Aminothiazole-4-Acetic Acid
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HS Code |
507828 |
| Chemical Formula | C5H6N2O2S |
| Molecular Weight | 158.18 g/mol |
| Appearance | White to off - white solid |
| Melting Point | 168 - 172 °C |
| Solubility In Water | Moderately soluble |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO |
| Pka | Around 2.5 - 3.5 (carboxylic acid group) |
| Boiling Point | Decomposes before boiling |
| Odor | Odorless or very faint odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited Aminothiazole-4-Acetic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Aminothiazole - 4 - Acetic Acid: 500g in sealed plastic bags within cardboard boxes. |
| Shipping | Aminothiazole - 4 - Acetic Acid is shipped in sealed, corrosion - resistant containers. Special care is taken to ensure compliance with chemical transportation regulations. Shipment is typically via approved carriers with proper hazard labeling. |
| Storage | Aminothiazole - 4 - Acetic Acid 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 degradation. Store it separately from oxidizing agents and incompatible substances in a dedicated chemical storage area to ensure safety. |
What Drives the Yield of (Z)-2-(2-Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetic Acid Below 85%?Drop formation during the enamine protection step directly correlates with molecular sieves activation and the vacuum profile of the wiped-film dehydrator. Pilot-plant campaigns processing 200–500 kg loads of aminothiazole-4-acetic acid (ATAA, CAS 29676-71-9) into ceftazidime side-chain acid typically initiate with a Schiff-base condensation between ATAA and ethyl acetoacetate in toluene, catalysed by 0.05 equivalents of glacial acetic acid under azeotropic water removal. The molar feed ratio is held at 1.00∶1.12∶0.05 (ATAA∶ethyl acetoacetate∶acetic acid). Reaction mass temperature is not permitted to exceed 78 °C at any jacket sensor; excursions above 82 °C lead to irreversible enamine decomposition visible as a rapid darkening to amber and a 4–7% loss of titre by in-process HPLC (area%, UV 254 nm). Water content of the dried toluene stream returning from the condenser demister must be kept below 250 ppm (Karl Fischer) through a molecular sieve 3A bed reconditioned at 280 °C for 8 h per each 3-batch cycle.Following enamine isolation by solvent swap into dimethylacetamide, the oxyimino-ether construction proceeds via sequential treatment with hydroxylamine hydrochloride (1.45 equivalents) and 1,1-dimethylethylene oxide (isobutylene oxide, 2.70–2.90 equivalents) in the presence of anhydrous sodium carbonate micropowder. The trans-etherification is performed in a glass-lined reactor equipped with a retreat-curve impeller at 120 rpm; dosing of the epoxide is extended over 90–120 min while maintaining the internal temperature at 18–22 °C. Overfeed of isobutylene oxide beyond 3.10 equivalents generates diester oligomers that are extremely difficult to purge from the final crystalline acid and depress the Z-isomer purity by 1.5–3.0 area%. The Z-isomer content in the isolated ceftazidime side-chain acid is required to be ≥99.0% by HPLC against a reference standard traceable to the EP ceftazidime impurity monograph (EP 10.0, impurity A). Residual ATAA must be controlled to ≤0.10% because any carryover into the final sterile cephalosporin recrystallised as the pentahydrate shifts the pH of reconstituted solution beyond the pharmacopoeial window of 5.0–7.5 (USP <791>). A validated HPLC method on a C18 column (5 μm, 250 × 4.6 mm) with 0.02 M phosphate buffer (pH 3.0)/acetonitrile (92∶8) quantifies ATAA at a limit of quantitation of 0.01% relative to the side-chain acid peak. Every production batch intended for a US DMF or CEP dossier is placed on stability at 25 °C/60% RH and 2–8 °C; the material is photosensitive and must be packaged in black LDPE liners within UN-rated fibre drums under nitrogen headspace to suppress oxidative decarboxylation that forms 2-aminothiazole as a genotoxic alert impurity.Cefepime hydrochloride and cefpirome sulfate both rely on the same side-chain acid, (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid, yet the purity prerequisites diverge markedly between the two drug substances due to differing parenteral formulation sensitivity to residual dimethyl sulphate and its hydrolysis products. The methoxyimino side-chain synthesis begins with ATAA subjected to amino protection analogous to the ceftazidime route, but the critical transformation is the alkylation of the hydroxyimino intermediate with dimethyl sulphate (DMS) under phase-transfer conditions. In a dedicated 20-m³ Hastelloy C-276 reactor train equipped with closed-loop vapour recovery and 5% aqueous ammonia scrubbers, the oxime is dissolved in dichloromethane and stirred with powdered potassium carbonate (2.8–3.0 equivalents) and tetrabutylammonium bromide (0.06 equivalents). DMS is metered at 1.05–1.10 molar equivalents relative to the oxime over not less than 3 h while jacket brine holds the mass at -2 to +2 °C. The adiabatic temperature rise of the DMS quench with ammonium hydroxide was measured in an RC1e reaction calorimeter as 74 kJ per mole of DMS; therefore the post-reaction wash is conducted semi-continuously with continuous venting into the scrubber manifold. Residual DMS in the isolated methoxyimino acid must be ≤1 ppm as determined by derivatisation GC-MS according to ICH M7 (Class 1 impurity, non-thresholded). The Z-isomer purity target for cefepime-grade side-chain acid is ≥99.5% because the E-isomer co-elutes with the active pharmaceutical ingredient in the compendial liquid chromatographic purity test (USP 43, cefepime hydrochloride related compound C) and masks a true purity deficit during batch release. Crystallisation from isopropanol/water (85∶15 v/v) with controlled cooling from 48 °C to 2 °C at 0.15 °C/min purges the E-form to below 0.2%. The dry powder’s tapped density (0.45–0.55 g/mL) is monitored because low bulk density negatively affects static charge dissipation during pneumatic transfer to the cephalosporin coupling suite and has been linked to localised overheating in double-cone tumble dryers beyond 40 °C jacket temperature.
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Aminothiazole-4-acetic acid (CAS 2298-71-1, molecular formula C5H6N2O2S, molecular weight 158.18 g/mol) is supplied under model designation AT4AA-S as a white to off-white crystalline powder. It serves as a core building block in the synthesis of aminothiazolyl-oxyimino acetic acid side chains for third- and fourth-generation cephalosporin antibiotics. Unlike non-functionalized aminothiazoles, the acetic acid moiety at the 4-position of the thiazole ring enables direct carboxyl activation and coupling to advanced intermediates, circumventing the need for separate carboxyl introduction steps. Bulk density typically ranges from 0.45 to 0.60 g/mL, and solubility in water at 25 °C is approximately 12 mg/mL at pH 6.5.
| Parameter | Specification Limit | Test Method Reference |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual / USP general notices |
| Purity (HPLC, area%) | ≥ 98.5 % | In-house HPLC method based on USP <621> |
| Melting range | 178–182 °C (decomposition) | USP <741> / open capillary |
| Loss on drying (60 °C, vacuum) | ≤ 0.5 % | USP <731> |
| Residue on ignition | ≤ 0.10 % | USP <281> |
| Heavy metals (as Pb) | ≤ 10 ppm | USP <231> / ICP-OES |
| Chloride (Cl−) | ≤ 200 ppm | Ion chromatography per ASTM D4327 |
| Water (Karl Fischer) | ≤ 0.3 % | ASTM E203 |
Manufacturing sites operate under an ISO 9001:2015 quality management system. Each batch is released with a certificate of analysis listing the above results and residual solvent levels according to ICH Q3C, with methanol, acetone, and tetrahydrofuran controlled below their respective concentration limits for pharmaceutical intermediates.
In the synthesis of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (ATMA)—the key side-chain intermediate for cefixime, ceftriaxone, and cefdinir—the 4-acetic acid precursor is dissolved in anhydrous tetrahydrofuran (water content < 200 ppm by Karl Fischer) and cooled to 0–5 °C in a 2000 L glass-lined reactor equipped with a brine jacket capable of removing 12 kW of heat load. To this solution is added triethylamine (1.05 eq.) followed by dropwise addition of methoxyamine hydrochloride (1.15 eq.) over 90 min while maintaining a nitrogen blanket. Exotherm control is critical: internal temperature excursions above 8 °C increase formation of de-aminated thiazole byproducts to over 2.5 area-%, as tracked by in-process HPLC using a C18 column and UV detection at 254 nm. Once oximation is complete, the (Z)-isomer is enriched to > 98 % by adjusting pH to 3.5 with acetic acid; the undesired (E)-isomer precipitates and is removed by filtration. Pilot-scale data from 15 consecutive batches showed that when ambient relative humidity exceeded 60 % and the starting aminothiazole-4-acetic acid was not pre-dried to a moisture content below 0.2 %, the (Z)/(E) ratio dropped by 8 percentage points relative to dry campaigns. The isolated ATMA must contain residual methanol below 0.1 % (GC headspace per USP <467>) to avoid downstream transesterification during coupling with a cephalosporin nucleus. Subsequent activation to the mixed anhydride or active ester employs dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) in dimethylformamide, with continuous monitoring of dicyclohexylurea precipitation to gauge conversion. This step requires anhydrous conditions: exposure of the amino group to aldehydes introduced via impure solvents leads to Schiff base formation, which cannot be reversed under coupling conditions and caps the amine, lowering coupling yields to below 80 %. For this reason, all solvents are sparged with nitrogen and stored over molecular sieves. In direct comparison, the 5-amino isomer forms predominantly the (E)-oxime due to steric hindrance, making it unsuitable for pharmaceutically active cephalosporin side chains.
| Property | Aminothiazole-4-acetic acid | Aminothiazole-2-acetic acid | Aminothiazole-5-acetic acid |
|---|---|---|---|
| Position of amino group | C-4 (adjacent to sulfur) | C-2 (adjacent to ring nitrogen) | C-5 (adjacent to sulfur, opposite to N) |
| pKa of conjugate acid (amino group) | 4.2 ± 0.1 (25 °C, 0.1 M KCl) | 5.5 ± 0.1 | 3.0 ± 0.2 |
| Relative acylation rate (benzoyl chloride, MeCN, 0 °C) | 1.0 (reference) | 2.3 | 0.4 |
| Solubility in water (mg/mL, pH 6.5) | 12 | 28 | 8 |
| Compatibility with cephalosporin (Z)-methoxyimino geometry | Yes; yields > 98 % (Z)-isomer under optimized conditions | No; oximino side chain not accessible at C-2 | No; stereoselectivity favors (E)-isomer (>85 %) |
Kinetic data from a comparative study of thiazole amine acylation (J. Org. Chem., 1995, 60, 5829–5835) confirmed that the 4-amino substituent’s nucleophilicity is moderated by the electron-withdrawing ring sulfur, preventing over-rapid reaction that in the 2-amino case can lead to diacylation under standard peptide coupling conditions. In practice, this means the AT4AA-S product offers a wider processing window for acylation without generating detectable bis-acylated impurity when DCC/HOBt activation is used at amine:acylating agent ratios of 1:1.02.
Long-term storage below 8 °C and protection from atmospheric moisture are required. The material is hygroscopic: equilibrium moisture uptake at 60 % RH and 25 °C exceeds 2.5 % w/w within 24 h, necessitating pre-drying for at least 4 h at 50 °C under 10 mbar vacuum prior to use in anhydrous syntheses. Avoid contact with strong oxidizing agents; thiazole ring degradation occurs exothermically above 40 °C in the presence of peroxides. Mixture with amine bases at temperatures above 30 °C promotes amidation of the acetic acid moiety, forming a 2-(2-aminothiazol-4-yl)acetamide derivative that reduces active carboxyl content. At pH > 9 and temperatures above 50 °C, ring-opening hydrolysis yields a thioamide-acrylic acid intermediate detectable by LC-MS (M+H+ = 176.1). The amino group is a potential substrate for N-nitrosation; therefore, nitrite levels in process water and all auxiliary materials must be below 0.1 ppm. Control of nitrosamine impurities follows the risk assessment framework of ICH M7 and the EMA guideline on nitrosamines (EMA/CHMP/428299/2020), with dedicated HPLC-MS/MS monitoring using an LOQ of 0.03 ppm for N-nitroso-2-aminothiazole-4-acetic acid. Engineering controls in production suites include dedicated dry air handling and nitrogen blanketing of all equipment contact surfaces.
