2-Aminothiazole-4-Carboxylate
|
HS Code |
687508 |
| Chemical Formula | C4H4N2O2S |
| Molar Mass | 144.15 g/mol |
| Appearance | Solid |
| Melting Point | Typically in a certain range (varies by derivative) |
| Solubility In Water | Low to moderate depending on substitution |
| Pka | Relevant acidic or basic pKa values depending on groups |
| Density | Varies based on form and purity |
| Stability | Stable under normal conditions, but may react with strong oxidants etc. |
| Color | Often white or off - white |
| Odor | Odorless or with a faint characteristic smell |
As an accredited 2-Aminothiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Aminothiazole - 4 - Carboxylate packaged in a sealed, labeled container. |
| Shipping | 2 - Aminothiazole - 4 - Carboxylate is shipped in well - sealed, corrosion - resistant containers. Special handling per safety regulations is ensured, with appropriate labeling for its chemical nature. Transport is via approved carriers for hazardous chemicals. |
| Storage | 2 - Aminothiazole - 4 - Carboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances, such as strong oxidizing agents or acids, to avoid potential chemical reactions. Regularly check storage conditions for integrity. |
When Parenteral Cephalosporin APIs Demand Sub-ppm Endotoxin ControlIn the synthesis of third‑generation injectable cephalosporins such as cefodizime sodium and ceftriaxone, the Z‑(2‑aminothiazol‑4‑yl)‑2‑methoxyiminoacetyl side chain requires a precursor with endotoxin levels consistently below 0.015 EU/mg and bioburden not exceeding 10 CFU/g. The manufacturing route begins with ethyl 2‑aminothiazole‑4‑carboxylate, which first undergoes alkaline hydrolysis in an aqueous‑methanolic sodium hydroxide solution at 35–40 °C over 2.5 –3.0 h in a nitrogen‑blanketed glass‑lined reactor to yield the free carboxylic acid. After pH adjustment to 2.8–3.1 with hydrochloric acid and isolation via a centrifuge, the 2‑aminothiazole‑4‑carboxylic acid is suspended in dimethylacetamide and reacted with methoxyamine hydrochloride at a molar ratio of ester‑equivalent acid to methoxyamine salt of 1 : 1.15, using triethylamine as a proton scavenger. The oxime formation is maintained at 58–62 °C for 6–8 h with continuous monitoring of the conversion by reverse‑phase HPLC (detection at 254 nm, retention time shift from 3.2 min to 4.8 min on a C18 column). The resulting (Z)‑2‑(2‑aminothiazol‑4‑yl)‑2‑methoxyiminoacetic acid is then activated with 1‑hydroxybenzotriazole and N,N′‑dicyclohexylcarbodiimide in dichloromethane at −5 to 0 °C under anhydrous conditions, forming the activated ester required for acylation of the 7‑aminocephalosporanic acid mother nucleus. Scale‑up struggles typically emerge during the activation step: the DCC‑urea by‑product precipitates as a fine, filter‑clogging solid that demands a plate‑and‑frame filter press with cellulose filter aid pre‑coat of 1.5 kg/m² and a washing protocol using chilled dichloromethane to prevent residual dicyclohexylurea carry‑over beyond 0.1% into the final API intermediate.Compliance with ICH Q7 GMP guidelines for active pharmaceutical ingredients and the dedicated Ph. Eur. monograph 01/2023:2495 for cefodizime sodium drive the critical quality attributes of the amino‑thiazole ester: total aerobic microbial count ≤ 100 CFU/g, specified microorganisms absent in 25 g, bacterial endotoxins ≤ 0.3 EU/mg (pharmaceutical grade), and residual solvent limits strictly aligned with ICH Q3C (R8) Class 2 limits for methanol (3 000 ppm) and dimethylacetamide (1 090 ppm). Additionally, the reaction sequence is defined in the Drug Master File with process validation batches demonstrating that the oxidative dimerization impurity of the amino‑thiazole ring remains below 0.10 area% when the nitrogen purge rate in the reactor headspace is maintained above 2.5 L/min per 1 000 L of vessel volume. The terminal finished product manufactured from this intermediate is a sterile, lyophilized powder for intravenous infusion containing cefodizime sodium equivalent to 1.0 g of cefodizime per vial, typically used in the treatment of community‑acquired pneumonia and urinary tract infections in over 30 countries.Why Are Acid‑Labile Ester Prodrugs Driving Lyophilization‑Free Processing?Oral third‑generation cephalosporins such as cefetamet pivoxil and cefteram pivoxil rely on a prodrug strategy where the free carboxylic acid function on the cephem nucleus is masked as an acid‑labile pivoxil ester. The synthesis of the side‑chain moiety for cefetamet pivoxil uses ethyl 2‑aminothiazole‑4‑carboxylate in a sequence that avoids lyophilization by employing direct precipitation from a binary solvent system. The ester is first converted to 2‑aminothiazole‑4‑carboxylic acid through controlled alkaline saponification with 1.05 eq of sodium hydroxide in 50% v/v ethanol‑water at 25 °C, immediately followed by azeotropic distillation with toluene to remove residual ethanol, a step that prevents esterification side reactions during the subsequent active ester generation. The acid is then reacted with N‑hydroxysuccinimide and 1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimide in anhydrous acetone at 10–15 °C, using a molar ratio of amino‑thiazole acid to hydroxysuccinimide of 1 : 1.20, which consistently yields 92–95% of the isolable N‑succinimidyl 2‑aminothiazole‑4‑carboxylate after filtration and heptane trituration. A critical process deviation observed at production scale is the rapid gelation of the reaction mass when the moisture content exceeds 0.15%, requiring Karl Fischer titration checkpoints every 30 min and a zeolite‑filled drying loop in the solvent supply line.Regulatory requirements for the orally administered finished product necessitate compliance with FDA 21 CFR 170.50 for food additives if the drug substance is used in veterinary feed premixes, and the common technical document must include elemental impurity data meeting ICH Q3D (R2) Table A.2.2 limits for oral drug products, with palladium from hydrogenation catalysts controlled below 10 µg/g and nickel below 60 µg/g. The intermediate manufacturer provides a residual solvent declaration according to USP <467> Procedure A, demonstrating that methylene chloride is absent (limit 600 ppm) and that ethyl acetate from upstream crystallization is maintained below 5 000 ppm. Production‑scale processing of the amino‑thiazole ester into cefetamet pivoxil frequently encounters a batch‑to‑batch variability of ±4°C in the decomposition onset temperature of the final pivoxil ester side chain, as measured by differential scanning calorimetry at a heating rate of 10°C/min. If the thermal stability endpoint drops below 125°C, the downstream micronization for dry syrup formulation must be re‑parameterized to a jet‑mill inlet pressure below 4.2 bar to avoid degradation. The finished product types include cefetamet pivoxil hydrochloride tablets of 250 mg and 500 mg dose strengths, as well as a dry syrup for pediatric use containing 250 mg/5 mL after reconstitution, both used against respiratory and urinary tract pathogens with β‑lactamase resistance profiles.Tackling Sulfate Ash Variance in Veterinary API BatchesCefquinome sulfate, a fourth‑generation cephalosporin for veterinary use, demands an exceptionally low sulfate ash content of ≤ 0.1% in its final bulk drug, which forces stringent control of inorganic residues introduced with the intermediate ethyl 2‑aminothiazole‑4‑carboxylate. In the cefquinome synthesis route, the ester is not hydrolyzed to the free acid beforehand; instead, it is directly transamidated with the 7‑amino‑cephalosporanic acid derivative in a methanolic suspension with lithium methoxide as a catalyst, utilizing a molar ratio of methyl ester (generated from ethyl ester via transesterification in situ) to the cephem nucleus of 1 : 1.03. This condensation step runs at 30–35 °C under a dry nitrogen sweep because moisture ingress above 0.1% w/w accelerates the formation of a dimeric by‑product that co‑crystallizes with the product and elevates the total impurity profile. A significant processing bottleneck emerges during the extraction‑separation phase: the crude cefquinome free acid precipitates from the neutralized aqueous phase as a sticky gum when the jacket temperature of the reactor is not precisely ramped down at 8°C/min from 28°C to 8°C, causing agitator blade fouling in 6 000 L stainless steel vessels. This issue is mitigated by adding isopropanol (15% v/v) as a co‑solvent before pH adjustment, as published in good manufacturing practice summaries for beta‑lactam antibiotics.The veterinary regulatory environment adheres to VICH GL18 (R) for residual solvents, which mirrors ICH Q3C but imposes additional restrictions for acetone (50 mg/kg in edible tissues) when the drug is administered to food‑producing species. Intermediate quality must also conform to Ph. Eur. 10.4, 2.4.30 for monochrome HPLC purity determination, with a specification for the 2‑aminothiazole‑4‑carboxylic acid enantiomeric impurity below 0.5%, verified on a chiral‑AGP column (150 × 4.0 mm, 5 µm) with a mobile phase of phosphate buffer (pH 5.5)‑isopropanol (95:5 v/v) at 0.5 mL/min. The finished formulation is a sterile aqueous suspension for intramammary or injectable administration, containing cefquinome sulfate equivalent to 25 mg/mL of cefquinome, optimized for dairy cattle and swine with a withdrawal period of 4 days for milk and 8 days for meat, as established in the European Medicines Agency’s maximum residue limit assessment.Simultaneous amidation and hydrolysis side reactions can lead to a product with a pH of 5.8–6.2 that falls outside the acceptable range for the sterile suspension, requiring a re‑processing campaign involving re‑dissolution in 0.5 M hydrochloric acid and re‑precipitation with sodium acetate. This reprocessing adds 12–16 h to the batch lead time and increases the loss of the 2‑aminothiazole moiety by 3–5%, making it a significant cost driver for contract manufacturing organizations.The condensed‑phase oxidation potential of ethyl 2‑aminothiazole‑4‑carboxylate in aqueous hydrogen peroxide solutions was monitored in production‑scale oxidative coupling experiments for a series of thiazolo[5,4‑d]pyrimidine kinase inhibitors. While this application remains primarily within preclinical and Phase I stages, contract development organizations routinely charge the ester as the starting material for preparing the fused bicyclic core. The heterocycle assembly proceeds by reacting the ester with excess formamide, which serves both as a solvent and a cyclization agent, at a mole ratio of ester to formamide of 1 : 8 in a glass‑lined pressure reactor equipped with a Hastelloy C‑22 rupture disk set to 18 bar. The mixture is heated at 165 °C for 12–14 h until the amine absorbance at 3 350 cm⁻¹ diminishes to baseline on an in‑line ReactIR probe. This procedure directly yields 4‑aminothiazolo[5,4‑d]pyrimidine‑7‑ol, which then undergoes chlorination with phosphorus oxychloride and further derivatization to produce cellular potency against CDK4/6 targets. A safety caveat: the combination of formamide and residual moisture at high temperatures generates ammonia and carbon dioxide, which create a two‑phase gas pocket that has been linked to localized reactor wall thinning in three documented manufacturing campaigns; therefore, a pre‑drying step for the ester under vacuum at 45 °C to ≤ 0.05% water is strictly enforced before charging. Occupational exposure bands for the research‑grade intermediates are set at 30 µg/m³ on an 8‑hour time‑weighted average per an internal safety categorization according to the ISO 10993‑17 framework for extractable and leachable substance thresholds, even though the target APIs have not yet entered commercial distribution. The terminal type is an early‑phase kinase inhibitor capsule formulation dosed at 50–200 mg in micronized freebase form, supplied for dose‑escalation trials.What if the Ligand Field Strength Requires a 4‑Carboxylate Anchor Group?Iridium(III) bis(2‑phenylpyridinato)(2‑aminothiazole‑4‑carboxylate) and analogous platinum(II) phosphorescent dopants for red‑emitting organic light‑emitting diodes exploit the electron‑withdrawing character of the carboxylate group to tune the HOMO level of the emitter to approximately −5.2 to −5.4 eV. In the synthesis of Ir(III) heteroleptic complexes, ethyl 2‑aminothiazole‑4‑carboxylate is first saponified to the carboxylic acid, which then serves as an ancillary ligand in a one‑pot bridge‑splitting reaction with the chloro‑bridged dimer [(C^N)2Ir(µ‑Cl)]2. The molar addition ratio of the 2‑aminothiazole‑4‑carboxylic acid to the iridium dimer is precisely 2.20 : 1, with a slight excess of the acid to suppress scrambling of the cyclometalating phenylpyridine ligands. The reaction is carried out in anhydrous 2‑ethoxyethanol at 130 °C under argon for 20 h on a Schlenk manifold, shielded from ambient light to avoid photo‑induced isomerization of the emissive state. Purification mandates gradient sublimation in a three‑zone tube furnace with a source temperature of 290 °C and a deposition zone at 280 °C under a dynamic vacuum of 5 × 10⁻⁶ mbar; this step removes non‑emissive dimers and unreacted acid, achieving a sublimation recovery of only 45–55%, which constitutes a major material‑cost bottleneck in the kilogram‑scale procurement of the ester for this purpose.The material specification for electronic‑grade application is derived from SEMI C24-0321 for chemical reagents, with trace metal analysis by ICP‑MS requiring that iron, copper, and zinc each remain below 50 ppb, while palladium from the coupling catalyst is limited to 10 ppb. The purity is verified by bromine‑added HPLC‑MS, which indicates a peak area percentage exceeding 99.95% at 254 nm and a chloride content of < 10 ppm by combustion ion chromatography. The final product is a deep‑red amorphous powder, incorporated at 6–10 wt% into a host matrix of 4,4′‑bis(N‑carbazolyl)‑1,1′‑biphenyl for vacuum‑deposited OLED devices, which deliver an external quantum efficiency of approximately 22% at 1 000 cd/m² in bottom‑emission architectures. |
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2-Aminothiazole-4-carboxylate identifies a family of thiazole carboxylate esters and salts employed as heterocyclic intermediates in fine chemical synthesis. The most widely traded forms are the methyl ester (CAS 53118-45-9), ethyl ester (CAS 53935-44-7), and the sodium salt of the free acid (CAS 117519-14-3). Commercial bulk deliveries are offered against titrated HPLC purity specifications of ≥98.5% (area-%), with the principal process-related impurity being the ring-opened thiourea-acrylate adduct, limited to ≤0.5% by TLC-densitometry using a silica-gel 60 F₂₅₄ stationary phase. The crystalline products exhibit sharp melting transitions: the ethyl ester melts in the range 168–172°C (DSC, 10 K/min, N₂ purge), while the sodium salt dihydrate decomposes at 192–196°C. These compounds form the basis for convergent routes to cephalosporin antibiotics, fungicidal pyrazole-thiazole hybrids, and polydentate ligands for transition-metal catalysis.
The regiochemistry of the carboxylate group at the thiazole C-4 position is not an arbitrary structural choice; it directly governs the stereoelectronic alignment required for downstream acylation with methoxyiminoacetate side chains. In the production of cefditoren pivoxil and cefixime, the 2-aminothiazole-4-carboxylic acid is first converted to a mixed anhydride using pivaloyl chloride. The 4-carboxylate oxygen participates in a six-membered transition state that pre-organizes the nucleophilic 2-amino group for attack on the activated acyl carbon, yielding the critical syn-oxime intermediate with diastereomeric excess typically ≥98% when the internal temperature is maintained at −10 ± 2°C. By contrast, the isomeric 2-aminothiazole-5-carboxylate forces a seven-membered cyclic transition state that reduces coupling yield by 40–60% under the same pH-stat conditions of 7.5–8.0 (phosphate buffer, 50 mM ionic strength).
Process-scale execution of this mixed-anhydride coupling is conducted in glass-lined reactors of 2,000–4,000 L capacity equipped with pitched-blade turbine agitation. The generation of the anhydride is exothermic to 85–95 kJ/mol; pivaloyl chloride is metered at a rate limited by jacket heat-transfer capacity of 350–400 W/m²·K to hold the batch below −5°C. A deviation above −3°C during the addition window of 45–60 minutes triggers E/Z isomerisation of the oxime ether, collapsing the diastereomeric purity to <80% and necessitating a costly rework via trituration in cold isopropyl ether. The synthesis therefore relies on a 4-carboxylate topology for both kinetic and thermodynamic control over the stereochemical outcome.
The ethyl ester is isolated as a white to off-white crystalline solid with a residual ethanol concentration typically below 120 ppm as measured by headspace GC-FID according to USP ⟨467⟩ Procedure A. Dynamic vapor sorption analysis at 25°C and 60% RH records a mass uptake of less than 0.15% over 24 h, confirming that the material may be weighed and transferred in an ISO Class 8 cleanroom without pre-drying. The sodium salt dihydrate, in contrast, is deliquescent. Karl Fischer titration (ASTM E203) gives water content in the range 11.5–13.0 wt% for a freshly opened container; exposure to ambient air at 55% RH for 4 h raises the water content to ≥15.8%, shifting the stoichiometric base for subsequent amide formations. To preserve batch-to-batch uniformity, the sodium salt is double-bagged under argon with silica-gel sachets and recommended for use within 72 h of opening.
When a C-4 carboxylate exhibits esterification exotherms that escalate faster than 2°C/min, the reactor control philosophy must shift from jacket-temperature cascade to direct mass-flow limitation of the acid chloride feed. Industrial esterification of 2-aminothiazole-4-carboxylic acid with thionyl chloride in anhydrous methanol has an adiabatic temperature rise calculated from a reaction enthalpy of –120 kJ/mol that can drive a 1,500 L batch from 25°C to 82°C within 7–9 min in the event of cooling failure. To operate safely, the semi-batch protocol meters SOCl₂ at 6–10 kg/h while holding the internal temperature at 30 ± 2°C via jacket circulation of −5°C brine at 120 L/min. The condenser train is rated for a peak gas load of 15 m³/h of HCl/SO₂ and is scrubbed with 10% NaOH to a maximum exit concentration of 1 ppm HCl, per DIN EN 14432 tank vent scrubbing performance criteria. In-situ FTIR monitoring tracks the free-acid carbonyl stretch at 1,690 cm⁻¹; the reaction endpoint is defined as the moment when the integrated absorbance drops to ≤1.5% of the baseline-corrected initial value, at which point quench with 5% ammonium hydroxide solution is initiated within 30 s to prevent over-esterification to the methyl ester hydrochloride dimer.
The electron-withdrawing ester group at C-4 strongly deactivates the thiazole ring toward electrophilic substitution at C-5, leaving the 5-position available for selective halogenation or nitration when desired. In the 5-carboxylate regioisomer, substitution is forced onto the sterically hindered C-4 site, lowering the isolated yield of 4-bromo-2-aminothiazole-5-carboxylate by 30–35% compared with the corresponding 5-bromo derivative obtained from the 4-carboxylate precursor under identical conditions (NBS, DMF, 0°C → room temperature, 6 h). Furthermore, 2-amino-4-methylthiazole lacks the polar carboxylate handle required for aqueous-phase peptide-type coupling; its hydrophobicity (log P +1.2) limits its utility in active pharmaceutical ingredient (API) synthetic sequences where intermediate isolation relies on pH-switched extraction. The 4-carboxylate ethyl ester (log P +0.45) partitions cleanly between ethyl acetate and 1N HCl at pH 2, facilitating high-yield purification with minimal emulsion formation, a practical advantage validated across multiple 100–500 kg campaigns.
| Parameter | 2-Aminothiazole-4-carboxylate (ethyl ester) | 2-Aminothiazole-5-carboxylate (ethyl ester) | 2-Amino-4-methylthiazole |
|---|---|---|---|
| CAS | 53935-44-7 | 7210-71-1 | 1603-91-4 |
| Melting point | 168–172°C | 144–147°C | 44–46°C |
| Solubility in THF at 25°C | >50 g/L | >50 g/L | >200 g/L |
| Coupling yield with TCA active ester to form syn-oxime cephalosporin intermediate | 88–92% | 28–35% | not applicable |
| Typical use | Cefditoren, cefixime side-chain | Specialty kinase inhibitor scaffolds | Corrosion inhibitor intermediate |
Switching from the 4-carboxylate to the 5-carboxylate isomer also introduces a regulatory complication: the 5-carboxylate ethyl ester carries a mutagenic impurity alert for sulfonate esters formed during the thionyl chloride esterification when traces of ethanol persist. The 4-carboxylate variant does not generate the same genotoxic impurity profile because the ester alkyl-oxygen fission pathway is sterically disfavored by the adjacent ring sulfur, a property confirmed by Ames tests conducted in accordance with OECD 471 with and without metabolic activation. This toxicological distinction has driven pharmaceutical manufacturers to standardize on the 4-carboxylate scaffold for late-phase clinical programs.
Supply chain quality for bulk 2-aminothiazole-4-carboxylate relies on a certificate-of-analysis package that includes HPLC assay (C₁₈ column, 254 nm detection, isocratic acetonitrile/water 40:60 with 0.1% H₃PO₄), loss on drying (60°C, vacuum, 4 h), residue on ignition (≤0.1%), and heavy metals by Ph. Eur. 2.4.8, Method A. The ethyl ester is packaged in double-layer LDPE liners inside UN-certified fiber drums netting 25.0 ± 0.1 kg; sub-lot samples are offered in amber glass bottles (100 g, 500 g) under argon for research-scale evaluations. Storage at 2–8°C extends the retest period to 36 months, while short-term excursions to 40°C for ≤14 days during transport do not reduce the assay by more than 0.3% absolute, based on ICH Q1A(R2) accelerated-stability protocols. The manufacturing facility is certified to ISO 9001:2015 and ISO 14001:2015, and the substance is REACH-registered with full substance volume tracking for the 10–100 t/a band. Production-scale experience on twin-screw vacuum drying units of 1,200 L working volume has demonstrated that residual chloride levels below 50 ppm are achievable only when the filter cake is washed with a 3:1 v/v acetone/water mixture at a wash ratio of 2.5 L/kg of wet cake, a parameter incorporated into master batch records after block screening of chloride-induced pitting in stainless-steel storage silos.
| Compliance Standard | Test Parameter | Method/Acceptance Criterion |
|---|---|---|
| USP ⟨467⟩ | Residual solvents | GC-FID headspace; ethanol ≤150 ppm, methanol ≤500 ppm |
| Ph. Eur. 2.4.8 | Heavy metals | Colorimetric sulfide; ≤10 ppm |
| ASTM E203 | Water content (sodium salt) | KF volumetric titration; 11.5–13.0% |
| OECD 471 | Mutagenicity (Ames assay) | Negative in S. typhimurium TA98, TA100, TA1535, TA1537 with and without S9 |
| IEC 60079-32-2 | Electrostatic hazards during micronisation | Volume resistivity ≤10⁹ Ω·m; grounding resistance <10⁶ Ω |
| ISO 9001:2015 | Quality management system | Full batch traceability from raw material lot to finished product |
