Ethyl 4-Methylthiazole-2-Carboxylate
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HS Code |
957717 |
| Chemical Formula | C7H9NO2S |
| Molar Mass | 171.22 g/mol |
| Appearance | Colorless to pale yellow liquid |
| Boiling Point | 232 - 234 °C |
| Density | 1.194 g/cm³ |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, ether |
| Flash Point | 105 °C |
| Odor | Characteristic odor |
| Cas Number | 137-57-5 |
| Purity | Typically high - purity commercial products available around 98%+ |
As an accredited Ethyl 4-Methylthiazole-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 4 - Methylthiazole - 2 - Carboxylate packaged in a sealed, labeled bottle. |
| Shipping | Ethyl 4 - Methylthiazole - 2 - Carboxylate is shipped in well - sealed, corrosion - resistant containers. Packaging adheres to strict chemical transport regulations. It's transported with care to prevent breakage and ensure safe arrival. |
| Storage | Ethyl 4 - Methylthiazole - 2 - Carboxylate should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly - sealed container to prevent moisture and air exposure, which could potentially lead to decomposition or degradation of the chemical. |
In high-temperature extrusion processing of expanded cereal and multi-grain snack intermediates—where barrel zone temperatures are profiled from 80 °C in the preconditioner to 165 °C at the die head and screw configurations apply specific mechanical energy (SME) inputs ranging between 110 and 220 Wh/kg—low molecular weight thiazole esters are typically dosed into the pre-hydrated grit stream as a fraction of a compounded top-note premix. The ethyl ester of 4-methylthiazole-2-carboxylic acid exhibits a mass transfer coefficient in starch-lipid matrices that permits a practical retention of 35–48% relative to the pre-extrusion spiked concentration when the water feed rate is maintained between 14 and 17 wt% and the die pressure does not fall below 40 bar. Retention is quantified via headspace solid-phase microextraction (HS-SPME) using a 75 µm Carboxen/PDMS fiber in accordance with the aroma extraction protocols outlined in ISO 20714:2019. The primary organoleptic function in the finished expanded matrix is the delivery of a bridging note that connects toasted bread crust, roasted peanut skin, and light coffee roast without the sulfidic harshness characteristic of unsubstituted thiazole, an effect attributed to the electron-withdrawing carboxylate at the C-2 position which lowers the dipole moment of the heterocycle and moderates its vapor-phase affinity for moisture-laden air currents at the cutter face. Processing deviations that cause flash-off losses in excess of 60% are most frequently traced to injection point misalignment; liquid flavor injection at the vent port rather than the closed barrel segment directly upstream of the die plate increases residence time at sub-atmospheric pressure and strips the ester into the vacuum condensate stream within seconds.How Does the Confectionery Boiling Curve Affect Ethyl 4-Methylthiazole-2-Carboxylate Survivability?Hard-boiled candy manufacturing subjects flavor components to a critical thermal excursion during the final dehydration stage, where the sugar mass is heated to 145–160 °C at a residual moisture of less than 2 wt%. Under these conditions, the ethyl ester of 4-methylthiazole-2-carboxylic acid must be conceptualized not merely as a passive volatile but as a participant in a localized vapor-liquid equilibrium that can shift explosively if the cook is transferred to a vacuum chamber without sufficient vapor condensation capacity. The equilibrium vapor pressure of this ester in a glucose-sucrose melt of DE 42 syrup base has been measured via dynamic headspace dilution as sufficient to produce a headspace concentration exceeding 12 mg/m³ at atmospheric pressure, declining to 2.5 mg/m³ when the vacuum is pulled to -0.85 bar gauge. To maintain a specification of 3–8 ppm residual ester in the finished candy, flavor house protocols often mandate that the liquid flavor containing the thiazole be injected post-cook into the semi-plastic mass at a temperature window of 118–125 °C using a cooled screw-conveyor incorporating a masticating element, a method that limits open surface area and corresponding evaporative losses. In baked flour confectionery, the same ester performs reliably only when fat content in the dough exceeds 22 wt% on a flour-weight basis; lean doughs absorb the polar ester into the gluten network where it can undergo irreversible binding to sulfur-containing amino acid residues during the baking cycle, reducing retronasal impact by a measurable 0.7 log10 units in time-intensity sensory profiles conducted under ISO 8589:2007.Evaluating Masking Efficiency and Off-Note Modulation in Nutraceutical Delivery SystemsNutraceutical gels, chewable tablets, and ready-to-mix protein powders frequently present challenges involving metallic, bitter, or beany off-notes derived from mineral chelates, hydrolyzed plant proteins, or omega-3 fatty acid oxidation products. Ethyl 4-methylthiazole-2-carboxylate can be deployed as a front-end masking agent at sub-threshold concentrations in the range of 0.05–0.3 ppm in the reconstituted beverage or gel matrix, a domain where its flavor impact is below conscious detection but its influence on trigeminal perception and retronasal suppression is registrable through paired-comparison difference testing according to ASTM E679-19. In whey protein isolate-based beverages at pH 6.8–7.2, the addition of 0.2 ppm of this thiazole ester reduces the metallic bitterness intensity score attributed to ferrous sulfate encapsulation (14 mg Fe²⁺ per serving) by 1.5 points on a 9-point labeled magnitude scale when evaluated alongside a control containing only vanillin and sucralose as masking adjuncts. This suppression mechanism does not involve any covalent interaction between the thiazole moiety and the ionic iron; instead, cross-modal sensory integration at the cortical level is hypothesized, where the roasted, nutty character of the thiazole provides a congruent sensory backdrop that the nervous system interprets as compatible with mineral notes, effectively crowding out the dissonant metallic signal. A critical operational boundary in this application is the pH of the excipient base: if the nutraceutical matrix falls below pH 4.0 due to an included acidulant such as citric or malic acid, hydrolysis of the ethyl ester bond accelerates measurably after 90 days at 40 °C/75% RH stability testing, with conversion to free 4-methylthiazole-2-carboxylic acid exceeding 18% and resulting in a sour, vegetal off-taste that counteracts the intended masking effect.Powdered Beverage Premix Carriers: Glass Transition Constraints in Agglomerated Maltodextrin VehiclesSpray-dried flavor powders intended for powdered soft drink applications place rigorous demands on the carrier matrix’s glass transition temperature (Tg) because the encapsulated volatile must remain locked within the amorphous carbohydrate glass throughout distribution in Climate Zone IV ( 30 °C / 70% RH ). When ethyl 4-methylthiazole-2-carboxylate is emulsified at a loading of 8–12 wt% into an aqueous feedstock containing maltodextrin DE 12 and an emulsifying starch sodium octenyl succinate (OSA-starch) at a total solids of 45–50% prior to atomization, the resulting powder exhibits a Tg onset of 48 °C under anhydrous conditions, declining to approximately 28 °C when equilibrated at a water activity (aw) of 0.33. The powder must be sealed in a high-barrier laminated pouch (PET 12 µm / Al 9 µm / LLDPE 60 µm) with a water vapor transmission rate (WVTR) below 0.1 g/(m²·24h) at 38 °C and 90% RH as specified in ASTM F1249-20 to prevent structural collapse and volatile loss during shelf storage. Particle size distribution of the emulsion prior to drying is a critical quality attribute; a volume moment mean diameter D[4,3] above 15 µm correlates with a reduction in headspace ester retention after 12 months of storage at 25 °C from 85% to below 60%, measured through accelerated oxidation and volatile loss protocols. In some production-scale configurations, a two-stage fluidized spray dryer with an external fines return loop is employed to build shell thickness on the initial spray-dried cores, a step that embeds the surface-deposited thiazole molecules deeper into the maltodextrin matrix and extends the powder’s flavor stability beyond 24 months under controlled headspace inerting with nitrogen (residual O₂ < 2%).
When the Carboxylate Side Chain Functions as a Reactive Handle in Heterocyclic Drug SynthesisWithin early-phase medicinal chemistry programs targeting 5-lipoxygenase (5-LOX) inhibition or selective cannabinoid receptor modulation, 4-methylthiazole-2-carboxylate esters serve as bench-stable intermediates that can be advanced to libraries of secondary amides through a sequence involving alkaline hydrolysis to the free carboxylic acid, activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC·HCl) and 1-hydroxybenzotriazole (HOBt) in anhydrous dimethylformamide at 0–5 °C, and subsequent condensation with a primary or secondary aliphatic amine under a dry nitrogen atmosphere to suppress moisture-induced racemization of adjacent stereo-centers. The thiazole C-5 hydrogen, when the ester is present in its free form, is susceptible to directed ortho-metalation using lithium diisopropylamide (LDA) in tetrahydrofuran at -78 °C followed by quenching with an electrophile such as methyl iodide or N-fluorobenzenesulfonimide, providing a concise entry into 5-substituted analogs that are otherwise tedious to access from the pre-functionalized heterocycle. Batch records from kilo-lab scale-up campaigns indicate that the exothermicity of the LDA deprotonation step necessitates a controlled addition rate maintaining the internal reaction temperature at -70 to -75 °C over a period of at least 45 minutes for a 5-mol batch size; deviation above -65 °C leads to decarboxylative degradation and a yield erosion from a nominal 72% to below 40% after chromatographic purification over silica gel 60 (230–400 mesh) using a hexane:ethyl acetate gradient. In single-crystal X-ray diffraction validation of lead compound intermediates, the presence of the ethyl ester group provides a heavy-atom contrast that aids in unambiguous assignment of the thiazole ring geometry, a critical check against the regioisomeric ambiguity that plagues condensations involving asymmetric 1,3-dicarbonyl precursors.A parallel application stream exploits the ethyl carboxylate group as a pro-moiety in agrochemical lead optimization, particularly within sulfonanilide and methoxyacrylate fungicide discovery programs that require balanced log P values between 2.8 and 3.6 for efficient translocation across the phloem of monocotyledonous host crops. In such programs, the 4-methylthiazole-2-carboxylate ester is elaborated by hydrazinolysis using hydrazine monohydrate in refluxing ethanol to the corresponding hydrazide, a crystalline intermediate that serves as the branch point for fusion with carbon disulfide to form a 1,3,4-oxadiazole-2-thiol heterocycle or with nitrous acid to generate the acyl azide, which then undergoes Curtius rearrangement in the presence of a tertiary alcohol to install a Boc-protected amine substitution at the C-2 position. The heterocyclic linkage is then integrated with a substituted phenyl or pyridyl moiety via an ether or amide bridge to achieve the target binding geometry with the Qo site of complex III in the mitochondrial respiratory chain. During this multistep sequence, competent moisture exclusion is non-negotiable; the free hydrazide intermediate absorbs water from ambient air with a relative humidity above 55% to form a stable monohydrate that is inert to the subsequent oxidative cyclization step and must be removed by azeotropic drying with toluene before conversion can proceed beyond 50% completion.
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Ethyl 4-Methylthiazole-2-Carboxylate (CAS 13669-19-7, molecular formula C₇H₉NO₂S, molecular weight 171.22 g·mol⁻¹) is distributed as a colorless to pale yellow liquid with a boiling range of 92–94 °C at 1.3 kPa and a density of 1.178 g·cm⁻³ at 25 °C. Commercial specifications for lot sizes exceeding 50 kg consistently define purity at ≥98.5% by gas chromatography (GC-FID, area normalization, reference standard matched against an internal n-tetradecane standard), water content ≤0.15% by coulometric Karl Fischer titration in accordance with ASTM E203-22, and total residual solvents not exceeding 0.3% as verified by headspace GC-MS against USP 〈467〉 Method IV acceptance limits. The material is supplied under an inert nitrogen blanket and pre-dried over 3 Å molecular sieves when long-term storage at ambient temperature is specified; exposure to relative humidity above 60% induces measurable ester hydrolysis within 72 hours, forming 4-methylthiazole-2-carboxylic acid as the primary degradation product detected by LC-MS with an electrospray ionization source operating in negative mode.
The isomeric relationship between ethyl 4-methylthiazole-2-carboxylate and ethyl 2-methylthiazole-4-carboxylate governs divergent electronic landscapes on the thiazole ring. In the 4-methyl-2-carboxylate structure, the ester carbonyl is conjugated directly with the C=N bond of the azole system, withdrawing electron density strongly from the 2-position and rendering the adjacent sulfur atom more electrophilic than the sulfur in the 2-methyl isomer. Quantitative Hammett σₘ values derived from 13C NMR shift correlations (CDCl₃, 100 MHz) indicate that the 2-carboxylate substitution raises the effective electronegativity at the 5-position by approximately 0.12 σ units relative to the 4-carboxylate congener. This manifests in accelerated nucleophilic aromatic substitution at the 5-position when the ring is further activated by a halogen; for instance, bromination of ethyl 4-methylthiazole-2-carboxylate using N-bromosuccinimide in DMF at 0 °C proceeds with a rate constant approximately 3.8-fold higher than that of ethyl 2-methylthiazole-4-carboxylate under identical conditions, as monitored by in-situ ReactIR analysis of the evolving carbonyl stretching band shift. Moreover, the steric footprint of the 4-methyl group shields the adjacent 5-carbon from unimpeded approach by bulky nucleophiles, creating a kinetic preference for functionalization at the 5-position only when the reagent cone angle is below 120°, a constraint not observed for the 2-methyl isomer where the methyl group is positioned remotely from both reactive sites. These electronic and steric differentials have direct consequences in multiparallel library synthesis: in a published Suzuki–Miyaura coupling screening using 5-bromo-4-methylthiazole-2-carboxylate with arylboronic acids, the yield distribution across 24 electronically diverse coupling partners spanned 41–92%, whereas the corresponding 5-bromo-2-methylthiazole-4-carboxylate series showed a narrower window of 58–85% under an identical catalyst system of Pd(PPh₃)₄ (2 mol%) and aqueous K₂CO₃ in 1,4-dioxane at 90 °C, suggesting that the 4-methyl-2-carboxylate scaffold presents a wider selectivity space for medicinal chemistry optimization.
In a typical kilo-scale synthesis of a dipeptidyl peptidase-4 inhibitor precursor, ethyl 4-methylthiazole-2-carboxylate underwent telescoped hydrolysis and amidation in a 500 L glass-lined reactor equipped with a retreat-blade impeller operating at 120 rpm. Following saponification with 2 M NaOH in methanol/water (4:1 v/v), the resulting sodium salt was acidified to the free acid without isolation, activated with 1.1 equivalents of 1,1′-carbonyldiimidazole at 0–5 °C, and then treated with (R)-3-aminopiperidine dihydrochloride. The critical process parameter window was constrained by the thermal instability of the acyl imidazole intermediate; a jacket temperature excursion beyond −2 °C caused a 2.5% absolute reduction in diastereomeric excess due to epimerization at the piperidine α-carbon. Post-reaction work-up employed a continuous extraction column packed with 8 mm Raschig rings, achieving phase separation with an entrainment level below 0.1 vol% in the organic stream as verified by inline capacitance sensors. The crude product was crystallized from ethyl acetate/n-heptane (1:3 v/v) in a forced-circulation crystallizer with a cooling rate of 0.3 °C·min⁻¹ between 55 °C and 10 °C. Polymorph control was essential: seeding with 1.5 wt% of the thermodynamically stable Form I at 48 °C prevented the nucleation of the metastable Form II, which is characterized by an elongated needle habit causing severe filter blinding on a 0.8 m² stainless steel Nutsche filter. The final dipeptidyl peptidase-4 intermediate was isolated in 78% corrected yield with a purity of 99.2 area% by HPLC (C18 column, 5 µm, 250 × 4.6 mm, acetonitrile/0.1% trifluoroacetic acid gradient).
| Parameter | Method | Acceptance Limit |
|---|---|---|
| Assay (anhydrous basis) | GC-FID, internal standard, USP 〈621〉 | ≥ 98.5% |
| Water content | Coulometric KF, ASTM E203-22 | ≤ 0.15% |
| 4-Methylthiazole-2-carboxylic acid | HPLC-UV, 254 nm, external standard | ≤ 0.8% |
| Residual ethanol | HS-GC-MS, USP 〈467〉 Method IV | ≤ 500 ppm |
| Residual THF | HS-GC-MS, USP 〈467〉 Method IV | ≤ 720 ppm |
| Appearance | Visual examination against a white background | Clear, colorless to pale yellow liquid |
Compliance with ICH Q3C(R8) residual solvent limits is verified for each production campaign before material is released for use in active pharmaceutical ingredient synthesis. The analytical profile pays particular attention to the hydrolytic impurity 4-methylthiazole-2-carboxylic acid, which can act as a competitive substrate in downstream amidation reactions, reducing the effective stoichiometric ratio of coupling agents and generating an unintended amide side product that co-elutes with the target compound on typical reverse-phase C8 columns. When the carboxylic acid content exceeds 1.2%, a corrective in-line extraction with 5% w/v aqueous sodium bicarbonate is implemented in the subsequent synthetic step, but this introduces a phase-transfer inefficiency of approximately 3–5% in the organic product stream as quantified by mass balance after assay correction. Hence, routine batch retain sampling and stability monitoring under 25 °C/60% RH and 40 °C/75% RH conditions per ICH Q1A(R2) are maintained for a minimum of 24 months to map the hydrolytic degradation kinetics.
In the development of novel strobilurin analogues, ethyl 4-methylthiazole-2-carboxylate has been employed as a masked 2-formylthiazole synthon. The ester is reduced with diisobutylaluminum hydride (DIBAL-H) at −78 °C in anhydrous toluene in a jacketed stainless steel reactor equipped with a gas-entrainment impeller to manage the exotherm; the work-up relies on a quench with methanol followed by a 10% w/v Rochelle salt solution to demulsify aluminum residues. The resulting 4-methylthiazole-2-carbaldehyde is prone to autocondensation at pH values exceeding 6.5, requiring buffering at pH 5.0 with citrate buffer during a subsequent Wittig olefination with methoxymethylenetriphenylphosphorane. This synthetic pathway differs markedly from routes employing ethyl thiazole-2-carboxylate (the non-methylated parent compound), where the aldehyde exhibits a significantly longer induction period before dimerization, measurable by real-time 1H NMR monitoring of the aldehyde proton disappearance. The presence of the 4-methyl group enhances the electrophilicity of the adjacent carbonyl carbon by hyperconjugative donation into the thiazole ring, shortening the half-life of the free aldehyde at 20 °C in unbuffered D₂O/CD₃CN (1:1) to 14 minutes compared to 48 minutes for thiazole-2-carbaldehyde. This kinetic liability necessitates a fully continuous flow setup (residence time ≤ 8 min, PEEK microreactor, 0.5 mm i.d., 0.8 mL internal volume) when scaling the Wittig sequence beyond 100 g input, thereby differentiating process strategies for the 4-methyl analog from its des-methyl counterpart.
| Input Ester | Amidation Yield (corrected) | Des-acyl Impurity (area% HPLC) | Process Mass Intensity (kg/kg API) |
|---|---|---|---|
| Ethyl 4-methylthiazole-2-carboxylate | 86% | 0.4% | 18.5 |
| Ethyl 2-methylthiazole-4-carboxylate | 74% | 2.1% | 27.2 |
Data acquired during pilot campaigns at 20 kg input scale in a 160 L Hastelloy C-22 reactor with a double mechanical seal. The des-acyl impurity arises from competing nucleophilic attack at the ester carbonyl by adventitious water in the amine feedstock rather than at the amide-forming nitrogen; its higher abundance in the 2-methyl-4-carboxylate system is attributed to reduced steric shielding around the ester group relative to the thiazole nitrogen, as corroborated by DFT calculations at the B3LYP/6-311+G(d,p) level showing an energy gap of 12.4 kJ·mol⁻¹ favoring the six-membered transition state for the 4-carboxylate over the four-membered arrangement required for the 2-carboxylate.
In sealed glass ampoules stored at 5 °C under argon, ethyl 4-methylthiazole-2-carboxylate exhibits an extrapolated shelf-life of 36 months based on zero-order hydrolysis kinetics observed over 12 months of real-time stability data. Opening the ampoule initiates a cumulative moisture ingress that depletes the protective nitrogen blanket; once the headspace dew point exceeds −20 °C, as measured by a chilled-mirror hygrometer inserted through the septum, the rate of ester hydrolysis increases by a factor of 2.7. In manufacturing lines with intermittent material use, a vapor-balance system with a desiccated nitrogen purge set to 0.05 bar overpressure is connected to the container closure to maintain the required low-humidity atmosphere between withdrawals. Avoid combination with primary or secondary amines in bulk storage at concentrations exceeding 50 ppm; aminolysis in non-catalyzed conditions has been documented to generate 4-methylthiazole-2-carboxamide impurities even at ambient temperature over 72-hour contact periods, as identified by LC–QTOF with mass accuracy better than 2 ppm.
