Ethyl 2-Amino-4-Thiazoleacetate
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HS Code |
907936 |
| Chemical Formula | C7H10N2O2S |
| Molecular Weight | 186.23 g/mol |
| Appearance | White to off - white solid |
| Melting Point | 104 - 107 °C |
| Solubility In Water | Slightly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Odor | Odorless or very faint odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited Ethyl 2-Amino-4-Thiazoleacetate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of Ethyl 2 - Amino - 4 - Thiazoleacetate in sealed, chemical - resistant packaging. |
| Shipping | Ethyl 2 - Amino - 4 - Thiazoleacetate is shipped in properly sealed, corrosion - resistant containers. It's transported under regulated conditions to prevent exposure, ensuring compliance with chemical shipping safety standards. |
| Storage | Ethyl 2 - Amino - 4 - Thiazoleacetate should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly sealed container to prevent moisture absorption and contamination. It is advisable to store it in a dedicated chemical storage cabinet, clearly labeled to ensure proper handling and safety. |
In commercial production of Cefotaxime Sodium, the active ester derived from Ethyl 2‑Amino‑4‑Thiazoleacetate—typically the 2‑mercaptobenzothiazole‑activated ester (MAEM)—is employed as the acyl donor in the N‑acylation of 7‑aminocephalosporanic acid (7‑ACA). Industrial batch records from production facilities equipped with 5,000 L glass‑lined reactors specify a molar charge ratio of MAEM to 7‑ACA of 1.10–1.25, adjusted based on the purity of the 7‑ACA lot; exceeding 1.30 promotes formation of Δ³‑isomer impurities that are difficult to purge during the final crystallization. The reaction is executed in a dichloromethane/water biphase under automated pH control (7.2–7.8) maintained by metered triethylamine dosing. Localized overheating at the injection point—frequently observed when the MAEM solution is added in less than 30 min—induces hydrolytic cleavage of the β‑lactam ring, reducing yield by 3–5 % as quantitated by HPLC versus USP Cefotaxime Sodium RS. Process optimization therefore enforces an addition window of 45–60 min at 0–5 °C, monitored by in‑line FTIR for carbonyl conversion and validated against Off‑Line UPLC impurity profiles. Compliance: the entire synthesis train falls under ICH Q7 GMP for active pharmaceutical ingredients; residual solvent limits (dichloromethane ≤ 600 ppm) adhere to ICH Q3C Class 2 thresholds; elemental impurities are managed per ICH Q3D risk assessment. The final product is a sterile crystalline powder meeting USP monographs and Ph. Eur. 7.0, with no single 2‑aminothiazole‑related substance above 0.10 %.Why Does Ceftriaxone Coupling Demand Strict Anhydrous Conditions?In the downstream synthesis of Ceftriaxone Sodium, the same active ester MAEM interacts with 7‑amino‑3‑[(2,5‑dihydro‑6‑hydroxy‑2‑methyl‑5‑oxo‑1,2,4‑triazin‑3‑yl)thio]methyl cephalosporanic acid (7‑ACT). The prescribed charge ratio of MAEM to 7‑ACT is 1.15–1.30 on a mole basis; overdosing beyond 1.35 leads to di‑acylated by‑products that co‑precipitate with the antibiotic and elevate total impurities above the USP <621> acceptance threshold. The acylation is performed in dimethylacetamide (DMAc) with a water content strictly below 0.05 % (Karl Fischer), because adventitious moisture hydrolyzes the active ester and generates free 2‑aminothiazoleacetic acid, which subsequently forms a poorly soluble calcium salt during the downstream aqueous work‑up—a chronic fouling problem documented in multi‑purpose plants using the same equipment for calcium‑salt precipitation. Plant‑scale controls include nitrogen‑blanketed solvent delivery and in‑situ moisture monitoring with a NIR immersion probe. Post‑acylation, the triazine‑dione ring is constructed via carbonyldiimidazole (CDI)‑mediated cyclization at 20–25 °C over 4 h; deviation outside this interval causes incomplete ring closure, leaving residual hydrazino intermediates that must be tracked by a dedicated HPLC method (LOD 0.03 %). Regulatory references: ICH M7 for mutagenic impurities (hydrazine derivatives), EU GMP Annex 15 for process validation, and compliance with the Ph. Eur. 2.5.32 sub‑visible particle specification after sterile filling. The terminal product is a dry‑powder injectable Ceftriaxone Sodium conforming to USP 43‑NF 38 and supplied as a 10 g or 250 mg vial fill.Oximation Kinetics of the Ceftazidime Side ChainProduction of Ceftazidime pentahydrate requires conversion of Ethyl 2‑Amino‑4‑Thiazoleacetate into the (Z)‑2‑(2‑aminothiazol‑4‑yl)‑2‑methoxyiminoacetic acid (ATMAA) side‑chain precursor. The process sequence begins with alkaline hydrolysis of the ester to the free 2‑aminothiazoleacetic acid, followed by oximation with O‑methylhydroxylamine hydrochloride under strictly controlled pH (4.8–5.2) and temperature (45–50 °C). Plant data show that at pH < 4.5 the Z‑isomer purity drops below 98.5 %, forcing a subsequent recrystallization from methanol/water to meet the 99.5 % Z‑isomer requirement of the downstream coupling. The molar ratio of Ethyl 2‑Amino‑4‑Thiazoleacetate (calculated as free acid equivalent) to the oximation reagent is 1.00 : 1.05–1.10; excess reagent is quenched with acetone and the resultant oxime assayed by potentiometric titration against NaOH 0.1 N. The isolated ATMAA is activated as a mixed anhydride with pivaloyl chloride in N‑methylpyrrolidone at ‑10 ± 2 °C and coupled to 7‑amino‑3‑(1‑pyridiniomethyl)cephalosporanic acid dihydrochloride. This coupling step suffers a documented process sensitivity: the activated anhydride half‑life is ≤ 8 min at ‑5 °C, requiring dosing pumps with ±1 % accuracy and short transfer lines to avoid dead‑volume degradation. Regulatory framework: ICH Q11 for starting material justification, ICH Q3A for unspecified impurity thresholds, and EP 2.2.25 for related substances via UV‑HPLC. The drug substance is released as Ceftazidime pentahydrate blended with 10 % sodium carbonate for injectable formulations.Acylation Window Conflicts in Cefodizime SodiumWhen Ethyl 2‑Amino‑4‑Thiazoleacetate is converted into the reactive thioester (DMAT‑SMe) for Cefodizime synthesis, the acylation of the protected 7‑amino‑3‑(5‑carboxymethyl‑4‑methyl‑thiazol‑2‑ylthiomethyl)‑cephalosporanic acid core faces a narrow processing window caused by the low solubility of the core in methylene chloride. Industrial development reports indicate that the optimum molar excess of the active thioester over the core is 1.05–1.15; higher ratios generate an intractable emulsion during the aqueous sodium bicarbonate wash. The reaction is run in a CH₂Cl₂/MeOH (9 : 1) mixture with 1.2 eq of N,O‑bis(trimethylsilyl)acetamide as an in‑situ silylating agent to maintain dissolution; silylation efficiency drops sharply if the reactor moisture exceeds 300 ppm—a limit verified by on‑line hygrometers. Process deviations in the 15–20 °C range are tolerated only ±3 °C before the formation of the Δ²‑isomer surpasses 0.8 %. Downstream, the O‑demethylation with aluminium chloride‑anisole is quenched by pouring the reaction mass into ice‑cold 2 N HCl; incorrect quenching rates lead to a gelatinous aluminium hydroxide precipitate that blocks the centrifuge drain lines—a recurrent bottleneck cited in plant debottlenecking studies. Standards invoked: 21 CFR 211 for finished pharmaceuticals when the sodium salt is lyophilized, ICH Q3D for aluminium residual analysis, and Ph. Eur. 5.1.4 for microbiological quality of non‑sterile intermediates before terminal sterilization. The final dosage form is a sterile dry powder for reconstitution.Heavy demand for low‑cost agrochemical thiazole building blocks has driven the adaptation of Ethyl 2‑Amino‑4‑Thiazoleacetate into a commercial intermediate for the systemic fungicide Ethaboxam (ISO 1750). In a dedicated multipurpose chemical plant operating under OECD GLP, the ester is first saponified to 2‑amino‑4‑thiazolecarboxylic acid with aqueous NaOH (2 N) at 80 °C; the acid is converted in the same vessel to the acid chloride by treatment with thionyl chloride (1.3 eq) in toluene at 60 °C. The charge ratio of Ethyl 2‑Amino‑4‑Thiazoleacetate (fed as a 95 %‑purity industrial‑grade liquid) to the downstream chiral amine coupling partner is 1.00 : 0.98, with the slight excess of acid chloride compensating for hydrolysis during amide bond formation in an aqueous‑organic biphase. Typical batch-scale issues involve the presence of 0.3–0.5 % dimeric impurity arising from self‑condensation of the acid chloride; this is suppressed by maintaining the toluene solution at ≤ 10 °C and employing loop‑reactor technology with a 10 s residence time in the heat exchanger. The raw amide is purified by recrystallization from isopropanol/water (70 : 30 v/v) and the crystal habit is carefully controlled by a linear cooling rate of 0.2 °C/min to ensure particle size D₅₀ 200–300 µm, essential for formulation grinding. Regulatory compliance: FAO Specification 508/TC for technical material, EPA 40 CFR Part 158 residue chemistry studies, and EU Regulation (EC) 396/2005 maximum residue limits. The final article is Ethaboxam technical concentrate (≥ 97 % purity) packaged in 25 kg fibre drums.Disperse‑dye manufacturers leverage the heterocyclic amine functionality of Ethyl 2‑Amino‑4‑Thiazoleacetate as a diazo component for high‑washfastness monoazo dyes applied to polyester‑microfibre automotive upholstery. In a typical campaign in a 5,000 L jacketed glass‑lined diazotization unit, the ethyl ester (diazo feedstock) is dissolved in 82 % sulfuric acid and diazotized with 40 % sodium nitrite solution at ‑5 to 0 °C over 2 h. The molar ratio of diazo component to coupling component—commonly N‑ethyl‑N‑(2‑cyanoethyl)aniline or a related dialkylamino‑acetaniline—is controlled at 1.00 : 0.99 to avoid excess unreacted coupler that would generate effluent color loadings above ADMI 500. The coupling step is carried out at pH 2.0–2.5, maintained by glacial acetic acid buffer, and the resulting crude dye cake is filtered through a plate‑and‑frame filter press and washed until the filtrate conductivity is < 50 µS/cm. Drying in a fluidized‑bed dryer at 80 °C lowers moisture to < 0.5 %. Finished dyes formulated with this intermediate typically achieve a polyester fastness to light of 6–7 (ISO 105‑B02) and sublimation fastness of ≥ 4 (ISO 105‑P01). Compliance obligations include the OEKO‑TEX Standard 100 Annex 6 restricted substances list, ZDHC MRSL v3.1 for dyeing auxiliaries, and ECHA REACH registration obligations (> 1 t/a tonnage band). The output is a commercial monoazo disperse dye supplied as a press cake or spray‑dried powder in the red‑to‑rubine shade zone.When the Ester Group Survives: Polymer‑Bound Thiazole ModifiersIn a niche but industrially validated segment, Ethyl 2‑Amino‑4‑Thiazoleacetate is polymerized via ring‑opening of the thiazole ring or used as an end‑capping agent for polyester‑urethane prepolymers. The ester entity reacts selectively with terminal hydroxyl groups on polyethylene glycol (PEG‑4000) under titanium tetrabutoxide catalysis (0.1 wt%) at 150 °C melt conditions, yielding a polymeric thiazole‑end‑capped hydrophilic segment. The charge stoichiometry is fixed at 1.0 mol ethyl ester per 1.0 eq of terminal ‑OH, corresponding to a 2.3 wt% loading relative to the PEG backbone; higher loadings (≥ 3.5 wt%) result in phase separation and a build‑up of unreacted yellow monomer on the reactor walls, observable in batch vacuum‑melt polycondensation units with 30 L helical‑ribbon agitators. The modified prepolymer is subsequently chain‑extended with 1,6‑hexamethylene diisocyanate (HDI) in a twin‑screw extruder (ZSK‑30, L/D = 44) to produce a thermoplastic polyurethane (TPU) exhibiting enhanced adhesion to polyamide‑6,6 fabrics. Peel‑strength values measured according to ISO 11339:2022 increase from 5 N/25 mm for an unmodified TPU to 12 N/25 mm at a 2.3 wt% thiazole modifier content. The process must rigorously exclude amines, as unintended secondary‑amine formation with the aminothiazole ring triggers premature chain termination and reduces Shore A hardness below specification. Regulatory references: EU 10/2011 for food‑contact migration testing (if applicable), ISO 10993‑5 cytotoxicity for medical‑device‑grade TPU, and FDA 21 CFR 177.1680 for indirect food additives. The final commercial form is a pelletized, thiazole‑functionalized TPU with a hardness of 85 ± 2 Shore A.
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| Attribute | Ethyl Ester (This Product) | Methyl Ester | Benzyl Ester |
|---|---|---|---|
| Melting range (°C) | 91–94 | 79–82 (softens with decomposition) | 54–57 (waxy solid) |
| Solubility in DMF at 25 °C (g·L⁻¹) | >60 | >80 | >100 |
| Hydrolytic stability (t½, phosphate buffer pH 7.4, 37 °C) | ~48 h | ~22 h | ~8 h (autocatalytic due to benzyl alcohol release) |
| By-product risk during acyl chloride formation | Ethyl chloride (Bp 12.3 °C, easily vented) | Methyl chloride (Bp ‑23.7 °C, requires cryogenic scrubber) | Benzyl chloride (lachrymator, Bp 179 °C, requires dedicated scrubbing) |
| Typical assay of commercial material (%) | ≥99.0 | ≥98.5 | ≥97.0 (due to residual benzyl alcohol) |
| Parameter | Acceptance Criterion | Analytical Procedure |
|---|---|---|
| Appearance | Off-white to pale yellow crystalline powder | Visual inspection (Ph. Eur. 2.2.1) |
| Assay (anhydrous, solvent-free basis) | 98.5–101.5% | HPLC, external standard; column: C18, 5 µm; mobile phase: acetonitrile/water/trifluoroacetic acid (40:60:0.1 v/v/v); detection at 254 nm. Method validated per ICH Q2(R1) with LOD 0.02%, LOQ 0.05%. |
| Water content | ≤ 0.5% | Karl Fischer coulometric titration (USP <921> Method Ic) |
| Residual solvents (acetone, ethyl acetate, ethanol) | Acetone ≤ 5000 ppm; Ethyl acetate ≤ 5000 ppm; Ethanol ≤ 5000 ppm | Headspace GC-FID, column DB-624 (30 m × 0.32 mm, 1.8 µm); quantification per ICH Q3C option 1 limits. |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14, residue on ignition at 600 ± 50 °C |
| Heavy metals (as Pb) | ≤ 10 ppm | ICP-MS, Ph. Eur. 2.4.20, Method II |
| Individual specified impurity (2,4-diaminothiazole isomer) | ≤ 0.3% | Same HPLC method as assay, RRT 0.87 |
| Total unspecified impurities | ≤ 0.5% | Same HPLC method |
