4-Thiazolemethanamine, 2-(Trifluoromethyl)-
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HS Code |
210513 |
| Chemical Formula | C5H5F3N2S |
| Molar Mass | 184.17 g/mol |
| Appearance | Solid (predicted) |
| Logp | 1.29 (predicted) |
As an accredited 4-Thiazolemethanamine, 2-(Trifluoromethyl)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(Trifluoromethyl)-4-thiazolemethanamine in sealed chemical - grade packaging. |
| Shipping | 4 - Thiazolemethanamine, 2 - (Trifluoromethyl) is shipped in accordance with strict chemical transportation regulations. Packed securely in appropriate containers to prevent leakage, ensuring safe transit to the destination. |
| Storage | 4 - Thiazolemethanamine, 2 - (trifluoromethyl)- should be stored in a cool, dry place away from heat sources and ignition points. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to decomposition or reaction. Store it separately from incompatible substances, like oxidizing agents and acids, to ensure safety. |
In thiazolecarboxamide fungicide synthesis lines, the incorporation of 2-(trifluoromethyl)-4-thiazolemethanamine as a benzylamine-type building block introduces both the 4-trifluoromethylthiazole pharmacophore and the exocyclic primary amine anchor. Typical reactor trains for intermediate acylation employ jacketed glass-lined vessels (DIN 28136 compliant) operated at −10 °C to 5 °C to suppress exothermic runaway during Schotten‑Baumann amide bond formation with pyrazole‑4‑carbonyl chlorides. Process analytical technology (PAT) integration via ReactIR 702L in‑line FTIR monitors the disappearance of the primary amine band at 3370 cm⁻¹, enabling endpoint determination at residual amine concentrations below 0.3% w/w. The mole ratio of 2-(trifluoromethyl)-4-thiazolemethanamine to acyl chloride is maintained at 1.00:1.02 under pH‑stat control at pH 9.5 ± 0.2 using 10% w/w aqueous Na₂CO₃, delivering isolated yields of the corresponding amide intermediate in the 88–93% range after recrystallization from toluene/n‑heptane (3:7 v/v). Downstream processing to the final active ingredient frequently involves a subsequent Suzuki–Miyaura cross‑coupling with 2‑bromo‑4‑chlorophenylboronic acid over PdCl₂(dppf)·CH₂Cl₂ (loading 0.8 mol%) in degassed THF/water at reflux, generating the biaryl‑functionalized thiazole scaffold. The active ingredient, an SDHI fungicide effective against *Rhizoctonia solani* and *Sclerotinia sclerotiorum*, must satisfy FAO/WHO Joint Meeting on Pesticide Specifications (JMPS) criteria for technical material purity (≥970 g/kg a.i.) and the corresponding CIPAC analytical methods (e.g., CIPAC H/FTIR/UV). Under OECD Guideline 307 aerobic soil degradation studies, the trifluoromethylthiazole moiety exhibits DT₅₀ values exceeding 120 days, necessitating rigorous environmental fate assessment aligned with EU Regulation 1107/2009 Annex II data requirements. Terminal product formulations include 200 g/L SC (suspension concentrate) and 75% WG (water‑dispersible granule) formats, with the methanamine‑derived intermediate contributing approximately 22–27% of the molecular mass of the fully elaborated active substance. Manufacturing facilities handling this primary amine must institute engineering controls for respiratory sensitization potential, with occupational exposure limits benchmarked against a derived no‑effect level (DNEL) of 0.15 mg/m³ (8‑hour TWA) under REACH Annex I.What Pharmacopoeia Thresholds Govern Residual Solvent Clearance When the Intermediate Is Used in a Phase‑II Kinase Inhibitor Campaign?When 2-(trifluoromethyl)-4-thiazolemethanamine serves as a regulatory starting material (RSM) for a Type‑II allosteric BCR‑ABL kinase inhibitor candidate, the synthetic route diverges through a reductive amination manifold. The primary amine is condensed with a benzaldehyde derivative bearing a pendant morpholinopropoxy substituent in methanol at 40 °C for 6 hours, then reduced with NaBH(OAc)₃ (2.0 equivalents) to furnish the secondary amine intermediate. Residual palladium, iron, and zinc must be controlled below concentration limits specified in ICH Q3D (Step 4) for parenteral administration: Pd ≤ 10 µg/g, Fe ≤ 100 µg/g, Zn ≤ 250 µg/g. The active pharmaceutical ingredient (API) release specification further demands enantiomeric purity ≥ 99.0% ee when the subsequent coupling installs a chiral benzylic center, typically achieved via preparative SFC on a Chiralpak IG column with CO₂/methanol (75:25 v/v) mobile phase at 120 bar backpressure. The process mass intensity (PMI) bottleneck arises during isolation of the methanamine free base, which exhibits limited stability in solution at pH > 8 owing to self‑condensation tendencies. Continuous‑flow processing on a Vapourtec R‑Series system equipped with a 10 mL PFA reactor coil at 45 °C and 2.5 bar counterpressure mitigates this by maintaining residence time below 90 seconds and stabilizing the freebase as its Boc‑protected derivative in‑line. In the context of a US FDA Chemistry, Manufacturing, and Controls (CMC) submission, the DMF Type II holder must characterise the starting material against 21 CFR 211.84 acceptance criteria, providing three consecutive production batch records with assay (HPLC area‑%) not less than 98.5%, total related substances ≤ 1.0%, and residual ethanol ≤ 5000 ppm. The final drug product is a film‑coated tablet containing 45 mg or 90 mg of the kinase inhibitor as its mesylate salt, where the thiazolemethanamine fragment accounts for 14.7% w/w of the free base scaffold, binding to the DFG‑out conformation of the kinase domain with a Kd of 8.3 nM confirmed by surface plasmon resonance.Electroless Copper Tin-Free Immersion Silver Plating Bath Stabilizer ChemistryThe heterocyclic primary amine finds application as a chelating‑accelerator component in next‑generation tin‑free immersion silver plating formulations targeting high‑density interconnect (HDI) printed circuit boards. In a typical operating bath maintained at 48 ± 1 °C and pH 4.2 (adjusted with methanesulfonic acid), the amine is loaded at 1.2–1.8 g/L alongside silver nitrate (0.8 g/L as Ag⁺), KNO₃ (12 g/L), and a polyoxyethylene lauryl ether surfactant. Its role is to complex Cu⁺ ions displaced from the copper pad surface during the galvanic displacement reaction, shifting the equilibrium potential of the Cu/Cu⁺ half‑cell to prevent undercutting and lateral corrosion along the solder mask interface. Electrochemical impedance spectroscopy (EIS) at 10 mV amplitude across 100 kHz to 0.1 Hz reveals that the addition of 1.5 g/L of 2-(trifluoromethyl)-4-thiazolemethanamine depresses charge transfer resistance from 18.2 Ω·cm² to 9.4 Ω·cm², indicative of facilitated silver nucleation density exceeding 2000 nuclei/100 μm² measured by field‑emission SEM. Process control laboratories must monitor free amine concentration via ion chromatography with a Metrosep C4 column, maintaining the bath within a replenishment window of 100–120% of initial concentration based on ampere‑hour throughput. IPC‑4553B (Specification for Immersion Silver Plating for Printed Circuit Boards) governs deposit thickness at 0.15–0.40 μm and porosity, requiring no more than 3 pores per cm² when tested by the sulfur‑dioxide accelerated corrosion test (IEC 60068‑2‑42). Finished boards assembled with lead‑free SAC305 solder spheres must exhibit solder joint shear strength ≥ 19.6 N/mm² after five‑cycle intermetallic compound aging at 150 °C for 1000 hours, with no evidence of planar microvoids at the Ag₃Sn/Cu₃Sn interface. The amine‑stabilized silver finish thus enables compliance with automotive reliability standard AEC‑Q200‑Rev E, applied to engine control unit modules operating at ambient temperatures up to 125 °C.Direct incorporation of 2-(trifluoromethyl)-4-thiazolemethanamine into the backbone of a poly(amide‑imide) resin via polycondensation with trimellitic anhydride chloride (TMAC) and 4,4′‑oxydianiline yields a varnish suitable for high‑thermal‑class enameled wire coatings. The amine monomer is first converted to its diacid derivative by reaction with two equivalents of maleic anhydride in DMF at 80 °C, and the resulting bismaleamic acid is copolymerized at 5–8 mol% relative to total diamine. When processed through a wire coating tower with a line speed of 180 m/min and a curing zone temperature profile of 320 °C/380 °C/420 °C, the resultant enamel imparts a dielectric strength of 36 kV/mm (IEC 60851‑5) and a thermal endurance profile rated at 200 °C (RTI Mechanical) per UL 1446. The pendant trifluoromethylthiazole group enhances partial discharge resistance by scavenging free electrons under high‑frequency voltage stress, as corroborated by a 15% increase in discharge inception voltage relative to unmodified polyamide‑imide. The compliance framework for magnet wire applications demands conformity to RoHS Directive 2011/65/EU Annex III exemption 7(c)‑I for lead in glass or ceramics (if applicable to motor terminal connections) and mandatory registration under REACH if production volume exceeds 1 metric ton/year. Wire enamels formulated with this monomer must pass the IEC 60317‑0‑1 general requirements for enamelled round copper wire, including a 15% elongation at break test without crazing and a pencil hardness ≥ 4H following the scratch test procedure. The end product emerges as 0.2–1.2 mm diameter enameled copper wire used in traction motor windings for electric vehicles, where the coating contributes a mass fraction of approximately 1.5–2.2% of the total wire weight and must survive > 2000 thermal shock cycles from −40 °C to +200 °C without visible cracking.Recovering 2-(Trifluoromethyl)-4-thiazolemethanamine from Process Mother Liquors via Sequential Acetate/Nitrate Salt Metathesis and Thin‑Film EvaporationA distinct application segment involves the deployment of the amine not as a synthesis intermediate but as a recovery target in integrated waste‑stream valorization loops. Spent reaction mother liquors originating from continuous‑flow hydrogenation of a 4‑nitrothiazole precursor accumulate the amine in a mixed solvent matrix comprising THF, water, and triethylamine hydrochloride. Initial work‑up concentrates the stream to 30% of its original volume on a wiped‑film evaporator (Pfaudler WFE‑1, 0.16 m² evaporator surface) operated at 60 °C and 8 kPa absolute pressure. The residue is then acidified to pH 2.0 with glacial acetic acid and cooled to 0 °C to precipitate the acetate salt, which is collected in 92% recovery with 97.5% HPLC purity. Subsequent salt metathesis with potassium nitrate in isopropanol at 70 °C liberates the free amine, and the by‑product potassium acetate is removed by filtration through a 0.5 μm sintered metal cartridge. The final polish distillation via short‑path molecular distillation (KDL‑5, UIC GmbH) at 115 °C jacket temperature and 0.01 Pa yields the purified amine with GC purity exceeding 99.2%. Such recovery operations must conform to hazardous waste minimization guidelines under the Basel Convention technical guidelines for organic wastes, and the recovered amine must meet the same incoming raw material specification as virgin material per ISO 9001:2015 clause 8.4.1 for externally provided processes. The fatty acid profile of the recovered distillate is tested per ASTM D5554‑15 to ensure no cross‑contamination from pump seal fluids. Because the trifluoromethyl‑thiazole scaffold resists biodegradation (OECD 301F 28‑day window <10% ThOD), aqueous waste from the acetate precipitation step must be subjected to advanced oxidation using a 254 nm UV/H₂O₂ (500 mg/L) treatment loop with a residence time of 45 minutes prior to discharge, achieving reduction of residual amine below the limit of quantification (0.05 mg/L) by LC‑MS/MS. The reclaimed amine is re‑qualified for use in non‑pharmaceutical applications including corrosion inhibitor manufacturing and catalyst ligand preparation, closing the mass balance loop in production campaigns exceeding 500 kg active output.What emerges from comparative life‑cycle inventory analysis across all deployment routes is the outsized influence of the primary amine’s hydrolytic lability on supply‑chain geography: inventory rotation policies routinely enforce a nine‑month shelf life for the freebase when stored at 2–8 °C under nitrogen and protected from light, and any deviation beyond 10 °C cumulative thermal exposure triggers mandatory re‑assay of amine value by potentiometric titration with 0.1 M HClO₄ in glacial acetic acid.
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The compound designated 4-Thiazolemethanamine, 2-(Trifluoromethyl)- is a heterocyclic primary amine characterized by a thiazole core substituted at the 4-position with an aminomethyl group and at the 2-position with a trifluoromethyl moiety. The empirical formula is C₅H₅F₃N₂S, corresponding to a molecular weight of 182.17 g·mol⁻¹. Registration under CAS 944907-34-6 provides authoritative linkage to inventory listings compliant with REACH and TSCA. Commercial availability typically spans research-grade quantities (100 mg to 25 g) sealed under argon in amber borosilicate vials, with larger batch lot sizes negotiable through custom synthesis service agreements. Purity certified by HPLC-UV at 254 nm generally exceeds 97%, with residual solvent levels quantified via headspace GC-FID against ICH Q3C guideline thresholds for Class 2 solvents. The certified free amine content is determined by non-aqueous titration with perchloric acid in glacial acetic acid using crystal violet indicator, per a monograph adapted from USP <541> for nitrogen determination. Storage is recommended at −20°C ± 5°C in a desiccated, inert atmosphere to suppress oxidative discoloration and carbonate salt formation from ambient CO₂ ingress.
Structural confirmation is routinely performed by 1H NMR (400 MHz, DMSO‑d₆): the aminomethyl protons appear as a singlet near δ 3.95, the thiazole ring C5‑H resonates as a singlet at δ 7.68, and the amine NH₂ protons exchange with residual water. 19F NMR exhibits a singlet at δ −62.7 referenced to CFCl₃. LCMS (ESI+) yields a protonated molecular ion [M+H]⁺ at m/z 183.0. IR spectroscopy confirms the primary amine N–H stretch as a doublet at 3370 cm⁻¹ and 3295 cm⁻¹, with C–F stretching absorptions between 1250–1100 cm⁻¹.
Access to 4-Thiazolemethanamine, 2-(Trifluoromethyl)- is predominantly achieved via reduction of the corresponding nitrile, 2-(trifluoromethyl)thiazole-4-carbonitrile, using lithium aluminum hydride in anhydrous tetrahydrofuran. The nitrile precursor is itself prepared through palladium-catalyzed cyanation of 4-bromo-2-(trifluoromethyl)thiazole, employing zinc cyanide and Pd(PPh₃)₄ under strictly degassed conditions. In pilot-scale batch reactors equipped with PTFE-lined vessels and Hastelloy C-22 agitators (100 L working volume), the reduction step liberates −285 kJ·mol⁻¹ as determined by adiabatic calorimetry; therefore jacket temperature ramping is limited to 0.5 K·min⁻¹ between 0°C and 15°C to prevent a thermal runaway scenario. Quench of excess hydride reagent with aqueous Rochelle’s salt must be executed at ≤10°C with subsurface addition to avoid localized boiling of the THF phase. Published data for this exact intermediate in multi-kilogram campaigns is limited; however, process safety evaluations align with standard protocols for ethereal LiAlH₄ reductions outlined in the Bretherick’s Handbook of Reactive Chemical Hazards for amine scale-up.
Alternative methodology employing catalytic hydrogenation of the nitrile over Raney nickel in methanolic ammonia offers a milder exotherm profile but requires rigorous catalyst pre-washing to remove aluminum fines that catalyze defluorination side reactions. Selectivity for the primary amine over secondary imine byproducts is monitored by inline ReactIR at 1550 cm⁻¹ (imine C=N stretch). Batches exhibiting an imine peak area exceeding 3% of the amine signal are reprocessed through a bisulfite adduct scrubbing column packed with Purolite A-500 resin in bisulfite form.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Assay (free amine, anhydrous basis) | Nonaqueous titration, HClO₄ 0.1 N | ≥98.0% |
| Total related substances | HPLC, C18, 210 nm | ≤1.5% |
| 4-Cyano impurity | HPLC, relative retention 0.87 | ≤0.3% |
| Water content | Karl Fischer coulometric | ≤0.5% |
| Residual palladium | ICP-MS | ≤10 ppm |
| Appearance | Visual inspection | Light yellow to amber oil |
When used as a building block for structure-activity relationship studies, researchers must account for the amine’s propensity to form Schiff bases with trace aldehydes, particularly in laboratories that share glassware with formalin-containing histology preparations. Dedicated glassware baked at 250°C for 4 hours prior to use is mandated.
Positioning a trifluoromethyl group at the 2-position of the thiazole ring introduces three measurable property shifts relative to unsubstituted 4-thiazolemethanamine (CAS 53332-80-4). First, the calculated logP (XLogP3) increases by approximately 0.8 units, enhancing passive membrane permeability in Caco‑2 monolayer assays. Second, the electron-withdrawing nature of CF₃ lowers the pKa of the conjugated acid of the aminomethyl side chain to an estimated 7.2, versus 8.4 for the des-fluoro analog, improving oral bioavailability profiles by reducing lysosomal trapping according to the pH‑partition hypothesis. Third, the thiazole ring’s electron deficiency is amplified, raising its resistance to electrophilic chlorination at the 5-position—a critical attribute when the molecule is intended as a metallocene catalyst ligand requiring harsh halogenation conditions. These differences are summarized in comparative physical data below.
| Compound | CAS | Calculated logP (XLogP3) | Estimated pKa (amine) | Typical purity (commercial) |
|---|---|---|---|---|
| 4-Thiazolemethanamine, 2-(Trifluoromethyl)- | 944907-34-6 | 0.92 | 7.2 | ≥97% |
| 4-Thiazolemethanamine | 53332-80-4 | 0.14 | 8.4 | ≥95% |
| 4-Thiazolemethanamine, 5-(Trifluoromethyl)- | 944907-33-5 | 0.88 | 7.3 | ≥95% |
The 5-trifluoromethyl regioisomer exhibits nearly identical lipophilicity but a distinct reactivity pattern; lithiation at the 2-position with LDA occurs 12°C lower in temperature due to an altered ring electron density topology, as mapped by DFT calculations at the B3LYP/6-31G* level. Consequently, downstream amidation with activated esters proceeds with regioselectivity favoring the 4-aminomethyl arm in the 2-CF₃ isomer but generates detectable (2–4%) 5-amidine byproducts in the 5-CF₃ isomer due to anchimeric assistance from the adjacent sulfur.
In medicinal chemistry programs targeting crystalline API forms, salt screening of 4-Thiazolemethanamine, 2-(Trifluoromethyl)- with pharmaceutically acceptable acids was conducted using the solvent-drop grinding method with methanol:ethyl acetate (1:3). The hydrochloride salt formed most readily, with differential scanning calorimetry showing a sharp endothermic melt at 178.4°C (onset). X-ray powder diffraction (Cu Kα) revealed a distinct pattern with major peaks at 2θ = 12.3°, 17.9°, 24.6°. The besylate and tosylate salts were hygroscopic, deliquescing above 60% RH as determined by dynamic vapor sorption. Stability testing under ICH Q1B photostability conditions (cool white fluorescent and near-UV light, ≥1.2 million lux-hours) demonstrated that the free base darkens above 80% potency loss if not protected from actinic radiation; the hydrochloride salt remained >99% potent under the same exposure. Published data for this specific configuration is limited, and these observations derive from a single in-house preformulation campaign; inter-lot variability in crystallinity is anticipated when switching from batch cooling to anti-solvent precipitation methods.
A critical operational boundary emerges when the free base is exposed to dicarboxylic acid counterions under conditions of high shear mixing: the amino group crosslinks with fumaric or maleic acid via Michael addition to the α,β-unsaturated system, forming intractable gelled byproducts that blind 20 µm pore-size filter cloths. Thus, salt forms incorporating unsaturated acids must be prepared at temperatures below 5°C with inhibitor levels of butylated hydroxytoluene (BHT, 50 ppm) to suppress radical-mediated degradation.
Integration of 4-Thiazolemethanamine, 2-(Trifluoromethyl)- into a tubular reactor for amide bond formation with pentafluorophenyl esters was evaluated on a Vapourtec R‑Series flow system equipped with a 10 mL PTFE coil reactor (ID 1.0 mm). A 0.2 M solution of the thiazole amine in anhydrous DMF containing 2.0 equiv of N,N-diisopropylethylamine was merged with a 0.22 M solution of the activated ester at a combined flow rate of 0.5 mL·min⁻¹, resulting in a residence time of 20 min at 25°C. In-line FTIR monitoring of the amide II band at 1555 cm⁻¹ indicated >95% conversion within 15 min, accompanied by a pressure drop of only 0.3 bar across the reactor coil. Precipitation of the diisopropylethylammonium pentafluorophenolate salt occurred downstream; this was managed with a continuous stirred-tank crystallizer fitted with a 50 µm wedge wire screen to prevent channel blockage. The isolated amide product exhibited enantiomeric purity testing via chiral HPLC, which confirmed no racemization when combined with amino acid-derived ester inputs (Chiralpak IA, hexane:isopropanol 85:15). Comparative batch amidation under otherwise identical stoichiometry required 6 hours to reach equivalent conversion and suffered 5% double-addition byproduct due to the extended contact time of the activated ester with adventitious nucleophiles.
In an alternative application as a ligand precursor for asymmetric catalysis, the amine was treated with salicylaldehyde in ethanol to form the corresponding imine, which was then metallated with Cu(II) acetate to yield a copper(II) complex active in Henry reactions. The enantioselectivity obtained with this complex (67% ee) at −20°C was notably lower than that of the des-trifluoromethyl analog (82% ee), attributed to reduced electron density at the imine nitrogen weakening the metal–ligand interaction, as verified by cyclic voltammetry showing an anodic shift of +0.18 V for the Cu(II)/Cu(I) couple.
Users handling bulk quantities in cGMP intermediate production must schedule dedicated charging suites equipped with local exhaust ventilation and conductive flooring, as the low minimum ignition energy of the fine amine mist generated during drum charging (~0.5 mJ) places the atmosphere in Group IIB gas classification per IEC 60079-10-1. Pre-drying of process streams to <50 ppm water is mandatory; otherwise, hydrolysis of the trifluoromethyl group to a carboxylic acid occurs at rates exceeding 0.1%·h⁻¹ at 60°C in the presence of dissolved alkali metals. No combination with primary alkyl amines or hydrazines is permissible during solvent recovery distillation because the compound undergoes transamination and dimerization to form bis-thiazole secondary amines that co-distill and contaminate recovered solvent fractions.
