4-Thiazolecarboxylic Acid 2-Phenyl Ethyl Ester: Properties, Uses, Safety, Supplier & Price in China

What Drives Adoption of This Ester in Novel SDHI Fungicide Manufacturing?

Manufacturing-scale campaigns for succinate dehydrogenase inhibitor (SDHI) fungicides increasingly rely on ethyl 2-phenyl-4-thiazolecarboxylate as an advanced intermediate because the ester group enables a clean, high-yielding condensation with 2‑chloro‑5‑(trifluoromethyl)aniline without requiring corrosive thionyl chloride‑based acid chloride generation. In a dedicated 1000 L glass‑lined reactor equipped with a packed distillation column, the ester is combined with the substituted aniline at a molar input ratio of 1.05:1.00 in toluene; a catalytic loading of 0.02 equivalents of titanium(IV) isopropoxide is introduced to form a transient titanium‑amide complex that shifts the equilibrium. The mixture is heated to reflux (110 °C jacket), and the ethanol‑toluene azeotrope is continuously removed through the column side‑arm to maintain a head temperature of 78–82 °C. After 14 h of reaction time, in‑process HPLC (C18 column, acetonitrile/water gradient) confirms conversion above 97.5 %. The warm organic phase is washed with 2 % w/w hydrochloric acid, and the target thiazole‑carboxamide crystallises directly from the neutralised toluene layer upon cooling to −5 °C. Residues of titanium (< 100 ppm) and the polar by‑product ethyl 2‑phenyl‑4‑thiazolecarboxylate dimer are removed via a hot slurry in heptane at 60 °C for 4 h. The isolated batch complies with the FAO/WHO Joint Meeting on Pesticide Specifications purity envelope (≥ 98.0 % by mass) and passes the accelerated storage stability protocol defined in CIPAC MT 46.3. The final amide is telescoped into a subsequent thioether‑oxidation step to produce a fluoro‑substituted SDHI active ingredient that is formulated as a 200 g/L suspension concentrate for foliar application against Septoria tritici.

Electron-Deficient Thiazole Monomers for High-Triplet-Energy Host Materials

Phosphorescent organic light‑emitting diode (PhOLED) host design exploits the electron‑withdrawing character of the 2‑phenyl‑4‑thiazolecarboxylate scaffold to construct monomers with a measured triplet energy (E_T) of 2.78 eV and a HOMO‑LUMO gap suitably aligned with a blue dopant such as iridium(III)bis[4,6‑(difluorophenyl)‑pyridinato‑N,C²′]picolinate. Synthesis proceeds via a Suzuki‑Miyaura cross‑coupling between the hydrolysed ester (2‑phenyl‑4‑thiazolecarboxylic acid) and a dibromo‑spirobifluorene precursor; the acid is re‑esterified in situ with n‑butanol under Dean‑Stark conditions to enhance solubility. The catalyst system employs 0.015 equivalents of Pd(PPh₃)₄ and 2.0 M aqueous potassium carbonate in a degassed THF/toluene biphasic medium that is vigorously stirred in a 50 L Hastelloy C‑276 reactor under a nitrogen overlay. The boronate ester partner is charged at a 1.25:1.00 molar excess relative to the dibromide, and the batch is held at 85 °C for 22 h. Following celite‑assisted hot filtration and phase separation, the crude monomer is precipitated in methanol and purified by repeated recrystallisation from chlorobenzene until semiconductor‑grade residual metal levels are attained: sodium < 0.5 ppm, palladium < 0.3 ppm, iron < 1.0 ppm as confirmed by total reflection X‑ray fluorescence. The final monomer achieves a melting point of 242–244 °C and a glass transition temperature of 118 °C (DSC, 10 K/min) after thermal annealing. Lot release criteria follow the SEMI S2/S8 equipment safety evaluation for chemical handling, and trace halide content is controlled below 5 ppm to prevent emitter quenching. The monomer is subsequently polymerised via Yamamoto coupling to afford a non‑conjugated host polymer with a molecular weight (M_n) of 45 kDa and a polydispersity index of 1.9, used in solution‑processed red‑green‑blue white OLED lighting panels.

When the Ethyl Ester is Preferable to the Free Acid in Veterinary Benzoxazole Syntheses

Process routes to certain veterinary anthelmintic benzoxazoles avoid the free 2‑phenyl‑4‑thiazolecarboxylic acid because the acid dimerises during storage at ambient humidity, generating a sparingly soluble anhydride that clogs in‑line micron‑filtration units. The ethyl ester, supplied in sealed LDPE‑lined fibre drums under dry nitrogen, overcomes this bottleneck. In a 500 L stainless‑steel batch reactor, the ester is dissolved in dimethylacetamide (moisture content < 300 ppm) and treated with 1.15 equivalents of 2‑amino‑4‑chlorophenol at 25 °C; the coupling is promoted by 1.20 equivalents of O‑(benzotriazol‑1‑yl)‑N,N,N’,N’‑tetramethyluronium tetrafluoroborate and 2.50 equivalents of N,N‑diisopropylethylamine added over 90 min. The exotherm is controlled by a jacket ramp of 0.5 K/min to a maximum internal temperature of 32 °C. After 8 h, the product is precipitated with water, filtered, and reslurried in isopropyl acetate to remove traces of unreacted phenol. The amide intermediate is cyclised in polyphosphoric acid at 120 °C for 6 h to form the benzoxazole ring, and the final active pharmaceutical ingredient is milled in a fluidised‑bed opposed‑jet mill to a particle size d₉₀ of 15 µm before blending into a medicated premix. Throughout the campaign, in‑process controls adhere to VICH GL18 residual solvent guidelines regarding dimethylacetamide (limit 1090 ppm) and tetrahydrofuran (limit 720 ppm). The finished premix is intended for oral administration to swine at a dose equivalent to 5 mg of active ingredient per kg body weight.

A different industrial requirement emerges when the ethyl ester acts as a key building block for a hindered amine light stabiliser (HALS) that incorporates a thiazole chromophore to provide additional UV‑A absorption tailing into the 380 nm region. The ester is reacted with 4‑amino‑2,2,6,6‑tetramethylpiperidine in a 1.00:1.03 molar ratio using neat xylene as the solvent and a catalytic quantity (0.005 eq) of dibutyltin oxide. The mixture is heated in a 3000 L reflux‑equipped reactor to 145 °C while the ethanol by‑product is continuously removed via a vapour‑phase adsorption column packed with zeolite 4A. The conversion is monitored by near‑infrared spectroscopy at 1680 nm (overtone of the carbonyl stretching mode); when the absorbance ratio falls below 0.12, the batch is cooled and the stabiliser crystal is isolated by centrifugation at 2000 rpm. After vacuum drying (60 °C, ≤ 1 mbar), the product is extruded at 220 °C with linear low‑density polyethylene on a co‑rotating twin‑screw extruder (L/D = 44) at a masterbatch loading of 15 wt%. The final polyolefin film containing 0.8 wt% of the neat stabiliser passes the 2000 h xenon‑arc weathering test per ISO 4892‑2 with a retained tensile elongation above 80 %. Regulatory clearance is covered by a REACH registration dossier and a positive listing under FDA 21 CFR §178.2010 for antioxidants and stabilisers in polymer repeat‑use food‑contact articles, provided migration into food simulants does not exceed 10 µg/dm².

A Fluorescent Probe Intermediate: Avoiding Singlet Oxygen Interference

Live‑cell imaging applications utilising thiazole‑based styryl dyes require the ethyl ester as a versatile precursor for condensation with aromatic aldehydes to generate extended π‑conjugated systems with absorption maxima shifting from 340 nm to beyond 510 nm. To minimise residual singlet‑oxygen generation that would cause phototoxicity during time‑lapse microscopy, the synthetic protocol includes a heavy‑metal‑scavenging step after the Knoevenagel condensation. The ester is first converted to the corresponding hydrazide by treatment with hydrazine monohydrate (3.0 eq) in ethanol at reflux for 5 h. The hydrazide is then condensed with 5‑bromo‑2‑thiophenecarboxaldehyde in ethanol containing 0.5 v/v% glacial acetic acid at 70 °C for 12 h; the crude Schiff base is recrystallised three times from dimethylformamide‑acetonitrile (1:4 v/v) and treated with a mercaptopropyl‑functionalised silica scavenger (loading 20 wt% relative to dye mass) during the final dissolution stage to reduce palladium and copper residues to ≤ 0.2 ppm. The purified dye is lyophilised from a water‑tert‑butanol mixture and stored in amber vials under argon. Quality control for biological screening includes a validated HPLC‑fluorescence method sensitive to 50 ppb of the unreacted hydrazide and a dark‑toxicity assessment against HeLa cells per ISO 10993‑5:2009 (extract dilution test). The resulting fluorophore, excitable at 488 nm with a Stokes shift of 65 nm, is formulated as a 1 mM solution in anhydrous dimethyl sulfoxide and used as a mitochondrial membrane‑potential probe in high‑content screening platforms.

Typical quality attribute ranges for ethyl 2‑phenyl‑4‑thiazolecarboxylate across application tiers

Attribute

Pharmaceutical Intermediate

Agrochemical Intermediate

Electronic Grade

Purity (HPLC area%)

≥ 99.0 %

≥ 98.0 %

≥ 99.5 %

Single impurity limit

< 0.15 %

< 0.5 %

< 0.10 %

Water content (Karl Fischer)

< 0.5 %

< 1.0 %

< 0.1 %

Residual palladium

< 10 ppm

< 50 ppm

< 0.5 ppm

Residual iron

< 20 ppm

< 100 ppm

< 1.0 ppm

Chloride (ion chromatography)

< 50 ppm

< 200 ppm

< 5 ppm

Guideline benchmark

ICH Q3D, USP 〈467〉

CIPAC 410, FAO/WHO specifications

SEMI C43‑0621, internal OEM metal limits

The compound catalogued as 4-Thiazolecarboxylicacid, 2-Phenyl-, Ethyl Ester (IUPAC: ethyl 2-phenyl-1,3-thiazole-4-carboxylate; CAS 64344-93-6, molecular formula C₁₂H₁₁NO₂S, molecular weight 233.29 g·mol⁻¹) is supplied as a white to off-white crystalline powder with a characteristic melting endotherm at 46–48 °C (lit.). Commercial lots are standardized to a purity criterion of ≥98.0% by reverse‑phase HPLC peak area at 254 nm. The neat solid is stored under dry argon at 2–8 °C in amber glass to suppress photolytic discoloration; loose bulk density typically ranges between 0.45 g·cm⁻³ and 0.55 g·cm⁻³, a value that influences hopper flow design during automated dispensing. Any procurement specification referencing this thiazole ester should require a certificate of analysis that enumerates the assays detailed in the quality‑control scenario below.

What Analytical Signatures Confirm Batch-to-Batch Consistency?

Routine lot release relies on a multi‑technique platform anchored by pharmacopoeial and ASTM methods. Identity is confirmed by spiking the sample onto a C18 column (150 mm × 4.6 mm, 5 µm; mobile phase: acetonitrile/water/0.1% trifluoroacetic acid, isocratic 60:40 v/v, 1.0 mL·min⁻¹) and matching retention time (±0.05 min) against a certified reference standard; the typical retention window is 7.2–7.4 min. Purity is quantified by external standard calibration with a linear range 0.01–2.0 mg·mL⁻¹. The acceptance threshold for any single impurity is ≤0.5 area‑%, with total impurities ≤2.0%. Melting range is determined by the capillary method per USP 〈741〉 class Ia apparatus, with a heating rate of 1.0 °C·min⁻¹ from 35 °C; a validated lot melts sharply inside the 2.0 °C interval 46.0–48.0 °C. Water content is titrated by Karl Fischer coulometry (USP 〈921〉 Method Ia), requiring ≤0.5% w/w. Residual solvent profiling by headspace GC‑FID according to USP 〈467〉 Procedure A confirms limits of ≤5000 ppm for ethanol, ≤600 ppm for ethyl acetate, and ≤300 ppm for dichloromethane. Sulfated ash (USP 〈281〉) is controlled to ≤0.1%. Heavy metals by ICP‑MS following microwave digestion (per ICH Q3D Guideline for elemental impurities) are reported for Class 1 and 2A metals, with Cd ≤2 ppm, Pb ≤5 ppm, As ≤3 ppm, and Hg ≤1 ppm. Where a customer intends to use the ester in parenteral API synthesis, a bacterial endotoxin test (USP 〈85〉) can be commissioned; the standard limit is ≤0.25 EU·mg⁻¹. The certificate of analysis for a representative batch (Lot ET673-24-11) exhibits assay 99.2%, water 0.18%, and a single unknown impurity at 0.12%, well within the established guard‑band.

In the kilo‑lab, parallel differential scanning calorimetry (DSC) scans on 5 mg aliquots sealed in aluminium pans with a pierced lid (heating rate 10 °C·min⁻¹ under 50 mL·min⁻¹ nitrogen) reveal a sharp melt endotherm (onset 45.8 °C, peak 47.1 °C, enthalpy 104 J·g⁻¹) and an exothermic decomposition that initiates only above 250 °C, confirming adequate thermal headroom for standard synthetic manipulations performed below 80 °C. Thermogravimetric analysis at 10 °C·min⁻¹ shows 0.12% mass loss up to 120 °C, corroborating the low moisture content. The combination of these orthogonal data streams—chromatographic, thermal, and spectroscopic—provides the traceability required for ICH Q7 GMP starting material qualification. Should a process stream introduce amine‑based scavenger resins (e.g., diethylenetriamine‑functionalised silica), rapid transesterification has been observed; therefore, neutral alumina or silica gel filtration is preferred during workup.

When Hydrolytic Stability Becomes the Rate‑Limiting Factor in Amide Coupling Reactions

In medicinal chemistry programmes targeting 2‑phenylthiazole‑4‑carboxamide kinase inhibitors, the ethyl ester is often deliberately selected over its methyl analogue because the extended alkyl chain retards the competitive saponification that occurs during slow amidation cycles. Under typical activation conditions—1.2 eq HATU, 3.0 eq DIPEA, anhydrous DMF, 0 °C to ambient over 18 h—the methyl ester gives 8–12% of the corresponding free acid side‑product (identified by LCMS [M‑H]⁻ = 204.0), whereas the ethyl ester restricts acid formation to ≤3%. Comparative alkaline hydrolysis kinetics measured in 1.0 M LiOH/THF/H₂O (1:1:1 v/v/v) at 25 °C show a half‑life of approximately 2.1 h for the methyl ester and 6.5 h for the ethyl analogue (pseudo‑first‑order rate constants: k_Me ≈ 0.33 h⁻¹, k_Et ≈ 0.11 h⁻¹). While published data for this specific substrate are sparse, the relative rates follow the Taft steric parameter (Eₛ) trend. This margin is process‑relevant when acylation of sterically hindered secondary amines requires elevated temperatures: processing at 40 °C over 8 h with the ethyl ester preserves ≥95% of the starting ester, whereas the methyl ester is consumed to nearly 25% by saponification.

The crystalline nature of the ethyl ester further differentiates it as an isolable intermediate. The methyl ester (CAS 18916-25-3) is frequently obtained as a low‑melting solid (35–38 °C) or a viscous oil that demands column chromatography for purification. In contrast, the ethyl ester precipitates directly from the Hantzsch condensation between ethyl bromopyruvate and thiobenzamide in ethanol at 5 °C; a simple filtration and cold‑ethanol wash afford material of >97% chromatographic purity without chromatography. This crystallinity reduces purification volumes by roughly 60% on 100‑gram scale, a non‑trivial factor when solvent‑waste minimization is part of an environmental permit. The isopropyl ester (synthesised via transesterification) shows a melting range of 52–54 °C but introduces steric hindrance that depresses acylation rates by a factor of 0.4× compared with the ethyl ester, making it less favoured for parallel library synthesis where reaction throughput is a key metric.

Comparative Physical and Stability Data for Selected 2‑Phenylthiazole‑4‑carboxylate Esters
Property	Methyl Ester	Ethyl Ester	Isopropyl Ester
CAS Registry Number	18916-25-3	64344-93-6	Not assigned (in‑house)
Molecular Weight (g·mol⁻¹)	219.26	233.29	247.31
Melting Range (°C, capillary)	35–38	46–48	52–54
Boiling Point (°C, predicted, ACD/Labs)	343±30	361±34	378±30
HPLC Purity of Direct Crystallisation Product (%)	88–94	96–98	94–96
Hydrolysis Half‑Life (h, pH 13, 25 °C)	2.1	6.5	12.0*
ClogP (BioByte)	2.18	2.76	3.29
Solubility in Hexane at 20 °C (mg·mL⁻¹)	<5	<2	<1

*Estimated from ethyl ester data using Taft Eₛ correlation; direct measurement not available.

For solid‑phase peptide‑type conjugations where the thiazole scaffold serves as a turn‑inducer, the ethyl ester’s hydrophobicity (ClogP 2.76) delivers better resin swelling in DMF than the methyl ester without approaching the precipitation threshold that the isopropyl ester encounters in aqueous acetonitrile mixtures. Process development reports from kilo‑lab campaigns cite that switching from methyl to ethyl ester eliminated a silica plug step, reduced overall cycle time by 4.2 h per batch, and cut dichloromethane consumption by 18 L·kg⁻¹ of final intermediate. These operational advantages, when multiplied over a 50‑kg annual API campaign, translate into a measurable cost avoidance that raw material price comparisons alone fail to capture.

Specification Sheet and Standardized Quality Metrics

Release Specification — Ethyl 2‑Phenylthiazole‑4‑carboxylate (Technical Grade)
Test	Method	Limit
Appearance	Visual inspection under white light	White to off‑white powder, free of visible extraneous matter
Identification (HPLC)	USP 〈621〉 — retention time comparison	Sample RT within ±0.05 min of reference standard
Assay (anhydrous, solvent‑free)	HPLC area‑% at 254 nm	≥98.0%
Water Content	Karl Fischer coulometry, USP 〈921〉 Method Ia	≤0.5% w/w
Melting Range	USP 〈741〉 Class Ia, 1.0 °C·min⁻¹	46.0–48.0 °C
Sulfated Ash	USP 〈281〉	≤0.1%
Residual Ethanol	USP 〈467〉 Procedure A, GC‑HS	≤5000 ppm
Residual Ethyl Acetate	USP 〈467〉	≤600 ppm
Residual Dichloromethane	USP 〈467〉	≤300 ppm
Cadmium	ICP‑MS (microwave digestion), ICH Q3D	≤2 ppm
Lead	ICP‑MS	≤5 ppm
Total Aerobic Microbial Count	USP 〈61〉	≤100 CFU·g⁻¹
Total Yeast and Mould Count	USP 〈61〉	≤10 CFU·g⁻¹

The specification is aligned with the requirements of REACH registration dossier section 1.4 and is suitable for use as a non‑dedicated intermediate under ICH Q7 Section 8.3. When the ethyl ester is deployed in late‑stage cGMP steps, an additional control on endofrin levels is implemented via USP 〈85〉 with a limit of ≤0.25 EU·mg⁻¹. No pharmacopoeial monograph currently exists in the Ph.Eur., USP, or JP; the above internal specification is released on the basis of cross‑referenced general chapters.

From a dust‑explosion safety perspective, fines with particle size D₅₀ < 100 µm exhibit a minimum ignition energy below 10 mJ. Therefore, all drum‑offloading operations in production suites use dedicated inert‑gas purged gloveboxes or local exhaust ventilation designed for St1 dust classification (K_St ≤ 200 bar·m·s⁻¹) per EN 14034. The ester is incompatible with strong oxidizers (class 5.1) and anhydrous bases heated above 60 °C, where exothermic decomposition has been recorded by accelerating rate calorimetry with an onset temperature of 127 °C (phi‑factor 1.15). In aqueous acidic media (pH 1–2) at 25 °C, less than 2% of the ester is hydrolysed over 24 h, which allows for aqueous workup under acidic conditions without significant yield loss.

HS Code	514411
Chemical Formula	C12H11NO2S
Molar Mass	233.29 g/mol
Appearance	Typically a solid (description may vary based on purity and conditions)
Melting Point	Data may vary depending on purity, generally needs experimental determination
Boiling Point	Data may vary depending on purity, generally needs experimental determination
Solubility In Water	Expected to be low as it is an organic ester with a non - polar phenyl group
Solubility In Organic Solvents	Soluble in common organic solvents like ethanol, acetone, chloroform due to its organic nature
Density	Data may vary, requires experimental measurement
Odor	May have a characteristic organic odor, but specific description depends on sample
Flash Point	Needs experimental determination

Packing	100g of 2 - Phenyl - 4 - thiazolecarboxylic acid ethyl ester in sealed chemical - grade packaging.
Shipping	4 - Thiazolecarboxylic acid, 2 - Phenyl -, Ethyl Ester is shipped in properly sealed containers, compliant with chemical transport regulations. Care is taken to prevent breakage and ensure safe transit to the destination.
Storage	4 - Thiazolecarboxylic acid, 2 - Phenyl -, Ethyl Ester should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent exposure to moisture and air, which could potentially cause degradation. Store it separately from incompatible substances, like strong oxidizing agents or acids, to avoid chemical reactions.

4-Thiazolecarboxylicacid, 2-Phenyl-, Ethyl Ester