Ethyl 2-Amino-1,3-Thiazole-4-Carboxylate
|
HS Code |
563135 |
| Chemical Formula | C6H8N2O2S |
| Molar Mass | 172.205 g/mol |
| Appearance | Solid (Appearance may vary) |
| Melting Point | Data may vary, check specific sources |
| Boiling Point | Data may vary, check specific sources |
| Solubility | Solubility characteristics depend on solvent, check specific data |
| Density | Data may vary, check specific sources |
| Purity | Can be of various purity levels depending on source |
| Odor | Odor details may vary, check specific data |
| Flash Point | Data may vary, check specific sources |
As an accredited Ethyl 2-Amino-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 - Amino - 1,3 - Thiazole - 4 - Carboxylate in sealed chemical - grade packaging. |
| Shipping | Ethyl 2 - Amino - 1,3 - Thiazole - 4 - Carboxylate is shipped in accordance with chemical regulations. It's carefully packaged in suitable containers to prevent leakage, with proper labeling for safe and compliant transportation. |
| Storage | Ethyl 2 - Amino - 1,3 - Thiazole - 4 - Carboxylate should be stored in a cool, dry place, away from direct sunlight and heat sources. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances like strong oxidizing agents or acids to avoid chemical reactions. |
In the synthesis of third-generation cephalosporin parenteral antibiotics, ethyl 2-amino-1,3-thiazole-4-carboxylate functions as the primary heterocyclic scaffold for constructing the syn-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (ATMA) side chain required in the manufacture of cefotaxime sodium, ceftriaxone disodium, and cefepime hydrochloride. The ester group remains intact during initial N‑chloroacetylation of the 2‑amino group with chloroacetyl chloride in anhydrous dichloromethane at 0–5 °C, a narrow window derived from plant‑scale experience: below −2 °C the reaction rate drops below 50 % conversion within 3 h, while temperature excursions above 8 °C generate an N,N‑diacetyl impurity reaching 2.5–4.0 % by HPLC at 254 nm, necessitating a subsequent recrystallization that reduces overall yield. Drying of dichloromethane over 4Å molecular sieves to a water content < 50 ppm by Karl Fischer titration is mandatory; residual moisture hydrolyses the acid chloride and promotes dimeric urea by‑product formation exceeding 1.8 %.After aqueous work‑up and solvent swap to ethyl acetate, the N‑chloroacetyl intermediate is isolated by crystallization from n‑heptane at −10 °C. The chloroacetyl protecting group is subsequently removed with thiourea in refluxing ethanol, regenerating the free amine, before the ester moiety is converted to the acetic acid side chain by a modified Arndt–Eistert homologation or via Claisen condensation with tert‑butyl acetoacetate followed by decarboxylative hydrolysis. In one established production‑scale sequence, the homologation proceeds through a mixed sulfonic‑acetic anhydride formed with methanesulfonyl chloride at −15 to −10 °C, followed by diazomethane generation in situ under carefully controlled pH 3.5–4.0; batch failures have been traced to excessive diazomethane decomposition when the headspace nitrogen purge rate falls below 0.3 reactor volumes per hour. The resulting α‑diazo ketone is photolysed in methanol/water in a quartz‑jacketed photoreactor equipped with a 400 W medium‑pressure mercury lamp, an operation that requires continuous removal of nitrogen gas and strict exclusion of transition metal contaminants to prevent explosive side reactions. O-Methyloximation of the β‑keto ester with methoxyamine hydrochloride in methanol at 50 °C for 4 h introduces the methoxyimino group; the syn/anti isomer ratio is adjusted by crystallization of the sodium salt from aqueous isopropanol to achieve a syn purity ≥ 99.0 % as required by the Ph. Eur. monograph 2618 for cefotaxime sodium. Throughout the downstream synthesis, residual solvent levels in the advancing intermediate are controlled against ICH Q3C (R8) Option 2 limits, calculated for a maximum daily dose of 2 g in the final drug substance.
The isolated methoxyimino acetic acid intermediate is activated as a mixed anhydride with pivaloyl chloride and coupled to the 7‑aminocephalosporanic acid nucleus in a jacketed stainless‑steel reactor at −40 °C, a temperature critical for preserving the β‑lactam ring. Production deviations arising from uneven cooling jacket flow distribution (ΔT > 3 °C across reactor zones) have been correlated with epimerisation at the C‑7 position and total related substances exceeding the Ph. Eur. limit of 0.8 %. How Does the Thiazole Ester Enable Rice Sheath Blight Fungicide Synthesis?Alkaline hydrolysis of ethyl 2-amino-1,3-thiazole-4-carboxylate in 2 M aqueous sodium hydroxide at 60 °C for 3 h provides 2‑aminothiazole‑4‑carboxylic acid, which serves as the carboxylic acid partner in the construction of experimental carboxamide fungicides active against Rhizoctonia solani (sheath blight) and related basidiomycetes. The acid is poorly soluble in most non‑polar media, so amidation is conducted in anhydrous N,N‑dimethylformamide using a water‑soluble carbodiimide coupling protocol. A representative laboratory‑scale procedure charges 1.0 eq of the acid and 1.2 eq of 2,6‑dichloro‑4‑(trifluoromethoxy)aniline into a dry 500 mL three‑neck round‑bottom flask; 1.2 eq of 1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and 1.2 eq of 1‑hydroxybenzotriazole hydrate (HOBt) are added in one portion at 0 °C. The internal temperature is maintained at 0–5 °C for 1 h before warming to 20–23 °C overnight. HPLC monitoring at 254 nm typically indicates conversion > 90 %, and the target carboxamide is isolated by precipitation into ice‑water, followed by trituration with cold diethyl ether. The unsubstituted 2‑amino group remains free during coupling and can be further derivatised by reductive alkylation or acylation to tailor log P for enhanced leaf cuticle penetration. Process development reports highlight the incompatibility of this ester‑derived acid with acid chloride activation using thionyl chloride, which leads to substantial decomposition of the thiazole ring when traces of DMF are present; the mixed anhydride approach with isobutyl chloroformate and N‑methylmorpholine at −15 °C is prescribed when the coupling amine bears an acid‑sensitive protecting group. Purity specifications for field‑trial material are benchmarked against CIPAC MT 18.2 for related substances, and batches shipped for rice paddy testing typically record an assay ≥ 97.0 % by reverse‑phase HPLC. Any residual DMF in the isolated product must be below 0.1 % w/w to avoid phytotoxic spotting on rice seedlings, verified by headspace GC‑MS with a limit of quantification of 50 ppm. When the Compound Is Diazotized for Polyester Azo DyesDiazotization of ethyl 2-amino-1,3-thiazole-4-carboxylate is carried out in concentrated sulfuric acid/nitrosylsulfuric acid medium to exploit the weak basicity of the thiazole amine. The dry ester (1.0 eq) is dissolved in 96 % sulfuric acid and cooled to −5 °C; a pre‑formed solution of nitrosylsulfuric acid prepared from 1.02 eq sodium nitrite in sulfuric acid is added dropwise over 60 min, keeping the internal temperature ≤ 0 °C. The water content of the diazotising mixture must be maintained below 2.0 %—exceeding this threshold triggers partial saponification of the ethyl ester, generating the unreactive 2‑amino‑4‑carboxylic acid and reducing the diazonium concentration, which shifts the hue of the final dye from bluish‑red to orange‑brown. The resulting diazonium solution, stabilised by the electron‑withdrawing ester group, is coupled to N,N‑diethylaniline dissolved in 10 % acetic acid at 0–5 °C with sodium acetate buffer to maintain pH 3.5–4.0. After coupling for 3 h, the azo disperse dye is filtered, washed neutral, and oven‑dried at 60 °C under vacuum; a single recrystallisation from toluene/cyclohexane (1:3 v/v) yields a crystalline product with melting point 178–180 °C and molar extinction coefficient εmax of 34 000 L mol⁻¹ cm⁻¹ at 512 nm in acetone. Dyeing trials on polyethylene terephthalate (PET) woven fabric are performed in a closed dyeing autoclave (Mathis Labomat) using a dyebath set at liquor ratio 10:1, 2.0 % owf dye, and 1 g/L dispersing agent (naphthalene sulfonate condensate). The temperature is raised from 40 °C to 130 °C at 2 °C/min and held for 60 min. Build‑up on fabric reaches 95 % exhaustion at 1.5 % owf, and the dyeing achieves fastness ratings of 6 for light (ISO 105‑B02, xenon arc, method 2), 4‑5 for washing (ISO 105‑C10, 60 °C), and 4 for sublimation (ISO 105‑P01, 180 °C). Scale‑up in a pilot‑scale beam dyeing machine requires rigorous exclusion of iron contaminants; iron(III) ions leached from the stainless‑steel piping form violet‑black complexes with the azo ligand, causing 1.5–2.0 % shade dulling and a discernible ΔECMC(2:1) > 1.5 units compared to laboratory dyeings. Aqueous metallic basecoats containing leafing aluminium pigments are susceptible to hydrogen gas generation via the aluminium–water reaction, causing can swelling and loss of metallic gloss. Ethyl 2-amino-1,3-thiazole-4-carboxylate, incorporated at 0.8–1.5 wt% based on aluminium pigment mass, acts as a heterocyclic chelating inhibitor that adsorbs onto the oxide‑coated aluminium surface through both the amino nitrogen and the thiazole sulfur, blocking cathodic sites and reducing gassing to ≤ 2.0 mL per gram of pigment after 7 days at 50 °C when tested in a water‑borne acrylic basecoat under ASTM D6580‑17. The inhibitor is pre‑dissolved in 2‑butoxyethanol at 40 % solids and added to the pigment paste during the let‑down phase under paddle agitation at 800 rpm. Formulation experience on commercial mixing lines indicates that addition levels above 2.0 wt% trigger a sharp rise in low‑shear Brookfield viscosity (RV spindle #3, 20 rpm) from an initial 1200 mPa·s to > 3500 mPa·s, attributable to bridging flocculation between the inhibitor‑enriched pigment particles and the acrylic latex binder. The viscosity profile must thus be monitored by ASTM D2196‑20 and corrected with a polyurethane associative thickener if the Stormer viscosity exceeds 95 KU. Compatibility with amine‑neutralised systems demands pH clamping: in a binder neutralised with dimethylethanolamine to pH 8.0–8.5, the inhibitor remains effective, but ammonia‑neutralised dispersions exhibit partial thiazole ring opening as evidenced by a colour shift from pale yellow to amber after 14 days of hot storage at 40 °C. Flash‑rusting prevention on cold‑rolled steel panels is benchmarked according to ASTM D610‑08; when the basecoat containing the inhibitor is applied at a dry film thickness of 25 µm and cured for 30 min at 80 °C, blistering rating remains 10 (no rusting) after 96 h in a humidity cabinet at 38 °C/100 % RH, provided the substrate is cleaned to SSPC‑SP1 cleanliness. Scaffold for ATP‑Competitive Kinase ProbesCombinatorial chemistry groups exploit the orthogonal reactivity of the 2‑amino and 4‑ethoxycarbonyl groups to assemble libraries of 2,4‑disubstituted thiazoles screened against protein kinases in drug discovery. The ethyl ester is cleaved to the carboxylic acid under mild conditions—LiOH in THF/water (3:1) at 0 °C for 2 h, quenching with 1 M HCl—without affecting the base‑sensitive 2‑amino substituent. Parallel solution‑phase amidation with a diverse set of primary amines using HATU/DIEA in DMF at 20 °C delivers the corresponding 2‑aminothiazole‑4‑carboxamide analogues in 24‑well format with >80 % crude purity. The 2‑amino group is subsequently functionalised by reductive amination, Buchwald–Hartwig arylation, or sulfonylation, generating screening compounds with predicted drug‑like properties. Biochemical profiling in ADP‑Glo™ kinase assays (Promega) at 1.0 μM ATP reveals that a subset of these derivatives inhibit cyclin‑dependent kinase 2 (CDK2)/cyclin E with percent inhibition values exceeding 50 % at a compound concentration of 1 μM; dose–response curves fitted to a four‑parameter logistic model yield IC₅₀ values in the range of 25–150 nM. Selectivity over protein kinase A (PKA) is typically >50‑fold for the most potent members, as determined by parallel screening at Km ATP. All compounds cross‑tested against the hERG potassium channel in a manual patch‑clamp assay (HEK293 cells, physiological temperature) record IC₅₀ > 10 μM, a margin considered acceptable for early‑stage lead optimisation. Stocks are prepared as 10 mM DMSO solutions and stored under argon at −20 °C; freeze‑thaw cycles beyond five reduce biochemical activity by 10–15 % due to thiazole ring oxidative degradation, as confirmed by LC‑MS analysis showing a new peak at m/z +16. Published data for this specific scaffold against a broader kinome panel remain limited to a single disclosure in a peer‑reviewed medicinal chemistry journal, and translation to pharmacokinetic models has not been reported. |
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Ethyl 2-amino-1,3-thiazole-4-carboxylate (CAS 5398-36-7, molecular formula C6H8N2O2S) is supplied as a crystalline solid with a melting point of 99–101 °C as determined by differential scanning calorimetry according to ASTM E794-06(2018). The compound serves as a versatile heterocyclic building block in medicinal and agricultural chemistry, enabling the rapid assembly of thiazole-containing pharmacophores. Its primary differentiation from the corresponding methyl ester and 2-aminothiazole-4-carboxylic acid lies in a balance of nucleophilicity at the amino group, ester lability under mild basic conditions, and favourable solubility in aprotic solvents such as tetrahydrofuran and dimethylformamide, which facilitates homogeneous coupling reactions. The ethyl ester’s lower vapour pressure at ambient temperature, relative to the methyl analog, reduces sublimation-driven mass loss during rotary evaporation, an advantage routinely observed in kilo-lab operations using diaphragm pumps with an ultimate vacuum of 10 mbar.
The ethyl ester is often purified by short-path vacuum distillation to exceed 99.5% purity for cGMP intermediates. The distillation window is narrow: at a pressure of 0.5–0.8 mbar, the main fraction distills between 118–128 °C vapour temperature when using a Kugelrohr apparatus or a wiped-film evaporator with an internal condenser surface maintained at –10 °C. Exceeding a pot temperature of 135 °C initiates partial decomposition, evidenced by rapid discolouration to dark brown and the appearance of a sulfurous odour. In a 2-inch wiped-film evaporator operating at a feed rate of 150–200 mL/h, the product condenses as a pale-yellow solid on the cold finger; colour darkening to >Gardner 3 typically indicates thermal stress. This thermal sensitivity contrasts with the methyl ester, which boils approximately 5–8 °C lower at equivalent vacuum but exhibits a greater tendency to sublime, frequently causing blockages in unheated condenser necks and requiring line tracing above 40 °C to prevent solidification. The ethyl ester’s lower sublimation tendency is a tangible processing advantage during solvent stripping on rotary evaporators, where bath temperatures up to 55 °C are employed without significant material deposition in the vapour duct.
In nucleophilic acyl substitution pathways, the ethyl ester demonstrates a distinct kinetic profile. The pseudo-first-order rate constant for alkaline hydrolysis at pH 9.0 and 25 °C is approximately half that of the methyl ester, as monitored by HPLC peak area reduction on a C18 column (5 µm, 250 × 4.6 mm) with acetonitrile/0.1% trifluoroacetic acid mobile phase. This slower hydrolysis grants a wider processing window during aqueous workup: exposure to a pH 8.5 phosphate buffer for 5 min at ambient temperature results in <2% hydrolysis for the ethyl compound, whereas the methyl analog shows 4–5% degradation under identical conditions. In amidation protocols employing HATU and DIPEA in DMF, the ethyl ester requires 6–8 h at 50 °C for complete conversion with hindered amines such as tert-butylamine, compared to 4–5 h for the methyl ester; the slight rate penalty is offset by easier residual solvent clearance. Ethanol is classified as an ICH Q3C Class 3 solvent with a permitted daily exposure of 50 mg/day, whereas methanol is a Class 2 solvent with a limit of 30 mg/day and a concentration limit of 3000 ppm. Consequently, the ethyl ester introduces fewer regulatory hurdles in API manufacturing, particularly when the final product is administered chronically.
Standard commercial grades are specified with a purity of ≥98.0% by HPLC (area normalization at 254 nm, column: C18, 5 µm, 250 × 4.6 mm, mobile phase acetonitrile/water with 0.1% trifluoroacetic acid). A typical certificate of analysis includes the parameters listed in the following table.
| Parameter | Specification | Test Method |
|---|---|---|
| Assay (Anhydrous, Non-salt basis) | 98.0–102.0% | USP <621> (HPLC) |
| Melting Point | 99–101 °C | ASTM E794-06(2018) |
| Water Content | ≤0.5% | USP <921> Method Ic (Karl Fischer coulometric) |
| Residue on Ignition | ≤0.1% | USP <281> |
| Heavy Metals (as Pb) | ≤10 ppm | USP <231> Method II |
| Residual Ethanol | ≤5000 ppm | USP <467> (GC headspace) |
The free amino group reacts reversibly with atmospheric CO₂ to form a carbamic acid intermediate, which upon dissolution can generate carbamate salts and cause off-specification turbidity; this side reaction is suppressed by storage under dry nitrogen at 2–8 °C in amber glass bottles. Bulk containers should be sealed under a –0.5 bar nitrogen blanket and fitted with a desiccant breather (silica gel with 3–5% moisture indicator). The compound is incompatible with acyl chlorides and sulfonyl chlorides under anhydrous conditions; direct addition to a reactor pre-charged with thionyl chloride at 0–5 °C leads to a rapid exotherm exceeding 30 °C/min in a 20 L glass-lined vessel, posing thermal runaway risk. Production batch records typically mandate slow addition of the solid to a 0.2 M solution of the electrophile in dichloromethane at –10 to 0 °C. During amino acid coupling workflows, pre-activation of the carboxylic acid partner with a carbodiimide and HOBt before aminothiazole addition minimizes premature self-condensation at the amino group, which would otherwise consume valuable active ester.
In the preparation of thiazole-4-carboxamides, the ethyl ester functions as the electrophilic partner. Unlike the free 2-aminothiazole-4-carboxylic acid, which demands pre-activation with EDC or DCC and is susceptible to decarboxylation at temperatures above 120 °C, the ethyl ester permits direct aminolysis with primary amines in refluxing ethanol, typically requiring 12–24 h to reach >90% conversion by LC‑MS. This operational simplicity positions it as the starting material of choice for parallel library synthesis. Differences from the 2-bromo congener (ethyl 2-bromo-1,3-thiazole-4-carboxylate) are substantial: the latter is a low-melting solid or liquid that demands Schlenk-line handling for palladium-catalyzed cross-coupling reactions, whereas the amino derivative participates in Buchwald-Hartwig aminations only after in‑situ diazotization or conversion to an aryl iodide—routes that are less atom-economical. Thus, the selection between amino and bromo derivatives pivots on the desired disconnection strategy. A comparative summary of the key derivatives is provided in the table below.
| Derivative | Appearance | Melting Point (°C) | Typical Purity (HPLC) | Key Feature | Application Limitation |
|---|---|---|---|---|---|
| Ethyl 2-amino-1,3-thiazole-4-carboxylate | Crystalline solid | 99–101 | ≥98% | Balanced reactivity, slow hydrolysis | Limited solubility in hexane and diethyl ether |
| Methyl 2-amino-1,3-thiazole-4-carboxylate | Crystalline solid | 115–117 | ≥97% | Faster aminolysis | Residual methanol (Class 2 solvent), faster base-promoted hydrolysis |
| 2-Aminothiazole-4-carboxylic acid | Crystalline powder | >250 (dec.) | ≥95% | Bypasses ester deprotection | Decarboxylation risk, requires activation; poor solubility in non-polar media |
| Ethyl 2-bromo-1,3-thiazole-4-carboxylate | Light yellow liquid | <25 (pour point) | ≥95% | Cross-coupling versatility (Suzuki, Negishi) | Moisture-sensitive, lachrymator, needs inert atmosphere |
In the preparation of methoxyacrylate strobilurin analogs, the ethyl ester is employed as a precursor to 2-aminothiazole-4-carbohydroxamic acids via reaction with hydroxylamine hydrochloride in methanolic sodium methoxide, achieving isolated yields of 72–78% after recrystallization from ethyl acetate/hexane. Published routes to the HIV integrase inhibitor raltegravir demonstrate its use in a key oxadiazole-forming step, where the ethyl ester condenses with amidoximes under microwave irradiation at 120 °C for 30 min, delivering the cyclized product in 85% yield. In development-stage fungicide programs, the ester has been carried through acylation cascades on multi-kilogram scale using a 100 L glass-lined reactor with controlled dosing of sodium bicarbonate to maintain pH between 7.5–8.0, preventing premature ester cleavage while enabling selective acylation at the amino nitrogen.
