2-({[5-(1,3-Benzodioxol-5-Yl)-4-Methyl-4H-1,2,4-Triazol-3-Yl]Sulfanyl}Methyl)-1,3-Benzothiazole

The compound 2-({[5-(1,3-Benzodioxol-5-Yl)-4-Methyl-4H-1,2,4-Triazol-3-Yl]Sulfanyl}Methyl)-1,3-Benzothiazole, molecular weight 381.47 g·mol⁻¹ (C₁₉H₁₅N₃O₂S₂), is supplied as a white to off-white crystalline powder with a melting range of 153–157 °C (differential scanning calorimetry, 10 °C/min, N₂ atmosphere). The substance is manufactured under a quality management system certified to ISO 9001:2015, with residual solvent levels controlled per ICH Q3C(R8). Identity is confirmed by ¹H‑NMR, ¹³C‑NMR, high‑resolution mass spectrometry, and elemental analysis. A validated reversed‑phase HPLC purity method employs a C18 stationary phase (5 μm, 4.6 × 250 mm), an isocratic mobile phase of acetonitrile/water 70:30 (v/v) containing 0.1% trifluoroacetic acid, a flow rate of 1.0 mL/min, and UV detection at 254 nm. Representative lot specifications are compiled in Table 1.

The product is hygroscopic; containers should be opened only after temperature equilibration and resealed under argon. Long‑term storage is required at 2–8 °C away from light. When used in moisture‑sensitive reactions, pre‑drying for 4 h at 40 °C under vacuum (10 mbar) is recommended. Avoid contact with strong oxidising agents that can convert the thioether to sulfoxide or sulfone, altering both solubility and biological profile.

What Role Does the 1,3-Benzodioxole Moiety Play in Binding Kinase Pockets?

This compound was disclosed in WO2014074069A1 as an exemplar of a series of c‑Met receptor tyrosine kinase inhibitors. In a time‑resolved fluorescence resonance energy transfer assay (TR‑FRET; CisBio HTRF® KinEASE‑TK kit, ATP concentration 10 μM), the compound exhibited an IC₅₀ of 0.032 μM against non‑phosphorylated c‑Met. The 1,3‑benzodioxole group functions as a conformationally constrained dimethoxy isostere, donating two hydrogen bonds to the hinge‑region residue Met1160 (backbone NH and side‑chain NH₂), as inferred from docking models and X‑ray co‑crystallography of a closely related analogue. Compared with the 3,4‑dimethoxyphenyl counterpart (Example 18 in the same patent), the benzodioxole substitution improves metabolic stability in human liver microsomes (NADPH regeneration system) while retaining comparable biochemical potency. Table 2 extracts key pharmacological data from the patent, highlighting the influence of the heteroaromatic substituent on target affinity, microsomal half‑life, and computed lipophilicity.

The benzodioxole‑bearing compound combines sub‑50 nM potency with a microsomal half‑life that supports once‑daily oral dosing, a characteristic not achieved by the mono‑ or dimethoxy analogues. Batch‑to‑batch consistency in the inhibition profile has been verified across three independent synthetic lots; the lot‑wise variance in pIC₅₀ remained ≤ 0.12 log units. This translates to a highly reproducible biochemical fingerprint that reduces the need for re‑qualification during hit‑to‑lead campaigns. Differences from other products built on the triazole‑thioether scaffold stem from the synergistic effect of the N‑methyl group—blocking the acidic triazole NH and diminishing CYP450‑mediated oxidation—and the oxygen‑rich benzodioxole, which provides an additional hydrogen‑bond acceptor network without introducing the metabolic liability of a free catechol.

Stability of the Thioether Bridge Under Simulated Sunlight Exposure

In agrochemical lead optimisation, photostability represents a critical parameter for field‑use candidates. Irradiation studies conducted in accordance with EPA OPPTS 835.2210 (xenon arc simulator, filtered to 300–800 nm, spectral irradiance 40 W/m²) on a series of triazolethiomethylbenzothiazoles demonstrate that the thioether linkage photolyzes with a quantum yield roughly one‑third that of an analogous methylene bridge. Although published half‑life data for this specific compound are limited, extrapolation from a model thioether (aqueous acetonitrile 50:50, 25 °C, monochromatic 400 nm irradiation, half‑life 68 h) predicts a ≥2‑fold improvement in photostability relative to the –CH₂‑linked congener. The benzothiazole chromophore (λ_max 295 nm, molar extinction coefficient 18,400 L·mol⁻¹·cm⁻¹) self‑shields the core scaffold, absorbing actinic radiation before it reaches the thioether sulfur. This feature distinguishes the compound from commercial triazole fungicides such as tebuconazole, which undergo rapid side‑chain scission under UV‑B exposure and require formulation with UV absorbers. Incompatibility with strong UV‑A radiation sources (e.g., pulsed xenon lamps operating below 315 nm) should be noted; for long‑term outdoor evaluation, the active ingredient must be encapsulated in a lignin‑based microdispersion to extend its half‑life beyond 5 days of continuous irradiance.

In homogenous catalysis, the thioether‑triazole donor set in 2-({[5-(1,3-Benzodioxol-5-Yl)-4-Methyl-4H-1,2,4-Triazol-3-Yl]Sulfanyl}Methyl)-1,3-Benzothiazole forms a six‑membered chelate with palladium(II) acetate in anhydrous acetonitrile at 25 °C, generating a single N,S‑coordinated complex (UV‑Vis λ_max shift from 340 nm to 390 nm). Published catalytic data for this specific ligand are limited, yet fundamental coordination chemistry principles permit reliable extrapolation from structurally analogous benzothiazole‑thioether palladacycles. The electron‑donating 1,3‑benzodioxole ring raises the HOMO energy of the palladium centre, lowering the activation barrier for oxidative addition to electron‑poor aryl chlorides. Comparative cyclic voltammetry on a series of closely related Pd‑L complexes (Bio‑Logic SP‑300 potentiostat, 0.1 M TBAP in CH₃CN, scan rate 100 mV/s, Ag/AgCl reference) revealed that substitution of the benzodioxole with a 4‑fluorophenyl group shifts the Pd(II)/Pd(0) reduction peak anodically by 92 mV, consistent with substantially reduced electron density at the metal. By extension, the benzodioxole derivative possesses the highest electron density in the series and is anticipated to facilitate oxidative addition kinetics at rates approximately 1.5–2.0 times those observed for the 4‑fluorophenyl analogue. The ligand’s hemilabile nature—where the thioether sulfur can decoordinate transiently—provides a stabilising effect on low‑coordinate Pd(0) intermediates, suppressing aggregation and extending catalyst lifetime under Buchwald‑Hartwig or Suzuki–Miyaura conditions. This subtle dissociation equilibrium differentiates the product from widely used phosphine‑based ligands (e.g., SPhos), delivering comparable turnover numbers while avoiding phosphine oxide formation in the presence of air. When preparing stock solutions for high‑throughput experimentation, the ligand should be dissolved in anhydrous acetonitrile and stored under argon at –20 °C for a maximum of one week; longer storage leads to gradual thioether oxidation to sulfoxide, as detected by a characteristic ¹H‑NMR resonance at δ 3.65 ppm (DMSO‑d₆).

Comparative Performance Against Des-Methyl and Phenyl-Substituted Analogues

The 4‑methyl group on the triazole ring constitutes a critical structural determinant: it eliminates the acidic N‑H proton that promotes rapid phase‑II glucuronidation and N‑hydrogen‑bond acidity that could interfere with hinge‑region recognition. In the patent dataset, the des‑methyl analogue (4‑H) lost 2‑fold cellular activity in A549 lung carcinoma proliferation assays, attributed to enhanced metabolic clearance and altered tautomeric equilibrium. The benzodioxol‑5‑yl substitution was superior to the 4‑yl isomer with respect to hinge‑binding geometry, as reflected in a 6‑fold selectivity window over VEGFR2 (IC₅₀ 0.032 μM c‑Met vs. 0.19 μM VEGFR2, giving a selectivity ratio >100). The benzothiazole core itself was selected over benzothiophene or benzimidazole variants to minimise off‑target hERG channel blockade; patch‑clamp experiments (performed at 37 °C on HEK‑293 cells expressing hERG) reported an IC₅₀ > 30 μM, well above the therapeutic exposure window projected from the microsomal stability data. Plasma protein binding, measured by equilibrium dialysis (human plasma, 4 h, 37 °C), is 92.3% for the benzodioxole compound, compared with 97.8% for the unsubstituted phenyl Example 5, indicating a higher free‑drug fraction and improved tissue penetration. Finally, the thioether‑based connectivity demonstrates a clear advantage over methylene‑bridged isosteres in terms of photochemical robustness and metabolic lability, as quantified earlier. These interrelated properties position the compound as a reference probe for structure‑activity‑relationship studies aiming to decouple kinase potency from pharmacokinetic liabilities.