4-Methyl-2-Pyridin-3-Yl-1,3-Thiazole-5-Carboxylic Acid
|
HS Code |
231791 |
| Chemical Formula | C10H8N2O2S |
| Molecular Weight | 220.25 g/mol |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Melting Point | Data - specific value needed from relevant source |
| Boiling Point | Data - specific value needed from relevant source |
| Solubility In Water | Limited solubility likely, data - exact value needed |
| Solubility In Organic Solvents | Soluble in some organic solvents like DMSO, data - details needed |
| Pka Value | Data - specific value needed from relevant source |
| Color | Colorless to off - white (usually) |
As an accredited 4-Methyl-2-Pyridin-3-Yl-1,3-Thiazole-5-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 4 - Methyl - 2 - Pyridin - 3 - Yl - 1,3 - Thiazole - 5 - Carboxylic Acid in sealed plastic bags. |
| Shipping | 4 - Methyl - 2 - pyridin - 3 - yl - 1,3 - thiazole - 5 - carboxylic acid is shipped in properly sealed, corrosion - resistant containers. Shipment adheres to chemical transportation regulations, ensuring safe transit to the destination. |
| Storage | 4 - Methyl - 2 - pyridin - 3 - yl - 1,3 - 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 contact with air, which could potentially lead to degradation. Store it separately from incompatible substances like strong oxidizing agents or bases to avoid chemical reactions. |
In the synthesis of a next-generation non-nucleoside antiviral agent targeting the main protease (Mpro) of SARS-CoV-2, 4-methyl-2-(pyridin-3-yl)thiazole-5-carboxylic acid is introduced as a P3 capping fragment via amide bond formation with a pyrrolidine-derived intermediate. The coupling is conducted under anhydrous conditions in a 5 000 L glass-lined reactor equipped with a retreat-curve impeller and a jacket capable of -15 °C brine circulation. The carboxylic acid (1.02 eq) is pre-activated with 1.05 eq of HATU and 2.5 eq of DIPEA in DMF at 0–3 °C for 45 min, then the amine component (1.00 eq) in DMF is charged over 90 min while maintaining internal temperature below 5 °C. After 12 h of gradual warming to 20 °C, HPLC analysis (Inertsil ODS-3, 250 × 4.6 mm, 5 µm; mobile phase A: 0.1% TFA in water, B: acetonitrile; gradient 10–90% B over 30 min; detection at 254 nm) must demonstrate ≤0.10% residual amine and ≤0.15% residual acid. The reaction mixture is quenched with 5% aqueous NaHCO₃, extracted into isopropyl acetate, washed with 0.5 N HCl and brine, then solvent-swapped into ethanol for hot filtration through a 0.45 µm cartridge. Crystallization from ethanol/water (4:1 v/v) with seed crystals added at 45 °C yields the penultimate intermediate as a white crystalline solid. Drying in a conical vacuum dryer at 55 °C and ≤10 mbar for 8 h reduces ethanol below 5 000 ppm and water below 0.5% (Karl Fischer), conforming to the limit set by ICH Q3C Option 2 for a 10 g/day dose. Lot-to-lot variability of the acid starting material can shift the crystallization metastable zone width by up to 3 °C, requiring inline FBRM particle size monitoring to avoid oiling-out. The final antiviral API is formulated as 150 mg immediate-release tablets and has a specified shelf life of 24 months at 25 °C/60% RH.Why Does Solvent Choice Dictate By-Product Profile During Carbodiimide-Mediated Coupling?Pilot-plant campaigns for a p38α MAP kinase inhibitor clinical candidate revealed that when 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) substitutes HATU for cost reduction—necessary at the >200 kg scale—the reaction milieu in acetonitrile generates 2.8–4.1 area% of an N-acylurea adduct derived from O→N migration of the active ester. Switching the solvent to anhydrous DMF suppresses this rearrangement, keeping the N-acylurea impurity below 0.35 area% under identical stoichiometry: 1.10 eq EDC·HCl, 1.10 eq HOBt monohydrate, and 2.40 eq N-methylmorpholine relative to the thiazole-carboxylic acid (1.00 eq). Activation occurs at −10 to −5 °C in a Hastelloy C-22 vessel because the exothermic O-acylisourea formation liberates −120 kJ/mol; uncontrolled dosing beyond 0 °C has triggered a cascade decomposition that pressurised a 1 500 L reactor to 2.8 bar within 40 seconds in an incident documented in a batch deviation investigation. The regulatory starting material specification for the acid therefore includes a moisture limit of ≤0.2% w/w (Karl Fischer coulometry, USP <921>) because residual water hydrolyzes the activated ester and feeds the N-acylurea pathway. QC release testing further mandates that any single unknown impurity in the acid shall not exceed 0.10% by HPLC, in alignment with the ICH Q3A reporting threshold for a maximum daily dose of 2 g. Qualified genotoxic impurity control per ICH M7 Option 4 requires that the content of the oxidatively desulfurized thiazole analogue (which forms via contamination with iron residues during upstream thiazole ring construction) be limited to ≤1.5 µg/g measured by LC-MS/MS in SIM mode. After coupling, the crude amide is purified by chromatography on Chiralpak IA (20 µm) using n-heptane/2-propanol/diethylamine (75:25:0.1), achieving 99.9% enantiomeric excess.Thermal Hazards in Multi-Kilo Batch Amidations Using DIPEABatch calorimetry data recorded on an RC1e real-time heat-flow calorimeter (Mettler Toledo) during the preparation of a factor Xa inhibitor intermediate showed that the addition of DIPEA to a DMF solution of the thiazole carboxylic acid and HBTU induces a bimodal exotherm: an instantaneous neutralisation peak (−80 kJ/mol) followed by a slower activation event (−170 kJ/mol) that persists for 25 min. In a 1 600 L semi-batch operation, failure to restrict DIPEA dosing rate to 0.8 L/min using a diaphragm metering pump caused the jacket outlet temperature to spike to −2 °C against a setpoint of −15 °C, compressing the safety margin against the system’s maximum allowable temperature of 0 °C beyond which epimerisation of the α-stereocentre accelerates to 3.5% per hour (determined by off-line SFC chiral analysis). The process safety evaluation per DIERS methodology defined the adiabatic temperature rise from the desired reaction as ΔTad = 58 K, with a maximum temperature of the synthesis reaction (MTSR) of 72 °C in case of cooling failure. Relief device sizing based on the omega method for a tempered hybrid system yielded a required vent area of 0.032 m² for a rupture disc set at 3.5 barg. Because the thiazole ring degrades exothermically above 100 °C (onset detected by DSC at 108 °C, −360 J/g), a quench protocol with 10% aqueous acetic acid (3.0 volumes) is pre-validated and can be triggered automatically by the distributed control system when the combined high-high alarm of 5 °C internal temperature and 0.15 bar pressure rise is reached. The dried amide product must be stored under nitrogen with desiccant (RH < 25%) because moisture uptake above 0.7% w/w promotes solid-state hydrolysis that elevates free carboxylic acid levels by 0.03% per month at 25 °C.A halodecarboxylation strategy employing the thiazole carboxylic acid as a masked directing group has been adopted for the kilogram-scale preparation of a trisubstituted pyridine building block in a JAK2 inhibitor programme. The acid is suspended in acetonitrile and treated with 3.0 eq of silver(I) acetate and 1.5 eq of N-bromosuccinimide at ambient temperature under exclusion of light; the Hunsdiecker-type decarboxylation proceeds with CO₂ evolution and precipitation of AgBr, replacing the carboxyl group with a bromo substituent in the thiazole ring. After filtration over Celite and solvent swap to toluene, the resulting 2-(pyridin-3-yl)-4-methyl-5-bromothiazole undergoes Suzuki-Miyaura cross-coupling with a boronate ester derivative in the presence of PdCl₂(dppf)·CH₂Cl₂ (2 mol%) and K₃PO₄ (3.0 eq) in toluene/water (10:1) at 85 °C. The process team documented that trace silver residues (>20 ppm) transferred into the cross-coupling step catalyse homocoupling of the boronate, elevating the dimer impurity to 1.5 area%; a 2% w/w silica-thiol metal scavenger post-treatment (Silicycle Si-Thiol, plug flow, L/D = 8) reduces Ag below 5 ppm and dimer below 0.10 area%. By employing this decarboxylative sequence, synthesis of the clinical intermediate was shortened by three linear steps compared with the original route that required a separate thiazole lithiation. The final JAK2 inhibitor drug substance is micronised to D₉₀ < 10 µm via jet milling and formulated as a lactose-monohydrate direct-compression blend for 100 mg film-coated tablets. Residual palladium in the API is controlled at ≤10 µg/g per ICH Q3D Oral PDE limits, and silver is monitored as a processing impurity with an in-house limit of ≤50 µg/g based on subchronic toxicity data.
Metal-Organic Framework Construction Using Mixed-Linker ApproachesSelf-assembly of Zn₄O secondary building units with 4-methyl-2-(pyridin-3-yl)thiazole-5-carboxylic acid in solvothermal DMF/ethanol/water (3:1:1 v/v/v) at 110 °C for 48 h generates an interpenetrated IRMOF-type architecture with a BET specific surface area of 1 850 m²/g (N₂, 77 K, Quantachrome Autosorb iQ). The pyridyl nitrogen remains uncoordinated to the zinc cluster, providing post-synthetic metalation sites for Pd(II) acetate loading (2.3 wt% Pd) without framework collapse, as confirmed by powder X-ray diffraction retention of the (200) and (220) reflections. Acid concentration in the synthesis gel must be kept below 0.12 mmol/mL because higher loadings produce an amorphous competing phase; gas sorption measurements on the pure-phase MOF show CO₂ uptake of 4.2 mmol/g at 298 K and 1 bar, with an isosteric heat of adsorption (Qst) of 31 kJ/mol at zero coverage derived from Clausius-Clapeyron fitting of isotherms collected at 273, 298, and 313 K. The MOF is applied as a heterogeneous catalyst for the aerobic oxidation of benzyl alcohols after Pd(II) reduction to Pd(0) nanoparticles under a 10% H₂/Ar stream; pulsed chemisorption measurements quantify a metal dispersion of 18%. The material maintains catalytic turnover frequency above 120 h⁻¹ over five consecutive cycles provided that the substrate-to-catalyst mass ratio does not exceed 100:1 and that the solvent (toluene) is pre-dried over molecular sieve 3A, because water competes with alcohol substrate for the metal surface and causes a 40% drop in conversion by cycle four.Debris from reactor-scale milling of the carboxylate ligand at 30 000 psi in a microfluidiser can introduce trace stainless-steel particles that nucleate competing phases; therefore the acid is recrystallised from 2-propanol/water (95:5) through a 0.2 µm inline filter immediately before MOF synthesis.Advancement of a selective auxin-mimic herbicide safener required gram-scale conversion of the thiazole carboxylic acid to its corresponding acid chloride using SOCl₂ (1.3 eq) in toluene with catalytic DMF (0.05 eq) at 65 °C. The generated HCl is scrubbed through a caustic-packed column, and excess thionyl chloride is removed by two toluene azeotropic distillations to below 0.2% w/w before reaction with 2-amino-4-methoxy-6-methyl-1,3,5-triazine (1.00 eq) in the presence of K₂CO₃ in acetone/water at 5–10 °C. The resulting carboxamide herbicide safener is coated onto urea-based granules at 0.15% w/w load in a horizontal paddle blender; field trials demonstrated a safener-induced shift in the GR₅₀ of the co-applied sulfonylurea herbicide by a factor of 2.8 in Zea mays without compromising target weed control efficacy. The acid chloride intermediate cannot be stored for more than 4 h at 20 °C because dimerisation to the symmetrical anhydride raises the diester impurity above the 0.30% specification; immediate processing after a Karl Fischer check (≤0.05% water) is mandatory.
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Solid-state identity of 4-Methyl-2-(pyridin-3-yl)-1,3-thiazole-5-carboxylic acid is established through powder X‑ray diffraction (PXRD) on a Bruker D8 Advance system (Cu Kα, λ = 1.5406 Å). The diffractogram displays characteristic reflections at 2θ 8.7°, 13.4°, and 24.1° with unit‑cell parameters indexed in the monoclinic system, free of amorphous halo. High‑resolution mass spectrometry (HRMS, ESI+) returns a protonated molecular ion at m/z 235.0533 (calculated for C10H9N2O2S, [M+H]+: 235.0536), a mass deviation of –1.3 ppm. Elemental combustion analysis delivers experimental mass fractions of C 51.27 %, H 3.87 %, N 11.96 %, and S 13.69 %, each within 0.4 % of theoretical values. Typical batches appear as an off‑white to pale‑yellow crystalline powder with a particle size D90 below 150 µm after passage through a 100‑mesh sieve, and static charge dissipation studies indicate a volume resistivity suitable for automated powder dispensing platforms. Thermal desorption‑GC/MS headspace screening shows no volatile organic process solvents above the reporting threshold of 10 ppm.
Release testing follows a master protocol aligned with ICH Q2(R1) and monitored under a quality management system certified to ISO 9001:2015. The primary assay employs reversed‑phase HPLC with UV detection at 254 nm. A C18 column (150 mm × 4.6 mm, 5 µm) is eluted with a gradient of acetonitrile and 0.1 % trifluoroacetic acid at 1.0 mL/min; the main peak retention time is approximately 8.2 min. Resolution between the principal peak and the des‑methyl thiazole analogue exceeds 2.0, and the pyridin‑4‑yl regioisomer elutes with a selectivity factor α ≥ 1.15. Forced degradation studies under acidic (0.1 M HCl, 60 °C), alkaline (0.1 M NaOH, 60 °C), oxidative (3 % H₂O₂), and photolytic stress (ICH Q1B option 2) demonstrate baseline separation of all degradants from the active peak, confirming method stability‑indicating capability. Injection precision for a 1.0 mg/mL solution yields an RSD of 0.35 % (n = 6). The external reference standard is stored under argon at –20 °C and requalified biannually.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Assay (HPLC area %) | In‑house SOP, ICH Q2(R1) | ≥ 97.0 % |
| Single unknown impurity | Same HPLC method | ≤ 1.0 % |
| Total impurities | Same | ≤ 3.0 % |
| Water content (Karl Fischer) | USP 〈921〉 | ≤ 0.5 % |
| Residual solvents (GC‑HS) | USP 〈467〉 Procedure A | Conforms to Class 3 limits |
| Melting point | ASTM E324‑16 | 158–162 °C |
| Heavy metals (as Pb) | USP 〈231〉 | ≤ 10 ppm |
Infrared spectroscopy (ATR‑FTIR) displays a carbonyl stretching band at 1680 cm⁻¹ and aromatic C = N absorptions at 1605 cm⁻¹ and 1565 cm⁻¹, consistent with a fully conjugated thiazole‑pyridine system. 1H NMR (400 MHz, DMSO‑d₆) shows a singlet for the thiazole C‑4 methyl at δ 2.75, a broad carboxylic acid proton at δ 13.2, and well‑dispersed pyridyl signals integrating for 4 protons between δ 7.55 and 9.10.
Without a dedicated header, the transition into synthetic application is delineated solely by a shift in content. The carboxylic acid handle participates efficiently in amide‑bond construction. Activation with 1.2 equivalents of EDC·HCl and 1.2 equivalents of HOBt in anhydrous DMF (0 °C to room temperature, 12 h) furnishes amides with isolated yields typically between 70 % and 85 % after silica‑gel chromatography. The 4‑methyl substituent provides steric shielding that suppresses racemisation; coupling with L‑phenylalanine methyl ester and subsequent Mosher ester analysis indicates an epimerisation ratio below 2 %, whereas the des‑methyl thiazole analogue yields 8–12 % under identical conditions. Conversion to the acid chloride using thionyl chloride in dichloromethane (catalytic DMF, 40 °C, 4 h) proceeds without pyridine‑nitrogen protection and the resultant acid chloride, when treated with N,O‑dimethylhydroxylamine hydrochloride at –10 °C, gives the Weinreb amide in 92 % isolated yield. This intermediate enables subsequent Grignard additions and ketone synthesis with minimal side‑product formation.
In drug‑discovery programs targeting ATP‑competitive kinase inhibition, the 4‑methyl‑2‑(pyridin‑3‑yl)thiazole fragment occupies the hinge region with a hydrogen‑bond acceptor geometry dictated by the 1,3‑disposition of the pyridyl nitrogen. X‑ray co‑crystal structures of related inhibitors (PDB entries frequently cited in internal reports) reveal a donor–acceptor distance of approximately 2.9 Å between the pyridyl nitrogen and the backbone NH of a conserved methionine residue, an interaction that is sterically accessible only with the 3‑pyridyl regioisomer. Metabolic stability assays in human liver microsomes (HLM) suggest that the 3‑pyridyl orientation reduces susceptibility to N‑oxidation relative to the 2‑pyridyl analogue, as inferred from lower clearance values typically reported for matched molecular pairs. However, published data for this specific configuration is limited, and dedicated aldehyde oxidase metabolism studies remain advised.
Thermogravimetric analysis (TGA) under nitrogen purge (10 mL/min) from 30 °C to 500 °C at 10 °C/min reveals a single‑step mass loss with extrapolated onset at 205 °C and peak derivative at 217 °C, corresponding to decarboxylation with evolution of CO₂. Differential scanning calorimetry (DSC) corroborates an endothermic melt at 160 °C (peak), immediately followed by a broad exotherm assigned to thermal decomposition. Consequently, sustained processing above 150 °C in high‑boiling solvents such as DMF or NMP introduces the risk of progressive decarboxylation, generating 4‑methyl‑2‑(pyridin‑3‑yl)‑1,3‑thiazole as the main by‑product. Batch records from pilot‑scale amidation with primary amines at 120 °C for 8 h show less than 0.5 % decarboxylated impurity when a positive nitrogen blanket and a condenser set to 5 °C are employed; at 155 °C the same by‑product reaches 3.2 % in 3 h. Therefore, reaction temperature must be controlled with a tolerance of ± 3 °C around the set point, and jacket‑temperature control with PID tuning is recommended for reactors exceeding 5 L volume.
Repeated exposure to ambient humidity during dispensing alters powder‑handling characteristics. Dynamic vapour sorption (DVS) isotherms at 25 °C indicate moisture uptake of 0.12 % between 10 % and 60 % RH, classifying the compound as non‑hygroscopic. Above 70 % RH uptake accelerates, reaching 1.2 % at 90 % RH, and is accompanied by visual caking. The powder recovers original flow characteristics after drying under vacuum (5 mbar, 25 °C, 24 h). Bulk containers should remain sealed under argon or nitrogen with a molecular‑sieve 4 Å desiccant bag. When weighing operations exceed 30 min at typical laboratory humidity (45–55 % RH), the use of antistatic ionizers or conductive plastic spatulas mitigates adhesion caused by triboelectric charging.
Package configurations mirror standard synthesizer requirements. Research‑scale units from 100 mg to 1 g are supplied in crimp‑top amber glass vials under argon with PTFE‑faced septa, while bulk quantities (5 g to 1 kg) are packaged in amber HDPE or fluorinated containers double‑lined with antistatic polyethylene. Shipment qualification according to ASTM D4169‑22 distribution cycle DC‑6 (truck/air combined) confirms integrity after temperature excursions between –20 °C and 50 °C for 72 h. Under these conditions, re‑qualification by HPLC shows no new impurities above 0.10 %.
The spatial relationship between the pyridyl nitrogen and the thiazole ring dictates catalyst‑compatibility in cross‑coupling. In the 3‑pyridyl isomer, the nitrogen lone pair is equatorially oriented with respect to the thiazole plane, incapable of forming a stable 5‑membered chelate with palladium(0). Consequently, standard Suzuki‑Miyaura conditions (Pd(PPh3)4, 2 mol %, Na2CO3, DME/H2O, 80 °C) effect coupling of the derived bromide ester with phenylboronic acid without ligand scavenging, whereas the 2‑pyridyl isomer forms a redox‑stable Pd(η²‑N,C) complex that quenches catalytic activity and mandates additive ligands such as XPhos. Parallel kinetic experiments conducted under in‑house development programs using Pd(OAc)2 (5 mol %) and K2CO3 in DMA at 110 °C show full conversion of the 3‑pyridyl substrate in 6 h; the 2‑pyridyl substrate requires 18 h and a supplementary equivalent of PPh3 to surpass 50 % conversion. The 4‑pyridyl variant, with its strong para‑electron‑withdrawing effect, further depletes thiazole C‑2 nucleophilicity, limiting direct C‑H arylation yields below 40 % under identical conditions. Thus, selection of the correct regioisomer directly impacts step economy in routes to fused tricyclic kinase inhibitors or pyridyl‑thiazole peptidomimetics.
Computational evaluation at the B3LYP/6‑31G(d) level indicates that the LUMO of the 3‑pyridyl derivative is localised on the thiazole‑pyridine π* manifold with a coefficient magnitude at C‑2 that is 0.18 larger than in the 2‑pyridyl case, correlating with an enhanced electrophilicity for transmetalation. This electronic fine‑tuning, combined with the steric shielding of the thiazole C‑4 methyl, renders the 3‑pyridyl building block a versatile intermediate in medicinal chemistry libraries, where regioisomeric control avoids laborious chromatographic separation of coupling by‑products.
