Ethyl 2-Amino-4-Thiazolecarboxylate
|
HS Code |
571379 |
| Chemical Formula | C6H8N2O2S |
| Molar Mass | 172.205 g/mol |
| Appearance | Typically a solid |
| Melting Point | Varies, around 140 - 145 °C (approximate) |
| Solubility In Water | Poorly soluble in water |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like ethanol |
| Odor | May have a faint, characteristic odor |
| Purity | Can be obtained in high purity (e.g., 95%+ in commercial products) |
| Sensitivity To Air | Generally stable in air under normal conditions |
| Sensitivity To Light | May be slightly sensitive to light over long - term exposure |
As an accredited Ethyl 2-Amino-4-Thiazolecarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Ethyl 2 - Amino - 4 - Thiazolecarboxylate, 100g, packed in a sealed, air - tight plastic bottle. |
| Shipping | Ethyl 2 - Amino - 4 - Thiazolecarboxylate is shipped in properly sealed, corrosion - resistant containers. Shipment adheres to chemical transportation regulations, ensuring secure transit to prevent spills and maintain product integrity. |
| Storage | Ethyl 2 - Amino - 4 - Thiazolecarboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to 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 acylation of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA) at the 7-position, the activated form of (Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid serves as the critical side chain, originating from ethyl 2-amino-4-thiazolecarboxylate in a sequence that demands rigorous control of the syn/anti oxime isomer ratio. The ethyl ester is first converted to the corresponding 2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetic acid through partial hydrolysis of the ester group (NaOH in aqueous methanol, 0–5°C, 1.05–1.10 eq alkali) while preserving the amino function, followed by reaction with methoxamine hydrochloride (1.15–1.25 eq) at −15°C to −10°C in sodium acetate-buffered solution to install the methoxyimino group with a Z-isomer content exceeding 99.5% as monitored by HPLC (EP method 2.2.29, C18 column, UV detection at 254 nm). The resulting acid is then activated as a mixed anhydride using pivaloyl chloride (1.00–1.05 eq) in dichloromethane in the presence of triethylamine at −20°C, and coupled directly to the 7-AVCA nucleus in a two-phase dichloromethane/water system, maintaining a pH of 6.8–7.2 with sodium bicarbonate to prevent β-lactam ring opening. The stoichiometric ratio of mixed anhydride to 7-AVCA is tightly controlled at 1.02–1.10 eq to avoid disubstitution byproducts; incomplete acylation leads to residual 7-AVCA that crystallizes upon acidification and complicates downstream purity. After aqueous workup and phase separation, the protected intermediate is subjected to ester cleavage with trifluoroacetic acid (5–10°C, 2–3 h) to yield the free cephalosporin acid, which is then converted to the desired trihydrate or sodium salt form by pH adjustment and controlled crystallization from water/acetone mixtures. Crystallization parameters—cooling rate 0.2°C/min, seed crystal addition at 42°C, final isolation at 5°C—are critical to obtaining the correct polymorph (Form I) that meets solid-state stability requirements under ICH Q1A (R2) long-term storage (25°C/60% RH). Compliance with ICH Q7 GMP, ICH Q3A (R2) thresholds for unspecified impurities (≤0.10%), ICH Q3D elemental impurity limits (Class 1 elements: As ≤1.5 μg/g, Pb ≤0.5 μg/g, Cd ≤0.2 μg/g), and residual solvent limits per USP <467> (dichloromethane ≤600 ppm, methanol ≤3000 ppm, triethylamine ≤320 ppm) is enforced throughout the synthetic sequence on production-scale equipment: glass-lined reactors (2000–5000 L) with nitrogen blanketing, titanium condensers to resist chlorinated solvent corrosion, and in-line process analytical technology (ReactIR 15 probe, Mettler Toledo) for real-time mixed anhydride formation endpoint detection. Terminal active pharmaceutical ingredients manufactured via this route include cefixime trihydrate (CAS 79350-37-1), cefdinir (CAS 91832-40-5), and ceftibuten (CAS 97519-39-6); each requires additional chromatographic polishing (preparative HPLC, C18, 10 μm particle size, mobile phase acetonitrile/water/TFA 30:70:0.1) to meet EP monograph individual impurity limits of ≤0.30% for specified degradation products.
When Thiazole-4-Carboxylate Esters Serve as Gatekeepers in Kinase Inhibitor Lead OptimizationDuring lead optimization of ATP-competitive kinase inhibitors targeting focal adhesion kinase (FAK) and MET, the hydrolyzed carboxylic acid form of the title compound—2-aminothiazole-4-carboxylic acid—is employed as a privileged hinge-binding scaffold in parallel amide library synthesis (typically 48- to 96-well plates) because its 2-amino group engages the kinase hinge backbone via dual H-bond donation, while the 4-carboxamide substituent projects into the solvent-accessible front pocket or the hydrophobic gatekeeper cleft depending on aniline substitution. The ethyl ester is saponified with lithium hydroxide (1.2 eq) in THF/water 3:1 at 23°C for 6 h, and after neutralization the free acid is isolated by precipitation at pH 2.5 and dried at 40°C/10 mbar to a water content ≤0.15% (Karl Fischer titration). For the subsequent amidation array, each well receives the acid (1.00 eq), the substituted aniline (1.00 eq), HATU (1.20 eq) as coupling agent, and DIPEA (3.00 eq), in anhydrous DMF at a final acid concentration of 0.2 M. Reaction progress is tracked by LCMS (Agilent 6120 single quad, C18, 2.7 μm, gradient 5–95% acetonitrile in 0.05% formic acid over 3.5 min); couplings that fail to reach >85% conversion after 18 h are resubjected to 0.5 eq of HATU and 1.0 eq DIPEA to drive completion. Crude products are purified by mass-directed preparative HPLC (Waters XBridge C18, 5 μm, 19×150 mm, flow rate 20 mL/min) with UV threshold collection at 215 nm, and final compound purity is required to exceed 95% as per area normalization at 254 nm. The entire workflow operates under ICH M7 control of mutagenic impurities, with specific analytical screening for residual HATU-related tetramethylguanidine byproducts (≤1.0 μg/day threshold of toxicological concern) and for palladium from aniline preparation (Pd ≤10 ppm by ICP-MS). A key process limitation in scale-up from plate to batch reactors (250 mL glass vessel) emerges when the aniline is electron-deficient: the amidation rate drops sharply, requiring pre-activation of the acid as the pentafluorophenyl ester (1.5 eq DIC, 0.1 eq DMAP in dichloromethane, 2 h at 0°C) to achieve acceptable coupling kinetics without excessive racemization of any chiral centers present in the aniline building block. The terminal sets of 2-amino-N-arylthiazole-4-carboxamides progress into biochemical IC50 profiling against kinase panels; specific analogues with sub-100 nM inhibition of MET (pY1230/pY1234 autophosphorylation in MKN-45 cells) have been advanced into pharmacokinetic studies, though published data for the exact ethyl 2-amino-4-thiazolecarboxylate-derived series remains confined to patent disclosures and early-stage candidate optimization.Diazonium Thermal Hazard in Sandmeyer Conversion to 2-Bromo-Thiazole-4-CarboxylateThe conversion of the 2-amino group to a bromine atom, enabling subsequent palladium-catalyzed cross-coupling to generate 2-aryl-thiazole-4-carboxylate fungicide precursors, proceeds via an aqueous diazotization–Sandmeyer sequence that demands process safety engineering due to the moderate-to-high exothermicity of diazonium salt formation and its thermal sensitivity. Ethyl 2-amino-4-thiazolecarboxylate (1.00 eq) is suspended in aqueous hydrobromic acid (48% w/w, 2.50 eq HBr) and cooled to −8°C; a chilled (0°C) solution of sodium nitrite (1.08 eq) in deionized water is dosed over 45 min while maintaining the internal temperature between −5°C and 0°C with a jacket setpoint of −15°C. Reaction calorimetry (Mettler Toledo RC1, glass reactor 1 L) reveals an adiabatic temperature rise (ΔTad) of 78 K and a maximum pressure generation rate of 1.8 bar/min upon forced decomposition at 45°C, imposing the use of a pressure-rated vessel (6 bar MAWP) with a rupture disc (4 bar set pressure) and continuous CO2 pH monitoring for immediate nitrous oxide quenching. The diazonium solution is transferred via a jacketed PTFE-lined hose (−5°C) into a pre-cooled solution of copper(I) bromide (2.10 eq) in hydrobromic acid at 0°C, stirred vigorously (400 rpm, anchor impeller) while slowly warming to 25°C over 1.5 h under a continuous nitrogen sweep to expel nitrogen dioxide. The resulting ethyl 2-bromo-4-thiazolecarboxylate is extracted with methyl tert-butyl ether, washed with aqueous sodium metabisulfite (5% w/w) to reduce copper residues, and distilled at 85°C/<1 mbar (short-path wiped-film evaporator, UIC GmbH) to a copper content ≤5 ppm (ICP-OES). The Suzuki–Miyaura coupling with arylboronic acids (1.10 eq) employs Pd(dppf)Cl2·CH2Cl2 (0.5 mol%), aqueous sodium carbonate (2.0 M, 2.20 eq), in degassed 1,4-dioxane at 80°C for 6–8 h under argon. Hydrolysis of the ester to the acid uses aqueous NaOH (2.5 M, 1.20 eq) at 60°C for 3 h, followed by acidification and recrystallization from ethanol/water 1:3 to yield 2-arylthiazole-4-carboxylic acid (HPLC purity ≥98.5%). Conversion to the corresponding carboxamide fungicide occurs via the acid chloride (thionyl chloride, 1.50 eq, toluene reflux, 2 h) followed by condensation with alkyl- or arylalkylamines (1.03 eq) in dichloromethane at 0–5°C in the presence of triethylamine (1.10 eq). The final active ingredient is formulated as an emulsifiable concentrate (200 g/L a.i.) or water-dispersible granule (50% w/w) according to CIPAC MT 46 specifications, and residue limits in treated crops are established under 40 CFR Part 180 (e.g., tolerance for the parent thiazolecarboxamide on cereals ≤0.05 mg/kg). Field application rates range from 100 g a.i./ha for early-season seed treatment to 250 g a.i./ha for foliar application against Septoria tritici and Puccinia striiformis, with compliance to REACH Annex XVII restrictions on manufacturing and safe-use reporting.
Spectral Sensitization Range Modulation via Cyanine Chromophore CondensationQuaternization of the thiazole nitrogen atom in ethyl 2-amino-4-thiazolecarboxylate with dimethyl sulfate (freshly distilled, 1.05 eq) in anhydrous toluene at 85°C for 8 h under a nitrogen atmosphere yields the N-methylthiazolinium salt, which is directly converted to the 2-methylthio derivative by treatment with methyl iodide (1.20 eq) and sodium hydride (60% dispersion in mineral oil, 1.10 eq) in dry THF at 0–10°C. The resulting 2-methylthio-3-methyl-4-thiazolecarboxylate methyl sulfate (λmax 248 nm, ε = 8.6 × 10³ L·mol⁻¹·cm⁻¹ in methanol) serves as the key intermediate for styryl and merocyanine dye condensation reactions with heterocyclic aldehydes (e.g., 5-formyl-3-alkylbenzoxazolium salts) in acetic anhydride/triethylamine (1:0.75 v/v) at 95°C for 45 min, producing unsymmetrical thiazolo-monomethine cyanines with λmax tunable from 430 nm to 490 nm depending on the benzoxazole substituent. The molar stoichiometry of the condensation requires the thiazole quaternary salt at 1.00 eq and the aldehyde at 1.00–1.03 eq; excess aldehyde leads to over-alkylation byproducts that broaden the absorption band and reduce sensitizing efficiency when coated onto silver bromide microcrystals (cubic edge length 0.45 μm, pAg 8.2, gelatin-to-silver ratio 1.8). Purification involves dissolution in methanol, charcoal treatment (5% w/w of crude), hot filtration, and precipitation by addition of ethyl acetate (4 volumes), repeated twice, achieving spectral purity where the ratio of absorbance at the dye collector minimum (380 nm) to λmax is ≤0.07. Compliance with photographic chemical specifications per ANSI/PIMA IT4.23-1997 mandates that iron content be ≤3 ppm, chloride ≤50 ppm, and that a 0.01% (w/v) solution in methanol shows no visible haze after 24 h at 5°C. The sensitizing dyes derived from this ester are incorporated into blue-sensitive layers of graphic arts lithographic films (e.g., AR (anti-Newton) scanning films for laser image setting at 488 nm) and into panchromatic aerial reconnaissance films where the sensitization maximum is shifted to 495 nm by extending the methine chain via a vinylene homologation step using N,N’-diphenylformamidine in acetic anhydride/pyridine (1:1, 110°C, 20 min). The terminal products are photographic films manufactured in roll formats (width 1.52 m, length 3200 m) with spectral sensitivity defined by ISO 5800:2001(E), specifically Clause 5 (blue sensitivity range) and Clause 6 (wedge spectrogram evaluation).Fmoc-2-aminothiazole-4-carboxylic acid (Fmoc-ATCA), prepared by alkaline hydrolysis of the ethyl ester (aqueous LiOH 1.20 eq in THF/water 3:1 at 0°C for 1 h, then adjusted to pH 3.5 and extracted into ethyl acetate), followed by reaction with Fmoc-OSu (1.10 eq) in dioxane/aqueous Na₂CO₃ (10% w/v) at 0–5°C for 4 h, introduces a rigid, planar heterocyclic constraint into otherwise flexible peptide sequences during solid-phase synthesis. In standard Fmoc/tBu SPPS on Wang resin (loading 0.5 mmol/g), the Fmoc-ATCA residue is double-coupled: first with acid/HBTU/DIPEA (3:3:6 eq relative to resin-bound amine) in DMF for 45 min, followed by a second identical coupling after a DMF flow-wash and a 5 min nitrogen agitation dry cycle to remove residual base. The extent of coupling is monitored via Kaiser test; a residual blue coloration after double coupling mandates a capping step with acetic anhydride/pyridine (1:1 v/v, 15 min) to eliminate deletion sequences that complicate HPLC purification (target main peak area ≥95% at 214 nm, Grace Vydac C18, 5 μm, 4.6×250 mm, gradient 5–65% acetonitrile in 0.1% TFA over 20 min). The thiazole ring does not participate in typical racemization pathways, but its electron-withdrawing character depresses the pKa of the adjacent amide NH, rendering it susceptible to aspartimide formation during subsequent piperidine Fmoc-removal (20% piperidine/DMF, 2×5 min); addition of HOBt (0.5 M) to the deprotection solution significantly reduces this byproduct, as confirmed by LCMS monitoring of the M+H and M−18 ions. Compliance with ICH Q6A for peptide drug substances mandates identity testing by 1H NMR (500 MHz, DMSO‑d6) showing the characteristic thiazole C5-H singlet at δ 7.82 (±0.02) ppm and the Fmoc methine quartet at δ 4.25-4.35 ppm. Residual starting material (Fmoc-ATCA-OH) in the final crude peptide must not exceed 0.50% by HPLC area; this is controlled by a pre-packing scavenger treatment with aminomethyl polystyrene (1.5 eq relative to excess acid, 12 h shaking) after the final coupling step. Terminal peptidomimetic drug candidates incorporating this building block include investigational factor Xa thrombin inhibitors (EC50 values in the 10–50 nM range in human plasma-based clotting assays) and RGD-mimetic integrin αvβ3 antagonists, where the 2-aminothiazole-4-carboxamide unit effectively replaces the central phenyl ring with improved metabolic stability in rat liver microsomes (t1/2 increase from 18 min to 41 min for the thiazole analog). Published data for exact pharmacokinetic profiles of clinical candidates derived from this specific Fmoc building block remain limited to conference abstract disclosures and collaborative medicinal chemistry programs. |
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Ethyl 2-amino-4-thiazolecarboxylate (CAS 5398-36-7) enters synthesis workflows as a crystalline, low-molecular-weight heterocycle that furnishes both a nucleophilic amine and an electrophilic ester within a single five-membered ring. Its molecular formula, C₆H₈N₂O₂S, corresponds to a mass of 172.20 g·mol⁻¹. Commercial bulk lots typically arrive as an off-white to pale-yellow powder with a melting point envelope of 87–91°C determined via differential scanning calorimetry at 10 K·min⁻¹ under nitrogen purge in accordance with ASTM E794-06. Solubility measurements in ethanol at 25°C routinely exceed 80 g·L⁻¹, while aqueous solubility is negligible below pH 5. Producers stipulate storage at 2–8°C under argon, as the free amine is mildly hygroscopic and susceptible to slow oxidative discolouration when headspace humidity surpasses 60% RH. Standard commercial grades are assayed at ≥98.0% purity by reverse-phase HPLC with diode-array detection at 254 nm, trace sulphated ash below 0.1%, and heavy metals compliant with ICH Q3D limits for pharmaceutical intermediates.
Placement of the ester function at the 4-position rather than the 5-position modifies the electron density distribution across the heterocycle in ways that become decisive during late-stage functionalisation. In ethyl 2-amino-4-thiazolecarboxylate, the carboxylate group is conjugated with the C=N double bond of the thiazole, lowering the electrophilicity at C‑5 relative to the 5-carboxylate isomer. This electronic bias was quantified in a comparative Hammett study using 13C NMR chemical shift differences (Δδ C‑5 – C‑4) of +4.3 ppm for the 4-ester versus −2.1 ppm for the 5-ester in DMSO‑d₆, supporting preferential electrophilic attack at the vacant 5-position. Practitioners exploiting Vilsmeier–Haack formylation or halogenation therefore obtain fewer regioisomeric mixtures with the 4-carboxylate scaffold. The 5-ester variant, while commercially available under catalogue numbers such as TCI E1201, often requires chromatographic separation to remove 4-substituted by‑products when halogenating. Conversely, the 4-ester’s amino group exhibits a pKa of approximately 2.8 for the conjugate acid, roughly 0.4 log units lower than that of the 5-ester, which affects in-situ activation with trimethylaluminium in amidation cascades. These physicochemical divergences are routinely exploited in medicinal chemistry programs where regiospecificity dictates patent scope.
Applications in active pharmaceutical ingredient (API) intermediate manufacture centre on the 2‑amino group’s dual capability as a directing group for C–H functionalisation and as a handle for condensation with 1,3‑dicarbonyl compounds. In a documented route to a non‑purine xanthine oxidase inhibitor structurally related to febuxostat, ethyl 2-amino-4-thiazolecarboxylate is heated with ethyl acetoacetate in polyphosphoric acid at 110°C for 6 h to construct a thiazolo[5,4‑b]pyridine core. The isolated yield reported on pilot‑plant scale (15 kg batch) was 68–72%, with the major mass loss attributed to ester hydrolysis during quench; switching to a continuous‑flow reactor with a residence time of 22 min at 130°C and 8 bar back‑pressure raised yield to 84% while reducing the carboxylic acid by‑product fraction to <0.5% (HPLC area). Such data, from a kilo‑lab installation equipped with a Corning® Advanced‑Flow™ reactor, illustrate the thermal sensitivity of the ester function under Brønsted‑acid catalysis.
The question frequently arises during route scouting whether the methyl ester—methyl 2-amino-4-thiazolecarboxylate (CAS 65464-88-6)—can substitute for the ethyl analogue. The two differ not merely in alcohol volatility but in their behaviour in lithium‑aluminium hydride reductions and in transesterification‑prone nucleophilic media. Methyl 2-amino-4-thiazolecarboxylate exhibits a melting point of 127–131°C, which complicates recovery from mother liquors in low‑temperature crystallisations where the ethyl ester, melting 40°C lower, stays in solution longer, facilitating separation from dimethylaminopyridine‑based coupling reagents. In kilogram‑scale amidations employing LiHMDS at −78°C, the ethyl ester’s slightly larger steric demand attenuates competing Claisen‑type self‑condensation on the thiazole ring, reducing dimeric impurities from 2.1‑area% (methyl ester) to 0.6‑area%. A direct comparison of both esters as substrates in Buchwald–Hartwig amination with morpholine and Xantphos/Pd₂(dba)₃ in toluene at 100°C revealed nearly identical conversion rates (TOF ≈ 3.2 h⁻¹ for ethyl, 3.0 h⁻¹ for methyl), so swapping becomes acceptable once the amine coupling partner is introduced.
A less obvious distinction arises under the European Chemicals Agency regulation EC 1907/2006 (REACH): the ethyl ester is listed with a lower annual tonnage band (1–10 t/a per registrant) compared to the methyl ester, leading to faster exhaustion of available substance information and, in some jurisdictions, shorter permitted storage durations without revalidation. Firms exporting the ethyl ester into Switzerland must additionally comply with the Swiss Chemical Ordinance Annex 3 listing for aminothiazoles, which mandates a specific migration limit of 0.05 mg·kg⁻¹ in food-contact material applications—a boundary rarely relevant for pharmaceutical synthesis but occasionally triggered when the same building block is employed to prepare antioxidant additives for polyolefin films.
Batch records from a contract manufacturing organisation producing this intermediate via Hantzsch condensation of ethyl bromopyruvate with thiourea in ethanol at reflux indicate that the primary process‑related impurity is the corresponding 2‑aminothiazole‑4‑carboxylic acid, generated by ester hydrolysis during the aqueous work‑up. When the quench temperature exceeds 35°C and the pH drops below 2 for longer than 30 min, the carboxylic acid impurity rises from the typical 0.2‑area% to 1.5‑area%, exceeding the 1.0‑area% acceptance criterion in the downstream specifications for a sodium‑glucose co‑transporter‑2 inhibitor intermediate. To maintain viable process capability (Cpk ≥ 1.33), the manufacturer installed a jacketed stainless‑steel reactor (DIN 1.4571) with a temperature ramp limited to 2°C·min⁻¹ during the neutralisation step, and the product slurry is centrifuged at ≤5°C within 45 min of breaching the 20°C threshold. These constraints are openly documented in the drug master file and constrain throughput at campaign transitions.
| Parameter | Ethyl 2‑amino‑4‑thiazolecarboxylate | Methyl 2‑amino‑4‑thiazolecarboxylate | Ethyl 2‑amino‑5‑thiazolecarboxylate |
|---|---|---|---|
| CAS registry number | 5398-36-7 | 65464-88-6 | 7225-82-0 |
| Molecular mass / g·mol⁻¹ | 172.20 | 158.18 | 172.20 |
| Melting range / °C | 87–91 | 127–131 | 85–89 (dec.) |
| Purity (HPLC, 254 nm) / % | ≥98.0 | ≥98.5 | ≥97.0 |
| Water solubility / g·L⁻¹ (25°C) | <0.1 | <0.05 | <0.08 |
| Primary amine pKa (conj. acid) | 2.8 | 2.7 | 3.2 |
| Key synthetic advantage | Low‑temperature crystallisation, reduced dimerisation | Higher atom economy | Direct electrophilic substitution at C‑4 |
Within a fragment‑based drug discovery workflow, the 2‑amino‑4‑carboxylate motif is valued for its minimal rotatable‑bond count (3) and its capacity to present both hydrogen‑bond donor and acceptor vectors across a planar scaffold. Surface plasmon resonance screening against a bacterial dihydropteroate synthase panel returned a measured KD of 18 µM for the free amine ester, which improved to 2.4 µM upon conversion to the corresponding amide with 4‑aminobenzoic acid—an increase in residence time attributed to a 1.8‑Å shift in the Phe‑189 side chain observed in co‑crystal structures. While these biophysical data come from a single academic centre using a Biacore T200 instrument with CMS‑chip immobilisation, they illustrate how the intact ester can serve as an initial probe before being elaborated into a lead series.
When the molecule is handled outside a strictly anhydrous synthesis context—for example, while preparing stability‑indicating samples for forced‑degradation studies under ICH Q1A—its behaviour diverges from that of simple benzoate esters. Ethyl 2‑amino-4‑thiazolecarboxylate hydrolyses under alkaline stress (0.1 M NaOH, 40°C, 24 h) to give the 2‑aminothiazole‑4‑carboxylic acid with a pseudo‑first‑order rate constant of 1.2 × 10⁻⁵ s⁻¹; under acidic conditions (0.1 M HCl, 40°C) half‑life exceeds 120 h. Photolytic exposure per ICH Q1B Option 2 (cool white fluorescent light plus near‑UV, overall illumination 1.2 × 10⁶ lux·h) produces a 0.3‑area% ring‑opened oxamide derivative characterised by LC‑ESI‑MS as m/z 207.04 [M+H]⁺. These degradation profiles inform the shelf‑life specification of 24 months when stored in opaque HDPE containers with desiccant packs at −20°C; open‑container bench‑top stability under standard laboratory conditions (22±2°C, 45±10% RH) is not guaranteed beyond 72 h.
Production‑scale supply chains for ethyl 2-amino-4‑thiazolecarboxylate are concentrated in a small cluster of fine‑chemical manufacturers in eastern China and central India, with lead times extending to 10–14 weeks for custom lot sizes exceeding 100 kg. The compound is not considered a substance of very high concern (SVHC) under REACH, but its classification as a skin sensitiser (H317) and an eye irritant (H319) under the Globally Harmonized System requires operators to employ nitrile gloves of minimum thickness 0.11 mm tested according to EN 374‑3, and eye‑washing stations must be located within 10 m of charging isolators. Residual ethanol content from the final recrystallisation is controlled to ≤0.15% by headspace GC–FID using a DB‑624 column (30 m × 0.53 mm, 3 µm film), which is critical when the material is charged into air‑sensitive organometallic reactions where free alcohols can quench Grignard or organolithium intermediates preferentially over the intended substrate.
A specific batch failure mode encountered during the 2023 monsoon season in a facility near Hyderabad involved a gradual uptake of moisture through damaged aluminium‑laminate bags, culminating in a carboxylic acid level of 2.8‑area% and a differential scanning calorimetry endotherm shift to 78–85°C. Root cause investigation traced the defect to a heat‑sealing jaw alignment drift that reduced seal width from the validated 8 mm to 4.5±0.8 mm. Subsequent corrective action included a quantitative seal‑strength test per ASTM F88-21 on every production bag, with a minimum burst force of 25 N/15 mm, and a transition to multi‑layer EVOH‑PE overwrap. These mundane but operationally critical details underscore the importance of packaging integrity for this hygroscopic aminothiazole ester when specifying it for synthetic campaigns spanning more than a single production shift.
Given the chemical’s preponderance as a building block in CRBN‑based proteolysis‑targeting chimera (PROTAC) linker design, its dial‑in order quantities are shifting from tonne‑scale to kilogram‑scale high‑purity lots accompanied by a certificate of analysis detailing residual palladium (<10 ppm) and a polymorphic form confirmation by powder X‑ray diffraction against reference pattern PXRD‑2A‑Thiaz. The required turnaround for such lots often collides with the economic batch size of a standard Hantzsch condensation, forcing custom synthesis providers to run at reduced vessel occupancy and charge a premium of 2–3‑fold over catalogue pricing. Published data on the chronic toxicology of ethyl 2‑amino‑4‑thiazolecarboxylate are limited; an Ames fluctuation assay in Salmonella typhimurium strains TA98 and TA100 conducted by an ISO 17025‑accredited laboratory showed no mutagenic potential up to 5 mg/plate in the presence or absence of metabolic activation, but an in vitro micronucleus test and a full 28‑day repeated‑dose oral toxicity study in rodents have not been deposited in the public domain.
| Grade designation | Assay method | Key residual limit | Typical packaging |
|---|---|---|---|
| Research (R) | HPLC–UV 254 nm, internal | Water ≤0.5% (Karl Fischer) | 25 g amber glass |
| Pharma Intermediate (PI) | HPLC–UV, ICH Q2(R1) validated | Pd <10 ppm, carboxylic acid <1.0% | 5 kg LDPE‑lined fibre drum |
| Custom (GMP‑ready) | HPLC–CAD, residual solvents per USP <467> | Ethanol ≤0.15%, 2‑aminothiazole <0.1% | 25 kg EVOH‑barrier drum |
When integrating ethyl 2‑amino‑4‑thiazolecarboxylate into a multi‑kilogram process, the engineering team at a European CDMO observed that mechanical agitation in a 200 L glass‑lined reactor (DIN 28136) required a retreat‑curve impeller speed of 90–110 rpm to maintain suspension of the crystalline solid in toluene, rather than the 70 rpm typical for its methyl analogue, because the ethyl ester’s larger aspect‑ratio crystals (median particle size 180 µm, span 1.4) settle more rapidly. In‑situ FT‑IR monitoring tracked the ester carbonyl stretch at 1712 cm⁻¹ as a reliable endpoint indicator during conversion to amides, unaffected by the thiazole ring breathing mode at 1530 cm⁻¹. These practical elements, while unglamorous, delineate the operational subtleties that distinguish a standard‑grade building block from a manufacturing‑ready intermediate supplied with full technical dossier support. The compound’s chemical identity may appear straightforward—a simple aminothiazole ester—yet the interplay between its regioisomeric placement, its ester‑alkyl chain length, and the strict impurity control mandated by contemporary drug‐substance purity profiles makes it a molecule where seemingly minor ordering specifications have an outsized impact on downstream synthesis economy.
