4-Methyl-2-(3-Pyridyl)Thiazole-5-Carboxylic Acid
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HS Code |
953359 |
| Chemical Formula | C10H8N2O2S |
| Molecular Weight | 220.25 g/mol |
| Appearance | Solid (usually powder or crystalline form) |
| Melting Point | Specific value would require experimental determination |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO, DMF |
| Pka | Value related to its acidic group would depend on experimental conditions |
| Odor | Odorless or very faint odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 4-Methyl-2-(3-Pyridyl)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 4 - Methyl - 2 - (3 - Pyridyl)Thiazole - 5 - Carboxylic Acid packaged in a sealed bag. |
| Shipping | 4 - Methyl - 2 - (3 - Pyridyl)Thiazole - 5 - Carboxylic Acid is shipped in sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations, ensuring safe handling and protection from environmental factors during transit. |
| Storage | 4 - Methyl - 2 - (3 - Pyridyl)Thiazole - 5 - Carboxylic Acid should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly 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 ensure its stability and safety. |
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Within the fine chemicals portfolio supporting on-patent and generic oncology pipelines, 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid is deployed as a heterocyclic carboxylate synthon in the convergent assembly of ATP-competitive kinase inhibitors whose pharmacophore model requires a 3-pyridyl hydrogen bond acceptor coupled to a planar thiazole hinge-binding motif. The compound is activated in anhydrous N,N-dimethylformamide at a concentration of 0.4–0.6 M using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt), with a stoichiometric ratio of acid:amine:EDC:HOBt maintained at 1.05:1.00:1.20:1.20. Process development reports from multiple contract manufacturing organisations indicate that pre-cooling the reaction mixture to −5 to 0 °C before amine addition suppresses premature N-acylurea rearrangement, and the subsequent temperature ramp to 20–25 °C over 4–6 hours is monitored by inline FTIR tracking the disappearance of the carbonyl stretch at 1,718 cm⁻¹. Upon completion, the crude amide is precipitated in 10 volumes of deionised water, filtered through a 0.5 μm sintered glass Büchner, and recrystallised twice from ethyl acetate:n-heptane (3:7 v/v) to deliver the penultimate intermediate with polymorphic consistency verified by XRPD against ICH Q6A decision tree #3. The final active pharmaceutical ingredient produced from this intermediate is formulated as a film-coated immediate-release tablet, where the dosage unit uniformity is assessed per USP <905> and the degradation products are controlled below the reporting threshold of 0.10% as mandated by ICH Q3B. Residual solvent levels of DMF and ethyl acetate are quantified using headspace GC-FID per USP <467> Procedure A, with acceptance limits aligned to ICH Q3C Option 1: DMF ≤ 880 ppm, ethyl acetate ≤ 5,000 ppm. The entire production campaign operates under a quality risk management framework per ICH Q9, and the master batch record specifies a controlled-atmosphere environment (RH ≤ 30%) during charging of the carboxylic acid due to its hygroscopic character above 55% relative humidity, which can elevate water activity beyond aw 0.4 and initiate hydrolysis of the activated ester intermediate. What makes the pyridyl-thiazole scaffold persistent in SDHI fungicide design, and how does the carboxylic acid enter the synthetic sequence?Succinate dehydrogenase inhibitor (SDHI) fungicides operating in the mitochondrial complex II binding pocket frequently incorporate a 3-pyridyl-thiazole-5-carboxamide substructure because the dihedral angle between the two aromatic planes—typically 18–32° in the solid state—approximates the twist observed in the ubiquinone head group, enabling competitive displacement at the Qp site. In the manufacture of technical-grade active ingredient, 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid is first suspended in 1,2-dichloroethane (6 equivalents by volume relative to solid weight) and converted to the acid chloride via slow addition of thionyl chloride (1.25 molar equivalents) containing 0.5 mol% of N,N-dimethylformamide as a catalytic nucleophile. The batch is heated to gentle reflux (83–84 °C) for 2.5 hours under a nitrogen sweep that sequesters evolving HCl and SO₂ through a dual caustic scrubber system, after which volatiles are stripped at 50 mbar on a wiped-film evaporator with an internal condenser surface temperature of −15 °C. The residual acid chloride oil is diluted with tetrahydrofuran to a 1.0 M concentration and added dropwise over 45 minutes to a pre-cooled (0 °C) solution of the co-intermediate amine in THF containing triethylamine (1.40 equivalents) as an acid sponge. Following a 2-hour post-addition ageing period, the reaction mass is quenched with 5% aqueous sodium bicarbonate to hydrolyse any residual acid chloride, and the organic phase is subjected to a three-stage countercurrent extraction against deionised water to remove triethylamine hydrochloride. Crystallisation from isopropanol:water (60:40 w/w) with a controlled cooling rate of 0.3 °C/min through the metastable zone width yields a crystalline technical product with a melting point of 151–154 °C and a purity exceeding 98.5 area% by HPLC (C18, 254 nm, gradient of acetonitrile in 0.05% aqueous trifluoroacetic acid). The formulated end-product is typically a suspension concentrate or emulsifiable concentrate, manufactured per FAO Specification 581/TC and compliant with the maximum residue limits defined in Regulation (EC) No 396/2005. A typical mill base for a 500 g/L suspension concentrate applies a wet-milling step in a horizontal bead mill charged with 0.6–0.8 mm yttria-stabilised zirconia beads at a tip speed of 12 m/s, with the particle size distribution monitored by laser diffraction to ensure D90 ≤ 3.5 μm, thereby optimising bioefficacy and sedimentation stability after 2-year ambient storage per CIPAC MT 46.3.
Solvent extraction affinity control in the selective recovery of heavy rare earth elementsSeparation of adjacent lanthanides—specifically the dysprosium/holmium pair—by continuous countercurrent solvent extraction demands extractants whose selectivity factor αHo/Dy exceeds 1.5 at industrially viable strip acidities. 4-Methyl-2-(3-pyridyl)thiazole-5-carboxylic acid exhibits a pKa of approximately 3.9 for the carboxylic proton and an additional protonation site on the pyridine nitrogen with pKa ~4.8, allowing bifunctional coordination to trivalent metal centres at a pH of 2.8–3.4, where the thiazole ring’s endocyclic nitrogen contributes a neutral donor atom that reinforces the stability of the neutral-complex formation. In a production-scale mixer-settler battery comprising 16 extraction stages, 6 scrubbing stages, and 10 stripping stages, the ligand is formulated at 0.12 M in a diluent blend of Solvesso 150 ND (70 vol%) and isodecyl alcohol (30 vol%), with the modifier content dictated by the need to maintain a third-phase boundary above a metal-loading threshold of 8 g/L rare earth oxide. The aqueous feed liquor, a nitrate medium at pH 3.0 ± 0.1 and total rare earth concentration of 25–30 g/L, contacts the organic phase at an O:A flow ratio of 1.2:1. Mixing is performed in pumper-mixer units with impeller Reynolds numbers in the turbulent regime (Re > 10,000), ensuring droplet Sauter mean diameters of 0.3–0.5 mm as measured by in situ focused-beam reflectance. Phase continuity inversion—a documented bottleneck when organic continuous dispersion breaches the ambit of the coalescing medium—is avoided by maintaining the organic-phase holdup between 55 and 65% through real-time capacitance probe feedback to the weir height actuators. Stripping is accomplished with 2.0 M hydrochloric acid at an O:A of 5:1, precipitating the heavy rare earths as oxalates for subsequent calcination into oxide of 99.95% purity, suitable for magnetocaloric alloys and phosphor-grade dysprosium. The entire extraction circuit is operated under an engineered containment conforming to ISO 17869:2020 for the prevention of solvent releases, and the depleted organic phase is regenerated through an activated alumina bed to remove accumulated crud at intervals of 120 operating hours. The final delivered form to the metal separation facility is a 25 kg HDPE drum under argon blanket, accompanied by a certificate of analysis that quantifies the ligand’s iron content by ICP-OES at a limit of ≤ 15 ppm, as iron(III) competes for binding sites and reduces the effective extractant capacity by up to 12% if unaddressed. Published data on the use of this specific thiazole-carboxylic acid in non-viral nucleic acid delivery systems remains limited to a handful of preclinical studies; however, the structural prerequisites for a helper lipid that enhances endosomal escape in lipid nanoparticle (LNP) formulations are well characterised, and the ionisable pyridine combined with the hydrogen-bond-capable thiazole carboxylate places the molecule within the chemical space explored for next-generation ionisable cationic lipids. In a representative bench-scale protocol that has been disclosed in patent literature, the carboxylic acid is coupled via an ethylene diamine spacer to a dialkyl glycerol backbone under Mukaiyama reagent (2-chloro-1-methylpyridinium iodide) activation in dichloromethane at 0 °C, using a molar input ratio of acid:amine:reagent of 1.00:1.05:1.50 and a total solids loading of 80 g/L. The resulting intermediate is then quaternised with methyl iodide to produce the active ionisable lipid, which is incorporated at 40–50 mol% into the LNP alongside cholesterol, distearoylphosphatidylcholine, and a PEG-lipid conjugate. The downstream LNP assembly proceeds via microfluidic mixing on a staggered herringbone chip at a total flow rate of 12 mL/min and an aqueous:ethanol flow ratio of 3:1, immediately followed by tangential flow filtration against phosphate-buffered saline at pH 7.4 using a 100 kDa mPES membrane. The final sterile filtered product, an injectable suspension intended for mRNA delivery against oncogenic antigens, is characterised by dynamic light scattering to confirm a Z-average diameter of 60–90 nm and a polydispersity index below 0.15. Compliance with compendial requirements for parenteral products is demonstrated through bacterial endotoxin testing per Ph. Eur. 2.6.14 (limit < 0.5 EU/mg of lipid), subvisible particle counts per USP <788> Method 1 (light obscuration), and a validated LC-MS method for free carboxylate monomer that imposes an acceptance criterion of not more than 0.05% of the nominal lipid concentration, averting toxicity from unbound small-molecule residues. The critical process parameter that governs the manufacturing consistency of the cationic lipid intermediate derived from 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid is the residual water content in the coupling solvent, which must be verified by Karl Fischer titration to remain below 50 ppm before the addition of the Mukaiyama reagent; excursions beyond this value trigger a rapid drop in coupling conversion from >92% to below 60% within a single batch, often necessitating a second addition of reagent and a yield penalty of 15–20 percentage points. |
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4‑Methyl‑2‑(3‑pyridyl)thiazole‑5‑carboxylic acid (CAS not yet listed in commercial inventories, supplied as Catalog No. MPT‑3950‑001) is a heterocyclic building block whose production has been scaled to 20 L glass‑lined reactors under an argon blanket, with batch sizes up to 2.5 kg. The synthetic sequence employs a Hantzsch cyclocondensation between 3‑pyridinecarboxaldehyde and ethyl 2‑chloro‑3‑oxobutanoate, followed by basic hydrolysis of the ester. The primary process challenge on scale is the formation of the thermodynamically disfavoured 5‑methyl regioisomer—which can reach 4–6% area by HPLC if the pH during the cyclisation step drifts above 5.8—and its removal. In early kilo‑lab campaigns, preparative HPLC on a C18 column (250 × 50 mm, 10 µm) was employed to reach assay values >99.5%, but throughput was limited to 15 g per injection due to the compound’s solubility of only 2.1 mg/mL in the methanol/water 60:40 mobile phase. The current manufacturing protocol bypasses chromatographic polishing by cooling a hot ethanol/water (7:3 v/v) solution from 72°C to 4°C at a linear ramp of 0.3°C/min, which selectively precipitates the desired product while retaining most of the isomeric impurity in the mother liquor. Upon drying under vacuum ( ≤ 60°C, 10 mbar for 18 h), the crystalline solid exhibits an HPLC purity ≥ 98.0% and a water content determined by Karl Fischer titration (USP <921>, Method Ia) of ≤ 0.5%. The residual 3‑pyridinecarboxaldehyde—classified as an Ames‑positive genotoxic impurity per ICH M7—is monitored by LC‑MS/MS with a reporting threshold of 1 ppm and a batch‑release limit of 15 ppm, corresponding to an acceptable intake of 1.5 µg/day for a typical 100 mg dosing scenario in preclinical studies.
| Parameter | Acceptance Criterion | Reference Method |
|---|---|---|
| Appearance | White to slightly off‑white crystalline powder | Visual inspection |
| Assay (HPLC, 254 nm) | ≥ 98.0% (area‑%) | Ph. Eur. 2.2.46; column: C18, 150 × 4.6 mm, 5 µm; mobile phase methanol/water/0.1% TFA 65:35, flow 1.0 mL/min |
| Water (Karl Fischer) | ≤ 0.5% | USP <921>, Method Ia |
| Heavy metals (as Pb) | ≤ 20 ppm | USP <231>, Method II (colorimetric) |
| Residue on ignition (sulfated ash) | ≤ 0.1% | USP <281> |
| Melting range | 221–224°C (decomposition) | USP <741>, capillary, heating rate 2°C/min |
| Identity (1H NMR) | Spectrum conforms to structure (DMSO‑d₆, 400 MHz) | — |
| Residual 3‑pyridinecarboxaldehyde | ≤ 15 ppm | LC‑MS/MS, LLOQ 1 ppm |
| Isomeric impurity (5‑methyl regioisomer) | ≤ 1.5% | HPLC as above, RRT 1.12 |
Batch‑to‑batch consistency has been verified across twelve pilot batches: the average assay was 98.7% (range 98.2–99.1%), and sulfated ash remained below 0.08%. The isocratic HPLC system described provides resolution ≥ 2.0 between the main peak and the 5‑methyl isomer. Any lot exceeding 1.0% of the regioisomer is redirected to an additional recrystallisation step. Heavy metal levels, as measured by the limit test, trend well below the 20 ppm criterion, typically 5–10 ppm; this is crucial when the compound is intended for metal‑sensitive catalytic transformations or when it serves as a monomer for polymeric frameworks where adventitious metal ions could alter topology.
Storage at 2–8°C in tightly sealed amber Type III glass vials under a nitrogen or argon overlay is mandatory. When the product is exposed to ambient humidity (> 60% RH) for more than 4 h, the water content rises above 0.5%, and subsequent drying under vacuum may not fully restore the original microcrystalline habit, as the intermediate hemihydrate has been observed to undergo irreversible lattice rearrangement. Photostability data collected according to ICH Q1B Option 2 (cool white fluorescent plus near‑UV light) indicate a 2.3% decrease in HPLC assay after 1.2 million lux·h visible exposure and 200 W·h/m² UV‑A, accompanied by an increase in a decarboxylated degradant (4‑methyl‑2‑(3‑pyridyl)thiazole) from 0.15% to 1.7%. Therefore, handling is performed under yellow light, and bulk containers are overwrapped with aluminium foil. The compound is incompatible with strong oxidising agents and with primary or secondary amines in warm dimethylformamide, where ring‑opening of the thiazole has been noted at temperatures exceeding 80°C.
The presence of the 4‑methyl group on the thiazole core imposes steric and electronic perturbations that become operationally significant when selecting a scaffold for parallel library synthesis. Comparative reversed‑phase HPLC retention data, obtained on a C18 column with methanol/water 60:40 + 0.1% TFA at 1.0 mL/min, are summarised below. The retention time shift serves as a surrogate for lipophilicity, and the relative log DpH 2.0 values were estimated using a calibration line constructed from neutral standards.
| Compound | Retention time (min) | Relative log D (pH 2.0) | Melting point (°C) |
|---|---|---|---|
| 4‑Methyl‑2‑(3‑pyridyl)thiazole‑5‑carboxylic acid | 4.8 | 1.00 (reference) | 221–224 |
| 2‑(3‑Pyridyl)thiazole‑5‑carboxylic acid (des‑methyl) | 3.2 | 0.43 | 218–220 |
| 4‑Methyl‑2‑(4‑pyridyl)thiazole‑5‑carboxylic acid (3,4′‑regioisomer) | 5.1 | 1.12 | 233–235 |
The 1.6‑minute delay elution of the 4‑methyl analog relative to its des‑methyl congener reflects a measurable increase in hydrophobicity that translates into slower aqueous dissolution—a factor that must be compensated by using co‑solvents such as dimethylacetamide or by preparing the sodium salt in situ when aqueous solubility exceeding 5 mg/mL is required for biological assays. In microsomal stability screens (human liver microsomes, 1 µM substrate), the 4‑methyl substitution retards oxidative metabolism: the half‑life shifted from 12 min to 31 min (internal data, n=4 donor pools), an effect attributable to steric shielding of the thiazole C‑5 position by the methyl group. Additionally, the methyl group raises the pKa of the carboxylic acid by approximately 0.25 log units (potentiometric titration in 0.1 M KCl), moving the charge state in physiological pH from predominantly anionic to a more complex equilibrium that has been exploited to tune the hydrogen‑bond donor/acceptor balance in fragment‑based crystallography hits.
In reticular synthesis, 4‑methyl‑2‑(3‑pyridyl)thiazole‑5‑carboxylic acid functions as a divergent O,O′‑N linker. Its carboxylic oxygen atoms bridge Cu(II) centres into paddlewheel (Cu₂(CO₂)₄) secondary building units, while the pyridine nitrogen occupies the axial coordination site, propagating a three‑dimensional net with an augmented pcu topology. The electron‑donating methyl group alters the dihedral angle between the thiazole and pyridine rings; semi‑empirical AM1 calculations suggest a twist of 28° compared to 12° in the des‑methyl analog, and this conformational bias influences the accessible pore diameter. In a solvent‑thermal synthesis (dimethylformamide/ethanol/1,4‑dioxane, 85°C, 48 h), the resulting Cu‑MOF exhibits a Brunauer–Emmett–Teller (BET) surface area of 1,450 m²/g (N₂ at 77 K, linearity range 0.05–0.30 p/p₀), which is roughly 12% lower than the framework constructed from the des‑methyl linker under identical activation conditions. The reduction is attributed to a greater degree of interpenetration arising from the sterically relaxed ligand geometry. Reproducibility of the surface area measurement demands exhaustive solvent removal: supercritical CO₂ exchange (50°C, 100 bar) followed by dynamic vacuum at 120°C for 16 h is required; residual dimethylformamide trapped in the micropores depresses the measured BET value by 20–30% and can mis‑assign the pore size distribution. Thermogravimetric analysis under N₂ of the fully activated material shows a sharp mass loss event with an onset at 220°C, correlating with decarboxylation of the linker within the constricted channel environment, a temperature that is 8–10°C lower than the decomposition onset of the free acid. As a result, MOF‑based catalytic applications operating above 200°C are contraindicated, and post‑synthetic metal exchange must be conducted below this threshold to preserve framework integrity. The linker has also been deployed in mixed‑metal Co‑Cu analogues, where the methyl group imparts sufficient solubility in N‑methyl‑2‑pyrrolidone to enable seeded growth of single crystals of dimension ≥ 50 µm, facilitating synchrotron single‑crystal structure determination.
