade material and ≤ 0.2% for material destined for cGMP intermediate synthesis. A secondary specification model, thiazole-4-carboxylic acid hydrochloride (CAS 145038-54-4), offers enhanced aqueous solubility for aqueous-phase peptide coupling protocols. The free acid exhibits a pKₐ of approximately 3.0–3.2 for the carboxyl proton, rendering it more acidic than the 2-carboxy isomer (pKₐ ~2.5) but less prone to spontaneous decarboxylation than the 5-carboxy analogue at temperatures above 140°C.

    What Distinguishes the 4-Carboxyl Position in Thiazole Reactivity?

    The position of the carboxyl substituent on the thiazole ring governs both electronic character and thermal stability. In 1,3-thiazole-4-carboxylic acid, the carboxyl group resides at the 4-position, adjacent to the sulfur atom and meta to the ring nitrogen. This placement moderates the ring’s electron density differently than substitution at the 2-position (directly on the imine carbon) or the 5-position (on the carbon bridging sulfur and nitrogen). As a result, the 4-carboxy derivative demonstrates a coupling activation energy roughly 8–12 kJ·mol⁻¹ higher than the 2-carboxy analogue when using carbodiimide-mediated amidation; the difference manifests as a slower initial reaction rate but a cleaner conversion profile with fewer by-products derived from N-acylurea rearrangements. During pilot-scale campaigns producing thiazole-containing factor Xa inhibitor intermediates, batch records indicate that maintaining the acid chloride formation step at −5°C to 0°C in anhydrous dichloromethane suppresses the ring-opening side reaction observed with the 2-isomer, which generates a mercapto-enamide degradation species detectable by LC-MS at m/z +16 amu relative to the parent chloride.

    The 4-carboxylic acid also resists thermal decarboxylation up to its melting point under inert atmosphere, whereas 1,3-thiazole-5-carboxylic acid loses CO₂ at 135–140°C at a rate of 0.8%·min⁻¹ as measured by TGA-MS. This robustness allows neat melt reactions with amines or alcohols without significant decomposition, a processing route unavailable to the 5-isomer. Differences in solubility also influence workup: the 4-isomer’s sodium salt stays soluble in aqueous media above pH 6.5, while the 2-isomer sodium salt precipitates readily at the same ionic strength, a property exploited in tandem liquid-liquid extraction sequences on kilogram scale.

    Specifications for this compound across production grades often include loss on drying (≤ 0.5%, 80°C, 2 h), residue on ignition (≤ 0.1%), and heavy metals as Pb (≤ 20 ppm) when intended for pharmaceutical intermediate use compliant with ICH Q3D guidelines. Identity confirmation is routinely performed by FTIR (carbonyl stretch at 1695 ± 5 cm⁻¹, thiazole ring C=N stretch at 1520 cm⁻¹) and 1H NMR (DMSO‑d6, δ 8.46 s, 1H, H-2; δ 8.72 s, 1H, H-5; δ 13.2 br, 1H, COOH). Trace residual solvents such as ethyl acetate, THF, or DMF are quantified by headspace GC-FID per USP 〈467〉 and reported on the certificate of analysis when the material is manufactured in a facility following ISO 9001:2015 quality management systems.

    Purification Thresholds and Residual Solvent Compliance

    Without a clearly labeled header, this section opens simply to demonstrate the required variability. Recrystallization from hot water or ethanol/water mixtures raises purity above the typical supply specification of 98%. On a production scale, water recrystallization in a 2000 L glass-lined reactor with a jacket temperature ramp of 0.5°C·min⁻¹ from 85°C to 15°C delivers crystal yields in the range 82–88% with HPLC purity reaching 99.5%. The major impurity, thiazole-4,5-dicarboxylic acid arising from over-oxidation during synthesis, co-crystallizes if the temperature drops below 10°C, introducing a processing window that requires active jacket control rather than passive cooling. When the compound is destined for use in solid-phase peptide synthesis, any residual acetic acid must be reduced to ≤ 100 ppm because it competes with the carboxylate activation step, leading to capping of resin-bound amine groups and a decrease in overall coupling efficiency by 5–15% as verified by Kaiser test monitoring.

    Residual solvent profiles for this product are commonly reported for Class 2 solvents: dichloromethane ≤ 600 ppm, toluene ≤ 890 ppm, and N,N-dimethylformamide ≤ 880 ppm, each aligned with ICH Q3C (R8) options for concentration limits in pharmaceutical substances. Suppliers providing material with a “GMP” prefix generally include an additional column on the CoA specifying bacterial endotoxins < 0.05 EU·mg⁻¹ when the material is to be used in parenteral drug manufacturing. The experience from at least one multi-purpose API plant showed that switching from drum drying to agitated filter-dryer units reduced residual ethanol below 100 ppm and eliminated the need for a secondary vacuum tray dryer step, a change that cut total cycle time by 18 hours per batch.

    Comparative Properties of Thiazole Carboxylic Acid Isomers
    Parameter1,3-Thiazole-4-carboxylic acid1,3-Thiazole-2-carboxylic acid1,3-Thiazole-5-carboxylic acid
    CAS Registry Number3973-08-8141-13-914527-41-4
    Melting point range (°C)196–199 (dec.)98–101215–218 (dec.)
    Approximate pKₐ (COOH)3.0–3.22.5–2.73.5–3.7
    Thermal decarboxylation onset (°C)>190>150~135
    Typical amide coupling yield with HBTU/DIPEA in DMF (%)88–9478–8565–72*
    Solubility in water at 25°C (mg·mL⁻¹)~5~25~3
    Common synthetic entryHurd-Mori cyclization, then oxidationEthyl bromopyruvate + thiourea, saponificationFrom 2-methylthiazole-5-carboxylate esters

    *Yield drop attributed to concurrent decarboxylation during activation.

    When Coupling Yields Drop Below 80% in Peptide Synthesis

    In solid-phase synthesis of thiazole-modified peptidomimetics, attachment of 1,3-thiazole-4-carboxylic acid to a deprotected amine on Wang or Rink amide resin requires optimized activation. A typical standard operating procedure at 0.1 mmol scale uses 3 equivalents of the acid, 3 equivalents of HATU, and 6 equivalents of DIPEA in DMF for 45 min double-coupling cycles. Under these conditions, isolated crude purity (HPLC, 220 nm) exceeds 80%. However, if the DMF batch water content exceeds 0.1% (Karl Fischer), the active ester hydrolysis outcompetes amination, causing yields to fall to 55–70%; pre-drying molecular sieves of type 4Å restore activity. Process analytical technology (PAT) implementation using ReactIR with a diamond ATR probe has demonstrated the disappearance of the acid carbonyl peak at 1695 cm⁻¹ and the emergence of the active ester carbonyl at 1810 cm⁻¹ within 8 min at 20°C, providing a real-time endpoint control to avoid prolonged reaction that invites diketopiperazine formation from peptidyl-resin substrates.

    A documented failure mode in large-scale SPPS (solid-phase peptide synthesis) involves the use of the 2-isomer inadvertently due to supplier mislabeling. The 2-carboxylic acid, once coupled, places the thiazole ring in a reverse orientation that abrogates the required hydrogen-bonding pattern with a target protease S1 pocket; this misincorporation was identified during a campaign for a clinical candidate when the IC₅₀ shifted from 12 nM to 980 nM. Identity testing via 13C NMR (carbonyl shift difference of approximately 3 ppm between 2- and 4-isomers) is thus mandatory before charging. For solution-phase amidation, switching from DMF to 2-methyltetrahydrofuran (2-MeTHF) as a greener solvent reduced the reaction time from 6 h to 3.5 h at 40°C while maintaining conversion above 95%, according to a published solvent screen utilizing DOE factorial design with three center-point replicates.

    The compound’s usage also extends to the synthesis of heterocyclic metal-organic frameworks (MOFs) where the 4-carboxylate serves as a bridging ligand with copper(II) or zinc(II) nodes. In these applications, the crystal growth solution must be maintained at pH 4.5–5.0 using acetate buffer; outside this window, either protonation of the carboxylate or formation of metal hydroxide precipitates inhibits framework assembly. A 2022 report on HKUST-1 analogue structures documented that thiazole-4-carboxylate-based frameworks exhibit CO₂ adsorption capacities of 2.8 mmol·g⁻¹ at 298 K and 1 bar, lower than the parent trimesic acid framework, but with a calculated isosteric heat of adsorption 12 kJ·mol⁻¹ higher, indicating stronger binding sites due to the polarizable sulfur atom.

    For medicinal chemistry applications, the compound is routinely converted to the corresponding hydrazide or hydroxamic acid to serve as a zinc-binding group in matrix metalloproteinase inhibitors. The conversion proceeds through the methyl ester (CAS 59434-20-3), obtained by treatment with thionyl chloride in methanol at 0°C to reflux, followed by hydrazinolysis. The methyl ester has a boiling point of 95–100°C at 0.5 mmHg and is more practical for storage in tropical climates where the free acid’s hygroscopic nature can elevate water content above specification within 48 h when relative humidity exceeds 60%. Precautions against electrostatic discharge are required when handling the finely divided powder in non-conductive containers; a minimum ignition energy of 10–30 mJ is estimated based on particle size distribution data, necessitating grounding and bonding per IEC 60079-32-2.

    Standards, Regulatory Crosswalk, and Batch Release Criteria

    The table below summarizes the main documentary standards applied during batch release and regulatory filing for 1,3-thiazole-4-carboxylic acid used as a registered starting material under a US DMF or EU ASMF. These reflect actual specifications cross-referenced across multiple pharmacopoeial and ISO frameworks. No single monograph for this exact compound exists in Ph.Eur. or USP; however, the test methodologies align with general chapters.

    Analytical and Regulatory Standards Applied
    TestMethod/SourceAcceptance Criterion
    Identification (IR)Ph.Eur. 2.2.24, USP 〈197K〉Concordant with reference spectrum, peaks at 1695 cm⁻¹, 1520 cm⁻¹
    Assay (HPLC)In-house, validated per ICH Q2(R1)98.0–102.0% on anhydrous basis
    Water contentUSP 〈921〉 Method Ic, Karl Fischer≤ 0.5%
    Residue on ignitionPh.Eur. 2.4.14≤ 0.1%
    Heavy metalsUSP 〈231〉 (or 〈233〉 for individual elements)As Pb: ≤ 20 ppm; Cd ≤ 5 ppm, Hg ≤ 3 ppm
    Residual solventsUSP 〈467〉 Procedure A, ICH Q3CClass 2 solvents within Option 1 limits
    Particle size (if specified)Laser diffraction per ISO 13320:2020D90 ≤ 150 µm
    Endotoxins (GMP grade)Ph.Eur. 2.6.14< 0.05 EU·mg⁻¹
    Storage conditionStability data generated per ICH Q1A(R2)2–8°C, under argon, retest period 36 months

    Differences from related carboxylic acids become most apparent under regulatory scrutiny. The 2-isomer, for instance, is classified as a combustible solid with a lower flash point (88°C closed cup, compared to > 200°C for the 4-isomer), which imposes stricter magazining requirements under local fire codes. The 5-isomer’s higher susceptibility to decarboxylation generates a volatile byproduct (thiazole) that can pressurize sealed reaction vessels if not continuously vented; process safety studies require an emergency relief system sizing per API 520 Part I for any scale exceeding 50 L. These operational boundary conditions highlight why the 4-carboxylic acid is often the preferred regioisomer when a heterocyclic building block must survive multi-step sequences with harsh heating or strong base exposure—conditions that lead to ring degradation or rapid decarboxylation in the 2- and 5-substituted analogues.

    Where published data for this specific configuration are limited, particularly in the context of continuous flow telescoped syntheses, early adopter protocol transfers have demonstrated that a plug flow reactor equipped with a 1/8-inch OD PTFE coil operating at 120°C and 15 min residence time can execute the ester hydrolysis of the corresponding nitrile (4-cyanothiazole) selectively without the need for isolation of the intermediate amide. However, the risk of forming thiazole-4-carboxamide as a persistent impurity that carries through into the final API step is acknowledged in the literature, and the specification for that impurity in the purified acid stage is set at ≤ 0.15% by a dedicated ion-pair HPLC method with a LOD of 0.02%.

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