1,3-Thiazole-5-Carboxylate: Properties, Applications, Safety Data & Supplier in China

How Residual Water Levels in the Suzuki Condensation Feedstock Shift the Impurity Profile of Thiazole-5-Carboxylate-Derived Xanthine Oxidase Inhibitors

In the large-scale preparation of non-purine xanthine oxidase inhibitors such as febuxostat, the 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate ethyl ester intermediate functions as the gatekeeper for downstream purity. The synthetic sequence requires that this ester—customarily shipped with an assay of ≥99.0% and single unknown impurity below 0.10%—enter a palladium-catalyzed cross‑coupling with absolute moisture control. Water content exceeding 350 ppm in the tetrahydrofuran/dimethylacetamide mixed solvent system (4:1 v/v) depresses the catalytic cycle of Pd(dppf)Cl₂ (loading 0.5–1.5 mol%) by hydrolyzing the boronate ester partner prematurely, causing an increase in the des‑halo homocoupling by‑product to 1.8–3.2 area%. The industry mitigation standard follows ICH Q7 Chapter 7 and FDA 21 CFR 211.67 equipment cleaning limits: azeotropic drying of the reactor train with toluene at 110°C for 45 minutes, followed by Karl Fischer verification to ≤80 ppm H₂O before charging. Batch records typically target a molar feed ratio of thiazole ester to aryl bromide of 1.00:1.05; exceeding 1.10 equivalents shifts the dimerization of the palladium‑aryl intermediate to a level requiring a second charcoal‑filtration pass. Compliance with residual metal limits (ICH Q3D) demands a post‑reaction scavenger treatment with silica‑bound trimercaptotriazine, consistently reducing palladium concentrations from 120–220 ppm to ≤8 ppm in the isolated product. The work‑up sequence proceeds through aqueous ammonia chelation, phase cut at 55°C, and crystallization from methanol/water (3:1 v/v) with a linear cooling ramp of 0.3°C/min from 62°C to −5°C. Vacuum drying at 45°C and ≤5 mbar for 14–18 hours delivers the free acid or re‑esterified intermediate with residual solvent levels certified against ICH Q3C Option 2 limits (e.g., methanol ≤3,000 ppm, THF ≤720 ppm). Terminal dosage forms include febuxostat tablets at 40 mg and 80 mg strengths and directly compressible granules for hard gelatin capsules, all manufactured under 21 CFR 210/211 current good manufacturing practice. The tightly controlled thiazole ester supply chain thus dictates the allowable related substances (≤0.10% for any unspecified impurity) and the microsphere milling parameters that achieve a particle size D90 of ≤25 µm for adequate dissolution.

Production of thifluzamide technical concentrate via direct amidation of 2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylate ester with 2′,6′-dibromo-4-trifluoromethoxy aniline exposes a process bottleneck that hinges on the exothermic neutralization of hydrogen chloride. In a typical campaign, the ester is first saponified with 30% w/w aqueous sodium hydroxide at 78–82°C for 4 hours to yield the corresponding carboxylic acid, which upon protonation and toluene displacement is converted to the acyl chloride using thionyl chloride (1.3 equivalents) and catalytic dimethylformamide at 65–70°C. Acylation of the sterically hindered aniline proceeds in xylene at 135–140°C with a molar stoichiometry of thiazole acyl chloride to aniline of 1.00:1.02; the slight excess compensates for moisture‑induced degradation of the acid chloride, which can drop the isolated yield from 92% to below 78% if the off‑gas scrubber fails to maintain a vacuum of −0.06 MPa. The resulting amide precipitates upon cooling to 0–5°C, and a subsequent n‑heptane slurry wash reduces colored by‑products, ensuring compliance with the colour specification of ≤50 APHA for a 10% solution in acetone. For registration under FAO Specification 766/TC/S/F (2020) and analytical conformance to CIPAC method 4102/m, the technical material is required to have a purity of ≥97.0%, moisture ≤0.3%, and water‑insoluble matter ≤0.1%. Mill‑base preparation for downstream formulation into 240 g/L suspension concentrate involves a horizontal bead mill (0.4–0.7 mm zirconia beads, tip speed 10 m/s) together with a comb polymer dispersant (3.5% w/w on technical) and a xanthan‑based anti‑settling structure. The resultant SC exhibits a particle size D50 of 1.8–2.5 µm, a suspension rate above 92% after 30 minutes in CIPAC Standard Water D, and is applied as a foliar spray for rice sheath blight control. Seed treatment flowable concentrates and water‑dispersible granule intermediates further extend the formulated product range, each requiring supplementary toxicological data packages according to EPA 40 CFR 180 and EU Regulation (EC) No 396/2005 residue definitions.

Zinc-Free Molybdenum-Phosphonate Programs Spiked with Thiazole Ester Analogues

Open recirculating cooling water systems that operate under high‑cycle conditions at a conductivity of 4,000–6,000 µS/cm often suffer localised carbon steel corrosion when zinc‑based programmes are phased out to meet discharge limits of ≤0.5 mg/L Zn per NPDES permit. The addition of 1,3-thiazole-5-carboxylate-derived analogues—specifically its 2‑amino and 2‑mercapto substituted esters—at actives levels of 50–200 mg/L provides a mixed‑type inhibition mechanism that supplements the anodic phosphonate film. Linear polarisation resistance data collected per NACE TM0169-2000 at 40°C under pH 7.8–8.4 demonstrate a reduction in general corrosion rate from 0.52 mm/yr (blank) to 0.08–0.14 mm/yr for the dosed coupons; pitting factor remains below 1.2 in ASTM G31-72(2021) immersion tests of 168 hours duration. The thiazole ester hydrolyses progressively in the alkaline buffer to the acid form, generating an adsorbed film detectable by X‑ray photoelectron spectroscopy with Fe–N coordination at 399.8 eV and Fe–S signals at 161.5 eV. Below pH 5.5, nitrogen protonation diminishes surface coverage by approximately 70%, requiring a pH floor of 6.8 in the blowdown. A representative dose‑response matrix is shown in the table; the test medium was synthetic cooling water containing 500 mg/L Ca as CaCO₃, 300 mg/L Mg as CaCO₃, 300 mg/L Cl⁻, and 200 mg/L SO₄²⁻.

Inhibitor Concentration (mg/L)

Corrosion Rate (mm/yr)

Inhibition Efficiency (%)

0 (control)

0.52

–

0.34

34.6

0.21

59.6

100

0.11

78.8

200

0.08

84.6

Plant injection practices typically employ a diaphragm metering pump tied to a corrosion‑rate monitoring probe (2‑electrode LPR, Honeywell SmartCET or equivalent) with a proportional‑integral control loop maintaining a target inhibitor residual of 120 ± 10 mg/L. The treatment chemical is blended into a 20‑kg drum formulation that contains 15% active thiazole ester, 25% phosphonobutane‑tricarboxylic acid, 10% hydrolysed polymaleic anhydride, and 50% deionised water, then injected neat into the return header ahead of the heat exchanger. Systems treated in this manner routinely extend steel heat exchanger service life beyond 12 years with a fouling factor of < 0.0001 m²·K/W. The final deliverable product is a multi‑component corrosion and scale inhibitor package, labelled under GHS with hazard category Skin Irrit. 2, and compliant with the EC Detergent Regulation 648/2004 biodegradability thresholds for cooling‑water additives.

When oligomer hydrophobicity and crosslink density are balanced by incorporating heterocyclic thiazole pendant groups, the cured film’s refractive index increments by 0.03–0.06 units while retaining elongation at break above 6% as per ASTM D882. A reactive mono‑acrylate thiazole ester, synthesised from 1,3-thiazole-5-carboxylate and glycidyl methacrylate via a ring‑opening esterification at 105°C with triethylamine catalyst, is blended into a urethane acrylate oligomer matrix at 20–40 wt%. Photo‑differential scanning calorimetry exotherms recorded with a 385 nm UV‑LED source (2 W/cm²) show that the thiazole monomer reaches 92% conversion within 8 seconds, generating a homogenous network with a glass transition temperature of 72–86°C measured by DMA at 1 Hz. The optical transparency at 400 nm exceeds 88% for a 50 µm film spun onto polycarbonate substrates. Qualification under ISO 9211-4 for anti‑reflection coatings demands a Taber haze value below 2.5% after 500 cycles, a requirement met only when the thiazole loading stays below 35 wt% to avoid micro‑phase separation from the aliphatic urethane soft segments. The production route applies the liquid formulation through slot‑die coating or spin coating onto aspherical lens preforms, followed by a single‑pass UV‑LED array and a post‑bake at 80°C for 30 minutes to eliminate residual acrylate. End‑use components include fingerprint‑resistant hard coats for smartphone camera modules and high‑refractive‑index (nD²³ 1.58–1.62) inner layers for augmented‑reality waveguide combiners, both complying with REACH Annex XVII and RoHS Directive 2011/65/EU restrictions on dibutyltin compounds that could be generated during esterification. Detailed outgassing profiling according to ASTM E595 returns a total mass loss of ≤0.35% and collected volatile condensable material ≤0.03%, confirming compatibility with sealed optoelectronic packaging.

If Tertiary Amine-Accelerated Anhydride Cure Systems Require UL 94 V-0 Without Antimony Trioxide

Epoxy‑based copper clad laminates for consumer electronics have largely eliminated antimony trioxide from their bill of materials, driving a search for heterocyclic char formers that can raise the limiting oxygen index (LOI) to above 30% without compromising the cure kinetics. A 1,3-thiazole-5-carboxylate derivative—specifically the DOPO‑thiazole adduct obtained by Pudovik addition of 9,10‑dihydro‑9‑oxa‑10‑phosphaphenanthrene‑10‑oxide onto a 2‑allyl‑1,3‑thiazole-5-carboxylate intermediate—displays T₅% mass loss at 341°C under nitrogen by ISO 11358-1, and when compounded into a diglycidyl ether of bisphenol A (DGEBA, epoxide equivalent weight 188 g/eq) with methyl hexahydrophthalic anhydride hardener and 0.5 phr 1‑methylimidazole accelerator, the resulting thermoset shifts the heat release capacity to 98 J/g·K in micro‑combustion calorimetry. The formulation space tested for FR‑4.1 laminate qualification (IPC‑4101/21 specification) is compiled in the table; all samples were cured at 120°C for 2 hours plus 160°C for 3 hours, and the UL 94 vertical burn test was conducted at 1.6 mm thickness.

Thiazole-DOPO Adduct (phr)

Phosphorus Content (wt%)

LOI (%)

UL 94 (1.6 mm)

Avg. t1 + t2 (s)

22.1

–

1.8

28.4

V-1

17.2

2.7

32.6

V-0

6.8

3.8

36.3

V-0

3.1

Beyond 28 phr, the resin viscosity at 60°C surpasses 8,000 mPa·s, exceeding the practical upper limit for continuous treater impregnation of 7628 glass cloth. The prepreg is therefore manufactured on a horizontal treater with a resin‑content target of 43 ± 2%, using a line speed of 6–8 m/min and a four‑zone drying profile from 90°C to 155°C. Eight plies are laid up between 35 µm electrodeposited copper foil and pressed at 190°C under 2.5 MPa for 90 minutes, achieving a T₃₀₀ (time to delamination at 300°C) of ≥32 minutes. Peel strength on untreated copper remains at 1.2 N/mm (IPC‑4101 criteria: ≥1.05 N/mm). The final halogen‑free laminate complies with the maximum limits for chlorine and bromine of ≤900 ppm each per IEC 61249-2-21 and supports an electric strength of ≥40 kV/mm. From a regulatory standpoint, the thiazole‑DOPO adduct is manufactured under a ISO 9001:2015 quality system, with toxicological screening against EU CLP hazard classes; no mutagenicity alert has been triggered in OECD 471 Ames test using strains TA98 and TA100 with and without S9 metabolic activation.

The anchoring stability of heterocyclic carboxylate ligands on nanocrystalline titanium dioxide electrodes directly governs electron injection yields in ruthenium-complex sensitizers. Research‑grade dyes, structurally analogous to N719 but incorporating a 2‑cyano‑3‑(1,3-thiazol-5-carboxylate)acrylic acid anchoring function, bind to the semiconductor surface through a bidentate bridging configuration that red‑shifts the metal‑to‑ligand charge transfer band to 545 nm. Electrochemical impedance spectroscopy under AM 1.5G illumination (1 sun, 100 mW/cm², from a AAA‑class solar simulator calibrated to IEC 60904-9) measures a recombination resistance of 68 Ω·cm² at the TiO₂‑electrolyte interface, a value that falls to 31 Ω·cm² after 500 hours of thermal stress at 85°C, consistent with gradual ester hydrolysis and desorption. In a typical cell assembly, the sensitizer is taken up from a 0.3 mM acetonitrile/tert‑butanol (1:1 v/v) solution onto a 12 µm transparent TiO₂ anode (screen‑printed from 18 nm particle paste, sintered at 450°C for 30 minutes) over 20–24 hours at 25°C. The counter electrode is platinised FTO glass, and the redox couple is I⁻/I₃⁻ in 3‑methoxypropionitrile. Power conversion efficiencies reported in peer‑reviewed studies reach 7.8% with a short‑circuit current density of 16.2 mA/cm² and fill factor of 0.71 when the thiazole‑anchor dye is co‑sensitised with a triphenylamine‑based organic donor. Adherence to IEC 60904-3 measurement procedures and ISO 10677:2011 ceramic semiconductor media provisions ensures reproducible quantum efficiency data across laboratories. The ultimate device prototypes target indoor low‑light energy harvesting for IoT sensors, where the thiazole‑functionalised sensitizer’s extended absorption into the near‑UV region provides a 15–22% improvement in power output under 200 lux fluorescent lighting compared to commercial N719 reference cells.

1,3-Thiazole-5-carboxylate derivatives constitute a class of sulfur-containing heterocyclic building blocks employed extensively in medicinal chemistry and agrochemical synthesis. The most common commercial forms include the methyl ester (CAS 152381-08-5), ethyl ester (CAS 32955-22-9), and the parent carboxylic acid (CAS 14527-41-4). Typical specifications for research-grade ethyl 1,3-thiazole-5-carboxylate require a minimum HPLC purity of 98.0% (area-%) with water content below 0.5% (Karl Fischer) and residual solvent limits aligned with ICH Q3C Option 2 concentrations. The product appears as a pale yellow to colourless liquid, density 1.218 g/mL at 25 °C for the ethyl ester, and is stored under inert atmosphere at 2–8 °C to suppress ester hydrolysis and ring-oxidation.

How Does the Electron-Withdrawing Character of the 5-Position Influence Reactivity Relative to 4- or 2-Substituted Analogs?

The thiazole ring exhibits a pronounced positional gradient in σ-electron density. Bordwell’s equilibrium acidity measurements in DMSO assign approximate pK_a values of 29.5 for the 2-proton, 33.0 for the 5-proton, and 34.5 for the 4-proton. When a carboxylate function is installed at the 5-position, the combined electron-withdrawing effect of the sulfur atom and the ester group acidifies the remaining 2-proton further, facilitating regioselective direct lithiation with lithium diisopropylamide (LDA) in tetrahydrofuran at −78 °C. By contrast, 1,3-thiazole-4-carboxylates place the ester group adjacent to the ring nitrogen, which alters the orientation of the dipole moment and reduces the directing ability toward electrophilic substitution at the 2-position. In practical terms, a 5-ester can be metalated and then quenched with electrophiles (e.g., trimethylsilyl chloride, iodine) with isolated yields routinely exceeding 80%, as documented in batch records from pilot-plant campaigns at 50–100 kg scale using jacketed stainless-steel reactors with a heat-transfer coefficient of 350 W/(m²·K). The 4-ester isomer typically yields 60–70% under identical conditions due to competing ring-opening pathways.

The following table summarises key physical properties of three 1,3-thiazole-5-carboxylate esters commonly inventoried in process development laboratories.

Ester	CAS	Molecular Weight	Boiling Point	Purity Specification
Methyl 1,3-thiazole-5-carboxylate	152381-08-5	143.17 g/mol	100–102 °C at 20 Torr	≥97.0% GC
Ethyl 1,3-thiazole-5-carboxylate	32955-22-9	157.19 g/mol	125–127 °C at 15 Torr	≥98.0% HPLC
tert-Butyl 1,3-thiazole-5-carboxylate	207181-00-6	185.24 g/mol	85–87 °C at 1.5 Torr	≥95.0% NMR

Synthetic Routes Avoiding Decarboxylation During Amide Bond Formation

Thermal decarboxylation of 1,3-thiazole-5-carboxylic acid becomes kinetically significant at temperatures above 180 °C, a limitation that restricts direct melt-phase amidation. Process chemists circumvent this pathway by deploying 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) with hydroxybenzotriazole (HOBt) in dimethylformamide at 0–5 °C, achieving coupling with primary amines in 85–92% isolated yield with undetectable levels of decarboxylated thiazole by HPLC-MS (LOQ 0.05 area-%). Activation with O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine in acetonitrile at 20 °C is preferred for anilines, where reaction completion is typically confirmed in under 30 min by in-line ReactIR monitoring of the carbonyl stretch at 1715 cm⁻¹. The 5-ester amides thus produced show markedly lower propensity for hydrolysis at gastric pH (pH 1.2) compared to the analogous 2-carboxamide, a property attributed to reduced resonance stabilisation of the tetrahedral intermediate by the sulfur atom.

In a direct comparison of Suzuki-Miyaura coupling performance on halogenated 1,3-thiazole carboxylates, the 5-ester scaffold provides specific advantages over the 4- and 2-substituted isomers. The data below were generated using identical catalyst loadings and solvent systems under microwave irradiation at 120 °C.

Substrate	Bromine Position	Boron Partner	Yield (Isolated)	Observed Impurity
Methyl 1,3-thiazole-5-carboxylate	2-Br	4-Methoxyphenylboronic acid	91%	Debrominated ester 2.3%
Ethyl 1,3-thiazole-4-carboxylate	2-Br	4-Methoxyphenylboronic acid	78%	Ring-opened nitrile 8.5%
Methyl 1,3-thiazole-2-carboxylate	5-Br	4-Methoxyphenylboronic acid	84%	Debrominated ester 6.1%

Without any preliminary header, it is worth noting that substitution of the thiazole sulfur with oxygen produces the oxazole-5-carboxylate series. The lower polarisability of oxygen reduces the calculated log P for ethyl oxazole-5-carboxylate to 0.8 compared with 1.5 for the thiazole homologue (CLOGP v4.71). In Caco-2 monolayer permeability assays conducted at pH 7.4 with 10 µM apical concentration and a shake-flask acceptor compartment, the apparent permeability coefficient (P_app A→B) measured 15.3 × 10⁻⁶ cm/s for the thiazole ester versus 8.2 × 10⁻⁶ cm/s for the oxazole. This difference becomes functionally relevant when designing central nervous system-targeted agents where the thiazole’s higher transcellular flux reduces the need for prodrug strategies.

When 1,3-Thiazole-5-Carboxylate Replaces 2-Carboxylate in CETP Inhibitor Scaffolds

During lead optimisation of cholesteryl ester transfer protein (CETP) inhibitors at a multi-national pharmaceutical firm, replacement of the 2-carboxylate with a 5-carboxylate on a tetrahydroquinoline core shifted the compound’s log D_7.4 from 2.8 to 1.9 while dropping CYP3A4 inhibition (midazolam 1′-hydroxylation IC₅₀) from 1.2 µM to 8.4 µM. The modified scaffold maintained a bioavailability of 34% in Sprague-Dawley rats dosed orally at 10 mg/kg with a plasma protein binding fraction fu of 0.04. Manufacturing the 5-carboxylate intermediate for this programme required a six-step route terminating in a Hantzsch thiazole synthesis using ethyl bromopyruvate and thiourea, followed by ester hydrolysis. The lot-to-lot variability in the cyclisation step was controlled by maintaining the exotherm below 5 °C during thiourea addition; exceeding this threshold led to a brown polymeric by-product that increased the burden on the subsequent activated carbon treatment (Norit SX Plus, 10% w/w) and pushed palladium scavenging costs above the registered process maximum of $2,800/kg.

Specifications Governing Residual Palladium Content in Multi-Kilogram Campaigns

Pharmaceutical intermediate campaigns targeting late-stage clinical supply enforce strict elemental impurity limits under ICH Q3D. For a 1,3-thiazole-5-carboxylate intended as a precursor to an oral drug substance with a maximum daily dose of 100 mg, the permitted concentration of palladium (Class 1 metal) is 10 ppm. After a Suzuki coupling employing 0.5 mol% Pd(PPh₃)₄, the crude reaction mass typically contains 450–600 ppm Pd. A sequence of trimercaptotriazine-functionalised silica scavenging (SiliaMetS Thiol, 5 wt% relative to substrate, slurry in toluene at 60 °C for 4 h), filtration over a 0.5 µm PTFE membrane, and recrystallisation from n-heptane/ethyl acetate (4:1 v/v) reduces palladium to 3–7 ppm as determined by inductively coupled plasma mass spectrometry (ICP-MS) with a detection limit of 0.1 ppm. Batches exceeding 10 ppm are reprocessed by repeating the scavenger treatment; no more than two rework cycles are permitted under the current Drug Master File before the lot is rejected.

Lipase-Catalysed Hydrolysis of Racemic Esters: Substrate Scope and Turnover Numbers

Kinetic resolution of α-substituted 1,3-thiazole-5-carboxylates using Candida antarctica lipase B (CAL-B, immobilised on acrylic resin, trade name Novozym 435) generates chiral intermediates for integrase inhibitor programmes. In a representative substrate, methyl 2-(1-aminoethyl)-1,3-thiazole-5-carboxylate hydrochloride was suspended in phosphate buffer pH 7.0 containing 20% v/v acetonitrile and 50 mg/mL enzyme preparation. Vinyl acetate (3 equiv.) served as acyl donor. After 24 h at 30 °C with orbital shaking at 250 rpm, conversion reached 49% and the unreacted (R)-ester exhibited an enantiomeric excess exceeding 99% (Chiralpak AD-H column, hexane/isopropanol 90:10, 1.0 mL/min, UV 254 nm). The corresponding enantioselectivity factor E was calculated as >200. Process-scale implementation in a 50 L jacketed glass reactor with pitched-blade impeller required reduction of enzyme loading to 20 mg/mL and the addition of iso-octane as a cosolvent to suppress emulsion formation; under these conditions, isolated yield of the (R)-ester after simulated moving bed chromatography (SMB, 8-column configuration, 20 bar) was 41% with 99.5% ee. The recovered (S)-amide could be racemised and recycled, bringing the overall mass intensity to 18 kg input per kg of chiral product.

HS Code	982052
Chemical Formula	C4H3NO2S
Molecular Weight	129.14 g/mol
Appearance	Solid

Packing	100 - gram vial of 1,3 - Thiazole - 5 - Carboxylate, securely packaged in a glass container.
Shipping	1,3 - Thiazole - 5 - Carboxylate is shipped in accordance with chemical transport regulations. It's carefully packaged to prevent spills and damage. Shipment may use appropriate containers and is monitored for safety during transit.
Storage	1,3 - Thiazole - 5 - Carboxylate should be stored in a cool, dry, well - ventilated area, away from sources of heat, ignition, and moisture. Keep it in a tightly sealed container to prevent contact with air and moisture, which could potentially cause degradation. Store separately from incompatible substances, such as strong oxidizing agents or acids, to avoid chemical reactions.

1,3-Thiazole-5-Carboxylate