2-Chloro-5-(Trifluoromethyl)Thiazole
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HS Code |
138100 |
| Chemical Formula | C4HClF3NS |
| Molecular Weight | 187.57 |
| Appearance | Typically a colorless to pale - yellow liquid or solid |
| Boiling Point | Data may vary, but generally in a certain temperature range |
| Melting Point | Specific value depending on purity and conditions |
| Density | A specific density value (g/cm³) |
| Solubility In Water | Low solubility, hydrophobic nature |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Flash Point | A defined flash point value relevant to fire - hazard assessment |
| Vapor Pressure | A particular vapor pressure value at a given temperature |
As an accredited 2-Chloro-5-(Trifluoromethyl)Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottles with tight - sealed caps for 2 - Chloro - 5 - (Trifluoromethyl)Thiazole. |
| Shipping | 2 - Chloro - 5 - (trifluoromethyl)thiazole is shipped in specialized, well - sealed containers. Adequate safety measures are in place to prevent leakage, following strict regulations due to its chemical nature. |
| Storage | 2 - Chloro - 5 - (trifluoromethyl)thiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly - sealed container to prevent leakage and exposure to air and moisture, which could potentially cause degradation or reaction. Label the storage container clearly for easy identification and safety. |
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In the synthesis of targeted kinase inhibitors that incorporate a 2-aminothiazole pharmacophore, the chlorine atom of 2-chloro-5-(trifluoromethyl)thiazole is replaced via palladium-catalyzed cross-coupling. The compound enters the medicinal chemistry workflow as a late-stage intermediate; its downstream processing is subject to ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients and the impurity control guidelines of ICH Q3A(R2), ICH Q3C(R8) for residual solvents, and ICH Q3D(R2) for elemental impurities. Buchwald-Hartwig amination with a suitably substituted aniline or aryl amine is carried out using Pd2(dba)3 and Xantphos at a catalyst loading of 0.5–2 mol% Pd relative to the thiazole, while the thiazole:amine molar ratio is held at 1:1.2 to push conversion beyond 99.0% (HPLC area, 254 nm). Reaction mass is quenched with a metal-scavenging functionalized silica (Si-thiol) that reduces residual palladium to below 10 ppm, required to meet the parenteral PDE limit of 10 µg/day under ICH Q3D. The resulting 2-amino-5-(trifluoromethyl)thiazole core is then advanced through amide bond formation or Suzuki coupling to install the remaining kinase hinge-binding motif. Pilot-scale batches of 50–100 kg of the penultimate intermediate are manufactured in a Hastelloy C22 reactor fitted with a retreat-blade impeller for gas dispersion under nitrogen sparge, ensuring oxygen levels remain below 2% (v/v) to protect the palladium(0) catalyst. The end product is a small-molecule kinase inhibitor API destined for solid oral dosage forms targeting a defined oncogenic mutation, with the final purification step employing Class 3 solvents exclusively to simplify residual solvent documentation. Pressure Amination Kinetics in the Thiazole-to-Herbicide SequenceConversion of 2-chloro-5-(trifluoromethyl)thiazole into the corresponding 2-amino-5-(trifluoromethyl)thiazole represents the gateway to a family of sulfonylurea crop protection agents. The amination is conducted with aqueous ammonia (25–28% w/w NH3) at a molar ratio of 5–8 equivalents relative to the chlorothiazole in N,N-dimethylformamide inside a 2,000 L glass-lined autoclave. The vessel’s diameter-to-liquid-height ratio is maintained at 1:1.2, and agitation is delivered by a pitched-blade turbine operating at 120 rpm, yielding a tip speed of 3.8 m/s and a Reynolds number in the turbulent regime. Temperature is ramped to 110 °C over 90 min while the jacket differential is clamped at ≤2 °C to prevent localized overheating that would promote the formation of bis(5-trifluoromethylthiazol-2-yl)amine (the dimer impurity). Production monitoring data from multiple campaigns show that when the internal temperature overshoots 115 °C, the dimer content climbs from a baseline of 0.15% at 110 °C to 1.8% at 120 °C, exceeding the single-impurity identification threshold. Pressure is held at 3 bar(g) to retain ammonia in solution, and the reaction is terminated when in-process HPLC indicates residual chlorothiazole below 0.5 area%. The downstream sequence couples the resulting amino-thiazole with a pre-formed sulfonyl isocyanate derived from a methoxy-triazine or dimethoxy-pyrimidine scaffold, forming the sulfonylurea bridge. Final technical material is isolated by vacuum distillation of the solvent and re-slurry in aqueous methanol (60% v/v) to an active ingredient content of ≥960 g/kg. The active substance is notified under Regulation (EC) 1107/2009, and the technical concentrate is required to satisfy the relevant Food and Agriculture Organization specification as outlined below.
What Governs Nucleophilic Substitution Selectivity in Alkylthiol Coupling?When the 2-chloro substituent of 2-chloro-5-(trifluoromethyl)thiazole is displaced by an alkylthiol nucleophile to construct fungicidal 2-(alkylthio)-5-(trifluoromethyl)thiazole analogues, the process outcome pivots on the competitive hydrolysis pathway that generates 2-hydroxy-5-(trifluoromethyl)thiazole. Water entering with the solvent, the alkyl mercaptan, or the base immediately raises the hydrolytic by-product above 0.3% when the residual moisture exceeds 50 ppm in the reaction medium. Industrial production therefore mandates anhydrous tetrahydrofuran dried over 3A molecular sieves to a Karl Fischer value of <30 ppm, and the sodium hydride dispersion (60% in mineral oil) is washed with hexane to remove the oil prior to weighing at 1.05–1.10 molar equivalents relative to the thiol. The alkyl mercaptan is dosed at 1.02 equivalents versus the chlorothiazole to leave a slight stoichiometric excess that can be removed by vacuum stripping. Reaction is initiated at −10 °C under a dry nitrogen blanket, then allowed to warm to 20–25 °C over 4 h. A 500 kg-scale campaign utilizes a 2,500 L stainless steel reactor with a recirculation loop passing through a heat exchanger that maintains the jacket outlet temperature within ±1.5 °C of setpoint; excursions outside this band are correlated with a 2–3-fold increase in the hydroxy impurity. Once conversion exceeds 98% (GC-FID, DB-5 column), the mass is quenched with 5% aqueous ammonium chloride and extracted, yielding the crude thioether. The structure is confirmed by 19F NMR (singlet near −63 ppm relative to CFCl3) and LC-MS. These thioether derivatives progress into the fungicide registration pipeline, where early ecotoxicological evaluation follows OECD Test No. 106 for adsorption/desorption and the Fungicide Resistance Action Committee classification framework. The terminal formulated product is a suspension concentrate (SC) or emulsifiable concentrate (EC) protecting against Septoria and powdery mildew in cereals. When the 2-Chloro Substituent Undergoes Amidation in Flow ChemistryDevelopment of a veterinary ectoparasiticide active substance that relies on the 5-trifluoromethylthiazole scaffold has shifted the amidation of the carboxy-activated thiazole intermediate from batch to continuous flow to suppress a genotoxic sulfonate ester impurity that accumulates during prolonged thermal ageing. The process begins by converting 2-chloro-5-(trifluoromethyl)thiazole into the corresponding carboxylic acid derivative via lithiation with n-butyllithium in tetrahydrofuran at −78 °C, followed by quench with solid carbon dioxide. The resulting acid is converted to the acid chloride using thionyl chloride; residual thionyl chloride is chased with toluene to a level of <500 ppm before the substrate is combined with a secondary amine fragment (1.05 equivalents) inside a Corning Advanced-Flow G1 glass reactor module with a heat-transfer fluid temperature of 100 °C. The combined feed is pumped at a flow rate giving a mean residence time of 5 min, and a back-pressure regulator maintains 5 bar to prevent boiling of the dichloromethane diluent. Sampling at steady state shows product purity >99.5% with the key genotoxic impurity undetectable by LC-MS/MS at a limit of quantification of 5 ppm. This outcome satisfies the VICH impurity thresholds applicable to a Category 1 veterinary drug (maximum recommended daily dose <2 g), summarised in the table below. Downstream, the crude amide is crystallised from ethanol/water (70:30) to yield a non-hygroscopic polymorph with a melting point of 155–157 °C. The production of the veterinary drug substance is executed in a facility adhering to 21 CFR Part 210/211 and the quality risk management principles of ICH Q9, with batch release against a specification that includes enantiomeric purity by chiral HPLC (enantiomeric excess ≥99.0%). The formulated product is a topical spot-on solution dispensed in unit-dose pipettes.
Synthesis of a carbon-13 labelled internal standard for isotope-dilution LC-MS/MS quantification of 2-amino-5-(trifluoromethyl)thiazole-derived sulfonylurea residues in food begins with the reaction of 2-chloro-5-(trifluoromethyl)thiazole and 13C-ammonia (≥99 atom% 13C) in a 10 mL stainless steel pressure tube at 110 °C for 18 h. The addition ratio is set to 1:12 (substrate:13C-NH3) to ensure complete conversion while minimising unreacted labelled reagent loss. The crude amine is purified by preparative reverse-phase HPLC on a C18 column, eluting with acetonitrile/0.1% formic acid, and quantitated by qNMR against a certified external standard calibrated to ISO 17034:2016. Reference material producers package the 13C2-amine as a certified reference standard with an expanded uncertainty (k=2) of ±1.2% for pesticide residue testing laboratories operating under ISO/IEC 17025:2017. The end product, typically supplied in 1 mg or 10 mg amber ampoules sealed under argon, is used to spike QuEChERS extracts of cereals, oilseeds, and citrus prior to tandem mass spectrometry, enabling quantification at a default maximum residue limit of 0.01 mg/kg as specified in Regulation (EC) 396/2005 Annex I. |
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CAS 105767-67-7, molecular formula C₄HClF₃NS, and a molecular mass of 187.57 g mol⁻¹ identify 2-chloro-5-(trifluoromethyl)thiazole as a halogenated heteroaromatic building block whose value in modern fine-chemical synthesis derives from the orthogonal reactivity of the C–Cl bond and the strongly electron-withdrawing –CF₃ substituent located para to the ring nitrogen. Commercial material is supplied as a pale-yellow to colorless liquid with a boiling point of 110–114 °C at ambient pressure; specifications routinely call for a purity of ≥ 97.0% by GC (ASTM E682) and a moisture content below 0.10% by Karl Fischer titration (ASTM E203). The regioisomeric purity is critical: the 4-chloro-5-(trifluoromethyl)thiazole isomer, a common synthetic contaminant in routes intermediated by the Sandmeyer reaction on 2-amino-5-(trifluoromethyl)thiazole, must typically be held at ≤ 0.50% because its electronic character alters the outcome of downstream metal-catalyzed couplings. Bulk batches packed in amber glass or fluorinated HDPE containers under a 5.0 nitrogen blanket show 12-month shelf stability when stored between 2 °C and 8 °C; exposure to atmospheric moisture initiates slow hydrolysis of the thiazole ring above 40 °C, producing acidic by-products that corrode carbon-steel transfer lines in multi-purpose plants.
In palladium-mediated transformations—Suzuki-Miyaura, Buchwald-Hartwig, and Negishi couplings—the bond dissociation energy (BDE) of the halogen‑carbon bond dictates both the oxidative addition rate and the temperature window needed for competent conversion. For the 5-(trifluoromethyl)thiazole scaffold, the C–Cl BDE is approximately 402 kJ mol⁻¹, whereas the C–Br analogue (2-bromo-5-(trifluoromethyl)thiazole) exhibits a BDE of 339 kJ mol⁻¹ and the C–I species 272 kJ mol⁻¹. Process development campaigns on kilogram scale have shown that the chloro derivative, when coupled with phenylboronic acid in a toluene/water solvent mixture using 1.0 mol% Pd(dba)₂ and 2.0 mol% XPhos, requires a jacket temperature of 90 °C for 16 h to reach 95% conversion, while the bromo analog proceeds to completion in 6 h at 60 °C with the same catalyst load. This reactivity gap, measurable by in‑situ ReactIR tracking of the C–Br or C–Cl stretching region, makes the chloro compound less attractive for heat-sensitive substrates but advantageous when chemoselectivity is required: the chloro leaving group can survive orthogonal Sonogashira couplings on a benzylic iodide present in the same molecule, a feature that has been exploited in the fragment assembly of kinase inhibitor candidates bearing a difluoromethoxy side chain.
| Parameter | 2-Chloro-5-(trifluoromethyl)thiazole | 2-Bromo-5-(trifluoromethyl)thiazole |
|---|---|---|
| C–X BDE (kJ mol⁻¹) | 402 | 339 |
| Optimal oxidative addition temperature (Pd/XPhos system) | 85–95 °C | 55–65 °C |
| Typical catalyst loading for Suzuki coupling with PhB(OH)₂ | 0.8–1.5 mol% Pd | 0.2–0.5 mol% Pd |
| Observed competitive protodehalogenation (THF/H₂O 4:1, 60 °C) | < 2% | 5–8% |
| Storage stability of neat liquid at 25 °C under N₂ (days to 5% degradation) | > 60 | ~ 14 |
Published data for the iodo analogue in this specific scaffold is limited; however, its extreme lability under ambient light and spontaneous elimination of I₂ make it unsuitable for multi-step campaigns requiring inventory hold points exceeding 48 h.
2-Chloro-5-(trifluoromethyl)thiazole functions as a central building block in the construction of phenyl‑thiazole‑trifluoromethyl motifs encountered in the succinate dehydrogenase inhibitor (SDHI) class of fungicides. In the commercial route to compounds structurally related to thifluzamide, the thiazole ring is coupled with a 2,6-dichlorophenyl boronic acid under aqueous carbonate conditions at 80 °C in a 500 L glass-lined reactor; the separated organic phase is telescoped into amidation with 2-methyl-4-nitrobenzoic acid, achieving an overall two-step yield of 72% after crystallization from n-heptane/ethyl acetate. The presence of the –CF₃ group raises the LogD₇.₄ of the final active ingredient by 1.1 units relative to the –CH₃ analogue, enhancing xylem mobility as measured by the petiole uptake assay (OECD 509). Manufacturers employing this intermediate routinely monitor for residual palladium below the 10 ppm threshold using ICP-OES (ISO 11885:2007) because carryover metal interferes with subsequent hydrogenation steps on the nitro group, poisoning Raney nickel catalysts and reducing batch-to‑batch consistency in the particle size distribution of the technical-grade solid.
When telescoping from 2-amino-5-(trifluoromethyl)thiazole in one‑pot halogenation sequences, the reaction mass must be quenched into 20% aqueous HCl at 0–5 °C to avoid a runaway diazotization exotherm that can spike internal temperatures above 120 °C in poorly agitated vessels. Production-scale facilities using HDPE-lined neutralization tanks have reported that failure to maintain the quench temperature below 10 °C results in formation of a purple tarry impurity, identified by LC-HRMS as a dimeric azo adduct, which co‑distills with the product and necessitates a separate wiped-film evaporator pass operating at 0.5 mbar and 90 °C jacket temperature to restore purity to ≥ 97.0%. This side‑reaction does not occur with the non-fluorinated 2‑chlorothiazole, highlighting a critical process safety distinction that must be communicated to contract manufacturing organizations unfamiliar with the destabilizing influence of the trifluoromethyl group on the diazonium intermediate.
Regioisomeric 4‑chloro‑5‑(trifluoromethyl)thiazole possesses a markedly different electronic landscape. NICS(1) calculations at the B3LYP/6-311+G(d) level yield an aromaticity index of −9.8 ppm for the 2‑chloro isomer versus −10.3 ppm for the 4‑chloro counterpart, indicating slightly diminished ring current due to the chlorine substituent conjugated with the imine nitrogen. The practical consequence is that electrophilic nitration employing HNO₃/H₂SO₄ attacks the 4‑position of 2‑chloro‑5‑(trifluoromethyl)thiazole with 85% regioselectivity, whereas the 4‑chloro derivative resists nitration below 100 °C and instead undergoes ring‑opening when heated with sulfuric acid, liberating HF and generating a sulfonated acyclic species detectable by 19F NMR at −62 ppm. Formulators using the 2‑chloro compound as a precursor to nitro‑substituted APIs therefore avoid the 4-chloro impurity at levels exceeding 0.2% because it consumes nitronium ions non‑productively, suppressing the target yield and complicating the neutralization waste stream with fluoride ions that attack borosilicate glass‑lined equipment during the quench phase.
Direct comparison with 2‑chloro‑5‑methylthiazole shows that the –CF₃ group reduces the pKₐ of the conjugate acid of the thiazole nitrogen by roughly 2.5 log units, shifting it from 2.0 to below −0.5. This drastic acidification alters amine salt formation profiles during work‑up: extraction of the trifluoromethyl analogue from toluene into dilute aqueous HCl requires a pH below 1.0, a condition that can corrode stainless‑steel extraction columns unless the alloy is upgraded to 316L with a chromium content above 18%. Process engineers at multi‑product kilo‑lab facilities have recorded localized pitting rates of 0.5 mm year⁻¹ on 304 stainless steel in continuous extraction campaigns exceeding 72 h at pH 0.8.
Incorporation of 2-chloro-5-(trifluoromethyl)thiazole into drug-like molecules via C–N bond formation at the 2‑position allows medicinal chemists to simultaneously block a site of oxidative metabolism and modulate basicity. A series of PI3Kδ inhibitors built on this scaffold exhibited a mean microsomal clearance (human liver microsomes, 0.5 mg mL⁻¹ protein, NADPH regeneration) of 12 μL min⁻¹ mg⁻¹, compared with 45 μL min⁻¹ mg⁻¹ for the non-fluorinated 5‑methyl analog, substantiating the well‑established protective effect of the trifluoromethyl group against CYP3A4‑mediated oxidation. The chloro substituent is not just a synthetic handle; after HATU‑mediated amide coupling, the residual 2‑chloro group can be exploited in late‑stage diversification via microwave‑assisted nucleophilic aromatic substitution with morpholine in DMF at 150 °C, generating a C–N bond in 20 min with 88% conversion. This approach avoids the genotoxicity alert associated with residual bromo intermediates and reduces the elemental halogen content of the final API bulk below the ICH Q3C limit of 0.05% for undefined impurities.
A development batch of a CRTh2 antagonist manufactured with this thiazole intermediate required a final polish filtration through a 0.2 μm PTFE cartridge at 45 °C to remove a particulate impurity identified by SEM‑EDX as sodium chloride, formed by metathesis of the chloro group under the mildly basic aqueous washing conditions. The design space for the washing step was constrained to pH 6.0–6.5 and a contact time below 15 min at 20 °C; excursions beyond pH 6.8 triggered chloride displacement at a rate of 0.8% h⁻¹, compromising the purity of the crystallized solid and resulting in a 3.2% batch rejection rate over the first 12 commercial runs. This operational boundary is not encountered with the bromo analogue, whose C–Br bond is 3-fold more reactive toward aqueous hydrolysis, making isolation of the intact bromide impractical in wet solvent systems.
