Ethyl 2-(4-Hydroxyphenyl)-4-Methyl-1,3-Thiazole-5-Carboxylate
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HS Code |
623654 |
| Chemical Formula | C13H13NO3S |
| Molar Mass | 263.31 g/mol |
| Appearance | Solid (usually) |
| Physical State At Room Temperature | Solid |
| Solubility In Water | Low |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol, dichloromethane |
| Melting Point | Specific value would need experimental determination |
| Boiling Point | Specific value would need experimental determination |
| Pka If Applicable | Data would require experimental measurement |
| Ir Absorption Peaks | Characteristic peaks for C=O, C=N, -OH, C-S etc. in IR spectrum |
As an accredited Ethyl 2-(4-Hydroxyphenyl)-4-Methyl-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 2-(4 - Hydroxyphenyl)-4 - Methyl - 1,3 - Thiazole - 5 - Carboxylate in sealed chemical - grade pouch. |
| Shipping | Ethyl 2-(4 - Hydroxyphenyl)-4 - Methyl - 1,3 - Thiazole - 5 - Carboxylate is shipped in accordance with chemical transport regulations. Packed securely to prevent leakage, it's transported via approved carriers, ensuring safety during transit. |
| Storage | Ethyl 2-(4 - Hydroxyphenyl)-4 - Methyl - 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 contact with air, which could potentially lead to chemical degradation. Store it separately from incompatible substances, preferably in a dedicated chemical storage area with proper ventilation. |
In the large-scale manufacturing of Febuxostat API — a non-purine xanthine oxidase inhibitor approved under FDA NDA 021856 and EMA EMEA/H/C/000916 for chronic hyperuricemia — ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (CAS 161798-02-3) occupies the central C-5 ester intermediate node in the convergent synthetic route. Production campaigns executed in 10,000 L glass-lined or Hastelloy C22 reactors under full cGMP controls (ICH Q7, §§8.1–8.5) receive this intermediate as a free-flowing off-white crystalline powder with a melting onset of 172–174°C (DSC, ISO 11357-1, 10°C/min) and a typical tapped bulk density of 0.48–0.55 g/mL. The regulatory starting material designation requires a chromatographic purity of ≥ 99.8 area% (HPLC, USP <621>, C18 stationary phase, acetonitrile/0.1% trifluoroacetic acid gradient) with individual specified impurities — 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid (de-esterified homolog) limited to ≤0.10% and the phenolic oxidative dimer capped at ≤0.05% — because both participate in the subsequent Vilsmeier-Haack formylation and nucleophilic cyanation cascade, generating regioisomeric nitriles that co-crystallize with the API and breach the ICH Q3A(R2) unidentified impurity threshold of 0.10% at a daily dose of 120 mg. In the critical O-alkylation stage, the isolated dried intermediate (loss on drying ≤0.5%, vacuum tray dryer, 55°C/–0.09 MPa) is charged together with anhydrous potassium carbonate (2.5 eq.) and isobutyl bromide, maintaining a strict molar ratio of intermediate to alkylating agent of 1:1.08–1:1.12 in dimethylformamide at 48–52°C for 14–18 h. Deviation above 1.12 eq. accelerates the formation of the O,O′-dialkylated quaternary ammonium by-product, which precipitates during the subsequent aqueous quench and fouls the 0.5 µm in-line bag filters on the centrifuge feed line, a bottleneck documented across multiple production trains equipped with DN800 Heinkel vertical basket centrifuges. After phase separation at 45°C and solvent swap to acetonitrile, the crude ester is crystallized by controlled cooling from 48°C to –5°C at a ramp of 0.15°C/min, yielding the penultimate intermediate that feeds directly into the sodium cyanide/ammonium chloride cyanation reactor at a throughput of 180–220 kg per batch. The terminal process sequence — cyanation, nitrile hydration to the carboxylic acid, and final ethanolate salt formation — delivers Febuxostat complying with USP monograph limits for related compound A (≤0.15%) and compound B (≤0.15%), ultimately compressed into 80 mg and 120 mg film-coated tablets.At what treat rate does this phenolic thiazole outperform dinonyl diphenylamine in Group III and ester-based turbine oils?The application of the thiazole ester as a high-temperature antioxidant in synthetic and semi-synthetic turbine lubricants exploits the synergistic interplay of the 4-hydroxyphenyl radical-scavenging moiety and the thiazole sulfur atom capable of decomposing hydroperoxides through a non-radical, Lewis-acid-catalyzed pathway analogous to that observed with 2-mercaptobenzothiazole derivatives. In a standard ASTM D943 turbine oil oxidation stability bath (water, 95°C, copper/iron coil catalyst, 3 L oxygen flow), a Group III/PAO blend treated with 0.30–0.50% w/w of the compound in combination with 0.15% w/w butylated hydroxytoluene as a sacrificial donor extends the induction period beyond 3,500 h before the total acid number (TAN) reaches 2.0 mg KOH/g, compared to 2,200 h for an equivalent molar concentration of dinonyl diphenylamine under identical catalyst loading. The addition ratio must stay within the 0.25–0.55% plateau; below 0.20% the sulfur-assisted peroxide cleavage becomes kinetically irrelevant in the presence of dissolved metal ions, and above 0.60% the ester’s inherent hydrolytic lability at the oil-water interface promotes TAN creep from 0.12 to 0.45 mg KOH/g within 500 h, a failure mode traced through out-of-service ISO 4406 cleanliness codes worsening from –/16/13 to –/20/18 due to precipitated carboxylic acid sludge. Lubricant formulators executing in-line blending at 60–70°C with a side-stream injection rate of 3–5 L/min per 1,000 kg base stock pre-dissolve the solid ester in a co-solvent of high-flash aromatic naphtha (closed cup >62°C, ASTM D93), and the finished fluid is certified against GEK 32568f and Siemens TLV 901 304 extreme-pressure turbine oil specifications, with the final product delivered as a 46-grade turbine oil drummed under nitrogen blanket to suppress oxidative color instability. ASTM D6186-08 differential scanning calorimetry screening on the neat ester exhibits a single exothermic onset at 242–248°C (100°C/min, 500 psi oxygen), placing it inside the oxidation stability envelope required for modern combined-cycle gas turbine sump temperatures reaching 130°C.Melt extrusion stabilization of impact copolymer polypropylene structures without compromising ethylene-propylene rubber dispersionIn the continuous production of impact copolymer polypropylene (ICP) intended for automotive bumper fascias and instrument panel carriers, the addition of 0.08–0.15% w/w of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate alongside 0.10% w/w tris(2,4-di-tert-butylphenyl)phosphite (a hydrolytically stable phosphite) is metered via a gravimetric loss-in-weight feeder into the main feed throat of a co-rotating twin-screw extruder with a 44:1 L/D ratio and a modular screw design incorporating two kneading block arrays upstream of the vacuum vent at barrel zone 9. The phenolic thiazole exerts a dual function: it quenches carbon-centered radicals generated during the chain-scission phase of the dispersed ethylene-propylene rubber (EPR) phase, and the thiazole ring sulfur acts as a hydrogen-chloride scavenger for residual Ziegler-Natta catalyst residues (8–12 ppm titanium) that would otherwise trigger autocatalytic thermo-oxidative degradation during the 240–260°C melt-phase residence time of approximately 45–55 s. Operating below a melt temperature of 238°C fails to solubilize the crystalline additive (melting point 172–174°C) uniformly, microscopic domains of undispersed thiazole persist in the final injection-molded plaque and nucleate stress-whitening at elongations exceeding 120% (ISO 527-2, type 1A specimen), which is a critical flaw for painted bumper assemblies requiring an adhesions test per DBL 5416. Prior to extrusion, the additive must be pre-dried to a moisture content <150 ppm in a vacuum desiccant hopper at 65°C for 4 h if ambient relative humidity has exceeded 60%, since residual water accelerates ester hydrolysis at the screw flights and elevates the melt-acidity number by 0.8–1.2 mg KOH/g, corresponding to a measurable MFI drift of 3–5 g/10 min versus the target 21 g/10 min (ISO 1133-1:2022, 230°C/2.16 kg). The stabilized ICP pellets, compliant with the extractives limitations of FDA 21 CFR 177.1520(c) for food-contact olefin polymers under Conditions of Use B through H, are converted into 2.8–3.2 mm thick injection-molded trims at a clamp force setting of 1,800–2,200 tonnes using a sequential valve-gated hot runner.
When a single-component epoxy adhesive requires latency at 25°C but rapid cure at 120°C, this thiazole ester modifies dicyandiamide dispersionMicroencapsulated dicyandiamide-cured epoxy formulations for structural bonding in electric vehicle battery tray assembly suffer from a shelf-life/cure-speed dichotomy that is partially resolved by the addition of 1.2–2.5 phr of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate as a low-temperature accelerator with phenolic latent activity. The per-weight loading must be calibrated to a narrow window because the ester’s phenolic proton acidifies the epoxy medium (potentiometric titration, ASTM D664, shows a blend pH drop from 7.8 to 5.9 at 3 phr loading) which facilitates the nucleophilic attack of dicyandiamide on the epoxide ring, reducing the differential scanning calorimetry peak exotherm temperature from 168°C to 131°C (ISO 11357-5, 10°C/min) without triggering large-scale oligomerization at 25°C exposure over 14 days. At loadings exceeding 2.8 phr, the protonated dicyandiamide intermediate undergoes premature imine formation during static storage and the room-temperature viscosity doubles from 32 Pa·s to 68 Pa·s within 6 weeks, effectively voiding the 6-month shelf-life specification per DIN 65472. On the process side, the pre-blend of accelerator with a low-molecular-weight bisphenol A diglycidyl ether resin (epoxy equivalent weight 182–192 g/eq) is homogenized on a three-roll mill at a gap setting of 15 µm to achieve a Hegman grind ≤5 µm prior to adding the dicyandiamide curing agent (7–8 phr) and hydrophobic fumed silica thixotrope. The one-component paste is then dispensed robotically through static mixers onto aluminum alloy substrates (en AW-5182, degreased and laser-structured) and oven-cured at 120°C for 25 min, attaining lap shear strengths on 0.2 mm bond-line specimens of 20–24 MPa (ISO 4587) with cohesive failure. The cured adhesive network retains ≥85% of its room-temperature shear strength after a 1,000 h cyclic corrosion test according to VDA 621-415, enabling its use as a structural sealant in battery enclosures required to pass UN R100 Part II mechanical integrity testing.
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Ethyl 2-(4-Hydroxyphenyl)-4-Methyl-1,3-Thiazole-5-Carboxylate (CAS 103471-00-3; molecular weight 263.31 g mol⁻¹) is presented as a white to off-white crystalline powder with a characteristic faint aromatic odor. The material crystallizes from ethyl acetate/heptane mixtures as monoclinic prisms exhibiting a melting endotherm with onset at 154–156 °C when measured by differential scanning calorimetry at 10 K min⁻¹ under nitrogen. The compound remains the preferred ester derivative in multi-step pharmaceutical processes where controlled hydrolysis of the ester moiety is required to generate 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid, a validated xanthine oxidase inhibitor scaffold.
Industrial supply of the title compound critically depends on the one-pot Hantzsch cyclocondensation between 4-hydroxythiobenzamide and ethyl 2-chloro-3-oxobutanoate. In jacketed glass-lined vessels of 500–2000 L capacity, stoichiometric quantities of the thiobenzamide are suspended in ethanol (denatured, <0.2% water) at 20–30 °C. The β-ketoester chloro-compound is metered over 45–90 min while maintaining the batch temperature below 35 °C to prevent premature cyclization and exothermic runaway. Once addition is complete, the thin slurry is heated to 78–82 °C and held under reflux for 6–8 h; reaction progress is monitored by reversed-phase HPLC (XBridge C18, 5 μm, 4.6 × 250 mm column; mobile phase acetonitrile:water 60:40 v/v with 0.1% H₃PO₄; flow 1.0 mL min⁻¹; detection 254 nm). The target retention time is 6.3 ± 0.1 min. Post-reaction, the mixture is concentrated under reduced pressure (200–250 mbar, jacket 45–50 °C) to approximately one-third volume, then quenched into deionized water at 0–5 °C. The resulting off-white precipitate is isolated on an agitated nutsche filter, washed with chilled DI water until conductivity of the filtrate falls below 50 μS cm⁻¹, and vacuum-dried at 50 °C (10–20 mbar) for 12 h. This protocol routinely yields crude purities of 97–98% by area normalization, with the primary impurity being the dechlorinated 4-oxo ester, controlled to <1.0% through precise temperature ramping during the condensation stage.
Recrystallization from a ternary solvent system of ethyl acetate/n-heptane/methanol (5:4:1 v/v) elevates the assay to ≥99.8%. The hot solution is polish-filtered through a 0.45 μm PTFE membrane at 65–70 °C and cooled under linear ramp control (0.3 °C min⁻¹) to 15 °C. Isothermal hold for 4 h precipitates pure needle crystals, which are recovered by centrifugation and dried to a final moisture content of <0.5% w/w (Karl Fischer, USP⟨921⟩ Method Ic). At no stage should the mother liquor pH fall below 3.0, as acid-catalyzed cleavage of the thiazole ring generates a colored furane-derived impurity detectable by LC-MS at m/z 221.1 that compromises subsequent acylation steps.
The ethyl ester function serves as a latent carboxylic acid precursor, liberated under alkaline conditions immediately prior to the construction of the febuxostat pharmacophore. Saponification is conducted with 1.0–1.2 molar equivalents of sodium hydroxide in a co-solvent of ethanol/water (70:30 v/v) at 35–40 °C. Exceeding 40 °C accelerates decarboxylation of the resultant acid to 2-(4-hydroxyphenyl)-4-methylthiazole, a dead-end byproduct whose accumulation is tracked by HPLC at RRT 0.62. The reaction endpoint is judged by disappearance of the ester peak; typically 3–4 h. Seizure of the hydrolysis at pH 4.2–4.5 with 10% v/v acetic acid precipitates the free acid, which is isolated via centrifuge and washed with n-heptane to remove trace neutral organics. Residual sodium is held to <100 ppm (ICP-OES) by a final aqueous slurry wash. It is at this junction that the ethyl ester’s crystallinity advantage becomes economically tangible—the intermediate ethyl ester can be stored under nitrogen at 2–8 °C for 12 months without degradation, whereas the free acid discolors within 4 weeks at ambient temperature due to oxidative phenolic coupling.
In the manufacture of febuxostat, the isolated acid undergoes Williamson etherification with isobutyl bromide in dimethylformamide in the presence of anhydrous potassium carbonate (1.5 eq.) at 60 °C for 8–12 h, yielding the 4-isobutoxy intermediate. Here the choice of the ethyl ester precursor influences downstream purity: residual ester in the acid batch reacts with isobutyl bromide to generate an ethyl-isobutyl mixed diester impurity that co-distills during subsequent cyanation, requiring an additional silica plug. Therefore, the supplied ethyl ester must exhibit ester-base content ≥98.5% and total impurities ≤0.5% to avoid this pathway. Process engineers operating twin-column distillation for solvent recovery have noted that methanol content from the recrystallization step must be stripped to <0.05% w/w in the recycled ethyl acetate, as methanol transesterifies the ester to the methyl analog, creating a trace contaminant that confounds in-process quantitative NMR analysis at the 600 MHz level.The methyl ester is chemically feasible but introduces a critical purification bottleneck. The methyl derivative crystallizes as fine, low-filterability platelets that blind 0.5 μm nutsche filters and necessitate extended centrifugation cycles of 90–120 min, compared to the 15–20 min achievable with ethyl ester prisms. Table 1 collates the distinguishing process-critical attributes across the ester series.
| Parameter | Ethyl Ester (title product) | Methyl Ester | Free Acid |
|---|---|---|---|
| Melting range (°C, DSC onset) | 154–156 | 178–181 | 242–244 (decomp.) |
| Residual solvent after drying (ppm) | EtOAc <200, n-heptane <100 | MeOH >500 (difficult to purge) | N/A |
| HPLC purity attainable (area%) | ≥99.8 | 98.5–99.0 | 99.2–99.6 |
| Filtration time index (min·m²·kg⁻¹ at 0.8 bar ΔP) | 4.2 | 18.7 | — |
| Half-life of alkaline hydrolysis (min, 0.05 M NaOH, 30 °C) | 17.3 | 4.8 | — |
| Oxidative stability (weeks to 5% discoloration, 25 °C/60% RH) | >24 | 14 | 3 |
The ethyl ester’s interplay of moderate hydrolytic half-life and sharp melting behavior makes it uniquely suitable for sequential functionalization of the phenolic site without significant ester scission. This balance is exploited in the synthesis of 2-(4-alkoxyphenyl)-4-methylthiazole-5-carboxylates, where the ethyl ester is retained through the alkylation step and then hydrolyzed in a separate vessel, circumventing purification difficulties associated with the free phenolic acid. Regulatory dossiers referencing this intermediate typically include an ICH Q3C residual solvent declaration: ethanol <5000 ppm, ethyl acetate <5000 ppm, n-heptane <5000 ppm, and methanol (<3000 ppm), verified by headspace GC-FID according to USP⟨467⟩ Procedure A.
Ligating capacity of the molecule has been evaluated in a series of homogeneous catalyst preparations. The deprotonated phenolic oxygen and the thiazole nitrogen create a five-membered chelate with Cu(II), with a log K₁ stability constant of 12.4 ± 0.2 (potentiometric titration in 50% aqueous dioxane, 25 °C). The resulting complex, isolated as a green crystalline solid, catalyzes the aerobic oxidation of benzyl alcohol to benzaldehyde at 60 °C with turnover frequencies of 1200 h⁻¹ in acetonitrile. While this application remains at the laboratory scale (100 mL stirred Parr reactor), the ligand solubility advantage of the ethyl ester over the carboxylate salt (solubility in acetonitrile: 85 mg mL⁻¹ versus <1 mg mL⁻¹) directs the selection of the ester form for non-aqueous metal-organic framework precursor syntheses.
A second comparative data set addresses the quality specification gradient that differentiates the title compound from generic thiazole esters used only in academic libraries. Table 2 distills the typical certificate-of-analysis envelope required when the intermediate is supplied under full cGMP for a registered API starting material.| Attribute | Specification Limit | Analytical Method |
|---|---|---|
| Assay (anhydrous) | 98.5–101.5% | HPLC external standard, USP⟨621⟩ |
| Water content | ≤0.3% w/w | Karl Fischer coulometric, USP⟨921⟩ Ic |
| Residue on ignition | ≤0.1% | USP⟨281⟩, 800 °C |
| Heavy metals (as Pb) | ≤10 ppm | USP⟨231⟩ Method II |
| Individual unspecified impurity | ≤0.10% | HPLC (same conditions as above) |
| Chloride (as Cl⁻) | ≤50 ppm | Ion chromatography, USP⟨1065⟩ |
| Residual isobutanol (if used in down-stream) | ≤500 ppm | GC-FID, USP⟨467⟩ Procedure A |
Meeting the chloride limit requires an extra aqueous displacement wash on the nutsche filter; failure to reduce chloride below 50 ppm results in pitting corrosion of stainless-steel (316L) reactors during subsequent hydrolysis at elevated temperature. Operators monitoring the drying curve observe that the critical moisture content of 0.3% is attained only after LOD (loss on drying) plateaus for 3 consecutive 30‑min intervals at 50 °C under 20 mbar. Attempts to accelerate drying with higher temperatures above 60 °C induce partial sublimation of the compound, forming needle-like deposits on condenser surfaces that require mechanical removal and batch reconciliation delays.
When the ethyl ester is shipped to sites operating under Q7 guidelines, dedicated isotopic labeling (¹³C at the C-2 methyl group) has been prepared for in-house kinetic isotope effect studies; the labeled derivative exhibits an identical DSC profile but a slightly longer retention time of 6.6 min under the standard HPLC method due to deuterium exchange effects, confirming the robustness of the chromatographic procedure as a release test.
