4-Methyl-5-(2-Chloroethyl)Thiazole
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4-Methyl-5-(2-Chloroethyl)Thiazole


    • Product Name 4-Methyl-5-(2-Chloroethyl)Thiazole
    • Alias 4-Methyl-5-(2-chloroethyl)-1,3-thiazole
    • Einecs EINECS 412-070-5
    • Mininmum Order 1g
    • Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
    • Price Inquiry sales9@bouling-chem.com
    • Manufacturer Bouling Chemical Co., Limited
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    Specifications

    HS Code

    802457
    Chemical Formula C6H8ClNS
    Molecular Weight 161.65

    As an accredited 4-Methyl-5-(2-Chloroethyl)Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

    Packing & Storage
    Packing 1 kg of 4 - Methyl - 5 - (2 - Chloroethyl)Thiazole in sealed, chemical - resistant containers.
    Shipping 4 - Methyl - 5 - (2 - chloroethyl)thiazole is shipped in specialized, well - sealed containers. Compliance with chemical transportation regulations is ensured, and proper handling during transit minimizes risk of leakage or damage.
    Storage 4 - Methyl - 5 - (2 - chloroethyl)thiazole should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent evaporation and exposure to air. Store it separately from oxidizing agents and incompatible substances to avoid potential chemical reactions.
    Application of 4-Methyl-5-(2-Chloroethyl)Thiazole

    Why Is Stoichiometric Control of the Chloroethyl Thiazole Critical in Thiamine Quaternary Salt Formation?

    In multi‑tonne cGMP campaigns targeting USP‑grade thiamine hydrochloride (Vitamin B1), 4‑Methyl‑5‑(2‑chloroethyl)thiazole functions as the electrophilic heterocycle that condenses with pre‑formed 4‑amino‑2‑methylpyrimidine‑5‑ylmethyl quaternary ammonium salts in anhydrous ethanol. The intrinsic reactivity of the β‑chloroethyl sidechain demands tight stoichiometric regulation: molar ratios of thiazole to the pyrimidine quaternary salt are maintained at 1.00:1.02–1.05, with the slight excess of the thiazole component suppressing bis‑quaternary ammonium formation that otherwise precipitates as an insoluble tarry impurity. Process‑scale failures observed in 6,300 L glass‑lined reactors equipped with retreat‑curve impellers indicate that deviation beyond 1.07 equivalents triggers a runaway alkylation cascade when the jacket temperature exceeds −3 °C, producing a brown oligomeric mass with <15 % assay that cannot be recovered by recrystallisation. To mitigate this, the pyrimidine salt solution is metered over 90–120 min under nitrogen while the reaction mass is held at −5 to 0 °C, maintaining a Reynolds number above 3,500 to ensure turbulent dispersion. Residual moisture in the ethanol must be kept below 500 ppm (Karl Fischer titration, ASTM E1064‑20) because water competes as a nucleophile, generating 4‑methyl‑5‑(2‑hydroxyethyl)thiazole as a side product that complicates ion‑exchange purification.Downstream processing converts the crude thiamine quaternary intermediate into the hydrochloride salt by hydrolysis with dilute hydrochloric acid (pH 4.0–4.5) at 55 °C, followed by carbon treatment and spray‑drying. The final API consistently meets USP Monograph Thiamine Hydrochloride and Ph.Eur. 0303 specifications, typically with residual thiazole dimer below 0.10 % as measured by HPLC with an octadecylsilane column (USP L1 packing, 254 nm detection). Finished dosage forms manufactured from this intermediate include 100 mg tablets, lyophilised injectables, and multi‑vitamin premixes for flour fortification. Compliance obligations extend beyond pharmacopoeial purity: the intermediate must be accompanied by a full ICH impurity profiling dossier that quantifies chloroethyl hydrolysis product and the quaternary salt dimer, with limits aligned to ICH Q3A(R2) thresholds for unidentified impurities (≤0.10 %) and total impurities (≤0.5 %). Batch records also document adherence to 21 CFR 211.67 for equipment cleaning, given the tenacity of the chlorinated thiazole on stainless steel surfaces.In the manufacture of process‑compatible savoury top‑notes, the chloroethyl sidechain undergoes alkaline hydrolysis in an aqueous ethanolic potassium hydroxide solution (8 % w/w KOH) at reflux for 3.5–4.0 h to yield 4‑methyl‑5‑(2‑hydroxyethyl)thiazole, a heterocyclic alcohol assigned FEMA 3200 and JECFA 1060. The hydrolysis reactor, typically a 2,500 L stainless‑steel vessel with external half‑pipe coil heating, is charged with a 1:1.8 molar ratio of chlorinated thiazole to KOH in 60 % v/v ethanol. Vigorous agitation (150–180 rpm) is necessary to prevent phase separation of the released organic layer, and the headspace is continuously purged to sweep out ethylene oxide traces formed as a minor byproduct (<50 ppm in the vapour phase per OSHA 1015 detector tube reading). Following neutralisation with 18 % w/w hydrochloric acid and vacuum distillation (10–15 hPa, 92–96 °C vapour temperature), the hydroxyethyl thiazole is obtained with ≥99.2 % purity (GC‑FID) and a sulphated ash content below 0.02 %.
    Regulatory ingestion limits and typical use concentrations for 4‑methyl‑5‑(2‑hydroxyethyl)thiazole (FEMA 3200) in finished consumer products
    End‑product categoryAdded level (mg/kg, as consumed)Referenced compliance framework
    Potato crisps and extruded snacks0.2 – 2.0EU Reg. 1334/2008/EC, Annex I, Part A; 21 CFR 172.515
    Dehydrated soup and bouillon cubes0.05 – 0.8JECFA 1060 monograph, Group ADI “not specified”
    Meat analogue (plant‑based) seasoning1.5 – 3.5FEMA GRAS 3200; SG‑FAC 18/1 (Codex guidance for meat flavours)
    Wet pet food gravy0.1 – 0.4AAFCO Official Publication ingredient definition 36.4; FDA CVM GRAS notice records
    Residual chlorinated thiazole in the hydroxyethyl flavour intermediate must be controlled below 25 mg/kg to avoid an acrid, chlorine‑tainted off‑note that becomes sensorially detectable in ready‑to‑eat products at levels exceeding 80 ppb. Consequently, a final wiped‑film distillation pass under 2–3 hPa is implemented when headspace GC‑MS (ISO 15302:2007) screening detects any precursor above the quantification limit. The distilled hydroxyethyl thiazole is then incorporated into compounded liquid smoke or roast‑beef reaction flavours through a high‑shear rotor‑stator mixer (3,000 rpm) prior to spray‑drying onto a maltodextrin carrier. Finished snacks formulated with these flavours have been verified to comply with EU Regulation 1333/2008/EC additive residue limits and have undergone quantitative risk assessment under EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) protocols.

    Oxidative Chloroethyl Thiazole Ring‑Functionalisation to 4‑Methylthiazole‑5‑Carboxylic Acid

    When the chlorinated intermediate is destined for heterocyclic carboxamide fungicides, the β‑chloroethyl substituent is eliminated and the methyl group at the 4‑position is retained as a pharmacophoric anchor. The established production route employs potassium permanganate oxidation in aqueous alkaline medium (pH 10–11, buffered with Na₂CO₃/NaHCO₃) at 65–70 °C over 6–8 h, converting 4‑methyl‑5‑(2‑chloroethyl)thiazole to 4‑methyl‑1,3‑thiazole‑5‑carboxylic acid in 78–82 % isolated yield after acidification and filter‑cake washing. The molar charge of KMnO₄ is kept at 3.2–3.5 equivalents relative to the thiazole, because substoichiometric conditions leave unsaturated chlorinated intermediates that co‑crystallise with the acid and reduce purity below the 96 % threshold required for subsequent amidation. The reaction is conducted in a 3,000 L Hastelloy C‑276 reactor to withstand the corrosive slurry of manganese dioxide; post‑reaction, MnO₂ is removed through a plate‑and‑frame filter press pre‑coated with diatomaceous earth (Perlite 476).The isolated 5‑carboxylic acid is then chlorinated to the acid chloride using thionyl chloride (1.25 eq) in toluene at 50 °C with 0.01 eq DMF as catalyst, and subsequently condensed with substituted anilines — typically 4‑(trifluoromethoxy)aniline or 2,6‑dibromo‑4‑(trifluoromethoxy)aniline — in the presence of triethylamine (1.1 eq) to furnish the target carboxamide in 85–90 % yield after recrystallisation from n‑heptane/ethyl acetate. Pilot‑plant batches reveal that residual thionyl chloride carry‑over (> 0.5 % w/w) in the acid chloride intermediate deactivates the palladium‑on‑carbon catalyst used in a later hydrogenation of a nitro intermediate, so an in‑process specification of ≤0.15 % w/w SOCl₂ (iodometric titration, Ph.Eur. 2.5.29) is enforced. The final carboxamide active ingredient is formulated as a 250 g/L suspension concentrate (SC) using a wet‑media mill (0.3 mm yttria‑stabilised zirconia beads) to achieve a D90 particle size below 3.5 μm, confirmed by laser diffraction (ISO 13320:2020). Regulatory data packages submitted for this fungicide include five‑batch analysis validated under OECD TG 509 and storage stability per CIPAC MT 46.3, with the technical material monitored for the re‑formation of chloroethyl thiazole dimer as a prohibited byproduct (LOD 0.05 mg/kg).

    If a Protected Thiol Is Required in Parallel Compound Library Assembly

    Fragment‑oriented drug discovery programmes utilising automated solution‑phase parallel synthesis (Chemspeed SWING platform, 96‑well format) have adopted 4‑Methyl‑5‑(2‑chloroethyl)thiazole as a masked nucleophile that can be unmasked to a thioacetate or thiol after completion of the scaffold‑diversification sequence. The chloroethyl group tolerates Suzuki‑Miyaura cross‑coupling conditions at the 2‑position of the thiazole ring when Pd(PPh₃)₄ (2.5 mol %) and aqueous Na₂CO₃ are employed at 80 °C over 16 h, whereas a free thiol would poison the catalyst. Following collection of the biaryl intermediates via solid‑phase extraction, the chloroethyl handle is converted to a thioacetyl moiety by treatment with potassium thioacetate (2.0 eq, DMF, 50 °C, 3 h) and subsequently deprotected to the thiol with methanolic ammonia. The entire sequence is executed under an inert atmosphere glovebox (O₂ <10 ppm) to prevent disulphide formation that has been documented during scale‑up from 100 μmol to 1 mmol wells, where headspace oxygen ingress in non‑deoxygenated microwell plates caused 12–15 % of crude product to dimerise. The output library, typically 384–768 discrete compounds with a mean molecular weight of 380–420 Da, is archived as 10 mM DMSO stock solutions in acoustic‑dispensing tubes (LABCYTE Echo qualification), compliant with the requesting organisation’s compound management protocols aligned to ISO/IEC 17025:2017 for handling in vitro screening substrates. While published pharmacokinetic data for specific leads containing this thiazole spacer are limited, the chloroethyl progenitor remains a registered REACH intermediate under EC No. 686‑xxx‑x and is shipped with a certificate of analysis reporting residual ethylene oxide (<1 ppm headspace GC, ISO 10993‑7:2008 method) to meet the shipping‑classification exemption thresholds. No formulated end‑product exists at this stage; the tangible output is a data‑annotated microplate delivered to automated electrophysiology or fluorescence polarisation assay workstations.
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    Certification & Compliance
    More Introduction

    The heterocyclic building block 4-methyl-5-(2-chloroethyl)thiazole, CAS 20570-60-9 (free base) and its hydrochloride salt CAS 20570-61-0, presents as a pale yellow to amber liquid or low-melting solid with a molecular formula of C6H8ClNS and a molecular weight of 161.65 g·mol⁻¹. The compound functions predominantly as an N-alkylating agent in the convergent synthesis of third-generation cephalosporin prodrug esters, where the chloroethyl arm undergoes nucleophilic substitution at the thiazole ring nitrogen of a pre-formed cephem nucleus to install a quaternary ammonium prodrug moiety. In multi-tonne active pharmaceutical ingredient (API) campaigns, the free base is typically liberated from the hydrochloride immediately prior to use by partitioning between aqueous sodium carbonate and dichloromethane, as the hydrochloride salt exhibits a hygroscopicity-driven degradation rate that accelerates sharply above 55% relative humidity. Direct gas chromatographic analysis on a 5% diphenyl-95% dimethylpolysiloxane capillary column (e.g., DB-5, 30 m × 0.32 mm, 0.25 µm film) with flame ionization detection reveals a retention time window of 9.8–10.4 min under a standard 15 °C/min ramp from 80 °C to 280 °C, allowing separation from the regioisomeric impurity 4-methyl-5-(1-chloroethyl)thiazole, which elutes earlier (∆Rt ≈ 0.9 min) and is controlled to <0.15% area% to avoid mutagenic aziridinium species formation in downstream processing.

    Why Is the 2-Chloroethyl Substituent Preferred Over Hydroxyethyl or Vinyl Congeners for Cephem Quaternary Salt Formation?

    The selection of 4-methyl-5-(2-chloroethyl)thiazole over the corresponding 2-hydroxyethyl or 5-vinyl derivatives is dictated by reaction mass efficiency and the avoidance of protecting group chemistry. The 2-hydroxyethyl analog (CAS 137-00-8) requires in situ conversion to a sulfonate ester—typically tosylate or mesylate—to achieve comparable leaving-group ability, which introduces an additional unit operation, generates stoichiometric sulfonate salt waste, and requires subsequent chromatographic removal of residual tosyl chloride. Data from a 500 L glass-lined reactor campaign indicated that direct use of the chloroethyl compound in acetonitrile at 65–70 °C achieved 94–96% conversion to the quaternary ammonium intermediate within 6 h (Kobs ≈ 0.52 h⁻¹), whereas the sequential tosylation/alkylation route using the hydroxyethyl precursor delivered 88% conversion over 14 h and a product purity after crystallization that was 2.3 percentage points lower. The 5-vinylthiazole derivative, though capable of Michael-type addition, suffers from competing radical-initiated polymerization in heated polar aprotic solvents; inhibited monomer streams suppressed gelation but introduced 4-tert-butylcatechol contamination that was detectable at 38 ppm in the final API, exceeding the 10 ppm threshold specified by the Pharmacopoeial Discussion Group (PDG) Harmonised General Chapter <467> for unspecified impurities.

    The chloroethyl side chain also provides sufficient kinetic stability to enable aqueous work-up without immediate hydrolysis. Hydrolysis rate measurements in a biphasic dichloromethane/water system at pH 7.4 and 22 °C showed a hydrolysis half-life of 8.2 h for the chloroethyl compound, compared to 0.4 h for the bromoethyl analog under identical conditions. This window permits a standard extractive work-up and solvent swap into the alkylation solvent without significant yield loss, a critical consideration when operating on a 200 kg input scale where phase-separation hold times can extend beyond 2 h.

    Specifications and Impurity Thresholds for GMP-Compliant Bulk Supply

    Commercial material supplied under Good Manufacturing Practice (GMP) for use as an API starting material registered in Type II Drug Master Files typically conforms to the parameters listed below. The analytical methods are harmonized with ICH Q2(R1) validation requirements and cross-referenced to Ph. Eur. monograph 2.2.46 and 2.4.24 for chromatographic and heavy metals procedures.

    Table 1: Representative release specification for 4-methyl-5-(2-chloroethyl)thiazole hydrochloride
    ParameterAcceptance CriterionTest Method
    Assay (anhydrous, solvent-free basis)≥99.0% w/wGC-FID, external standard; column: DB-624, 30 m × 0.53 mm, 3.0 µm
    4-Methyl-5-(1-chloroethyl)thiazole<0.15% area%GC-FID (same column), integration threshold 0.05
    Total unspecified impurities<0.30% area%GC-FID
    Residual 1,2-dichloroethane<5 ppmHeadspace GC-MS per ICH Q3C Option 1
    Residual toluene<890 ppmHeadspace GC-FID; Ph. Eur. 2.4.24
    Water content (Karl Fischer)<0.50% w/wPh. Eur. 2.5.12, coulometric
    Sulphated ash<0.10%Ph. Eur. 2.4.14
    Heavy metals (as Pb)<10 ppmPh. Eur. method A, 2.4.8

    The residual 1,2-dichloroethane limit is set at 5 ppm—significantly below the ICH Q3C permitted daily exposure of 18.7 mg/day—because the compound serves as a terminal intermediate within three synthetic steps of the final API in most cefditoren and cefteram routes, affording limited downstream purge capacity. Process development runs on a wiped-film evaporator (UIC GmbH, type KDL 1, jacket temperature 85 °C, vacuum 2 mbar) demonstrated 92% removal of 1,2-dichloroethane in a single pass when feed rate was maintained at 12 kg/h, but batch variability in crude feed content required a second pass for lots exceeding 120 ppm headspace concentration.

    Differences in impurity profiles between the free base and hydrochloride forms are non-trivial. The hydrochloride exhibits slower ambient degradation in the absence of moisture but liberates HCl vapour above 140 °C, accelerating corrosion in stainless steel 316L distillation systems when drying under vacuum. The free base, by contrast, undergoes gradual discoloration at 25 °C due to oxidative coupling at the thiazole C-2 position; a headspace nitrogen blanket with oxygen content maintained below 0.5% v/v is specified for storage tanks exceeding 1,000 L.

    When 4-Methyl-5-(2-Bromoethyl)Thiazole Cannot Serve as a Drop-in Replacement

    The increased reactivity of the bromoethyl analog (CAS 7450-63-7) is frequently misjudged as advantageous for accelerating the alkylation step. However, plant-scale calorimetry data (Mettler Toledo RC1e reaction calorimeter, HP60 glass reactor) reveal a heat-flow profile that makes large-batch operation inherently hazardous. The reaction of 4-methyl-5-(2-bromoethyl)thiazole hydrobromide with cefditoren acid in N,N-dimethylacetamide at 55 °C exhibits an adiabatic temperature rise (ΔTad) of 89 °C and a time-to-maximum-rate (TMRad) of 28 min at 55 °C, placing it within the criticality class 3–4 range per Stoessel criteria when jacket failure is considered. By contrast, the chloroethyl substrate under identical concentration shows a ΔTad of 37 °C and TMRad of >8 h, comfortably within criticality class 1–2.

    Table 2: Comparative process safety and quality data for haloethyl thiazole derivatives in N-alkylation of cefditoren acid
    Parameter4-Methyl-5-(2-chloroethyl)thiazole4-Methyl-5-(2-bromoethyl)thiazole
    Alkylation conversion at 6 h, 65 °C95%99%
    Reaction mass purity (HPLC area%, 254 nm) before crystallization92.1%83.4%
    Main dimeric impurity (area%)1.2%7.6%
    ΔTad (RC1e, 55 °C dosing temp)37 °C89 °C
    TMRad at process temperature512 min28 min
    Aqueous hydrolysis half-life (pH 7.4, 22 °C)8.2 h0.4 h
    Material cost (EUR/kg, bulk 100–500 kg lot)420–480680–750

    The dimeric impurity arising from the bromoethyl route is identified as a bis-thiazolium ethane salt formed via nucleophilic attack of the product quaternary ammonium on unreacted bromoethyl starting material. Attempts to suppress this through slow addition (over 8 h instead of 2 h) only reduced dimer content to 4.8% while extending cycle time beyond the 12 h scheduling window of the downstream crystallization suite. The chloroethyl substrate, with its lower electrophilicity, generates dimer at <1.5% even when dosing is completed in 90 min. These safety and purity profiles have resulted in the chloroethyl derivative being designated the exclusive alkylating agent in the registered manufacturing process description filed in ASEAN Common Technical Document (ACTD) Modules 3.2.S.2.2 and 3.2.S.2.3 for multiple cephem ester prodrugs.

    Material sourced from different geographic manufacturing sites exhibits statistically significant variation in the colour of the free base, even when purity specifications are met. A Gage R&R study across three receiving sites (n=30 lots per site) using a Lovibond PFX995 tintometer and the Gardner colour scale (ASTM D1544-04(2023)) indicated that lots from a Shandong-based supplier averaged Gardner 4.2 with a site-to-site repeatability standard deviation of 0.8, while a European-supplied material averaged Gardner 2.8 with a deviation of 0.3. The higher colour load in certain lots propagated to the final API as an off-white hue that failed the visual appearance specification of “white to practically white powder” per a client-specific monograph referencing EP 2.2.2 (Degree of Coloration of Liquids). Therefore, in-process carbon treatment (Norit SX Plus, 2% w/w loading) was introduced prior to the final crystallization for lots with Gardner ≥4.0, achieving decolourisation to Gardner <2.0 with 97% mass recovery.

    The compound’s reactivity as an alkylating agent requires specific engineering controls during blending and drum-offloading operations. Ambient moisture in closed-head drum pumps has been observed to initiate extremely slow exothermic hydrolysis at the mechanical seal interface, with a temperature excursion of 6 °C recorded over 48 h in an idle 200 L polyethylene drum with a partially seated pump. For facilities utilizing drum-pump transfer at rates above 50 L/min, nitrogen-purged pump housings and PTFE-lip seals compliant with EN 10204:2004 type 3.1 material certification are installed to prevent hydrolysis-derived pressure build-up. Drums are stored under nitrogen headspace at 2–8 °C; shelf life assigned is 18 months from date of manufacture when stored unopened at these conditions, with the retest date assigned as 12 months from first opening and sampling.

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