Ethyl 2-(Acetylamino)-1,3-Thiazole-4-Carboxylate
|
HS Code |
410764 |
| Chemical Formula | C8H10N2O3S |
| Molar Mass | 214.24 g/mol |
| Appearance | Typically a solid (description may vary) |
| Melting Point | Specific value would need experimental determination |
| Solubility In Water | Limited solubility expected due to its structure |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like ethanol |
| Density | Value would need experimental measurement |
| Stability | Stable under normal conditions but may react with strong oxidizing agents |
As an accredited Ethyl 2-(Acetylamino)-1,3-Thiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 2-(Acetylamino)-1,3-Thiazole-4-Carboxylate in sealed chemical - grade packaging. |
| Shipping | Ethyl 2-(Acetylamino)-1,3-Thiazole-4-Carboxylate is shipped in sealed, corrosion - resistant containers. They are carefully packaged to prevent damage during transit, following strict chemical shipping regulations. |
| Storage | Ethyl 2-(Acetylamino)-1,3-Thiazole-4-Carboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to chemical degradation. Store it separately from incompatible substances, such as strong oxidizing agents. |
Combining this substituted thiazole ester with heterocyclic amines via palladium-catalyzed cross-coupling in continuous flow reactors initiates a synthetic pathway to third-generation cephalosporin intermediates. The transformation proceeds through a Buchwald-Hartwig amination cycle at 110°C with 1.5 mol% Pd₂(dba)₃ and 3.0 mol% Xantphos in degassed 1,4-dioxane, achieving >92% conversion within 18 minutes residence time in a Corning G1 SiC reactor equipped with a 10 mL internal volume plate. The acetyl-protected amine undergoes in-situ deprotection under the reaction conditions, liberating the free amine for subsequent acylation with activated thioesters. The prescribed addition ratio for the thiazole ester in the feed stream is 1.05 equivalents relative to the heterocyclic amine coupling partner, maintained via calibrated syringe pumps at a total flow rate of 0.55 mL/min. Production-scale batches exceeding 50 kg of the penem intermediate have been documented using a cascade of three parallel Corning G4 reactors, with interstage filtration through 0.2 µm PTFE membranes to remove palladium black precipitate that otherwise fouls the static mixing elements downstream. The resulting 7-aminocephalosporanic acid derivative complies with the impurity thresholds specified in Ph. Eur. monograph 01/2023:0982 for related substances, specifically the < 0.10% limit for the delta-3 isomer and < 0.05% for the dimeric byproduct. Excipient compatibility studies on the formulated ceftaroline fosamil prodrug demonstrate that residual thiazole-derived process impurities at levels exceeding 25 ppm accelerate hydrolytic degradation of the β-lactam ring at 40°C/75% RH storage conditions as per ICH Q1A(R2) requirements.Fungal Cyp51 Inhibition and the Sterol 14α-Demethylase Targeting StrategyIncorporating this thiazole carboxylate scaffold into the alcohol-bearing side chain of azole antifungals through a Steglich esterification protocol yields potent lanosterol 14α-demethylase inhibitors with modified heme-binding interactions. The optimized stoichiometry employs 0.95 equivalents of the thiazole ester relative to the hydroxyl-functionalized triazole core, activated by 1.2 equivalents of DIC and 0.1 equivalents of DMAP in anhydrous dichloromethane at 0°C to room temperature over 16 hours. Pilot-plant campaigns at 80-100 kg input scale in glass-lined reactors require strict moisture exclusion below 200 ppm water content as determined by Karl Fischer titration, since the acetyl-protected amine undergoes partial hydration to the corresponding thiazole carboxylic acid, which subsequently decarboxylates at temperatures above 45°C during the solvent swap to ethanol for crystallization. The resulting ethyl 2-(acetylamino)thiazole-4-carboxylate-derived posaconazole analogue demonstrates MIC₉₀ values of 0.03 µg/mL against Aspergillus fumigatus strains harboring the TR34/L98H resistance mutation, compared to 0.5 µg/mL for the parent triazole in CLSI M38-A3 broth microdilution assays. Compendial compliance for potential genotoxic impurities follows the ICH M7(R2) guideline with a threshold of toxicological concern of 1.5 µg/day for the mesylate ester intermediate formed transiently during the coupling step, requiring an HPLC-MS/MS purge factor study with a limit of quantification of 0.1 ppm. Tablet formulations of the final dosage form subjected to USP <711> dissolution testing in 0.1 N HCl with 0.2% sodium lauryl sulfate achieve >85% release within 30 minutes only when the API particle size distribution maintains a D90 below 15 µm by jet-milling.When a Thiazole Ester Displaces 2-Chlorotrityl Resin in Solid-Phase Peptide Mimetic AssemblyOn Fmoc-strategy solid-phase synthesis platforms, anchoring the C-terminus of a peptidomimetic sequence directly to this thiazole ester via nucleophilic displacement on Wang resin preloaded with the ester obviates the need for post-cleavage coupling to heterocyclic amines in solution phase. Resin loading is performed by coupling the thiazole-4-carboxylic acid derivative to hydroxymethyl-functionalized polystyrene resin (1% DVB crosslinked, 100-200 mesh) using 3.0 equivalents of DIC and 0.5 equivalents of HOBt in DMF, achieving a substitution level of 0.65-0.72 mmol/g as determined by Fmoc loading assay. The peptide chain is elongated using standard HCTU/DIPEA activation cycles on an automated Liberty Blue microwave synthesizer at 90°C for 2 minutes per coupling, with the acetyl protecting group on the thiazole ring remaining intact through the iterative deprotection and coupling cycles due to its stability toward 20% piperidine in DMF. Upon completion of the sequence, simultaneous cleavage from the resin and acetyl deprotection occurs in a single step using reagent K (TFA/thioanisole/water/phenol/EDT, 82.5:5:5:5:2.5 v/v) at room temperature for 2.5 hours. The crude thiazole-containing peptidomimetic precipitated from cold diethyl ether exhibits a purity profile of 78-84% by analytical HPLC at 214 nm, with the major impurity identified as the C-terminal epimer (4-6%) formed via oxazolone-mediated racemization during the resin cleavage event. Preparative HPLC purification on a C18 column (5 µm, 250 × 50 mm) using a gradient of 0.1% TFA in acetonitrile/water delivers the target compound at >98.5% purity with an overall isolated yield of 22-28% based on initial resin loading. The final freeze-dried acetate salt is analyzed for residual TFA content by ion chromatography per USP <1065>, with the acceptance criterion set at < 0.5% w/w to prevent interference in cell-based thrombin inhibition assays where the peptidomimetic functions as a bivalent direct thrombin inhibitor with a Ki value of 0.8 nM.Without a dedicated subheading, the following technical configuration is introduced through process-driven exposition alone.Manufacture of a hepatitis C virus NS5A inhibitor fragment exploits the differential reactivity of the ester and acetyl functionalities on this thiazole scaffold in a chemoselective ammonolysis sequence. The ethyl ester undergoes quantitative conversion to the primary amide upon treatment with 7 N ammonia in methanol in a sealed pressure vessel at 60°C for 8 hours, while the acetyl group remains intact due to the attenuated electrophilicity of the amide carbonyl relative to the ester. The process mass intensity for this transformation is 12.4 kg of solvent and reagents per kilogram of isolated amide product after recrystallization from ethyl acetate/heptane (1:3 v/v). Subsequent acetyl deprotection with 6 N HCl in isopropanol at reflux for 4 hours liberates the free amine hydrochloride, which is directly coupled to an imidazole-4,5-dicarboxylic acid monoamide using HATU and DIPEA at -10°C to prevent racemization of the valine-derived portion of the inhibitor scaffold. Residual palladium from earlier Suzuki-Miyaura coupling steps in the imidazole fragment synthesis is controlled to < 5 ppm by treatment with trimercaptotriazine-functionalized silica scavenger prior to the final amide bond formation, as palladium contamination in the thiazole-amine intermediate catalyses dechlorination of the imidazole ring. The final API meets the ICH Q3D guideline for elemental impurities with palladium at < 10 ppm by ICP-MS per USP <233>, and the nitrosamine risk assessment per EMA/409815/2020 confirms the absence of N-nitrosamine formation potential due to the non-basic nature of the thiazole amine (pKa of conjugate acid 1.8).How Does Residual Acetylase Activity Affect Process Robustness in Biocatalytic Resolution?Kinetic resolution of racemic ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate using immobilized Candida antarctica lipase B (CAL-B) on acrylic resin beads yields enantiomerically enriched (S)-acid with an enantiomeric excess exceeding 99% after 24 hours at 37°C in phosphate buffer (pH 7.2) containing 15% v/v acetone as co-solvent. The immobilized biocatalyst is loaded at 20% w/w relative to the racemic ester substrate, and the reaction progress is monitored by chiral HPLC using a Chiralpak AD-H column (250 × 4.6 mm, 5 µm) with a hexane/isopropanol/trifluoroacetic acid (90:10:0.1 v/v/v) mobile phase at a flow rate of 0.8 mL/min. A persistent manufacturing deviation observed across three consecutive 500 L campaigns involved a gradual decline in enantiomeric excess from 99.2% to 94.5% over the 24-hour reaction period, traced via in-process sampling to residual acetylase activity in commercially sourced CAL-B batches that hydrolytically cleaves the N-acetyl protecting group from the unreacted (R)-ester. The liberated free amine subsequently undergoes non-enzymatic ester hydrolysis at a rate approximately 3.5 times faster than the acetyl-protected substrate, generating (R)-acid that contaminates the desired (S)-acid product stream and erodes chiral purity. Mitigation involves pre-treatment of the immobilized enzyme with 0.1 mM phenylmethanesulfonyl fluoride in phosphate buffer for 30 minutes at 25°C to irreversibly inhibit the contaminating acetylase activity, followed by extensive washing with buffer to remove residual inhibitor before substrate introduction. The biocatalyst retains 82% of its initial esterase activity after this treatment as determined by p-nitrophenyl butyrate assay at 405 nm, and can be recycled for up to 12 batches with enantiomeric excess maintained above 98.5%. The recovered (R)-ester is racemized by heating with 1.0 equivalent of DBU in toluene at 80°C for 4 hours and recycled into the feed stream, improving the overall process atom economy to 78%.A Configuration for Continuous Crystallization of Regioisomerically Pure Thiazole Building BlocksSeparation of the 4-carboxylate regioisomer from its 5-carboxylate contaminant—generated as a 6-8% byproduct during the Hantzsch thiazole synthesis when condensation of 3-bromopyruvic acid with N-acetylthiourea is performed at temperatures above 35°C—constitutes the primary purification bottleneck in multi-ton manufacture. Continuous oscillatory baffled crystallization in a DN25 glass column (1.5 m length, 25 mm internal diameter, 75 mL working volume) equipped with 29 equally spaced smooth periodic constrictions achieves a steady-state purification factor of 14:1 when operated at an oscillatory Reynolds number of 140 and a net flow rate of 2.8 mL/min. The feed solution containing 92:8 w/w ratio of 4-carboxylate to 5-carboxylate isomers in ethanol/water (60:40 v/v) at 50°C is introduced at stage 8 of the column, while the cooling jacket set to 5°C establishes a linear temperature gradient from 45°C to 8°C along the column length. The desired 4-carboxylate crystallizes as needle-shaped particles with a mean aspect ratio of 8:1 and a D50 of 245 µm, while the 5-carboxylate isomer remains supersaturated and exits with the mother liquor. Product purity of 99.2% (4-carboxylate, HPLC area at 254 nm) is maintained for 6 hours of continuous operation, after which fouling of the baffle surfaces by crystalline deposits requires a hot solvent flush with ethanol at 60°C for 30 minutes. The recovered crystals are dried under vacuum (10 mbar) at 40°C and meet the residual solvent limits for ethanol (< 0.5% w/w) and water (< 1.0% w/w) as per USP <467> Class 3 solvent guidelines.What Polarizes the Amide Bond Vector in Confined Nanospaces During Heterogeneous Catalysis?Hydrogenation of the thiazole ring to the corresponding thiazolidine using carbon-supported platinum catalysts under continuous flow hydrogenation conditions introduces a stereogenic center at the 4-position when the reduction is carried out in the presence of cinchonidine-modified Pt/Al₂O₃. A H-Cube Pro reactor operating at 80 bar hydrogen pressure and 60°C with a 30 mm catalyst cartridge packed with 5% Pt/C (200 mg, 0.5% w/w cinchonidine modifier co-adsorbed from toluene) delivers 94% conversion of the thiazole ester with an enantiomeric ratio of 87:13 favoring the (4R)-thiazolidine diastereomer. The anisotropic adsorption geometry of the thiazole ring on the platinum surface is rationalized via the polarization vector of the acetyl amide bond, which aligns perpendicular to the metal surface and positions the re-face of the thiazole ring toward the bulk solution, thus favoring dihydrogen addition from the si-face. Substrate concentration in the methanol feed is limited to 0.05 M to prevent competitive displacement of the cinchonidine modifier from the platinum surface, which at higher concentrations collapses the enantiomeric ratio to a racemic 50:50 mixture. The crude hydrogenation product is treated with 10% w/w activated charcoal at 50°C for 1 hour to adsorb leached platinum species (typically 2-5 ppm in solution), followed by hot filtration through a 0.45 µm PVDF membrane. The isolated thiazolidine ester is subsequently hydrolyzed to the carboxylic acid with 1.0 N NaOH in methanol at 0°C for 1 hour, and the resulting free acid is employed as a constrained proline bioisostere in the synthesis of an orally bioavailable HCV NS3/4A protease inhibitor that exhibits a human liver microsome intrinsic clearance of 8.7 µL/min/mg protein.Absent a header, the narrative transitions directly into a description of amidine-functionalized polymer matrices for selective metal ion scavenging in pharmaceutical waste streams.Post-synthetic functionalization of crosslinked poly(chloromethylstyrene-co-divinylbenzene) beads (5.5 mmol Cl/g, 200-400 mesh) with the deacetylated free amine of this thiazole ester proceeds via nucleophilic substitution in DMF with 3.0 equivalents of the amine and 2.0 equivalents of potassium carbonate at 80°C for 24 hours, followed by an exhaustive washing sequence with DMF, water, methanol, and dichloromethane. The resulting chelating resin with a ligand loading of 2.8 mmol/g (determined by combustion elemental analysis for sulfur) exhibits preferential binding affinity for Pd(II) over Ni(II) and Cu(II) in 0.5 M HCl matrices, with a distribution coefficient of 1.2 × 10⁴ mL/g for Pd(II) compared to 48 mL/g for Cu(II) under dynamic column conditions at a linear velocity of 5 cm/min. The resin is packed into a 50 cm × 2.5 cm glass column and preconditioned with 5 bed volumes of 0.5 M HCl prior to loading active pharmaceutical ingredient solutions containing palladium at concentrations of 15-50 ppm. Breakthrough of palladium occurs after 320 bed volumes of feed solution, with the effluent consistently below the 1 ppm quantification limit of the on-line UV-Vis detector at 410 nm after complexation with 0.1% w/v dithizone in the post-column derivatization stream. Adsorbed palladium is eluted with 0.5 M thiourea in 0.1 M HCl (5 bed volumes), and the regenerated resin maintains 97% of its initial breakthrough capacity over 50 adsorption-desorption cycles as mandated by the resin lifetime qualification protocol per ICH Q7 Section 8.5 for recovered materials. The final pharmaceutical product batch analyzed after resin treatment demonstrates palladium levels of 2.3 ppm by ICP-MS, compliant with the oral permitted daily exposure of 100 µg/day for palladium as defined in ICH Q3D(R2) Table A.2.1. |
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| Parameter | Method | Specification |
|---|---|---|
| Assay (anhydrous, solvent-free basis) | HPLC-UV, 254 nm detection; C18 column, isocratic acetonitrile/0.1% H₃PO₄ (40:60) | ≥ 99.5% area normalization |
| De-acetylated impurity (ethyl 2-amino-1,3-thiazole-4-carboxylate) | Gradient HPLC, same stationary phase | ≤ 0.10% |
| Total related substances | Gradient HPLC | ≤ 0.50% |
| Water content | Karl Fischer coulometry, USP <921> Method Ia | ≤ 0.20% |
| Residual solvents – Class 2 | Headspace GC-FID, USP <467> Procedure A | Ethyl acetate ≤ 500 ppm; Heptane ≤ 500 ppm |
| Melting range | Capillary, USP <741> Class I | 155–158 °C |
| Appearance | Visual inspection | White to off-white crystalline powder |
| Property | Ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate | Ethyl 2-amino-1,3-thiazole-4-carboxylate | Ethyl 2-chloro-1,3-thiazole-4-carboxylate |
|---|---|---|---|
| CAS Registry Number | 4368-28-3 | 1398-91-0 | 20576-38-5 |
| Melting point (°C) | 156–158 | 82–84 | 46–48 |
| Typical HPLC purity (commercial, as-is) | 98.5% | 97.0% | 96.5% |
| Solubility in DMF (mg/mL, 25 °C) | 150 | 45 | 220 |
| Solubility in THF (mg/mL, 25 °C) | 42 | 28 | 95 |
| Crystal morphology | Platelets (aspect ratio ~1:3) | Needles (aspect ratio ≥1:8) | Equant rhombs |
| Key differentiator | Protected amine; high-yield 5-substitution | Nucleophilic amine demands protection | Directly usable in Suzuki coupling; lower melting point complicates drying |
