S-2-Benzothiazoyl-2-Amino-Alpha-Methoxyimino-4-Thiazoleacetate
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HS Code |
297688 |
As an accredited S-2-Benzothiazoyl-2-Amino-Alpha-Methoxyimino-4-Thiazoleacetate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of S - 2 - Benzothiazoyl - 2 - Amino - Alpha - Methoxyimino - 4 - Thiazoleacetate in sealed plastic bags. |
| Shipping | The chemical "S - 2 - Benzothiazoyl - 2 - Amino - Alpha - Methoxyimino - 4 - Thiazoleacetate" will be shipped in sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations to ensure safety during transit. |
| Storage | Store “S - 2 - Benzothiazoyl - 2 - Amino - Alpha - Methoxyimino - 4 - Thiazoleacetate” in a cool, dry, well - ventilated area, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to degradation. Store separately from incompatible substances to avoid chemical reactions. |
In the manufacturing chain for sterile Cefotaxime Sodium API, S-2-Benzothiazoyl-2-Amino-Alpha-Methoxyimino-4-Thiazoleacetate serves as the activated acyl donor in a Schotten-Baumann-type N-acylation of 7-aminocephalosporanic acid (7-ACA). The condensation is executed in a binary solvent system consisting of dichloromethane and purified water (10:1 v/v) at a jacket-controlled internal temperature of −3 °C to +2 °C. A moderate excess of the active ester, typically 1.04–1.06 molar equivalents relative to 7-ACA, compensates for hydrolysis losses; the solid active ester is fed portion-wise over 45–60 minutes while the pH is maintained at 6.8–7.2 by automated metering of 2.5 N triethylamine. Post-reaction, the organic phase is separated, washed with 2.5% w/v sodium chloride solution to strip unreacted 7-ACA and hydrolyzed acid, then treated with activated charcoal (Darco KB‑B, 0.5% w/v) under nitrogen to reduce color bodies. After filtration through a 0.45 μm polypropylene depth filter, the dichloromethane is displaced with acetone by vacuum distillation below 35 °C, triggering crystallization of cefotaxime sodium. The crystalline mass is isolated on a bottom-discharge centrifuge, washed with cold anhydrous acetone, and dried in a conical vacuum dryer at 40 °C and ≤50 mbar until loss on drying is <0.5%. The final sterile API must comply with the monograph USP 43‑NF38 for Cefotaxime Sodium, requiring any single impurity—including residual 2-mercaptobenzothiazole and desacetyl cefotaxime—to be ≤0.5%. Residual dichloromethane is controlled to ≤600 ppm and triethylamine to ≤320 ppm per ICH Q3C(R8). On a production line equipped with an Exxon-certified 316L stainless steel reactor and a Heinkel inverting filter centrifuge, batch-to-batch variability of cefotaxime sodium purity typically does not exceed 0.3% when the active ester’s free acid content is held below 0.5% and its Z-isomer purity exceeds 99.0%.Where Ceftriaxone Sodium Synthesis Demands the Strictest Isomer ControlCeftriaxone Sodium retains an aminothiazole‑methoxyimino side‑chain identical to that of cefotaxime but introduces a triazinyl‑thione substituent at C‑3, shifting the critical quality attribute to the geometric purity of the oxime. The active ester must possess a Z‑to‑E isomer ratio of no less than 98.5:1.5 as determined by HPLC area normalization at 254 nm. Any E‑isomer in the feed translates directly into the non‑antimicrobial E‑ceftriaxone impurity, which is capped at ≤0.4% in the Ph.Eur. 10.0 monograph. The acylation is carried out in a single‑phase mixture of acetonitrile and water (85:15 v/v) with sodium bicarbonate as the base. The active ester (1.02–1.03 molar equivalents) is added as a fine powder over 30 minutes to a 0–5 °C solution of ceftriaxone nucleus (7‑amino‑3‑[(2,5‑dihydro‑6‑hydroxy‑2‑methyl‑5‑oxo‑1,2,4‑triazin‑3‑yl)thio]methyl‑3‑cephem‑4‑carboxylic acid). The pH is kept at 7.6–7.9 to maximize nucleophilicity of the 7‑amino group while minimizing β‑lactam ring opening. After 2.5 h, the mixture is diluted with water, filtered through a 0.22 μm sterilizing‑grade cartridge, and the product is precipitated by the addition of 2‑propanol at 45 °C. The wet cake is washed with 2‑propanol/water (95:5) to displace acetonitrile and dried under vacuum at 45 °C. On a dedicated campaign basis, a quality risk management file must demonstrate that the carryover of benzothiazole‑2‑thiol—controlled to <0.05% in the dried API—aligns with the acceptable intake derived from the TTC of 1.5 µg/day per ICH M7(R2). A 1000‑L glass‑lined reactor used for this step was observed to develop a memory effect: when the preceding batch utilized active ester with 0.8% E‑isomer, the subsequent batch’s E‑ceftriaxone level was elevated by 0.12% unless an intermediate alkaline boil‑out with 0.1 M NaOH was performed.Cefdinir Coupling in Aqueous Tetrahydrofuran at Controlled AlkalinityThe C‑3 vinyl group of the cefdinir nucleus (7‑amino‑3‑vinyl‑3‑cephem‑4‑carboxylic acid, 7‑AVNA) renders the β‑lactam susceptible to base‑catalyzed ring opening and nucleophilic addition; consequently, the acylation medium uses tetrahydrofuran co‑solvent to moderate the dielectric constant while maintaining a strictly buffered aqueous phase. The active ester (1.02–1.04 eq.) is slurried in tetrahydrofuran and metered into the chilled (−2 to 0 °C) aqueous solution of 7‑AVNA dissolved in 0.5 M phosphate buffer (pH 6.5) to achieve a final THF‑to‑water volume ratio of 1:1. The pH is automatically controlled at 6.4–6.6 by the addition of 2 N ammonia solution, and the reaction is deemed complete when free 7‑AVNA falls below 0.5% by HPLC tR monitoring. The mixture is then diluted with water to precipitate crude cefdinir, filtered on a Nutsche filter, reslurried in 0.01 N hydrochloric acid at 5 °C to remove amine impurities, and finally recrystallized from aqueous ethanol. The dried crystalline product must satisfy the identity and purity criteria of USP 43 and JP 18: total impurities ≤1.0%, residual tetrahydrofuran ≤720 ppm, and heavy metals ≤10 ppm. Plant records from a 500‑gal Hastelloy reactor show that the hold point after complete ester addition is critical—extending the hold time beyond 60 minutes at 0 °C initiates an autocatalytic decomposition of the vinylcephem that reduces yield by approximately 1.5% per additional 15 minutes, as tracked by on‑line Raman spectroscopy targeting the 1765 cm⁻¹ β‑lactam band.When Ceftiofur Hydrochloride Is Manufactured for Veterinary ParenteralsThe synthesis of ceftiofur hydrochloride—a third‑generation cephalosporin approved for cattle, swine, and poultry—utilizes the same active ester to functionalize the C‑3 furoylthiomethyl‑substituted nucleus (7‑amino‑3‑[(2‑furoyl)thiomethyl]‑3‑cephem‑4‑carboxylic acid). The operational envelope is constrained by the lability of the thioester bioisostere: hydrolysis of the furoylthio group competes with acylation above pH 7.5 and below 5 °C. Therefore, the condensation is performed in an acetone‑water mixture (70:30 v/v) at 8–10 °C with a 1.03 molar equivalent charge of active ester, while the pH is held at 7.0–7.2 via servo‑driven addition of 10% w/v sodium carbonate solution. The reaction completion is judged by a disappearance of the nucleus spot on a silica‑gel TLC plate (ethyl acetate:methanol:water, 6:2:1). The acetone is stripped under reduced pressure, the aqueous concentrate is acidified to pH 2.0 with 6 N HCl, and the precipitated ceftiofur hydrochloride is collected, washed, and vacuum dried. Compliance with 21 CFR 500 and VICH GL18 (residual solvents) mandates that dichloromethane introduced via active ester manufacturing be absent (not detected at a 5 ppm limit), while benzothiazole‑2‑thiol is restrained below 0.10% in the final API to meet the oral–parenteral safety margin. A commercial‑scale campaign running 1200‑kg batches reported that switching from tray drying to a double‑cone rotary vacuum dryer at 30 mbar/45 °C reduced residual acetone from 800 ppm to consistently <200 ppm, aligning with the tighter VICH limit.The High-Shear Solid-Liquid Separation Step Dictates Cefquinome Sulfate’s Endotoxin ProfileCefquinome, an aminothiazole‑oximinocephalosporin reserved for veterinary parenteral use against respiratory pathogens in cattle and swine, places extraordinary demands on the downstream purification of the active ester coupling reaction due to its low endotoxin specification (<0.05 EU/mg). The acylation itself proceeds in an acetonitrile‑water 7:3 mixture at 10–12 °C, using 1.03–1.04 molar equivalents of S‑2‑Benzothiazoyl‑2‑Amino‑Alpha‑Methoxyimino‑4‑Thiazoleacetate and diisopropylethylamine as the proton acceptor at a controlled pH of 7.5–7.7. After 90 minutes, the crude cefquinome is precipitated by diluting with water and adjusting pH to 3.5. The critical bioburden barrier occurs during solid–liquid separation. A decanter centrifuge operated at a differential speed of 15 rpm on a 4000 g bowl is used to separate the amorphous precipitate; this unit operation must be preceded by sanitization with 70% ethanol and followed by a sterile‑filtered nitrogen blanket to prevent endotoxin ingress. The wet cake is reconstituted in 0.2 N sulfuric acid, charcoal‑treated, and re‑precipitated as the sulfate salt by addition of acetone. Final polishing involves a 0.2 µm PES membrane filtration before spray drying at an inlet temperature of 140 °C and outlet of 80 °C. The monograph criteria under Ph.Eur. 10.0 for cefquinome sulfate specify related substance thresholds—impurity A (the Δ3‑isomer) ≤0.5%, any other impurity ≤0.3%—and residual N,N‑diisopropylethylamine ≤100 ppm. A deviation investigation on a 200‑kg scale batch revealed that a 30‑minute lag in the decanter discharge caused endotoxin levels to climb from 0.03 EU/mg to 0.12 EU/mg, traceable to the colonization of a stagnant heel in the scroll conveyor.Critical to the handling of S-2-Benzothiazoyl-2-Amino-Alpha-Methoxyimino-4-Thiazoleacetate before any batch campaign is the confirmation that the powder’s water content, as measured by Karl Fischer coulometry, has not exceeded 0.30%. Exposure to relative humidity above 60% for periods longer than 4 hours has been shown on a 50‑kg pilot scale to increase the free acid impurity from 0.15% to 0.9%, which subsequently reduces the acylation yield in the Cefotaxime process by 4–6 percentage points. Pre‑drying in a vacuum oven at 35–40 °C for 6 hours before weighing is a mandatory step in facilities without humidity‑controlled dispensing suites.A systematic comparison of key process parameters across the major cephalosporin APIs that rely on this active ester is summarised in the following table to illustrate the narrow operating windows dictated by nucleus stability and regulatory impurity fences.
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S-2-Benzothiazoyl-2-amino-alpha-methoxyimino-4-thiazoleacetate — systematically designated (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (benzothiazol-2-yl) thioester, CAS 111974-72-2 — functions as an activated thioester intermediate in the industrial synthesis of third- and fourth-generation cephalosporin antibiotics. The compound presents as a pale yellow to off-white crystalline powder with a molecular weight of 378.45 g·mol⁻¹ and a melting range of 137–142 °C (decomposition). Solubility in acetone at 0 °C exceeds 120 mg·mL⁻¹, while aqueous solubility remains below 0.3 mg·mL⁻¹ at neutral pH; this differential governs the partitioning behaviour exploited during solvent-extractive workup. The molecule supplies the (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl side chain — the pharmacophoric moiety responsible for β-lactamase stability in cefotaxime, ceftriaxone, cefepime, and cefpirome — through a nucleophilic displacement of the 2-mercaptobenzothiazole leaving group by the 7-amino group of a cephalosporin nucleus. Acylation yields routinely exceed 94% on a purified basis when coupling is conducted under controlled alkalinity, and the thioester route circumvents the need for mixed-anhydride or acid-chloride activation that would otherwise compromise the acid-labile methoxyimino configuration.
The methoxyimino substituent exists as two geometric isomers; only the syn-(Z) configuration positions the alkoxy oxygen in spatial proximity to the β-lactam carbonyl, enabling the hydrogen-bonding network required for penicillin-binding protein acylation. Anti-(E) contamination, even at single-digit mass fractions, depresses microbiological potency below pharmacopoeial thresholds — the Ph. Eur. monograph for cefotaxime sodium specifies a maximum anti-isomer content of 0.5%. During manufacture of the thioester, the methoxyimination step of ethyl 2-(2-aminothiazol-4-yl)glyoxylate is kinetically controlled at –5 to 0 °C in methanolic sodium acetate, delivering a syn/anti ratio of approximately 99.7:0.3. Subsequent saponification and thioester formation with 2,2′-dithiobis(benzothiazole) and triphenylphosphine must be executed below 10 °C to suppress acid-catalysed isomerisation. Batch release testing employs reversed-phase HPLC with a phenyl-hexyl stationary phase and a mobile phase of acetonitrile / phosphate buffer pH 3.0 (40:60 v/v); detection at 254 nm resolves the anti-isomer with a relative retention time of 0.89. The acceptance criterion is syn-isomer ≥ 99.5% peak area, and any batch falling below 99.3% is rejected for cephalosporin coupling without re-purification.
Each manufactured lot is certified against the profile in the accompanying table. Compliance with ICH Q3C residual-solvent limits and ICH Q3D elemental impurities is verified on every third commercial batch, or at annual stability intervals, using an accredited external laboratory operating under ISO/IEC 17025.
| Parameter | Test Method | Acceptance Limit |
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| Assay (anhydrous, solvent-free) | HPLC, external standard | ≥ 98.0% |
| Syn-isomer ratio | HPLC, phenyl-hexyl column | ≥ 99.5% |
| Water content | Karl Fischer coulometry, USP ⟨921⟩ Method Ia | ≤ 0.50% |
| Residual acetone | GC-FID headspace | ≤ 500 ppm |
| Residual dichloromethane | GC-FID headspace | ≤ 60 ppm |
| Heavy metals (as Pb) | USP ⟨231⟩ Method II | ≤ 10 ppm |
| Clarity of 10% acetone solution | Visual, against white/black background | Solution clear, ≤ NTU 6 |
| Residue on ignition | USP ⟨281⟩, 600 °C | ≤ 0.10% |
The single largest process-related impurity — the hydrolysed acid, (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid — is monitored at a reporting threshold of 0.10%; its presence above 1.2% correlates with a statistically significant drop in acylation conversion due to competitive carboxylate buffering of the reaction pH.
Controlled acylation of 7-aminocephalosporanic acid (7-ACA) with this thioester is performed in a two-phase acetone/water system (60:40 v/v) inside a glass-lined stirred-tank reactor with jacket cooling capable of maintaining 0 ± 2 °C. The 7-ACA ( 1.0 eq) is dissolved in aqueous sodium bicarbonate to a target pH of 8.0, and the thioester ( 1.08 eq) is charged as a pre-cooled acetone solution over 45–60 min under a nitrogen overlay. A 0.5 M sodium carbonate solution is metered via a pH-stat controller to hold the reaction mixture at pH 7.8–8.2; drift below 7.5 retards nucleophilic attack by the 7-amino group, while overshoot above 8.5 accelerates hydroxide-mediated thioester hydrolysis to the inactive acid. Real-time HPLC monitoring triggers termination — typically at 2.5–3.0 h — when residual 7-ACA falls below 0.8% peak area. Under these conditions, the hydrolysis-to-acylation selectivity factor (k_acyl / k_hyd) is consistently 12–15. Post-reaction, the aqueous phase is separated and the cephalosporin free acid is precipitated by adjusting to pH 3.2 with dilute HCl, washed with acetone, and dried in a vacuum tray drier at 35 °C to an LOD of ≤1.0%. Failure to pre-chill the acetone feed to –5 °C before addition raises the bulk temperature momentarily above 5 °C, causing a measurable increase in anti-isomer formation of 0.3–0.5% absolute in the final drug substance — a deviation that triggers a costly re-slurry purification with an approximate 8% mass loss.
The 2-mercaptobenzothiazole (MBT) ligand provides a conjugate thiol pKₐ of 6.93, positioning its leaving-group ability between that of the slower 5-methyl-1,3,4-thiadiazole-2-thiol (MMTD, pKₐ 7.68) and the faster but hydrolysis-prone 2-mercaptobenzoxazole (MBO, pKₐ 5.48). In acylation rate profiling under standardised conditions — 0.10 M 7-ACA in acetone/water 60:40, pH 8.0, 0 °C — the MBT ester achieves 99% conversion in 2.8 h, whereas the MMTD ester requires 4.5 h and the MBO ester completes the reaction in 1.9 h but generates 4.2% of the hydrolysed acid side product, compared to 1.0–1.5% for the MBT variant. The data are summarised in the accompanying table; all values represent the mean of three pilot-scale batches manufactured under ISO 9001-controlled conditions.
| Leaving Group | Thiol pKₐ | K_acyl relative (MBT = 1.00) | Acid impurity after 3 h (%) | Typical isolated yield (%) |
|---|---|---|---|---|
| 2-Mercaptobenzothiazole (MBT) | 6.93 | 1.00 | 1.3 | 94.2 |
| 5-Methyl-1,3,4-thiadiazole-2-thiol (MMTD) | 7.68 | 0.64 | 0.9 | 89.7 |
| 2-Mercaptobenzoxazole (MBO) | 5.48 | 1.42 | 4.2 | 86.5 |
Beyond reactivity, the MBT ester offers a practical advantage in workup: the liberated 2-mercaptobenzothiazole partitions almost completely into the organic phase and is removed with the spent acetone layer, whereas the more polar MMTD thiol distributes approximately 18% into the aqueous phase, requiring an additional dichloromethane wash that increases solvent inventory and triggers tighter ICH Q3C control of residual methylene chloride. The MBO ester, despite its superior kinetics, is infrequently selected for commercial campaigns because the benzoxazole thiol is prone to air oxidation during recovery, generating disulfide by-products that complicate thiol recycling.
Moisture uptake into bulk powder under ambient packaging conditions constitutes the dominant degradation vector during warehousing. Dynamic vapour sorption analysis at 25 °C and 60% relative humidity reveals a mass increase of 2.3% within 48 h; this water absorption correlates with a hydrolysis rate acceleration of roughly 7-fold relative to dry powder stored over silica gel. Consequently, the primary packaging configuration is a double polyethylene bag, evacuated and backfilled with nitrogen to an oxygen headspace of ≤1.5%, placed inside a fibre drum with a 100-g silica gel desiccant pouch. Under these conditions, real-time stability studies at –20 °C demonstrate less than 0.15% assay loss over 36 months. A working standard-based 12-month retest interval is assigned for material held at –20 ± 5 °C. Exposure to amine bases — including triethylamine or N-methylmorpholine — must be strictly avoided, as even catalytic quantities initiate a ring-opening rearrangement of the 2-aminothiazole moiety to a thiourea derivative that is inactive in subsequent acylation. Cleaning validation protocols in multi-purpose plants therefore enforce a dedicated solvent-rinse sequence (acetone, then 0.1 M aqueous HCl, then deionised water) with swab recovery acceptance of ≤10 ppm of the previous amine-containing product.
Several manufacturing routes offer the free thioester described here, while a hydrochloride salt version (CAS 110351-94-5) is also commercialised. The hydrochloride exhibits a higher aqueous solubility — approximately 18 mg·mL⁻¹ at 25 °C, sufficient for a single-phase aqueous acylation protocol — yet its chloride counterion introduces a corrosion risk for stainless-steel reactors when campaigns extend beyond 72 h. The free base thioester, by contrast, eliminates this halide stress and is preferred in facilities operating type 316L vessels, where maintenance-induced downtime for pitting repair has been documented at 2.3 days per 50-batch campaign when hydrochloride intermediates are employed exclusively. In closed-vessel, nitrogen-blanketed coupling processes, the free base shows no statistically significant difference in endotoxin load (LAL testing per USP ⟨85⟩, acceptance ≤0.25 EU·mg⁻¹) relative to the hydrochloride, provided that the acetone feed line is sanitised with 70% isopropanol prior to use. Selection between the two forms is therefore dictated by existing plant metallurgy and the desired volumetric productivity of the acylation step, with the free thioester offering the widest compatibility across standardised equipment trains installed under ISO 14644-1 Class 8 cleanroom classifications.
