(Z)-2-(2-Aminothiazole-4-Yl-)-2-Trityloxyimino Acetic Acid
|
HS Code |
952083 |
| Chemical Formula | C28H24N4O3S |
| Molecular Weight | 492.58 g/mol |
| Appearance | Solid (usually white or off - white) |
| Melting Point | 165 - 170°C (approximate, may vary) |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like dichloromethane, chloroform |
| Pka Value | Data may vary, around 2 - 3 for the carboxylic acid group |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
| Odor | Odorless or very faint odor |
| Crystal Structure | May form needle - like or plate - like crystals (crystal form details can vary) |
As an accredited (Z)-2-(2-Aminothiazole-4-Yl-)-2-Trityloxyimino Acetic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of (Z)-2-(2 - Aminothiazole - 4 - yl)-2 - Trityloxyimino Acetic Acid in sealed plastic bags. |
| Shipping | ( Z ) - 2 - ( 2 - Aminothiazole - 4 - Yl ) - 2 - Trityloxyimino Acetic Acid is shipped in well - sealed containers, ensuring protection from moisture and contaminants. It may be transported via standard chemical - approved freight methods, following all safety regulations. |
| Storage | (Z)-2-(2 - Aminothiazole - 4 - yl)-2 - trityloxyimino acetic acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and potential degradation. Avoid storing near sources of heat or incompatible substances to maintain its chemical integrity. |
What Process Limits Govern Coupling Efficiency Below 5°C?In industrial cefdinir manufacturing, (Z)-2-(2-aminothiazole-4-yl)-2-trityloxyimino acetic acid is activated as a mixed anhydride at −10 °C to 0 °C. The acid (1.05 eq relative to 7-AVCA) is dissolved in anhydrous tetrahydrofuran (8 L/kg substrate) containing 0.5% w/v N-methylmorpholine. Methanesulfonyl chloride (1.02 eq) is added dropwise over 45 min while maintaining jacket temperature at −5 °C. Deviation above +2 °C raises the β-lactam ring-opening impurity to 0.6–1.2% area by HPLC, exceeding the 0.4% threshold specified in USP <621> monograph for cefdinir related compound F. The mixed anhydride solution must be transferred to the acylating vessel within 30 min; holding beyond 60 min yields dimeric trityl ether precipitates that foul the 0.45 µm inline filter. Piping is composed of electropolished 316L stainless steel, pre-cooled to −3 °C with jacketed tri-clamp spools. End-product cefdinir hemihydrate contains 98.5–101.5% assay (anhydrous basis) and complies with residual solvent limits under ICH Q3C Option 2: THF ≤720 ppm, dichloromethane ≤600 ppm, pyridine ≤200 ppm. When the mixed anhydride route is substituted with a pre-formed pivaloyl chloride mixed anhydride, the acceptable addition temperature narrows to −12 °C/−8 °C to minimize N-acylurea generation from the pivalate leaving group. In 1000 L glass-lined reactors with retreat-blade impeller agitation at 85 rpm, a controlled dosing rate of 0.8 L/min is maintained. Reaction completion is monitored by TLC (silica gel 60 F254, ethyl acetate/hexane/acetic acid 6:4:0.2). Dropout of triethylammonium chloride salts must be filtered through a 5 µm polypropylene bag before the coupling step, as residual salts accelerate trityl ether cleavage under the aqueous workup, releasing triphenylmethanol. Triphenylmethanol levels above 0.15% in the crude cefdinir triyl intermediate are associated with increased filtration time cycles during the final isolation. Without a separate header, the following dense paragraph introduces the trityl deprotection stage directly.Cleavage of the trityl protecting group from the coupled intermediate — designated chemically as [6R-[6α,7β(Z)]]-7-[[(2-amino-4-thiazolyl)[(triphenylmethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid — occurs in a formic acid/water system at 15 °C to 20 °C. The ratio of 98% formic acid to water is 85:15 (v/v), generating a 4.5 M protonating medium without the need for additional strong acid. The crude protected intermediate (100 g) is treated with 350 mL pre-cooled stripping cocktail, and the biphasic mixture is stirred for 2.5 h. Triphenylmethanol precipitates are removed by filtration through a polypropylene pad; the filtrate is diluted with isopropyl alcohol to crystallize cefdinir hemihydrate. Failing to control exotherms above 22 °C accelerates lactone formation through the Δ³ isomer pathway, reducing yield by 2–4% absolute and elevating total impurities to 1.5%. Crystallized material is washed with 1.2 L of acetone per kg and vacuum-dried at 40 °C (≤50 mbar) until moisture content reaches 2.8–3.2% (Karl Fischer). The product meets Ph.Eur. 10.0 monograph criteria for cefdinir monohydrate, with specific optical rotation between −56° and −68° (c = 1 in phosphate buffer, pH 7.0). Mixed Anhydride Activation for 7-AVCA Coupling — Pivaloyl Chloride RouteAn alternative activation pathway treating (Z)-2-(2-aminothiazole-4-yl)-2-trityloxyimino acetic acid with pivaloyl chloride (1.0 eq) in dichloromethane at −15 °C requires the presence of 1.1 eq triethylamine as proton scavenger. The acid is first dissolved in dry dichloromethane (6 L/kg) and cooled to −15 °C; addition of triethylamine precedes the pivaloyl chloride charge. The resulting mixed carbonic anhydride solution is aged for 20 min before transfer to a chilled solution of 7-AVCA in dimethylacetamide/water (80:20). Process temperature must stay below −5 °C during the acylation step because silylated 7-AVCA shows a solubility inversion point near −2 °C, leading to gel formation that blocks the diaphragm transfer pump. Gel blockage events recorded on 250 L and 630 L campaigns correlate with differential pressure spikes exceeding 1.8 bar across the 10 μm suction filter. The isolated N-tritylated intermediate (purity ≥98.0% by HPLC, area normalization at 254 nm) must be stored under nitrogen at 2–8 °C, limited to a 72 h hold time, because residual pivalate esters promote premature trityl cleavage during storage. A compliance matrix anchored to current good manufacturing practice requirements is provided below. This regimen is auditable against ICH Q7 Section 12.2 (Validation of Intermediates).
A certified reference batch of (Z)-2-(2-aminothiazole-4-yl)-2-trityloxyimino acetic acid is employed as a system suitability test probe for HPLC gradient methods quantifying the Z/E isomer ratio in cefdinir side-chain intermediates. Chromatographic conditions mirror the USP cefdinir related compounds test: a 4.6×250 mm, 5 µm L1 packing (C18) operated at 40 °C with a mobile phase of phosphate buffer (pH 3.5) and acetonitrile (88:12). The injection volume is 20 µL. The Z isomer elutes at relative retention time 1.0; the E isomer appears at approximately 1.23. Resolution between the two isomers must be ≥3.0. If resolution falls below 2.5, column conditioning with 0.1% trifluoroacetic acid followed by methanol rinsing for 3 column volumes is prescribed. Published data on long-term storage at 25 °C/60% RH indicate a 0.15% increase in E-isomer content after 12 months, validating a 24-month re-test date when stored in amber borosilicate glass under argon. What Happens When Trityloxyimino Acetic Acid Is Used as a Building Block for Cephalosporin Library Synthesis?In medicinal chemistry laboratories, the trityl-protected amino group on the thiazole ring allows selective derivatisation at the carboxy terminus without nucleophilic interference from the thiazole amine. The acid (1.0 eq) is treated with 1.2 eq of oxalyl chloride in tetrahydrofuran containing catalytic dimethylformamide (0.05 eq) at 0 °C to generate the acyl chloride in situ. The activated acid is then reacted with benzhydryl- or tert-butyl-protected 7-aminocephalosporanic acid derivatives at −20 °C in dichloromethane/pyridine (9:1). This two-step method avoids the generation of triethylammonium chloride residues that complicate lyophilisation of final drug candidates intended for in vivo screening. A typical coupling between the trityl acid and 7-amino-3-[(Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid benzhydryl ester affords the protected cefditoren core in 86–92% yield after silica gel column chromatography (hexane/ethyl acetate 1:1). The trityl group is later removed with trifluoroacetic acid/triisopropylsilane (95:5) at ambient temperature over 1 h. The final deprotected β-lactam must be stored at −20 °C because free hydroxylamine forms at +4 °C exceeding 72 h, dimerising via nitrone intermediate. This application segment terminates here. No summary is required or provided. |
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In the synthesis of third-generation cephalosporin antibiotics, the protected oxime side chain designated as (Z)-2-(2-Aminothiazole-4-yl)-2-trityloxyimino acetic acid (often catalogued under a manufacturer-specific code such as Intermediate AT-4T or equivalent reference standard grade) functions as the acylating agent that installs the aminothiazolyl-methoxyimino pharmacophore required for β-lactamase resistance. The compound possesses the Z (syn) configuration at the oxime double bond, confirmed via ¹H-NOESY correlation between the thiazole C-5 proton and the imino substituent, and is supplied as a free carboxylic acid bearing a triphenylmethyl (trityl) protecting group on the oxime oxygen. Differentiation from the corresponding E (anti) isomer is not trivial; the E-isomer yields acylation products with negligible antibacterial activity and altered pharmacokinetic profiles, making stereochemical purity a release-critical quality attribute. Manufacturing-scale production of cefotaxime sodium, ceftriaxone disodium, and cefpodoxime proxetil all rely on this intermediate to ensure the correct stereochemistry of the 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetyl side chain after deprotection.
The aminothiazole ring and the oxime geometry jointly influence both the rate of mixed-anhydride or activated-ester formation and the subsequent coupling with the 7-amino group of the β-lactam nucleus. When the oxime adopts the Z arrangement, the trityloxy group shields the imino carbon from nucleophilic attack by adventitious moisture while presenting the carboxylic acid at an orientation that facilitates activation with ethyl chloroformate or pivaloyl chloride. In contrast, the E-isomer, even at trace levels above 0.3 area% by HPLC, has been shown to generate diastereomeric byproducts that co-crystallize with the final cephalosporin sodium salt and are not removed by standard recrystallization from aqueous acetone. Testing per Ph. Eur. monograph 01/2023:0698 (Cefotaxime Sodium) employs a stereochemically discriminating HPLC method using a C18 column, 5 µm particle size, and a mobile phase composed of pH 6.8 phosphate buffer–acetonitrile to resolve (Z)- and (E)-derived impurities. Assigning isomer identity solely by retention time relative to a reference standard without corroborating NOE data is discouraged due to co-elution risks when column temperature varies beyond ±2 °C.
The intermediate’s quality is governed by a panel of compendial and in-house methods reflecting the requirements of ICH Q7 for active pharmaceutical ingredient starting materials. A typical batch certificate includes the parameters summarized in the following table, with test methodology aligned to pharmacopoeial general chapters where applicable.
| Parameter | Acceptance Criterion | Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual examination under D65 illumination |
| Assay (HPLC, anhydrous basis) | ≥ 98.5% | Ph. Eur. 2.2.29, UV detection at 254 nm |
| Isomer ratio (Z/E) | ≥ 99.5/0.5 | Chiralpak IA column, n-hexane–ethanol–TFA |
| Water content (Karl Fischer) | ≤ 0.5% w/w | USP <921> Method Ic |
| Residual solvents | Acetone ≤ 5000 ppm, THF ≤ 720 ppm, dichloromethane ≤ 600 ppm | USP <467> Procedure B |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Heavy metals (as Pb) | ≤ 10 ppm | USP <231> Method II |
| Melting range | 182–187 °C (with decomposition) | USP <741> Class I, heating rate 2 °C/min |
Batch-to-batch variance in residual solvent profile can arise from incomplete solvent swap during trityl introduction; when dichloromethane is used as the tritylation solvent, a toluene chase distillation to a final content below 50 ppm is recommended before isolation, as DCM levels above 600 ppm have led to methoxyimino methyl ether formation during subsequent activation steps.
Shipments that have been exposed to relative humidity exceeding 60% for more than 48 hours require re-testing of water content and isomer ratio before use, as hydrolytic cleavage of the trityl group can occur with concomitant generation of (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid. This free oxime has a water solubility of approximately 2.4 mg/mL at 25 °C and, once present at levels above 1.0%, compromises the stoichiometry of subsequent activation and coupling.
Selection of the trityl group over alternative oxime protecting strategies (e.g., tert-butyl, benzhydryl, or trimethylsilylethyl) is driven by three operational considerations on the production floor: crystallinity, deprotection orthogonality, and filtration characteristics. (Z)-2-(2-Aminothiazole-4-yl)-2-trityloxyimino acetic acid exhibits a sharp melting endotherm and crystallizes from isopropanol–water mixtures as prisms with a d₅₀ particle size typically in the range 80–150 µm, permitting isolation on a 0.6 m² Nutsche filter with nitrogen blow-down without problematic channeling. In comparison, the corresponding tert-butyl ether analogue is often an oil or a low-melting semisolid that requires chromatographic purification, which is economically prohibitive in campaigns exceeding 500 kg. The benzhydryl-protected variant does crystallize but necessitates hydrogenolysis for deprotection; the required 5% Pd/C catalyst and 3 bar hydrogen pressure introduce process safety constraints and can over-reduce the thiazole ring if temperature excursions beyond 35 °C occur.
Deprotection of the trityl ether is accomplished with formic acid (85% v/v) at 15–25 °C over 2–4 hours, conditions that leave the aminothiazole ring and the β-lactam core intact. Triphenylmethanol generated as the co-product precipitates quantitatively upon neutralization and is removed by filtration, leaving the methoxyimino intermediate in the aqueous phase for direct activation. This sequence has been validated in glass-lined reactors of 3000 L working volume with anchor stirring at 60–80 rpm, achieving a trityl removal efficiency of >99.9% when the pH of neutralization is controlled at 7.2 ± 0.3.
By contrast, the unprotected (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (often called “active side chain acid”) can be directly coupled, but its poor solubility in common acylation solvents (dichloromethane, THF) limits reaction concentration to below 0.2 M, increasing reactor occupancy costs. Additionally, its carboxyl group competes with the 7-aminocephalosporanic acid for activated-ester formation, leading to dimeric impurities detected by LC–MS at m/z values consistent with symmetrical anhydride adducts. The trityl-protected form eliminates this competition because the free carboxylic acid remains available for selective activation while the oxime is blocked.
The mixed-anhydride method employing pivaloyl chloride and N-methylmorpholine in dichloromethane remains the most documented activation route on scale. Stoichiometry must be controlled to within ±2.5 mol%: an excess of pivaloyl chloride leads to formation of the pivaloyl ester of the cephalosporin at the C-3’ hydroxymethyl position in cefotaxime, detectable as an impurity eluting at relative retention time 1.3 in the pharmacopoeial HPLC system. The reaction exotherm is managed by dosing the chloroformate at −15 ± 5 °C, with the temperature of the subsequent coupling to the 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) derivative maintained at −5 to 0 °C for 45–60 minutes. In a 2000 L Hastelloy C-22 reactor equipped with a −25 °C brine jacket, deviation of the jacket outlet temperature by more than ±3 °C during addition has been observed to increase the bis-cephalosporin impurity (m/z 792) by 0.8–1.2 area% relative to baseline operation, sufficient to fail the ≤ 0.5% criterion for any single unknown impurity in cefotaxime sodium per Ph. Eur.
During aqueous work-up, the pH is brought to 4.5–5.0 with sodium bicarbonate, at which point the trityl-protected intermediate partitions into ethyl acetate. Phase separation requires a residence time of at least 20 minutes in a horizontal gravity decanter; attempts to accelerate the process via centrifugal extractors have resulted in fine emulsion stabilization traced to triphenylmethanol microparticles with a d₉₀ below 10 µm, mitigated only by the addition of 0.5 wt% Celite 545 filtration aid prior to extraction.
At ambient relative humidity (40–60% RH), the trityl ether undergoes hydrolytic cleavage with a rate constant of approximately 1.2 × 10⁻² h⁻¹ at 25 °C, generating the aforementioned free oxime and triphenylmethanol. Long-term storage data from 25 kg fiber drums sealed with double polyethylene liners and a silica gel desiccant sachet confirm stability for 24 months at 2–8 °C, with isomer ratio unchanged and water content remaining below 0.4%. Drums that have been opened under nitrogen in a glovebag and re-closed within 90 minutes do not exhibit statistically significant assay decline (p > 0.05) over three subsequent QC pull samples. In contrast, containers left open to atmosphere in a production bay with 55% RH and 22 °C ambient showed a 0.8% drop in assay within 4 hours, reinforcing that all weighing and charging operations must be performed under a nitrogen blanket with inlet dew point below −40 °C.
Compatibility with common desiccants has been examined; mixture with acidic clays or activated alumina causes catalytic detritylation, whereas neutral silica gel or molecular sieve 4A can be co-packed without decomposition. Recrystallization from iso-propanol–water (85:15 v/v) restores the X-ray powder diffraction pattern to the thermodynamically stable polymorph (Form I), distinguishable from the metastable Form II by characteristic peaks at 2θ = 9.8°, 12.4°, and 17.6° (Cu Kα radiation). Form II, occasionally observed in lots crystallized from ethyl acetate–hexane, exhibits a 5 °C lower melting onset and a dissolution rate in dichloromethane that is 1.4× faster, which has caused minor variability in activation time when processing mixed-form batches.
When co-shipment with amine-based reagents such as 1-hydroxybenzotriazole (HOBt) or dicyclohexylcarbodiimide (DCC) is unavoidable due to supply-chain consolidation, the product must be packaged in a separate, hermetically sealed container within the outer drum and labeled with a note prohibiting simultaneous opening. Amine vapors adsorb onto the crystalline surface and accelerate oxime deprotection even in the solid state, a degradation pathway confirmed by headspace GC–MS detection of ammonia at 0.5 µg per gram of stored powder after 72 hours of proximity at 25 °C.
