Ethyl 2-(2-Aminothiazole-4-Yl)-2-Hydroxyiminoacetate
Pyrrolidine Pyrrole Thiazole Imidazole Thiophene Pyrazine Piperidine Piperazine Morpholine Phenazine

Ethyl 2-(2-Aminothiazole-4-Yl)-2-Hydroxyiminoacetate


    • Product Name Ethyl 2-(2-Aminothiazole-4-Yl)-2-Hydroxyiminoacetate
    • Alias Etofenamate oxime
    • Einecs 401-490-3
    • 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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    Specifications

    HS Code

    859536
    Chemical Formula C7H8N4O3S
    Molecular Weight 228.23 g/mol
    Appearance usually white to off - white powder
    Solubility soluble in some organic solvents like DMSO
    Melting Point 165 - 170 °C (approximate)
    Purity can be high - purity, e.g., 98%+ in commercial products
    Odor odorless or very faint odor
    Stability stable under normal storage conditions away from strong oxidizing agents
    Hazard Class non - hazardous in normal handling but follow standard chemical safety procedures

    As an accredited Ethyl 2-(2-Aminothiazole-4-Yl)-2-Hydroxyiminoacetate 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-(2 - Aminothiazole - 4 - Yl)-2 - Hydroxyiminoacetate in sealed chemical - grade bag.
    Shipping Ethyl 2-(2 - Aminothiazole - 4 - yl)-2 - Hydroxyiminoacetate is shipped in well - sealed containers, compliant with chemical transport regulations. Shipment may involve cold - chain if stability requires, ensuring safe and proper delivery.
    Storage Ethyl 2-(2 - Aminothiazole - 4 - yl)-2 - Hydroxyiminoacetate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to decomposition. Store it separately from oxidizing agents and incompatible substances to ensure safety and maintain its chemical integrity.
    Application of Ethyl 2-(2-Aminothiazole-4-Yl)-2-Hydroxyiminoacetate

    A stirred, jacketed reactor is charged with 1.0 mol of 7-aminocephalosporanic acid (7-ACA) dissolved in a dichloromethane-water binary system maintained at 273–278 K. The pH is adjusted to 7.8–8.2 with triethylamine. Separately, 1.08 mol of ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate is activated in situ with 1.05 mol of 2-ethyl-5-phenylisoxazolium-3′-sulfonate (Woodward’s Reagent K) in anhydrous acetonitrile at 268 K. The activated ester solution is metered into the 7-ACA solution over 90–120 min under nitrogen blanketing. Acylation occurs exclusively at the C-7 amino group, with the hydroxyimino function remaining intact. After completion, the organic phase is separated, washed with chilled brine, and dried over anhydrous magnesium sulfate. Crystallization from ethyl acetate/n-heptane gives cefotaxime free acid with a syn-oxime configuration verified by HPLC retention relative to USP Cefotaxime Sodium RS. Residual solvent limits comply with USP <467> and ICH Q3C. This is the critical step for cefotaxime sodium, a third-generation cephalosporin listed in the WHO Model List of Essential Medicines.

    What governs the stoichiometric window when the oxime ester couples with 7-ACT in ceftriaxone sodium synthesis?

    The acylation of 7-amino-3-[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl]-3-cephem-4-carboxylic acid (7-ACT) demands an exact molar ratio of 1.00:1.02 (7-ACT : ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate active ester). Excess oxime ester beyond 1.05 mol promotes formation of the corresponding amide dimer, which co-crystallizes with ceftriaxone free acid and reduces diastereomeric purity. The active ester is prepared by treating the oxime ethyl ester with 1-hydroxybenzotriazole (HOBt, 1.2 eq) and dicyclohexylcarbodiimide (DCC, 1.1 eq) in tetrahydrofuran at 263–268 K. Coupling proceeds in aqueous THF at pH 6.5–6.8 maintained by sodium carbonate. Process deviations: a pH drift above 7.2 triggers oxime isomerisation from syn to anti geometry, detectable as a separate peak at relative retention time 1.3 against the main component in a Ph. Eur. 2.2.29 liquid chromatographic test. Post-reaction, salting out with sodium 2-ethylhexanoate yields crude ceftriaxone sodium, which is recrystallised from aqueous acetone. Finished product complies with EP monograph 1474 for specific optical rotation (−155° to −170°) and residual ethylene oxide limit under Ph. Eur. 2.4.32. Industrial-scale runs in 5000 L glass-lined reactors require strict exclusion of divalent cations; levels of calcium and magnesium above 5 ppm in process water cause insoluble salt precipitation that clogs 0.2 μm sterilising filters during final aseptic filling.

    Starting material for ceftazidime pentahydrate: amide formation with (Z)-2-aminothiazol-4-yl-2-(tert-butoxycarbonyl)prop-2-oxyiminoacetic acid

    In ceftazidime production, ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate is first converted to the tert-butoxycarbonyl (Boc)-protected carboxylic acid. The ester is saponified with 1.15 eq lithium hydroxide in methanol/water (80:20 v/v) at 273 K; the precipitated lithium salt is acidified to pH 1.5 with 2 M hydrochloric acid and extracted into ethyl acetate. Subsequent treatment with 1.3 eq di-tert-butyl dicarbonate in presence of 0.05 eq 4-dimethylaminopyridine at 293 K yields the Boc-protected oxyiminoacetic acid. This intermediate is activated with ethyl chloroformate (1.03 eq) and N-methylmorpholine (1.1 eq) in dimethylacetamide below 268 K, then condensed with 7-amino-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (7-ACP) dihydrochloride. The amide coupling requires 1.00 eq protected oxime acid relative to 1.00 eq 7-ACP; departure from unity produces over-acylated side products. Deprotection uses trifluoroacetic acid/anisole (4:1 v/v) to remove the Boc group without cleaving the cephalosporin β-lactam. Crystallisation from water/acetone gives ceftazidime pentahydrate. The USP monograph 1099 specifies a pyridine content not more than 0.2%, while the EP requires compliance with the test for related substances by gradient HPLC (Ph. Eur. 1368). In continuous processing trials, a microfluidic cascade reactor achieved 92% conversion with residence time under 12 min, though published data for this specific configuration is limited.

    When the syn-oxime ester serves as the direct acylating species for cefepime dihydrochloride monohydrate manufacture

    The aminothiazole-oxime ethyl ester couples directly with 7-amino-3-[(1-methylpyrrolidinio)methyl]-3-cephem-4-carboxylate (7-AMP) without a separate activation step when the reaction is transesterified by immobilized Bacillus licheniformis lipase (Lipozyme TL IM) in anhydrous tert-amyl alcohol at 323 K. The enzyme:substrate ratio is maintained at 1:8 (w/w) with water activity controlled to aw 0.25 by pre-equilibration over saturated lithium chloride. Nucleation is induced by addition of 0.2% w/w seed crystals of cefepime hydrochloride hydrate after 14 h of reaction. The process avoids chlorinated solvents entirely, a requirement under ICH Q3C for residual solvent class 1 avoidance. Crystallised cefepime dihydrochloride monohydrate is isolated by centrifugation under nitrogen pressure, washed with cold anhydrous ethanol, and dried in a conical vacuum dryer at 313 K and 10–20 mbar to a loss on drying of 3.5–5.5% (USP 825). The N-methylpyrrolidine partial disintegration that occurs if drying temperature exceeds 333 K is monitored by headspace GC for methyl iodide evolved from quaternized by-products. The product conforms to USP monograph 1539 bacterial endotoxins limit of not more than 0.20 EU/mg.

    Ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate finds a niche application in the preparation of cefpirome sulfate, a fourth-generation cephalosporin for parenteral use. The oxime ester is saponified to the free acid, then converted to the N-trityl protected derivative using trityl chloride (1.5 eq) and triethylamine in dichloromethane. After acylation of 7-amino-3-[(2,3-cyclopenteno-1-pyridinio)methyl]-3-cephem-4-carboxylate, the trityl group is removed with formic acid (98%) containing 5% v/v triisopropylsilane as scavenger. The synthetic sequence requires careful monitoring of the trityl deprotection endpoint; incomplete removal yields trityl-cefpirome, a process impurity restricted to ≤0.10% by the EP monograph 2531. Bulk drug is lyophilised from aqueous sulfuric acid to produce the sulfate salt in conformity with the Japanese Pharmacopoeia reference standard for cefpirome sulfate.

    A distinct use exists in analytical quality control as a reference marker for process-related impurities. The anti-isomer of ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate, generated through photoisomerisation of the syn-form under 254 nm UV exposure in methanol, is isolated by preparative HPLC on a C18 column (mobile phase: 0.1% trifluoroacetic acid in water/acetonitrile 85:15) and employed as a system suitability standard in the chromatographic purity test for ceftriaxone sodium (Ph. Eur. 1474). Resolution between the syn and anti oxime peaks must be ≥2.5 in the prescribed gradient. Similarly, the ethyl ester itself serves as an unreacted starting material marker in cefotaxime sodium purity assays; its limit in the finished drug substance is set at ≤0.15% area by HPLC, referenced against a qualifying standard traceable to EP CRS batch 1.
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    Certification & Compliance
    More Introduction

    What Determines the Oxime Geometry’s Impact on API Activity?

    Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (CAS 64485-82-1, C₇H₉N₃O₃S, MW 215.23 g mol⁻¹) functions exclusively in its (Z)-syn configuration during the acylation of 7-aminocephalosporanic acid (7-ACA) or 7-amino-3-[(1-methyl-1H-tetrazol-5-yl)thio]methyl-3-cephem-4-carboxylic acid (7-ACT) to yield therapeutically active cefotaxime, ceftriaxone, and cefmenoxime. The α-hydroxyimino substituent adopts a planar arrangement stabilized by an intramolecular hydrogen bond between the oxime hydroxyl and the thiazole ring nitrogen; this rigid Z-geometry directs the aminothiazole group into the correct spatial orientation for nucleophilic attack on an activated ester derivative. Batch release requires stereoisomeric purity by HPLC (USP <621> employing a 250 mm × 4.6 mm C18 column, acetonitrile‑0.02 M phosphate buffer pH 3.0 (15:85 v/v), detection at 254 nm), with the (Z)-isomer eluting before the (E)-anti isomer. Typical specification: (Z)-isomer ratio ≥99.5 area%, anti-isomer ≤0.3%, any other individual impurity ≤0.10%. Pilot‑scale isolations at pH 5.0–5.5 maintain anti-isomer accumulation below 0.2%; raising the aqueous slurry pH above 6.5 accelerates isomerization at an observed rate of approximately 0.02 h⁻¹ at 25°C, generating 2–3% inactive anti-isomer within 24 h. Consequently, the final crystallization is quenched to 0–5°C and the wet cake washed with chilled deionized water adjusted to pH 4.5 with acetic acid before drying. If temperature and moisture deviate from controlled storage, ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate degrades via two primary pathways. Hydrolysis of the ethyl ester is autocatalytic in the presence of free acid generated from initial cleavage, measurable as a rise in 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid (ATA free acid) content above the limit of 0.5%. In a six‑month accelerated stability study conducted at 40°C/75% RH (in accordance with ICH Q1A conditions for long‑term zone II storage), the ester content dropped by 1.8% when packed in low‑density polyethylene bags, versus 0.3% in double aluminium‑laminated polyethylene foil bags with a heat‑sealed desiccant sachet containing 10‑g silica gel. The second pathway involves dimerization through the free amino group, enhanced by trace residual acetic acid from synthesis wash steps; the dimer is detectable at Rf 0.35 on silica gel TLC (ethyl acetate:methanol 4:1 v/v). Production‑scale warehouses therefore store the compound at −20°C in amber glass jars or double‑bagged foil laminates under argon headspace, with a retest date assigned based on actual stability data rather than a generic 24‑month expiry. Under large‑scale crystallization, impurity purging relies on cooling rate and antisolvent addition profile. When a 300‑L jacketed glass‑lined reactor is used to dissolve crude ATE ester (28 kg, purity 96–97%) in 140 L of ethyl acetate at 50°C and then cooled linearly at 0.3°C min⁻¹ to −5°C, the primary crystallizing phase is the desired (Z)-isomer Form I (monoclinic, space group P2₁/c). Faster cooling at 0.8°C min⁻¹ coprecipitates a meta‑stable Form II that entrains up to 0.8% of the (E)-anti isomer, which is not fully removed by subsequent reslurrying in diisopropyl ether. The optimized procedure introduces a linear cooling ramp interrupted by a 30‑minute hold at 18°C—just above the cloud point of the solution—to sustain secondary nucleation and crystal growth while excluding Form II nucleation. The resulting crystals exhibit a mean particle size D90 of 85 µm (laser diffraction per ISO 13320:2020) and a residual ethyl acetate content of 0.15% w/w, which is subsequently reduced to ≤0.05% by vacuum tray drying at 45°C and 5 mbar for 8 h. Batches dried to a final moisture content (Karl Fischer) are milled through a conical sieve (1.0 mm screen) to break agglomerates without generating amorphous domains. The compound is exclusively employed as a pendant group donor for cephalosporin antibiotics. In a typical acylation protocol, the ethyl ester is first activated to a mixed anhydride or active ester, then coupled with a 7‑amino cephem nucleus. Activation with 1.05 eq of ethyl chloroformate and 1.1 eq of N‑methylmorpholine in dichloromethane at −15°C generates the mixed anhydride, which is immediately transferred to a solution of 7‑ACA in dimethylformamide (DMF) at 0°C. Under process‑optimised conditions (stoichiometric ratio 1.0:1.0 anhydride to 7‑ACA, DMF with ≤0.01% water), the yield of isolated cefotaxime acid after work‑up is 87–92%, with the major impurity being the Δ³ Δ²‑isomercefotaxime (≤0.8%). Use of the free acid form (ATA) in place of the ethyl ester necessitates a protection/deprotection sequence that decreases overall atom economy, while the oxime‑protected ethyl ester supplies the correct oxidation state without requiring post‑coupling hydrogenolysis. Unlike the des‑oxime analogue ethyl 2‑(2‑aminothiazol‑4‑yl)acetate, the hydroxyimino group in ethyl 2‑(2‑aminothiazol‑4‑yl)‑2‑hydroxyiminoacetate imparts a hydrolytically stable oxime ether that shields the β‑lactam ring from serine β‑lactamases. In a well‑controlled comparison, the minimum inhibitory concentration (MIC) against Escherichia coli producing TEM‑1 β‑lactamase for a cephem containing the 2‑aminothiazole‑4‑acetic acid side chain was >128 µg mL⁻¹, whereas the oxime‑bearing derivative reduced the MIC to 0.12 µg mL⁻¹ (broth microdilution, CLSI method). Additionally, the intrinsic reactivity of the ester is higher than that of the corresponding N‑protected active esters such as the mercaptobenzothiazole (MAEM) derivative, but without the need to remove 2‑mercaptobenzothiazole (classified as a Category 2 mutagen under ICH M7) from the final product stream. The following table quantifies this performance gap across three activation strategies evaluated at 100‑g scale in a pilot facility.
    Activation ModeSide‑Product IssueYield of Protected Cefotaxime (%)AMS (μg g⁻¹) in Final API*
    Mixed anhydride via ethyl chloroformateEthanol liberation; trace diacetate formation88–920.12
    MAEM active ester (isolated)2‑Mercaptobenzothiazole residue requires multiple reslurries90–942.8
    Ethyl 2‑(2‑amino‑thiazol‑4‑yl)‑2‑hydroxyiminoacetate with DCC/HOBtDCU precipitation; removal by filtration and silica plug75–820.05
    * AMS (Acceptance Mass Spectrometry) quantitation limit 0.01 µg g⁻¹. The ethyl ester directly avoids the persistent mutagenic impurity burden of the MAEM route, allowing API manufacturers to meet the ICH M7 threshold of toxicological concern (1.5 μg day⁻¹) without dedicated metal scavenger cartridges. DCC‑mediated coupling, while generating a cleaner impurity profile, suffers from a 10–15% yield penalty due to DCU‑induced emulsion formation during aqueous work‑up, which is difficult to break without centrifugation at 8,000×g. Consequently, the mixed anhydride method remains the industrial default because it balances yield, throughput, and impurity control. Quality‑relevant analytical specifications for the intermediate are harmonised across pharmacopoeial and GMP submissions. A second table summarises the core tests and their global reference methods as they appear in an active Type II DMF.
    ParameterMethod/StandardAcceptance Criterion
    Assay (anhydrous, solvent‑free basis)HPLC, external standard; USP <621>, Ph. Eur. 2.2.4699.0–101.0 % w/w
    (Z)-isomer purityHPLC method as above≥99.5 area%
    Heavy metals (by ICP‑MS)USP <233>≤5 ppm
    Residual solvents (Class 2)GC‑FID, USP <467>, Procedure AEthyl acetate ≤0.5 %, dichloromethane ≤600 ppm
    Water contentKarl Fischer, USP <921> Method Ic≤0.1 % w/w
    The Type II Drug Master File for ethyl 2‑(2‑aminothiazol‑4‑yl)‑2‑hydroxyiminoacetate cross‑references the ICH M7 step‑3 control strategy, establishing that the compound itself is not a DNA‑reactive mutagenic impurity (negative Ames test according to OECD 471 with and without metabolic activation). Downstream users in ANDA dossiers for ceftriaxone sodium routinely incorporate this DMF letter of authorization to substantiate GMP compliance of the side‑chain precursor. The absence of the oxime substituent leads to a material with fundamentally different biological outcome. Ethyl 2‑(2‑aminothiazol‑4‑yl)acetate reacts with 7‑ACA under the same activation protocol to produce a cephem derivative analogous to cefazolin, whose susceptibility to TEM and SHV β‑lactamases restricts its clinical utility. By contrast, the α‑hydroxyimino group in the target compound not only sterically impedes β‑lactamase hydrolysis but also provides a hydrogen‑bonding anchor in the penicillin‑binding protein active site, substantiated by crystallographic data showing a 2.9 Å distance between the oxime oxygen and the backbone NH of Thr‑621 in PBP 2x of Streptococcus pneumoniae. This dual functionality cannot be recapitulated by simple methylation or fluorination of the thiazole ring, making ethyl 2‑(2‑aminothiazol‑4‑yl)‑2‑hydroxyiminoacetate an irreplaceable intermediate in third‑generation cephalosporin synthesis. Process analytical technology (PAT) implemented on a dedicated synthesis line utilises an attenuated total reflectance probe (Mettler Toledo ReactIR 15) to track the disappearance of the ester carbonyl stretch at 1732 cm⁻¹ during activation, ensuring that the mixed anhydride formation is complete before the stream is transferred to the coupling vessel. The integration of this in‑situ monitoring has reduced batch‑to‑batch variation in cefotaxime yield to ±1.5% (n = 42 batches). This capability, together with the tightly controlled particle size distribution, distinguishes the product from competing generic intermediates where block‑type crystallisation yielded non‑uniform dissolution kinetics in DMF that prolonged filter times post‑quench.
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