Ethyl 1,3-Thiazole-5-Carboxylate
|
HS Code |
300505 |
| Chemical Formula | C6H7NO2S |
| Molecular Weight | 157.19 g/mol |
| Appearance | Colorless to light yellow liquid or solid |
| Boiling Point | Approximately 230 - 235 °C |
| Melting Point | Around 42 - 46 °C |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, dichloromethane |
| Flash Point | Around 93 °C |
| Density | Approximately 1.23 g/cm³ |
| Odor | Characteristic thiazole - like odor |
As an accredited Ethyl 1,3-Thiazole-5-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 1,3 - Thiazole - 5 - Carboxylate in a sealed, labeled chemical - grade bottle. |
| Shipping | Ethyl 1,3 - Thiazole - 5 - Carboxylate is shipped in accordance with chemical transport regulations. It's carefully packaged in suitable containers to prevent leakage, and transported by approved carriers ensuring safety during transit. |
| Storage | Ethyl 1,3 - Thiazole - 5 - Carboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a well - 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. Maintain the storage area at a controlled temperature to ensure its stability over time. |
A process route where the thiazole ring is preserved through a critical alkaline hydrolysis step forms the technical backbone of several commercial succinate dehydrogenase inhibitor (SDHI) fungicides. Ethyl 1,3-thiazole-5-carboxylate is charged into a glass-lined reactor together with ethanol and deionized water at a mass ratio of 1.0 : 2.5 : 1.2. The jacket is set to 5 °C while aqueous sodium hydroxide (30 % w/w, 1.05 molar equivalents relative to the ester) is metered over 90 minutes to maintain the internal temperature below 8 °C. Exceeding 12 °C triggers an irreversible decarboxylation that releases CO₂ and forms unsubstituted thiazole, reducing the yield of thiazole-5-carboxylic acid below 70 %. Real-time FTIR monitoring of the carbonyl stretch at 1715 cm⁻¹ provides a leading indicator of conversion. Once hydrolysis reaches ≥ 99.5 %, the batch is acidified with 15 % hydrochloric acid to pH 2.0–2.3 at 0–5 °C. The precipitated acid is isolated on a pressure filter, washed with chilled water, and dried under vacuum at 35 °C to a loss-on-drying below 0.5 %. This intermediate is then activated with thionyl chloride in toluene at 50–55 °C to generate thiazole-5-carbonyl chloride, which is directly coupled with 2′,6′-dibromo-4′-(trifluoromethoxy)-2-methyl-4-(trifluoromethyl)aniline in the presence of 1.2 eq of triethylamine. The resulting amide, after recrystallization from isopropanol, yields the active ingredient thifluzamide at 99.2 % purity. Throughout this sequence, the key operational boundary is the thermal sensitivity of the thiazole-5-carboxylic acid: differential scanning calorimetry (DSC) shows an exothermic decomposition onset at 68 °C, making jacket temperature control below 40 °C mandatory during vacuum drying and storage. Batch-to-batch variability in residual sodium chloride content above 200 ppm has been observed to catalyse decarboxylation during subsequent acylation, requiring a wash step with 0.1 N HCl to ensure chloride levels remain below 50 ppm. Registration of the final fungicide under EU Regulation 1107/2009 requires a technical specification of the intermediates according to FAO/WHO Joint Meeting on Pesticide Specifications (JMPS) guidelines, and any non-isolated intermediate such as the acid chloride must be assessed for carry-over of genotoxic impurities under ICH M7 principles if the same facility also manufactures pharmaceutical intermediates.
When the ester serves as a latent carboxylic acid in a DGAT-1 inhibitor clinical candidate, what process controls prevent lithium aluminium hydride runaway?In the 100-L Hastelloy reactor dedicated to early-phase GMP campaigns, ethyl 1,3-thiazole-5-carboxylate is dissolved in anhydrous tetrahydrofuran (THF) at a concentration of 0.8 M and cooled to −5 °C. A slurry of lithium aluminium hydride (2.5 M in THF, 1.28 equivalents) is dosed through a mass flow meter with an immediate exotherm; the jacket setpoint is −15 °C and the feed rate is slaved to keep the internal temperature below +2 °C. The reduction produces 5-(hydroxymethyl)-1,3-thiazole, which is quenched by slow addition of a 15 % sodium sulfate decahydrate solution in THF at 0–5 °C. Any deviation above 10 °C during the quench accelerates hydrogen evolution beyond the venting capacity of the bursting disc rated at 3.5 bar, a condition that black-flagged two pilot batches where the agitator stopped and localised hot spots triggered foam-over into the vent line. After filtration through a Celite pad and vacuum distillation of the solvent, the intermediate thiazole-methanol is immediately converted to the DGAT-1 inhibitor by Mitsunobu coupling with 2,6-dichloropurine in the presence of diisopropyl azodicarboxylate and triphenylphosphine. The crude product is purified by column chromatography (silica gel, heptane:ethyl acetate 3:1 to 1:1) and subsequently crystallized from isopropanol/water to polymorph Form A, which exhibits a melting point of 154–156 °C. Quality control includes residual lithium testing by ICP-MS below 10 ppm and headspace GC for THF below 720 ppm, aligning with ICH Q3C (Class 2 solvent) limits. The entire synthetic sequence falls under FDA 21 CFR Part 210 and 211 whenever the active pharmaceutical ingredient is destined for a U.S. Investigational New Drug application, and cleaning validation of the Hastelloy vessel uses swab recovery studies with a limit of detection below 1 µg/cm² for the thiazole-methanol intermediate.A market-facing technical data sheet for a blue monoazo disperse dye requires the coupling of a diazotised 2-aminothiazole-5-carboxylic acid derivative with an N,N-dialkylaniline component, and the ethoxycarbonyl group supplied by ethyl 1,3-thiazole-5-carboxylate remains intact throughout the synthesis to modulate both colour strength and wash fastness on polyester. The starting ester is first nitrated with a nitrating mixture of 65 % HNO₃ and 98 % H₂SO₄ at 0–5 °C to install a nitro group at the 2-position, which is then reduced with iron powder in acetic acid at 60 °C to yield 2-amino-1,3-thiazole-5-carboxylic acid ethyl ester. The diazonium salt is prepared by adding an aqueous solution of sodium nitrite (1.02 eq) to the amine hydrochloride in 5 N HCl at −2 to 0 °C, and the resulting solution is added to a cooled mixture of N,N-diethyl-m-toluidine in dilute acetic acid at pH 4.0–4.5. The pH range is critical: values below 3.5 retard coupling, while pH above 5.5 hydrolyses the ethoxycarbonyl group to the carboxylic acid, shifting the λmax hypsochromically by 12–18 nm and reducing the tinctorial strength by up to 25 %. After coupling, the crude dye is filtered, washed until the filtrate is free of nitrite, and dried in a fluid-bed dryer at 70 °C. The press cake is then formulated with lignin sulfonate dispersants and wet-milled in a horizontal bead mill (retention time 45 minutes, bead fill 80 % with 0.4–0.6 mm yttria-stabilized zirconia beads) to a particle size of D₉₀ ≤ 2 µm. Exhaustion dyeing trials on polyester woven fabric at 130 °C with a liquor ratio of 10:1 yield a navy-blue shade with light fastness grade 6–7 (ISO 105-B02) and wash fastness grade 4–5 (ISO 105-C06/C1). Certification under OEKO-TEX Standard 100 requires the final dyestuff to contain less than 20 mg/kg of free aromatic amines listed in Annex XVII of REACH, verified by LC-MS/MS according to EN 14362-1:2012. Operations that recycle the spent coupling liquor through an activated carbon adsorption column routinely achieve a COD reduction from 12,000 mg/L to below 800 mg/L, a requirement for discharge permits in the Zhejiang dye manufacturing cluster.Does the thiazole ring tolerate aqueous ammonia at elevated pressure, or must the amidation be rerouted through the intermediate acid chloride?Direct conversion of ethyl 1,3-thiazole-5-carboxylate to the primary amide using 25 % aqueous ammonia in a 5-L stirred autoclave proceeds smoothly at 80 °C and 8 bar over 6 hours, producing thiazole-5-carboxamide in 93 % isolated yield after vacuum stripping of the ammonia and recrystallization from water. The process avoids the thermal decarboxylation that plagues the acid chloride route, but the autoclave alloy must be Hastelloy C-276 because small concentrations of thiosulfate generated through ring oxidation at the sulfur atom cause pitting corrosion in standard 316L stainless steel after only 10–15 batches. Once the primary amide is isolated, it serves as a common scaffold for a family of negative dielectric anisotropy liquid crystal monomers. Reaction with 4-bromo-2,6-difluorobenzoyl chloride in the presence of 1.15 eq of potassium carbonate in refluxing acetonitrile yields an imide-type monomer that, upon Suzuki coupling with a 4-propylcyclohexylboronic acid, delivers a compound with a clearing point of ≥ 180 °C and a dielectric anisotropy of −6.8 at 1 kHz and 25 °C. A rigorous specification for ionic impurities is enforced: chloride content below 5 ppm, sodium below 2 ppm, and water below 50 ppm, all measured before the monomer is released for mixture formulation under an inert atmosphere in cleanroom class ISO 5 conditions. The voltage holding ratio of a test cell filled with the monomer and photolytically aligned polyimide is specified to be ≥ 99.5 % at 60 °C after 100 hours of DC stress at 5 V, measured by a sinusoidal wave method described in IEC 62317-2. Calibration of the filling robot must account for the viscosity of the monomer solution at 25 °C being 34.2 mPa·s, which increases to 41.7 mPa·s when the crystallisation inhibitor 2,6-di-tert-butyl-4-methylphenol is added at 0.2 wt%.Coupling at the electronically less activated 5-position of the thiazole ring with an electron-deficient arylboronic acid requires a fine-grained catalyst-ligand selection that empirical high-throughput screening in a pharmaceutical process chemistry group narrowed to a system of Pd₂(dba)₃ and SPhos. Ethyl 1,3-thiazole-5-carboxylate is combined with 3-cyano-4-fluorophenylboronic acid (1.28 eq), potassium phosphate tribasic (2.5 eq), and the catalyst pre-mix in degassed toluene/water (4:1 v/v) and heated to 75 °C for 18 hours under a nitrogen blanket. Oxygen ingress below 20 ppm in the headspace, verified by a gas-phase oxygen sensor, is essential to maintain the palladium(0) active species; a single excursion above 200 ppm O₂ during the addition of the solid base was tracked as the root cause of a 22 % yield drop in a 20-L scale-up run, traced to catalyst oxidation. The biaryl product, after extraction and chromatography, serves as a penultimate intermediate for a peripherally selective κ-opioid receptor agonist whose development programme is detailed in a published Investigational New Drug application summary. Residual palladium is controlled to < 5 ppm through a trimercaptotriazine-functionalized silica gel cartridge step, and the ethyl ester is subsequently hydrolysed under a design of experiments-optimised parameter set (18 % HCl, 55 °C, 4 h) to the free acid for the final active pharmaceutical ingredient salt. The manufacturer’s quality agreement with the innovator specifies that any lot of the ethyl 1,3-thiazole-5-carboxylate starting material exhibiting an isomeric impurity (thiazole-4-carboxylate) above 0.15 area% by GC must be quarantined, because the regioisomeric ester co-crystallises with the desired biaryl intermediate and raises the purification burden at the chrial resolution step downstream. |
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Ethyl 1,3‑thiazole‑5‑carboxylate, routinely catalogued as ethyl thiazole‑5‑carboxylate, is a five‑membered heterocyclic ester of molecular formula C₆H₇NO₂S and molecular mass 157.19 g mol⁻¹. It presents as a colourless to pale‑yellow liquid at ambient temperature, with a boiling range reported between 120 °C and 130 °C at 13–15 hPa in pilot‑scale vacuum distillations; the exact value shifts with isomeric purity and the presence of residual ethanol. The compound carries the CAS registry 100367‑80‑4 in numerous fine‑chemical directories, though verification against an in‑house ¹H NMR standard (characteristic thiazole ring protons at δ 8.9–9.2 for C‑2 and δ 8.4–8.6 for C‑4 in CDCl₃) is recommended prior to use in regulated syntheses, because hydrate and salt forms occasionally appear under the same catalog number. It is supplied in amber glass containers under inert gas and stored at 2–8 °C; when unopened and correctly kept, the assay remains ≥98.0% (GC area%) for 24 months.
Commercial demand for this building block is driven by its ability to install a thiazole‑5‑carboxylate handle in pharmacophoric structures without the handling hazards of the free carboxylic acid. Its regiospecificity — the ester group is locked at the position flanked by the ring sulfur — imparts a distinct electronic profile that influences both the nucleophilic and electrophilic chemistry of the heterocycle. The material crosses the supply chain as a research‑grade liquid (25 g to 1 kg units) and as a cGMP intermediate at the 50–200 kg scale, the latter typically accompanied by a full residual‑solvent and metal‑impurity certificate aligned with ICH Q3C and USP <467>.
The ester linkage is susceptible to moisture‑driven hydrolysis. At 25 °C and 65% relative humidity, a headspace‑exposed sample showed a 0.8% drop in assay over 30 days with concurrent formation of thiazole‑5‑carboxylic acid, a species that crystallizes and acts as an autocatalyst accelerating further cleavage. In a production‑site incident at a tropical warehouse (ambient 30–35 °C, RH >80%), a 5 kg drum that had lost nitrogen blanket developed 4.5% free acid within 6 weeks; the batch was rejected for downstream amidation because the acid impurity sequestered the coupling reagent. Consequently, bulk containers are fitted with sealed‑cap adapters and a molecular‑sieve desiccant insert (4A, activated at 300 °C for 12 h). Before critical reactions, the liquid is dried over 4A sieves to a Karl‑Fischer titre ≤0.05% w/w. Refrigeration at 2–8 °C suppresses hydrolysis: in a stability study performed according to ICH Q1A conditions (25 °C/60% RH and 40 °C/75% RH), the unopened package retained >97% assay after 12 months. The compound is incompatible with strong aqueous alkali; at pH >9 the half‑life drops below 48 h at room temperature. No polymerisation has been observed, but exposure to direct sunlight for extended periods generates a faint brown discoloration without altering the GC purity beyond 0.2%.
The most common manufacturing route starts from thiazole‑5‑carboxylic acid, which is suspended in absolute ethanol (5–7 volumes) and treated with thionyl chloride (1.10–1.25 eq) at 0–5 °C. The addition is strongly exothermic; plant‑scale campaigns in a 500 L glass‑lined vessel equipped with a −20 °C brine jacket require a feeding rate controlled by a mass‑flow meter so that the internal temperature never exceeds 8 °C. One batch log recorded a temperature excursion to 22 °C when the jacket setpoint oscillated; the resulting spike of chloro‑by‑products lowered the distilled yield from 85% to 62%. After the addition, the mixture is warmed to 40 °C for 6 h, quenched into chilled water, and extracted with methyl tert‑butyl ether. The crude ester is washed with 5% aqueous sodium bicarbonate to remove residual acid and then concentrated. Final purification by short‑path fractional distillation (0.5–1.0 mbar, head temperature 95–105 °C) routinely delivers an assay of 99.0–99.5% with total unspecified impurities below 0.5%.
PAT‑guided campaigns track the acid‑to‑ester conversion by inline Raman spectroscopy (peak at 1712 cm⁻¹ versus the acid carbonyl at 1680 cm⁻¹), enabling a real‑time endpoint determination that has cut heat‑up time by 30 min and reduced solvent usage by 15%. The process complies with the ISO 9001:2015 quality management framework; for cGMP deliveries, the dedicated equipment train is cleaned to ≤10 ppm of the preceding product, verified by rinse‑water TOC analysis per USP <643>. Metal catalysts are not employed in the standard esterification, so the palladium and copper content is typically <1 ppm.
In pharmaceutical research and kilogram‑scale production, the ethyl ester of 1,3‑thiazole‑5‑carboxylic acid functions as a protected acid synthon that withstands standard peptide‑coupling activation. When treated with HATU (1.05 eq) and DIPEA (2.5 eq) in DMF at 0 °C, the ester is smoothly converted to the corresponding HATU‑active ester, which reacts with primary amines within 2 h to furnish the thiazole‑5‑carboxamide in 88–94% isolated yields after aqueous work‑up. In a campaign for a clinical‑stage STING agonist, a 2.5 kg batch of the ester was amidated with a cyclohexylamine derivative using EDC·HCl (1.2 eq) and HOBt hydrate (0.1 eq) in acetonitrile; the isolated product, after crystallisation from 2‑propanol/water, showed 92% yield and residual palladium below 10 ppm as determined by ICP‑MS (Ph. Eur. 2.4.8). The ester has also been utilised as a precursor for thiazole‑5‑carbohydrazide, obtained by treatment with hydrazine monohydrate in ethanol at reflux; the hydrazide serves as a hinge‑binding motif in a series of CNS‑penetrant kinase inhibitors. Because the ester is a liquid, automated solid‑dispensing systems cannot handle it; manufacturing suites therefore rely on calibrated peristaltic pump modules with PTFE tubing that deliver the reagent at flow rates of 5–20 mL min⁻¹ to the reaction vessel, an arrangement that has reduced operator exposure to <0.1 ppm (8‑h TWA) in a containment‑level 2 plant.
The orientation of the ester group on the thiazole scaffold dictates the outcome of directed metalation reactions. With ethyl 1,3‑thiazole‑5‑carboxylate, the carbonyl oxygen can chelate the lithium counterion and direct deprotonation to the adjacent C‑2 position. Treatment with lithium diisopropylamide (1.1 eq) in THF at −78 °C for 45 min generates the 2‑lithio species, which is trapped with electrophiles: DMF quench provides 2‑formyl‑thiazole‑5‑carboxylate (73% yield), while iodine gives the 2‑iodo analogue (81%). In contrast, ethyl 1,3‑thiazole‑4‑carboxylate undergoes lithiation at C‑5, yielding a regioisomeric aldehyde that positions the carboxaldehyde at the opposite ring vertex. This divergence is exploited when constructing 2,5‑disubstituted thiazoles for medicinal chemistry: the 5‑carboxylate ester enables a one‑pot lithiation‑iodination‑Suzuki sequence that installs an aryl group at C‑2 while retaining the ester handle at C‑5 for subsequent amidation. Published data for the Suzuki coupling of 2‑iodothiazole‑5‑carboxylate with 4‑cyanophenylboronic acid (Pd(PPh₃)₄ 2 mol%, K₂CO₃, dioxane/water, 80 °C) indicates a yield of 78% for the 5‑carboxylate versus 52% for the analogous 4‑carboxylate, a difference attributed to the reduced steric congestion around the carbon‑boron bond in the 5‑substituted isomer. Suppliers therefore offer the 5‑ester as a specialty building block for projects where the final bioactive molecule requires a 2,5‑disubstitution pattern; the 4‑ester, by contrast, is more common in 4,5‑disubstituted arrays found in certain PPARγ modulators.
The ethyl ester has also been leveraged as an intermediate in the synthesis of succinate dehydrogenase inhibitor (SDHI) fungicides, most notably thifluzamide. Hydrolysis of the ester using 2 M NaOH in aqueous ethanol at 50 °C followed by acidification delivers thiazole‑5‑carboxylic acid in quantitative yield; this acid is then coupled with 2′,6′‑dibromo‑2‑methyl‑4′‑trifluoromethoxy‑4‑trifluoromethylaniline under EDC/HOBt conditions to afford the active ingredient. Technical‑grade requirements for the acid precursor stipulate >99.0% purity with the dibromo‑aniline‑derived amide impurity below 0.1% — levels that are only met when the starting ester already shows an individual impurity profile ≤0.3%. Because the free thiazole‑5‑carboxylic acid is a corrosive solid with dust‑handling concerns, the liquid ethyl ester simplifies multi‑ton campaigns: it can be pumped, precisely metered, and hydrolyzed in situ without breaking containment. Process‑analytical monitoring (FTIR, peak at 1700 cm⁻¹) ensures the saponification endpoint is reached within 4 h, and the aqueous solution of the sodium salt is directly transferred to the coupling step, avoiding isolation of the solid acid. This integrated workflow has been demonstrated at the 10–20 metric ton annual capacity in dedicated SDHI manufacturing trains.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | Colourless to pale‑yellow liquid | Visual inspection |
| Assay (GC) | ≥98.0% area | In‑house GC‑FID aligned with USP ⟨621⟩ |
| Water (KF) | ≤0.5% w/w | ASTM E203 |
| Largest unspecified impurity | ≤1.0% area | GC‑FID, same conditions |
| Residual ethanol | ≤5000 ppm | HS‑GC per ICH Q3C |
| Heavy metals (as Pb) | ≤10 ppm | USP ⟨231⟩ (or ICP‑OES) |
| pH of 1% aq. extract | 5.0–7.0 | Ph. Eur. 2.2.3 |
| Solvent | Concentration Limit (ppm) | Class |
|---|---|---|
| Ethanol | 5000 | Class 3 |
| Acetone | 5000 | Class 3 |
| Isopropyl acetate | 5000 | Class 3 |
| Toluene | 890 | Class 2 |
| Dichloromethane | 600 | Class 2 |
Occupational health assessments classify the ester as a mild skin and eye irritant; acute oral toxicity by the OECD 423 protocol places the LD₅₀ in the rat above 2000 mg kg⁻¹. Handling protocols mandate chemically resistant gloves meeting EN 374 (breakthrough time > 30 min), safety goggles, and local exhaust ventilation when processing open containers. Spilled material is absorbed onto vermiculite or bonded universal sorbent; contact with strong oxidisers (perchlorates, peroxides) generates sulfur oxides and must be avoided. In combustion scenarios, use CO₂ or dry chemical extinguishers; water spray may accelerate hydrolytic decomposition, releasing ethanol vapour. Waste streams that contain the ester are incinerated in a ≥1100 °C afterburner with alkaline scrubbing to meet EU Directive 2010/75/EU emission limits. Empty containers retain vapour residues and should be triple‑rinsed and processed through a certified solvent‑recovery loop.
