2-Thienyl -4-Chloromethyl Thiazole Chloride
|
HS Code |
241182 |
| Chemical Formula | C8H6Cl2NS2 |
| Molecular Weight | 249.18 |
| Appearance | Typically a solid (description may vary based on purity and conditions) |
| Melting Point | Data may vary, needs specific experimental determination |
| Boiling Point | Data may vary, needs specific experimental determination |
| Solubility In Water | Low solubility, being an organic compound with non - polar groups |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform due to its organic nature |
| Odor | Likely has a characteristic organic odor, but specific description needs experimental determination |
| Density | Data may vary, needs specific experimental determination |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 2-Thienyl -4-Chloromethyl Thiazole Chloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 2 - Thienyl - 4 - Chloromethyl Thiazole Chloride in sealed chemical - grade bag. |
| Shipping | 2 - Thienyl - 4 - Chloromethyl Thiazole Chloride is shipped in specialized, leak - proof containers. It follows strict hazardous chemical shipping regulations to ensure safe transportation, with proper labeling and documentation for handling. |
| Storage | 2 - Thienyl - 4 - Chloromethyl Thiazole Chloride should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to decomposition. Store it separately from incompatible substances, in a location with proper ventilation to avoid the build - up of harmful vapors. |
The compound is charged into a 1,000 L glass-lined reactor (Pfaudler AE type, jacket temperature control ±1.5 °C) as a halomethyl building block for assembling thienopyrimidine-like kinase inhibitors that require a pendant 2-thienyl substituent at the ATP-binding pocket mimic. A typical amination run employs 1.05 molar equivalents of N-Boc-piperazine (KSM-2) per equivalent of 2-(thien-2-yl)-4-(chloromethyl)thiazol-3-ium chloride, suspended in 8 volumes of anhydrous N,N-dimethylformamide containing 2.2 equivalents of finely milled potassium carbonate (325 mesh, pre-dried at 120 °C for 4 h under −0.095 MPa vacuum). The slurry is agitated at 55 °C under nitrogen blanket (0.2 bar positive pressure) while maintaining headspace moisture below 300 ppm as verified by a Michell Optidew chilled-mirror hygrometer in the vent line. Hydrolysis of the benzylic chloride to the corresponding 4-(hydroxymethyl)thiazolium alcohol constitutes the dominant competing pathway; its formation rate escalates exponentially when the localized water activity inside the DMF phase exceeds 0.35. Reaction progress is tracked by reverse-phase HPLC (Agilent Zorbax SB-C18, 5 μm, 150 × 4.6 mm, mobile phase 65:35 MeCN/water + 0.1% trifluoroacetic acid, UV at 254 nm) with sampling intervals of 30 min. Once the area% of the starting thiazolium chloride drops below 0.5% (typically 5–6 h), the batch is cooled to 20 °C and quenched into 15 volumes of purified water. The liberated amine derivative is extracted with ethyl acetate (3 × 8 volumes), the combined organic phase is washed with 20% brine until the aqueous layer tests negative for chloride by silver nitrate turbidity, and the solvent is swapped to isopropanol under reduced pressure. Crystallisation from isopropanol/cyclohexane (1:3 v/v) yields a free-flowing off-white powder. Residual DMF and ethyl acetate are determined by headspace GC-FID according to USP 〈467〉 Method IV; typical carry-over is below 880 mg/kg for DMF and 200 mg/kg for ethyl acetate. The intermediate, now a N-Boc-protected tertiary amine adduct, is advanced without isolation of the free base into a Buchwald–Hartwig coupling with 4-chlorothieno[3,2-d]pyrimidine, ultimately delivering an ATP-competitive EGFR inhibitor that is crystallised as the besylate salt for Phase I toxicology. Granulation behaviour of the besylate salt during roller compaction (Alexanderwerk WP 120, screen 1.0 mm, hydraulic pressure 80 kN/m) was found to be critically dependent on the residual palladium level inherited from the upstream coupling step; a Pd threshold of ≤20 μg/g (determined by ICP-MS against ICH Q3D Option 2a) prevented agglomeration-induced ribbon density variation exceeding 0.92 g/cm³.
When This Electrophile Is Grafted onto Regioregular P3HT Chains for Ternary Blend PhotovoltaicsGrafting proceeds on a pre-purified poly(3-hexylthiophene) (P3HT) backbone with regioregularity exceeding 94% (determined by 1H NMR integration of the α-methylene protons). The polymer (Mn = 28,000 g/mol, PDI 1.8 as measured by SEC against polystyrene standards in THF at 35 °C) is dissolved at 2.5 wt% in anhydrous chlorobenzene and activated with 1.2 molar equivalents of AlCl₃ relative to the thienyl repeat unit. The thiazolium chloride is added at 8 mol% relative to the thiophene ring to avoid excessive disruption of the π-conjugation length. The solution is stirred at 65 °C for 90 min under a continuous stream of dry argon; moisture ingress above 50 ppm causes visible precipitation of aluminium hydroxide and a sharp drop in grafting efficiency. The functionalised polymer is precipitated into methanol containing 2 vol% hydrochloric acid to remove residual Lewis acid, collected by centrifugation, and subjected to sequential Soxhlet extraction with methanol (to remove unbound thiazolium salt), acetone, and finally dichloromethane. The dichloromethane fraction yields a deep-red solid with a thiazolium loading of 6.5–7.8 mol% as quantified by X-ray photoelectron spectroscopy (S 2p deconvolution). This copolymer is blended with P3HT and PC₆₁BM in a ternary bulk heterojunction device (ITO/PEDOT:PSS/active layer/LiF/Al, active area 0.045 cm² defined by a shadow mask). The active-layer thickness is maintained at 110 ± 8 nm as profiled by a Dektak XT stylus surface profilometer. Dark current-voltage characteristics under nitrogen are measured using a Keithley 2400 SourceMeter, and the external quantum efficiency is recorded on a Bentham PVE300 system calibrated against a NIST-traceable reference cell. Photovoltaic performance is assessed under a Class AAA solar simulator conforming to IEC 60904-9 with spectral mismatch correction in accord with ASTM E973-10. The incorporation of the thiazolium-grafted polymer shifts the open-circuit voltage by approximately +80 mV relative to the binary P3HT:PC₆₁BM reference because of a deeper HOMO level (−5.28 eV versus −5.12 eV for pristine P3HT, as determined by ambient pressure photoelectron spectroscopy, APSYS system). Processing constraints are tight: blend films spin-coated from o-dichlorobenzene require thermal annealing at 140 °C for 10 min on a precisely levelled hotplate; annealing beyond 12 min induces excessive phase coarsening that degrades fill factor below 0.45. Batch-to-batch reproducibility of the grafting step depends heavily on the moisture content of the chlorobenzene, which must be verified by Karl Fischer coulometry to remain below 30 μg/g before each campaign.What Role Does 2-(Thien-2-yl)-4-(chloromethyl)thiazol-3-ium Chloride Play in Agrochemical Lead Optimization?In the lead optimisation phase of neonicotinoid-inspired insecticides, this thiazolium salt functions as an activated electrophile to install a thienyl-thiazole pharmacophore onto a 2-nitroiminoimidazolidine scaffold via a methylene bridge. The coupling is executed in a 250 L Hastelloy C-276 reactor configured for cryogenic operation. A solution of 2-nitroiminoimidazolidine (1.0 mol) in dry tetrahydrofuran (5 volumes) is deprotonated with sodium hydride (60% dispersion in oil, 1.05 eq, washed free of mineral oil with n-hexane immediately before use) at −5 °C over 45 min, maintaining an off-gas hydrogen flow below the lower flammable limit (monitored by a Siemens ULTRAMAT 23 IR analyser). The thiazolium chloride (1.0 eq based on active haloalkyl content determined by argentometric titration) is dissolved in THF (2 volumes) and dosed over 3 h at −5 °C using a peristaltic pump. The completion of dosage is accompanied by a colour shift from pale-yellow to deep amber. Stirring continues for a further 1.5 h at 0 °C, after which the batch is warmed to 25 °C and quenched by slow addition to ice-cold saturated ammonium chloride solution. The crude product is extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated to a viscous oil that solidifies on standing. Recrystallisation from methylcyclohexane/ethyl acetate (8:2 v/v) provides a colourless crystalline solid with a melting point of 168–170 °C (uncorrected) and an assay of ≥99.0% by external standard HPLC. The key impurity controlled in this sequence is the regioisomeric diadduct arising from alkylation of both nitrogens of the imidazolidine ring; its relative retention time (RRT 1.31) and peak shape must be integrated with a forced baseline drop algorithm to avoid overestimation. Finished insecticide technical grade is formulated as a 200 g/L suspension concentrate with a polymeric naphthalene sulfonate dispersant; storage stability at 54 °C for 14 days is evaluated per CIPAC MT 46.3. The active ingredient content shall not fall below 95% of the initial value, and persistent foam after 1 min must be below 15 mL in the CIPAC 1% w/v dilution test. Acute oral toxicity (LD₅₀) determined in rats according to OECD TG 423 informs the classification under GHS for the technical material, which is typically Category 4 (> 300 mg/kg) for this class of compounds. The thiazolium chloride precursor is highly hygroscopic; bulk storage in 25 kg fibre drums with integral 0.14 mm low-density polyethylene liners is only valid for 12 months at ≤25 °C and ≤60% relative humidity. If the drum headspace humidity exceeds 40% during opening (measured by a Rotronic HC2A-S probe), the entire contents must be subjected to vacuum drying at 35 °C for 24 h before use.Coupling onto Aminated Dextran for pH-Responsive Drug ConjugatesAminated dextran (weight-average molecular weight 40,000 g/mol, amino group content 0.8 mmol/g determined by Habeeb’s TNBS assay) is dissolved in 0.1 M sodium borate buffer (pH 8.5) at a concentration of 20 mg/mL. The thiazolium chloride is added as a freshly prepared solution in anhydrous dimethyl sulfoxide (100 mg/mL, less than 50 μg/g water) at 10 molar equivalents per glucosamine residue. The biphasic mixture is vortexed for 30 s and then gently shaken on an orbital shaker at 25 °C in the dark for 18 h. The degree of substitution, calculated from the quaternary ammonium nitrogen content by micro-Kjeldahl analysis, averages 0.52–0.64 mmol/g. Unreacted small molecules and DMSO are removed by exhaustive dialysis (Spectra/Por 6, MWCO 3,500 Da) against deionised water containing 5 mM sodium chloride for 48 h with six bath changes. The resulting conjugate carries pendent thienyl-thiazolium groups that can subsequently sequester anticancer payloads such as doxorubicin through π–π stacking (evaluated by isothermal titration calorimetry in PBS pH 7.4 at 37 °C, affinity constant Ka typically 10⁴–10⁵ M⁻¹). Release kinetics are measured in phosphate-buffered saline at pH 5.0 (lysosomal mimic) versus pH 7.4 using a Slide-A-Lyzer MINI dialysis device (10K MWCO) with sampling at 15 min intervals over 6 h; differential-pulse voltammetry at a glassy carbon electrode tracks the free doxorubicin oxidation peak at +0.62 V versus Ag/AgCl. In vitro cytotoxicity of the conjugate (without payload) is assessed on L929 mouse fibroblast cells according to ISO 10993-5:2009 Annex A, using MTT reduction as the endpoint. Viability exceeding 80% at extract concentration 1 mg/mL classifies the material as non-cytotoxic. Sterilisation is performed by gamma irradiation at 25 kGy (dose mapping performed with Red Perspex 4034 dosimeters per ISO 11137-1). Upon rehydration, the number of free chloride counter-ions liberated during irradiation must be monitored by ion chromatography (Dionex IonPac AS18 column); values above 0.15 meq/g correlate with cross-batch variability in swelling ratio that can compromise IV injectability.
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2-Thienyl-4-chloromethyl thiazole chloride, catalogued under product designation TC-4C-250, is supplied as a crystalline solid with a minimum assay of 98.5% by HPLC (area normalization, detection at 254 nm). The molecular formula C8H5Cl2NS2 corresponds to a molecular weight of 250.2 g·mol−1. The substance functions primarily as an electrophilic building block in pharmaceutical synthesis, where the chloromethyl substituent undergoes nucleophilic displacement under mild anhydrous conditions. Residual solvent levels comply with USP <467> Class 3 limits, with acetone and ethyl acetate each controlled below 5000 ppm. Total heavy metals by ICP-OES are specified at ≤20 ppm, and water content by Karl Fischer titration (USP <921>) is maintained below 0.5% due to the hydrolytic lability of the chloromethyl group. The product is packaged in amber HDPE jars double-lined with low-density polyethylene bags, each container purged with nitrogen to a residual oxygen level of ≤0.2% v/v.
Batch homogeneity data gathered from 15 consecutive production campaigns at the 500 L glass-lined reactor scale confirms an isomeric purity exceeding 99.2% for the para-substituted thienyl regioisomer. The manufacturing route proceeds via Vilsmeier–Haack chlorination of 2-thienyl-4-hydroxymethyl thiazole, followed by quaternization with hydrogen chloride gas in toluene. Off-line Raman spectroscopy deployed at the reactor circulation loop provides real-time tracking of the formylation intermediate, enabling precise end-point determination and suppressing over-chlorination byproducts that otherwise manifest as a deep amber discoloration and elevate the total halogenated impurity burden above the 0.8% rejection threshold.
Variability in coupling efficiency during cephalosporin core elaboration has been traced to the presence of the N-methyl quaternary ammonium byproduct, a degradation product generated when the thiazole ring undergoes adventitious alkylation at the endocyclic nitrogen during the final salt formation step. Proton NMR analysis (Bruker Avance III HD 400 MHz, DMSO-d6) of sublots exhibiting reduced reactivity consistently identifies a singlet at δ 4.31 corresponding to the N-methyl adduct, which co-crystallizes with the target chloride salt and resists removal by static recrystallization in acetonitrile. Introduction of a kinetic quench protocol—injecting the reaction mass into pre-cooled 0 °C methyl tert-butyl ether under high-shear mixing (Silverson L5M rotor-stator at 6000 rpm)—reduces the N-methyl impurity below the 0.3% limit of quantitation and restores a consistent second-order rate constant of 1.2 × 10−2 L·mol−1·min−1 for the coupling with 7-aminocephalosporanic acid. Contract manufacturing organizations adopting this quench have reported a normalized yield improvement of 12–14% across three validation batches run in 1000 L Hastelloy C-22 vessels.
Particle size distribution exerts a secondary but measurable influence on dissolution-controlled reaction kinetics. Laser diffraction data (Malvern Mastersizer 3000) indicate that milled product retained on a 45 μm sieve progresses to full solution in anhydrous DMF at 20 °C in 22 ± 3 s, whereas the unmicronized fraction with D90 of 180 μm requires 68 ± 7 s. This lag is magnified in plant-scale operations when agitation power per unit volume falls below 0.5 W·L−1, a condition often encountered during the initial charge in legacy multi-purpose reactors. Specification TC-4C-250 therefore ships with a controlled D50 of 50–75 μm and a span [(D90−D10)/D50] of ≤1.4.
| Parameter | 2-Thienyl-4-chloromethyl thiazole chloride | 4-Chloromethylthiazole hydrochloride | 2-Bromomethylthiazole |
|---|---|---|---|
| Electrophilic carbon 13C shift (δ, CDCl3) | 47.1 | 43.8 | 32.6 |
| Hydrolysis half-life at pH 7.0, 25 °C | 8.2 h | 3.5 h | 21 h |
| Typical coupling yield with thiol nucleophile | 87–92% | 68–75% | 82–88% |
| Storage humidity threshold (RH, 25 °C) | ≤30% | ≤20% | ≤40% |
| UN hazard classification | UN 3261 (8, III) | UN 3261 (8, III) | UN 1759 (8, II) |
The electron-withdrawing character of the 2-thienyl substituent deshields the adjacent chloromethyl carbon to a greater extent than the unsubstituted thiazole analog, as quantified by the 13C NMR shift differential of approximately 3.3 ppm. This polarization increases susceptibility to nucleophilic attack but also accelerates hydrolytic degradation in protic media. Processes employing this intermediate must be designed with strictly anhydrous solvent trains; activated molecular sieve columns (3A, regenerated at 300 °C for 12 h) placed in the solvent feed loop upstream of the reactor are recommended. Monitoring at-line with a Metrohm 901 Titrando system confirms water levels remain ≤50 ppm in the reaction solvent, a practical threshold below which hydrolysis accounts for less than 1% of material loss over an 8 h processing window.
Substitution of DMF by THF as the reaction medium for the nucleophilic displacement with amine nucleophiles introduces a solubility boundary that is often overlooked. In THF at 0 °C, the solubility of 2-thienyl-4-chloromethyl thiazole chloride is limited to 12 mg·mL−1, compared with >200 mg·mL−1 in DMF. Below this concentration, heterogeneous reaction mixtures display a significant mass-transfer limitation; the observed rate deviates from the predicted pseudo-first-order model beyond an initial 15% conversion, after which the reaction stalls unless supplemented with a phase-transfer catalyst. Addition of tetrabutylammonium bromide at 5 mol% relative to the electrophile restores homogeneous kinetics, achieving >98% conversion within 4 h, but requires a subsequent aqueous workup to remove the ammonium salt that otherwise interferes with crystallization of the downstream intermediate. In DMF, the same transformation reaches completion in under 90 min without additives, but DMF decomposition traces—detectable as dimethylamine by headspace GC-MS—introduce a competing alkylation pathway when reaction temperatures exceed 30 °C. The selection between solvents therefore becomes a trade-off between conversion speed and impurity control, a decision point that has led several kilo-lab campaigns to adopt a binary THF/DMF (3:1) mixture, which balances solubility (≥60 mg·mL−1 at 0 °C) and suppresses thermal runaway onset by approximately 8 °C relative to neat DMF, as measured by adiabatic calorimetry (ARC).
Storage conditions during intercontinental freight have been identified as a critical variable affecting the crystalline form delivered to end users. X-ray powder diffractograms (Rigaku SmartLab, Cu Kα) of product stored for 30 days at 40 °C/75% RH within sealed NG-purged drums show no crystalline transition; the characteristic peaks at 2θ = 12.8° and 24.5° remain unchanged. However, product subjected to multiple freeze–thaw cycles between −20 °C and +25 °C in a non-insulated container developed 0.9 wt% of an amorphous fraction (quantified by dynamic vapor sorption isotherm hysteresis), which correlated with an 18% increase in residual solvent after vacuum drying. Logistics protocols therefore specify shipment in vacuum-insulated panel containers when the expected transit temperature range exceeds a 15 °C diurnal swing.
A scan rate of 10 °C·min−1 under nitrogen (TA Instruments DSC 2500) reveals a sharp melting endotherm with onset at 157.2 °C and peak at 159.8 °C, followed immediately by a broad exothermic decomposition initiating at 171 °C and reaching an energy release of −1100 J·g−1. The proximity of melt and decomposition onsets constrains any thermal processing—such as drying under vacuum at elevated temperature—to a maximum jacket temperature of 120 °C with a 10 °C safety margin. Accelerating rate calorimetry confirms that decomposition becomes autocatalytic above 140 °C, with a time-to-maximum-rate of under 30 min at 150 °C. Facilities storing quantities exceeding 25 kg should be equipped with explosion relief panels dimensioned per NFPA 68 and deluge systems rated for the chloride gas evolution that characterizes the decomposition pathway. Published data for this specific configuration in open spray-dryer equipment is limited, and pilot studies are recommended before any attempt at particle size reduction via micronization in a drying gas stream.
| Test | Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual (EP 2.2.1) | White to off-white crystalline powder |
| Assay (HPLC) | In-house Method TM-452B; C18, 1.0 mL·min−1, 254 nm | ≥98.5% |
| Water content | USP <921> Karl Fischer | ≤0.5% |
| Residue on ignition | USP <281> | ≤0.1% |
| Heavy metals | USP <233> ICP-OES | ≤20 ppm |
| Chloride ion content | Argentometric titration (ASTM D512) | 14.0–14.8% |
| N-Methyl impurity | 1H NMR (DMSO-d6, 400 MHz) | ≤0.3% |
Regulatory classification under REACH assigns a registration number specific to the tonnage band of 1–10 tonnes per annum per legal entity. The substance meets criteria for classification as Skin Corrosion Category 1B (H314) based on rabbit skin irritation studies cited in the REACH lead registration dossier. Eye damage Category 1 (H318) is assigned, and respiratory sensitization Category 1 (H334) is under review following an occupational exposure case at a tablet-generation facility where insufficient local exhaust ventilation resulted in airborne dust levels of 0.3 mg·m−3 (measured by NIOSH 0500 filter cassette sampling). Handling therefore mandates self-contained breathing apparatus during any open-powder transfer operation when the mass exceeds 500 g. Engineering controls should maintain the 8-hour time-weighted average below 0.05 mg·m−3, a value derived from a modifying factor of 6 applied to the Lowest Observed Adverse Effect Level established in the sensitization study.
Differences from the analogous 2-bromothiazole and 2-chlorothiazole derivatives manifest most acutely in the work-up profile after nucleophilic substitution. The thienyl-thiazole chloride salt liberates a water-soluble chloride ion upon displacement, which partitions cleanly into an aqueous phase during bicarbonate washing, eliminating the need for metal-scavenging resins required when bromide byproducts from 2-bromomethylthiazole contaminate the product stream. In continuous flow setups equipped with a Corning Advanced-Flow G1 reactor, the chloride salt processing permits a single-stage liquid-liquid extraction at a flow ratio of 1:0.8 (organic:aqueous) to achieve a product purity of 99.0% before chromatography, substantially simplifying the purification sequence relative to the three-cascade counter-current extraction required for the corresponding bromide electrophile. This operational simplicity, coupled with the higher reactivity attributable to the thienyl electronic effect, has positioned the product as the first-choice electrophile for the synthesis of thiol- and amine-linked heterocyclic libraries in early-phase drug discovery where intermediate purification throughput is the rate-determining step.
