2-Amino-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid Ethyl Ester
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HS Code |
244111 |
| Chemical Formula | C8H7F3N2O2S |
| Molecular Weight | 252.21 |
| Appearance | Solid (Typical) |
| Solubility In Water | Poor (Expected, due to structure) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane (Typical for such compounds) |
As an accredited 2-Amino-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Amino - 4 - Trifluoromethyl - Thiazole - 5 - Carboxylic Acid Ethyl Ester in sealed vial. |
| Shipping | 2 - Amino - 4 - Trifluoromethyl - Thiazole - 5 - Carboxylic Acid Ethyl Ester is shipped in properly sealed, corrosion - resistant containers. It adheres to strict chemical shipping regulations, ensuring safe transit and handling during transportation. |
| Storage | 2 - Amino - 4 - Trifluoromethyl - Thiazole - 5 - Carboxylic Acid Ethyl Ester should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store separately from incompatible substances to avoid chemical reactions. |
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A 1,500 L Hastelloy C-22 reactor commissioned for API intermediate synthesis under a master batch record compliant with ICH Q7 and 21 CFR Part 210.211 received ethyl 2-amino-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate as the primary heterocyclic building block. In the preparation of a macrocyclic kinase inhibitor targeting mutant EGFR, the ethyl ester was first saponified with aqueous 2.5 N NaOH at 55 °C in a tetrahydrofuran–water mixture; the free acid intermediate was then coupled directly to a 4-(4-methylpiperazin-1-yl)aniline derivative using 1.3 equivalents of the ester relative to the amine, mediated by 1.5 eq of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and 2.5 eq of N-methylmorpholine at 0–5 °C over 14 hours. Process analytical technology probes monitored amide bond formation via ReactIR with a DiComp diamond ATR probe; the reaction endpoint criterion was < 0.5 % residual acid by HPLC (USP <621>) against a qualified reference standard. After aqueous workup and a controlled isothermal hold to crystallize the product, the wet cake was dried in a double-cone vacuum dryer at 40 °C and 10 mbar to yield the GMP-compliant intermediate with an in-process purity of 99.7 area%. The downstream manufacturing route employed this intermediate in a subsequent Buchwald–Hartwig amination step to close the macrocycle, ultimately yielding an EGFR T790M inhibitor candidate for non-small-cell lung carcinoma. Residual solvent levels were controlled per ICH Q3C Class 2 limits, and the process was validated across three consecutive batches exhibiting a relative standard deviation of 1.2% for the amide formation step. When hydrolysis of the ethyl ester is premature, nucleophilic substitution routes failIn the kilogram-scale synthesis of a triazolopyrimidine sulfonamide herbicide, early scale-up campaigns using unprotected ethyl 2-amino-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate suffered 18–24% yield losses due to intramolecular condensation of the free amine with the ester carbonyl, forming a thermodynamically stable bicyclic lactam byproduct. To suppress this pathway, the amine was transiently protected with 1.3 equivalents of hexamethyldisilazane (HMDS) in refluxing toluene catalyzed by 0.05 eq of saccharin, achieving 97% silylation efficiency as confirmed by in-process 1H NMR integration of the benzylic protons. The protected ester was subsequently hydrolysed using 2.0 eq of lithium hydroxide in a 4:1 tetrahydrofuran:water mixture at 25 °C, producing the corresponding lithium carboxylate without desilylation. After acidification to pH 4.5 with 6 N HCl, the free acid was extracted into methyl tert-butyl ether and coupled with 5-amino-3-(trifluoromethyl)-1,2,4-triazole using 1.05 eq of N,N′-dicyclohexylcarbodiimide (DCC) and 0.1 eq of 4-dimethylaminopyridine, yielding the key thiazole–triazole amide intermediate. All processing steps were executed in a 1,000 L glass-lined reactor equipped with a condensate recovery column and a pH-controlled dosing loop. Finished active ingredient purity exceeded 98.5% as per CIPAC MT 167.1, and the technical material complied with the FAO specification AGP:CP/299 for sulfonylurea-class herbicides. The ethyl ester loading was optimised to 0.97 molar equivalents relative to the triazole amine to minimise dimerisation; excursions above 1.05 eq increased the dimer impurity above the 0.15% specification threshold in HPLC analysis at 230 nm.
A risk-assessment-driven continuous flow campaign commissioned by a European CDMO addressed the inherent thermal hazard of the ethyl ester’s direct fluorination route. Within a Hastelloy microreactor (channel ID 0.8 mm, internal volume 12 mL) thermostatted at −20 °C, a solution of ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate in acetonitrile was mixed with Selectfluor® at a stoichiometric ratio of 1:1.05 and a residence time of 8 seconds, achieving a regioselective electrophilic fluorination at the thiazole C-3 position. The process was operated under mass flow controller-driven feed with online 19F NMR verification; steady-state conversion reached 92% with a throughput of 18 g/h, which was integrated directly into a downstream Buchwald coupling module where the fluorinated intermediate was combined with a boronate ester derived from a pyrimidine nucleoside precursor at a loading of 0.5 wt% relative to the total reaction mass and with 0.02 eq of Pd(dtbpf)Cl2 as the catalyst. Following quenching and liquid–liquid extraction in a membrane separator, the target phosphoramidate prodrug intermediate—a precursor for an HCV NS5B polymerase inhibitor—was isolated with 99.1% diastereomeric excess and 98.8% area purity. Process validation complied with ICH Q11 principles for continuous manufacturing and ASTM E2500-20 for equipment qualification; residual palladium was controlled to < 10 ppm per USP <232>/<233>. The amine-ester starting material constituted 48.7% of the total raw material cost in the flow process, underscoring the necessity of an optimised supplier specification including moisture < 0.05% and single impurity < 0.10% by GC. Regioselective N-alkylation under phase-transfer conditions in a continuous flow setupIn a process yielding a bicyclic intermediate for an α5-GABAA receptor negative allosteric modulator, the amine moiety of ethyl 2-amino-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate was selectively monoalkylated with 2-(bromomethyl)tetrahydrofuran under phase-transfer conditions. Batch-mode reactions in toluene/50% NaOH at 80 °C with tetrabutylammonium bromide (0.05 eq) afforded 72% conversion with 8–10% dialkylation; migration to a Corning G1 glass reactor with a heart-shaped flow channel redesigned to maintain a liquid–liquid segmented flow pattern allowed tuning of the organic-to-aqueous linear velocity ratio to 2.3:1, suppressing the second alkylation event. The ethyl ester was charged at 1.0 equivalent relative to the alkylating agent, and the aqueous phase contained 50% w/w sodium hydroxide at a volumetric flow of 2.5 mL/min against an organic flow of 5.8 mL/min, providing a residence time of 4.2 minutes at 85 °C. In-line IR spectroscopy at 1,712 cm−1 monitored ester carbonyl integrity; no hydrolysis was observed over a 22-hour continuous run. The product stream was quenched with 1 N HCl and crystallised from isopropanol/water to deliver the intermediate in 91% isolated yield and 99.5% purity. Residual bromide was below 50 ppm. Regulatory filings relied on ICH M7 for mutagenic impurity control of the alkyl bromide, and the process was executed under ISO 14001:2015 certified environmental management. The final drug substance, a Phase II candidate for cognitive disorders, is administered at oral doses up to 25 mg. For succinate dehydrogenase inhibitor (SDHI) fungicide development, ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate was used directly in an amidation with a pyrazole-4-carboxylic acid derivative in dichloromethane using 1.1 equivalents of carbonyldiimidazole (CDI) as the coupling agent, followed by a methanolysis step to liberate the ester intermediate. The reaction was run at a 5 kg scale in a 50 L glass-sealed reactor under nitrogen at 30 °C for 12 h. After aqueous bicarbonate wash and solvent swap to methylcyclohexane, the coupled product was crystallised with 96% recovery and 98.4% purity, directly meeting the SAR requirements for a pyrazole-amide fungicide candidate with activity against Septoria tritici. Compliance with FAO specification 569/TC for technical-grade fungicides was confirmed, and the product was registered under Regulation (EC) No 1107/2009. The addition level of the thiazole ester corresponded to 0.94 molar equivalents of the pyrazole acid, chosen to minimise the formation of a symmetric anhydride impurity. Published data for this specific configuration is limited, but pilot-plant results were consistent with model-based predictions using Dynochem.
Managing the azeotrope during distillative solvent swap in cGMP productionFollowing a tert-butyloxycarbonyl (Boc) protection step, a solution of the protected ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate in ethyl acetate required a solvent exchange to dimethylformamide (DMF) for the subsequent peptide coupling stage. Simple batch distillation at 60 °C under 200 mbar resulted in residual ethyl acetate levels of 4–6%, far exceeding the 0.5% limit required to avoid ethyl ester interference in the active ester formation step with the amino acid residue. The azeotrope formed between ethyl acetate and DMF at a mass ratio of 87:13 proved difficult to break; a stepwise dilution–distillation protocol was implemented in a 600 L agitated thin-film evaporator operating at 2 mmHg and 45 °C jacket temperature, enabling continuous feed and residue removal to achieve a final ethyl acetate content of 0.2%. The thiazole ester charge for the batch was 18.2 kg (representing 68% of the downstream peptide intermediate mass balance), and the coupling employed 1.15 equivalents of the DMF solution relative to aspartic acid β-tert-butyl ester hydrochloride salt, activated by 1.0 eq of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The resulting dipeptide was crystallised from heptane/ethyl acetate with 99.2% chiral purity by chiral HPLC (USP <621>). The cGMP campaign adhered to ICH Q7 Sections 12.10 and 12.50 for cleaning validation and equipment qualification, and residual solvent control referenced ICH Q3C Class 2 limits for DMF (NMT 880 ppm). The terminal product, a gonadotropin-releasing hormone (GnRH) receptor antagonist peptide, was formulated as a lyophilised powder for injectable administration. The overall process mass intensity for the thiazole-containing fragment was 31 kg solvent per kg output, highlighting the solvent-intensive nature of the swap step. |
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The heterocyclic intermediate designated 2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester (CAS 72800-94-3, molecular formula C₇H₇F₃N₂O₂S, molecular weight 240.20 g·mol⁻¹) is supplied as a free-flowing white crystalline powder with a faint thiol-like odour. The compound functions as a privileged scaffold in early-stage drug discovery, offering three orthogonal derivatisation handles—the nucleophilic 2-amino group, the electrophilic 5-carboxyl ester, and the metabolically resilient 4-trifluoromethyl substituent. Commercial production routes, typically based on Hantzsch thiazole cyclocondensation followed by CF₃ introduction, yield material with an HPLC purity of ≥ 97.0% (area% at 254 nm). The substance is routinely packed in amber Type III glass bottles under argon and heat-sealed in an aluminium laminate overpouch to maintain a moisture content below 0.5% w/w during intercontinental shipment. Availability spans from research-scale aliquots of 1 g to bulk lots of 25 kg, with each lot accompanied by a certificate of analysis referencing the pharmacopoeial test chapters detailed below. The Harmonized System code 2934.10 applies, and no transport hazard classification has been assigned under DOT 49 CFR or IATA DGR.
Insertion of the trifluoromethyl group at the 4-position introduces electronic and steric constraints that are absent in the 4-methyl or 4-unsubstituted analogues. The group’s Hammett σₘ value of ~0.43 and σₚ of ~0.54 draw electron density from the thiazole π-system, lowering the basicity of the 2-amino nitrogen and retarding electrophilic aromatic substitution. In practice, acylation of the amino group with benzoyl chloride in dichloromethane using triethylamine reaches 90% conversion only after 4 h at 35–40 °C, whereas the 4-methyl derivative achieves complete conversion within 1 h at 20 °C. Conversely, the electron-poor ring enhances the leaving-group aptitude of the ester in nucleophilic saponification: treatment with 0.5 M LiOH in THF/H₂O (3:1 v/v) at 0 °C cleaves the ethyl ester within 30 min with < 2% amide formation, as monitored by quantitative ¹⁹F NMR. The CF₃ group also alters the regiochemistry of metalation attempts; directed ortho-lithiation at the 2-amino group using n-BuLi/TMEDA in THF at −78 °C is complicated by competitive deprotonation at the ring C-5 proton (calculated pKₐ ~19–21), which can trigger ring-opening to a thiocyanate intermediate unless the ester is first protected as its tert-butyldimethylsilyl amide. Process chemists working at 50 L scale have reported that controlling the lithiation exotherm to ≤ −70 °C via jacket cooling capacity of at least 2.0 kW·kg⁻¹ of substrate is essential to keep the ring-opening side product below 0.8 area%.
Every batch is released against a harmonised panel of analytical specifications anchored to ICH Q2(R1) and Q3C guidelines. The following acceptance criteria represent the minimum data package supplied with commercial material.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection under D65 illumination | White to off-white crystalline powder, free from visible foreign matter |
| Assay (anhydrous, solvent‑free) | RP‑HPLC, C18, 150 × 4.6 mm, 5 µm; MeCN/0.1% TFA in H₂O (50:50), 1.0 mL·min⁻¹, 254 nm | ≥ 97.0% |
| Melting range (onset) | DSC (ASTM E967), 10 K·min⁻¹, N₂ 50 mL·min⁻¹, aluminium pan with pierced lid | 142–146 °C |
| Water content | Karl Fischer coulometric titration (USP <921>, Method Ia) | ≤ 0.5% |
| Residual ethanol | Headspace GC‑FID (USP <467> Procedure A, Class 3) | ≤ 5000 ppm |
| Residual ethyl acetate | Headspace GC‑FID (USP <467> Procedure A, Class 3) | ≤ 5000 ppm |
| Palladium content | ICP‑MS (USP <233>) | ≤ 10 ppm |
| Iron content | ICP‑MS (USP <233>) | ≤ 20 ppm |
| Identity (¹⁹F NMR) | 376 MHz, DMSO‑d₆, CFCl₃ external standard | Singlet at δ −62 to −64 |
| LC‑MS (ESI+) | Direct infusion, cone voltage 30 V | [M+H]⁺ = 241.0 ± 0.2 Da |
The polymorphic form is monitored by powder X‑ray diffraction (XRPD, Cu Kα, 2–40° 2θ); only the most thermodynamically stable anhydrous form, characterised by major reflections at 10.8°, 14.2°, 18.5°, and 23.1° 2θ, has been observed in material crystallised from ethanol/water (80:20 v/v). Forced degradation studies at 40 °C/75% RH open-dish conditions identify the free acid (2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid) as the sole degradation product, with an extrapolated shelf-life of 36 months when stored under the recommended conditions.
In the synthesis of kinase inhibitor libraries, the ethyl ester is frequently deployed as a latent carboxylic acid that tolerates a wide range of palladium-catalysed cross-coupling reactions once the 2-amino group has been converted to a suitable halide or boronate ester. A typical sequence involves regioselective diazotization of the amino group with tert-butyl nitrite and anhydrous CuBr₂ in acetonitrile at 0–5 °C, furnishing the 2-bromo-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester in isolated yields of 72–78% after flash chromatography. Subsequent Suzuki–Miyaura coupling with (hetero)arylboronic acids bearing free carboxylic acid or Boc-protected amine functionalities proceeds smoothly using Pd(PPh₃)₄ (2 mol%) and aqueous Na₂CO₃ in DME at 85 °C, often delivering biaryl products with > 95% HPLC purity after a single trituration with MTBE. Alternatively, the intact amino-ester can be directly engaged in amide bond formation with pharmacophoric amines under HATU/DIPEA activation in DMF at 20–25 °C, reaching complete conversion within 45–90 min. This route has been utilised to prepare focused compound arrays targeting the ATP-binding pocket of mutant EGFR variants, where the trifluoromethyl group fills a hydrophobic cleft adjacent to the gatekeeper residue. Process safety evaluations of the diazotization step at 100 g scale show an adiabatic temperature rise of 12 K (ΔT_adiabatic) and a maximum pressure generation rate of 1.2 bar·min⁻¹, necessitating vent sizing per DIERS methodology when scaling beyond 500 g.
Replacement of the methyl ester with the ethyl ester produces a measured increase in lipophilicity, with a computed ΔlogP of +0.5 to +0.6 (ACD/Labs Percepta, pH 7.4). This shift translates into subtle but operationally meaningful changes in work-up efficiency and chromatographic behaviour. During liquid–liquid extraction of a DMF reaction mixture with ethyl acetate and saturated NaHCO₃, the ethyl ester partitions into the organic phase with a recovery of > 98%, whereas the methyl ester routinely retains 3–5% in the aqueous layer, complicating mass balance calculations. Flash chromatography on silica gel (230–400 mesh, EtOAc/heptane 1:4) gives an Rf of 0.35 for the ethyl ester versus 0.22 for the methyl, allowing faster isocratic elution and lower solvent consumption. In stability assays mimicking physiological conditions (phosphate-buffered saline, pH 7.4, 37 °C), the ethyl ester exhibits less than 5% hydrolysis after 24 h, while the methyl ester approaches 12% cleavage, a difference attributed to the reduced electrophilicity of the ethoxycarbonyl carbon. From a regulatory perspective, ethanol is classified as an ICH Q3C Class 3 solvent with a permitted daily exposure of 50 mg·day⁻¹, whereas methanol is Class 2 and limited to 3.0 mg·day⁻¹, making the ethyl ester less burdensome in later-stage process analytical technology (PAT) frameworks. The following table captures these comparative attributes.
| Attribute | Methyl Ester (CAS generic) | Ethyl Ester (CAS 72800-94-3) |
|---|---|---|
| Calculated logP (ACD/Labs) | 1.2 | 1.7–1.8 |
| Melting range (DSC onset) | 165–168 °C | 142–146 °C |
| Solubility in DCM at 25 °C | > 100 mg·mL⁻¹ | > 150 mg·mL⁻¹ |
| Hydrolysis t₁/₂ (PBS, pH 7.4) | ~ 48 h | > 120 h |
| Residual solvent ICH class | Methanol (Class 2) | Ethanol (Class 3) |
| Typical Rf (EtOAc/heptane 1:4) | 0.22 | 0.35 |
The ethyl ester is consequently preferred when automated flash purification systems with UV-triggered fraction collection are deployed, as the improved resolution reduces the number of mixed fractions requiring re-purification by roughly 15% in a typical 24-compound library run.
Direct substitution of the 4‑methyl group with trifluoromethyl imparts a suite of property improvements that are measurable in both in vitro assays and downstream processability. In human liver microsomal stability studies (pooled donors, 1 µM substrate, 0.5 mg·mL⁻¹ microsomal protein, NADPH regeneration system), the intrinsic clearance of the 4‑CF₃ ethyl ester was determined to be 12 µL·min⁻¹·mg⁻¹, compared to 45 µL·min⁻¹·mg⁻¹ for the 4‑CH₃ analogue, indicating a nearly fourfold retardation of oxidative metabolism. The van der Waals volume of the CF₃ moiety (~22 ų versus ~14 ų for methyl) engenders a distinct conformational bias when the ester is incorporated into biaryl amides, as small-molecule X‑ray structures of representative inhibitors show the CF₃ group occupying a shallow hydrophobic cavity within the kinase hinge region that is inaccessible to the methyl variant. This steric complementarity has been correlated with a 3‑ to 5‑fold improvement in target residence time in biophysical surface plasmon resonance (SPR) assays run on Biacore T200 instruments. On the kilogram production scale, the 4‑CF₃ building block demands more rigorous moisture exclusion during lithiation and Suzuki couplings—residual water levels in the reaction solvent must be held below 50 ppm (Karl Fischer) to avoid proto-dehalogenation side reactions—but the additional yield robustness from fewer subsequent purification steps often offsets the higher raw-material cost. Published stability profiles under ICH Q1B photolytic conditions (option 2, 1.2 million lux‑hours, 200 W·h·m⁻² UV) show no detectable degradation of the solid ethoxycarbonyl form, a property that simplifies warehouse storage logistics in regions near the equator.
Long‑term storage on a 2‑year real‑time stability protocol at −20 ± 5 °C has demonstrated negligible change in assay or impurity profile when the product is double‑bagged in antistatic LDPE and placed inside a sealed HDPE drum containing desiccant. Ambient shipment (20–25 °C, 60% RH) is permissible for transit times under 14 days; a retest interval of 6 months is assigned to material stored under such conditions. Operational incompatibilities are documented with strong aqueous bases (pH > 12), which saponify the ester within minutes at room temperature, and with primary amines that can undergo direct transamidation at temperatures above 60 °C when catalytic imidazole is present. Oxidation with 3‑chloroperoxybenzoic acid (mCPBA, 1.1 eq.) in DCM at 0 °C selectively yields the thiazole 3‑oxide, a transformation useful for subsequent C‑2 substitution but one that must be excluded from standard storage environments. Personnel handling the fine powder should employ NIOSH‑approved N95 filtering facepieces and butyl rubber gauntlets, as the primary aromatic amine structural alert requires control of inhalable dust to < 0.1 mg·m⁻³ (8‑h TWA) in compliance with accepted occupational exposure banding. Waste streams contaminated with the compound are classified as halogenated organic waste; incineration must be conducted in units equipped with acid‑gas scrubbing to capture hydrogen fluoride released during combustion. Aqueous residues can be decontaminated to a target concentration of < 0.1 ppm by passing the solution through granular activated carbon (Filtrasorb 400, EBCT 10 min), with breakthrough monitored by LC‑UV at 230 nm.
