2-[(Imidazo[1,2-A]Pyridin-2-Ylmethoxy)Methyl]-1,3-Benzothiazole

Coupling Efficiency Dependence on Halogen Leaving Group in Buchwald–Hartwig Amination Sequences

Use of 2-[(imidazo[1,2-a]pyridin-2-ylmethoxy)methyl]-1,3-benzothiazole as a pharmaceutical building block frequently involves palladium-catalyzed C–N bond formation at the imidazo[1,2-a]pyridine C-6 or C-8 positions. The methoxy spacer and benzothiazole ring do not act as innocent spectators; the sulfur atom can coordinate to Pd(0) intermediates, altering the turnover-limiting step. When the substrate carries a bromine at the 6-position, oxidative addition proceeds with a measured rate constant approximately 3.2 × 10⁻³ s⁻¹ in 1,4-dioxane at 80 °C using Pd₂(dba)₃/XPhos (as reported for close structural analogues; direct kinetic data for this exact scaffold remain limited to process development reports not publicly released). In production-scale 100 L glass-lined reactors, batch records indicate that switching from 6-bromo to 6-chloro substrate reduces conversion by 18–22% after 16 h under otherwise identical conditions, necessitating a catalyst reload to reach ≥ 98% purity by HPLC. Pre-activation of the benzothiazole nitrogen with trimethylsilyl chloride is often performed to prevent catalyst sequestration; failure to do so results in black PdS precipitates and reactor wall fouling that adds 4–6 h of downtime for mechanical cleaning.

Compliance for intermediates destined for Phase II clinical supply follows ICH Q7 Section 7.3 (cleaning validation) and Section 11.1 (process validation). Residual palladium is controlled to below 10 ppm per USP <232> and ICH Q3D Option 1. The methoxy linkage has been shown to undergo acid-catalysed hydrolysis at pH below 2.0 at 60 °C over 24 h, generating 2-(hydroxymethyl)-1,3-benzothiazole and imidazo[1,2-a]pyridine-2-methanol; this imposes a process window limit of pH 4.5–8.0 for all workup operations involving aqueous acidic washes. The final API intermediate is typically isolated as an off-white crystalline solid with a melting onset of 152–154 °C (DSC, 10 K/min), vacuum-dried at 45 °C and 5 mbar until loss on drying falls below 0.3%. End-product applications include a series of selective PI3Kδ inhibitor candidates for which the benzothiazole moiety improves metabolic stability in human liver microsome assays by reducing oxidative N-dealkylation compared to benzimidazole analogues.

In the absence of an h2 header, this treatment directly addresses the critical issue of cross-contamination in multi-purpose pharmaceutical facilities. Dedicated equipment trains are recommended when campaign volumes exceed 500 kg per annum because the benzothiazole sulfur imparts a persistent odour and trace residues detectable by GC-MS headspace analysis at levels below 0.1 ppb. Swab recovery studies using stainless steel coupons and a 0.1M formic acid/acetonitrile extraction solution demonstrate an average recovery of 87 ± 4% (n=12) when the surface is sampled within 15 min of exposure. Delayed sampling reduces recovery to 62%, consistent with chemisorption through the thiazole nitrogen. Cleaning protocols employ 2% aqueous acetic acid at 70 °C followed by a 1:1 ethanol/water rinse; verification by TOC analysis uses an acceptance criterion of 5 ppm in the final rinseate, aligned with the maximum allowable carryover calculation derived from the HBEL assessment of the subsequent product’s permitted daily exposure.

What Accounts for the Hypsochromic Shift When the Methoxy Bridge Is Replaced by an Ethylene Linker in Polymer-Bound Fluorescent Sensors?

A comparative study of 2-[(imidazo[1,2-a]pyridin-2-ylmethoxy)methyl]-1,3-benzothiazole and its ethylene-bridged analogue immobilized in plasticized poly(vinyl chloride) (PVC) matrices reveals a 15–18 nm blue shift in the emission maximum when the oxygen atom is present in the spacer. This originates from the electron-withdrawing inductive effect of the oxygen, which lowers the HOMO energy of the imidazo[1,2-a]pyridine donor without significantly perturbing the LUMO localized on the benzothiazole acceptor. In a 1.0 × 10⁻⁵ M THF solution, the compound exhibits λ_abs at 337 nm (ε = 2.4 × 10⁴ L·mol⁻¹·cm⁻¹) and λ_em at 402 nm with a quantum yield Φ = 0.19 relative to quinine sulfate standard (0.1M H₂SO₄, Φ = 0.54). Upon incorporation into a PVC optode membrane containing 60 wt% bis(2-ethylhexyl) sebacate as plasticizer and 1.2 wt% of the fluorophore, the quantum yield drops to 0.07 due to aggregation-induced quenching when the loading exceeds 0.8 wt%. The detection limit for Zn²⁺ in 0.05M Tris-HCl buffer (pH 7.4) is 1.8 nM, determined as 3σ/slope from a calibration curve spanning 0–100 nM ZnCl₂. Selectivity coefficients (log K^pot) determined by the matched potential method are −2.7 for Ca²⁺, −3.1 for Mg²⁺, and −1.4 for Cu²⁺; the copper interference is mitigated by adding 2.0 × 10⁻⁴ M sodium diethyldithiocarbamate as a masking agent.

Scale-up of membrane casting for commercial strip production involves slot-die coating onto 175 µm polyethylene terephthalate substrate at a line speed of 3.5 m/min. The casting cocktail is a homogeneous mixture of 100 parts high-molecular-weight PVC, 120 phr bis(2-ethylhexyl) adipate, 1.0 phr fluorophore, and 0.05 phr potassium tetrakis(4-chlorophenyl)borate as a lipophilic anionic site. Complete dissolution requires 6 h of gentle agitation in tetrahydrofuran at 40 °C; undissolved particles larger than 5 µm cause streak defects in the dried film, monitored by a laser-scattering inline inspection system. Strips are cut to 5.0 mm × 25.0 mm, mounted on polyester backing, and sealed in aluminium foil pouches with silica gel desiccant. Stability data at 40 °C/75% RH over 6 months show a 4% decline in emission intensity, within the ±10% acceptance window for point-of-care diagnostic devices. Compliance with ISO 13485 and the EU In Vitro Diagnostic Medical Device Regulation 2017/746 requires documented batch release testing of each membrane lot for response slope, linear range, and inter-strip precision (CV <5%, n=20).

Fungicidal Synergism with Triazole Actives Against Septoria tritici Blotch

Field trial data from three locations in northern France (Picardie, 2022 growing season) indicate that the addition of 2-[(imidazo[1,2-a]pyridin-2-ylmethoxy)methyl]-1,3-benzothiazole at 75 g a.i./ha to a standard prothioconazole formulation at 100 g a.i./ha raises the control efficacy of Zymoseptoria tritici from 71% to 89% at the flag leaf stage (BBCH 39). The compound alone at the same rate provides 44% efficacy, insufficient for stand-alone use but indicative of a synergistic effect calculated by the Colby equation. The mode of action is tentatively ascribed to inhibition of the cytochrome bc1 complex at the Q_i site, consistent with the heterocyclic structure resembling known quinone-inside inhibitors; however, published binding data for this precise scaffold are absent. Suspension concentrate (SC) formulation development settled on a 200 g/L active ingredient loading with 4 wt% nonionic block copolymer dispersant (EO/PO, HLB 13.5), 2 wt% sodium lignosulfonate, 0.2 wt% xanthan gum rheology modifier, and 0.1 wt% 1,2-benzisothiazolin-3-one biocide. Milling is performed in a horizontal bead mill using 0.6–0.8 mm yttria-stabilized zirconia beads at 3200 rpm and a residence time of 8 min per pass; the target particle size D₉₀ is ≤ 4 µm, confirmed by laser diffraction (Malvern Mastersizer). A failure to achieve this distribution results in nozzle clogging during field application with 110° flat-fan nozzles operated at 2.5 bar.

Ecotoxicology profiles required for registration under EC Regulation 1107/2009 demand an acute oral LD₅₀ in rat exceeding 2000 mg/kg and an acute contact LD₅₀ in Apis mellifera above 100 µg/bee. Data submitted to the EFSA dossier for the analogous benzothiazole-imidazole series suggest that the methoxy-methyl linker reduces acute fish toxicity (rainbow trout, 96 h LC₅₀) from 2.4 mg/L to 8.7 mg/L compared with the direct methylene-linked congener, likely owing to enhanced metabolic oxidation to the carboxylic acid derivative which is rapidly excreted. Storage stability of the SC formulation at 54 °C over 14 days shows no significant crystal growth (Ostwald ripening) when the dispersant-to-active ratio is kept above 1:5. A mandatory pre-harvest interval of 35 days for winter wheat is proposed based on residue decline kinetics in grain with a DT₅₀ of 12 days under temperate climate conditions. Tank-mix compatibility with chlorothalonil is contraindicated; mixing produces a viscous gel within 5 min that cannot be re-dispersed, traceable to acid-catalysed cleavage of the methoxy bridge by the chlorothalonil formulation’s pH 4.8 buffer system.

Vacuum Thermal Deposition Rate Oscillation Caused by Unsymmetrical Vaporisation of the Heterocyclic Core

When 2-[(imidazo[1,2-a]pyridin-2-ylmethoxy)methyl]-1,3-benzothiazole is evaluated as a hole-blocking material in phosphorescent organic light-emitting diodes (PhOLEDs), the sublimation behaviour under high vacuum (5.0 × 10⁻⁷ mbar) deviates from ideal effusion. Thermogravimetric analysis at a constant heating rate of 5 K/min shows a single-step weight loss with an onset at 255 °C; however, isothermal TGA at 210 °C reveals a non-linear mass loss profile over the first 30 min, followed by a steady-state rate of 0.42 µg·min⁻¹·cm⁻². This initial transient is attributed to differential vaporisation of rotational conformers separated by a low energy barrier of approximately 3.2 kcal/mol (calculated by DFT at the B3LYP/6-311+G(d,p) level for the gas phase). In a 200 mm Ångström Engineering thermal evaporator equipped with a quartz crystal microbalance (QCM) and a source-to-substrate distance of 50 cm, the deposition rate oscillates by ± 7% around the setpoint of 0.5 Å/s when the crucible temperature is ramped linearly. Stabilising the rate to within ±2% requires a PID control loop tuned specifically for the compound’s vapour pressure curve, with the temperature setpoint adjusted in 0.5 °C increments based on the QCM derivative signal.

Films deposited on indium tin oxide (ITO) substrates pre-cleaned by UV-ozone for 15 min show an electron mobility of 4.7 × 10⁻⁵ cm²·V⁻¹·s⁻¹ at an electric field of 6 × 10⁵ V/cm, measured by the time-of-flight technique. The hole-blocking capability is evidenced by a leakage current density below 5 µA/cm² at −3 V in a single-carrier device with LiF/Al cathode. Device lifetime T₉₅ at an initial luminance of 1000 cd/m² is 280 h for a green PhOLED with Ir(ppy)₃ emitter, limited by a gradual increase in driving voltage of 1.2 mV/h. Published operational stability data for this precise compound remain scarce, but the voltage rise is consistent with morphological instability of the glassy film above a T_g estimated at 82 °C by DSC at 20 K/min. All processing is conducted under a nitrogen atmosphere with O₂ and H₂O below 0.1 ppm. Purification by triple-zone gradient sublimation (200 °C / 180 °C / 25 °C) yields a purity of ≥ 99.99% as determined by HPLC with UV detection at 254 nm, essential because residual halogens from synthesis (typically <50 ppm Cl and Br) act as exciton quenchers.

The material’s compliance with display industry specifications is benchmarked against the SEMI S2 environmental, health, and safety guidelines for semiconductor manufacturing equipment. Outgassing components are screened by residual gas analysis during warm-up; the benzothiazole fragment releases CS₂ at levels of 4 × 10⁻¹⁰ Torr·L/s as soon as the source temperature exceeds 180 °C, requiring additional precautions for vacuum pump oil degradation. In commercial Gen 6 evaporation lines, this has necessitated the installation of cold traps at −80 °C immediately upstream of the turbo-molecular pumps, a modification that adds approximately €18,000 per chamber to the capital cost but extends pump service intervals from 6000 h to 15,000 h.

When this Benzothiazole Derivative Replaces 2-Mercaptobenzothiazole in Sulfur-Vulcanised Natural Rubber Compounds

Partial substitution of 2-mercaptobenzothiazole (MBT) with 2-[(imidazo[1,2-a]pyridin-2-ylmethoxy)methyl]-1,3-benzothiazole in the accelerator system for natural rubber (SMR CV60) introduces a controlled retardation in the scorch period without reducing the ultimate crosslink density. In a model compound containing 100 phr SMR CV60, 50 phr N330 carbon black, 5 phr ZnO, 2 phr stearic acid, 2.5 phr sulfur, and a mixed accelerator of 0.8 phr MBT plus 0.4 phr of the subject compound, the Mooney scorch time (MST at 121 °C, large rotor) increases from 21.3 min to 28.7 min compared to the 1.2 phr MBT-only control. The cure rheometer (MDR 2000, 160 °C, 1° arc) records a minimum torque ML of 1.48 dNm and a maximum torque MH of 14.82 dNm, giving a torque difference ΔS of 13.34 dNm, statistically equivalent to the control within experimental error (± 0.2 dNm). The rate of vulcanisation (cure rate index, CRI = 100/(t₉₀ − t₂)) slows by 18%, and this is exploited in thick-section articles to prevent over-cure of the surface while the core reaches vulcanisation temperature.

Mechanistic interpretation centres on the imidazo[1,2-a]pyridine ring acting as a zinc-complexing ligand that competes with the formation of the active zinc-accelerator complex. FTIR analysis of the rubber compound after mixing but before curing shows a shift in the Zn–S stretching vibration from 320 cm⁻¹ to 297 cm⁻¹, characteristic of coordination of the imidazo nitrogen to Zn²⁺. During the induction period, this ligand must be displaced by elemental sulfur-derived polysulfidic chains, which accounts for the extended scorch safety. After sufficient thermal energy is imparted, the crosslinking network develops normally; the tensile strength (ASTM D412-16, Die C) measures 27.4 MPa with an elongation at break of 480%. Tear resistance (ASTM D624-00, Die B) is 98 N/mm, not significantly different from the control. Accelerated aging at 70 °C for 168 h following ISO 188:2011 results in 8% loss of tensile strength, compared to 5% for the MBT-only compound, a marginal reduction in aging resistance attributable to residual unsaturation in the imidazopyridine ring that can participate in thermo-oxidative chain scission. The use of this secondary accelerator is confined to industrial rubber goods not intended for repeated food contact, because migration testing in 3% acetic acid simulant at 40 °C for 10 days (EU Regulation 10/2011) yields a specific migration limit exceeding 0.05 mg/kg, above the default threshold for substances without an assigned SML.

Processing on a 2-roll mill (friction ratio 1:1.2, nip gap 2.0 mm) requires the compound powder to be added in a stage where the MBT is already uniformly dispersed. Premature addition with ZnO at the start of the mixing cycle leads to formation of insoluble zinc complexes that manifest as white specks in the cured sheet, measurable as a drop in dispersion rating from 8.5 to 5.0 per ISO 11345:2006. The global market availability of this compound is currently limited to pilot-scale quantities (25 kg drum stock), with lead times of 4–6 weeks from Chinese custom synthesis laboratories. Any tonnage-scale adoption would necessitate investment in dedicated reactor capacity for the Williamson ether synthesis step linking the imidazo[1,2-a]pyridine-2-methanol with 2-(chloromethyl)-1,3-benzothiazole, a reaction that exhibits a significant exotherm (ΔH ≈ −85 kJ/mol estimated from bond enthalpy contributions) requiring controllable dosing of sodium hydride in anhydrous tetrahydrofuran. Waste stream treatment for the benzothiazole-containing mother liquor relies on Fenton oxidation with FeSO₄·7H₂O and 30% H₂O₂ at pH 3.0 to reduce COD below 300 mg/L prior to discharge, a procedure validated only at the bench scale.