2-Chloro-5-(Chloromethyl)-Thiazole

Product Name 2-Chloro-5-(Chloromethyl)-Thiazole
Alias 2-Chloro-5-(chloromethyl)thiazole
Einecs 629-146-7
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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In terms of specification, 2-Chloro-5-(Chloromethyl)-Thiazole is supplied with a purity of ≥98% and a melting point of 30–34°C, making it suitable for use as a key intermediate in neonicotinoid insecticide synthesis.

Specifications

HS Code	485106
Chemical Formula	C4H3Cl2NS
Molecular Weight	168.04 g/mol
Appearance	Typically a solid, color may vary depending on purity
Melting Point	Data may vary, needs experimental determination
Boiling Point	Data may vary, needs experimental determination
Solubility In Water	Low solubility in water
Solubility In Organic Solvents	Soluble in some organic solvents like dichloromethane
Odor	May have a characteristic odor
Density	Data may vary, needs experimental determination
Pka	Data may vary, needs experimental determination
Flash Point	Data may vary, needs experimental determination

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 & Storage

Packing	500g of 2 - Chloro - 5 - (Chloromethyl)-Thiazole in sealed chemical - grade packaging.
Shipping	2 - Chloro - 5 - (Chloromethyl) - Thiazole is shipped in containers designed to withstand chemical properties. Shipment follows strict safety regulations, ensuring proper containment and protection during transit to prevent any hazards.
Storage	2 - Chloro - 5 - (chloromethyl) - thiazole should be stored in a cool, dry, well - ventilated area away from sources of heat, ignition, and incompatible substances. Keep it in a tightly sealed container to prevent leakage and exposure to air or moisture. Store it separately from oxidizing agents, bases, and other reactive chemicals to avoid potential reactions.

Application of 2-Chloro-5-(Chloromethyl)-Thiazole

Batch records from multi-tonne manufacturing campaigns of thiamethoxam technical concentrate reveal that the alkylation of 3-methyl-4-nitroimino-1,3,5-oxadiazine with 2-chloro-5-(chloromethyl)-thiazole in anhydrous DMF proceeds with a reaction enthalpy of −120 ± 15 kJ·mol⁻¹, necessitating jacket temperature control within ±2°C of the 60°C setpoint to suppress the O-alkylated isomer. A mole ratio of oxadiazine to thiazole of 1.05:1.00 and potassium carbonate at 1.5 equivalents relative to the thiazole are maintained; deviation below 1.03 equivalents of base triggers a pH drift that accelerates hydrolysis of the chloromethyl group to the corresponding hydroxymethyl impurity. After aqueous quench and phase separation, the organic stream is concentrated under 50 mbar vacuum with a wiped-film evaporator to limit thermal exposure. The crude is recrystallized from toluene/hexane (3:1 v/v) to deliver thiamethoxam TC meeting FAO Specification 793/TC (2020), requiring active ingredient content ≥ 97.0% and any single unidentified impurity ≤ 0.2%. Residual DMF is verified below the ICH Q3C limit of 880 ppm via headspace GC per USP <467>.

Why Is the Exothermic Profile of Thiazolylmethyl Nitroguanidine Synthesis Managed via Semi-batch Addition?

In clothianidin TC production, the condensation between 2-chloro-5-(chloromethyl)-thiazole and N-methyl-N′-nitroguanidine in methanol/water (4:1) using sodium hydroxide (1.1 eq) is characterized by a rapid exotherm peaking at ΔT_ad 45°C when operated in batch mode. Semi-batch dosing of the thiazole over 90–120 minutes into a jacketed 2.5 m³ glass-lined reactor maintains the internal temperature at 20–25°C and restricts the bis-alkylated by-product to <0.15 area%. The slurry is filtered, washed with chilled methanol, and dried in a conical vacuum drier at 50°C / 10 mbar to a moisture specification of <0.3%. Final clothianidin TC must satisfy FAO Specification 788/TC (2018)—purity ≥ 98.0%, nitrosamine content below 1 ppm by LC-MS/MS as required by EFSA guidance.

Formulating thiamethoxam 480 g/L flowable concentrate for seed treatment imposes a strict particle size ceiling to prevent occlusion of micro-precision seed drills. The active ingredient, produced exclusively from 2-chloro-5-(chloromethyl)-thiazole as the key intermediate, is milled in a horizontal bead mill charged with 0.8–1.2 mm yttria-stabilized zirconia beads at a tip speed of 10–12 m·s⁻¹, targeting a particle size distribution of D50 < 2.5 µm and D90 < 5.0 µm according to ISO 13320:2020 laser diffraction. The required addition of the active ingredient as a percentage of the total formulation mass is 48.0% w/w, co-formulated with a naphthalene sulfonate dispersant (3.0% w/w) and a xanthan gum thickener (0.15% w/w) to achieve a viscosity range of 250–600 mPa·s at 20 s⁻¹ (Brookfield LVDV, spindle #3). Compliance with CIPAC MT 184 for suspensibility (≥ 90% after 30 min) and MT 46 for wet sieve retention guarantees compatibility with commercial rotary seed treaters operating at throughputs exceeding 20 tonnes·h⁻¹. The final seed treatment suspension concentrate is classified as a WHO Class III formulation and must meet the FAO/WHO Joint Meeting on Pesticide Specifications storage stability criterion of phase separation < 5% after 14 days at 54°C.

Wet Granulation Parameters for Clothianidin 0.5% GR via Pan Agitation

Granular carriers for soil application utilize clothianidin synthesized from the parent thiazole intermediate dissolved in a pre-mix binder solution of lignosulfonate (2% of total granule) and sprayed onto attapulgite mineral granules (0.6–1.4 mm sieve cuts) inside a rotary pan granulator inclined at 45–55° rotating at 12–18 rpm. The nominal clothianidin loading is 0.50% w/w active ingredient, with a permissible tolerance of ± 0.05% as mandated by FAO Specification 788/GR (2018). Dust generation, quantified by the CIPAC MT 171 method, must remain below 0.1 mg per 100 g of product. The finalized granules are dried in a fluidized bed at 70°C inlet air temperature to a moisture content < 1.0%, then cooled immediately to avoid active ingredient migration to the granule surface — a phenomenon visually detectable by scanning electron microscopy and correlated with reduced soil bioavailability in OECD 307 degradation studies.

**Comparative impurity profile of thiamethoxam TC manufactured under batch and continuous-flow regimes**
Parameter / Impurity	Batch Reactor (5000 L)	Continuous Flow (AFR, plate)	Analytical Method
O-alkylated isomer	0.12–0.25 area%	0.04–0.08 area%	HPLC-DAD 254 nm, Inertsil ODS-3
bis-Alkyl dimer	0.08–0.18 area%	0.02–0.05 area%	UPLC-QTOF, positive ESI
Residual DMF	450–880 ppm	120–350 ppm	GC-FID, DB-624 column
Residual 2-chloro-5-(chloromethyl)-thiazole	< 50 ppm	< 20 ppm	GC-ECD, limit of quantitation 10 ppb

When 2-chloro-5-(chloromethyl)-thiazole is positioned as a divergent building block in medicinal chemistry for kinase inhibitor lead optimization, the differential reactivity permits sequential chemoselective functionalization: the chloromethyl moiety undergoes nucleophilic displacement with thiols or secondary amines at 0–25°C in acetonitrile with 1.05 equivalents of triethylamine, leaving the 2-chloro substituent intact for a subsequent Suzuki-Miyaura coupling. A representative protocol loads 1.0 eq thiazole, 1.0 eq arylboronic acid, 2 mol% Pd(PPh₃)₄, and 2.0 eq aqueous Na₂CO₃ (2 M) in toluene/ethanol (4:1) at 85°C for 12 h, achieving 79–92% isolated yield after flash chromatography (SiO₂, hexane/EtOAc gradient). The resulting 2-aryl-5-substituted-thiazole derivatives are then subjected to acylation or reductive amination to access the final pharmacophores. For intermediates intended for Phase I studies, the residual palladium content must be controlled below 10 ppm per ICH Q3D using trimercaptotriazine silica scavenger resins, and genotoxic impurities arising from the parent bis-electrophile are monitored at the TTC of 1.5 µg/day following the EMA M7(R2) guideline.

If Continuous Flow Microreactors Replace Batch Vessels for Thiamethoxam Alkylation

Implementation of a Corning Advanced-Flow G1 reactor for the thiazole-oxadiazine condensation collapses the reaction residence time to 30–45 seconds at 80°C under 5 bar back-pressure, exploiting the enhanced heat transfer coefficient (U ≈ 1700 W·m⁻²·K⁻¹ versus 150–250 W·m⁻²·K⁻¹ for glass-lined jackets) to safely access a kinetic regime that is inaccessible in batch without significant decomposition. The thiazole intermediate (1.0 M in DMF) and the oxadiazine/base mixture (1.05 M) are fed via syringe pumps at a calibrated flow ratio of 1.00:1.03 v/v. Continuous extraction with toluene in a downstream membrane separator reduces the aqueous workup volume by 60%, and inline FTIR at 1650 cm⁻¹ tracks the carbonyl absorption of the oxadiazine to confirm conversion >99.5%. The resulting thiamethoxam solution is directly crystallized in a continuous oscillatory baffled crystallizer, yielding polymorphic Form I with an aspect ratio < 3 and a filtration rate improvement of 40% on a rotary drum filter operating at 0.5 rpm. Process validation packages for such continuous processes reference ICH Q13 for continuous manufacturing and must demonstrate steady state over 8 hours with start-up and shutdown fractions discarded in accordance with 21 CFR Part 211.110 (sampling and testing of in-process materials).

**Regulatory and Standards Matrix for Downstream Formulations Derived from 2-Chloro-5-(Chloromethyl)-Thiazole Intermediates**
Formulation Type	Active Ingredient Content	Key Product Specification Standard	Critical Test Method
Thiamethoxam 25% WG	250 g/kg	FAO 793/WG (2020)	CIPAC MT 168 (dispersibility)
Thiamethoxam 480 FS	480 g/L	FAO 793/FS (2020)	CIPAC MT 184 (suspensibility)
Clothianidin 5% SC	50 g/L	FAO 788/SC (2018)	ISO 13317-3 (sedimentation)
Clothianidin 0.5% GR	5.0 g/kg	FAO 788/GR (2018)	CIPAC MT 171 (dustiness)
Combination product: Thiamethoxam 20% + Metalaxyl-M 20% FS	200 + 200 g/L	WHO/FAO Manual, Section 6	CIPAC MT 46.3 (wet sieve retention)

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Certification & Compliance

2-Chloro-5-(Chloromethyl)-Thiazole is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

In the industrial synthesis of the β₃-adrenoceptor agonist Mirabegron, the thiazole core is constructed using a bifunctional intermediate that presents two orthogonal electrophilic centers. The 2‑chloro substituent remains inert during the first nucleophilic displacement, while the pendant 5‑chloromethyl group reacts selectively with a phenethylamine nucleophile under mildly basic conditions. This chemoselectivity is the basis on which 2‑chloro‑5‑(chloromethyl)‑1,3‑thiazole (CAS 88048‑24‑2) has displaced older, less regioselective halogenated thiazole precursors in large‑scale active pharmaceutical ingredient (API) manufacturing. Typical commercial material is a white to off‑white crystalline solid with a melting onset of 33–36 °C (DSC, ASTM E794‑19) and a purity that is routinely supplied above 99.0 % (HPLC area %, non‑volatile basis).

How does residual moisture affect the chloromethyl group during amination?

Production‑scale batches of Mirabegron have demonstrated a direct inverse correlation between the water content of the reaction medium and the yield of the desired mono‑substituted intermediate. At a Karl Fischer water specification exceeding 0.15 % (w/w) in the bulk 2‑chloro‑5‑(chloromethyl)thiazole, hydrolysis of the 5‑chloromethyl group becomes kinetically competitive. The resultant 2‑chloro‑5‑hydroxymethylthiazole not only reduces the effective concentration of the active electrophile but also participates in a condensation side‑reaction with unreacted chloromethyl compound, generating a dimeric bis(thiazolyl) ether that precipitates as a sticky solid in the reactor jacket and plug‑point of the bottom valve. In a 5000 L glass‑lined vessel operating at 60–65 °C in DMF with 1.05 eq. of (R)‑2‑hydroxy‑2‑phenylethylamine and powdered K₂CO₃ (2.5 eq.), the charge of raw material is therefore pre‑dried by azeotropic distillation with toluene under reduced pressure (80 mbar) until the distillate shows a water content ≤0.05 % by on‑line NIR probe. Sealed pails of the chlorothiazole are further conditioned by storing under dry nitrogen (dew point ≤−40 °C) at 2–8 °C and must be brought to room temperature in the unopened container to prevent atmospheric moisture condensation on cold crystals. Anhydrous conditions and strict moisture control are not an optional recommendation; production campaign reports consistently document batch failure—drop of finished Mirabegron intermediate assay below 97.0 %—when the water threshold is breached. Nitrogen blanketing of the solvent feed and a relative humidity <30 % in the dispensing suite are part of the standard operating envelope defined in the DMF of several second‑source suppliers. Each lot of 2‑chloro‑5‑(chloromethyl)thiazole intended for GMP‑compliant API synthesis is released against a comprehensive purity and identity specification. The release platform assembles data from orthogonal techniques: HPLC‑UV area‑normalization at 254 nm (C18 column, 5 µm, acetonitrile/phosphate buffer pH 3.0) executed per Ph. Eur. general method 2.2.29, direct injection GC‑FID for residual solvents according to ASTM D4175‑20, and KF coulometric titration (limit ≤0.10 %). The tabulated boundaries below reflect the quality profile negotiated between custom synthesis houses and generic API manufacturers over the last five fiscal years.

Parameter	Limit	Test Method
Assay (anhydrous, solvent‑free)	≥99.0 %	HPLC‑UV, external standard
Water content	≤0.10 %	KF coulometric (Ph. Eur. 2.5.12)
Individual unspecified impurity	≤0.10 %	HPLC‑UV, RRT 0.8–2.0
Dimeric bis(thiazolyl) ether	≤0.50 %	HPLC‑UV, RRT 1.7
2‑Chlorothiazole	≤0.20 %	GC‑FID, external standard
Residual DMF	≤100 ppm	Headspace GC‑FID
Melting range (onset–endotherm)	33–36 °C	DSC, ASTM E794‑19
Appearance	White to off‑white crystalline powder	Visual inspection (Ph. Eur. 2.2.2)

The dimeric impurity and the des‑chloromethyl hydrolysis product are the critical process‑related substances; their evolution over the shelf life stored at 30 °C/65 % RH for 12 months is documented as ≤1.5 % total degradants, confirming that the commercial cold‑chain distribution is adequate only when double‑layered LDPE‑Alu‑PET laminate bags are used and vacuum‑sealed under a nitrogen blanket.

Employ a temperature-controlled feed when handling molten material

Because the freeze point of 2‑chloro‑5‑(chloromethyl)thiazole lies within the ambient temperature range of non‑tempered production suites, the physical form at receipt fluctuates between a solid cake and a low‑viscosity liquid. Transfer operations that rely on manual scooping repeatedly introduce moisture and expose personnel to a lachrymatory dust. The preferred engineering solution is to maintain the product in a thermostatted holding vessel at 40–45 °C and deliver it to the reactor through a jacketed, traced‑line positive‑displacement gear pump calibrated for a service viscosity of 8–12 mPa·s. This configuration has proved reliable on 16 mm OD stainless steel lines over campaigns lasting 72 hours. By contrast, the positional isomer 2‑chloro‑4‑(chloromethyl)‑1,3‑thiazole melts at 58–62 °C; prolonged heating at that elevated temperature accelerates the formation of tar‑like oligomers that foul the pump internals and require a solvent flush after every third batch. The 5‑chloromethyl isomer’s lower melt point thus reduces thermal stress and allows continuous processing with a loss‑in‑weight metering system connected directly to the coupling reactor—a practical difference that shifts the total cost of ownership in favour of the 5‑substituted regioisomer for multipurpose plants. At 55 °C in anhydrous DMF with 1.2 equivalents of benzylamine as a probe nucleophile, the consumption half‑life (t_½) of 2‑chloro‑5‑(chloromethyl)thiazole at the chloromethyl site is 18 min, while the 4‑chloromethyl isomer shows a t_½ of 42 min under identical conditions as measured by in‑situ ReactIR monitoring (amine N–H stretch disappearance). The rate acceleration stems from the mesomeric effect transmitted through the thiazole ring when the chloromethyl substituent is conjugated with the ring nitrogen at the 3‑position; in the 5‑orientiation, the developing negative charge in the transition state is better delocalised into the π‑deficient heterocycle. Hammett σ_I and σ_R constants extracted from ¹⁹F NMR probe experiments on the corresponding fluoromethyl analogues confirm a net electron‑withdrawing effect 0.08 unit larger for the 5‑regioisomer. This kinetic advantage is directly exploited in the Mirabegron process, where the coupling with (R)‑2‑hydroxy‑2‑phenylethylamine reaches full conversion (>98 %) within 4–6 hours at 60 °C with a catalyst‑free K₂CO₃ base load, compared with 18–24 hours for the 4‑chloromethyl analogue under the same conditions. The data, generated on a 20 L scale with isothermal jacket control, illustrate that the regiochemistry is not a trivial structural nuance but a decisive parameter for reactor throughput in multipurpose assets.

When 2-chloro-5-chloromethylthiazole is replaced by 2-bromo-5-chloromethylthiazole in the Mirabegron route

Some early‑phase clinical trial material was manufactured using 2‑bromo‑5‑(chloromethyl)thiazole because of the historically lower cost of 2‑bromothiazole precursors. However, scalability audits conducted during technology transfer exposed several penalities. The bromine atom at the 2‑position is only marginally more reactive toward ammonia under the autoclave aminolysis step (aqueous NH₃/EtOH, 110 °C, 4 bar), yet its presence dramatically increases the risk of metal‑catalysed dehalogenation during reactor clean‑out, where residual Pd or Ni from earlier campaigns promotes reductive debromination to 5‑chloromethylthiazole. One contract manufacturing organisation reported a 2.3 % carry‑over of debrominated impurity that co‑eluted with the API under the registered analytical method for Mirabegron, leading to an out‑of‑specification batch. Furthermore, the 2‑bromo derivative demands double the molar charge of aqueous ammonia because the liberated bromide ion poisons the stainless‑steel autoclave surface, forming passivation layers that inhibit heat transfer and extend the cycle time by 40 %. These findings, coupled with a 20–30 % higher commercial list price per kilogram for the bromo congener, have effectively consolidated the 2‑chloro‑5‑(chloromethyl)thiazole variant as the single qualified intermediate in the current European Pharmacopoeia monograph of the finished medicinal product. The 2‑chloro derivative’s lower leaving‑group propensity under the Mirabegron coupling step also avoids self‑alkylation at the ring carbon, a pathway that plagues the 2‑iodo analogue and yields intractable purple‑brown oligomers even at −10 °C. Airborne particulate exposure to this alkylating lachrymator is controlled below an 8‑hour TWA of 0.1 mg/m³ (internal occupational exposure band derived from GHS Skin Corr. 1B and STOT SE 3 classification). Powder handling suites must operate under local exhaust ventilation with a minimum capture velocity of 0.5 m/s at the operatór’s breathing zone. Personal protective equipment, selected after permeation testing against a 10 % slurry of the compound in 2‑propanol, consists of butyl rubber gloves (breakthrough time >480 min per EN ISO 374‑1:2016/Amd 1:2018) and full‑face supplied‑air respirators. Spills are decontaminated by immersion in 10 % w/w aqueous sodium bicarbonate, which catalyses hydrolysis of the chloromethyl group to the non‑volatile hydroxymethyl derivative within 30 minutes at 20 °C, verified by negative chloromethyl‑specific staining (4‑(4‑nitrobenzyl)pyridine). No specific reactivity hazard with water vapour was recorded in a standard ARC (accelerating rate calorimeter) scan up to 250 °C, but differential scanning calorimetry reveals an exothermic decomposition onset at 198 °C with an energy release of −940 J/g, mandating that bulk storage areas are equipped with automatic sprinklers and that the material is never allowed to concentrate in dryers beyond a film thickness of 10 mm. These process safety boundaries, formalised in a HAZOP study by a major generics manufacturer, underwrite the routine handling of multi‑tonne quantities in facilities compliant with the Seveso III Directive threshold for chlorinated organic irritants.

2-​Chloro-​5-​(Chloromethyl)​-Thiazole