Ethyl2-(3-Formyl-4-Hydroxyphenyl)-4-Methylthiazole-5-Carbox
|
HS Code |
126606 |
| Chemical Name | Ethyl 2-(3-Formyl-4-Hydroxyphenyl)-4-Methylthiazole-5-Carbox |
As an accredited Ethyl2-(3-Formyl-4-Hydroxyphenyl)-4-Methylthiazole-5-Carbox factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of "Ethyl 2-(3 - Formyl - 4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carbox" in a sealed chemical - grade container. |
| Shipping | Ethyl 2-(3 - Formyl - 4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carbox is shipped in accordance with strict chemical regulations. It's carefully packaged to prevent leakage and damage, transported by carriers licensed for chemical shipments. |
| Storage | Ethyl 2-(3 - Formyl - 4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carbox should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and reaction with air components. Store it separately from incompatible substances to avoid potential chemical reactions. |
Achieving a consistent crystalline form of febuxostat (USP Febuxostat, CAS 144060-53-7) on a production scale of 500 kilograms per batch demands that the penultimate intermediate, ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, undergo a regiochemically precise saponification without perturbing the electrophilic aldehyde group. The compound is introduced into a 2,000-L glass-lined reactor equipped with a three-stage retreat-curve impeller and a jacket capable of delivering a heating ramp of 1°C/min. A validated master batch record specifies that 180 kg of the dry intermediate (purity ≥ 98.5% by HPLC, LOD <0.2%) is dissolved in 1,200 L of anhydrous methanol (water content <0.1% by KF) under a nitrogen blanket pressurized to 0.2 barg. To this solution, an aqueous sodium hydroxide stream (30% w/w, 1.05 molar equivalents relative to the ester) is metered through a dip tube over 45 minutes while the internal temperature is maintained at 22–28°C. Deviation from the stoichiometric window is process-limiting: excess NaOH above 1.15 equivalents initiates a Cannizzaro disproportionation of the formyl moiety, generating the corresponding benzyl alcohol and carboxylic acid derivatives that co-elute with the desired 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid on a C18 reversed-phase column (in-process check performed on a Waters Symmetry C18, 5 µm, 4.6×250 mm column, mobile phase 0.1% TFA in water/acetonitrile, UV at 315 nm). After the saponification endpoint is confirmed (residual ester ≤ 1.0% area), the reaction mass is concentrated under reduced pressure (100 mbar, 45°C) and the resulting sodium carboxylate is acidified with 37% hydrochloric acid to a final pH of 2.5–3.0. The precipitated free acid is isolated with a bottom-discharge basket centrifuge (800 rpm), washed with deionized water until the filtrate conductivity falls below 10 µS/cm, and dried in a vacuum tray dryer at 50°C for 12 hours under a continuous nitrogen sweep to prevent aerial oxidation of the aldehyde. This isolated acid then enters a sequence in which the formyl group is converted to a cyano function via oxime formation with hydroxylamine hydrochloride (1.2 equivalents, sodium formate, 85% formic acid, 105°C) followed by Williamson etherification with isobutyl bromide (1.3 equivalents, potassium carbonate, DMF, 65°C, 6 hours). The final febuxostat crude is recrystallized from ethanol/water (7:3 v/v), micronized to a D90 of ≤25 µm (Malvern Mastersizer 3000), and released under a certificate of analysis invoking ICH Q7, 21 CFR 211.84, USP <621>, USP <467>, and ICH Q3D elemental impurity risk assessment. The terminal pharmaceutical product is febuxostat 40-mg and 80-mg film-coated tablets, manufactured at a site holding a valid ISO 9001:2015 certification and an FDA establishment registration.Can a Residual Intermediate in the Final Synthetic Step Serve as the Critical Impurity Marker for Febuxostat ANDA?During the compilation of an Abbreviated New Drug Application (ANDA) for a generic febuxostat formulation, the identification and quantification of process-related impurities that persist into the drug substance must satisfy the thresholds articulated in ICH Q3A(R2) and the corresponding pharmacopoeial monographs. The compound ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate has been observed as a late-eluting contaminant (relative retention time 1.34 versus the febuxostat peak) when the intermediate wash during the work-up is truncated. USP Febuxostat and EP 10.0 stipulate that any single unspecified impurity must not exceed 0.10% area by HPLC, with total impurities capped at 1.0%. To provide a shelf-certified, identity-confirmed marker for system suitability testing, a reference standard of this intermediate is manufactured under a scope of accreditation compliant with ISO 17034:2016 and characterized according to ISO/IEC 17025:2017. The production of the reference standard is orthogonal to the active-ingredient synthesis: a 25-gram lot of technical-grade intermediate (purity 97.5% area) is purified by flash chromatography on a Biotage Isolera platform with a SNAP Ultra C18 400 g cartridge, employing a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid. The target fraction, collected under an argon atmosphere, is concentrated by rotary evaporation and lyophilized in amber glassware to a residual water content below 0.5% w/w (Karl Fischer coulometry). The neat lyophilized powder is aliquoted into 100-mg amber glass vials, sealed under argon, and stored at −20°C with a data-logger monitoring compliance to ±2°C. A comprehensive certificate reports the assigned purity by mass balance (combined HPLC-DAD, DSC endothermic purity, 1H qNMR at 600 MHz against an internal standard, TGA residual mass) and an expanded measurement uncertainty of 0.4% (k=2). In the ANDA context, a pharmaceutical development scientist spikes this standard into a febuxostat placebo matrix at 0.1% w/w to demonstrate that the stability-indicating HPLC method achieves a limit of quantification (LOQ) of ≤0.03%, fully meeting ICH Q2(R1) criteria for accuracy and precision. The full data package references FDA Guidance for Industry: ANDAs: Impurities in Drug Substances (Revision 2, August 2014), and the cold-chain shipment includes a NIST-traceable temperature logger for the entire transit period. A dedicated track within structure-based drug design campaigns that focus on non-purine xanthine oxidoreductase antagonists has exploited the aldehyde handle of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate in automated parallel reductive amination protocols. On a Chemspeed SWING robotic synthesis workstation, the intermediate is dissolved in anhydrous dimethylformamide at a concentration of 0.5 M and distributed via a syringe head into 24-well reactor blocks. Each well receives 1.5 equivalents of a primary amine selected from a pre-plated library of 96 structurally diverse aliphatic, benzylic, and heteroaryl-methyl amines. Sodium triacetoxyborohydride (2.0 equivalents) and acetic acid (0.1% v/v relative to DMF) are added sequentially, and the blocks are agitated under an argon headspace for 18 hours at 25°C. After evaporation of the solvent on a Genevac HT-12 centrifugal evaporator, the crude secondary amine products are purified by cation-exchange solid-phase extraction (Isolute SCX-2 columns, elution with 2 M ammonia in methanol). These intermediates are then coupled with a set of carboxylic acid synthons in a second amide-bond-forming step to yield a collection of 2-(3-aminomethyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxamides. Each library member is submitted for biochemical evaluation in a fluorescence polarization displacement assay on a PerkinElmer EnVision multimode plate reader (ex/em 485/535 nm) to determine equilibrium dissociation constants against recombinant human xanthine oxidase. The stoichiometric input translates to a library preparation yield of 15–20 mg of the common intermediate furnishing a single purified analogue at a 50 µmol scale, corresponding to an 85% molar incorporation efficiency. Although no health-authority regulation governs exploratory library synthesis, data integrity principles consistent with ISPE GAMP 5 guide the electronic lab notebook and instrument qualification. If a lead fragment demonstrates an IC50 below 100 nM and favorable ADME properties in microsomal stability assays, the synthetic pathway is re-scaled to a 100-gram campaign in a 50-L jacketed reactor within an ISO 5 cleanroom, generating a characterized lead compound with certificates that include HRMS (ESI+) mass accuracy within 3 ppm and full 13C NMR (100 MHz) assignments. The final output of this workflow is not a registered pharmaceutical dosage form but a pre-IND candidate with an integrated data package suitable for preliminary toxicological assessment. A Schiff Base Probe Based on the Salicylaldehyde Moiety Discriminates Cu(II) from Zn(II) in Aqueous MediaThe 2-formyl-4-hydroxyphenyl architecture embedded in ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate constitutes a salicylaldehyde fluorophore precursor that, upon condensation with a heterocyclic hydrazine, generates a turn-on chelation-enhanced fluorescence (CHEF) sensor. In a validated synthesis, the compound is refluxed with 2-hydrazinobenzothiazole in absolute ethanol (molar ratio 1:1, substrate concentration 10 mM) for 6 hours under a nitrogen atmosphere, and the resultant hydrazone is purified by recrystallization from ethyl acetate/n-heptane (1:1 v/v) to afford dark-yellow needles with a melting point of 214–216°C. To prepare the working sensor solution, a 1 mM stock is prepared in anhydrous DMSO and subsequently diluted to 10 µM in HEPES buffer (10 mM, pH 7.4) containing 50% (v/v) acetonitrile. Fluorescence titration experiments executed on a Horiba FluoroMax-4 spectrofluorometer equipped with a thermostated cell holder (25±0.1°C, slit widths 2 nm, integration time 0.5 s) reveal a 17-fold emission enhancement at 485 nm upon cumulative addition of CuCl₂. Application of the 3σ/slope method to 10 independent blank measurements yields a limit of detection of 0.08 µM for Cu2+, well below the US EPA maximum contaminant level goal of 1.3 ppm (20 µM) for copper in drinking water. Interference studies performed with Na⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺, Fe³⁺, and Mn²⁺ (each at 50 µM) indicate no significant cross-response; the addition of Hg²⁺ produces a minor quenching (<12% reduction in intensity), which can be masked by the inclusion of 2 equivalents of EDTA in the buffer matrix. The manufacturing of pre-dosed detection kits occurs in an ISO Class 7 cleanroom, where a Flexicon peristaltic filling pump dispenses 0.5 mg of the crystalline probe into 2-mL amber glass vials that are then purged with argon and induction-sealed. Each kit contains 10 such vials along with 50 mL each of concentrated buffer stock (pH 7.4 and pH 9.2) and a calibration certificate referencing NIST SRM 1640a (trace elements in natural water). Laboratories employing this kit for water quality screening operate under ISO/IEC 17025:2017 and validate their internal methods against EPA Method 200.7 for trace metal analysis. The finished product shipped to contract testing facilities is a Cu²⁺ Fluorometric Detection Kit, intended as a portable, calibration-free complement to ICP-MS confirmatory platforms.
Agrochemical discovery workflows targeting oomycete pathogens have incorporated 2-(substituted phenyl)-4-methylthiazole-5-carboxylic acid ester scaffolds because the thiazole ring electronically recapitulates the oxazole pharmacophore of commercial strobilurin and oxazolidinedione fungicides such as famoxadone. A Knoevenagel condensation between ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate and Meldrum’s acid (molar ratio 1:1.05, piperidinium acetate catalysis, toluene reflux) yields an arylidene adduct that is subjected to a one-pot cyclocondensation with urea in glacial acetic acid at 118°C for 12 hours, furnishing a dihydropyrimidine-thiazole hybrid. The entire transformation is executed in a 5-L borosilicate round-bottom flask with a continuous nitrogen sparge (0.5 L/min) to suppress oxidative coupling of the phenol during the prolonged heating. The crude product is isolated by vacuum filtration through a sintered glass funnel and recrystallized from ethyl acetate/n-hexane (8:2 v/v) to a purity exceeding 97.0% (HPLC). Processing of these test articles adheres to an internal standard operating procedure aligned with the OECD Principles of Good Laboratory Practice ( ENV/MC/CHEM(98)17 ) prior to submission for microtiter-based bioassays. In the 96-well zoospore motility inhibition assay against Phytophthora infestans, compounds are dissolved in a vehicle consisting of 10% acetone/water (v/v) and 0.05% Tween 80 to achieve a concentration equivalent to 200 g active ingredient per hectare at an application volume of 200 L/ha. Published data from structurally proximal benzothiazole esters indicate that the free hydroxyl group contributes moderate symplastic mobility (log P 2.9, determined by the shake-flask method per OECD 107), yet empirical translocation behavior of this precise molecule in Solanum tuberosum foliage has not been reported in the open literature. Active leads identified in primary screening are scaled to a 500-gram pilot synthesis in a facility certified to ISO 14001 for environmental management, ensuring that halogenated solvent waste is recovered by fractional distillation. The formulated products that exit the pilot plant exist as 20% w/w wettable powders (WP) and are packaged into 1-kg LDPE-lined aluminum bags for refrigerated transfer to field-trial stations in accordance with the FAO Specifications for Agricultural Pesticides. |
Competitive Ethyl2-(3-Formyl-4-Hydroxyphenyl)-4-Methylthiazole-5-Carbox prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.
We will respond to you as soon as possible.
Tel: +8615651039172
Email: sales9@bouling-chem.com
Flexible payment, competitive price, premium service - Inquire now!
Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate appears as a pale yellow, free-flowing crystalline powder and occupies a defined niche as a dual-functional late-stage intermediate in heterocyclic synthesis. The molecule presents an electrophilic aromatic aldehyde at the meta-position, a nucleophilic para-hydroxyl, and a sterically accessible thiazole ring whose C5-ethyl ester can be hydrolysed or amidated. A typical production batch exhibits a melting endotherm from 155 °C to 158 °C by capillary method (Ph. Eur. 2.2.14) and a purity not less than 98.5% area by HPLC on a C18 column (4.6 × 150 mm, 5 µm) with UV detection at 254 nm, employing an isocratic acetonitrile/water (60:40 v/v) mobile phase containing 0.1% trifluoroacetic acid. Retention time under these conditions is routinely observed between 4.1 and 4.3 min. Residual palladium, carried forward from Suzuki–Miyaura coupling steps, is controlled below 20 ppm and quantified by ICP-MS per USP ⟨232⟩. The compound’s principal distinction from its 3-nitro precursor rests on its capacity to undergo chemoselective reductive amination without attendant nitro-group reduction, thereby circumventing catalytic hydrogenation steps that can compromise the thiazole ring.
Solubility data obtained from pilot-scale recrystallisation lots directly influence solvent selection for downstream amide coupling. In tetrahydrofuran at 25 °C the equilibrium solubility approaches 82 mg mL⁻¹, furnishing a 0.28 M feed stream compatible with HATU‑mediated activations. Acetonitrile delivers only 12 mg mL⁻¹ under the same conditions, restricting its use in polar aprotic protocols unless a co-solvent such as N,N‑dimethylformamide is incorporated at 15–20 vol%. When the coupling partner is a sterically hindered secondary amine, the addition of 1.0 equiv of 1‑hydroxybenzotriazole and a non-nucleophilic base such as N,N‑diisopropylethylamine (2.5 equiv) in THF at 0–5 °C consistently achieves conversion above 92% within 6 h, as tracked by in‑process HPLC. The absence of a free carboxylic acid on the thiazole avoids competitive acylation at the phenolic oxygen, a side-reaction observed in the corresponding acid intermediate that can generate 3–5% recalcitrant dimer.
| Parameter | Acceptance Criterion | Reference Method |
|---|---|---|
| Description | Pale yellow to off-white powder | Visual (in-house SOP VIS‑01) |
| Melting range | 155–158 °C | Capillary, Ph. Eur. 2.2.14 / DSC per ASTM E794‑06(2018) |
| Purity (HPLC area‑%) | ≥ 98.5% | USP ⟨621⟩, Supelco Ascentis Express C18, 4.6 × 150 mm, MeCN/H2O 60:40 + 0.1% TFA, 1.0 mL min⁻¹, 254 nm |
| Individual impurity | ≤ 0.5% | Same HPLC system |
| Residual palladium | ≤ 20 ppm | ICP‑MS, USP ⟨232⟩ |
| Residual solvents | Ethyl acetate ≤ 500 ppm, Heptane ≤ 500 ppm, Toluene ≤ 890 ppm | GC‑headspace, USP ⟨467⟩ Option 1 |
| Water content | ≤ 0.3% | Karl Fischer titration, USP ⟨921⟩ Method Ia |
| Assay (anhydrous basis) | 97.0–102.0% | ¹H NMR (400 MHz, DMSO‑d6) integration of formyl proton vs. internal standard |
The formyl substituent is susceptible to autoxidation when the dry powder is exposed to ambient atmosphere (≈ 21 vol% O₂, 55% RH) at 25 °C. A controlled-stability study recorded a 1.8% loss of the aldehyde ¹H NMR signal at 10.25 ppm (relative to the unchanging thiazole methyl singlet at 2.62 ppm) after 72 h of such exposure, with a concomitant rise in the corresponding 3‑carboxylic acid peak at 12.8 ppm. To maintain material quality for GMP campaigns, the solid is packaged under a nitrogen headspace (<1 % O₂) in double-layered LDPE bags inside an aluminium foil laminate; under these conditions, re-test dating of 24 months at storage temperatures of 2–8 °C has been validated with no increase in acid impurity beyond 0.2%. In solution, the degradation rate accelerates: stirring a 0.2 M THF solution in an open flask results in 6 % oxidation within 4 h, making on-site preparation and immediate consumption mandatory when performing aldehyde-targeted transformations. The pH of the medium further modulates stability—maintaining an apparent pH > 7.5 in aqueous DMF leads to rapid Cannizzaro‑type disproportionation, generating equimolar alcohol and acid adducts that co‑crystallise with the target intermediate.
Direct comparison with the widely employed 3‑nitro analogue, ethyl 2-(4‑hydroxy‑3‑nitrophenyl)-4‑methylthiazole‑5‑carboxylate, illustrates the operational advantage of the aldehyde intermediate. The nitro compound requires a catalytic hydrogenation step (typically Pd/C, 1–5 bar H₂, MeOH) to furnish the aniline, a transformation that can partially saturate the thiazole moiety if pressure control wanders above 3 bar. In contrast, the aldehyde intermediate circumvents hydrogenation entirely, enabling direct reductive amination with primary amines (NaBH(OAc)₃, dichloromethane, 25 °C) and producing the corresponding benzylamine derivative in a single operation. The synthesis of the aldehyde itself utilises a Vilsmeier–Haack formylation on the de‑nitro precursor, affording a 72–76% isolated yield after crystallisation from ethyl acetate/heptane (1:1 v/v). Table 1 captures the key differentiating attributes.
| Property | Ethyl 2-(3‑formyl‑4‑hydroxyphenyl)-4‑methylthiazole‑5‑carboxylate | Ethyl 2-(4‑hydroxy‑3‑nitrophenyl)-4‑methylthiazole‑5‑carboxylate | Ethyl 2-[3-(aminomethyl)-4-hydroxyphenyl]-4‑methylthiazole‑5‑carboxylate hydrochloride |
|---|---|---|---|
| Molecular weight (g mol⁻¹) | 291.32 | 322.30 | 340.82 |
| Melting range (°C) | 155–158 | 198–201 | 225–228 (dec.) |
| Key synthetic utility | Reductive amination, Knoevenagel condensations, Grignard additions | Reduction to aniline, acylation | Direct amide coupling without a reductive step |
| Catalytic hydrogenation required for amine derivative | No | Yes (Pd/C, H₂) | No (already benzylamine) |
| Stability in DMF solution (25 °C, 24 h) | <2% degradation under N₂ | <1% decomposition | 5–8% imine formation if trace aldehyde present |
In a 20 L glass-lined reactor, the final recrystallisation of the crude formyl intermediate (obtained from a Vilsmeier–Haack quench) demands controlled cooling kinetics to avert oiling-out. The dissolution stage employs ethyl acetate/heptane (1:1 v/v) at 60 °C with a concentration of 0.12 g mL⁻¹. Cooling at a ramp rate greater than 0.5 °C min⁻¹ between 50 °C and 15 °C triggers a metastable liquid–liquid phase separation that solidifies as a gum, reducing isolated yield below 65%. Adhering to 0.3 °C min⁻¹ yields a well‑faceted crystalline bed that is filterable on a Büchner funnel with a 10–15 µm porosity cloth, achieving 99.5% wet‑cake deliquoring within 20 min under 0.5 bar vacuum. Drying proceeds under a nitrogen purge at 40 °C and ≤10 mbar for 16 h; this protocol reliably reduces ethyl acetate below the 500 ppm ICH Q3C limit without promoting ester hydrolysis, as verified by post‑drying Karl Fischer water content of <0.2%. The main source of palladium contamination is the immediate precursor, 2‑bromo‑4‑hydroxybenzaldehyde, whose residual catalyst is carried forward. Treatment of the crude reaction mixture with activated carbon (Darco G‑60, 5 wt% relative to expected product) at 45 °C for 2 h before filtration through a 0.45 µm capsule filter reduces Pd levels from an initial 80–120 ppm to the targeted ≤20 ppm threshold.
Evaluation on an agitated thin‑film evaporator (Pfaudler WFE type, 0.06 m² internal area, jacket temperature 55 °C, pressure 5 mbar) has been explored for solvent‑switch from THF to DMAc in preparation for peptide coupling sequences. The short residence time (30 s) suppresses thermal aldehyde degradation, retaining 99.2% purity in the concentrate, whereas batch distillation at the same jacket temperature left 2.3% of the acid impurity. This operational boundary underscores the compound’s sensitivity to cumulative thermal load and the necessity of continuous‑processing equipment when a high‑boiling amide solvent is required for downstream transformations.
