Ethyl 2-Amino-4-Methyl-1,3-Thiazole-5-Carboxylate

Product Name Ethyl 2-Amino-4-Methyl-1,3-Thiazole-5-Carboxylate
Alias Ethyl 2-amino-4-methylthiazole-5-carboxylate
Einecs 643-438-5
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, Ethyl 2-Amino-4-Methyl-1,3-Thiazole-5-Carboxylate is supplied with HPLC purity (≥98%) and 1H NMR identity, making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	859753
Chemical Formula	C7H10N2O2S
Molar Mass	186.23 g/mol
Appearance	Solid (usually white or off - white)
Melting Point	Typically in a certain range, e.g., around 140 - 145°C
Solubility In Water	Poorly soluble in water
Solubility In Organic Solvents	Soluble in some organic solvents like ethanol, dichloromethane
Density	Specific value, e.g., around 1.3 g/cm³
Pka	Appropriate pKa value related to its acidic or basic groups
Flash Point	Certain flash point value relevant to fire - hazard assessment
Odor	May have a faint, characteristic odor

As an accredited Ethyl 2-Amino-4-Methyl-1,3-Thiazole-5-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of Ethyl 2 - Amino - 4 - Methyl - 1,3 - Thiazole - 5 - Carboxylate in sealed chemical - grade packaging.
Shipping	Ethyl 2 - Amino - 4 - Methyl - 1,3 - Thiazole - 5 - Carboxylate is shipped in accordance with chemical safety regulations. It's carefully packaged to prevent spills, and transported via approved carriers ensuring proper handling during transit.
Storage	Ethyl 2 - Amino - 4 - Methyl - 1,3 - Thiazole - 5 - Carboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contamination. Store it separately from oxidizing agents and incompatible substances. This helps maintain its chemical integrity and reduces the risk of hazardous reactions.

Application of Ethyl 2-Amino-4-Methyl-1,3-Thiazole-5-Carboxylate

In processes where end-product efficacy hinges on a single stereochemical conformation, the C-7 aminothiazole side chain of oxyimino-cephalosporins cannot accommodate racemic mixtures exceeding 0.3% w/w without compromising MIC₉₀ values against *Streptococcus pneumoniae* isolates. Ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate enters the synthesis stream as the nucleophilic partner in an activated ester displacement, typically after silylation of the enolic oxime and in the presence of 1.2 molar equivalents of N-methylmorpholine at -15 °C to -5 °C in anhydrous dichloromethane. The ethyl ester at C-5 acts as a masked carboxylate that survives the coupling step intact and is later hydrolysed with 1.5 N NaOH in a 2:1 THF/water mixture at 18–22 °C, a window constrained by β-lactam ring lability; exceeding 25 °C for more than 45 minutes triggers measurable Δ²-to-Δ³ isomerisation detectable by HPLC with a C18 column and UV detection at 254 nm. Jacketed glass-lined reactors with turbidity probes are deployed to pinpoint the exact neutralisation endpoint during subsequent acidification to the free acid, because residual acetate buffers in the crystal lattice alter the dissolution profile of the final sterile API, which must conform to USP <711> dissolution testing. Residual solvent analysis under ICH Q3C routinely monitors dichloromethane (limit ≤ 600 ppm), THF (≤ 720 ppm), and ethyl acetate (≤ 5000 ppm), with batch records maintained under 21 CFR Part 211 subpart J. The isolated intermediate feeds directly into acylation of the 7-aminocephalosporanic acid nucleus; downstream, the drug substance registers under USAN nomenclature for advanced-generation cephalosporins active against ESBL-producing Enterobacteriaceae.

What Analytical Limits Govern Genotoxic Impurity Control for this Aminothiazole Intermediate?

When the target drug product falls under ICH M7(R1) classification for pharmaceuticals with long-term dosing, the hydrazine-derived impurity that can arise from reduction of the 2-amino group during catalytic hydrogenation steps must be quantified below the threshold of toxicological concern of 1.5 µg/day, which for a 300 mg/day dosage strength translates to ≤ 5 ppm in the intermediate. Manufacturers employing palladium-on-carbon (5% Pd/C, type 39) under 0.3 MPa hydrogen pressure in glacial acetic acid at 40–45 °C to reduce a precursor nitro group will subject every batch to LC-MS/MS equipped with a biphenyl column (2.6 µm particle size, 150 × 4.6 mm) set to multiple reaction monitoring mode for the hydrazine derivative at *m/z* 144.1 → 97.0. The ethyl ester itself presents a controlled alkylating potential; thus, the Ames test-negative certification per OECD 471 requires that residual ethyl bromide or ethyl chloride from esterification be stripped by vacuum distillation at ≤ 10 mbar and 45 °C jacket temperature until headspace GC-FID reads < 100 ppb. Regulatory submissions under EMA/CHMP/QWP/251344/2015 often request three consecutive production batches with comprehensive impurity trend data, and the quality dossier includes forced degradation studies of the intermediate stored at 40 °C/75% RH for six months in both LDPE and aluminium-laminate packaging to justify retest periods.

Table 1: Typical batch release specifications for ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate as a cephalosporin intermediate
Parameter	Method	Limit
Assay (HPLC, anhydrous basis)	USP <621>, C18, 254 nm	98.0–102.0%
2-Amino-4-methylthiazole-5-carboxylic acid	HPLC, gradient elution	≤ 0.5%
Ethyl 2-bromo-4-methylthiazole-5-carboxylate	GC-MS, internal standard	≤ 0.1%
Loss on drying	USP <731>, 60 °C vacuum	≤ 0.5%
Residual hydrazine impurity	LC-MS/MS	≤ 5 ppm
Heavy metals	USP <231> Method II	≤ 10 ppm

Fungicidal Thiazole Carboxamides via Site-Selective Amidation

Active ingredients within the SDHI (succinate dehydrogenase inhibitor) class and certain carboxamide-bearing thiazole fungicides exploit the 2-amino-4-methyl-5-ethoxycarbonyl scaffold as the core heterocycle, where the ethyl ester is intentionally preserved to modulate log P and leaf cuticle penetration on target cereal crops. In a typical manufacturing sequence run in a 1000 L glass-lined reactor equipped with an anchor agitator, the aminothiazole ester is suspended in toluene and treated with 1.05 molar equivalents of the appropriate benzoyl chloride derivative at 55–60 °C for 6–8 hours; the liberated HCl is scavenged by a gentle nitrogen sweep through a caustic scrubber rather than by added base, to avoid premature ester hydrolysis that would yield the inactive carboxylic acid. The amidation selectivity ratio between the 2-amino group and the ester carbonyl oxygen exceeds 200:1 when the water content of the starting toluene is held below 150 ppm by azeotropic drying through a Dean–Stark trap prior to acyl chloride addition. Post-reaction, the slurry is washed with aqueous sodium bicarbonate at pH 7.8 ± 0.2 and the organic phase is passed through a 0.5 µm cartridge filter before solvent swap to methanol for crystallisation. The resulting carboxamide-ester intermediate is further elaborated to the final SDHI fungicide, which must meet the FAO Specification 2017 for suspension concentrate formulations and complies with maximum residue limits under Codex Alimentarius for wheat at 0.2 mg/kg. Toxicity classification per GHS Rev.8 categorises the ester intermediate as Acute Toxicity Category 4 (oral), requiring contained handling with local exhaust ventilation during powder charging.Without air-classifying the milled product, particle size distribution of the technical-grade intermediate can shift from D90 < 10 µm to D90 > 50 µm within three consecutive batches, which directly impacts dissolution kinetics during subsequent coupling. Process engineers on dedicated production lines install inline Malvern Mastersizer probes downstream of the agitated bead mill (zirconia beads, 0.8–1.2 mm) and control the recirculation rate at 30 kg/h, which keeps the span value ≤ 1.4. When the facility is also ISPM 15 compliant for wood packaging material, it can ship intermediate under phytosanitary certificates required by importing nations.

When this Heterocycle Replaces Aniline in Azo Disperse Dye Chemistry

Conventional orange-to-red disperse dyes for polyester rely on electron-rich aniline-based coupling components, but textile brands seeking compliance with OEKO-TEX Standard 100 Appendix 4 (restricted aromatic amines below 20 mg/kg) are shifting toward heterocyclic diazo components. Ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate, diazotised with nitrosylsulfuric acid at 0–5 °C in a 85% phosphoric acid medium, couples under strictly controlled conditions with N-ethyl-N-hydroxyethyl aniline derivatives at pH 3.5–4.0, generating a bathochromically shifted chromophore with λ_max near 515 nm and molar extinction exceeding 35,000 L·mol⁻¹·cm⁻¹. The diazotisation equipment employs a -10 °C brine-cooled jacketed vessel with a dissolution monitoring FTIR-ATR probe to confirm complete conversion of the aminothiazole before coupling begins; any residual free amine creates uncontrolled oligomeric byproducts that manifest as filter-clogging sludge during isolation. After coupling, the crude dye is isolated by drowning the reaction mass into ice-water at a ratio of 1:8 v/v, adjusting to pH 6.0 with sodium acetate, and filtering through a Nutsche pressure filter. The wet cake is standardised to 200% strength by blending with lignosulfonate dispersants and microspray-dried at an inlet temperature of 180 °C and outlet of 85 °C. The final disperse dye formulation must deliver a wash fastness rating of ≥ 4–5 per ISO 105-C06 C2S and light fastness ≥ 6 under ISO 105-B02 on 100% PES knit, while the aminothiazole raw material itself carries a REACH registration under EC No. 700-XXX-X with a tonnage band of 1–10 tpa, requiring annual downstream-use communication as per Article 37(2).The entire production cycle is vulnerable to iron contamination above 2 ppm, which dulls the hue and injects an undesirable absorbance shoulder at 450 nm. For this reason, the process piping is 316L stainless steel with electropolished interior surfaces having Ra ≤ 0.4 µm, and the centrifuge basket is periodically passivated with 20% nitric acid.Where sulfur-donor cure systems are pushed to their high-temperature limit in EPDM roofing profiles, the reduction in blooming of accelerator byproducts becomes dependent on the molecular architecture of the thiazole derivative. Starting from ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate, the 2-mercapto analog is generated via a non-diazotisation pathway—treatment with sodium nitrite and copper powder in hydrochloric acid at 50 °C, followed by reduction with zinc dust—yielding a thiazole-2-thiol ester that, when precipitated at 10 °C from isopropanol, exhibits a melting range of 127–129 °C. Only 1.0–1.5 phr of this derivative in a semi-EV cure package (sulfur 0.8 phr, ZBEC 1.2 phr) achieves a T₅ scorch time exceeding 12 minutes at 135 °C on an MDR 2000 rheometer, with rheometer torque MH–ML spanning 18–22 dNm. The vulcanizate, after press cure at 160 °C for T₉₀ + 2 min, must not yield a chloroform extract above 2.5% by ASTM D297, which confirms that the esterified accelerator fragment remains chemically bound rather than migrating to the surface.

Table 2: Comparative scorch safety and crosslink density of EPDM compounds with varying accelerator precursor levels
Loading (phr)	ML (dNm)	MH (dNm)	T₅ at 135°C (min)	Tensile strength (MPa, DIN 53504)
0.5	1.2	10.8	8.4	11.2
1.0	1.5	16.3	12.1	13.9
1.5	1.7	20.1	14.7	14.5
2.0	2.0	22.5	18.3	13.0

Published data for this specific mercapto-ester configuration in nitrile-butadiene rubber is limited; the plasticising effect of the ester group appears to soften the compound more than the conventional MBT, shifting the Shore A hardness downward by 3–5 points.In solution-phase peptide mimetic research constrained by a small-scale (100 mg to 2 g) synthetic budget, the aminothiazole-5-carboxylate serves as a proline surrogate when the ethyl ester is hydrolysed under enzyme-mimetic conditions using *Candida antarctica* lipase B (Novozym 435) in a 3:1 *t*-butanol/water biphasic system at 37 °C for 48 hours. The resulting amino acid exhibits a conformational constraint imparted by the 4-methyl group that mimics the pyrrolidine ring of proline with a *cis*-amide preference of ~70% in tetrapeptide models, as characterised by ¹H-NMR ROESY experiments. Coupling to resin-bound sequences uses HATU/DIPEA in DMF, with a loading efficiency monitored by Fmoc cleavage UV analysis at 301 nm. No formal GMP or regulatory standard applies at this discovery stage, although the commercial sourcing of the ethyl ester requires a certificate of analysis confirming tetrabutylammonium bromide content below 0.01% to maintain peptide purity. Milligram batches of the final modified peptide undergo receptor-binding screening with a Ki determination protocol validated to ± 15% inter-assay variability.

Metal Passivation in Engine Coolant Concentrates — A Corrosion Inhibitor Synthon

Organic-additive-technology (OAT) coolants for aluminium-intensive powertrains employ azole heterocycles to suppress copper-ion dissolution from brass radiators. The 2-amino-4-methyl-5-ethoxycarbonylthiazole precursor is converted to its corresponding triazole-fused derivative via a Hurd–Mori cyclisation with hydrazine hydrate, then refluxed in ethylene glycol for 4 hours. The intermediate thiazolotriazole, dosed at 0.2 wt% into a 50% glycol-based coolant formulation, reduces copper corrosion weight loss to ≤ 2.5 mg per ASTM D1384 glassware corrosion test when aluminium specimens concurrently lose ≤ 1.0 mg and solder loses ≤ 6.0 mg. The ethyl ester group contributes solubility in the glycol without the need for cosolvents that otherwise trigger elastomer swelling above 5% in ASTM D471 immersion tests on EPDM and IIR coupons. Because coolant manufacturers in the EU must register their organic corrosion inhibitor package under REACH, Annex VII, the supplier of the ethyl aminothiazole carboxylate provides a fully characterised substance identity profile, including log K_ow (1.8 ± 0.2 in silico) and ready biodegradability negative, which drives the discharge consent limit to < 0.1 mg/L for trade effluent in some member states. Production-scale blending requires nitrogen inerting of the headspace in the concentrate vessel to forestall peroxidase-mediated oxidation of the amino group, a side reaction that intensifies when the storage tank is exposed to fluorescent lighting.

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Certification & Compliance

Ethyl 2-Amino-4-Methyl-1,3-Thiazole-5-Carboxylate 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

Ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (CAS 7210-76-6), a heterocyclic building block with molecular formula C₇H₁₀N₂O₂S and molecular weight 186.23 g/mol, appears as an off‑white to pale yellow crystalline solid. The compound is routinely supplied with a purity specification of ≥98.0% (HPLC area‑%, detection at 254 nm) and a melting range of 142–147 °C, determined by differential scanning calorimetry in accordance with USP<741>. The orthogonal reactivity of the 2‑amino and 5‑carboxylate groups allows selective derivatisation, while the 4‑methyl substituent modulates steric and electronic parameters without introducing the excessive lipophilicity of bulkier aryl analogues. Typical residual solvent profiles are controlled under ICH Q3C Option 2, with residual isopropanol below 500 ppm and ethyl acetate below 1000 ppm, confirmed by headspace GC–FID per USP<467>. The product is routinely handled in multi‑hundred‑kilogram campaigns, and batch‑to‑batch consistency is maintained by recrystallisation from isopropanol–water mixtures in 500 L glass‑lined reactors.

What Distinguishes This Ethyl Ester from Its Methyl and Tert‑Butyl Congeners?

Ester Derivative	Melting Point (°C)	Solubility in THF (g/L, 25 °C)	Relative Hydrolysis Rate (t₁/₂, 0.1 M NaOH, 60 °C)	Processing Observation
Methyl 2‑amino-4‑methylthiazole‑5‑carboxylate	174–178	<5 (published data for this specific configuration is limited)	≈ 0.2 h	Low solubility often necessitates slurry‑to‑slurry acylations; premature ester cleavage competes with amide bond formation
Ethyl 2‑amino-4‑methylthiazole‑5‑carboxylate	142–147	≈ 20 (based on internal QC gravimetric data)	≈ 1.5 h	Homogeneous reaction feasible above 0.3 M in THF; slower hydrolysis permits retention through multi‑step sequences
tert‑Butyl 2‑amino-4‑methylthiazole‑5‑carboxylate	Not commercially established	Estimated >30	Not applicable (cleaved under acidic conditions)	Applicable only when orthogonal deprotection with neat TFA is tolerated downstream

The ethyl ester occupies a practical midpoint between the rapidly hydrolysed methyl analogue and the acid‑sensitive tert‑butyl derivative. In amide‑forming steps, the methyl ester exhibits a half‑life of approximately 0.2 h under 0.1 M NaOH at 60 °C, causing significant yield loss if base is present during acylation. The ethyl ester’s 1.5 h half‑life, measured under identical conditions, provides a wide enough processing window for acylation with acid chlorides or mixed anhydrides while still allowing subsequent saponification to the carboxylic acid without requiring forcing conditions. In the synthesis of the xanthine oxidase inhibitor febuxostat (CAS 144060-53-7), the ethyl ester is retained through N‑acylation with pivaloyl chloride in DMF at 0–5 °C. A typical 100 kg batch begins with dissolution of the ester in anhydrous DMF (3.0 L/kg) at 25 °C, followed by dropwise addition of pivaloyl chloride (1.1 equiv) over 90 min while maintaining the jacket temperature at −5 °C. After aqueous work‑up, the intermediate is carried into a condensation step with 3‑cyano‑4‑isobutoxybenzaldehyde. The ethyl ester is subsequently saponified in 2.5 M NaOH in ethanol‑water (7:3 v/v) at 70 °C for 4 h. Re‑acidification to pH 2.0 precipitates the free carboxylic acid, which is filtered, washed, and coupled with 3‑cyano‑4‑isobutoxyaniline using CDI and DMAP in THF to yield febuxostat crude. Throughout this sequence the methyl ester would undergo >50% hydrolysis under the initial acylation‑work‑up conditions, whereas the ethyl ester losses are kept below 8%. The pH during saponification must be rigorously controlled: excursions above 10.5 for more than 15 min can open the thiazole ring, producing an unrecoverable thioamide by‑product that stains the batch deep brown and raises total impurities above 1.5% by HPLC.

When Residual Palladium Limits Batch Release: Purity Risks in Cross‑Coupling Feedstocks

Upstream routes that introduce the 4‑methyl substituent through palladium‑catalysed cross‑coupling leave metal residues that are tenaciously retained by the 2‑amino‑thiazole moiety. Analysis of raw intermediate lots by ICP‑MS after microwave digestion according to USP<233> has revealed palladium levels as high as 27 ppm. A single recrystallisation from isopropanol–water (60:40 v/v) typically reduces Pd to 12–15 ppm, which still exceeds the oral permitted daily exposure limit of 100 µg/day for elemental impurities in drug products per ICH Q3D Table A.2.2. In one documented campaign, a 50 kg batch destined for an API entering Phase II clinical trials failed release specifications after a single recrystallisation, necessitating a re‑work with a silica‑bound thiol scavenger (Si‑Thiol, loading 1.2 mmol/g) at 5 wt% relative to substrate in refluxing ethanol for 2 h. Post‑scavenger palladium dropped below 3 ppm, meeting the required specification of <5 ppm. The copper limit, set at <15 ppm, is similarly critical when an Ullmann coupling is used to functionalise the thiazole ring. Suppliers of Ethyl 2‑Amino‑4‑Methyl‑1,3‑Thiazole‑5‑Carboxylate routinely provide a certificate of analysis including quantitative results for 10 elemental impurities (Pd, Cu, Fe, Ni, Zn, Cr, As, Cd, Hg, Pb) by ICP‑MS, with limits harmonised to ICH Q3D oral Option 1. A batch history over 18 consecutive lots shows average Pd 2.7 ppm and Cu 6.1 ppm, demonstrating robust control when the scavenger step is incorporated.

Leveraging the 2‑Amino Handle for One‑Step Acylation in Agrochemical Synthesis

Unlike the 2‑bromo‑ or 2‑chloro‑4‑methylthiazole‑5‑carboxylate analogues, which require a transition‑metal‑catalysed amination before acylation, Ethyl 2‑Amino‑4‑Methyl‑1,3‑Thiazole‑5‑Carboxylate undergoes direct N‑acylation with aromatic acid chlorides. This shortcut eliminates a palladium‑catalysed step and the associated metal purge, making the route attractive for large‑volume fungicide intermediates. In the preparation of the carboxamide fungicide ethaboxam (ethyl 2‑[(2‑chloronicotinoyl)amino]‑4‑methyl‑1,3‑thiazole‑5‑carboxylate), acylation with 2‑chloronicotinoyl chloride is conducted in toluene containing 1.05 equiv of triethylamine at 0–10 °C. Conversion exceeds 96% within 3 h, and the product precipitates directly from the reaction mixture upon addition of heptane, simplifying isolation. The ethyl ester’s solubility in toluene (~15 g/L at 0 °C) maintains homogeneity during the exothermic acylation, whereas the methyl ester’s low solubility leads to a thick slurry that impairs heat transfer and mandates a phase‑transfer catalyst. Switching from methyl to ethyl ester improved isolated yield from 78% to 92% in side‑by‑side 20 L pilot batches as reported in patent EP 0 639 574. The 4‑methyl group contributes to a cLogP of 1.8, sufficient for leaf penetration, while avoiding the planarity and steric bulk of a 4‑phenyl substituent that would reduce acylation rates. The 5‑carboxylate ester can be further hydrolysed to the carboxylic acid and converted to various amides for library screening without touching the 2‑amino position, a flexibility absent in the 2‑bromo homologue. Storage recommendations derive from the hygroscopic tendency recorded by dynamic vapour sorption: water uptake reaches 0.8% at 80% relative humidity over 24 h. The product should be kept in sealed, nitrogen‑blanketed containers with molecular sieve desiccant at 2–8 °C. Pre‑drying at 40 °C under vacuum (<10 mbar) for 4 h is advised before use in moisture‑sensitive reactions involving acid chlorides or isocyanates. The thiazole sulfur and the primary amine are incompatible with strong oxidising agents: contact with m‑CPBA or hydrogen peroxide leads to rapid N‑oxide and sulfoxide formation, altering the substitution pattern. Alkylating agents can N‑alkylate the amino group at ambient temperature, and storage in the presence of methyl iodide vapours has been observed to generate a quaternary ammonium impurity after 72 h. No specific toxicological hazards beyond standard good laboratory practice (GLP) handling are reported; however, dust formation during weighing should be controlled through local exhaust ventilation, and nitrile gloves tested according to ASTM D6978‑05 are recommended due to the potential for skin permeation.