4-Chloromethyl-Thiazole
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HS Code |
781189 |
| Chemical Formula | C4H4ClNS |
| Molar Mass | 133.599 g/mol |
| Appearance | Typically a colorless to pale - yellow liquid |
| Boiling Point | Approximately 190 - 195 °C |
| Density | Around 1.35 g/cm³ |
| Solubility In Water | Slightly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Odor | Characteristic, pungent odor |
| Flash Point | Caution: Flammable, flash point data may vary but is relatively low |
As an accredited 4-Chloromethyl-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Chloromethyl - Thiazole packaged in a sealed, chemical - resistant bottle. |
| Shipping | 4 - Chloromethyl - Thiazole is shipped in specialized, leak - proof containers compliant with chemical transport regulations. Packaging ensures stability during transit, safeguarding against spills and environmental exposure. |
| Storage | 4 - Chloromethyl - Thiazole should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. It should be kept in a tightly sealed container to prevent vapor leakage. Store it separately from oxidizing agents, bases, and incompatible materials to avoid potential reactions. Ensure proper labeling for easy identification and handling. |
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Substitution at the chloromethyl position of 4-chloromethylthiazole proceeds readily with primary and secondary amines under mild anhydrous conditions, making the scaffold a high-value electrophilic building block in generic active pharmaceutical ingredient (API) pipelines. In a representative batch protocol targeting a 2,4,5-trisubstituted thiazole kinase inhibitor intermediate, 1.0 equivalent of the chloromethyl compound is brought to reflux with 1.05 equivalents of a substituted aniline in acetonitrile containing 1.5 equivalents of anhydrous potassium carbonate. The suspension is held at 80–82 °C jacket temperature for 8–10 hours, with conversion monitored by in-process HPLC (area% threshold ≥99.0%). After salt filtration at 50 °C, the filtrate is concentrated below 200 mbar and the crude oil crystallised from n-heptane/ethyl acetate (4:1 v/v) to yield the N-benzylthiazole adduct as an off-white solid. Residual halogen content is the critical quality attribute for downstream Suzuki coupling; levels above 800 ppm organically bound chlorine poison palladium catalysts and reduce cross-coupling turnover numbers below an economically viable range. Manufacturers serving abbreviated new drug application (ANDA) dossiers therefore impose a limit of ≤500 ppm total halide, tested via combustion ion chromatography in compliance with USP <233>. The terminal drug substances are typically ATP-competitive inhibitors targeting oncogenic tyrosine kinases, requiring the thiazole intermediate to satisfy residual solvent specifications under ICH Q3C (acetonitrile ≤410 ppm) and mutagenic impurity control per ICH M7 with purge factor calculations supported by the raw process data generated at 200-litre glass-lined reactor scale. Residual Halide Interference in Late-Stage Buchwald–Hartwig Amination of Agrochemical CandidatesWhen 4-chloromethylthiazole is employed as a masked amine precursor in the synthesis of thiazole-containing carboxamide fungicides, the purity of the intermediate aminomethylthiazole directly determines the yield of the subsequent palladium-catalysed C–N coupling. The Delepine reaction is the preferred route at pilot scale: 1.0 equivalent of the chloride is combined with 1.1 equivalents of hexamethylenetetramine in dichloromethane at 0–5 °C, then stirred for 18 hours before filtering the quaternary ammonium salt. Hydrolytic cleavage with 37% hydrochloric acid in ethanol at 25–30 °C liberates the free amine, which must be isolated as the hydrochloride salt and dried to a water content below 0.15% (Karl Fischer) to prevent deactivation of the dialkylbiarylphosphine ligand system in the coupling step. Plant runs using a 500-litre Hastelloy reactor intermittently record a 3–8% drop in conversion when the incoming lot carries >700 ppm residual ionic chloride, a failure mode traced to ion exchange on the Pd(0) surface. Process validation therefore enforces a chloride specification of ≤300 ppm, verified by AgNO₃ potentiometric titration (DIN 38405-D1). The downstream product stream enters manufacturing of succinate dehydrogenase inhibitor (SDHI) fungicide classes, where the final wettable powder formulation is upheld to FAO specification 59/WP and requires the novel active ingredient to have passed the five-batch accelerated storage stability test at 54 ± 2 °C for 14 days. In flavour molecule synthesis, 4-chloromethylthiazole is most commonly converted to 4-thioacetylthiazole via a two-step thiourea route: the chloride undergoes nucleophilic substitution with thiourea (1.2 equivalents) in refluxing ethanol for 4 hours to yield the isothiuronium salt, which is cleaved with 3N sodium hydroxide during a 2-hour hydrolysis at 70 °C to liberate the thiol. In-line FTIR tracking of the C–Cl stretch at 680 cm⁻¹ provides real-time endpoint detection. The crude thiol is acylated in situ with acetic anhydride at 10–15 °C, yielding the target acetyl derivative after vacuum fractional distillation at 98–102 °C at 3 mmHg. The final aroma chemical is regulated under EU Regulation 1334/2008 and must be accompanied by a certificate of analysis confirming that the residual free thiol level is below the olfactory threshold of 0.2 ppb in air, assessed by GC-sniff port. This intermediate feeds the creation of thiazole-based process flavours for baked cereal and meat analogue applications, where the volatile profile is cross-referenced against FEMA GRAS listings and the finished flavour is formulated to comply with E 620–641 food additive purity criteria. Diazotization Window in Cold-Batch Thiazolyl Disperse Dye ManufacturingThiazole azo disperse dyes for polyester fibres are accessed by converting the chloromethyl substituent into a primary aromatic amine, followed by diazotization and coupling with N,N-dialkylaniline couplers. The conversion uses the Sommelet reaction: the chloromethylthiazole is heated with hexamethylenetetramine in 50% aqueous acetic acid at 100–105 °C for 2 hours, affording the formyl intermediate that is subsequently hydrolysed with 6N HCl to the aminomethylthiazole hydrochloride. The diazotization is performed by adding 1.02 equivalents of sodium nitrite solution to the amine hydrochloride suspended in 2.5N hydrochloric acid at −2 to 0 °C, with the reactor jacket brine temperature maintained at −10 °C to absorb the exotherm. Process safety analysis (RC1 adiabatic calorimetry) indicates that accumulation of unreacted nitrous acid can trigger a runaway decomposition above 8 °C; therefore, dosing is controlled over 45–60 minutes with in-process starch‑iodide paper checks at 5‑minute intervals. The resulting diazonium solution is coupled immediately with N,N-diethylaniline at pH 3.5–4.0, maintained by sodium acetate buffer. The pressed filter cake is washed to conductivity <200 µS/cm and dried at 60 °C under vacuum to yield a red-to-bluish-red dye powder with λmax in DMF at 515–525 nm. Finished dye lots intended for Oeko‑Tex certified fabrics require testing for 4‑chloroaniline and 2‑naphthylamine by GC-MS (detection limit <5 ppm), referencing the restricted substances list under Annex XVII of REACH.
When Metal-Coordinating Thioether Side Arms Are Built on a 4‑Methylene‑Thiazole PlatformIn the preparation of mixed-donor ligands for palladium and copper pre‑catalysts, the chloromethyl handle of 4-chloromethylthiazole permits direct attachment of thioether chains via deprotonated thiol nucleophiles. A representative ligand precursor is assembled by treating the thiazole chloride with the sodium salt of 2-(methylthio)ethanethiol (1.0 equiv.) in anhydrous tetrahydrofuran at 0–5 °C for 2 hours, producing the tridentate N,S,S-donor in 82–86% isolated yield after flash chromatography. The crude ligand is chelated with PdCl₂(PhCN)₂ in dichloromethane at room temperature to yield the square‑planar Pd(II) complex, whose single‑crystal X‑ray structure reveals a 176.3° S–Pd–N bite angle. The pre‑catalyst exhibits a turnover frequency of 18 000 h⁻¹ in Suzuki coupling of 4‑bromoanisole with phenylboronic acid at 80 °C in aqueous ethanol (1:1), a metric that must be reported with precise elemental analysis (CHNS deviation <0.3%) to exclude batch‑to‑batch variability in ligand loading. The metal complex synthesis operates under a nitrogen atmosphere with inline O₂ monitoring at the 0.1% alarm threshold, and the final ligand inventory is stored under argon at −20 °C to prevent the slow oxidative degradation of the thioether arms observed at ambient conditions beyond 90 days. |
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4-Chloromethyl-thiazole (CAS Registry Number 5350-95-4, IUPAC name 4-(chloromethyl)-1,3-thiazole, molecular formula C4H4ClNS, molecular weight 133.60 g·mol⁻¹) is supplied as a yellow to amber clear liquid with a pungent, halogenated odour. The product is typically identified under catalogue codes such as C1178 (Tokyo Chemical Industry) or analogous designations from fine-chemical distributors, and its assay specification for research-grade material is ≥95.0% (GC, flame ionisation detector, area%) with a maximum water content of 0.2% (Karl Fischer titration per ISO 15512:2019). Pilot-plant lots, purified by fractional distillation through a 30‑cm Vigreux column at 15‑20 mbar, exhibit a boiling point range of 95–98 °C at 20 mmHg and reach purities of 97.5‑98.2% (GC). Nuclear magnetic resonance spectra (1H NMR, 400 MHz, CDCl3) show diagnostic singlets at δ 4.73 (CH2Cl) and ring proton signals at δ 7.33 (H‑5) and δ 8.77 (H‑2). The electrophilic chloromethyl function at the 4‑position of the thiazole ring renders the molecule a versatile alkylating building block for pharmaceutical side‑chain construction, agrochemical intermediates, and metal‑catalysed cross‑coupling strategies.
In palladium‑mediated Negishi reactions with arylzinc halides, the regiochemistry of the chloromethyl substituent strongly influences turnover number and by‑product distribution. The 4‑chloromethyl isomer, when treated with 2.0 mol% Pd(PCy3)2Cl2 and 1.2 equivalents of 4‑fluorophenylzinc bromide in THF at 50 °C for 16 h, delivers the corresponding diarylmethane in 78% isolated yield (GC‑FID, internal standard method validated per ICH Q2(R1)). Under identical conditions, 2‑chloromethyl-thiazole (CAS 19406-23-2) yields less than 45% of the coupled product, with the mass balance accounted for by proto‑dehalogenation (22% 2‑methylthiazole) and homo‑coupling of the organozinc reagent. The performance gap originates from the differential electronic influence of the ring nitrogen. At the 2‑position the nitrogen exerts a stronger electron‑withdrawing effect, accelerating oxidative addition into the C–Cl bond but simultaneously stabilising the resulting Pd(II) intermediate toward β‑hydride elimination pathways; this leads to catalyst resting states that favour protonolysis over transmetallation. In the 4‑isomer, the nitrogen is meta to the chloromethyl carbon in the resonance framework, producing a modulated electron deficiency that balances oxidative addition (rate constant measured at 1.8 × 10⁻⁴ s⁻¹ under pseudo‑first‑order conditions) with an efficient transmetallation step. The 4‑chloromethyl variant also minimises the competing SN2‑type displacement of chloride by the amine ligand, a degradation path documented in the 2‑isomer when N‑heterocyclic carbene ligands are employed. On a 500‑mL scale in a jacketed glass reactor controlled to ±0.5 °C, the exotherm associated with the 4‑isomer Negishi coupling remains below 8 °C, whereas the 2‑isomer reaction has been observed to develop a self‑accelerating temperature ramp of 15‑18 °C between 30‑50% conversion, necessitating active cooling capacity of at least 50 W·L⁻¹ to avoid thiazole ring degradation.
Bulk storage and handling of 4-chloromethyl-thiazole require rigorous moisture exclusion because hydrolysis generates hydrogen chloride, which autocatalytically promotes N‑alkylation of the thiazole nitrogen. In a 50‑L glass‑lined De Dietrich reactor (jacketed, with 6‑bar steam capability), a batch of 8.5 kg of product exposed to ambient air (relative humidity 65%) for 3 hours during transfer recorded a calculated water ingress of 0.15 wt%. Upon subsequent heating to 70 °C for a planned distillation, the batch exhibited a self‑induced exotherm of 12 °C over 45 min, accompanied by a colour shift from pale yellow to dark brown. Gas chromatography of the residue indicated the formation of oligomeric tars (Mw > 800 Da by GPC‑RI) arising from step‑growth polymerisation via N‑alkylation, and the recovered yield of monomeric product after distillation dropped to 61%. Process safety evaluations (RC1e reaction calorimeter) on a 100‑g sample containing 0.1% added water show a heat release of −95 kJ·kg⁻¹ with an adiabatic temperature rise of 18 °C and a maximum self‑heat rate of 0.12 °C·min⁻¹ at 85 °C. Consequently, production‑scale batches are packaged under argon (oxygen < 5 ppm) in amber glass or HDPE containers dried to a dew point below −40 °C and are stored at −20 °C to suppress the hydrolysis rate to <1% per month. Pre‑drying of reaction solvents to < 50 ppm water (Karl Fischer, ISO 15512:2019) is mandated for any operation above ambient temperature; azeotropic distillation with toluene prior to reagent addition has been demonstrated effective in a 200‑L reactor campaign where moisture levels were held consistently at 12‑18 ppm. Vent scrubbers with 10% sodium hydroxide solution are installed on reactor vent headers to neutralise any HCl evolution, and personnel exposure limits follow an internal occupational exposure band of 0.05 mg·m⁻³ (8‑h TWA) based on the compound’s alkylating potential.
| Parameter | Supplier A – Research‑Grade (Cat. No. C1178) | Supplier B – Pilot‑Plant Lot (Batch 24-6002) | Test Method / Instrumentation |
|---|---|---|---|
| Purity (GC area%) | ≥95.0% | 97.8% | Aglient 7890B GC‑FID, column HP‑5 30 m × 0.32 mm, 0.25 μm film, carrier He 1.5 mL·min⁻¹ |
| Water content | ≤0.3% | 0.08% | Mettler Toledo C30S Karl Fischer coulometer, ISO 15512:2019 (direct injection, Hydranal‑Coulomat AG) |
| Appearance (APHA colour) | ≤200 | 45 | Lange Lico 690 spectrophotometer, ASTM D1209‑05(2019) |
| Storage temperature | 2‑8 °C | −20 °C under argon | Validated stability chamber, dataloggers ±0.5 °C |
| Typical lot size | 25 g/100 g glass bottle | 2.5 kg HDPE jerrican | — |
Displacement of chloride by sulfur nucleophiles provides a direct entry to 4‑(mercaptomethyl)thiazole, a thiol intermediate used in the synthesis of pyrethroid insecticide precursors and flavour‑fragrance heterocycles. Reaction with aqueous sodium hydrogen sulfide (NaSH, 40% solution, 1.1 equiv) in a 2:1 v/v toluene/water mixture at 60 °C in the presence of Aliquat 336 phase‑transfer catalyst (5 mol%) converts 95% of the chloromethyl substrate within 4 h (GC monitoring, n‑dodecane internal standard). Without phase‑transfer catalysis, interfacial mass transfer limits the overall rate and leads to a biphasic system that stalls at 62% conversion after 8 h; the unreacted organic phase shows gradual N‑alkylation side products due to prolonged exposure of thiazole nitrogen to the aqueous phase. The thiol product, 4‑(mercaptomethyl)thiazole, can be oxidised quantitatively to the corresponding disulfide using iodine in methanol, a transformation essential for generating sulfur‑bridged bioactive dimers. However, the use of strong bases such as sodium hydride or potassium tert‑butoxide to deprotonate the thiol in situ is contraindicated because the thiazole C‑2 proton (δ 8.77) is sufficiently acidic (pKa ≈ 18‑20 in DMSO, B3LYP/6‑31+G* calculated) to be abstracted by these bases, leading to ring‑opening by deprotonation‑induced fragmentation. In a 200‑mmol reaction with 1.0 equiv of NaH in THF at 0 °C, quenching with D2O revealed 68% deuterium incorporation at C‑2, and the isolated yield of the desired thiol dropped to 24%. The preferred deprotonation strategy employs 1.0 equiv of DBU (pKa of conjugate acid 12.5 in MeCN), which selectively deprotonates the thiol (pKa ≈ 9‑10), leaving the thiazole ring intact and enabling subsequent S‑alkylation without generating ring‑opened by‑products.
| Compound | CAS No. | Oxidative Addition Rate (relative to 4‑ClCH₂, Pd(PPh₃)₄) | Dominant Side Reaction in Negishi Coupling | Hydrolytic Stability (t½ in 50:50 THF/H₂O at 25 °C) | Key Differential |
|---|---|---|---|---|---|
| 4‑Chloromethyl-thiazole | 5350-95-4 | 1.0 (reference) | Proto‑dehalogenation (8‑12%) | 48 h | Balanced electrophilicity and cross‑coupling, preferred for multi‑step library synthesis |
| 2‑Chloromethyl-thiazole | 19406-23-2 | 2.4 | Proto‑dehalogenation (25‑35%) + homocoupling | 32 h | Faster oxidative addition offset by severe protonolysis; limited utility in Zn‑mediated couplings |
| 4‑Bromomethyl-thiazole | 117204-03-8 | 4.7 | Retro‑bromination (15‑20%) with electron‑rich ArZnCl | 22 h | Superior leaving group for SN2 displacements, but oxidative addition leads to higher Pd black formation |
| 4‑Methylthiazole | 693-95-8 | Not applicable | No cross‑coupling; C–H activation required | Stable | Non‑functionalised analogue used when thiazole ring needs to remain inert during synthesis |
Beyond the direct comparisons, 4‑chloromethyl-thiazole occupies a unique niche where the C–Cl bond strength (292 kJ·mol⁻¹ estimated) supports nickel‑catalysed Kumada‑type couplings with Grignard reagents without the extensive hydro‑dehalogenation that plagues the bromo analogue. In the synthesis of the histamine H2 receptor antagonist nizatidine (CAS 76963-41-2), the 4‑chloromethyl intermediate is condensed with N‑methyl‑1,2‑ethanediamine in isopropanol at reflux; the displacement proceeds with 1.05 equivalents of amine to suppress di‑alkylation, and conversion is tracked by HPLC‑UV (254 nm) using a C18 column and Ph.Eur. 2.2.46 acceptance criteria. Residual 4‑chloromethyl-thiazole below 0.15 area% is required before phase‑transfer work‑up, as carry‑over into the final API produces a mutagenic impurity alert (ICH M7 class 3), controlled by a purge factor calculation based on the purge ratio of the downstream crystallisation (acetonitrile/water, 5°C, solubility of the thiazole derivative measured at 0.4 mg·mL⁻¹).
Storage stability under regulated conditions points to a shelf life of 6 months when the material is maintained under argon at a maximum temperature of −15 °C. Longer storage, or exposure to temperatures above 0 °C for more than 48 hours, results in detectable levels ( >0.5% ) of 4‑hydroxymethyl-thiazole and 4,4′‑(thiazole‑4‑ylmethyl) ether, as verified by LC‑MS (ESI+, [M+H]+ 132.08 and 227.12). For shipping, UN‑subsidiary hazard class 8, packing group III applies, and double‑capped containers with PTFE‑faced septa are required to satisfy IATA 4.4‑Special Provision A3. The compound is classified under REACH Regulation (EC) No. 1907/2006 with pre‑registered tonnage band 1‑10 tonnes/year and does not appear on Annex XIV or XVII restriction lists; nevertheless, its manufacture is conducted in closed systems with emission control, and waste streams containing >100 ppm w/w 4‑chloromethyl-thiazole are treated by alkaline hydrolysis in a dedicated steel hydrolysis vessel at 80 °C for 2 h to destroy the alkylating character before release.
Process development reports from a 150‑L multi‑purpose good manufacturing practice (GMP) reactor at a contract manufacturing organisation document that the charge of 20 kg of 4‑chloromethyl‑thiazole into a pre‑cooled (−10 °C) toluene slurry of anhydrous K2CO3 (2.5 equiv) for a thioether formation shows a temperature spike of 4 °C over the first 15 min of addition, controlled by jacket set‑point ramping at −1 °C·min⁻¹. After the reaction, distillation of toluene at 45 mbar and 45 °C recovers the product in 91% yield, with residual palladium measured by ICP‑OES (ISO 11885:2007) below 10 ppm after charcoal treatment. Published data for long‑term storage of the neat liquid in carbon steel vessels is limited; however, accelerated rate calorimeter experiments on wetted carbon steel coupons at 100 °C indicate 0.02 mm·year⁻¹ corrosion rate, justifying the exclusive use of glass‑lined or Hastelloy C‑22 equipment in multi‑ton campaigns.
