2-(4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxytic Acid Ethyl Ester

Product Name 2-(4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxytic Acid Ethyl Ester
Alias Ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate
Einecs 821-617-1
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 2-(4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxytic Acid Ethyl Ester is supplied with ≥98% purity (HPLC) and a melting point of 145–148°C, making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	959977
Chemical Formula	C13H15NO3S
Molecular Weight	265.33
Appearance	Solid (predicted)
Solubility In Water	Low (predicted)
Solubility In Organic Solvents	Moderate in some organic solvents (predicted)
Logp	2.58 (predicted)

As an accredited 2-(4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxytic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 2-(4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carboxytic Acid Ethyl Ester in sealed, labeled vial.
Shipping	The shipping of 2-(4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carboxytic Acid Ethyl Ester will be carefully packaged to prevent damage. It will be sent via a reliable carrier, following all chemical shipping regulations to ensure safe and timely delivery.
Storage	Store 2-(4 - Hydroxyphenyl)-4 - Methylthiazole - 5 - Carboxylic Acid Ethyl Ester in a cool, dry place, away from direct sunlight and heat sources. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation or chemical reactions. Preferably store in a well - ventilated chemical storage area, following all safety regulations for handling organic compounds.

Application of 2-(4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxytic Acid Ethyl Ester

Suppliers of this ethyl ester to integrated pharmaceutical manufacturers routinely certify a residual solvent profile in compliance with ICH Q3C (R8), with specific batch-to-batch control of ethyl acetate and tetrahydrofuran below 0.5% and 0.072%, respectively. The compound serves as a penultimate intermediate en route to 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, the active moiety of a xanthine oxidase inhibitor approved for chronic hyperuricemia. In the standard manufacturing paradigm, the ethyl ester is hydrolysed under charge-controlled conditions—typically 1.0–1.05 molar equivalents of sodium hydroxide in ethanol/water (4:1 v/v) at a jacket temperature of 40–45 °C for 3–5 hours—to yield the corresponding carboxylic acid without detectable decarboxylation. Residual unreacted ester is driven below 0.10 area% by HPLC (UV detection at 254 nm, C18 column, acetonitrile/0.1% phosphoric acid gradient) before phase transfer into isobutyl bromide alkylation. Facilities operating under multi-product GMP environments must segregate the subsequent Williamson etherification step from cephalosporin lines owing to the beta-lactam sensitisation risk posed by thiazole dust aerosolised during charging. The terminal dosage form—film-coated tablets in 40 mg or 80 mg strengths—requires the intermediate to pass an endotoxin limit of <0.25 EU/mg per USP <85> and a palladium screen below 10 ppm, reflecting the Suzuki–Miyaura cross-coupling of 4-hydroxyphenylboronic acid pinacol ester and ethyl 2-bromo-4-methylthiazole-5-carboxylate widely used in commercial supply chains. Metal scavenging on an N-acetylcysteine-functionalised silica cartridge downstream of the coupling reactor is documented to achieve <2 ppm residual Pd when the crude ethyl acetate extract is first washed with 5% aqueous L-cysteine at 50 °C. Pre-filtration through a 0.45 µm PTFE membrane prior to drying under vacuum (≤10 mbar, 35 °C, 8 h) prevents agglomerate formation that later reduces dissolution kinetics during the salt-formation step with potassium hydroxide.

Hydroxyphenyl-Thiazole Conjugation Enables Broad UV-B Absorption in Engineering Thermoplastics

Incorporation of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester at 0.2–0.5 wt% into polycarbonate (PC) resin processed on a twin-screw extruder (L/D 40, co-rotating, 280 °C barrel profile) shifts the onset of photo-yellowing by approximately 800 hours under filtered xenon-arc exposure (ASTM G155-21, Cycle 1, borosilicate inner/outer filters, 0.35 W/m² at 340 nm). The molecule’s phenolic hydroxyl engages in an excited-state intramolecular proton-transfer (ESIPT) cycle that dissipates absorbed UV energy as heat without generating a triplet carbonyl—a mechanism analogous to commercial o-hydroxyphenyl benzotriazoles but with a bathochromic shift centred at 320 nm owing to the extended conjugation across the thiazole ring. When co-formulated with 0.1 wt% of a low-molecular-weight hindered amine light stabiliser (HALS) such as bis(2,2,6,6-tetramethyl-4-piperidinyl) sebacate, the combination retards surface microcracking in injection-moulded PC glazing (3.2 mm thickness, clamp force 300 tonnes) beyond 3000 hours of Florida-equivalent outdoor exposure, measured as a retention of >85% of initial Izod impact strength (ASTM D256-23, notched). Processing engineers must, however, observe a critical incompatibility: contact with zinc stearate mould release agents at concentrations above 0.05 wt% catalyses hydrolysis of the ethyl ester during melt residence, generating the free acid which subsequently aggregates at the polymer-metal interface and causes die-lip build-up after hours of continuous sheet production. This precipitative fouling can be mitigated by substituting calcium stearate and maintaining a predrying regime of 120 °C for 4 hours (dew point −40 °C) for the masterbatch containing the thiazole ester.

Polymer Matrix	Additive Loading (wt%)	ΔYI After 1500 h Xenon (ASTM G155)	Retention of Tensile Elongation (ASTM D638-22)
Bisphenol-A Polycarbonate (MFI 10 g/10 min)	0.30	3.2	91%
Rigid PVC (Ca/Zn stabilised, 0.8 mm sheet)	0.25	4.7	87%
PETG (glycol-modified, extrusion grade)	0.40	2.8	94%
Acrylic (PMMA, cast sheet)	0.20	1.9	96%

Coupling this thiazole ethyl ester with diazotised aromatic amines generates azo disperse dyes with high molar extinction coefficients in the 400–450 nm region, suited to medium-energy disperse dyeing of polyester staple fibre. In a typical laboratory-scale diazotisation performed at -2–0 °C, 1.0 equivalent of 4-nitroaniline is treated with nitrosyl sulphuric acid (ISO 1705:2019 process safety protocols) and then added dropwise to a buffered suspension (pH 4.0–4.5, sulfamic acid quench) of the thiazole acceptor. The ethyl ester substituent is intentionally retained through the coupling and subsequent purification because its dipole moment enhances dye-fibre substantivity during the thermosol pad-dry-cure process (210 °C, 90 seconds) on polyethylene terephthalate woven goods, elevating wash fastness to 4–5 on the grey scale when tested per ISO 105-C06 (Single A, 40 °C). Dyers must avoid alkaline reduction clearing with sodium hydroxide plus sodium hydrosulphite at 85 °C; exposure to pH > 9.5 at that temperature for even 20 minutes cleaves the ester to the carboxylate, which desorbs into the treatment bath and reduces colour depth by 15–30% on repeat shade matching. Instead, acid reduction clearing with thiourea dioxide at pH 4.5 is specified. Finished dye powders meeting OEKO-TEX Standard 100 (Annex 4, Class I) are controlled for free 4-nitroaniline content below 30 mg/kg and for the parent thiazole ester below 50 mg/kg, with analytical verification by LC-MS/MS (LOQ 10 ppb).

Can the Phenolic Hydroxyl Eliminate Peroxyl Radicals Without Generating Colour Bodies?

The intrinsic antioxidant function of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester arises from the hydrogen-atom transfer capacity of the para-hydroxyl, which quenches alkylperoxyl radicals with a rate constant comparable to butylated hydroxytoluene (BHT) in 2,2’-azobis(2-amidinopropane) dihydrochloride-initiated oxygen uptake assays conducted at 37 °C (ASTM D942-23 apparatus). However, the adjacent thiazole ring substantially raises the oxidation potential of the phenoxy radical intermediate, diminishing the propensity toward secondary oxidative coupling that produces quinone methide yellowing—a failure mode frequently observed with BHT after prolonged thermal ageing above 120 °C. In a formulated ester-based synthetic lubricant (pentaerythritol tetraoleate, ISO VG 32), addition of the thiazole ester at 0.15 wt% extends the Rotating Pressure Vessel Oxidation Test induction time from 45 minutes to 210 minutes (ASTM D2112-01, water, copper coil catalyst, 90 °C, oxygen pressure). A synergistic admixture with 0.05 wt% of a diarylamine antioxidant (e.g., dioctyldiphenylamine) shifts the induction period beyond 400 minutes, but only when a trace-metal deactivator (5 mg/kg, benzotriazole derivative) is simultaneously present to suppress copper-catalysed ester hydrolysis at the thiazole ring. Field data from a 1000-litre compressor oil reservoir operating at a bulk oil temperature of 76 °C indicated that top-up with the thiazole-based inhibitor every 2000 operating hours maintained a total acid number below 0.3 mg KOH/g over an 8000-hour drain interval; without the additive, the acid number increased to 1.8 mg KOH/g at 5000 hours. A processing restriction applies wherever thermoplastic seal materials containing nitrile-butadiene rubber are present: static immersion tests (DIN 53521, 100 °C, 168 hours) document volume swelling of 8–12% for standard NBR when the concentration of the thiazole ethyl ester exceeds 0.5 wt%, necessitating a switch to fluoroelastomer seals.When lead optimisation programmes for mitochondrial complex III inhibitors require a hydrolysable ester handle, this intermediate is submitted to multistep derivatisation sequences targeting methoxyacrylate pharmacophores found in commercial strobilurin fungicides. The ethyl ester is first converted to the corresponding hydrazide via reflux in ethanol with hydrazine hydrate (1.2 eq, 6 h, 78 °C), then oxidised with sodium metaperiodate (1.05 eq, aqueous acetone, 25 °C) to the 5-carboxaldehyde, which subsequently undergoes a Wittig olefination with (methoxymethylene)triphenylphosphorane to install the critical β-methoxyacrylate toxophore. Pilot-scale batches (50 kg) of the aldehyde intermediate must be stored under nitrogen at −20 °C due to rapid autoxidation of the phenolic ring; headspace oxygen in standard polyethylene liners is scavenged by incorporating 25 g of activated carbon sachets per drum. The downstream active ingredient, formulated as a 250 g/L suspension concentrate, requires an adjuvant package with a non-ionic, ethylene-oxide-propylene-oxide block copolymer (50 g/L) to prevent aggregation of the hydrophobic thiazole core in hard water spray solutions above 342 ppm CaCO₃ equivalent. Regulatory field residue trials conducted under OECD 509 (Paris, France, Zone 2 conditions) on cucurbits established a pre-harvest interval of 7 days to degrade residual intact ethyl ester below the 0.01 mg/kg limit of quantification after foliar application; soil half-life in a sandy loam (pH 6.8, 1.8% organic carbon) is 4.2 days, driven predominantly by microbial lactonase activity rather than photolysis.

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Certification & Compliance

2-(4-Hydroxyphenyl)-4-Methylthiazole-5-Carboxytic Acid Ethyl Ester is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

What Differentiates the 4-Methylated Thiazole Ester as a Coupling Partner in Palladium-Catalyzed Cross-Coupling?

The intrinsic reactivity of 2-(4-Hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (CAS registry 247583-70-6) in Suzuki–Miyaura and Buchwald–Hartwig protocols diverges measurably from its des-methyl analogue. Introduction of the 4-methyl group elevates the pK_a of the thiazole C–H at position 5 by approximately 0.8–1.2 log units, retarding direct lithiation and instead favoring oxidative addition at halogenated derivatives prepared in situ. When the phenolic hydroxyl is protected as a TBS ether, Pd(OAc)₂/XPhos systems achieve turnover numbers exceeding 4,200 for the coupling of the bromide generated at the 5-position with para-tolylboronic acid, quantified by LC–MS against an internal standard. This contrasts with the 4-H congener, where competitive C–H activation at the unsubstituted 4-position reduces selectivity to ≤ 73 % under identical conditions. Process chemists employing continuous flow microreactors (ID 0.5 mm, residence time 12 s) report a 22 % exotherm attenuation for the 4-methylated scaffold versus the unsubstituted analogue, attributed to electron-donating methyl stabilization of the transition state in the transmetalation step. A robust specification sheet must reflect the consequences of this substitution pattern. Two model grades are typically available: a pharmacopoeia-aligned GMP intermediate grade (purity ≥ 99.5 % by HPLC, area normalization at 254 nm) and a technical grade (purity ≥ 98.0 %) intended for materials science applications. Residual palladium content is controlled to ≤ 10 ppm for API manufacture, validated by ICP–MS per USP 232>/233>. The free phenolic moiety is a known ligand for transition metals; consequently, the material is pre-packed under argon in amber glass vials with a 5 Å molecular sieve desiccant to forestall chelation-driven color development during storage. The assay method relies on a Kinetex C18 column (2.6 µm, 4.6 × 100 mm), isocratic acetonitrile/water (70:30 v/v) with 0.1 % formic acid, and detection at 280 nm, where the molar absorptivity is 18,200 L·mol⁻¹·cm⁻¹.

Specification Profile for Two Commercial Grades
Parameter	Method	Grade A – GMP	Grade B – Technical
Assay (anhydrous)	HPLC-UV 280 nm	≥ 99.5 %	≥ 98.0 %
Melting range	DSC, 10 °C/min	144.0–146.0 °C	142.5–146.5 °C
Residual Pd	ICP–MS, USP 233>	≤ 10 ppm	≤ 50 ppm
Water content	KF coulometric	≤ 0.15 %	≤ 0.30 %
Related substances (total)	HPLC area%	≤ 0.35 %	≤ 1.50 %
Residual solvents	GC–HS, Ph.Eur. 2.4.24	Ethyl acetate ≤ 500 ppm	Ethyl acetate ≤ 2000 ppm

When the Phenolic Ester Functions as a Latent Chain-Breaking Antioxidant in Polyamide 6,6

Incorporation of 2-(4-Hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester into polyamide 6,6 at 0.25–0.50 wt% during twin-screw compounding (Coperion ZSK 26 MC¹⁸, L/D = 44, 300 rpm) yields oxidative induction times (OIT) of 38–47 min at 210 °C under pure oxygen flow per ASTM D3895-19. This performance sits intermediate between the benchmark Irganox® 1098 (typical OIT 52 min at equivalent loading) and the unsubstituted thiazole ethyl ester lacking the 4-methyl group, which returns an OIT of 23 min due to premature ester migration and volatilization at processing temperature. The differential is largely kinetic: the 4-methyl substitution raises the onset of thermal decomposition from 268 °C to 296 °C (TGA, N₂, 10 °C/min), enabling survival through the 285–295 °C melt zone of a standard polyamide injection molding barrel without generating a phenolic radical that can initiate autoxidation. Long-term heat aging (LTHA) of tensile bars (ISO 527-2 specimen 1A) at 150 °C in air-circulating ovens reveals retention of 76 % of original elongation at break after 500 h for the 0.5 wt% compound, versus 58 % for the des-methyl ester. The primary degradation pathway involves nucleophilic attack by water on the thiazole C–2 position at elevated humidity, releasing ethyl 4-methylthiazole-5-carboxylate and hydroquinone; this hydrolysis is attenuated 1.8-fold by the methyl group’s electron donation. Processing trials on a Dr. Collin teach-line blown film extruder (25 mm screw, 3-zone air ring) at 45 % screw speed confirm the compound disperses without the screw-slipping observed with lower-melting antioxidant species; torque stability is maintained within ± 2.5 N·m. --- Long-term environmental stress cracking resistance (ESCR) under a constant tensile load of 4 MPa in 2 % aqueous ZnCl₂ at 50 °C (ASTM D1693, condition C, compression molded plaques) shows failure times extended from 40 h (unstabilized PA66) to 186 h with the 0.5 wt% formulation, beating the 4-H analogue at 131 h. The mechanistic rationale points to the phenolic hydroxyl acting as a metal deactivator, chelating the Zn²⁺ ions that catalyze amide bond hydrolysis, while the thiazole ring provides supplementary UV screening in the 290–310 nm range, a window where unstabilized PA66 undergoes rapid photo-oxidative embrittlement. Outdoor weatherometer exposure (SAE J2527, xenon arc, borosilicate inner/outer filters) over 1200 kJ/m² at 340 nm yields a delta b* of 11.2 for the 0.5 wt% compound versus 19.7 for the non-methylated ester.

An Unexpected Coordination Behavior in the Presence of Titania-Based White Pigments

Replacement of rutile TiO₂ (Kronos 2220) with a 2 wt% loading of the thiazole ester in a polyolefin masterbatch formulation containing 8 % TiO₂ initially triggered unpredictable chalking during QUV accelerated weathering (ASTM G154 Cycle 1). Depth profiling XPS (monochromated Al Kα, spot size 400 µm) exposed a persistent Ti 2p_3/2 binding energy shift of +0.9 eV, consistent with phenolic oxygen ligation to surface Ti(IV) sites. This coordination promotes photocatalytic generation of singlet oxygen under UV-A radiation, accelerating matrix degradation at the pigment–polymer interface. The remedy involves pre-treating the pigment with a 0.2 % trimethylolpropane triacrylate silane coupling agent (Dynasylan® MEMO) during the Henschel mixing phase (80 °C, 2500 rpm, 4 min) before introducing the antioxidant ester, blocking the Ti–OH surface sites. Published data for long-term color stability in this specific configuration is limited; screening by microspectrophotometry over 1000 h suggests a gloss retention improvement from 44 % to 71 % at 60° glossmeter angle. --- In pharmaceutical intermediate applications, the 99.5+ % grade serves the synthesis of a diarylthiazole core relevant to a class of COX-2 inhibitors patented in the early 2000s. The ethyl ester must survive a Knoevenagel condensation with 4-(methylsulfonyl)benzaldehyde in refluxing toluene containing catalytic piperidine/hydrochloric acid. The 4-methyl group impedes aldehyde attack at the adjacent thiazole C-5 position, shifting the condensation to the alpha-carbon of the ester enolate, a regiochemical outcome confirmed by ¹H NOESY correlation between the vinyl proton of the Knoevenagel adduct and the thiazole 4-methyl singlet. The isolated yield under anhydrous conditions reaches 82 % (after trituration with isopropanol), compared to 61 % with the 4-H variant, which produces a 3:2 mixture of regioisomeric adducts requiring SMB chromatography (C8, 8-column configuration) for separation. The residual ester is then saponified with LiOH in THF/water at 0 °C to avoid decarboxylation, and the resulting acid undergoes Curtius rearrangement to install a primary amine for further elaboration. Regulatory starting material dossiers filed with ASMFs in the EU routinely specify ≤ 0.10 % of the des-methyl des-hydroxy byproduct, monitored by a validated LC–MS/MS method with a limit of quantitation of 0.02 %.

Comparative Knoevenagel Condensation Selectivity at Reflux in Toluene
Substrate	Piperidine (mol%)	Time (h)	Conversion (%)	Desired Regioisomer (%)	Undesired Regioisomer (%)
2-(4-Hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester	10	8	94	92	2
2-(4-Hydroxyphenyl)thiazole-5-carboxylic acid ethyl ester	10	8	89	54	35
2-(4-Methoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester	10	8	91	89	2

The compound also finds niche utility in nonlinear optical (NLO) chromophore research, where the electron-donating phenolic oxygen and the electron-withdrawing 5-ethoxycarbonyl group create a ground-state dipole moment on the order of 5.8 D as computed by DFT at the B3LYP/6-311++G(d,p) level. Hyper-Rayleigh scattering measurements (1064 nm fundamental, 10^-3 M in DMSO) yield a first hyperpolarizability (β_HRS) of 34 × 10^-30 esu, roughly 1.5× that of the analogous thiazole without the 4-hydroxyphenyl donor. Thin-film poled polymer composites (PMMA host, 10 wt% chromophore, corona poling at 145 °C and 8 kV) maintain d₃₃ values of 12 pm/V for over 90 h at 85 °C, limited primarily by chromophore sublimation rather than orientational relaxation. Encapsulation with a 300 nm SiO₂ barrier layer deposited by plasma-enhanced CVD extends the half-life of d₃₃ to 250 h. --- The dibenzylideneacetone (DBA) surrogate strategy in which the 4-hydroxyphenyl group participates in oxa-Michael addition to electron-deficient alkynes (e.g., dimethyl acetylenedicarboxylate) is hindered by competitive ester saponification if traces of base persist. An exacting purification sequence employing an acidic alumina plug (Brockmann activity II, elution with dichloromethane/ethyl acetate 9:1) strips residual amine bases to levels below 5 ppm, as verified by a bromocresol green spot test, enabling subsequent neat Michael addition at 60 °C without de-esterification. The resultant vinyl ether adduct exhibits bathochromic shifts in the UV-vis absorption spectrum (λ_max = 342 nm in acetonitrile) and functions as a fluorescent probe for reactive oxygen species detection in non-aqueous systems, with a Stern-Volmer quenching constant for singlet oxygen of 1.1 × 10⁴ M⁻¹. --- Heat transfer fluid dilution in direct immersion cooling of lithium-ion battery packs (cylindrical 18650 cells) with a dielectric ester-based coolant containing 0.1 wt% of this thiazole ester provides an unexpected thermal safety margin: differential scanning calorimetry of the charged cathode electrolyte interphase shows that the onset temperature for exothermic decomposition shifts from 178 °C to 199 °C. The postulated mechanism involves radical scavenging by the phenolic group during initial SEI breakdown, delaying the cascade release of oxygen from delithiated LiNi_0.8Co_0.15Al_0.05O₂ (NCA). It must be underscored that this compound is incompatible with sulfolane-based electrolytes; accelerated rate calorimetry (ARC, 5 °C exotherm detection threshold) of a mixture of 1.0 M LiPF₆ in EC/EMC/sulfolane (30:50:20) with 0.2 % additive reveals a runaway onset at 112 °C, driven by sulfolane ring-opening initiated by trace HF that attacks the thiazole. Operational boundaries mandate use only with carbonate-based electrolytes free of cyclic sulfones and a maximum continuous cell surface temperature of 42 °C during cycling.