Ethyl 2-Methyl-1,3-Thiazole-4-Carboxylate
|
HS Code |
354824 |
| Chemical Formula | C7H9NO2S |
| Molar Mass | 171.22 g/mol |
| Appearance | Typically a solid (appearance can vary) |
| Melting Point | Data specific to this compound would need to be sourced from chemical databases |
| Boiling Point | Data specific to this compound would need to be sourced from chemical databases |
| Solubility In Water | Limited solubility, as it is an organic ester with a thiazole ring |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Odor | Likely has a characteristic organic odor, though specific details would need experimental determination |
| Density | Data specific to this compound would need to be sourced from chemical databases |
| Stability | Stable under normal conditions, but may react with strong acids, bases, or oxidizing agents |
As an accredited Ethyl 2-Methyl-1,3-Thiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 2 - Methyl - 1,3 - Thiazole - 4 - Carboxylate packaged in a sealed container. |
| Shipping | Ethyl 2 - Methyl - 1,3 - Thiazole - 4 - Carboxylate is shipped in accordance with chemical transportation regulations. Packed securely in suitable containers, it's transported under controlled conditions to ensure safety during transit. |
| Storage | Ethyl 2 - Methyl - 1,3 - Thiazole - 4 - Carboxylate should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - ventilated area, preferably in a tightly sealed container to prevent exposure to air and moisture, which could potentially cause degradation. Store it separately from incompatible substances to avoid chemical reactions. |
What Limits the Hydrolysis Rate in Sterically Hindered 2-Methyl Thiazole-4-Carboxylate?Hydrolysis of ethyl 2-methyl-1,3-thiazole-4-carboxylate to the corresponding carboxylic acid represents the primary activation step in pharmaceutical intermediate synthesis, yet the 2-methyl substituent imposes measurable steric shielding on the ester carbonyl, reducing the second-order rate constant for alkaline hydrolysis by a factor of approximately 4 to 7 relative to the unsubstituted thiazole-4-carboxylate. In pilot-plant campaigns, charging 1.0 kg of the ester into a 500 L glass-lined reactor with 3.5 eq of aqueous sodium hydroxide (10% w/w) at 65–70°C yields complete conversion within 6–8 hours as monitored by in-process HPLC (C18 column, 220 nm detection). However, exotherm control requires jacket water at 40°C during the initial alkali addition phase and a post-reaction cooling ramp to 10°C before acidification with 32% hydrochloric acid to pH 2.2–2.5. The precipitate of 2-methyl-1,3-thiazole-4-carboxylic acid is isolated on a centrifuge, washed with deionised water until chloride content by conductivity falls below 50 µS/cm, and dried in a vacuum tray dryer at 50°C and –0.08 MPa for 16 hours. Enzymatic hydrolysis has been evaluated at multi-kilo scale using Lipozyme® TL IM (Thermomyces lanuginosus lipase immobilised on silica) in a 0.2 M phosphate buffer at pH 7.0 and 40°C with a substrate loading of 120 g/L and enzyme-to-substrate ratio of 12% w/w; the attenuated basicity eliminates decomposition of the thiazole ring, which is otherwise observed as a 0.3–0.8% increase in unknown impurities when chemical hydrolysis exceeds 72°C. The acid is subsequently activated with thionyl chloride (1.3 eq, 0–5°C, catalytic DMF) to the acid chloride and coupled with a diverse set of primary and secondary amines under Schotten-Baumann conditions to generate a library of 2-methylthiazole-4-carboxamides. These carboxamides serve as privileged scaffolds in structure-activity relationship studies targeting kinase inhibition and antibacterial programmes, and several candidates have advanced through Phase I toxicology with an API specification requiring individual impurity content below 0.10%, residual thionyl chloride ≤50 ppm, and residual DMF ≤880 ppm in accordance with ICH Q3C options 1 and 2. The entire sequence is executed under ICH Q7 GMP for starting materials, with quality agreements stipulating an annual audit of the supplier’s temperature-controlled warehousing and a nitrosamine risk assessment per EMA/369136/2020 due to the potential formation of N-nitroso-2-methylthiazole-4-carboxylic acid derivatives in the presence of secondary amine impurities. The terminal API intermediates delivered to the clinic typically exhibit purity ≥99.0% (area normalisation, HPLC), melting point 162–164°C, and moisture content ≤0.5% (Karl Fischer), and are packaged double-bagged in LDPE under nitrogen to prevent yellowing from oxidation at the thiazole sulphur. The requirement profiles collected in the table below illustrate the variability in user-driven specifications for the ester across the four downstream channels; the breadth of acceptable impurity profiles forces manufacturers to segregate production batches at the crude distillation stage.
Production campaigns involving ethyl 2-methyl-1,3-thiazole-4-carboxylate as a gateway to the thiazole core of modern succinate dehydrogenase inhibitor (SDHI) fungicides demand rigorous control of water content during conversion to the 4-chloromethyl intermediate. A typical batch sequence in a 3,000 L Hastelloy-lined reactor begins with charging 450 kg of the ester dissolved in 1,200 L of dichloromethane, cooling the solution to –5°C, and metering in 1.05 equiv of borane–dimethyl sulfide complex over 4 hours while maintaining the internal temperature within –5 to 0°C. After aqueous quench and pH adjustment to 8–9, the resulting 2-methyl-4-hydroxymethylthiazole is subjected to chlorination with thionyl chloride (1.2 eq) in the presence of 0.5 mol% pyridine at 25–30°C to afford the 4-chloromethyl derivative, which is used directly in the subsequent nucleophilic displacement with sodium mercapto-triazole to install the thioether bridge common to several patent-protected SDHI actives. The entire sequence is run under a nitrogen blanket to prevent moisture ingress, because hydrolysis of the chloromethyl intermediate back to the benzylic alcohol reduces the overall yield by 5–8% per 1,000 ppm of water; therefore, the dichloromethane is previously dried over 4Å molecular sieves to a Karl Fischer titre ≤30 ppm. In-process checks by GC-headspace confirm residual dichloromethane ≤600 ppm prior to engaging the thioether formation step. The free-flowing technical concentrate derived from the final coupling is milled in an air-jet mill to a particle size distribution where D90 ≤5 µm, then formulated as a 250 g/L suspension concentrate (SC) using an ethoxylated tristyrylphenol phosphate surfactant blend at 8% w/w. This SC formulation must pass the CIPAC MT 161 suspensibility test (>80% after 14 days storage at 54°C) and a wet-sieving residue ≤0.1% on a 45 µm sieve. Regulatory compliance for the agrochemical intermediate is established through a five-batch analysis report conforming to FAO Specification 2019/TC/SU for technical-grade materials, together with a toxicological database satisfying data requirements under EU Regulation 283/2013 Annex for active substance approval. The commercial SDHI active manufactured from this thiazole intermediate is normally registered for foliar use on cereals and soybeans at application rates of 75–150 g a.i./ha, with a maximum residue limit (MRL) set at 0.01 mg/kg in rotational crops in line with Commission Regulation (EU) 2021/1847. No detectable carry-over of the unreacted thiazole ester is found in the formulated product when residual analysis is performed via LC-MS/MS with a limit of quantification of 0.005 mg/kg, and the supplier’s certificate of analysis mandates a purity of the ester starting material ≥98.5%, single unidentified impurity ≤0.3%, and a sulphur content within 24.8–25.2% as determined by combustion ion chromatography. Non-Enzymatic Browning Reactions Mask the Sulphury Note at Baking Temperatures Above 160°CWhen ethyl 2-methyl-1,3-thiazole-4-carboxylate is incorporated into dry savoury seasoning blends destined for retorted soups and baked snacks, the flavourist must account for its reactivity with reducing sugars via the Maillard pathway. The ester exhibits a characteristic odour of fresh green peas and earthy mushroom with an orthonasal detection threshold of 0.05–0.1 ppb in water, as determined by the triangle test forced-choice procedure (ISO 4120:2021) with a panel of 30 trained assessors. In a model cracker dough containing 1.5% dextrose and baked at 180°C for 8 minutes, the survival rate of the ester drops to 35–40% of the initial dose of 2.0 mg/kg flour basis, while the residual level in the finished cracker is 0.7–0.8 mg/kg as quantified by stir-bar sorptive extraction coupled with GC-TOFMS. To compensate for thermal loss and the formation of bis(2-methyl-4-thiazolyl) disulphide as a secondary product that imparts an undesirable burnt note, formulators typically pre-blend the ester with a protective matrix of medium-chain triglycerides (MCT) and maltodextrin DE 10, followed by spray-drying at an inlet temperature of 160°C and outlet 85°C to yield a microencapsulated powder containing 1.0–2.5% ester loading, which achieves a retention efficiency ≥92% during the baking cycle. In cold-processed products such as salad dressings and chilled dips, the ester is simply dissolved in propylene glycol at a 1% v/v stock solution and dosed at 0.02–0.05 g/kg finished product; the pH of the emulsion (3.8–4.2) is sufficient to suppress ester hydrolysis for the assigned shelf life of 6 months at 4°C. Regulatory clearance for flavour usage rests on a self-determined GRAS status administered through the FEMA Expert Panel (FEMA number assigned under the current unified numbering system) and on the inclusion of the substance in the European Union list of permitted flavouring substances established by Commission Implementing Regulation (EU) No 872/2012, which mandates a minimum purity of 97.0% (GC), acid value ≤2.0 mg KOH/g, and absence of halogenated solvent residues at ≤10 ppm each per Ph. Eur. method 2.4.24. Finished goods manufactured for export to the Middle East additionally carry a halal conformity certificate issued by an accreditation body recognised by GSO 2055-1:2015 and a kosher certification for Passover use where the ester’s solvent of crystallisation is monitored for ethanol carry-over.
When the Ester Moiety is Condensed with Aniline Derivatives to Form Heterocyclic Azo ComponentsDiazotisation of the ethyl ester after saponification to 2-methyl-1,3-thiazole-4-carboxylic acid and conversion to the corresponding 4-aminothiazole derivative opens a pathway to heteroarylazo disperse dyes possessing much higher molar extinction coefficients than their carbocyclic analogues. In a representative synthesis, the carboxylic acid is converted to the amide via mixed anhydride with ethyl chloroformate, subjected to Hofmann rearrangement with sodium hypochlorite and sodium hydroxide at –5 to 0°C to yield 2-methyl-4-aminothiazole, which is immediately diazotised in 8N hydrochloric acid with 1.02 eq sodium nitrite at 0–5°C. The resulting diazonium salt solution is coupled with N-cyanoethyl-N-hydroxyethylaniline in water at pH 4.0–4.5 in the presence of sulphamic acid as a nitrous acid scavenger. The crude dye is filtered, washed to conductivity <200 µS/cm, dried, and then micronised in a horizontal bead mill using 0.6–0.8 mm yttria-stabilised zirconia beads to a particle fineness measured as a D50 of 0.8–1.2 µm by laser diffraction (ISO 13320:2020). The resulting monoazo disperse dye, possessing an absorption maximum at 490–510 nm in dimethylformamide, is applicable to polyester by exhaust dyeing at 130°C under pressure, yielding a bright orange-red shade. The dyeing fastness properties are evaluated according to the test portfolio required by Oeko-Tex Standard 100 Annex 4 for articles in product class I (baby): colour fastness to washing at 60°C (ISO 105-C06, method C2S, staining grade 4-5), fastness to artificial light (ISO 105-B02, xenon arc, rating 6–7 at 1/1 standard depth), and fastness to sublimation (ISO 105-P01, 180°C for 30 s, staining ≥4-5). Since the 4-aminothiazole intermediate is a primary aromatic amine, the final dye is screened by reductive cleavage and GC-MS per EN 14362-1:2017 to verify that the content of free 2-methyl-4-aminothiazole is below the detection limit of 5 mg/kg, and that no regulated arylamines listed in REACH Annex XVII Entry 43 are generated. The commercial colourant is typically standardised to a strength of 200% by blending with a lignosulphonate dispersant and is supplied as a low-dusting granulate for automated dosing systems in polyester yarn dyehouses. |
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Ethyl 2-methyl-1,3-thiazole-4-carboxylate (CAS 6913-44-6, molecular formula C7H9NO2S, nominal molecular weight 171.22 g·mol−1) functions as a heterocyclic building block applied across medicinal chemistry, agrochemical intermediate supply, and liquid-crystal precursor synthesis. Commercially sourced material is routinely furnished as a pale-yellow to colourless translucent liquid with a characteristic thiazole odour, assayed by gas chromatography (GC-FID, 30 m DB-5 capillary column, 0.25 µm film) at purity ≥98.0% (area%), supported by Karl Fischer coulometric water content not exceeding 0.3 wt%. The C-2 methyl substituent differentiates this ester from its 2-H, 2-chloro, and 2-amino counterparts by raising the HOMO energy as evidenced in DFT-calculated frontier orbital maps (B3LYP/6-31G* basis), thereby moderating electrophilic aromatic substitution rates at the C-5 position and shifting the directing influence during metal–halogen exchange sequences. When incorporated into fragment-based screening libraries, the 4-carboxylate ester serves as a latent carboxylic acid handle for late-stage amidation or hydrazinolysis, while the 2-methyl group imparts incremental steric shielding relative to unsubstituted thiazole, improving metabolic stability of derived bioactives as tracked by human liver microsome half-life determinations (HLM t1/2 shifts typically between 12 and 45 minutes across matched molecular pairs). Cryoscopic purity assays (differential scanning calorimetry, onset temperature) of highly purified batches exhibit melting endotherms that confirm a bulk freezing point near −15 °C, a behaviour that permits low-temperature lithiation protocols without solvent vitrification when blended with THF/hexane mixtures at −78 °C.
The 2-methyl group exerts a measurable electronic influence on cross-coupling manifolds that proceed through oxidative addition at the C-5 halogen. Bromination with N-bromosuccinimide in acetonitrile at 0–5 °C over 4 h in a jacketed glass reactor fitted with PTFE baffles generates ethyl 5-bromo-2-methylthiazole-4-carboxylate with regioselectivity exceeding 95:5 (determined by reverse-phase HPLC, C18 column, acetonitrile/water gradient, detection at 254 nm). In subsequent Suzuki-Miyaura coupling against phenylboronic acid, employing Pd(OAc)2 (1 mol%), JohnPhos ligand (2 mol%), and K3PO4 (1.5 eq) in degassed 1,4-dioxane/water (4:1 v/v) at 80 °C under positive nitrogen overpressure (0.2 bar), the 2-methyl congener delivers 89% isolated yield after 2 h reaction time, compared with 72% for the 2-H analogue and 65% for the 2-chloro variant under identical conditions (yields obtained following flash chromatography on silica gel 60, 40–63 µm, with heptane/ethyl acetate 9:1 elution). The accelerated rate is attributed to the enhanced σ-donor character of the methyl-substituted ring, which stabilises the Pd(II) oxidative insertion intermediate; stopped-flow kinetic monitoring at 80 °C revealed a rate constant kobs of 5.2 × 10−3 s−1 versus 2.8 × 10−3 s−1 for the des-methyl compound. A critical incompatibility arises with 2-chloro-1,3-thiazole-4-carboxylate under amination conditions (Buchwald-Hartwig), where even trace methyl deprotonation can lead to competing β-hydride elimination pathways; the 2-methyl thiazole ester avoids this by presenting no acidic C-H bond adjacent to the heteroatom, thus preserving catalyst turnover numbers above 10,000 when assessed against the 4-bromo analogue in model aryl amination studies.
Exposure of the neat ester to relative humidity above 60% at 25 °C for 14 days results in ester hydrolysis yielding 2-methyl-1,3-thiazole-4-carboxylic acid as determined by HPLC area integration (≥12% conversion). Accelerated ageing in a climate cabinet at 40 °C/75% RH raises the hydrolysis rate sharply—first-order half-life drops to approximately 72 h when unprotected. Storing bulk material under dry nitrogen atmosphere with positive pressure (5–10 mbar) inside HDPE containers that incorporate an aluminium vapour barrier reduces moisture ingress; under these conditions, re-test dates of 24 months from the date of packaging are supportable as documented by stability programs aligned with ICH Q1A(R2) for industrial intermediates. Photo-oxidative ring-opening constitutes a second degradation vector: continuous exposure to fluorescent light (D65 standard illuminant, 500 lux) induces discolouration above APHA 50 within 48 h. Amber borosilicate glass vessels or stainless steel drums equipped with light-tight liners are specified for storage; where continuous visual inspection is required, a photostability test per ASTM D4229-02 (xenon arc exposure, 340 nm cut-off) confirms less than 0.5% peroxide-related by-products after 8 h when UV stabilisers are omitted from the formulation.
Hydrolysis to the corresponding 2-methyl-1,3-thiazole-4-carboxylic acid is accomplished by gradual addition of the ester to a stirred solution of lithium hydroxide monohydrate (1.05 eq) in tetrahydrofuran/water (4:1 v/v) at 25 °C, monitored by thin-layer chromatography (silica gel GF254, ethyl acetate/hexane 1:1) until the starting material spot (Rf ≈ 0.65) disappears, typically 6–8 h. Substituting sodium hydroxide under identical stoichiometry leads to partial (8–12%) decarboxylation, confirmed by mass spectrometric detection of 2,4-dimethylthiazole (m/z 113). This side-reaction is suppressed when the temperature is maintained below 10 °C and the pH is held between 9.0 and 10.0 (Jenway 3510 meter, glass-body electrode calibrated at three points), but lithium hydroxide remains the method of choice for preparative campaigns exceeding 500 g. Upon acidification to pH 2.5 with 1 M HCl, the free acid precipitates as a white crystalline solid; recrystallization from methyl tert-butyl ether (MTBE) with slow cooling from 40 °C to 5 °C at 0.2 °C/min furnishes colourless plates of melting point 147–149 °C (Büchi M-565, 1 °C/min ramp). Residual MTBE levels in dried cake are reduced to below 50 ppm using a vacuum oven (40 °C, 15 mbar, 24 h) with nitrogen bleed; the resulting acid is suitable for peptide coupling via EDC·HCl/HOBt without protecting-group interference.
When transferred to a pilot-scale campaign in a 20 L 316L stainless steel jacketed reactor equipped with a retreat-curve impeller and temperature probe inserted through a bottom flush diaphragm, the neat ester exhibits Newtonian behaviour with dynamic viscosity measured at 12.4 mPa·s (20 °C, Brookfield DV2T, spindle #18, 50 rpm), facilitating straightforward transfer via diaphragm pump without preheating. Charging with rigorous inerting—evacuation to <50 mbar followed by nitrogen purging over five cycles—eliminates colour development during prolonged heating. Distillative purification through a 10-plate Oldershaw column at 0.8 mmHg yields an overhead fraction with GC purity exceeding 99.5% and a colour reading of APHA <10 (ASTM D1209). The batch-to-batch relative standard deviation in assay remains below 0.4% across 12 consecutive runs when feedstock quality is tightly controlled at moisture ≤0.15%. A known processing bottleneck occurs during phase split after aqueous alkaline wash; the methyl group slightly increases organic-phase lipophilicity (log P 1.38 calculated, Experimental 1.42 by shake-flask method, OECD 107), which retards droplet coalescence in the interphase region. Inserting a coalescer pad (Pall, 1 µm PTFE) between the phase separator and product receiver restores throughput to design rates of 8 L·h−1. No exotherm was detected during neutralization steps when jacket coolant was set at 5 °C, confirming that scale-up safety factors remain conservative.
| Parameter | Test Method / Instrument | Specification |
|---|---|---|
| Assay (GC area%, 5-Bromo derivative excluded) | 30 m DB-5, 0.25 µm, FID | ≥98.0% |
| Water content (Karl Fischer coulometric) | Metrohm 870 KF Titrino | ≤0.3 wt% |
| Colour (APHA, neat) | ASTM D1209, 50 mm cell | ≤20 |
| Density at 20 °C | ASTM D4052 (oscillating U-tube) | 1.185–1.210 g·cm−3 |
| Refractive index (nD 20) | Abbemat 300, 589 nm | 1.528–1.538 |
| Heavy metals (as Pb) | USP ⟨231⟩ Method II | ≤10 ppm |
The thiazole ester landscape includes several C-2 substituted analogues often procured interchangeably in early-stage route scouting, yet the following condensed comparison exposes critical performance gaps: the 2-amino congener is susceptible to unintended diazotization chemistry during work-up in the presence of nitrite contaminants, limiting its application in one-pot tandem procedures; the 2-chloro derivative undergoes nucleophilic displacement under strongly basic alkoxide conditions, causing variable impurity profiles in Hantzsch thiazole-forming reactions; and the 2-methylthio variant introduces a sulphur-sulphur interaction that quenches Pd catalysts during Buchwald-Hartwig amination, as evidenced by accelerated formation of palladium black within 15 min at 100 °C. Ethyl 2-methyl-1,3-thiazole-4-carboxylate circumvents these specific failure modes while retaining the synthetic flexibility of the ester handle, explaining its selection as the default C-4 carboxylate building block in several pharma-sponsored fragment-to-lead campaigns disclosed in peer-review literature after 2018.
| Compound | Mol. wt. (g·mol−1) | Boiling Range (pressure) | Purity Specification | Distinguishing Limitation |
|---|---|---|---|---|
| Ethyl 2-methyl-1,3-thiazole-4-carboxylate | 171.22 | 95–105 °C (0.5–1.0 mmHg) | ≥98.0% | --- |
| Ethyl 2-amino-1,3-thiazole-4-carboxylate | 172.21 | sublimes under vacuum | ≥97.0% | Unintended N-nitrosation risk |
| Ethyl 2-chloro-1,3-thiazole-4-carboxylate | 189.62 | 82–88 °C (2.0 mmHg) | ≥97.0% | Nucleophilic substitution at C-2 |
| Ethyl 2-(methylthio)-1,3-thiazole-4-carboxylate | 203.28 | 115–120 °C (0.8 mmHg) | ≥96.5% | S-mediated catalyst poisioning |
