2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid

Product Name 2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid
Alias 2-Methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid
Einecs 821-777-4
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid is supplied with a minimum purity of 98% (HPLC) and a melting range of 148–152°C, making it suitable for use as a building block in the synthesis of agrochemical and pharmaceutical active ingredients.

Specifications

HS Code	170592
Chemical Formula	C6H4F3NO2S
Molecular Weight	211.16
Appearance	Solid (Typical)
Melting Point	N/A (Check literature)
Boiling Point	N/A (Check literature)
Solubility In Water	Low (Estimated, check literature)
Solubility In Organic Solvents	Soluble in some organic solvents like DMSO (Estimated, check literature)
Pka	N/A (Check literature)
Density	N/A (Check literature)
Flash Point	N/A (Check literature)
Odor	Odorless or faint (Estimated, check literature)

As an accredited 2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 2 - Methyl - 4 - Trifluoromethyl - Thiazole - 5 - Carboxylic Acid in sealed plastic bag.
Shipping	2 - Methyl - 4 - trifluoromethyl - thiazole - 5 - carboxylic acid is shipped in sealed, corrosion - resistant containers. Special handling per safety regulations for chemicals. Shipment is insured and tracked to ensure safe and timely delivery.
Storage	2 - Methyl - 4 - trifluoromethyl - thiazole - 5 - carboxylic acid should be stored in a cool, dry, well - ventilated area. Keep it away from sources of heat, ignition, and direct sunlight. Store in a tightly closed container to prevent moisture absorption and contact with air, which could potentially cause degradation. Avoid storing near incompatible substances such as strong oxidizing agents.

Application of 2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid

The compound is introduced to a manufacturing campaign targeting pyridylmethylamine-substituted insecticidal actives through a carbodiimide-mediated coupling sequence executed in a glass-lined 2000 L reactor equipped with a retreat-curve impeller and jacket temperature control capable of maintaining ±1 °C deviation. A charge of 1.0 eq 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid (pre-dried over phosphorus pentoxide to moisture <0.2 % per ASTM E203-16) is dissolved in 9.5 vol of anhydrous dichloromethane and cooled to 0–3 °C. To this is added 1.08 eq of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) followed by 0.12 eq of anhydrous 1-hydroxybenzotriazole, and the suspension is stirred for 45 min until a clear solution of the active ester is obtained. A solution of 1.02 eq 3-(aminomethyl)pyridine in 1.5 vol DCM is dosed over 60 min while internal temperature is kept strictly below 5 °C; a delayed exotherm onset of 8–12 kJ/mol has been observed when dosing rate exceeds 0.4 eq h⁻¹, necessitating active jacket compensation. After overnight ambient ageing, the batch is washed with 2 × 3 vol saturated sodium bicarbonate, then 2 vol brine, concentrated under vacuum to 6 vol residual, and filtered through a 5 μm polypropylene bag filter. The crude cake is reslurried in 4 vol n-heptane at 40 °C for 1 h, cooled to −5 °C, isolated on an agitated nutsche filter-dryer, and dried under 10 mbar at 45 °C to deliver the target amide in 89–93 % isolated yield. Purity by HPLC-UV at 254 nm (USP <621>, C18, acetonitrile/water gradient) typically exceeds 98.7 area%, with the major process impurity—the N-acylurea deriving from O→N acyl migration—controlled below 0.15 % by strict anhydrous handling. The resulting N-(pyridin-3-ylmethyl)-2-methyl-4-trifluoromethyl-thiazole-5-carboxamide serves as a late-stage intermediate for a nicotinic acetylcholine receptor allosteric modulator class insecticide registered under EPA 40 CFR § 158 data requirements; five-batch analysis reports with ISO 17025-accredited certificate of analysis are mandated before shipment to formulation facilities in Southeast Asia. Residue limits in target crops are evaluated using the QuEChERS extraction protocol aligned with CIPAC MT 178.

When acid chloride generation is scaled beyond pilot stage in pyrazole-carboxamide SDHI production

Transfer of the crystalline acid from drum to reactor must occur under <30 % RH nitrogen-blanketed conditions because the hydrate form—which can constitute 3–7 % of the mass after 4 h ambient exposure—interferes violently with thionyl chloride. In a 5000 L Hastelloy C-22 vessel configured with a caustic scrubber loop capable of handling 12 kg h⁻¹ SO₂/HCl off-gas, the dried acid (1.00 eq) is suspended in 3.0 vol toluene containing 0.005 eq N,N-dimethylformamide as catalyst. Thionyl chloride (1.35 eq) is fed via a dip pipe below liquid surface at 18–22 kg min⁻¹ over 90 min with the jacket set to 50 °C; the endotherm moderates after 20 min and exothermic gas evolution dictates a stepwise ramp to 62 ± 2 °C. Reaction completion is verified by in-process HPLC of a methanol-quenched aliquot showing residual acid <0.5 area%. Vacuum distillation (60 mbar, 45 °C) strips volatiles to a final toluene volume of 1.8 vol, and the acid chloride solution is transferred through a 1 μm sintered-metal filter directly into the subsequent amidation vessel. The fate of the acid chloride stability is critical: solutions held above 10 °C for more than 6 h develop a purple chromophore tentatively assigned to a dimerization product that depresses coupling efficiency by 4–8 % absolute.

Acid chloride batch purity (GC-FID, area%)	Coupling yield with 2-isopropylphenylamine (%)	Final SDHI purity after recrystallization (%)
96.2	78.5	97.3
98.5	88.2	99.1
99.1	91.0	99.6

Amidation is conducted by feeding the filtered acyl chloride solution into a mixture of 1.00 eq 2-isopropylphenylamine and 1.15 eq triethylamine in 4 vol toluene at −8 °C, maintaining the addition rate such that the internal temperature never exceeds 0 °C. The resulting slurry is heated to 70 °C, washed with 1 × 2 vol 1 N HCl and 2 × 2 vol water, and crystallized by solvent swap to n-heptane, yielding the target carboxamide in 85–92 % isolated yield after vacuum drying. This intermediate is the key building block for a succinate dehydrogenase inhibitor (SDHI) fungicide registered under EU Regulation (EC) No 1107/2009 Annex II, where the residue definition includes the parent compound and the desmethyl metabolite; toxicological endpoints comply with OECD Test Guideline 407 and 408 repeated-dose studies. Importantly, the entire process is incompatible with protic polar solvents such as methanol or water above 0.3 % w/w at the acid chloride stage due to rapid hydrolysis that generates a recalcitrant dimeric anhydride impurity detectable by LC-MS at [2M+Na]⁺.

Methyl esterification yield profiles under Dean-Stark and molecular sieve dehydration

Methanolysis experiments conducted in a 100 L glass-lined vessel illustrate the sensitivity of the equilibrium to water removal method. When a charge of 1.0 eq acid and 12 eq methanol is heated at reflux with 0.08 eq sulfuric acid and a Dean-Stark trap charged with 3 Å molecular sieves, the conversion plateaus at 94 % after 12 h. Substituting the trap with an in-line recirculated molecular sieve bed (3 kg of 3 Å beads, regenerated at 260 °C) and operating at 1.2 bar gauge raises the conversion to 99.2 % within 7 h, as monitored by the acid value decline to <2 mg KOH g⁻¹ per ASTM D664-18e2. The crude methyl 2-methyl-4-trifluoromethyl-thiazole-5-carboxylate is neutralized with 1.05 eq sodium bicarbonate, washed with brine, dried over anhydrous sodium sulfate, and fractionally distilled under 15 mbar (boiling range 112–114 °C) to yield 96 % of product exceeding 99.8 % GC purity. This ester is the preferred masked form for downstream lithiation chemistry because the carboxylate anion competing behaviour is eliminated. In a subsequent herbicide elaboration, the ester undergoes regioselective bromination with N-bromosuccinimide in acetonitrile at 60 °C catalysed by 2 mol% benzoyl peroxide, furnishing a 5-bromo intermediate that is then coupled under Suzuki-Miyaura conditions to introduce a substituted phenyl ring. The final phenoxyphenyl-substituted thiazole ester is saponified to the free acid and converted to the propargyl amide, generating a protoporphyrinogen oxidase (PPO) inhibitor herbicide requiring compliance with EPA OPPTS 850.6100 environmental fate testing before registration. Large-scale production of the methyl ester has highlighted a safety constraint: the neat ester exhibits a flash point of 68 °C (ASTM D93-20, Pensky-Martens closed cup) and must be stored under nitrogen with 40 ppm BHT inhibitor to prevent peroxide formation during transoceanic shipment in isotanks.Assembly of a 2′-methyl-substituted nucleoside phosphoramidate prodrug required a transient protection of the 5′-hydroxyl with the 2-methyl-4-trifluoromethyl-thiazole-5-carbonyl group, chosen for its base-labile cleavage kinetics and its ability to enhance membrane permeability in Caco-2 monolayer assays (apparent permeability coefficient 8.2 × 10⁻⁶ cm s⁻¹ versus 3.1 × 10⁻⁶ cm s⁻¹ for the unprotected nucleoside). The acylation is executed by dissolving the nucleoside (1.0 eq, dried by azeotropic distillation with toluene) in anhydrous tetrahydrofuran (8 vol) and cooling to −15 °C. Solid 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid (1.4 eq) is added, followed by dicyclohexylcarbodiimide (1.6 eq) and 4-dimethylaminopyridine (0.1 eq), and the suspension is warmed to 20 ± 2 °C over 6 h. Dicyclohexylurea is removed by filtration through a 0.5 μm Teflon depth filter, and the filtrate is washed with 0.5 M citric acid, then saturated sodium bicarbonate. The organic layer is concentrated and the residue purified by flash chromatography (silica gel, ethyl acetate/heptane 1:4) to yield the 5′-O-(2-methyl-4-trifluoromethyl-thiazole-5-carbonyl) nucleoside in 72–78 % yield as a white foam. Critical quality attributes for the protected intermediate include residual THF below 720 ppm (ICH Q3C Class 2 limit), dicyclohexylurea below 0.1 % w/w, and enantiomeric excess > 99.5 % by chiral HPLC. Deprotection prior to phosphoramidation uses catalytic sodium methoxide in methanol at 0 °C; complete removal is confirmed within 15 min by the absence of the carbonyl absorbance at 1728 cm⁻¹ in the FTIR spectrum. The drug substance derived from this route is the subject of an active Investigational New Drug application with a chemistry, manufacturing, and controls section structured per ICH M4Q, and the foreign supplier of the thiazolecarboxylic acid must be audited for ICH Q7 GMP compliance for starting material qualification.

What governs residual solvent limits in veterinary sulfonamide drug substance manufacture?

Specifications governing residual solvents in intermediates destined for feed-grade sulfonamides derive from the intersection of ICH Q3C options and the specific toxicological profile of a coccidiostat candidate. When 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid is activated with N,N′-carbonyldiimidazole (1.15 eq) in anhydrous acetonitrile at 25 °C for 40 min and subsequently coupled with sulfanilamide (0.95 eq) in the presence of 1.2 eq 1,8-diazabicyclo[5.4.0]undec-7-ene, the process generates an acylsulfonamide linkage. The crude product is precipitated by pouring into 15 vol deionized water at 5 °C, filtered, and recrystallized from aqueous ethanol (1:1.5 v/v). After drying in a forced-air oven at 55 °C for 14 h, residual acetonitrile is consistently found at 280–350 ppm, approaching the 410 ppm permitted daily exposure limit. Three validated strategies bring this below 150 ppm: a post-drying humidification cycle (45 % RH, 40 °C, 6 h) that mobilizes trapped solvent, slurry washing with acetonitrile-free water, or replacement of acetonitrile with ethyl acetate (Class 3) during activation. The final acylsulfonamide intermediate is forwarded to a pelleting operation where it is combined with excipients at 6.5 g kg⁻¹ feed; uniformity of distribution is verified by testing 30 incremental samples per tonne according to EU Regulation (EC) No 152/2009 Annex IV. Exposure assessment for target animal safety requires measurement of plasma trough levels of the free acid hydrolysis product in broiler chickens after 21-day administration, with a lower limit of quantification of 0.5 ng mL⁻¹ achieved via LC-MS/MS in accordance with VICH GL49.Fluorinated amidoamine surfactants prepared from the parent acid and Jeffamine M-1000 (polyetheramine, approx. 1000 g mol⁻¹) have been evaluated as replacements for linear alkylbenzene sulfonates in low-foam metal cleaning formulations where rapid wetting on aluminium 2024-T3 substrates is required. The synthesis involves activating the acid with 1.03 eq of 2-chloro-4,6-dimethoxy-1,3,5-triazine and 1.1 eq N-methylmorpholine in tetrahydrofuran at 0 °C, then adding the jeffamine over 30 min and stirring at 22 °C for 8 h. After filtration and solvent removal, the waxy amidoamine is diluted in propylene glycol to 30 % actives. Dynamic surface tension measured at 1 Hz by maximum bubble pressure (Krüss BP100) decreases from 66 mN m⁻¹ to 32 mN m⁻¹ at 0.1 wt% concentration, outperforming typical nonionic alkyl polyglucosides at the same addition. The following table contrasts key performance parameters across three EO chain lengths.

Amidoamine surfactant (polyether chain MW)	Cloud point (°C, 1 % aq.)	Cp at CMC (mg L⁻¹)	γ at CMC (mN m⁻¹, 25 °C)
Jeffamine M-600 adduct	47	180	28.8
Jeffamine M-1000 adduct	62	95	31.2
Jeffamine M-2005 adduct	>100	42	34.5

Regulatory scrutiny under emerging PFAS frameworks demands that this trifluoromethyl-substituted surfactant—containing a non-polymeric –CF₃ group—is distinguished from long-chain perfluoroalkyl substances. The molecule exhibits a 28-day ready biodegradability of 42 % in the OECD 301B CO₂ evolution test, below the 60 % pass threshold, necessitating assessment under REACH Annex XIII for vPvB classification. Technical data submitted to ECHA must include a hydrolysis half-life of >365 days at pH 7, a log Kow of 3.8 (OECD 107 shake-flask), and a fish bioconcentration factor of 120 L kg⁻¹ (OECD 305), positioning it at the boundary of concern for bioaccumulative potential. In industrial cleaning baths, the surfactant is employed at 0.15–0.4 wt% under alkaline conditions (pH 9–10.5) where the amide bond shows a half-life of 18–22 h at 60 °C monitored by LC-MS; this hydrolysis liability limits bath lifetime but ensures downstream wastewater treatment plants receive a bolus of the free acid and short-chain polyether amine that can be mineralized in activated sludge with an extended hydraulic retention time of 18 h.

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Certification & Compliance

2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

A polycrystalline off-white solid with a melting endotherm onset of 162–164 °C (DSC, 10 K/min under nitrogen) and a sublimation threshold near 120 °C at 10 mbar defines the primary physical profile of 2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid (CAS 117857-22-0). In large-scale synthesis of succinate dehydrogenase inhibitor (SDHI) fungicides, this thiazole carboxylic acid serves as the essential heterocyclic building block that undergoes direct amidation with 2,6-dibromo-4-(trifluoromethoxy)aniline to yield thifluzamide. Manufacturing campaigns on 500-litre glass-lined reactors routinely require that the acid content exceeds 98.0% (HPLC area normalization, 254 nm), because dimeric and over-oxidised impurities, which appear at relative retention times of 1.18–1.24, reduce the yield of the subsequent acid chloride step by prematurely consuming thionyl chloride and generating tarry by-products. Drying in a vacuum tray dryer at 60 °C for a minimum of 4 hours is standard when residual moisture exceeds 0.3% w/w (Karl Fischer, ISO 760), as moisture contents above this limit depress acid chloride yields below 85% due to competitive hydrolysis of the acylating agent.

Physicochemical Specification and Analytical Benchmarks

The table below summarises release specifications applied to commercial quantities intended for agricultural active-ingredient synthesis. Limits derive from statistical process control data gathered across 34 production batches from a multi-purpose batch plant operating under cGMP for fine chemicals.

Parameter	Method	Specification
Appearance	Visual inspection	White to faint yellow crystalline powder
Purity (HPLC)	In-house LC-UV, C18 column, acetonitrile/0.1% H₃PO₄ gradient	≥ 98.5 area%
Melting range	DSC (onset), 10 K/min, N₂	162–164 °C
Water content	Karl Fischer coulometry (ISO 760)	≤ 0.5% w/w
Residue on ignition	Gravimetric, 800 °C	≤ 0.1% w/w
Sulphated ash	Ph. Eur. 2.4.14	≤ 0.2% w/w

Shipments leaving the plant are packaged in 25 kg fibre drums with an inner LDPE liner, under argon blanket. Stored at +2 to +8 °C and protected from ambient humidity, the solid shows a re-test interval of 24 months; beyond that period, an increase in the less-soluble decarboxylated impurity is occasionally observed when headspace oxygen exceeds 1%. In downstream coupling chemistry, the electron-withdrawing character of the trifluoromethyl substituent at the 4-position lowers the pKa of the carboxylic acid to approximately 2.1 (calculated; published experimental data for this specific configuration is limited), compared with a pKa of 3.7 for the non-fluorinated 2-methylthiazole-5-carboxylic acid. This acid-strength differential permits activation with milder bases, reducing salt formation with aniline substrates in Schlenk-type amidation protocols. Furthermore, the CF₃ group increases the calculated octanol–water partition coefficient (ClogP) by roughly 1.3 log units, translating into a longer soil half-life for the derived amide fungicide and improved foliar uptake in cereal crops.

How Does 2-Methyl-4-Trifluoromethyl-Thiazole-5-Carboxylic Acid Compare to Non-Fluorinated Analogues?

Systematic comparisons between this intermediate and its non-halogenated and chloro-substituted thiazole counterparts highlight three critical processing advantages that drive its selection in SDHI fungicide backbones.

Property	2-Methyl-4-CF₃-thiazole-5-COOH	2-Methylthiazole-5-COOH (non-fluorinated)	2-Chloro-4-CF₃-thiazole-5-COOH
Apparent pKa (computational, COSMO-RS)	2.1	3.7	1.8
Acid-chloride formation temperature (SOCl₂, toluene)	75–80 °C over 2 h	80–85 °C over 4 h	Exothermic; control at 55–60 °C recommended
Amidation selectivity (with aniline substrate)	> 99% conversion, <0.5% hydrolysed by-product	~ 95% conversion, 3–5% acid regeneration	> 99% conversion, but 2–4% ring-opening observed
Lipophilicity contribution to final active (LogP increase)	+ 1.3 units vs. non-fluorinated	Baseline	+ 1.5 units
Typical primary application	Thifluzamide and analogues	Simple thiazole-amide fungicide precursors	SDHI derivatives with altered resistance profile

The data underscore that the methyl-plus-trifluoromethyl substitution pattern achieves a favourable balance between activation energy and product purity. Excessive acid strength in the 2-chloro variant accelerates ring decomposition pathways when harsh chlorinating agents are present, whereas the non-fluorinated acid demands higher activation temperatures that lead to greater thermal loss of the thiazole core. Operators of a 200-litre Hastelloy C-22 loop reactor at a contract manufacturing organisation reported that reducing the jacket temperature by merely 5 °C from the standard protocol during acid chloride generation of the non-fluorinated analogue caused incomplete conversion, extending batch cycle time by 2.5 hours—a bottleneck not observed with the trifluoromethyl-bearing acid.

When Coupling with Aniline Derivatives Under Schlenk Conditions

The amidation of 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid with deactivated anilines such as 2,6-dibromo-4-(trifluoromethoxy)aniline is typically performed after the acid has been converted to its acid chloride using thionyl chloride in anhydrous toluene containing a catalytic amount of dimethylformamide (0.5 mol%). The reaction is run in a 100-litre glass-lined reactor equipped with a caustic scrubber for off-gas management; the effluent is monitored for HCl breakthrough via a calibrated pH probe in the scrubber loop, with a safe operating limit of pH < 9.5. Once conversion exceeds 99% by TLC (silica gel, n-hexane/ethyl acetate 3:1), the mixture is cooled to 0–5 °C before the aniline is added in a single portion. The exothermic coupling raises the internal temperature to 10–12 °C within 3 minutes, after which a warm water bath brings the mass to 60 °C for a 2-hour hold. Filtration and subsequent reslurry from aqueous isopropanol removes the bulk of dimethylformamide residues and any unreacted acid chloride, delivering thifluzamide in isolated yields of 92–94% (corrected for purity). Published data for this specific coupling sequence under micro-channel continuous-flow conditions is limited; however, preliminary experiments in a PFA tube reactor (inner diameter 0.8 mm, residence time 45 seconds) suggest that the acid can be directly amidated via a mixed anhydride method without full isolation of the intermediate, potentially raising yield above 96%. Any implementation in a production environment would require verification of the residence time distribution under scale-up and strict exclusion of moisture above 10 ppm in the feed stream. The carboxyl group also participates in esterification with methanol under acidic catalysis, giving the methyl ester (boiling point 108–110 °C at 12 mbar), a derivative sometimes preferred for Negishi-type cross-couplings where the free acid would interfere with organozinc reagents. Nevertheless, the free acid remains the dominant commercial form because the additional ester hydrolysis step introduces 5–7% yield loss and extends the overall sequence by two unit operations. During storage of the free acid, contact with primary or secondary amines must be strictly avoided: even vapour-phase contamination by morpholine or piperidine leads to rapid salt formation, producing a sticky agglomerate that blocks the discharge of rotary valves on the packaging line—a failure mode documented at a facility after a shared ventilation duct introduced traces of morpholine from an unrelated campaign.