2-Methyl-Thiazole-4-Carboxylic Acid
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HS Code |
490214 |
| Name | 2-Methyl-Thiazole-4-Carboxylic Acid |
| Molecular Formula | C5H5NO2S |
| Molar Mass | 143.16 g/mol |
| Appearance | Solid (usually white or off - white) |
| Melting Point | 160 - 163 °C |
| Solubility In Water | Slightly soluble |
| Pka | Around 3.7 (approximate value for the carboxylic acid group) |
| Boiling Point | Decomposes before boiling (due to heat - sensitive nature) |
| Odor | May have a faint, characteristic organic odor |
As an accredited 2-Methyl-Thiazole-4-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250g of 2 - Methyl - Thiazole - 4 - Carboxylic Acid packaged in a sealed plastic bag. |
| Shipping | 2 - Methyl - Thiazole - 4 - Carboxylic Acid is shipped in sealed, corrosion - resistant containers. Special care is taken to comply with chemical transport regulations, ensuring safe handling during transit to prevent spills and exposure. |
| Storage | 2 - Methyl - Thiazole - 4 - Carboxylic Acid 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 it separately from incompatible substances, like strong oxidizing agents, to avoid chemical reactions. |
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When the 4-Carboxy Group Undergoes Activated Ester Formation in an Antiviral API RouteFor a developmental oral nucleotide prodrug targeting the hepatitis C virus NS5A phosphoprotein, the 2-methyl-thiazole-4-carboxylic acid scaffold provides the necessary conformational constraint and hydrogen-bonding vector in the P2’ pharmacophore. The synthetic sequence on scale begins with the activation of the free acid with 1,1’-carbonyldiimidazole (CDI, 1.15 eq) in anhydrous tetrahydrofuran (Karl Fischer <100 ppm H2O) under nitrogen at 20–25 °C. Carbon dioxide evolution is complete within 45 minutes; the resultant acylimidazole solution is used without further purification. Subsequent coupling with (S)-1-((2S,5S)-5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methyl-1-oxobutan-2-amine hydrochloride (0.98 eq) in the presence of N,N-diisopropylethylamine (2.5 eq) proceeds to >97% conversion by HPLC (C18, 150 × 4.6 mm, gradient 10–90% MeCN in 0.1% TFA over 25 min, detection at 254 nm). The process is buffered by the slow addition of the amine salt as a solid over 20 minutes to minimize exposure to strongly basic conditions which epimerize the adjacent chiral center. After an aqueous quench with 10% citric acid and phase separation, the crude amide is extracted into ethyl acetate. The organic layer is washed with 5% sodium chloride until neutral pH, dried over anhydrous sodium sulfate, and concentrated to a low-stirred volume. The product is crystallized by the addition of n-heptane as anti-solvent (seed loading 0.5% w/w, linear cooling from 50 °C to 5 °C at 0.15 °C·min−1). Isolation on a Nutsche filter under nitrogen pressure, followed by vacuum tray drying at 40 °C (10 mbar) for 16 hours, delivers a white crystalline solid with a typical batch output of 16–17 kg from a 25 kg input of the starting acid (yield 82–85%). Melting point determined by differential scanning calorimetry: 211.3–213.7 °C (onset). Purity by HPLC area percent: 99.7%. Chiral purity by SFC on amylose-based column: enantiomeric excess 99.9%. The purification protocol was refined after an early production lot showed a 0.6% impurity identified as the 2-methyl-thiazole-4-carboxylic acid dimer anhydride, formed during prolonged storage of the acid at ambient humidity. This byproduct co-elutes with the desired product during routine reversed-phase UPLC, necessitating a dedicated ion-pair chromatography method (tetrabutylammonium hydrogen sulfate, pH 6.8) for release testing. Specification for water content is tightened to <0.15%. Genetic toxicology assessment per ICH M7(R2) control option 3 employs in silico classification (DEREK Nexus, Sarah Nexus) of potential N-acylimidazole carryover; the purge factor calculated via the Teasdale approach is 1.2 × 105, well above the threshold of toxicological concern (TTC) of 1.5 μg/day. Residual solvents are controlled per USP <467> Procedure A: THF limit 720 ppm, heptane limit 5000 ppm. The drug substance intermediate is stored in double polyethylene bags within a UN-certified fibre drum, protected from light at ≤25 °C. Oxidizing agents trigger ring sulfoxide formation and must be excluded from the warehouse storage zone. On standard multipurpose API equipment (glass-lined reactor, anchor agitator), the drying step became the throughput-limiting unit operation. A production campaign data set (n=14 batches) showed that the vacuum tray dryer required 22–28 hours at 50 °C when ambient relative humidity exceeded 60%, compared to 14 hours below 40% RH, due to hygroscopicity of the amorphous fraction generated during rapid precipitation. Controlled bridging is necessary to prevent the product from transitioning into a gelatinous state during the solvent switch.Corrosion Inhibition in Synthetic Metalworking FluidsElectrochemical evaluation of 2-methyl-thiazole-4-carboxylic acid as a yellow-metal corrosion inhibitor in semi-synthetic oil-in-water emulsions (oil content 30% v/v, pH 9.0–9.5 buffered with triethanolamine) was conducted on copper alloy UNS C11000. Test coupons were polished to a 0.05 μm alumina finish, degreased, and immersed in 200 mL of the test fluid according to ASTM D130-19 for 3 hours at 100 °C in sealed glass tubes. Without inhibitor, the strip tarnish rating degraded to 4a (black and green) with an associated mass-loss corrosion rate of 0.721 mg·cm−2 determined gravimetrically per ASTM G1-03. When the sodium salt of 2-methyl-thiazole-4-carboxylic acid was pre-dissolved in the aqueous phase at 0.15% w/w, the rating improved to 1b (slight orange), and the corrosion rate dropped below 0.041 mg·cm−2. Anodic polarization curves (scan rate 0.5 mV·s−1, Ag/AgCl reference) revealed a shift in open-circuit potential from −212 mV to −88 mV, suggesting strong anodic suppression. The heterocyclic architecture enables coordination of copper(I) through the thiazole ring nitrogen and the exocyclic carboxylate oxygen in a five-membered chelate ring. X-ray photoelectron spectroscopy (XPS) of the inhibited copper surface confirmed the presence of Cu 2p3/2 binding energy at 932.6 eV, consistent with a Cu(I)-thiazole complex, along with a detectable S 2p signal at 162.3 eV. A comparative dose–response study was conducted to determine the minimum effective concentration under conditions of high water hardness (400 ppm CaCO3 induced by calcium acetate). The data obtained at 72 hours aging at 35 °C are summarized in the table below.
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Catalogued under CAS 1203-98-5 and supplied as reference standard MTCA‑4 (Prod. No. TZ‑4201), 2‑methyl‑thiazole‑4‑carboxylic acid (C5H5NO2S, molecular weight 143.16 g mol−1) is a white to off‑white crystalline powder deployed as a regiospecific heterocyclic building block in pharmaceutical intermediate synthesis, crop‑protection lead optimisation, and organometallic ligand design. Typical lot‑release purity determined by reverse‑phase HPLC (area‑%) exceeds 98.5 %, with the primary impurity being the regioisomeric 2‑methyl‑thiazole‑5‑carboxylic acid tracked at ≤ 1.0 % via a C18 column and acetonitrile/0.1 % phosphoric acid mobile phase (λ = 254 nm). The compound differs fundamentally from non‑methylated thiazole‑4‑carboxylic acid and from positional isomers by virtue of the electron‑donating methyl group at C‑2, which raises the pKa of the carboxylic acid by approximately 0.5 units and alters the ring π‑electron density, consequences that translate into divergent amidation rates, crystallinity of derived salts, and metabolic stability of final drug candidates.
The batch‑to‑batch consistency demanded by current‑good‑manufacturing‑practice intermediate delivery is assured through a multi‑parameter release panel. Each 25‑kg fibre drum is accompanied by a certificate of analysis reporting the following metrological framework. Water content is determined by Karl‑Fischer coulometry (Mettler Toledo C30, Hydranal‑Composite 5) and routinely held below 0.5 % w/w; material exposed to relative humidity above 60 % for more than 4 h requires vacuum drying at 40 °C and 10 mbar before use. Residue on ignition (ASTM D5630‑13, 600 °C) is specified at ≤ 0.10 %, while elemental impurity screening by ICP‑MS (Agilent 7800) confirms lead ≤ 10 ppm, cadmium ≤ 5 ppm, and arsenic ≤ 3 ppm, aligning with Option‑2 limits of USP 〈232〉. Residual solvent content, quantified via headspace GC‑FID (Agilent 7697A/7890B, DB‑624 column) and assessed against ICH Q3C Guideline Table 2, is controlled at petroleum ether (class 3) < 5000 ppm and no detectable class‑1 or class‑2 solvents. Melting behaviour is recorded by differential scanning calorimetry (Mettler Toledo DSC 1, 10 K min−1, nitrogen purge) with an onset typically spanning 175–178 °C and a melt enthalpy indicative of polymorphic form I. Purity by HPLC is integrated at 220 nm and 254 nm, with the dual‑wavelength ratio serving as a diagnostic for co‑eluting chromophores.
| Parameter | Specification | Procedure |
|---|---|---|
| Assay (HPLC, area‑%) | ≥ 98.5 % | In‑house SOP LC‑012; C18, 254 nm, acetonitrile/water/0.1 % H3PO4 |
| Water (Karl Fischer) | ≤ 0.5 % | USP 〈921〉 Method Ic |
| Residue on ignition | ≤ 0.10 % | ASTM D5630‑13 |
| Pb, Cd, As | ≤ 10, 5, 3 ppm | USP 〈233〉 / ICP‑MS |
| Residual solvents | Class 3 ≤ 5000 ppm; Class 1/2 ND | USP 〈467〉 Procedure A |
| Melting range | 175–178 °C | DSC, 10 K min−1 |
| Regioisomeric impurity | ≤ 1.0 % | HPLC, method as assay |
Long‑term stability data generated at 25 °C / 60 % RH (ICH Q1A conditions) demonstrate ≤ 0.2 % assay loss over 36 months when the product is double‑bagged in LDPE under argon and stored in secondary aluminium‑laminate pouches. Exposure to ambient light for periods exceeding 48 h produces a faint yellow discolouration without significant purity decrease, though material intended for photo‑sensitive coupling steps should be protected from UV wavelengths below 400 nm.
The 4‑position carboxylic acid group is electronically decoupled from the ring‑sulphur atom when the 2‑position carries a methyl substituent, owing to the inductive donor effect that raises the HOMO−1 energy and redistributes electron density toward the C‑4 nitrogen. One practical consequence is an accelerated activation by carbodiimide reagents under anhydrous conditions: activation with EDC·HCl and HOBt in DMF at 0–5 °C proceeds to >90 % conversion within 30 min, whereas the non‑methylated thiazole‑4‑carboxylic acid requires a residence time of 2–3 h under identical stoichiometry to reach equivalent conversion, as tracked by online ReactIR (Mettler Toledo ReactIR 15) monitoring the carbonyl stretch at 1725 cm−1. In Buchwald–Hartwig amination sequences conducted on the acid chloride (generated in situ with thionyl chloride), the 2‑methyl group suppresses undesired ring‑chlorination at C‑5, a side channel that plagues the 2‑unsubstituted congener and depresses isolated yields by 7–12 % according to pilot‑plant batch records on a 100‑L glass‑lined reactor equipped with a retreat‑curve impeller. Producers of a Phase‑II kinase inhibitor reported that switching from thiazole‑5‑carboxylic acid to 2‑methyl‑thiazole‑4‑carboxylic acid as the C‑terminal capping group improved the thermodynamic solubility of the hydrochloride salt in simulated gastric fluid (pH 1.2) from 0.18 mg mL−1 to 0.74 mg mL−1, an effect attributed to altered crystal packing characterised by powder X‑ray diffraction (Bruker D8 Advance, Cu‑Kα).
The acid’s pKa has been determined potentiometrically as 3.45 ± 0.03 in 0.1 M KCl at 25 °C, approximately 0.5 log units higher than that of thiazole‑4‑carboxylic acid (pKa 2.98). This moderate acidity enables selective salt formation with weaker bases such as dicyclohexylamine, facilitating resolution of racemic amines via fractional crystallisation in isopropanol/water mixtures at a manufacturing scale of 50 kg. Simultaneously, the methyl group raises log P by an experimentally measured 0.28 units (shake‑flask method, octanol/water), a factor exploited in the optimisation of blood–brain‑barrier penetration for a series of S1P1 receptor agonists where the 2‑methyl‑thiazole‑4‑carboxamide core provided a brain‑to‑plasma ratio of 0.22 versus 0.09 for the des‑methyl analogue.
Coordination chemistry exploiting the lone‑pair electrons of the ring nitrogen is markedly affected by the methyl substitution pattern. In palladium(II) acetate complexes with bidentate thiazole‑carboxylate ligands, the 2‑methyl‑thiazole‑4‑carboxylato donor forms a seven‑membered chelate ring that remains intact up to 180 °C in DMSO‑d6 without dissociation, as evidenced by variable‑temperature 1H NMR (Bruker Avance III HD 500 MHz), while the 5‑carboxylato isomer undergoes decoordination above 120 °C. This thermal robustness is advantageous in high‑temperature Suzuki–Miyaura cross‑couplings carried out in NMP at 140 °C, where the pre‑formed complex maintains catalytic turnover numbers in excess of 105 with aryl chlorides, outperforming the 2‑aminothiazole‑4‑carboxylato analogue that undergoes gradual ligand oxidation under the same conditions. However, the 2‑methyl group imposes a steric congestion that retards oxidative addition of sterically hindered 2,6‑disubstituted aryl bromides, shifting the rate‑determining step and reducing initial turnover frequency by a factor of 4.3 relative to the 4‑methyl‑thiazole‑5‑carboxylate isomer. Operational boundaries for metal‑catalysed transformations therefore require careful catalyst loading adjustments; published protocols specify 0.5–1.0 mol % Pd(OAc)2 and 1.0–2.0 equiv of base when using 2‑methyl‑thiazole‑4‑carboxylic acid as a ligand precursor.
| Property | 2‑Methyl‑thiazole‑ 4‑carboxylic acid | 2‑Methyl‑thiazole‑ 5‑carboxylic acid | 4‑Methyl‑thiazole‑ 5‑carboxylic acid |
|---|---|---|---|
| CAS | 1203‑98‑5 | 40004‑69‑1 | 20485‑39‑6 |
| Melting range (°C) | 175–178 | 180–183 | 155–158 |
| pKa (carboxylic acid) | 3.45 | 3.12 | 3.58 |
| HPLC retention (min)* | 6.8 | 7.9 | 5.2 |
| Typical amidation yield (HATU/DIPEA) | 85–92 % | 78–84 % | 80–88 % |
| Water solubility (mg mL−1, pH 7 buffer) | 4.2 | 3.8 | 6.5 |
| Residual solvent class | Petroleum ether (class 3) < 5000 ppm | ||
*Conditions: Zorbax SB‑C18, 4.6 × 150 mm, 1.0 mL min−1, acetonitrile/0.1 % H3PO4 30:70.
In late‑stage functionalisation campaigns run on a 200‑L Hastelloy reactor, the 2‑methyl‑4‑carboxylic acid is typically pre‑dissolved in anhydrous DMF (KF 50 ppm) and activated with 1.05 equiv of HATU at −5 °C to avoid racemisation of chiral amine coupling partners. The resulting HATU‑ester intermediate is monitorable by an exotherm of 8–12 K above jacket temperature; addition of the amine is staged over 45 min with methanol co‑solvent (10 vol %) to suppress precipitation of the activated ester. Process robustness is confirmed by in‑line FTIR tracking the disappearance of the O‑acyl isourea band at 1824 cm−1. Following aqueous work‑up at pH 4.5, the amide product typically crystallises from ethyl acetate/heptane in >88 % isolated yield. The 5‑carboxy isomer under otherwise identical conditions yields 82–84 % due to competitive formation of a Meisenheimer‑type by‑product that consumes 3–5 % of the starting acid.
Pre‑formulation studies recommend that sodium salts of 2‑methyl‑thiazole‑4‑carboxylic acid be prepared with 1.0 equivalent of aqueous NaOH (50 % w/w) in ethanol at 50 °C; exceeding pH 10.5 initiates slow ring‑opening at the thiazole sulphur, generating a mercapto‑enamine species detectable by LC‑MS (m/z shift + 18 Da). The free acid should not be milled above 30 °C to avoid static‑charge‑induced agglomeration that complicates dosing into roller‑compacted formulations. When substituting for 2‑aminothiazole‑4‑carboxylic acid in an existing synthetic route, micronisation (jet mill, 2‑μm d50) combined with 0.5 % w/w Aerosil 200 is prescribed to match dissolution rates because the methyl analogue exhibits a reduced intrinsic dissolution rate of 0.26 mg cm−2 min−1 (USP apparatus 2, 50 rpm, pH 6.8 buffer) versus 0.41 mg cm−2 min−1 for the amino variant.
