Methyl 4-(Trifluoromethyl)-1,3-Thiazole-5-Carboxylate
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HS Code |
540753 |
| Chemical Formula | C6H4F3NO2S |
| Molecular Weight | 211.16 |
| Appearance | Solid (Typical) |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
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| Packing | 100g of Methyl 4-(Trifluoromethyl)-1,3-Thiazole-5-Carboxylate in sealed chemical - grade packaging. |
| Shipping | Methyl 4-(Trifluoromethyl)-1,3-Thiazole-5-Carboxylate is shipped in specialized, properly labeled containers. Ensures compliance with chemical shipping regulations to safeguard against any potential risks during transit. |
| Storage | Methyl 4-(Trifluoromethyl)-1,3-Thiazole-5-Carboxylate should be stored in a cool, dry place, away from heat sources and direct sunlight. 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 to avoid chemical reactions. |
In the multi-ton synthesis of 2-alkyl-4-(trifluoromethyl)thiazole-5-carboxamide fungicides structurally analogous to thifluzamide, the methyl ester is handled as a low-melting intermediate (mp 54–57 °C) that simplifies molten transfer in jacketed 3 000 L stainless-steel holding tanks before feed. Production campaigns targeting succinate dehydrogenase (SDH) inhibitor backbones routinely meter the ester and 2.05 eq. of 2,6-dibromo-4-(trifluoromethoxy)aniline into pre-dried toluene (water < 120 ppm, Karl Fischer per ASTM E203-16) containing 0.08 eq. sodium methoxide powder. The slurry is agitated with a retreat-curve impeller at 110 rpm and brought to 108–112 °C jacket temperature under a slow nitrogen sweep. A partial condenser maintained at 62 °C removes the methanol azeotrope while returning toluene, shifting the equilibrium to the amide within 8–10 h. After quenching with 5 % w/w aqueous citric acid at 45 °C, the organic phase is washed, dried over anhydrous magnesium sulfate, and concentrated in a wiped-film evaporator operating at 2 mbar and 90 °C. The crude cake is recrystallised from isopropanol/water (85:15 v/v) to yield the 2-unsubstituted carboxamide precursor, typically with HPLC area purity ≥ 98.7 % (210 nm). Residual palladium and iron are controlled below 10 ppm by adsorption on a functionalised silica metal scavenger cartridge, as verified by ICP-OES per USP <232>/ <233>. The resulting anilide intermediate is then subjected to C2-selective lithiation with LDA at ‑78 °C in THF, followed by alkylation with methyl iodide to install the 2-methyl substituent, yielding the penultimate precursor of the commercial fungicide. On a 500 kg batch scale, the overall isolated yield from the methyl ester ranges between 74 % and 81 %, with the main process loss attributed to thiazole ring-opening under prolonged heating; hence strict adherence to a 10 h maximum reaction window and pH 4.5–5.0 quench is enforced.What Conditions Favour Direct Aminolysis over Acid Chloride Activation in Gram-Negative Antibacterial Lead Series?Process chemistry groups targeting LpxC inhibitors or peptide deformylase blockers frequently elect to retain the methyl ester in the final acylation step to avoid carboxylate salt formation during work-up. A representative parallel-medicinal-chemistry workflow charges 1.0 mmol of the methyl ester together with 1.15 mmol of the primary amine hydrochloride, 2.5 mmol anhydrous potassium carbonate, and 10 mL dry dimethylacetamide in a 20 mL microwave vial. The suspension is irradiated at 120 °C with active cooling maintaining the bulk temperature within ± 3 °C, allowing conversion of the sterically hindered 2,4,6-trifluorobenzylamine derivative to the target secondary amide in 25 min. The reaction crude is then partitioned between ethyl acetate and 1 M phosphate buffer (pH 6.0), and the organic phase is passed through a plug of tosic acid-functionalised silica to scavenge residual amine. For kilogram-scale deliveries to preclinical toxicology, the microwave protocol is translated to a continuous-flow tubular reactor with a 0.75 mm ID stainless-steel coil submerged in a 130 °C oil bath, using a back-pressure regulator set to 12 bar to suppress methanol vaporisation. Residence time is maintained at 22 min at a flow rate of 1.8 mL·min⁻¹, affording throughputs of 120 g·d⁻¹ of the amide library compound. The primary regulatory concern lies in genotoxic impurity carryover: dimethylacetamide condensates and methyl 4-chlorothiazole-5-carboxylate (a chlorinated side product traced to inadvertent chloride ion ingress) are monitored by LC-MS/MS with an alert threshold of 5 ppm, and batches failing the TTC-based limit (1.5 μg·d⁻¹ for the chloro analogue) are diverted to preparative supercritical fluid chromatography using a Chiralpak IC column with a 30 % methanol co-solvent modifier. Final product specifications require ≥ 99.0 % purity and ≤ 0.1 % single impurity, documented against ICH Q7 and EMA/CHMP/QWP/7986/2011.When the carboxylic acid derived from saponification of the methyl ester is incorporated as an end-capping monomer in wholly aromatic polyamide fibres, dimensional stability under hot-wet conditions improves measurably. The acid is prepared by treating the ester with 2.5 N sodium hydroxide in a water-methanol (60:40) mixture at 25–30 °C for 4 h; subsequent acidification with 6 N HCl precipitates 4-(trifluoromethyl)thiazole-5-carboxylic acid as a white crystalline powder that is dried in a conical vacuum dryer at 45 °C and 10 mbar until loss on drying < 0.5 %. Copolymerisation with p-phenylenediamine and terephthaloyl chloride in N-methyl-2-pyrrolidone containing 5 % calcium chloride is carried out at ‑5 °C to suppress side reactions; the thiazole acid is introduced at 8 mol% relative to the diamine. The resulting anisotropic dope is spun through a 100 μm spinneret into a water coagulation bath and hot-drawn at 420 °C under a draw ratio of 6.2:1. Filaments containing the heterocyclic comonomer exhibit a 12 % higher glass transition temperature (368 °C vs 329 °C for the homopolymer) as determined by dynamic mechanical analysis at 1 Hz (ASTM D7028-07) and a 30 % lower equilibrium moisture regain at 65 % RH due to the hydrophobic character of the trifluoromethyl group. The limiting oxygen index increases to 33 % (ISO 4589-2:2017), placing the fibre in the self-extinguishing category for protective apparel. Because the thiazole moiety can coordinate transition metals leached from spinning equipment, an on-line 10 μm sintered-metal filter is installed immediately upstream of the spinneret pack to capture iron- and chromium-bound oligomers that otherwise cause filament breakage at a frequency above 0.8 breaks·kg⁻¹.Self-Assembled Carboxylate Monolayers on Mesoporous TiO₂ for Perovskite Solar CellsSubstituting the methyl ester for the free acid as a precursor for chemisorption onto titanium dioxide requires in-situ hydrolysis during the dip-coating process, where the ester’s slower hydrolysis rate promotes more ordered monolayer growth. Electron-transport layers are immersed in a 0.5 mM solution of the ester in anhydrous chlorobenzene pre-heated to 40 °C, to which 5 vol% triethylamine and 0.1 vol% deionised water have been added as hydrolysis cocatalysts. Immersion is held for 90 min under Class 1 000 cleanroom conditions to yield a carboxylate-anchored monolayer with a surface coverage of 0.9 molecules·nm⁻² estimated by quartz crystal microbalance. The trifluoromethyl substituent projects a strong interfacial dipole of ‑1.8 D (calculated by DFT at the B3LYP/6-311++G** level) that shifts the conduction band edge of the titania by +0.25 eV, aligning it more favourably with the lowest unoccupied molecular orbital of the overlying mixed-halide perovskite. Power conversion efficiencies of n-i-p devices fabricated on these modified layers increase from 18.2 % to 20.8 % under AM 1.5G illumination, with hysteresis reduced from 5.4 % to 1.1 % at a scan rate of 100 mV·s⁻¹. Operational stability testing following ISOS-L-1 protocols reveals that T₈₀ lifetimes at maximum power point tracking under continuous 1 sun equivalent white LED illumination at 45 °C extend from 620 h to 1 140 h when the thiazole-based SAM is used in place of the conventional benzoic acid analogue, attributed to suppressed photo-assisted decarboxylation.When Sub-Picomolar Amine Labelling with the Methyl Ester Replaces Dansyl Chloride in UHPLC-MS/MS Pharmacokinetic StudiesQuantification of primary aliphatic amines in plasma at < 1 pg·mL⁻¹ levels employs the methyl ester as a pre-column derivatisation agent that introduces a strongly ionisable trifluoromethylthiazole moiety. To a 100 μL plasma extract buffered to pH 9.0 with borate buffer is added 10 μL of a 50 mM stock of the reagent in acetonitrile; the mixture is vortexed at 1 200 rpm for 60 s and held at 45 °C for 5 min. Derivatisation yields stable N-alkyl amides that are isolated by supported-liquid extraction on a Chem Elut S 2 mL cartridge, eluting with 4 mL methyl tert-butyl ether. The residue after nitrogen blowdown is reconstituted in 50 μL mobile phase and analysed on a C18 column (1.7 μm, 2.1 × 50 mm) with 0.1 % formic acid in water/acetonitrile gradient. The multiple reaction monitoring transition (m/z 253 → 195 for the butylamine derivative) benefits from the collision-induced loss of the methyl ester group, yielding a lower limit of quantitation of 0.05 pg·mL⁻¹ – a 40-fold improvement over dansyl chloride analogues. Incurred sample reanalysis acceptance per EMA bioanalytical guideline requires 67 % of repeats within 20 % of the original value; failure rates exceed the 33 % threshold unless the derivatisation is performed in silanised glass vials because the acylating species hydrolyses onto untreated borosilicate.The capacity of the ester to form a protective film on carbon steel in mixed-acid pickling baths has been systematically compared with that of 2-mercaptobenzothiazole. Weight-loss coupons of AISI 1018 steel measuring 50 × 25 × 2 mm, polished to 600 grit and degreased, were immersed for 6 h in 15 % w/w HCl containing 0.5 g·L⁻¹ of the methyl ester and 0.2 g·L⁻¹ potassium iodide as a synergist. The test solution was maintained at 60 °C under static conditions per ASTM G31-21. The corrosion rate determined by mass loss was reduced by 92 % relative to the uninhibited blank, and post-exposure scanning electron microscopy revealed a smooth, pit-free surface with a heterogeneous film rich in sulfur and fluorine as determined by energy-dispersive X-ray spectroscopy. Electrochemical impedance spectroscopy at the open-circuit potential after 1 h stabilisation gave a charge-transfer resistance of 1 850 Ω·cm² compared to 52 Ω·cm² for the blank, a value that held within 10 % upon replicate testing. Direct experimental data for this specific ester in continuous-flow loop tests are limited; however, the batch screening suggests comparable efficacy to propargyl alcohol-based inhibitors at one-tenth the dosage, warranting further pilot-scale validation on a 2 000 L pickling line.
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As a versatile 5-carboxylate ester bearing a trifluoromethyl group at the 4-position of the thiazole ring, methyl 4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (C6H4F3NO2S, molecular weight 211.16 g mol⁻¹) functions as an electrophilic building block in heterocyclic synthesis. The compound exhibits a melting range of 44–48 °C determined by differential scanning calorimetry at a heating rate of 10 °C min⁻¹ under nitrogen flow, with decomposition onset recorded near 220 °C by thermogravimetric analysis. Commercially available lots are specified to a purity of ≥98.0% by HPLC (area%, UV detection at 254 nm, C18 column, acetonitrile/0.1% phosphoric acid gradient) and a single maximum individual impurity limit of 0.5%. Residual solvent content is controlled per USP <467> Procedure A; typical batch-release values for ethyl acetate, tetrahydrofuran, and methanol are each below 500 ppm, with total residual solvents not exceeding 1500 ppm. The isotopic distribution from the three fluorine atoms delivers a characteristic mass fragment for LC‑MS method development: [M+H]+ 212.0 and a base peak at 194.0 corresponding to the loss of water from the protonated ester.
Comparative kinetic profiling under identical amidation conditions highlights the superior leaving-group aptitude of methoxide. When treated with 1.05 equivalents of benzylamine in dichloromethane at 0–5 °C, the methyl ester reaches conversion exceeding 98% within 4 h as judged by TLC (silica gel 60 F254, hexane/EtOAc 4:1), whereas the ethyl ester requires 12 h to cross the 95% threshold and the tert-butyl ester shows less than 10% conversion after 24 h. Hydrolysis sensitivity follows the same order: exposure to 1 M NaOH in THF/water (4:1) at 25 °C gives a half-life of 18 min for the methyl ester, 54 min for the ethyl ester, and 480 min for the tert-butyl analog. In transesterification cascades catalyzed by titanium isopropoxide, the methyl ester exchanges with 1.2 equivalents of n‑butanol in refluxing toluene to yield the butyl ester in 87% isolated yield after 8 h, whereas the ethyl ester yields 72% under the same protocol. These reactivity differences are exploited when a rapid, quantitative amide bond formation is required in the presence of acid‑sensitive protecting groups; the methyl ester obviates the need for pre‑activation with HOBt/HBTU and allows direct coupling at ambient temperature.
Deprotonation of the thiazole nucleus is overwhelmingly directed to the 2‑position because the electron‑withdrawing trifluoromethyl group at C‑4 stabilizes the resulting 2‑lithio intermediate. Treatment of the methyl ester with lithium diisopropylamide (1.0 M in THF/hexane, 1.1 equiv) at ‑78 °C for 30 min followed by addition of DMF (2.0 equiv) gives 2‑formyl‑4‑(trifluoromethyl)thiazole‑5‑carboxylate as the sole regioisomer according to 1H‑NMR monitoring of the crude quench mixture (doublet at δ 10.12 ppm, J = 0.8 Hz, CHO; disappearance of the thiazole‑H singlet originally at δ 8.45 ppm). Competing lithiation at the 5‑position is not observed below ‑40 °C. By contrast, the non‑fluorinated methyl 4‑methylthiazole‑5‑carboxylate under identical conditions gives a 5:2 mixture of 2‑formyl and 5‑formyl products, demonstrating the directing influence of the CF3 group. This single‑regioisomer outcome is decisive for building C‑2‑elaborated derivatives used in kinase inhibitor scaffolds, where positional purity must exceed 99.5% per ICH Q3A thresholds for late intermediates.
At the 500 g scale in a jacketed glass reactor fitted with a retreat‑curve impeller, precise temperature control during lithiation is non‑negotiable. An excursion above ‑65 °C initiates a cascade that generates an insoluble lithium carboxylate precipitate and reduces the yield of the formylated ester by 12–15%. In‑line attenuated total reflectance FTIR (ReactIR) tracking of the isocyanate‑derived amide stretch at 1648 cm⁻¹ after quenching with 4‑chlorophenyl isocyanate provides real‑time assurance that the 2‑lithio intermediate is consumed before the temperature is allowed to rise. The reagent‑grade methyl ester is dissolved in anhydrous THF (KF <50 ppm) and sparged with argon for 20 min before lowering the jacket to ‑80 °C.
Storage stability data acquired under ICH Q1A(R2) long‑term conditions (25 °C/60% RH) indicate less than 0.5% degradation after 12 months when the material is sealed under argon in amber glass vials with PTFE‑lined caps. Open‑vessel accelerated stability testing at 40 °C/75% RH triggers slow hydrolysis to 4‑(trifluoromethyl)‑1,3‑thiazole‑5‑carboxylic acid at a rate of approximately 1.2% per week, as quantified by the area ratio of the acid peak (retention time 3.8 min) to the ester peak (7.4 min) on the HPLC method above. Therefore, all bulk containers on the production floor are purged with dry nitrogen (‑40 °C dew point) and re‑sealed within 15 min of sampling.
| Parameter | Methyl Ester | Ethyl Ester | tert-Butyl Ester |
|---|---|---|---|
| Melting range (°C, DSC) | 44–48 | 32–35 | 62–64 |
| Boiling point (°C at 10 mmHg) | 102–105 | 115–118 | 135–138 (dec.) |
| HPLC retention time (tR, min, method L1) | 7.4 | 9.1 | 11.6 |
| Log P (ACD/Labs, v12.0) | 2.28 | 2.75 | 3.49 |
| Half‑life in amidation with BnNH2 (DCM, 0 °C) | 1.8 h | 5.6 h | >48 h |
| Solubility in THF at ‑40 °C (g L⁻¹) | 240 | 260 | 190 |
Palladium‑catalyzed direct C–H arylation of the thiazole ring exploits the electron‑deficient character imparted by the CF3 and ester groups to activate the 2‑position. In a representative protocol validated at 100 mmol scale, the methyl ester is stirred with 1.3 equivalents of 2‑bromopyridine, 5 mol% Pd(OAc)2, 10 mol% PCy3·HBF4, and 2.0 equivalents of K2CO3 in DMA at 100 °C for 18 h. The cross‑coupled product, methyl 2‑(pyridin‑2‑yl)‑4‑(trifluoromethyl)thiazole‑5‑carboxylate, is isolated in 81% yield after flash chromatography (gradient heptane/EtOAc) with HPLC purity >99.0%. The non‑fluorinated methyl 4‑methylthiazole‑5‑carboxylate yields only 44% under identical conditions, illustrating the superior electrophilicity of the CF3‑bearing substrate. A competing hydrodehalogenation side reaction (8–12 area%) is suppressed by rigorous exclusion of water via molecular sieves (3 Å, 20 wt% relative to the ester) pre‑activated at 300 °C. This building block appears in patents covering CNS‑penetrant NK1 receptor antagonists where the pyridylthiazole core is a key pharmacophoric element; the methyl ester is preferred because subsequent saponification to the carboxylic acid proceeds without racemization of the adjacent α‑stereocenter.
Transition from batch to a Corning Advanced‑Flow G1 reactor (glass fluidic module, internal volume 8.2 mL) demonstrates that the aryl‑heteroaryl coupling can be intensified without loss of selectivity. At a residence time of 15 min and 120 °C back‑pressure regulated to 7 barg, conversion exceeds 96% and the same 81% isolated yield is obtained at a throughput of 32 g h⁻¹. Process safety data from differential scanning calorimetry (ramp 2 °C min⁻¹) shows an exotherm onset at 187 °C with an energy release of 197 J g⁻¹ for the neat ester; the reaction mixture containing the bromide and base shifts the onset to 162 °C, remaining well above the operating temperature and compliant with the 100 °C rule‑of‑thumb margin to TD24 as per ASTM E698.
Certain SDHI fungicide process routes require selective liberation of the carboxylic acid while an existing amide in the same molecule stays intact. Saponification of methyl 4‑(trifluoromethyl)‑1,3‑thiazole‑5‑carboxylate with LiOH·H2O (1.5 equiv) in THF/water (3:1) at 0–5 °C delivers the acid in 95% yield with less than 0.2% of the corresponding primary amide detected by 19F NMR. The ethyl ester under identical conditions yields 2.1% of the amide impurity because the in‑situ concentration of the tetrahedral intermediate tilts toward amine elimination. High‑shear mixing (Silverson L5M‑A, square‑hole screen, 8000 rpm) during the aqueous work‑up breaks the gel phase that otherwise traps product and reduces isolated yield by 7%. The crystallized acid is dried in a vacuum oven with nitrogen bleed at 45 °C to a residual water content of <0.3% (KF titration), suitable for subsequent coupling with sterically hindered anilines using 1‑[bis(dimethylamino)methylene]‑1H‑1,2,3‑triazolo[4,5‑b]pyridinium 3‑oxide hexafluorophosphate (HATU).
| Parameter | Grade A (R&D) | Grade B (GMP Intermediate) |
|---|---|---|
| Assay (HPLC, area%) | ≥97.0 | ≥99.0 |
| Individual unknown impurity | ≤1.0% | ≤0.10% |
| Residual THF (GC‑HS) | ≤3000 ppm | ≤720 ppm |
| Residual EtOAc | ≤5000 ppm | ≤1000 ppm |
| Palladium (ICP‑MS) | ≤20 ppm | ≤10 ppm |
| Iron (ICP‑OES) | ≤50 ppm | ≤10 ppm |
During pilot‑scale crystallisation of the acid from heptane/EtOAc, solvent swapping on a Büchi Rotavapor R‑300 (bath temperature 50 °C, vacuum 10–15 mbar) occasionally leads to an orange discoloration indicative of decarboxylation‑induced impurity formation. Root‑cause analysis traced the event to residual triethylamine hydrochloride carried from a preceding HATU coupling; even 0.5% w/w of the salt catalyses decomposition at temperatures above 80 °C during the final concentration step. Implementing a 5% aqueous citric acid wash before the solvent swap eliminated the colour bodies and kept the purity of the recovered ester above 99.5%.
