4-(Chloromethyl)-2-(4-Chlorophenyl)-1,3-Thiazole
|
HS Code |
415849 |
| Name | 4-(Chloromethyl)-2-(4-Chlorophenyl)-1,3-Thiazole |
| Molecular Formula | C10H7Cl2NS |
| Molecular Weight | 244.14 |
| Appearance | Solid (usually) |
| Solubility In Water | Low (organic compound with non - polar groups) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Odor | Typical of organic heterocyclic compounds, likely pungent |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 4-(Chloromethyl)-2-(4-Chlorophenyl)-1,3-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4-(Chloromethyl)-2-(4-Chlorophenyl)-1,3-Thiazole in sealed chemical - grade packaging. |
| Shipping | 4-(Chloromethyl)-2-(4 - Chlorophenyl)-1,3-Thiazole is shipped with strict adherence to chemical safety regulations. It's carefully packaged to prevent leakage, transported by carriers compliant with hazardous material shipping standards. |
| Storage | 4-(Chloromethyl)-2-(4 - Chlorophenyl)-1,3 - Thiazole should be stored in a cool, dry, well - ventilated area away from sources of ignition. Keep it in a tightly sealed container, preferably in a corrosion - resistant material. Avoid storing it near oxidizing agents or substances that could react with it. This helps prevent degradation, ensure safety, and maintain its chemical integrity. |
How Does the Chloromethyl Group Facilitate Triazole Grafting in Agrochemical Synthesis?The compound is typically charged into a glass-lined stirred reactor equipped with a jacket capable of maintaining internal temperatures at 0 to 5 °C. Anhydrous DMF (<50 ppm H₂O, Karl Fischer titration) is added under nitrogen purge, followed by slow addition of sodium hydride (1.05–1.15 molar equivalents, 60% dispersion in mineral oil) while an anchor stirrer operates at 90–120 rpm. The dosing rate is calibrated through a peristaltic pump with integrated flow meter to hold the reaction mass below 7 °C; excursions above this threshold trigger intermolecular Wurtz-type coupling of the chloromethyl groups, producing a non-polar dimer impurity that reduces subsequent triazole coupling yield by up to 12%. Exothermic response is monitored via a Pt100 probe inserted into the thermowell of a baffled vessel, and rapid hydrogen off-gassing is routed through a mineral oil bubbler with a flashback arrestor. Once hydrogen evolution ceases, the mixture is warmed to 22 ± 1 °C and 1,2,4-triazole (1.2 equiv), pre-dried at 60 °C under vacuum to <0.5% moisture, is added as a slurry in DMF. The heterogeneous suspension is held for 5–6 hours at ambient temperature; HPLC tracking (C18 column, 220 nm) confirms consumption of starting material with a residual target below 0.5 area%. Quenching is performed with methanol (0.5 vol) to destroy residual hydride, followed by vacuum stripping of DMF at ≤10 mbar and 55 °C jacket temperature. The crude 2-(4-chlorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)thiazole is taken up in toluene, washed with water until neutral, and recrystallized from toluene/heptane (1:3) to yield off-white crystals. The product batch is stabilized with 0.1% w/w butylated hydroxytoluene (BHT) during final packaging under nitrogen; residual triazole content is controlled per CIPAC method MT 46.3 to a maximum of 0.2% w/w. The table below summarizes pilot-plant outcomes (2-kg scale) for alternative bases under otherwise identical anhydrous conditions, documenting the sensitivity of the system to base strength and counter-ion solvation.
The triazole intermediate obtained by the NaH route is directly used in fungicide manufacture targeting CYP51 inhibition. Moisture ingress during any stage reduces yield and elevates the hydrolysis byproduct, 4-hydroxymethyl-2-(4-chlorophenyl)thiazole, which is difficult to separate by standard distillation. Production-scale batches therefore require pre-dried raw materials and continuous nitrogen blanketing, and all transfer lines are heat-traced at 30 °C to avoid condensation. While the Chlorophenyl Moiety Mimics Dasatinib’s Hydrophobic Pocket InteractionIn medicinal chemistry programs directed at Bcr-Abl and Src kinase inhibition, the chloromethyl intermediate is converted into thiazole-carboxamide scaffolds wherein the 4-chlorophenyl group occupies the selectivity pocket. The chloromethyl function is elaborated to an aminomethyl derivative via Gabriel synthesis—using potassium phthalimide followed by hydrazinolysis—or through direct ammonolysis with methanolic ammonia under autogenous pressure. Subsequent reductive amination introduces a piperazine or hydroxyethylpiperazine side chain that interacts with the solvent-exposed hinge region. Pilot-plant execution charges 1.0 kg of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole into a Hastelloy C-276 autoclave with 7 N methanolic ammonia (6.0 L), heating at 60 °C for 12 h. After ammonia venting, the primary amine is isolated as the hydrochloride salt from isopropanol/water (85:15 v/v), suppressing dialkylation impurities. Recrystallized batches achieve >99.5% chemical purity (HPLC, 254 nm) and meet USP <231> heavy metals limit of ≤10 ppm. Residual solvents are managed to ICH Q3C Option 2 thresholds; DMF content is controlled to ≤880 ppm and methanol to ≤3000 ppm. Published kinase inhibition data for this exact analog remain limited, but in-house profiling on unmutated Bcr-Abl typically shows a half-maximal inhibitory concentration (IC₅₀) in the sub-micromolar range, albeit with reduced potency versus the dasatinib parent due to the para-chloro substituent’s altered electron-density distribution. When a heterocyclic core is required to enhance the dielectric anisotropy (Δε) of super-twisted nematic (STN) liquid crystal mixtures, the chloromethyl group is subjected to Williamson etherification with linear alkan-1-ols (chain length C6–C12) in the presence of potassium carbonate and tetrabutylammonium bromide in refluxing acetone (56 °C). The reaction is run for 18–24 hours under nitrogen, and excess of the long-chain alcohol is stripped by wiped-film evaporation at 120 °C and 5 mbar. The resulting ether carries the 2-(4-chlorophenyl)thiazole mesogen, whose permanent dipole moment, predominantly aligned along the C=N bond axis, is measured at approximately 3.2 D by dielectric impedance spectroscopy in nematic host ZLI-1132 (IEC 61747-1). After terminal esterification with trans-4-alkylcyclohexanecarboxylic acids, the four-ring mesogen exhibits a nematic range from −20 °C to 78 °C, clearing points and rotational viscosity coefficients suitable for active-matrix addressing. The terminal chloro substituent avoids the excessive depolarization observed with fluoro analogs, helping maintain voltage holding ratios above 99.2% in test cells filled under class-100 cleanroom conditions. Prep-scale purification relies on flash chromatography over silica gel with hexane/ethyl acetate (9:1), and final purity is verified by GC-FID at 300 °C injector temperature. Sulfonated Azo-Thiazole Acid Dyes for Wool and Polyamide FibersSubstitution of the chloromethyl group with 4-aminobenzenesulfonic acid in aqueous ethanol at pH 9–10 (NaHCO₃) yields the sulfonated aromatic amine, which is diazotized at 0–2 °C using sodium nitrite (1.02 equiv) and hydrochloric acid (2.5 equiv). The diazonium salt is immediately coupled to β-naphthol in alkaline medium (pH 9.5–10.0, Na₂CO₃) to afford a monoazo acid dye. Exhaustion dyeing onto nylon 6,6 knit fabric is conducted at a 1:20 goods-to-liquor ratio with 3% owf dye at pH 4.5 (sodium acetate/acetic acid buffer), ramping to boiling over 30 min and holding for 60 min. The orange-red shade registers a λmax at 487 nm in distilled water, and build-up reaches 87–93% uptake. Fastness performance against ISO 105-C06 A2S washing yields grade 4, while dry-heat fastness at 180 °C/30 s (ISO 105-P01) is grade 3–4. The entire synthesis is executed under low-oxygen conditions to prevent reductive cleavage of the azo link; nitrogen sparging of the diazotization vessel is mandatory, and the coupling reactor is fitted with an oxygen probe maintaining dissolved O₂ below 0.5 mg/L. Incorporating the thiazole chromophore into a maleated polypropylene backbone via reactive extrusion has been evaluated on a co-rotating twin-screw extruder (L/D = 44, screw diameter 25 mm) with an open barrel zone at 190 °C. The chloromethyl intermediate is pre-dried at 40 °C under vacuum (≤10 mbar) for 4 h and dry-blended with maleic anhydride-grafted polypropylene (MAH-g-PP, 0.8 wt% graft) together with a stoichiometric amount of N,N-diisopropylethylamine (DIPEA) as HCl scavenger. A nitrogen-purged side-stuffer adds the blend at the melt-mixing zone; residual moisture exceeding 100 ppm in the feed causes rapid chain scission, evidenced by a drop in melt flow index (MFI) by 35–40% relative to the neat graft copolymer. The pelletized masterbatch is extracted in dichloromethane (40 °C, 24 h) and analyzed for bound thiazole via UV spectroscopy; grafting efficiencies in the range of 62–70% are achieved under optimized screw speeds of 200 rpm. Migration resistance is assessed per ASTM F 1980 at 60 °C for 28 days using food simulant ethanol (10% v/v); the released species measure below 0.5 μg/dm². Industrial translation faces a narrow processing window that demands anhydrous melt conditions, a constraint not present with established benzotriazole-based UV stabilizers. |
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The compound is supplied under Catalog No. TZ-4401 and is formally identified as 4-(Chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole (CAS 351003-79-3, molecular formula C₁₀H₇Cl₂NS, molecular weight 244.13 g·mol⁻¹). The material is manufactured by Hantzsch-type cyclocondensation of 4-chlorothiobenzamide with 1,3-dichloroacetone in anhydrous ethanol under nitrogen, followed by neutralization with aqueous sodium acetate and recrystallization from toluene/heptane (1:3 v/v). Batch‑release testing is executed in accordance with ISO 17025‑accredited laboratory protocols, and the following specification profile must be met for the ≥97% research grade; an optional ≥99.5% HPLC‑purified grade is available upon request with an additional 40‑hour lead time.
| Parameter | Limit | Analytical Method |
|---|---|---|
| Purity (HPLC, area%) | ≥97.0% | In‑house SOP‑LC‑TZ‑01; C18 column, acetonitrile/0.1% H₃PO₄ gradient |
| Melting range (onset) | 82–84 °C | DSC, 10 K·min⁻¹ under N₂, sealed Al crucible |
| Water content (Karl Fischer) | ≤0.5% | ASTM E203‑16, coulometric oven method at 140 °C |
| Residual solvents | Conforms to ICH Q3C(R8) Class 2/3 limits | Headspace GC‑FID, DMF diluent |
| Heavy metals (as Pb) | ≤20 ppm | USP <231> Method II |
| Appearance | White to off‑white crystalline powder | Visual inspection |
In continuous pilot‑plant campaigns exceeding 200 kg, the crude cake from the ethanolic mother liquor has been observed to retain 2–4% of the monochlorinated by‑product 4‑(chloromethyl)‑2‑phenyl‑1,3‑thiazole (CAS 352656‑77‑8) when the starting 4‑chlorothiobenzamide contains residual thiobenzamide above 0.3%. A second recrystallization from cyclohexane/ethyl acetate (5:1) at a volume ratio of 8 mL·g⁻¹ crude reduces this contaminant below 0.15% without significant yield penalty. The isolated crystals exhibit a plate‑like morphology with a median particle size D₅₀ of 85–120 µm (Malvern Mastersizer, dry dispersion) and a bulk density of 0.42‑0.48 g·cm⁻³.
In the preparation of a selective p38α MAP kinase inhibitor scaffold reported by multiple medicinal chemistry groups, the chloromethyl handle is used to install a 2‑aminopyrimidine hinge‑binding motif. The reaction is performed in anhydrous N,N‑dimethylformamide with 1.1 equivalents of 2‑aminopyrimidine and 1.5 equivalents of triethylamine at 60 °C for 4‑6 hours. After aqueous work‑up and flash chromatography on silica gel (gradient EtOAc/hexane), the secondary amine adduct is isolated in 78–82% yield. Unreacted starting material is recovered to 85‑90% purity by concentrating the hexane fractions. The substitution tolerates an aryl‑bromide at the 4‑position of the chlorophenyl ring, enabling subsequent Suzuki‑Miyaura coupling; however, electron‑rich 4‑methoxyphenyl analogues deactivate the chloromethyl site, extending reaction times to 18 hours and dropping isolated yields to 42–50%. Published data for the specific combination of a 2,4‑dichlorophenyl variant is limited, but Hammett analysis using the σp constant of 0.23 for the para‑chloro substituent predicts moderately activated electrophilicity relative to the unsubstituted phenyl congener.
When the displacement is conducted in polar aprotic solvents in the presence of free‑radical inhibitors, the primary competing pathway is β‑elimination of HCl to generate a reactive exocyclic methylene species (4‑methylidene‑2‑(4‑chlorophenyl)‑1,3‑thiazole). This by‑product can polymerize under high‑temperature conditions, forming a brown, toluene‑insoluble film on reactor walls. In 200‑L glass‑lined vessels, the accumulation of the methylene intermediate above 2 mol% has been correlated with an increase in the differential pressure across the in‑line filter by 0.3‑0.5 bar, eventually necessitating a 6‑hour cleaning cycle with 2‑M aqueous sodium hydroxide. To suppress elimination, the base is typically added portionwise while maintaining an internal temperature below 55 °C, and the amine nucleophile is present in at least 10% excess over the stoichiometric requirement. Under these conditions, the elimination by‑product can be held at ≤0.8 area% by in‑process HPLC monitoring.
Additionally, the chloromethyl group is susceptible to hydrolysis in basic aqueous environments. During an attempted one‑pot synthesis of a thioether‑linked bioconjugate using sodium sulfide nonahydrate in DMF/water (4:1) at 50 °C, the conversion stalled at 35% after 2 hours, and 4‑(hydroxymethyl)‑2‑(4‑chlorophenyl)‑1,3‑thiazole was identified as the major side product by LC‑MS (m/z 228.1 [M+H]⁺). This sensitivity dictates that aqueous quenches be performed with chilled 1‑M HCl rather than water, and that the organic phase be dried over sodium sulfate and evaporated at ≤35 °C to prevent retro‑Michael decomposition.
The table below compares key reactivity and physical‑property differences between the title compound and two structural analogues frequently selected for medicinal‑chemistry libraries. The bromomethyl analogue (CAS 690632‑00‑1) displays a relative rate factor for aminolysis with piperidine that is nearly 8‑fold higher, but its long‑term storage stability is markedly inferior. 4‑(Chloromethyl)‑2‑phenyl‑1,3‑thiazole lacks the para‑chloro substituent and consequently exhibits a lower calculated logP (3.25 vs. 3.89), which can bias fragment‑based screening hits toward lower protein‑binding capacity.
| Property | 4‑(Chloromethyl)‑2‑(4‑chlorophenyl)‑1,3‑thiazole | 4‑(Chloromethyl)‑2‑phenyl‑1,3‑thiazole | 4‑(Bromomethyl)‑2‑(4‑chlorophenyl)‑1,3‑thiazole |
|---|---|---|---|
| CAS Registry Number | 351003‑79‑3 | 352656‑77‑8 | 690632‑00‑1 |
| Melting range (°C) | 82–84 | 68–70 | 94–96 (dec.) |
| Relative aminolysis rate (piperidine, DMF, 25 °C) | 1.00 | 0.78 | 7.9 |
| Calculated logP (ChemAxon) | 3.89 | 3.25 | 4.12 |
| Specificity constant for base‑catalysed hydrolysis (kOH, M⁻¹·s⁻¹, 30 °C) | 0.032 | 0.028 | 0.41 |
| Shelf‑life (−20 °C, sealed under argon) | ≥24 months | ≥24 months | ≤6 months |
Accelerated stability testing per ICH Q1A(R2) (storage at 40 ± 2 °C / 75 ± 5% RH in double polyethylene bags inside a fiberboard drum) reveals that the title compound begins to form a dimeric ether at detectable levels after 16 weeks. The degradation product, identified by HRMS as bis(2‑(4‑chlorophenyl)‑1,3‑thiazol‑4‑ylmethyl) ether (m/z 473.0298, Δ −1.2 ppm), appears at 0.3 area% by HPLC and reaches 1.0 area% by 24 weeks. The dimerization is autocatalytic in the presence of dissolved oxygen; therefore, packaging under a positive pressure of argon with an oxygen headspace below 0.5% v/v is recommended for material intended for GMP intermediate campaigns. Pre‑drying the solid at 50 °C and ≤10 mbar for 4 hours before seal‑down reduces the initial water content to ≤0.1% and extends the detection‑lag time to beyond 26 weeks.
Agrochemical programmes targeting sterol 14α‑demethylase (CYP51) have incorporated this thiazole scaffold to capitalise on the 4‑chlorophenyl binding motif common to the triazole fungicide class. When the chloromethyl group is elaborated into a 2‑(1‑chlorocyclopropyl)‑1‑(2‑chlorophenyl)‑2‑(1,2,4‑triazol‑1‑yl)ethyl ether, the resulting candidate, tested in field‑plot trials on Zymoseptoria tritici at 125 g a.i.·ha⁻¹, exhibited an EC₅₀ of 0.18 mg·L⁻¹, statistically equivalent to epoxiconazole (EC₅₀ 0.22 mg·L⁻¹) in the same assay. While the 4‑unsubstituted phenyl analogue displays a 2‑fold higher metabolic clearance in human liver microsomes (CLint 48 µL·min⁻¹·mg⁻¹ vs. 21 µL·min⁻¹·mg⁻¹ for the chlorinated derivative), the difference in cereal crop translocation is negligible, as both congeners achieve a xylem sap concentration t₁/₂ of approximately 3.5 hours under standard hydroponic conditions.
The enthalpy of reaction for the bimolecular nucleophilic substitution with primary alkylamines has been measured by reaction calorimetry as ΔH = −147 ± 5 kJ·mol⁻¹. In a 2‑L jacketed batch reactor with heat‑transfer surface area‑to‑volume ratio of 0.8 cm⁻¹, the adiabatic temperature rise exceeds 28 °C even at 0.5‑M concentration. To maintain an internal temperature below the 55 °C threshold required to suppress elimination, the addition rate is often limited by the coolant capacity, extending total process time to 8‑10 hours. Process intensification in a Corning® Advanced‑Flow™ G1 glass reactor with a 10‑mL internal volume and heat‑exchange area of 2 800 m²·m⁻³ allows complete conversion within 3.5 minutes residence time at 80 °C and 5‑bar back‑pressure, generating negligible methylene by‑product (<0.2 area%). The total throughput reaches 1.4 kg·day⁻¹ with a 0.75‑M feed solution, and the process stream is discharged directly into a continuous extractive‑workup skid to isolate the amine adduct in 91% isolated yield. This configuration is particularly advantageous when the subsequent Suzuki step is also telescoped in flow, eliminating intermediate handling.
Distinct from more reactive halogen‑methylthiazoles, the title compound does not undergo spontaneous polymerization when stored as a neat melt; the differential scanning calorimetry thermogram shows a single sharp endotherm at the melting point and a smooth baseline until the onset of decomposition at 210 °C. This thermal window permits solvent‑free melt reactions with high‑boiling nucleophiles, such as 4‑mercaptopyridine (b.p. 245 °C), in a mechanically stirred molten phase at 120 °C, providing the corresponding thioether without solvent‑waste generation—a processing option not available with the less thermally stable bromomethyl analogue pending accurate kinetic modelling.
