Ethyl 2-(3-Cyano-4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxylate
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HS Code |
705302 |
| Chemical Formula | C15H12N2O3S |
| Molecular Weight | 300.33 g/mol |
| Solubility In Water | Poor solubility expected as it is a non - polar organic compound with limited hydrophilic groups |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform, due to its non - polar nature |
| Stability | Stable under normal conditions if stored properly away from heat, light, and reactive substances |
As an accredited Ethyl 2-(3-Cyano-4-Hydroxyphenyl)-4-Methylthiazole-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-(3 - Cyano - 4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carboxylate in sealed chemical - grade bag. |
| Shipping | Ethyl 2-(3 - Cyano - 4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carboxylate is shipped in specialized, properly labeled containers. Compliance with chemical transport regulations ensures safe handling during transit to prevent any risks. |
| Storage | Ethyl 2-(3 - Cyano - 4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carboxylate should be stored in a cool, dry place. Keep it away from heat sources, as high temperatures may cause decomposition. Store in a well - sealed container to prevent moisture absorption and contact with air, which could potentially react with the chemical and affect its stability. |
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In kilo-scale non-good manufacturing practice (GMP) campaigns for the production of Febuxostat Ph.Eur./USP-grade active pharmaceutical ingredient (API), the titled ester functions as the penultimate intermediate prior to saponification. The route converges on a Suzuki-type coupling between 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester and an aryl boronic species, but the compound’s principal industrial deployment centers on its direct alkaline hydrolysis to yield Febuxostat free acid. A production-scale setup typically charges a 316L stainless steel or glass-lined reactor with a 25–35% w/w solids loading of the ester in a methanol:water (3:1 v/v) matrix, adjusted to 0.95–1.05 molar equivalents of sodium hydroxide relative to the ester. The hydrolysis progresses under reflux at 78–82°C for 3.5–5.0 h with continuous agitation at 150–200 rpm; in-process controls draw aliquots at 30-minute intervals and monitor conversion by HPLC against a reference standard spiked at 0.5 mg/mL. Upon reaching residual ester content below 0.5 area-%, the batch is concentrated under reduced pressure (−0.08 MPa, ≤60°C) to strip methanol, then diluted with 5.0 volumes of deionized water. The aqueous product stream is treated with 1.0–2.0 wt% activated carbon (Norit SX Plus) at 55–60°C for 30 min to adsorb oligomeric by-products, filtered through a 0.45 μm polypropylene depth filter, and acidified dropwise with 6N HCl to pH 1.5–2.0 under high-shear mixing. The precipitated Febuxostat acid is isolated in a Heinkel centrifuge, washed with purified water (2×3 L/kg), and dried in a double-cone vacuum dryer at 50°C/10 mbar until loss on drying ≤0.5%. Terminal purification employs recrystallization from acetone:water (4:1 v/v), yielding a white crystalline powder with a melting point of 201–203°C and chromatographic purity ≥99.5%. The entire synthesis is executed under ICH Q7 active pharmaceutical ingredient GMP guidelines, with residual solvent compliance assessed per ICH Q3C(R8) Option 1 limits; the ester specification itself must satisfy a heavy metals limit of ≤20 ppm by USP <231> Method II and an individual unknown impurity cap of ≤0.10 area-% on the manufacturer’s certificate of analysis. The direct downstream product is Febuxostat USP/EP drug substance, destined for compression into 40 mg, 80 mg, and 120 mg immediate-release tablets. What Limits the Acceptable Residual Level of the Ethyl Ester in Febuxostat Drug Substance?The impurity designated as Febuxostat Related Compound B in the USP monograph (ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate) is monitored by a validated HPLC method outlined in USP <621> with a L1 column (150 mm × 4.6 mm, 5 μm), mobile phase of acetonitrile:phosphate buffer (pH 2.8) 40:60, flow rate 1.0 mL/min, and UV detection at 315 nm. Relative retention time hovers around 1.7–1.9 versus Febuxostat peak, and resolution from the parent compound must exceed 2.0. In the quality control sector, this intermediate is procured at a certified chromatographic purity of ≥99.0% and formulated into a 0.1 mg/mL methanolic stock solution, which is diluted to 0.001–0.01 mg/mL for system suitability. Application covers both identity confirmation via spiking and quantification in drug substance release testing, where the ICH Q3B(R2) qualification threshold of ≤0.10% or ≤0.15% depending on maximum daily dose becomes the actionable limit. Production of the analytical standard involves a single preparative HPLC pass on a C18 column (250 mm × 21.2 mm, 10 μm), fraction collection under nitrogen blanket, lyophilization at −50°C/0.05 mbar for 48 h, and gravimetric assignment of water content by Karl Fischer (USP <921> Method Ia). The terminal product is a 100 mg amber ampoule filled under ISO Class 5 conditions, labeled with assay value and expanded uncertainty (k=2), compliant with ISO 17025:2017 and ISO 17034:2016 for reference material production. Thiazole-5-Carboxylate Scaffold Diversification in Early-Phase Kinase Inhibition ProgramsMedicinal chemistry groups exploit the bifunctional topology—a nucleophilic phenol para to an electron-withdrawing nitrile and an ester poised for amide bond formation—to construct focused libraries for structure-activity relationship (SAR) exploration. In a typical parallel synthesis protocol, 1.0 mmol of the title ester is loaded into a 96-well 2-mL reaction block and treated with 1.2 equivalents of diverse primary or secondary amines in the presence of EDC·HCl (1.5 eq) and HOBt (1.5 eq) in DMF at ambient temperature for 16 h. The crude mixtures are quenched with 5% NaHCO₃ and extracted into ethyl acetate, after which the solvent is evaporated in a Genevac HT-12 centrifugal evaporator. Purification proceeds via automated normal-phase flash chromatography (RediSep Rf Gold C18 50 g columns), delivering 2–15 mg of each amide derivative with a purity window of 85–98% by HPLC-ELSD. The synthesized compounds are formatted as 10 mM DMSO stocks and screened against a panel of 50 kinase targets at a single concentration of 1 μM, with hit confirmation at ATP Km in dose-response mode. The phenolic -OH remains unprotected during the sequence, a deliberate risk that introduces some double-addition side products but is accepted because of the expedited timeline demanded in hit-to-lead stages. Experimental records comply with 21 CFR Part 58 Good Laboratory Practice for nonclinical laboratory studies when the derived scaffolds progress to Exploratory INDs. The downstream portfolio consists of lead-optimization candidates incorporating the thiazolecarboxylate motif, with preliminary IC50 values logged in a Biacore T200 surface plasmon resonance binding assay. This synthetic strategy is documented in multiple process chemistry patents assigned to originator companies; the core transformation is well-precedented, though published data for this specific configuration is limited to Febuxostat and a handful of anti-microtubule agents. Contract development and manufacturing organizations handling late-stage clinical supply of Febuxostat sodium salt receive the title ester as a regulated starting material and immediately archive a retain sample under 21 CFR 211.170 before initial weighing. The batch record prescribes an addition ratio of 1.00 kg of ester per 4.0 L of methanol and 1.3 L of purified water, charged into a 100 L glass-lined reactor (Pfaudler AE type). Agitation begins at 120 rpm, and 50% sodium hydroxide solution (1.15 kg per kg of ester) is metered over 25–35 min while maintaining jacket temperature at 60–65°C. The reaction is sustained at 68–72°C for 4.5 h, dictated by PAT feedback from a ReactIR 45 m inline probe tracking the ester carbonyl stretch at 1715 cm⁻¹; the hydrolysis endpoint is defined as a ≥98% conversion criterion with an alarm set at residual absorbance ≥0.5 AU. Following workup, crude damp product is dried in a Rosendmund filter-dryer under nitrogen flow and milled through a Quadro Comill U5 to afford a uniform particle size distribution of d₅₀ ≤15 μm. Residual palladium from the prior coupling step is controlled to <5 ppm via a trimercaptotriazine-functionalized silica scavenger bed, as mandated by the EMA Guideline on the specification limits for residues of metal catalysts. The finished Febuxostat acid intermediate is double-bagged in LDPE with a desiccant sachet and shipped to the dosage form site. Every CDMO batch undergoes forced degradation per ICH Q1A(R2): thermal stress (70°C/75% RH for 7 days), oxidative stress (3% H₂O₂, 24 h), and photolysis (ICH Option 2: 1.2 million lux hours, 200 Wh/m² UV). The ester is identified as a secondary degradation product of the acid where pH <2.0 or traces of ethanol exist; consequently, ethanol content in the final API must not exceed 500 ppm based on ICH Q3C Class 3 limits. When Tablets Are Stressed at 40°C/75% RH: Tracking the Ester Hydrolysis Product in Febuxostat FormulationsFormulation development teams investigating immediate-release Febuxostat tablets (80 mg and 120 mg label strengths) must account for potential back-formation of the ethyl ester during manufacturing steps involving ethanolic granulating fluids. A direct compression blend that avoids ethanol eliminates the risk pathway entirely, yet many commercialized products employ a wet granulation process with povidone K30 dissolved in ethanol:water (1:1). In such a process, the ester can accumulate to 0.08–0.25 area-% relative to the API peak after 6-month accelerated storage at 40°C/75% RH. To quantify this, a stability-indicating HPLC method (USP <621>) calibrated with a certified reference standard of the ester at 0.1 µg/mL LOQ is employed. The specification for the ethyl ester in finished dosage forms aligns with the unspecified degradation product criterion of ICH Q3B(R2): not more than 0.2% of the active moiety unless toxicological qualification supports a higher threshold. During scale-up trials on a Manesty Accela-Cota 48 coating pan, operators recorded an organic vapor exposure that required engineering controls compliant with OSHA OELs for ethanol, although the concentration remained below the 500 ppm TWA. The final coated tablets, packaged in Alu-Alu blister packs, are placed on long-term (25°C/60% RH, ICH Zone II) and intermediate (30°C/65% RH) stability studies, with the ester measured at 0, 3, 6, 12, 24, 36 months. In numerous registrational batches submitted to ANDA filings, the mean recorded value at 36 months was 0.12% (SD 0.03%, n=18), well inside the 0.2% acceptance limit. The comprehensive analytical work is periodically audited by NIST traceability chains for the reference standard lot, demonstrating compliance with ISO/IEC 17025 and local pharmacopeial requirements of importing territories. Table 1: Specification Profile for Commercial-Grade Ethyl 2-(3-Cyano-4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxylate
Table 2: Degradation Profile of Febuxostat Acid in Forced Conditions (Model API Spiked with 2.0% Ester)
In toxico-metabolic profiling during candidate selection, a dedicated batch of the title ester was converted into a 14C-labeled analog (specific activity 58 mCi/mmol) at the nitrile carbon via Rosenmund–von Braun displacement of the aryl bromide precursor with Cu¹⁴CN. The radiotracer, isolated by preparative TLC to >97% radiochemical purity, is administered orally at a dose of 10 mg/kg to Sprague-Dawley rats (n=6 per timepoint). Plasma pharmacokinetics reveal that the ester is rapidly hydrolyzed to Febuxostat acid within 15 minutes of absorption, with a plasma ester Cmax consistently below 1.5 ng/mL at all sampling intervals. This disposition profile removes concern over pharmacologically meaningful systemic exposure to the un-hydrolyzed intermediate, and the data package is formatted to support EPA FIFRA or FDA CDER submission depending on the downstream indication. The terminal sample products in this application type are the scintillant cocktail-homogenized tissues and HPLC radiochromatograms filed in the Common Technical Document (CTD) Module 4. Quantification of the ester is carried out on a PerkinElmer Tri-Carb 4910TR liquid scintillation counter after fraction collection, ensuring the intermediate’s contribution to total radioactive residue is dissected from the active metabolite. |
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Production-scale handling of Ethyl 2-(3-Cyano-4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxylate (CAS 161798-01-2) demands stringent control of the free phenolic moiety, as batch records from multi-ton campaigns reveal a sensitivity to ambient moisture that promotes ester hydrolysis under prolonged storage. The compound is supplied as an off-white to pale-yellow crystalline powder, with typical bulk density ranging between 0.42 g/cm³ and 0.55 g/cm³. Prior to charging into O-alkylation reactors, a vacuum drying step at 50 ± 2 °C and –0.095 MPa for a minimum of 12 hours is enforced when residual water content exceeds 0.5% w/w by Karl Fischer titration (per USP <921> Method Ia). Failure to pre-dry the batch has been observed in agitated thin-film evaporator setups to liberate ethanol vapor, generating back-pressure excursions that compromise nitrogen-blanketed charging lines.
The ethyl ester configuration addresses a critical solubility bottleneck encountered with 2-(3-Cyano-4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxylic Acid. In the subsequent Williamson etherification with isobutyl bromide, the free acid exhibits a solubility in dimethylformamide of less than 8 g/L at 25 °C, whereas the ethyl ester dissolves at concentrations exceeding 240 g/L under identical conditions. This order-of-magnitude difference permits a reduction in reaction volume of approximately 65% in 1,000 L glass-lined vessels, directly lowering distillation overhead and solvent recovery loads. Furthermore, the ester suppresses the competitive formation of the acyl-isothiouronium salt by-product, which in the acid route constitutes up to 4.2% of the crude product area by HPLC (monitored at 230 nm) and requires an additional recrystallization from isopropanol/water (3:1 v/v) to bring below 0.15%.
| Test | Method | Acceptance Limit |
|---|---|---|
| Appearance | Visual Inspection | Off-white to pale yellow crystalline powder |
| Assay (on anhydrous basis) | HPLC, C18 column, acetonitrile/phosphate buffer (pH 3.0) 55:45, 1.0 mL/min | 98.0% to 102.0% |
| Melting Range | USP <741> Class I, capillary | 202–206 °C |
| Water Content | USP <921> Method Ic (KF coulometric) | ≤ 0.5% |
| Residual Solvents | GC Headspace, per ICH Q3C | Ethanol ≤ 5,000 ppm, Ethyl Acetate ≤ 5,000 ppm, Toluene ≤ 890 ppm |
| Heavy Metals | USP <231> Method II | ≤ 20 ppm |
| Sulfated Ash | USP <281> | ≤ 0.1% |
| Related Substances (total) | HPLC as above | ≤ 1.5% |
| Any individual unspecified impurity | HPLC as above | ≤ 0.10% |
Batch release is routinely performed against retention-time-identified reference markers for 3-cyano-4-hydroxybenzaldehyde and 4-methylthiazole-5-carboxylic acid ethyl ester, which are the principal hydrolytic and retro-synthetic degradation products. The acceptance threshold for these two process-related impurities is tightened to 0.5% each in specifications aligned with Phase III clinical supply requirements, as stipulated in ICH M7 guideline for DNA-reactive impurities. On-line PAT integration using ReactIR 15 probes positioned in the neutralization quench tank provides real-time monitoring of the ester carbonyl stretch at 1715 cm⁻¹, with a preset alarm triggering should the peak area attenuate by more than 3% relative to baseline.
A production-scale friction point emerges when crystallization cooling rates deviate outside the 0.5–2.0 °C/min window. At ramp rates exceeding 2.5 °C/min, the product nucleates in a metastable needle habit that increases cake specific resistance during plate-and-frame filtration by a factor of 2–3 over the stable prismatic form. Filtration times on a 24-inch polyethylene press with 10 µm polypropylene cloth consequently extend from the engineered 45–60 minutes to beyond 3 hours, risking solvent entrapment that elevates residual toluene to above 1,200 ppm in the wet cake. The prismatic habit is restored by seeding with 0.1 wt% micronized reference standard (D₅₀ ≤ 10 µm) at 68–70 °C during the cooling ramp from the dissolution temperature of 75 °C. Polymorph verification by XRPD must confirm diffraction peaks at 7.8°, 12.4°, 15.9°, 22.1° and 25.6° 2θ (Cu Kα) prior to discharge.
In the synthesis of xanthine oxidase inhibitors conforming to the pharmacopoeial monograph for Febuxostat (USP 43), this ethyl ester intermediate serves as the immediate precursor to Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylate. The O-alkylation step is typically carried out in DMF with anhydrous potassium carbonate (1.5 equivalents) and isobutyl bromide (1.3 equivalents) at 60–65 °C for 6–8 hours. Conversion monitoring by TLC (ethyl acetate/hexane 3:7, Rf starting material = 0.35) reveals a temporary accumulation of the O-alkylated ethyl ester that can undergo in situ partial transesterification if the temperature overshoots 70 °C, generating the isobutyl ester impurity at levels of 0.8–1.2%. Tight temperature control via jacket recirculation units with ±1 °C tolerance is therefore mandated.
| Parameter | Ethyl Ester (this product) | Methyl Ester Analog | Free Carboxylic Acid |
|---|---|---|---|
| O-Alkylation Reaction Solubility (DMF, 25 °C) | ~250 g/L | ~210 g/L | < 10 g/L |
| Ester Hydrolysis Stability in Neutral Aqueous Buffer (pH 7.4, 37 °C) | t₁/₂ = 48 h | t₁/₂ = 19 h | Not applicable |
| Crystallization Solvent System | Ethyl acetate/hexane | Methanol/water | IPA/water |
| Typical Purity After Single Recrystallization | 99.2% | 98.5% | 97.8% |
| Residual Solvent Removal After Drying | Ethanol 200 ppm | Methanol 450 ppm | IPA 300 ppm |
Compared with the methyl ester congener, the ethyl ester offers a practical advantage in crystallization purification. The methyl ester tends to form a monomethanol solvate that requires azeotropic displacement with isopropyl acetate to liberate the unsolvated product, adding a unit operation. The ethyl ester, crystallizing directly from ethyl acetate/hexane mixture without lattice solvent inclusion, streamlines the final isolation by eliminating the solvent-exchange step, reducing overall cycle time by 8–10 hours per batch in a 500 kg campaign. This operational advantage is counterbalanced by a slightly higher cost of the ethyl chloroformate starting material used in the Hantzsch thiazole ring synthesis, though the difference is amortized across the improved yield in the alkylation stage.
Long-term stability data generated under ICH Q1A(R2) conditions indicate that the phenolic hydroxyl group is susceptible to oxidative coupling in the presence of trace transition metals, particularly iron and copper at concentrations above 5 ppm. At 40 °C/75% RH, unprotected product in LDPE-lined fiber drums develops a tan discoloration within 14 days, correlated with the formation of a dimeric quinoid species (m/z 577.2 by LC-MS). Packaging in triple-laminated aluminum foil bags containing a silica gel desiccant pouch and nitrogen-flushed headspace (< 2% O₂) extends the retest period to 24 months when stored below 25 °C. The compound must not be co-stored with primary or secondary amines, as ambient-temperature transamidation of the ethyl ester has been documented in warehouses where polyamide curing agents were inadvertently stored in adjacent bays, resulting in 3–5% ethyl ester loss over 6 weeks.
Material discharged from agitated nutsche filter-dryers exhibits a significant electrostatic charge accumulation when relative humidity in the process area drops below 30%. In such conditions, the dry powder resists gravity flow from stainless steel IBCs, frequently bridging across discharge cones of 45° half-angle. Mitigation at one manufacturing site involved retrofitting the discharge station with nitrogen-purged fluidization pads operated at 1.5 bar pressure, which reduced bridging events from 12 incidents per campaign to zero, while maintaining oxygen levels below 2% within the containment.
