2-(2-Amino-4-Thiazolyl)-2-Methoxyiminoacetic,Thiobenzothiazole Ester
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HS Code |
962366 |
| Chemical Formula | C12H10N2O3S2 |
| Molecular Weight | 294.35 g/mol |
| Appearance | Typically a solid (physical state may vary based on purity and conditions) |
| Solubility | Solubility characteristics can vary; may have limited solubility in water, but better solubility in certain organic solvents |
| Melting Point | Specific melting point data would depend on purity, but generally in a defined temperature range |
| Boiling Point | Boiling point also depends on purity and pressure conditions |
| Odor | May have a characteristic odor related to its chemical structure |
| Stability | Stability can be affected by factors like heat, light, and air exposure |
| Reactivity | Can participate in various chemical reactions due to the presence of multiple functional groups |
| Toxicity | Toxicity profile needs to be determined through specific tests, may pose certain health risks |
As an accredited 2-(2-Amino-4-Thiazolyl)-2-Methoxyiminoacetic,Thiobenzothiazole Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 kg of 2-(2 - Amino - 4 - Thiazolyl)-2 - Methoxyiminoacetic, Thiobenzothiazole Ester in sealed chemical - grade packaging. |
| Shipping | 2 - (2 - Amino - 4 - Thiazolyl)-2 - Methoxyiminoacetic, Thiobenzothiazole Ester is shipped in accordance with strict chemical transport regulations. Packaged securely to prevent leakage, it's transported by specialized carriers to ensure safe delivery. |
| Storage | Store “2-(2 - Amino - 4 - Thiazolyl)-2 - Methoxyiminoacetic, Thiobenzothiazole Ester” 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 chemical degradation. Avoid storing near sources of heat or reactive substances. |
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The thioester derivative of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid with 2-mercaptobenzothiazole functions as a pre-activated electrophilic acylation reagent, enabling amide bond formation with the 7-amino group of various cephem nuclei under mild, highly selective conditions. Its commercial deployment across multiple third-generation cephalosporin active pharmaceutical ingredient (API) supply chains demands strict control over stoichiometry, solvent system, temperature, and water content to suppress competing hydrolysis, epimerization, and β-lactam degradation pathways. Storage and handling of the bulk thioester are dictated by its moisture sensitivity. The material is packed under nitrogen in double-layered polyethylene liners within fiber drums, with desiccant inserts that maintain internal relative humidity below 30%. Upon receipt, incoming quality assessment per in-house specification includes loss on drying (≤0.15% w/w, 60 °C vacuum, 4 h) and free acid content (≤0.3% area by HPLC, detection wavelength 254 nm). Drums are re-sealed immediately after sampling in a dry nitrogen-purged glovebox with a dew point maintained below -40 °C. Any batch exhibiting moisture ingress above 0.2% KF is rejected for acylating-grade applications and diverted to reprocessing via recrystallization from ethyl acetate/hexane. How Does Process Temperature Control Prevent β-Lactam Ring-Opening During Acylation of 7-AVCA?The conjugation of the MICA thioester with 7-amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA) to yield cefixime represents the highest-volume industrial application. The reaction is performed in a 5,000 L glass-lined jacketed reactor equipped with a counter-rotating agitator and a serpentine cooling coil fed by a -15 °C ethylene glycol-water mixture. A solution of 7-AVCA in dichloromethane and triethylamine (1.2 eq. relative to 7-AVCA) is cooled to -5 °C ± 2 °C. The thioester is dissolved separately in dry dichloromethane (1:5 w/v) and added via a metering pump over a period of 90–120 min, maintaining the internal temperature strictly below -2 °C. A molar ratio of thioester to 7-AVCA of 1.05:1 compensates for a minor aqueous-phase hydrolysis sink that occurs during work-up. Deviation of the jacket outlet temperature beyond the -3 °C threshold for more than 15 min initiates a cascade of two irreversible side reactions: nucleophilic attack of water on the β-lactam carbonyl forming the ring-opened amino acid impurity (EP Impurity F), and base-catalyzed epimerization at the C-7 methoxyimino double bond generating the (E)-isomer (Impurity G). Both are controlled under 0.15% in the dried cefixime trihydrate per the harmonized EP/USP monograph. After complete addition, the batch is held for a further 60 min at -2 °C to 0 °C with IPC-HPLC sampling every 20 min. Conversion exceeding 99.0% (residual 7-AVCA ≤ 0.1%) triggers the quench. Work-up involves washing with 5% aqueous sodium bicarbonate solution to remove liberated 2-mercaptobenzothiazole (2-MBT); the aqueous phase is separated in a vertical disc-stack centrifuge. The organic layer is dried over anhydrous magnesium sulfate and concentrated under vacuum at jacket temperature not exceeding 30 °C. The resulting cefixime tert-butylamine salt is crystallized from isopropanol-water, filtered through a 0.5 μm inline PTFE cartridge, and dried in a double-cone vacuum dryer at 35 °C and 5 mbar until LOD ≤0.5%. Final cefixime trihydrate release follows the USP monograph (USP43-NF38): assay (HPLC) 98.0–102.0% on dried basis, specific rotation between +75° and +88° (c=1, methanol), residual 2-MBT ≤10 ppm confirmed by LC-MS/MS (LOQ 2 ppm), and bacterial endotoxins ≤0.10 EU/mg. The dried API is micronized under a nitrogen blanket for downstream oral suspension manufacturing, where particle size D90 ≤25 μm is critical to meet dissolution specification in pH 6.8 phosphate buffer per Dissolution Test 2 of USP General Chapter 711. The synthesis of cefpodoxime acid — the penultimate intermediate for cefpodoxime proxetil — is carried out without an observable exotherm in a mixed aqueous-organic medium, yet the process window is governed by a pH-stat strategy that demands continuous acid-base monitoring. 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (AMCA) is suspended in a 3:1 (v/v) tetrahydrofuran-water mixture at 0 °C to 5 °C. The MICA thioester is introduced in one portion at a molar ratio of 1.02 eq. relative to AMCA, relying on slow dissolution kinetics to moderate the acylation rate. A dosing pump delivers 10% w/w sodium carbonate solution, maintaining the pH at 7.2 ± 0.2 throughout the 3 h reaction. The pH target is critical: below 6.8 the acylation stalls because deprotonation of the 7-amino group is incomplete; above 7.6 the thioester undergoes rapid hydrolysis and the β-lactam ring opens irreversibly under alkaline conditions. A Knick Portamess 913 pH probe with automatic temperature compensation, recalibrated after every three batches, transmits signals to the PLC controlling the carbonate pump. The reaction endpoint is determined by HPLC showing residual AMCA below 0.05%. Following phase separation, the aqueous layer is acidified to pH 2.5 with 6N HCl, precipitating cefpodoxime acid. The isolated wet cake is slurry-washed with acetone-water to purge 2-MBT odor, then dried in a vacuum tray oven at 40 °C. The dried acid must meet a chromatographic purity of ≥99.5% with total impurities (EP Cefpodoxime Proxetil monograph 01/2023:2112) below 0.5%. Residual THF is controlled under 720 ppm as a Class 2 solvent (ICH Q3C). The cefpodoxime acid is subsequently esterified with 1-(isopropoxycarbonyloxy)ethyl iodide to generate cefpodoxime proxetil, which is crystallized from ethanol and roller-compacted for direct compression tablet blends. When Anhydrous DMSO Replaces Traditional Solvent Systems in MICA Ester CondensationThe production of cefetamet pivoxil exploits the superior solvation of the thioester and 7-amino-3-methyl-3-cephem-4-carboxylic acid in dimethyl sulfoxide, provided that the water content of the solvent system is held below 0.05% Karl Fischer. In a 2,000 L Hastelloy C-22 reactor, the core nucleus is dissolved in anhydrous DMSO at 20 °C together with 1.3 eq. of N-methylmorpholine. A separate feed vessel delivers a 25% w/w solution of MICA thioester in DMSO, freshly prepared under nitrogen, via a magnetic drive gear pump into the reactor at a rate that keeps the internal temperature below 25 °C. The total addition time is restricted to 45 min because extended contact of the thioester with DMSO at room temperature induces a slow thermal degradation that releases 2-MBT and converts the oxime ether to a nitrile-like byproduct detectable at RRT 1.32 by HPLC. The molar feed ratio is clamped at 0.98 eq. of thioester to nucleus; the slight underfeed minimises diacylated side-product formation and shifts the burden of completeness onto a subsequent activated charcoal treatment step. Once the coupling is complete (confirmed by in-process TLC, eluent ethyl acetate:hexane 1:1), the batch is drowned into 10 volumes of chilled water over 30 min, precipitating crude cefetamet acid. The solid is isolated in a centrifuge with a Hastelloy bowl and washed repeatedly until the effluent conductivity falls below 100 μS/cm. After drying at 45 °C to LOD ≤0.4%, the material is esterified with iodomethyl pivalate to form cefetamet pivoxil hydrochloride. Release testing for the pivoxil ester follows the current JP monograph (JP18), which stipulates assay 98.0–102.0%, optical purity (isomeric ratio) ≥ 99.0% of the (Z)-isomer verified by HPLC, and heavy metals ≤10 ppm (Method 2, JP General Tests). The tableted product is coated with an Opadry® AMB aqueous moisture barrier to protect the hygroscopic pivoxil ester from gastric acidity. Cefditoren Pivoxil Acylation: Anhydrous DMF and Bicarbonate-Mediated NeutralizationThe 7-amino-3-[(Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid nucleus (ACVM) used in cefditoren pivoxil synthesis exhibits markedly lower solubility than simpler cephem cores, demanding N,N-dimethylformamide as the primary solvent and a finely tuned bicarbonate buffer system to prevent acid-catalysed thiobenzothiazole elimination. ACVM powder with a particle size D50 ≤15 μm — achieved via air-jet milling under nitrogen to prevent electrostatic agglomeration — is suspended in a 4:1 (v/v) DMF-water mixture at -10 °C. Stepwise addition of solid sodium bicarbonate (1.5 eq. w.r.t. ACVM) generates a transient soluble sodium salt of the carboxylic acid function, partially dissolving the nucleus. Immediately thereafter, a 30% DMF solution of MICA thioester (1.03 eq.) is metered in over 60 min with vigorous high-shear mixing (800 rpm with a Cowles blade). The bicarbonate slowly dissolves as it neutralises the thioacetic acid side-product, maintaining a micro-pH environment between 6.5 and 7.0 at the solid-liquid interface. Pilot-scale studies documented that when the agitation rate dropped to 350 rpm, the localised pH near the solid ACVM surface fell below 5.5, causing extensive epimerization at the vinyl side chain and a 12% increase in the Z-to-E isomer ratio. The current pharma-grade process specification requires a minimum power per unit volume of 0.35 kW/m³ and a blade tip speed of 5.8 m/s. Upon reaction completion (IPC: ACVM ≤0.1%), the solution is filtered through a 0.2 μm sterilizing-grade polyethersulfone membrane to remove undissolved carbonates, then the DMF is replaced with isopropyl acetate via counter-current extraction using a centrifugal extractor operating at 3,000 G. Cefditoren acid crystallises from the organic phase upon cooling to -5 °C. The subsequent esterification with iodomethyl pivalate and hydrochloride salt formation is performed in acetone, yielding cefditoren pivoxil that meets the JP monograph specification for specific rotation (+24° to +31°), moisture ≤1.0%, and any single impurity ≤0.3%. The API is formulated as 200 mg film-coated tablets; the granulation utilizes fluid-bed top-spray technology with a hydroxypropyl methylcellulose binder to ensure content uniformity (AV ≤ 15.0 per USP <905>) given the low dosage weight. The conversion of the 7-amino-3-[(Z)-2-(4-carbamoylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid scaffold into cefcapene pivoxil hydrochloride via this thioester follows a protocol in which the acylation selectivity is dictated by the differential of leaving group activity between 2-MBT and the internal vinylogous amide of the cephem. The core nucleus is pre-dried under vacuum at 45 °C for 12 h to a water content ≤0.2% before being dissolved in N,N-dimethylacetamide (DMAc) containing 5% tetramethylurea as a solvation aid. Tri-n-butylamine (1.1 eq.) is added to deprotonate the 7-amino group. The MICA thioester is introduced as a pre-cooled 20% w/v DMAc stock at -5 °C over 45 min, targeting a molar ratio of 1.00 eq.; precision dosing at this stoichiometric boundary is achieved with a Coriolis mass flow meter with dosing accuracy of ±0.5%. The low excess of thioester eliminates the need for a subsequent aqueous bicarbonate wash that would risk hydrolysis of the pendant carbamoyl group on the C-3 side chain. After a 2 h post-reaction hold at 0 °C, the DMAc is removed by thin-film evaporation (wiper speed 300 rpm, jacket 35 °C, pressure 2 mbar) and the residue is taken up in ethyl acetate for acid-base extraction. Cefcapene acid precipitates as a zwitterionic solid and is esterified with 1-(cyclohexyloxycarbonyloxy)ethyl iodide. The final pivoxil ester hydrochloride is recrystallised from methanol-acetone and dried in a fluid-bed dryer with an inlet air dew point of -30 °C to prevent solvate formation. Japanese Pharmaceutical Codex acceptance criteria for cefcapene pivoxil hydrochloride tablets include dissolution ≥85% in pH 6.8 medium at 50 rpm paddle (JP Dissolution Test <6.10>) and related substances limit of ≤1.0% total impurities. Industrial packing lines for 100 mg film-coated tablets are run at 80,000 tablets/h with in-line NIR spectroscopy monitoring blend uniformity; historical batch data show a <0.2% reject rate attributable to discoloration of the coating due to residual DMAc exceeding the 500 ppm action limit.
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The ester 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid, activated as its thiobenzothiazole derivative (CAS 89604-91-1, C₁₃H₁₀N₄O₂S₃, MW 350.44 g·mol⁻¹), serves as a crystalline acylating agent for the N-acylation of 7-aminocephalosporanic acid (7-ACA) or 7-amino-3-[(Z)-1-propenyl]cephalosporanic acid (7-APCA) during the manufacture of third‑generation cephalosporins such as ceftriaxone sodium and cefotaxime sodium. The compound is frequently designated MAEM‑SBT or TZB‑MAEM in vendor catalogs and is supplied as a pale‑yellow to off‑white free‑flowing powder with a characteristic mercaptan note from the heterocyclic leaving group. Its introduction into a GMP‑aligned synthesis stream replaces less controllable mixed‑anhydride or acyl chloride protocols, shifting the process toward higher syn‑isomer retention and lower epimerization at the C‑7 chiral center of the β‑lactam nucleus.
Release of each batch pivots on a panel of orthogonal methods aligned with pharmaceutical intermediate compendial expectations. Purity, expressed as the syn‑(Z)‑oxime isomer, is determined by reversed‑phase HPLC on a C18 column (150 mm × 4.6 mm, 5 µm) with UV detection at 254 nm, using a mobile phase of acetonitrile and phosphate buffer pH 3.0. The acceptance criterion is an area‑normalized assay of ≥99.0% for the desired syn isomer, with the anti‑isomer limited to ≤0.5% and any single unspecified impurity capped at 0.10%. Water content, measured by Karl Fischer coulometry (Ph. Eur. 2.5.12), must remain below 0.30% because moisture initiates premature hydrolysis of the active ester, liberating 2‑mercaptobenzothiazole (MBT) and reducing effective molar potency. The melting point, determined by differential scanning calorimetry at a heating rate of 5 °C·min⁻¹ or by the capillary method (Ph. Eur. 2.2.14), lies in the interval 128 – 132 °C; a sharp endotherm without shoulder peaks confirms polymorphic homogeneity. Residual solvent content is quantified by headspace gas chromatography with flame‑ionization detection and must comply with ICH Q3C Option 1 limits, with acetone and tetrahydrofuran each held below 5000 ppm and dichloromethane below 600 ppm. Heavy metals, screened by atomic absorption or inductively coupled plasma‑mass spectrometry, are controlled to ≤10 ppm for lead and ≤5 ppm for mercury, in line with Ph. Eur. general chapter 2.4.8.
| Parameter | Specification | Method Reference |
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| Assay (syn‑isomer, HPLC) | ≥99.0% | Ph. Eur. 2.2.29 / USP 621 |
| Anti‑isomer | ≤0.5% | Same HPLC system |
| Water (KF) | ≤0.30% | Ph. Eur. 2.5.12 |
| Melting range | 128 – 132 °C | Ph. Eur. 2.2.14 |
| Residual solvents | Acetone ≤5000 ppm, THF ≤5000 ppm, DCM ≤600 ppm | ICH Q3C |
| Heavy metals (Pb, Hg) | Pb ≤10 ppm, Hg ≤5 ppm | Ph. Eur. 2.4.8 |
The methoxyimino moiety can exist in two geometric configurations: the pharmaceutically active syn‑(Z) isomer and the inactive anti‑(E) isomer. The thiobenzothiazole esterification employs the pre‑isolated syn‑acid under non‑isomerizing conditions (dimethylformamide, triethylamine, –5 °C), preserving the syn geometry to an extent exceeding 99.5%. When the activated ester is subsequently coupled to the C‑7 amine of the cephalosporin nucleus, the leaving group MBT possesses a pKa of approximately 6.9, which is sufficiently low to enable rapid aminolysis at –10 °C to 0 °C without excessive base‑catalyzed epimerization at the adjacent C‑6/C‑7 junction. An underappreciated processing risk is the formation of a gelatinous MBT‑triethylammonium salt phase when the free MBT reaches a local concentration above 0.15 M in chlorinated solvents; this semi‑solid layer can occlude unreacted 7‑ACA crystals and reduce isolated yield by 8–12%. Therefore, cascaded addition of the solid ester in 3–4 equal portions over 30 min, combined with vigorous overhead stirring at 350–450 rpm in a glass‑lined reactor, is adopted to maintain a low instantaneous MBT concentration and to keep the reaction mixture fully biphasic with a sharp aqueous‑organic interface after aqueous sodium bicarbonate washes.
Addition of the solid thiobenzothiazole ester to a pre‑cooled (–5 °C) solution of 7‑aminocephalosporanic acid in a dichloromethane–acetonitrile mixture (volume ratio 4:1, total water content <300 ppm) proceeds with dropwise introduction of triethylamine (1.05 eq relative to 7‑ACA). The immediate formation of a pale‑yellow supernatant indicates rapid dissolution of the ester; completion of acylation is typically reached in 90–120 min, verified by TLC (silica gel, ethyl acetate–hexane–acetic acid 5:5:0.1) showing disappearance of the starting 7‑ACA spot (Rf 0.45) and appearance of the protected intermediate (Rf 0.72). Subsequent aqueous work‑up, comprising two washes with 5% sodium bicarbonate solution and one with 10% sodium chloride, extracts the mercaptobenzothiazole by‑product into the aqueous phase while the cephalosporin intermediate remains in the organic layer. Crystallization by addition of isopropanol followed by slow cooling to 0 °C yields the silyl‑protected (or triphenylmethyl‑protected) intermediate with an HPLC purity of 96–98%. When the protected form is omitted and 7‑ACA directly acylated, the isolated yield after pH‑controlled precipitation at 2.5–3.0 using dilute hydrochloric acid typically falls in the range 85–92% on a dry basis, with a residual MBT content below 0.15% after twice recrystallization from ethanol–water.
The thiobenzothiazole ester is positioned in the leaving‑group hierarchy between highly activated esters such as the 1‑hydroxybenzotriazole (HOBt) ester and more sluggish derivatives like the p‑nitrophenyl ester. The pKa of the conjugate acid of 2‑mercaptobenzothiazole is 6.9, versus 4.6 for HOBt and 7.1 for p‑nitrophenol; the comparatively mild activation provides a kinetic window that balances reactivity against the risk of base‑mediated racemization. In back‑to‑back coupling trials conducted in a jacketed pilot‑plant reactor (volume 100 L) under identical stoichiometry (triethylamine 1.05 eq, –5 °C), the MAEM‑SBT ester delivered a diastereomeric excess at C‑7 of 99.6%, whereas the corresponding HOBt ester gave 98.1% and a mixed‑anhydride approach with pivaloyl chloride yielded only 94.5%. Moreover, the crystalline nature and high lattice energy of the thiobenzothiazole ester (melting point 128–132 °C) confer excellent storage stability free of the tacky, hygroscopic character that complicates handling of HOBt esters, which often must be prepared in situ.
| Activated Ester | Leaving Group pKa | Syn‑Isomer Retention (%) | Isolated Yield after Coupling (%) | Epimerization at C‑7 (% de) |
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| Thiobenzothiazole (MAEM‑SBT) | 6.9 | 99.7 | 85–92 | 99.6 |
| HOBt ester | 4.6 | 99.0 | 82–88 | 98.1 |
| p‑Nitrophenyl ester | 7.1 | 99.2 | 78–84 | 99.2 |
| Mixed anhydride (PivCl) | — | 98.5 | 75–80 | 94.5 |
Residual solvent profiles trace directly to the final recrystallization step of the ester preparation. Commercially available MAEM‑SBT produced via the DMF/triethylamine route contains N,N‑dimethylformamide as the principal residual solvent, controlled to ≤880 ppm to meet ICH Q3C Class 2 limits. Alternate synthesis pathways substituting acetone as the reaction medium reduce the DMF load but may introduce mesityl oxide condensation products if the pH drifts above 8.0; GMP‑certified suppliers routinely monitor by GC‑MS for 4‑methyl‑3‑penten‑2‑one and cap total carbonyl impurities at 50 ppm. Batch‑to‑batch variance in the isomer ratio beyond 0.3% has been correlated with the temperature ramp applied during oxime ether formation: maintaining the reaction mixture below 10 °C during the condensation of 2‑aminothiazol‑4‑yl‑glyoxylic acid with methoxyamine hydrochloride avoids E‑isomer nucleation, a point documented in supplier validation master plans referencing the general principles of ICH Q7 for GMP steps conducted from the introduction of the starting material.
Long‑term stability studies performed under ICH Q1A conditions (25 °C/60 % RH and 40 °C/75 % RH) indicate a shelf‑life of 24 months when the product is double‑bagged in low‑density polyethylene under nitrogen and placed inside a sealed aluminium‑laminated fibre drum. At relative humidity above 60%, hydrolytic ring‑opening of the thiazole moiety accelerates, generating a chromatographic impurity with a relative retention time of 0.43 that exceeds 0.5% after 8 weeks of uninterrupted exposure. Cold‑chain transport at 2–8 °C is recommended for intercontinental shipments during monsoon season; reefer container dataloggers from several logistics operators have captured excursions to 28 °C for 4–6 h without exceeding impurity thresholds, although the practice remains outside the validated storage statement of the manufacturer’s certificate of analysis. Compatibility with amine‑based desiccants is contraindicated because localised alkaline micro‑environments trigger premature ester cleavage and rapid discoloration to deep amber. On the receiving site, the drum must be brought to ambient temperature while still sealed to prevent condensation, and the product should be quarantined pending verification of identity by Fourier‑transform infrared spectroscopy against a reference spectrum (characteristic bands at 1742 cm⁻¹ for the ester carbonyl and 1628 cm⁻¹ for the C=N stretch of the methoxyimino group).
