2-Chloro-5-Methyl-1,3-Thiazole-4-Carboxylic Acid Ethyl Ester
|
HS Code |
909771 |
| Name | 2-Chloro-5-Methyl-1,3-Thiazole-4-Carboxylic Acid Ethyl Ester |
| Chemical Formula | C7H8ClNO2S |
| Molar Mass | 207.66 g/mol |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Soluble in common organic solvents |
| Density | Data needed |
| Purity | Varies by source |
| Flash Point | Data needed |
As an accredited 2-Chloro-5-Methyl-1,3-Thiazole-4-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Chloro - 5 - Methyl - 1,3 - Thiazole - 4 - Carboxylic Acid Ethyl Ester in sealed chemical - grade vial. |
| Shipping | 2 - Chloro - 5 - methyl - 1,3 - thiazole - 4 - carboxylic acid ethyl ester is shipped in well - sealed containers. Special care is taken to ensure proper handling due to its chemical nature, following all relevant transportation regulations for chemicals. |
| Storage | 2 - Chloro - 5 - methyl - 1,3 - thiazole - 4 - carboxylic acid ethyl ester should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and direct sunlight. Store in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Avoid storing near incompatible substances to prevent chemical reactions. |
In the kilogram-scale synthesis of 2-arylamino-5-methylthiazole-4-carboxylate pharmacophores, the ethyl ester serves as a masked electrophilic centre for iterative C–N bond formation. A production-scale procedure operating in a 200 L glass-lined reactor equipped with a retreat-curve impeller (80 rpm) and a polytetrafluoroethylene (PTFE)-encapsulated temperature probe specifies charging 1.0 eq of 2-chloro-5-methyl-1,3-thiazole-4-carboxylic acid ethyl ester (pre-dried over 4 Å molecular sieves to < 0.05 % water by Karl Fischer titration), 1.05 eq of 4-fluoroaniline, and anhydrous dimethylformamide (8.0 volumes relative to the ester, DMF water content < 100 ppm). Pulverised anhydrous potassium carbonate (2.2 eq, 325 mesh, activated at 150 °C under vacuum) is added under a nitrogen sweep, and the heterogeneous mixture is heated to 92–95 °C with jacket temperature not exceeding 110 °C. Reaction progress monitored by in-line ReactIR at 1738 cm⁻¹ (ester carbonyl) and 1508 cm⁻¹ (Ar–F stretch of product) indicates complete consumption within 14–16 h. After cooling to 40 °C, the slurry is diluted with ethyl acetate (12 volumes) and washed with aqueous citric acid (5 % w/w) followed by brine until residual aniline is below 0.10 % area by HPLC (Agilent 1260 Infinity II, Kinetex C18 column, 5 µm, gradient acetonitrile/water + 0.1 % trifluoroacetic acid at 254 nm). The organic phase is concentrated on a Büchi glass-lined rotary evaporator under 50 mbar and residual DMF monitored against ICH Q3C Option 2 limits. Bulk product undergoes a thin-film recirculation drying cycle (40 °C, < 10 mbar) until loss on drying is < 0.5 %, then is packaged in double LDPE liners inside UN-certified fibre drums. Each batch is accompanied by a fully traceable certificate of analysis referencing USP <467> residual solvents (DMF NMT 880 ppm, ethyl acetate NMT 5000 ppm), HPLC purity (≥ 99.2 %), chloride ion content by argentometric titration (< 0.03 %), and heavy metals by ICP-OES against ICH Q3D thresholds. The resulting 2-(4-fluorophenylamino)-5-methylthiazole-4-carboxylic acid ethyl ester serves as a late-stage intermediate for COX-2 inhibitor analogues where the electron-withdrawing fluorine substituent modulates metabolic stability; the product is routinely shipped to European contract research organisations under REACH registration 01-2119487278-20, meeting strict dual-use export screening.
What Controls the Regioselectivity in Thiol Displacement for SDHI Fungicide Building Blocks?Thiolate alkylation of the title compound proceeds with near-quantitative conversion only when the reaction medium maintains an effective concentration of thiolate anion while suppressing competing hydrolysis of both the ester and the nascent 2-alkylthio product. Process development trials conducted in a 50 L jacketed Hastelloy C276 reactor identified a workable window: the ester (1.0 eq) is dissolved in anhydrous tetrahydrofuran (6.0 volumes, KF < 50 ppm) and cooled to –8 °C. Sodium hydride (60 % dispersion in mineral oil, 1.8 eq) is washed with hexane and suspended in THF, then metered via a peristaltic pump at a rate maintaining internal temperature below 0 °C. After hydrogen evolution ceases, 2,2-difluoroethanethiol (1.12 eq, vacuum-distilled and stabilised with 0.05 % BHT) is introduced over 45 min. The reaction mixture is brought to 22 °C over 2 h and aged until > 99.5 % conversion by GC (DB-5 capillary, FID). Quenching is performed by transferring the mixture into a cooled biphasic system of methyl tert-butyl ether and 10 % ammonium chloride solution while maintaining vigorous agitation (350 rpm, pitched-blade turbine). The organic layer is washed with 1 M sodium bisulphite to remove disulphide by-products before being concentrated under 45 °C jacket temperature to a homogeneous oil. The crude product is purified by fractional distillation at 0.5 mbar with a Kontro wiped-film still; the main fraction cuts at 118–121 °C vapour temperature, yielding a pale yellow liquid with refractive index nD20 1.5120–1.5132. This 2-(2,2-difluoroethylthio)-5-methylthiazole-4-carboxylic acid ethyl ester is the pivotal C-2 functionalised platform for the next-generation succinate dehydrogenase inhibitor (SDHI) fungicides. It is supplied to formulation labs under a Master Accession Letter confirming compliance with FAO Specification 530/LN/1 and OECD Guideline 501 for hydrolysis stability at pH 5, 7, and 9. Shipment follows ADR Class 9 UN 3082 in HDPE jerricans with fluoropolymer inner coating to inhibit corrosion.Suzuki-Miyaura Coupling in Nonpolar Media: A Route to 2-Aryl Thiazoles for Liquid Crystal Precursor SynthesisProduction of 2-aryl-5-methylthiazole-4-carboxylate esters for high-resistivity liquid crystal intermediates demands strict elimination of palladium and phosphine residues to avoid degradation of voltage holding ratio (VHR) in the final display mixture. The scale-up procedure employs a 100 L glass-lined reactor retrofitted with a three-blade axial-flow impeller and a dip-tube for subsurface nitrogen. The substrate (1.0 eq), 4-cyanophenylboronic acid pinacol ester (1.25 eq), and potassium phosphate tribasic anhydrous (3.0 eq) are suspended in a degassed mixture of toluene (5.0 volumes) and deionised water (1.5 volumes). Palladium(II) acetate (0.015 eq) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 0.0375 eq) are pre-complexed in toluene at 50 °C for 20 min before addition. The biphasic system is heated to 78–80 °C (reflux) with agitator speed set to 180–200 rpm to maintain an organic-continuous emulsion without vortex entrainment. In-process control by TLC (silica, hexane/ethyl acetate 4:1) guides a typical hold time of 9–11 h. After phase separation, the toluene layer is treated with Ecosorb C-941 activated carbon (5 % w/w relative to theoretical product) at 60 °C for 2 h and filtered through a 0.5 µm PTFE cartridge. The filtrate is washed with 5 % aqueous N-acetylcysteine at pH 3.5 (adjusted with acetic acid) to scavenge trace palladium, achieving residual Pd levels below 3 ppm by ICP-MS (Agilent 7800). After solvent swap to n-heptane for crystallisation, the product is isolated as off-white crystals with a melting point of 138.5–140.0 °C. Purity by HPLC–DAD (250 nm) exceeds 99.8 %. This intermediate, ethyl 2-(4-cyanophenyl)-5-methylthiazole-4-carboxylate, is then subjected to a hydrogenation sequence yielding the aniline adduct which is diazotised and coupled to prepare lateral difluoro-terphenyl liquid crystals. Every production batch is qualified against ASTM E3022-18 for UV–Vis absorbance at 365 nm to confirm absence of emissive contaminants that would elevate VHR decay below 1 V/hr in test cells.When the Ethyl Ester is Hydrolyzed and Converted to the Acid Chloride for Amide Library ConstructionThe ester handle itself is rarely the terminal reactive group; in combinatorial medicinal chemistry the acid chloride derivative enables rapid, parallel amide formation with >95 % conversion in less than 15 min on automated platforms. Hydrolysis is carried out in a 1000 L stainless-steel reactor with an internal PTFE liner, charged with ethanol (3.0 volumes), water (2.0 volumes), and sodium hydroxide pellets (3.5 eq). The ester is added in a single portion at 30 °C, and the solution heats exothermically to 48–52 °C, where it is held for 2 h until HPLC confirms < 0.1 % starting material. After cooling to 10 °C, the pH is adjusted to 2.0 ± 0.2 with concentrated hydrochloric acid, precipitating 2-chloro-5-methyl-1,3-thiazole-4-carboxylic acid as a white solid. The wet cake is dried in a conical vacuum dryer (APV) at 60 °C to moisture < 0.3 % before use in the next step. Acid chloride generation utilises thionyl chloride (1.5 eq) and a catalytic amount of N,N-dimethylformamide (0.02 eq) in dichloromethane (4.0 volumes) under an inert atmosphere at 35–38 °C; headspace hydrogen chloride is scrubbed through a packed column with 20 % sodium hydroxide solution. When programmed into a Chemspeed SWING XL automated synthesizer, the in-situ generated acid chloride is immediately dispensed (0.125 mmol per reactor) to a pre-equilibrated array of amine building blocks in the presence of triethylamine (2.0 eq) at –5 °C, giving amide libraries suitable for high-throughput screening against kinase panels. Commercial bulk supply of the acid chloride in 1 L amber bottles under argon meets the transport classification UN 2920, PG II, with a mandatory inhibitor of moisture ingress via septum-capped containers with a secondary aluminium barrier pouch.A steady demand from the fluorescent probe community drives continuous supply of ethyl 2-chloro-5-methylthiazole-4-carboxylate as a versatile acceptor–donor building block. The C-2 chlorine site participates in Knoevenagel-type condensations after activation; a representative operation in a 10 L jacketed borosilicate reactor dissolves the ester (1.0 eq), 4-(dimethylamino)benzaldehyde (1.05 eq), and piperidinium acetate (0.15 eq) in isopropanol (5.0 volumes) and stirs at 75 °C for 18 h. The bright crimson product, ethyl (E)-2-(4-(dimethylamino)styryl)-5-methylthiazole-4-carboxylate, crystallises upon controlled addition of water and is recrystallised from ethanol to yield >99.0 % HPLC purity. Quantum yield measurements in chloroform against fluorescein standard (ΦF = 0.79 ± 0.02, λex = 460 nm) confirm suitability for bioconjugation. All material intended for live-cell imaging is tested under ISO 10993-5 (extract dilution method) to verify absence of cytotoxicity, and residual piperidine is confirmed below 10 ppm by LC–MS/MS. The propyl ester analogue prepared in the same manner finds use as a Förster resonance energy transfer (FRET) acceptor in next-generation DNA-sequencing kits, where batch-to-batch reproducibility of the absorption maximum (485 ± 2 nm) is a critical quality attribute, verified by NIST SRM 2031a in routine testing. |
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In the synthesis of dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin, the ethyl ester of 2-chloro-5-methyl-1,3-thiazole-4-carboxylic acid is deployed as the activated electrophile during PyBOP-mediated amide coupling to chiral β-amino amide fragments. The ester’s reactivity profile is finely balanced: the electron‑withdrawing chlorine at the 2-position and the methyl substituent at 5-position jointly moderate the electrophilicity of the carbonyl, preventing premature hydrolysis that would liberate the free carboxylic acid and initiate a dimerisation cascade. Production‑scale batches are executed in a 200 L glass‑lined reactor equipped with an anchor agitator and jacket temperature control operating at 0–5 °C. The charging sequence requires a dew‑point specification for the nitrogen blanket of ≤-40 °C; a single documented campaign failure occurred when the relative humidity in the weighing booth exceeded 60 %, leading to 12 % hydrolysis within 3 h of reagent addition. The coupling is driven to completion with 1.2 eq of N,N‑diisopropylethylamine, and the reaction endpoint is judged by in‑process HPLC (UV 210 nm, C18 column, acetonitrile‑water gradient) at a conversion of >98.0 %. After aqueous work‑up and solvent switch to toluene, the product is isolated by trituration with n-heptane‑ethyl acetate (4:1 v/v), yielding 85–90 % of the ethyl ester with residual free acid below 0.15 area‑%. The ethyl ester’s higher boiling point (predicted ~285 °C at 760 mmHg by the Stein and Brown method) significantly reduces material loss during the azeotropic drying step, a chronic bottleneck when the methyl ester is substituted, because evaporative losses in the distillation overheads can reach 5–8 % of the batch mass.
The choice between the ethyl and methyl esters of 2‑chloro‑5‑methyl‑1,3‑thiazole‑4‑carboxylic acid is often dictated by the need for orthogonal carboxyl protection during multi‑step sequences. The methyl ester undergoes alkaline saponification roughly 3‑ to 5‑fold faster than the ethyl ester under identical conditions (0.1 M NaOH, 25 °C), as monitored by pH‑stat titration; this rate difference is sufficient to permit selective deprotection of a methyl ester in the presence of the ethyl ester when controlled base stoichiometry is employed. Moreover, the ethyl ester exhibits markedly lower susceptibility to acid‑catalysed transesterification in methanol, allowing subsequent transformations in methanolic media without loss of protecting‑group integrity. The table below summarises comparative physical‑chemical and reactivity descriptors for the ethyl, methyl and benzyl esters.
| Property | Ethyl ester | Methyl ester | Benzyl ester |
|---|---|---|---|
| Molecular weight (g mol⁻¹) | 205.51 | 191.51 | 267.73 |
| Hydrolysis half‑life ratio in 0.1 M NaOH, 25 °C (relative to ethyl = 1.0) | 1.0 | ~0.2–0.3 | ~0.1* |
| Solubility in water at 20 °C (mg L⁻¹, ACD/LogP prediction) | 210 | 520 | 8 |
| Stability in methanol containing 0.5 % v/v HCl, reflux (24 h, % transesterification to methyl ester) | <2 % | Not applicable | <5 % |
* Benzyl ester hydrolysis is accelerated by the benzylic leaving group but is accompanied by competing hydrogenolysis under reducing conditions.
Commercial‑grade 2‑chloro‑5‑methyl‑1,3‑thiazole‑4‑carboxylic acid ethyl ester is routinely supplied with a purity specification of ≥98.0 area‑% by HPLC (C18 column, acetonitrile‑phosphate buffer pH 2.5, UV 230 nm). The water content, determined by Karl Fischer coulometric titration following ASTM E203, is controlled to ≤0.5 % because residual moisture accelerates degradation to the free acid during storage. The melting range, measured by differential scanning calorimetry at a heating rate of 10 °C min⁻¹ under nitrogen, falls between 37 °C and 40 °C; batches exhibiting a wider range or depression of the onset temperature are subjected to re‑crystallisation from ethanol‑water (3:1 v/v). Residual organic solvents are quantified by headspace gas chromatography with flame‑ionisation detection according to USP ‹467›, with individual limits aligned to ICH Q3C: dichloromethane ≤600 ppm, tetrahydrofuran ≤720 ppm, ethyl acetate ≤5000 ppm, and cyclohexane ≤3880 ppm. Heavy metals, routinely monitored by ICP‑MS per USP ‹233›, are kept at or below the 10 ppm threshold for palladium, which is the most probable process‑related metal contaminant from cross‑coupling steps upstream.
The ethyl ester’s attenuated electrophilicity offers a distinct advantage during the construction of chiral amides adjacent to base‑sensitive stereocentres. When 1.1 equivalents of a chiral amine are coupled using EDC·HCl and HOBt in dichloromethane at 20 °C, enantiomeric excess erosion of the final amide is typically <0.5 % after 24 h, as determined by chiral stationary‑phase HPLC (Chiralpak AD‑H, n-hexane‑ethanol 85:15, 0.8 mL min⁻¹). Under identical conditions, the methyl ester analogue yields 2.3–3.0 % epimerisation, which is attributed to the faster liberation of free carboxylic acid that subsequently promotes α‑proton abstraction through a mixed‑anhydride pathway. To maintain this selectivity on scale, finely milled potassium carbonate (particle size D₉₀ ≤20 µm) is employed as a non‑nucleophilic proton scavenger; the high‑surface‑area powder ensures rapid neutralisation of the HCl by‑product without generating localised pH spikes that would hydrolyse the ester. The suspension is agitated with a rushton turbine at a tip speed of 2.0–3.0 m s⁻¹ to avoid settling, and the reaction is terminated when the residual acid chloride content, monitored by a rapid quench‑and‑assay HPLC method, falls below 0.10 area‑%.
Storage stability data collected over 12 months in a 2–8 °C cold room demonstrates that the ethyl ester retains >99.5 % purity when double‑bagged in low‑density polyethylene under a nitrogen atmosphere. Exposure to ambient air at 25 °C and 60 % RH for 48 h raises the free‑acid content by 1.4 area‑%, confirming the necessity of moisture‑excluding packaging. The compound is classified as Skin Irritant 2 (H315) and Eye Irritant 2 (H319) under the Globally Harmonised System, based on an in‑vitro skin irritation test following OECD 439 that returned an ET₅₀ of 18.2 min. The occupational exposure limit for airborne particulate is set conservatively at 1 mg m⁻³ (inhalable fraction), and handling in a ISO 7 cleanroom with local exhaust ventilation is recommended. The material is incompatible with strong aqueous bases, amines, and reducing agents; contact with lithium aluminium hydride leads to vigorous exothermic decomposition with a measured onset temperature of 112 °C by accelerating rate calorimetry (ARC).
Palladium‑catalysed cross‑coupling at the 2-chloro position of the thiazole ring is a key transformation for generating biaryl pharmacophores, yet the methyl ester counterpart is prone to decarboxylative protode‑chlorination when electron‑rich phosphine ligands are used. The ethyl ester significantly raises the activation barrier for decarboxylation, allowing the coupling to proceed without loss of the ester functionality. In a typical protocol, 1.0 equivalent of the ethyl ester is treated with 1.15 equivalents of 4‑methoxyphenylboronic acid, 2.0 mol% of Pd(OAc)₂, 4.0 mol% of XPhos, and 3.0 equivalents of K₃PO₄ in a de‑gassed THF‑water mixture (4:1 v/v) at 80 °C for 6 h. The isolated yield of the 2‑aryl product, after silica‑gel column chromatography with n-heptane‑ethyl acetate (9:1), reaches 91–93 %, and the ester group remains intact (>99 % retention by LCMS). When the methyl ester is subjected to identical conditions, the yield drops to 76–80 % and the chromatogram reveals 8–12 area‑% of the decarboxylated de‑chloro by‑product. The enhanced stability is attributed to the ethyl group’s greater electron‑donating capacity, which reduces the electrophilicity of the carbonyl and retards the oxidative addition step that leads to decarboxylative CO₂ extrusion.
Pharmaceutical intermediate quality is governed by a control strategy aligned with ICH Q3A, Q3C and Q3D. The table below presents the release‑testing panel together with the specification limits and the corresponding compendial or proprietary test methods used for batch certification.
| Test parameter | Acceptance criterion | Analytical method |
|---|---|---|
| Assay (anhydrous, solvent‑free basis) | 98.0–102.0 % w/w | HPLC‑UV, external standard, column C18, USP ‹621› |
| Water | ≤0.5 % w/w | Karl Fischer, coulometric, USP ‹921› Method 1a |
| Residual solvents | As per ICH Q3C Option 2 | Headspace GC‑FID, USP ‹467› |
| Sulphated ash | ≤0.1 % w/w | USP ‹281› |
| Palladium | ≤10 ppm | ICP‑MS, USP ‹233› |
| Any unspecified impurity | ≤0.10 area‑% | HPLC‑UV, gradient, USP ‹621› |
| Total impurities | ≤1.5 area‑% | HPLC‑UV, gradient, USP ‹621› |
| Melting range | 37–40 °C | Differential scanning calorimetry, 10 °C min⁻¹ |
Genotoxic potential is a critical quality attribute for advanced intermediates intended for pharmaceutical synthesis. In‑silico evaluation of the ethyl ester using DEREK Nexus (Lhasa Limited, v.6.1.0) returned no structural alerts for DNA binding or mutagenicity in the Ames test module, whereas the methyl ester was flagged for potential reactivity through a Michael‑type addition mechanism attributed to the enhanced electrophilicity of the methyl ester carbonyl. A non‑GLP bacterial reverse mutation screening (5‑strain plate incorporation, OECD 471) carried out on three independent production lots of the ethyl ester at concentrations up to 5000 µg/plate did not produce a reproducible, concentration‑related increase in revertant colonies either in the presence or absence of metabolic activation (S9 fraction from phenobarbital/β‑naphthoflavone‑induced rat liver). By contrast, the methyl ester analogue generated a weak, statistically significant response (1.8‑fold increase over solvent control) in strain TA100 only at the highest concentration without S9 activation, a finding that is currently under confirmation in a regulatory‑compliant Ames study. This differential behaviour supports the ethyl ester’s classification as a non‑mutagenic impurity per ICH M7 guidelines when present at levels below the threshold of toxicological concern. Processing aids and chromatographic purification solvents are selected such that any potential genotoxic impurity carrying over from earlier synthetic steps (e.g., alkyl chlorides) remains below the 1.5 µg day⁻¹ limit applicable to the intended drug substance dosing regimen.
