4-Ethoxycarbonylthiazole
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HS Code |
803926 |
| Chemical Formula | C6H7NO2S |
| Molecular Weight | 157.19 g/mol |
| Physical State | Solid (usually) |
| Appearance | Typically white to off - white solid |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some common organic solvents like ethanol, acetone |
| Odor | May have a faint, characteristic odor |
| Stability | Stable under normal conditions if stored properly |
As an accredited 4-Ethoxycarbonylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 4 - Ethoxycarbonylthiazole packaged in a sealed, corrosion - resistant container. |
| Shipping | 4 - Ethoxycarbonylthiazole, a chemical, is shipped in specialized, sealed containers. Precautions are taken to prevent leakage, with proper labeling indicating its nature. Shipment follows strict chemical - handling regulations for safe transportation. |
| Storage | 4 - Ethoxycarbonylthiazole should be stored in a cool, dry, well - ventilated area, away from sources of heat, ignition, and direct sunlight. Keep it in a tightly closed container to prevent moisture and air exposure, which could potentially lead to degradation. Store separately from incompatible substances, such as strong oxidizing agents or acids, to avoid chemical reactions. |
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At the core of integrase inhibitor synthetic routes, 4-ethoxycarbonylthiazole functions as the masked acid equivalent for constructing thiazole-4-carboxamide pharmacophores. A typical downstream transformation documented in multi-kilogram pilot campaigns begins with alkaline hydrolysis of the ester under strictly controlled pH. In a 1000 L glass-lined reactor, the substrate is suspended in deionised water and treated with 30% w/w aqueous sodium hydroxide at a molar ratio of ester to NaOH of 1:1.12. The mass is held at 78–82 °C for 3.5 h under nitrogen blanket until in-process HPLC confirms residual ester below 1.0 area%. The resulting sodium 4-thiazolecarboxylate solution is cooled to 5 °C and acidified with 37% hydrochloric acid to pH 2.3–2.5. The precipitated free acid is isolated via centrifuge, washed with chilled water to conductivity <50 µS/cm, and dried in a conical vacuum dryer at 45 °C/–0.095 MPa to a loss-on-drying endpoint of ≤0.3%. Typical yield of 4-thiazolecarboxylic acid exceeds 95% with purity ≥99.5% by HPLC (C18, 254 nm, ACN/0.1% H₃PO₄ 30:70). The acid is subsequently converted to the acid chloride by treatment with thionyl chloride (1.4 equiv) in dichloromethane containing catalytic DMF at 35–40 °C for 6 h. After stripping volatiles, the crude acyl chloride is taken into THF and added dropwise to a pre-cooled (0–5 °C) solution of the required aniline derivative and triethylamine (1.2 equiv) in THF. The batch is warmed to 20 °C and stirred overnight. The carboxamide product is precipitated by drowning into 10 volumes of ice water, filtered, and recrystallised from ethanol/water 7:3 v/v. The final active pharmaceutical ingredient intermediate must comply with ICH Q7 Q&A level GMP and typically exhibits a residual palladium content <10 ppm (AAS), sulphated ash <0.1%, and any single unknown impurity limited to <0.10% per USP <461>. The above hydrolysis step tolerates a narrow processing window because over-hydrolysis can lead to ring-opening side products. Table 1 collates batch data from three separate campaigns that highlight the sensitivity of isolated purity to alkali strength and hold time.
Deviation beyond 1.15 equiv of base generates a persistent greenish discolouration and an unidentified polar impurity that co-elutes with the product on standard C8 columns, requiring preparative HPLC intervention. Consequently, the process is anchored at the 1.10–1.12 equiv range and enforced via PAT-driven pH monitoring at the plant-floor level. Where Does the Thiazole-4-Carboxylate Motif Appear in Commercial Fungicidal Chemistry?The transformation of 4-ethoxycarbonylthiazole into active fungicidal ingredients follows a hydrolysis–amidation sequence that has been validated in pilot-plant campaigns for multiple SDHI-type actives. After obtaining 4-thiazolecarboxylic acid as described, coupling with substituted 2-aminobenzonitriles or 2,6-dialkylanilines is performed under modified Steglich conditions to avoid racemisation and side-chain dehydration. A typical batch charge for a 200 kg scale campaign uses acid (1.0 equiv), the aniline partner (1.03 equiv), EDC hydrochloride (1.15 equiv), and HOBt monohydrate (0.10 equiv) in DMF at 0–5 °C during coupling, then allowed to reach 22 °C over 16 h. The reaction mass is quenched into 5% w/w aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer is washed with brine and concentrated under vacuum. The crude amide is recystallised from isopropyl acetate / n-heptane 1:4 v/v to deliver product with ≥98.0% HPLC purity and endothermic melting peak at 178–180 °C by DSC. Residual EDC-related urea is controlled to <0.15% as determined by LC-MS SIM at m/z 179. Compliance for the resulting thiazole-4-carboxamide technical active hinges on CIPAC MT 184 wet sieve retention (<1.0% on 45 µm), water content by Karl Fischer (<0.5%), and a mandatory five-batch accelerated storage study per FAO/WHO Manual Appendix D. In formulation, the active is wet-milled using a WAB Dyno®-Mill KDLA with 0.6–0.8 mm yttria-stabilised zirconia beads at 3000 rpm and recirculated until D90 particle size reaches 4–6 µm (Malvern Mastersizer). A representative 200 g/L SC formulation comprises the active (20.8% w/w), sodium lignosulfonate (3.0%), ethoxylated tristyrylphenol phosphate (2.5%), propylene glycol (5.0%), silicone antifoam (0.2%), and water to 100%. The suspension is brought to pH 6.5–7.0 with citric acid and demonstrates <2% syneresis after 14 days at 54 °C. Residue limits under EPA 40 CFR 180 for the parent compound on leafy vegetables are typically set at 0.01–0.05 mg/kg, driving the analytical clean-up protocol to utilise QuEChERS extraction with PSA/C18 dispersive SPE. Hydrolysis–Decarboxylation Sequences as an Entry to Nutty Flavour CompoundsWhen the acid intermediate derived from 4-ethoxycarbonylthiazole is subjected to thermal decarboxylation in the presence of a copper catalyst, a pathway to 4-methylthiazole is opened—a molecule registered under FEMA 3671 and recognised for its roasted, nut-like aroma profile at concentrations as low as 0.5 ppm in water. The acid (1.0 wt) is blended with copper powder (5% w/w, 325 mesh) and introduced into a high-temperature resistant reactor charged with quinoline as a heat-transfer medium. The heterogeneous mixture is rapidly heated to 180–185 °C while volatile products distil through a short Vigreux column. The distillate that collects between 124–128 °C at atmospheric pressure consists principally of 4-methylthiazole contaminated with traces of quinoline. Subsequent fractional distillation through a 30-tray Oldershaw column at a 15:1 reflux ratio yields product of >99% GC purity with a characteristic quinoline level <100 ppm. The overhead fraction is stabilised with 0.1% BHT to prevent auto-oxidation during storage under nitrogen. From a regulatory standpoint, the resulting 4-methylthiazole must satisfy EU 1334/2008/EC Annex I and JECFA specifications including identity by IR and refractive index nD20 1.520–1.526. In compounded chocolate and coffee flavour blends, the compound is incorporated as a 0.5% dilution in triacetin and dosed at 0.2–2.0 g per 100 kg of finished product. Process hygiene for flavour-grade intermediates additionally demands absence of Class 1 solvent residues (per CPMP/ICH/283/95); therefore the quinoline employed in decarboxylation is subsequently washed from the crude thiazole with 5% hydrochloric acid followed by water to pH 7, and residual copper is chelated with EDTA (0.01M) wash to meet the <10 ppm heavy metal specification. Published toxicological benchmarks (EFSA Panel) confirm a No Observed Effect Level of 10 mg/kg bw/day for the parent thiazole, which provides a margin of exposure exceeding 5000 at typical beverage flavour use rates. Direct C–H Arylation Substrates for Conjugated Ligand ArchitecturesDirect functionalisation at the 2-position of 4-ethoxycarbonylthiazole via palladium-catalysed C–H activation has opened a reliable pathway to 2-arylthiazole-4-carboxylates, a class of intermediates valued in phosphorescent OLED host design. In a standard protocol executed on 500 mmol scale, the thiazole ester (1.0 equiv), the selected aryl bromide (1.2 equiv), palladium acetate (0.05 equiv), tricyclohexylphosphine tetrafluoroborate (0.10 equiv), and potassium carbonate (2.0 equiv) are combined in anhydrous DMF under argon in a Schlenk flask. The suspension is degassed by three freeze-pump-thaw cycles and then heated to 100 °C for 12 h with vigorous magnetic stirring. After cooling, the mixture is filtered through a short Celite pad and partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over Na₂SO₄, and concentrated. The residue is purified by flash silica gel chromatography (eluent: hexane / ethyl acetate 9:1→4:1) to deliver the 2-aryl product in 78–85% isolated yield with >99% purity by GC. This building block is then reduced with LiAlH₄ (1.5 equiv) in THF to the corresponding 2-aryl-4-hydroxymethylthiazole, a key precursor for vinyl-functionalised monomers used in crosslinkable electron-transport layers. Material destined for organic electronics manufacturing must pass halogen anion residue limits per IEC 62321-3-1: total bromine <900 ppm, total chlorine <900 ppm, and the combined halogen content is verified by combustion ion chromatography before release. Because trace palladium can quench triplet excitons, the product is additionally polished with a trimercaptotriazine-functionalised silica scavenger until palladium drops below 5 ppm by ICP-MS. The ester hydrolysis number (ASTM D 1613-17) is monitored to confirm complete retention of the carboxylate function during the coupling sequence; a value of 280–295 mg KOH/g correlates with monomer purity suitable for UV-curable formulations. In final device fabrication, the 2-arylthiazole-4-methacrylate monomer is thermally co-deposited at 10⁻⁶ mbar with a carbazole host to achieve a refractive index of 1.72 at 450 nm, as measured by ellipsometry. A cross-sector compliance snapshot anchored to recognised international standards facilitates raw material qualification across disparate customer specifications.
When 4-Ethoxycarbonylthiazole Serves as a Neutral N,S-Donor LigandSupplementing its role as a synthetic intermediate, 4-ethoxycarbonylthiazole can be employed as a neutral N,S-bidentate ligand for transition metals under strictly anhydrous conditions. The ester-substituted thiazole ring coordinates through the ring nitrogen and the endocyclic sulphur atom, forming stable, charge-neutral complexes with palladium(II), platinum(II), and copper(I). In the specific context of a PdCl₂ complex applied to Suzuki-Miyaura cross-coupling of electron-deficient aryl chlorides, the ligand is dissolved in dry acetonitrile and combined with PdCl₂ (1.0 equiv) under argon. The mixture is heated at reflux (82 °C) for 4 h, during which the solution transitions from dark red to a clear yellow-orange. Upon cooling to –20 °C, trans-[Pd(4-ethoxycarbonylthiazole)₂Cl₂] crystallises as air-stable, yellow needles that are collected by filtration and washed with cold diethyl ether. Yield after vacuum drying at 40 °C reaches 92% based on palladium. The single-crystal X-ray structure (CCDC deposition accessible via Cambridge Structural Database) confirms a square-planar geometry with the two thiazole ligands in a trans arrangement, Pd–N bond lengths at 2.031 Å and Pd–S contacts at 2.294 Å. In a representative coupling protocol conducted on a 50 mmol scale, the pre-formed complex is used at 0.5 mol% loading for the reaction of 4-chlorobenzotrifluoride with phenylboronic acid. The reaction is carried out in a 4:1 v/v toluene / water biphasic system with K₃PO₄ (2.0 equiv) at 80 °C for 8 h. GC monitoring reveals >95% conversion to the biaryl product, and the organic phase retains less than 2 ppm Pd after a simple charcoal filtration. This performance is maintained over 12 consecutive batch recycles when the aqueous layer is replenished with base, offering a total turnover number exceeding 20,000. The ligand itself exhibits excellent thermal stability up to 220 °C by TGA, and its ethoxycarbonyl group stays intact throughout catalysis, as demonstrated by ¹³C NMR monitoring at 170.2 ppm (ester carbonyl). Quality control of the ligand lot for catalytic service mandates acid value below 0.5 mg KOH/g to avoid protonolysis of the Pd–S bond, and water content below 0.1% (KF) to prevent chloride-bridge hydrolysis. These narrow specifications have been codified in a technology transfer package for a dedicated fine-chemical plant operating under ISO 9001:2015. In the fine-chemical outsourcing environment where the complex is supplied as a ready-to-use catalyst kit, the solid is packed under argon in double-laminated, moisture-barrier bags and validated for catalyst activity retention over 24 months at ambient temperature. The ligand precursor 4-ethoxycarbonylthiazole taken for metalation must show a thiazole ring proton signal at 8.80 ppm (¹H, CDCl₃) with an integration ratio of 1.00 ± 0.02 relative to the ethoxy quartet; deviation hints at N-alkylation impurities that render the batch unsuitable for coordination chemistry and it is rejected under incoming QA protocol ASTM D 5296-19. |
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Ethyl 1,3-thiazole-4-carboxylate (4-ethoxycarbonylthiazole), CAS 14527-41-4, is a heterocyclic building block with a molecular formula of C₆H₇NO₂S and a relative molecular mass of 157.19 g·mol⁻¹. The compound is supplied as a colourless to pale yellow liquid, exhibiting a boiling point of 90–92 °C at 0.5 mmHg and a density of 1.218 g·cm⁻³ at 25 °C. Commercial grades typically achieve a chromatographic purity of ≥98.0% (GC-FID, area%), with water content controlled to ≤0.5% by Karl Fischer titration according to ASTM E203. The ester functionality at the 4-position renders the molecule susceptible to nucleophilic acyl substitution, while the thiazole nitrogen directs electrophilic substitution at the 2- and 5-positions, establishing a regiochemical profile that differentiates it from the 2- and 5-ethoxycarbonyl isomers in cross-coupling sequences.
The electronic landscape of the thiazole ring shifts measurably with the placement of the ethoxycarbonyl substituent. In the 4-isomer, the ester carbonyl is conjugated with the endocyclic double bond, withdrawing electron density from the C2–N3 region. This manifests in a downfield shift of the C2 proton in 1H NMR (CDCl₃, 400 MHz) to approximately δ 8.92, compared to δ 8.15–8.25 for the 2-isomer. The altered electron demand modifies the outcome of palladium-catalysed transformations: while 2-ethoxycarbonylthiazole undergoes oxidative addition at the C5 halogen more rapidly, the 4-isomer requires elevated catalyst loading (typically 2–5 mol% Pd(PPh₃)₄ versus 1–2 mol% for the 2-regioisomer under equivalent Suzuki–Miyaura conditions) to achieve complete conversion. Industrially, the 4-substitution pattern is preferred when a C2-functionalised thiazole scaffold is needed, because the ester can be retained as a protecting group during C2 lithiation with n-butyllithium at −78 °C, then hydrolysed late-stage to the carboxylic acid. Published data for the 5-ethoxycarbonyl isomer indicates a lower thermal stability during distillation, with observable decarboxylation above 120 °C at ambient pressure, whereas the 4-isomer tolerates brief excursions to 150 °C without significant colour development when blanketed with argon containing <10 ppm O₂.
| Parameter | 4-Ethoxycarbonylthiazole | 2-Ethoxycarbonylthiazole | 5-Ethoxycarbonylthiazole |
|---|---|---|---|
| CAS number | 14527-41-4 | 5398-10-9 | 32955-21-8 |
| Boiling point (°C/mmHg) | 90–92 / 0.5 | 76–78 / 0.3 | 85–87 / 0.4 (dec. observed) |
| Density (g·cm⁻³, 25 °C) | 1.218 | 1.205 | 1.211 |
| 1H NMR C2 proton shift (δ, CDCl₃) | 8.92 | — | 8.78 |
| Recommended storage temperature | −20 °C, under argon | 2–8 °C | −20 °C, desiccated |
Production of 4-ethoxycarbonylthiazole via Hantzsch condensation between ethyl glyoxylate and thiourea derivatives generates a mixture of regioisomers when symmetrical 1,2-dicarbonyl components are absent. To avoid costly chromatographic separation, process chemists have adopted the reaction of thiazole-4-carboxylic acid (CAS 14527-43-6) with ethanol in the presence of thionyl chloride at 0–5 °C, followed by neutralisation with 5% aqueous sodium bicarbonate. On a 500 L glass-lined reactor equipped with a retreat-curve impeller, the exotherm is managed by dosing SOCl₂ at a rate not exceeding 2.5 L·h⁻¹ to maintain a jacket temperature differential of ΔT ≤ 12 °C. After aqueous work-up, the crude ester is rectified through a 10-tray Oldershaw column at a reflux ratio of 3:1, yielding product with an isomeric purity exceeding 99.5% (area%). High-shear dispersion of the organic phase during extraction using an inline rotor-stator mixer (3000 rpm tip speed) reduces phase disengagement time from 45 minutes to 8 minutes, minimising ester hydrolysis at the interface. The distillate fraction collected between 89 °C and 93 °C at 0.5 mmHg is the primary commercial cut; lighter fractions contain ethyl formate residues, while heavier bottoms consist of dimeric ester-impurities identified via LC-MS (M+H⁺ = 313.1).
Carbon steel and copper alloys are incompatible with 4-ethoxycarbonylthiazole during prolonged storage, as the thiazole sulfur atom promotes pitting corrosion in systems where moisture ingress exceeds 100 ppm. Stainless steel grades 316L and 304 are acceptable for short-term (≤48 hours) hold tanks, but long-term warehousing in fluorinated high-density polyethylene drums fitted with PTFE-lined closures is stipulated for commercial quantities shipped in 25 kg and 50 kg units. The product is classified under GHS as a combustible liquid (H227) and a skin irritant (H315); respiratory protection with organic vapour cartridges meeting EN 14387 is mandatory during drum transfers in enclosed areas.
The ester group undergoes smooth aminolysis with primary amines in ethanol at reflux, affording the corresponding thiazole-4-carboxamides in isolated yields of 78–92%. Kinetic profiles derived from ReactIR monitoring (attenuated total reflectance, 4 cm⁻¹ resolution) indicate that n-alkylamines consume the ester within 3–6 hours, whereas aromatic amines such as 4-methoxyaniline require 12–18 hours under the same conditions, consistent with lower nucleophilicity. Potassium tert-butoxide (1.05 eq) in tetrahydrofuran at 0 °C cleaves the ester to the carboxylate quantitatively within 45 minutes, a pathway that allows late-stage diversification in telescoped process sequences. Reduction with lithium aluminium hydride in diethyl ether at −10 °C produces 4-hydroxymethylthiazole, an alcohol intermediate valued for Mitsunobu coupling to phenolic drugs, though the exotherm must be controlled by slow inverse addition so that the internal temperature never surpasses 15 °C. Published yields for this reduction exceed 85% when work-up employs a modified Fieser procedure using 1.0 mL water per gram of LiAlH₄.
The 4-ethoxycarbonyl group doubles as an orienting functionality in directed C–H functionalisation. Ortho-lithiation with lithium diisopropylamide (LDA, 1.1 eq) at −78 °C in THF generates the 5-lithio intermediate; quench with N,N-dimethylformamide yields the 5-formyl derivative suitable for Horner–Wadsworth–Emmons olefination. This sequence has been adopted in the kilogram-scale synthesis of thiazole-based dual inhibitors of PI3Kδ and BTK, wherein the aldehyde serves as a branch point for elongation. Anhydrous conditions (KF < 50 ppm) are non-negotiable: residual moisture at 500 ppm reduces lithiation selectivity by 14%, as determined by GC monitoring of the quenched aliquots.A validated reversed-phase HPLC method utilizing a C18 column (150 mm × 4.6 mm, 3.5 µm particles) with a mobile phase of acetonitrile/water (60:40 v/v, containing 0.1% trifluoroacetic acid) resolves seven known process impurities from the main chromatographic peak at a retention time of 6.8 minutes. The limit of quantitation for ethyl 4-ethoxycarbonylthiazole-5-carboxylate, a byproduct of C5 formylation reversal, is established at 0.05% (signal-to-noise ratio ≥ 10) using UV detection at 254 nm. For applications demanding C2 halogen-free material, ion chromatography coupled with suppressed conductivity detection (Dionex ICS-2100, AS18 column) confirms chloride and bromide levels below 5 µg·g⁻¹. Residual palladium analysis by ICP-MS following a typical Suzuki coupling sequence requires digestion in concentrated nitric acid and a reporting limit of 0.1 µg·L⁻¹ to meet the ICH Q3D elemental impurity guideline for oral drug substances.
| Test | Method | Acceptance Criterion |
|---|---|---|
| Assay (GC-FID) | In-house SOP, column DB-5 30 m | ≥98.0% (technical); ≥99.2% (pharma) |
| Water content | ASTM E203 (K-F coulometric) | ≤0.5% w/w |
| Colour (APHA) | ASTM D1209 | ≤50 (neat) |
| Isomeric purity (HPLC) | In-house gradient, 215 nm | ≤0.3% total other regioisomers |
| Residual solvents | USP <467> headspace GC-MS | Ethanol ≤0.1%, THF ≤0.04% |
| Heavy metals (Pb, As, Hg) | ICP-OES, method USP <233> | Each ≤5 µg·g⁻¹ |
| Shelf life (retest date) | Stability chamber, −20 °C ± 5 °C | 12 months from date of manufacture when stored unopened under argon |
Stability studies conducted under ICH Q1B conditions reveal that 4-ethoxycarbonylthiazole develops a pale yellow tint when exposed to cool white fluorescent light providing an illuminance of 1.2 × 10⁶ lux·h followed by 200 W·h·m⁻² near-UV energy. Liquid chromatography–mass spectrometry identifies the primary photo-degradant as diethyl 4,4'-bithiazole-2,2'-dicarboxylate (m/z 341.0 [M+H]⁺), formed via radical recombination at the 2-position. This pathway is suppressed by packaging in amber borosilicate glass and overlaying the headspace with argon containing less than 0.5% oxygen. Manufacturers supplying the ester for cGMP intermediates specify amber HDPE containers and incorporate oxygen-absorbing sachets in secondary packaging. When the material is drawn down from drums using nitrogen pressure transfer (0.2–0.5 bar), the photostability results correlate with that of material stored in complete darkness for up to 18 months. A recommendation to blanket analytical vials with argon after each use is standard protocol in quality control laboratories.
The 4-ethoxycarbonyl derivative exhibits marginal water solubility (<0.1 g·L⁻¹ at 20 °C), yet partial hydrolysis is catalysed by trace bases dissolved in tap water rinses. Glass-lined reactor surfaces conditioned with a 1% nitric acid passivation cycle prior to processing have been observed to reduce iron-mediated ester cleavage on pilot scale, where hydrolysis would otherwise introduce thiazole-4-carboxylic acid at levels of 0.5–1.2% in the centrifugal partition. The compound is incompatible with strong reducing agents such as borane–tetrahydrofuran complex unless tetrahydrofuran is freshly distilled from sodium-benzophenone ketyl, as adventitious peroxides cause rapid ester reduction to a complex mixture of oligomeric tars.
In a comparative evaluation of C4-substituted thiazole esters, 4-ethoxycarbonylthiazole occupies a distinct performance niche: it offers faster aminolysis kinetics than the corresponding methyl ester (factor of 2.3 measured by relative rate constants at 60 °C in ethanol) while retaining sufficient volatility for vacuum distillation without the polymerisation risks encountered with the allyl or tert-butyl carboxylates. Its vapour pressure of approximately 0.1 mmHg at 25 °C permits the use of short-path wiped-film evaporators for final polishing in high-purity grades, a step not practical with the higher-boiling 4-benzyloxycarbonylthiazole.
