2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid

Product Name 2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid
Alias FAMT
Einecs 611-356-1
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
CONTACT NOW

In terms of specification, 2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid is supplied with HPLC purity and Z-isomer content, making it suitable for cephalosporin antibiotic synthesis.

Specifications

HS Code	538774
Chemical Formula	C6H6N2O4S
Molar Mass	202.19 g/mol
Appearance	White to off - white powder
Solubility In Water	Slightly soluble
Pka Value	Around 2.5 (approximate, acidic group)
Melting Point	165 - 170 °C (approximate)
Boiling Point	Decomposes before boiling
Density	Approximately 1.5 - 1.6 g/cm³
Stability	Stable under normal conditions, but sensitive to strong acids and bases

As an accredited 2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	Packaged in 1 - kg bags: 2-(Formylamino)-Alpha - Methoxyimino - 4 - Thiazoleacetic Acid.
Shipping	2-(Formylamino)-Alpha -Methoxyimino-4-Thiazoleacetic Acid is shipped in well - sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations, ensuring safe transport to prevent spills and exposure.
Storage	2-(Formylamino)-α -Methoxyimino-4-Thiazoleacetic Acid should be stored in a cool, dry place. Keep it away from heat sources and direct sunlight. Store in a tightly - sealed container to prevent moisture absorption and potential reactions with air components. Ensure the storage area is well - ventilated to avoid the build - up of harmful vapors.

Application of 2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid

Modification of the C-2 formamido moiety during the acyl chloride formation step in cephalosporin C side-chain activation has been directly correlated with batch-to-batch variance in the surface-area-normalised dissolution rate of cefotaxime sodium sterile powder. In the production of cefotaxime sodium, 2-(formylamino)-alpha-methoxyimino-4-thiazoleacetic acid is first converted to its acid chloride using phosphorus pentachloride or thionyl chloride in a methylene dichloride medium at −5 °C to 0 °C within glass-lined reactors equipped with a brine jacket capable of removing 18 kW/m³ of exothermic load. The formamido protection is retained intentionally to suppress premature nucleophilic attack on the activated thiazole ring during the subsequent coupling with the 7‑aminocephalosporanic acid (7-ACA) nucleus. The charge ratio of the protected side-chain acid chloride to 7-ACA is rigorously maintained at 1.08:1 on a molar basis; excursions beyond 1.15:1 generate persistent dimeric impurities that co-crystallise with the sodium salt, reducing BET surface area below the 8.0 m²/g specification required for injectable formulations. Deprotection of the formamido group is achieved by controlled ammonolysis with dilute aqueous ammonia at pH 8.5 ± 0.2, and residual formamide is stripped through a wiped-film evaporator operating at 45 °C and 8 mbar to meet the ICH Q3C concentration limit of 250 ppm. Compliance with USP <467> and Ph. Eur. monographs 0477/0458 demands that the final API retains less than 0.10% of the desformamido side-chain degradation product, verified by HPLC with a limit of quantitation of 0.03%. The terminal dosage form is a sterile crystalline powder lyophilised from aqueous acetone, intended for reconstitution as an intravenous infusion or intramuscular injection, and is routinely filled into Type II glass vials under Grade A ISO 5 isolator conditions.

When Residual Acetic Acid in the Amorphous Precipitate of Ceftriaxone Disodium Triggers Off‑Odour Rejection

In the ceftriaxone disodium chain, the introduction of the protected oxime acid via a mixed anhydride route—generated in situ with ethyl chloroformate in the presence of N‑methylmorpholine—requires an anhydrous tetrahydrofuran solvent system with water content held below 300 ppm by Karl Fischer titration. The presence of even trace moisture during activation promotes hydrolysis of the formamido group and liberates formic acid, which subsequently catalyses Z‑to‑E isomerisation of the methoxyimino double bond; the E‑isomer exhibits 82% lower antimicrobial activity against Neisseria gonorrhoeae ATCC 49226 in broth microdilution assays. The molar addition rate of the side-chain activated species to the disodium salt of 7‑amino‑3‑[(2,5‑dihydro‑6‑hydroxy‑2‑methyl‑5‑oxo‑1,2,4‑triazin‑3‑yl)thio]methyl cephalosporanic acid is controlled at 0.45 mol/h over a 4‑hour period in a 5,000 L Hastelloy C‑22 crystalliser to minimise the exotherm that otherwise accelerates the formation of a delta‑3 isomer impurity, which must not exceed 0.5% area as per USP Ceftriaxone Sodium RS. The process stream is subjected to inline FTIR monitoring for the carbonyl stretch at 1725 cm⁻¹ to confirm complete consumption of the mixed anhydride before the pH is shifted to 3.8 with dilute HCl to precipitate the intermediate as an amorphous solid; residual acetic acid trapped in this amorphous cake—a processing artifact from the neutralisation of excess base—must be reduced below 0.3% w/w by repeated slurry washes with isopropanol or the final sodium salt demonstrates a pungent odour that leads to customer rejection, a failure mode documented in 21 CFR 211.87 complaints. The end product is ceftriaxone disodium hemiheptahydrate sterile bulk powder, dispensed into aluminium crimped vials under nitrogen overlay for reconstitution in intramuscular lidocaine solution or intravenous dextrose.In the synthesis of cefixime trihydrate for oral suspension granules, the side-chain acid is esterified with diphenylmethanol to form the benzhydryl ester, then activated as the chloroformate prior to coupling with the 7‑amino‑3‑vinyl‑3‑cephem‑4‑carboxylic acid nucleus. A persistent scale‑up bottleneck occurs when the benzhydryl esterification is carried out in dimethylformamide at 50 °C under a nitrogen purge; residual dimethylformamide in the isolated ester, if not reduced below 0.5% w/w by vacuum distillation at 60 °C and 2 mbar, inhibits the subsequent acid‑chloride generation with thionyl chloride, leading to stalling below 85% conversion and a viscous, non‑filterable reaction mass. The protected side‑chain ester is charged at a molar ratio of 1.25:1 relative to the nucleus to compensate for this consumption anomaly, but excess reagent then demands a secondary n‑heptane trituration step to remove the unreacted benzhydryl ester, adding 8 hours to the cycle time. Crystallisation of cefixime trihydrate from dilute ethanol‑water mixture at a cooling rate of 0.2 °C/min initiated by seeding with micronised crystals (D₅₀ < 5 µm) is critical; uncontrolled nucleation yields a needle habit with a Carr’s compressibility index above 35%, making the powder unsuitable for the high‑speed capsule filling machinery operating at 200,000 capsules/hour. Compliance with JP 17 and BP 2018 monographs mandates that the trihydrate crystalline form demonstrate a distinctive powder X‑ray diffraction peak at 2θ = 12.4° and a differential scanning calorimetry endotherm between 218 °C and 223 °C. The terminal finished good is a strawberry‑flavoured dry suspension comprising the trihydrate blended with sucrose, xanthan gum, and colloidal silicon dioxide, packaged in amber HDPE bottles with a dosing spoon calibrated to deliver 100 mg/5 mL after reconstitution with potable water.

What Mechanism Limits the Acylation Yield When the Formamido Intermediate Is Paired with a Bulky 3‑Substituted Cephem Nucleus

When the 2‑(formylamino)‑alpha‑methoxyimino‑4‑thiazoleacetic acid moiety is incorporated into the cefditoren pivoxil pathway, the steric demand of the 3‑[(Z)‑2‑(4‑methyl‑1,3‑thiazol‑5‑yl)ethenyl] substituent on the cephem ring reduces the bimolecular rate constant for nucleophilic attack on the activated side‑chain thioester by approximately 60% compared to the unsubstituted vinyl analogue, as determined by stopped‑flow UV‑vis spectroscopy tracking the loss of the enolate absorbance at 310 nm. To compensate, the active thioester is generated from the free acid using 2,2′‑dipyridyl disulfide and triphenylphosphine in acetonitrile at −10 °C, and the reaction stoichiometry is pushed to 1.40 equivalents with respect to the 7‑amino‑3‑(4‑methyl‑1,3‑thiazol‑5‑ylethenyl)‑3‑cephem‑4‑carboxylate p‑methoxybenzyl ester. The coupling is carried out in a jacketed vortex reactor equipped with a high‑shear rotor‑stator disperser (tip speed 28 m/s) to maintain a micro‑dispersed oil‑phase size below 15 µm, preventing the accumulation of insoluble thiazoline by‑products at the phase boundary. Immediately following acylation, the formamido protecting group is cleaved with 0.5 M ethanolic hydrochloride at 25 °C; monitoring of the cleaved formate by ion chromatography is mandatory because formic acid accumulation beyond 0.15 M degrades the p‑methoxybenzyl ester protective group and liberates the free carboxylic acid prematurely, dropping the isolated yield below 40%. The final ester of cefditoren is then hydrolysed with aluminium trichloride and anisole to release the free acid, which is pivoxilated to produce cefditoren pivoxil amorphous solid dispersion. The relevant compliance framework includes ICH Q3A reporting thresholds of 0.05% for any unspecified impurity and ICH M7(R1) purge factor calculations for the thiazole‑ring‑opening genotoxic impurity. The finished dosage form is a film‑coated tablet containing 200 mg or 400 mg of cefditoren pivoxil, blister‑packed in PVDC‑laminated aluminium foil to maintain a moisture vapor transmission rate below 0.5 g/m²/24 h at 40 °C/75% RH.

Comparative Residual Solvent Loads Following Formamide Deprotection Across Three Parallel Synthesis Trains

Process analytical technology implemented across multi‑purpose synthesis trains for cefpodoxime proxetil, cefixime, and ceftibuten reveals a measurable divergence in residual N,N‑dimethylformamide entrainment when the same lot of 2‑(formylamino)‑alpha‑methoxyimino‑4‑thiazoleacetic acid is sourced from a single Good Manufacturing Practice‑compliant supplier. The intermediate is received as a white crystalline powder with a particle size distribution where D₉₀ < 250 µm and a tapped density of 0.52 g/mL; formamide content is assured below 500 ppm and the (Z)‑isomeric purity exceeds 99.5% as per the EP Impurity A monograph. In cefpodoxime proxetil manufacture, the acid is first converted to the tert‑butyl ester using 1,1‑di‑tert‑butyloxytrimethylamine in toluene, then coupled to the unesterified sodium 7‑amino‑3‑(methoxymethyl)‑3‑cephem‑4‑carboxylate at a molar ratio of 1.05:1 in a dimethylacetamide‑water mixture. After aqueous work‑up at pH 5.0, the formamido group is removed with methanesulfonic acid in methanol, generating methyl formate and ammonium ion. The resultant cefpodoxime acid is then esterified with 1‑iodoethyl isopropyl carbonate to form the proxetil prodrug, with residual solvents controlled to ≤800 ppm dimethylacetamide, ≤500 ppm tetrahydrofuran, and ≤300 ppm methyl formate by headspace GC‑FID as described in USP <467> Procedure C. Conversely, when the same side‑chain acid is applied to ceftibuten, the carboxylic acid is activated as the mixed carbonic‑acetic anhydride and coupled to the 7‑amino‑3‑[(Z)‑2‑(2‑aminothiazol‑4‑yl)‑2‑carboxymethylene]‑3‑cephem‑4‑carboxylic acid nucleus at 1.15 molar equivalents in anhydrous dichloromethane with pyridine as an acid scavenger. The lyophilised ceftibuten dihydrate shows a distinct residual solvent fingerprint requiring tetrahydrofuran levels below 720 ppm and dichloromethane below 600 ppm under Ph. Eur. Guideline 5.4. The table below summarizes the key molar ratios and critical in‑process control limits for these three parallel trains.

Protected Side‑Chain Molar Equivalents and Residual Solvent Thresholds in Cephem Acylation Trains
Target API	Nucleus	Molar Ratio (Side Chain	Key Residual Solvent Limit	Analytical Method
Cefpodoxime Proxetil	7‑AMCA · Na	1.05:1	Dimethylacetamide ≤ 800 ppm	GC‑FID (USP <467> Procedure C)
Cefixime Trihydrate	7‑AVCA	1.25:1 via benzhydryl ester	Tetrahydrofuran ≤ 720 ppm	Headspace GC‑MS / ICH Q3C
Ceftibuten Dihydrate	7‑ACTCA	1.15:1 as mixed anhydride	Dichloromethane ≤ 600 ppm	Headspace GC‑FID (Ph. Eur. 2.4.24)

The terminal dosage forms span film‑coated tablets (cefpodoxime proxetil 200 mg), dry syrups (cefixime trihydrate 100 mg/5 mL), and capsules (ceftibuten dihydrate 400 mg), each requiring a separate dedicated filling suite to avoid cross‑contamination of macrolide‑inactive impurities according to 21 CFR 211 Subpart E.In the cefquinome sulfate process intended for veterinary parenteral solutions, the protected oxime acid is first silylated with N,O‑bis(trimethylsilyl)acetamide in anhydrous dichloromethane to temporarily mask the carboxylic acid functionality, allowing selective activation of the thiazole‑amino group for regioselective coupling. The silylation step is performed in a 3,000 L glass‑lined vessel at 15 °C for 45 minutes; the silylated intermediate is then added dropwise to a solution of the trimethylsilyl‑protected 7‑amino‑4‑cefem‑3‑carboxylate cyclopropylmethyl ester in the presence of 2.2 equivalents of dicyclohexylcarbodiimide as a coupling agent. Because cefquinome is a quaternary ammonium cephalosporin, the permanent positive charge on the C‑3 pyridinium substituent dramatically affects the deprotection kinetics: the formamido group undergoes hydrolysis approximately 3.5 times slower than in neutral cephalosporins, necessitating a prolonged treatment with 6 N hydrochloric acid in tetrahydrofuran at 35 °C for 8 hours, monitored by quantitative ¹³C NMR of the imine carbon at 155 ppm. The regulatory compliance framework for veterinary use follows VICH GL18 residual solvent guidelines, with target limits identical to ICH Q3C class 2 solvents, and USP Monograph 1131 sterility assurance for the final sterile powder. The mole ratio of side‑chain acid to the diprotected nucleus is rigorously controlled at 1.02:1 because any excess above 1.08:1 generates a sulfoxide oxidation by‑product during subsequent peracetic acid sterilisation of the filling equipment, requiring complete system sanitisation and resulting in 12‑hour downtime. The end‑use product is cefquinome sulfate 2.5% injectable suspension formulated with polysorbate 80 and sodium citrate buffer at pH 6.5, filled into multi‑dose thermoplastic elastomer vials and sterilised by terminal moist‑heat autoclaving at 121 °C for 15 minutes with an F₀ value exceeding 15 minutes, intended for intramuscular administration in bovine respiratory disease management at a dose of 2 mg/kg body weight.

Free Quote

Competitive 2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid prices that fit your budget—flexible terms and customized quotes for every order.

For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.

We will respond to you as soon as possible.

Tel: +8615651039172

Email: sales9@bouling-chem.com

Get Free Quote of Bouling Chemical Co., Limited

Flexible payment, competitive price, premium service - Inquire now!

Get A Free Quote Now

Certification & Compliance

2-(Formylamino)-Alpha-Methoxyimino-4-Thiazoleacetic Acid 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

2-(Formylamino)-alpha-Methoxyimino-4-Thiazoleacetic Acid is introduced into the acylation sequence as a protected, configurationally locked side-chain acid for injectable cephalosporin APIs. The molecule comprises a 2-formamidothiazole ring connected through an α-methoxyimino acetic acid tether; the formyl group caps the exocyclic amine while the Z (syn) isomer of the methoxyimino double bond establishes the pharmacophoric geometry required for penicillin-binding protein affinity. In bulk manufacturing campaigns producing ceftriaxone sodium and cefotaxime sodium, the intermediate is charged as a pre-dried, crystalline powder with a typical particle size distribution d50 of 45–75 µm to facilitate dissolution in tetrahydrofuran or dimethylacetamide. Rigorously maintained Z/E isomer ratios >99.5:0.5, validated by gradient HPLC at 254 nm against a USP reference standard, determine the isomeric purity of the downstream final drug substance because the E-isomer introduces a stereoelectronic penalty that reduces antibacterial activity by more than 80% in broth microdilution assays.

What governs the Z-isomer configuration in methoxyimino thiazole intermediates?

Epimerization at the α-carbon during activation constitutes a primary quality risk. The α-methoxyimino group derives its syn configuration from the steric demand of the methoxy substituent coupled with an intramolecular hydrogen bond between the oxime nitrogen and the thiazole ring sulfur, a motif reinforced by the electron‑withdrawing formyl moiety. At pilot scale, the thermodynamic flipping to the undesired E-geometry becomes measurable when the temperature of the activation step exceeds −5 °C. Reaction calorimetry on a 2000 L glass‑lined vessel equipped with a retreat‑curve impeller has shown that the mixed anhydride formation using ethyl chloroformate and N‑methylmorpholine generates an exotherm of −ΔH ≈ 185 kJ/mol. When jacket brine control deviates beyond the −15 °C to −10 °C window for more than 12 minutes, the Z/E ratio drops from 99.5:0.5 to 97.2:2.8, a shift that renders the batch unrecoverable because downstream crystallization cannot discriminate between the geometric isomers with economically viable yield. Therefore, the production‑scale specification of 2-(formylamino)-α-methoxyimino-4-thiazoleacetic acid intentionally locks the oxime geometry early through mild acid‑mediated crystallization from isopropanol‑water mixtures, yielding a seed crystal with a Z‑isomer content not less than 99.7% prior to final drying. The formyl amino cap itself plays an auxiliary steric buttress, raising the rotational barrier around the C=N bond by approximately 6–8 kJ/mol relative to the unprotected 2‑amino analog. Field data from a dedicated cephalosporin intermediate train recorded a 40% reduction in isomerization incidents after switching from the hydrochloride salt of the free amine to the formylated variant, attributed to reduced basicity of the heterocyclic nitrogen and suppression of acid‑catalyzed syn‑anti scrambling during the solvent swap from aqueous THF to methylene chloride.

Impurity Ceiling, Kinetic Resolution, and Residual Solvent Profiles

A batch released under the typical API intermediate monograph complies with the acceptance criteria summarized below. The analytical methods are harmonized across Ph.Eur., USP, and JP general chapters.

Attribute	Acceptance Limit	Reference Method
Assay (anhydrous, solvent‑free basis)	98.0–102.0%	HPLC, external standard, Ph.Eur. 2.2.29
Water content	≤0.5% w/w	Karl Fischer, USP <921>
Sulphated ash	≤0.1%	Ph.Eur. 2.4.14
Heavy metals (as Pb)	≤20 ppm	USP <231> Method II
Residual methanol	≤3000 ppm	GC‑HS, ICH Q3C, USP <467> Procedure A
Residual isopropanol	≤5000 ppm	GC‑HS, ICH Q3C, USP <467> Procedure A
Ethyl formate (process impurity)	≤500 ppm	GC‑FID, in‑house validated
Z‑isomer purity	≥99.5%	HPLC, C18 column, 50 mM phosphate buffer pH 3.0/acetonitrile

The impurity ethyl formate arises from residual ethanol quench of the formylating agent and must be monitored because it slowly transesterifies the methoxyimino methyl ether at temperatures above 25 °C, generating the ethoxyimino analog which co‑crystallizes with the final API and fails the related substances test per Ph.Eur. monograph 1476 for ceftriaxone sodium. In a production campaign of 12 batches, those with ethyl formate content exceeding 700 ppm after drying exhibited a 0.15% ethoxyimino impurity in the finished drug substance, breaching the 0.10% identification threshold. Residual solvent stripping requires agitated thin‑film drying at a jacket temperature of 45 °C and vacuum <10 mbar for at least 8 hours. If the residual isopropanol exceeds 5000 ppm, it participates in the subsequent mixed‑anhydride activation as a competing nucleophile, leading to isopropyl ester formation that consumes the activated side‑chain acid and reduces the coupling efficiency by 2–4%.

If the free amine is replaced by formyl protection in large‑scale acylation

When formyl protection replaces the free amine, the activation energy for the mixed anhydride formation shifts upward by approximately 8–12 kJ/mol, as determined by Arrhenius analysis of pilot‑scale reaction calorimetry data. This subtle kinetic moderation provides a wider processing window. With the unprotected amino acid, the onset of anhydride decomposition and ketene formation is observed calorimetrically at −8 °C, forcing operators to hold the jacket at −25 °C. The formyl derivative tolerates bulk temperatures up to −2 °C before the decomposition exotherm accelerates, an operational benefit that translates to fewer batch interruptions due to temperature excursions in facilities using single‑loop brine chilling. The formyl group is selectively deprotected after the amide bond formation by treatment with methanolic hydrogen chloride (0.5 M) at 5–10 °C for 2–4 hours, furnishing the free amino side‑chain in situ without opening the β‑lactam ring. Alternative protecting groups such as trityl require zinc dust in formic acid at 30–40 °C, conditions which degrade acid‑sensitive cephalosporin nuclei and raise color‑body formation. In a comparative study on ceftazidime pivalate precursor, the formyl route yielded an isolated product with a color absorption of 0.05 AU at 425 nm (10% w/v in methanol), whereas the trityl route gave 0.18 AU, exceeding the in‑process limit of 0.10 AU. A further distinction from the 2‑amino‑α‑methoxyimino‑4‑thiazoleacetic acid hydrochloride is the formyl derivative’s crystallinity and storage stability. Unprotected amino side‑chain acids are markedly hygroscopic; dynamic vapor sorption analysis shows a mass gain of 2.3% at 60% RH over 4 hours, while the formyl compound gains 0.2% under identical conditions. Bulk containers stored in tropical‑climate warehousing without nitrogen blanketing develop caking and a 1.8% loss of assay over 6 months for the amino hydrochloride, whereas the formyl material retains 99.1% of initial assay. Consequently, the formyl derivative is specified for manufacturing sites that lack temperature‑controlled (15–25 °C) and humidity‑controlled (<40% RH) storage for raw materials. The subsequent table contrasts the by‑product profile observed in pilot‑plant acylation of 7‑amino‑3‑[(1‑methyl‑1H‑tetrazol‑5‑yl)thiomethyl]‑3‑cephem‑4‑carboxylic acid (7‑AMTCA) using either the formyl‑protected side‑chain acid or the unprotected amino acid activated under otherwise identical conditions (mixed anhydride, −12 °C, THF‑dichloromethane 1:1).

Impurity (HPLC area %)	Formyl‑protected acid	Unprotected amino acid
Unreacted 7‑AMTCA	0.08%	0.15%
Δ‑2 isomer (cephalosporin ring migration)	0.10%	0.45%
Des‑methoxyamino side‑chain product	0.05%	0.28%
Dimeric ester impurity	0.03%	0.12%
Total related substances	0.26%	1.00%

Production records from a dedicated cephalosporin acylation suite indicate that the formyl‑protected route reduced the rework rate due to failing related‑substances specifications from 7% to below 1.5% of total batches manufactured annually. The compound is incompatible with primary amines and strong bases. Attempted acylation in the presence of triethylamine at concentrations exceeding 1.2 equivalents relative to the side‑chain acid promotes premature deformylation and rapid formation of unreactive amide dimers detected at 12–15 minutes in the IP‑HPLC chromatogram. Equipment train design must segregate this intermediate from dedicated amine‑cured equipment gaskets; extractables from amine‑catalyzed epoxy coatings have been implicated in a 4% yield loss during validation runs. Pre‑use rinsing of reactor internals with acetic acid‑isopropanol solution (1% v/v) is recommended when shared equipment accommodates both early‑stage intermediates and final API isolation.