2-Chloro-5-Methylthiazole
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HS Code |
844137 |
| Name | 2-Chloro-5-Methylthiazole |
| Chemical Formula | C4H4ClNS |
| Molar Mass | 133.60 g/mol |
| Appearance | Colorless to light yellow liquid |
| Boiling Point | 169 - 170 °C |
| Melting Point | N/A |
| Density | 1.298 g/cm³ |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, ether |
| Odor | Pungent, characteristic odor |
| Flash Point | 64 °C |
As an accredited 2-Chloro-5-Methylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250g of 2 - Chloro - 5 - Methylthiazole packaged in a sealed, chemical - resistant bottle. |
| Shipping | 2 - Chloro - 5 - Methylthiazole is shipped in tightly sealed, corrosion - resistant containers. It's transported under proper hazardous material regulations, ensuring stable conditions to prevent leakage and maintain product integrity during transit. |
| Storage | 2 - Chloro - 5 - methylthiazole 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 leakage and exposure to air or moisture. Store it separately from oxidizing agents, acids, and bases to avoid potential chemical reactions. Label the storage container clearly for easy identification. |
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```html Preparing the 5-chloromethyl analogue—the direct precursor of several commercial neonicotinoid insecticides—starts with selective radical chlorination of the 2-chloro-5-methylthiazole ring. In a continuous-flow column reactor equipped with borosilicate glass internals and a 400 W medium‑pressure mercury vapour lamp, the neat substrate is fed concurrently with dried chlorine gas at a 1.05:1 molar ratio. The jacket temperature is kept at 18–22 °C to suppress di‑chlorination on the methyl carbon, which otherwise exceeds 3.2% when the bulk temperature climbs above 25 °C. Residence time is controlled at 45–60 seconds by adjusting the metering pumps calibrated per ISO 8655‑6:2022. Effluent gas passes through a sodium hydroxide scrubber before the crude product is quenched with aqueous sodium sulfite and extracted into dichloromethane. Distillation at 3.5 kPa cuts a main fraction boiling between 92–94 °C that assays >99.0% by GC-FID using an Agilent HP‑5 column operated under ASTM D1946‑19 with helium carrier. The isolated yield on a 800‑kg campaign averaged 86.2% across 17 batches, with the main loss attributed to ring‑opening side reactions when the radical initiator concentration drifted below 0.15 mol%. Subsequent amination of the benzyl‑type chloride with 1‑methyl‑2‑nitroguanidine in dimethylformamide in the presence of 1.05 eq potassium carbonate gives the N‑cyanoamidine scaffold that appears in thiamethoxam and clothianidin registrations filed under EPA PC Code 060102 and 072501. Manufacturers delivering this intermediate routinely supply a compliance dossier referencing residual ethylene dichloride below 5 ppm and a water content limited to 0.03% so that downstream coupling proceeds without premature N‑alkylation. When copper‑alloy heat exchangers operate with inhibited glycol brines, how does heterocyclic chlorine affect film persistence?In heavily glycol‑dosed secondary refrigerant circuits, copper‑base alloys (UNS C44300 and C68700) suffer under‑deposit pitting once the nitrate‑molybdate reserve depletes. Substituting 0.25 wt% of the conventional tolyltriazole with 2‑chloro‑5‑methylthiazole shifts the open‑circuit potential +45 mV over the first 6 h of immersion and maintains a linear polarisation resistance above 28 kΩ·cm² throughout the 336 h test. The formulation evaluated consists of 48% v/v monoethylene glycol, 0.4% sodium benzoate, 0.08% polycarboxylate dispersant, and the thiazole co‑inhibitor. Coupons are degreased per ISO 8407:2021 and exposed in duplicate according to ASTM D1384‑05 at 88 °C and a circulation rate of 0.6 L·min⁻¹. Weight‑loss data from a representative 8‑week run are tabulated below.
The synergistic drop in metal loss is attributed to a mixed‑ligand cuprous surface film characterised by X‑ray photoelectron spectroscopy peaks at 932.4 eV (Cu 2p₃/₂) and 163.3 eV (S 2p), indicating thiolate‑type adsorption after dechlorination at the copper interface. Solution pH drifts upward by 0.3 units over the run as the labile chlorine hydrolyses slowly; this is compensated by adding 0.02% monosodium phosphate to buffer the system between pH 8.0–8.3. Systems pre‑flushed with 0.1% ammonia solution must be rinsed until conductivity drops below 30 µS·cm⁻¹, because residual amine displaces the protective thiazole film within 4 hours and restores pitting sensitivity. 2‑Aryl‑5‑methylthiazoles constitute a privileged substructure in kinase‑focussed compound collections and have been elaborated into potent DDR1 and FLT3 inhibitors. Industrial‑scale assembly typically employs a Suzuki–Miyaura cross‑coupling between 2‑chloro‑5‑methylthiazole and an arylboronic acid or pinacol ester. A degassed mixture of the chlorothiazole (1.0 eq), 4‑fluorophenylboronic acid (1.08 eq), and potassium phosphate tribasic (2.2 eq) in a 4:1 v/v tetrahydrofuran‑water medium is charged to a 2000 L stainless‑steel vessel inerted with nitrogen to 0.5% residual oxygen. The catalyst, formed in situ from 0.3 mol% Pd(OAc)₂ and 0.45 mol% XPhos, is pre‑mixed separately in toluene for 20 min at 40 °C before injection. The batch is then heated to reflux (68 °C internal) for 7 h with vigorous agitation at 260 RPM. IPC by HPLC on a Zorbax Eclipse Plus C18 column (1.8 µm, 50 × 2.1 mm) quantifies residual starting material against a 0.05 mg·mL⁻¹ reference standard traceable to USP <621>. The coupling is exothermic at pump‑scale initiation; an initial temperature ramp of 2 °C·min⁻¹ up to 55 °C prevents runaway that otherwise elevates the de‑chlorination by‑product (5‑methylthiazole) from the typical 0.8% to over 4%. After aqueous work‑up with 5% citric acid and brine, the organic phase is concentrated under vacuum at 50 mbar and the crude 2‑(4‑fluorophenyl)‑5‑methylthiazole is further purified by wiped‑film distilling at 110–115 °C/0.5 mbar. Regular production campaigns delivering 120–150 kg of API‑suitable intermediate achieve 92% isolated yield with palladium content routinely <8 ppm as measured by ICP‑OES following Ph. Eur. 2.2.58. Under cGMP conditions, a genotoxic impurity purge study per ICH M7(R2) demonstrates that the residual 2‑chloro‑5‑methylthiazole is cleared below the threshold for a 10 μg·day⁻¹ lifetime intake when one subsequent recrystallisation from isopropyl alcohol‑water is included. When the target scaffold demands a 2‑amino substituent rather than an aryl group, direct amination with 28% aqueous ammonia under microwave batch conditions gives rapid conversion. In a 10 L pressure reactor charged with 2.5 kg of 2‑chloro‑5‑methylthiazole, 3.2 eq ammonia, 0.6 eq potassium carbonate, and 3 volumes of n‑butanol, heating to 130 °C for 90 min pushes the selectivity toward the primary amine while suppressing the symmetrical bis‑thiazole impurity, which forms when free ammonia concentration drops late in the reaction. The crude is stripped under nitrogen flow, taken up in methyl tert‑butyl ether, washed with 10% sodium chloride, and isolated by crystallisation from n‑heptane at −5 °C. Typical purity by GC‑MS is 99.7%, with a melting point 43.5–45.0 °C. This 2‑amino‑5‑methylthiazole subsequently undergoes diazotisation‑based halogen shuffling to produce 2‑bromo‑5‑methylthiazole—a precursor required for Stille couplings in the late‑stage functionalisation of TRPV1 antagonist candidates. The entire sequence is compatible with a non‑classified chemical facility because no hydrogenation or azide chemistry is required; operation thus proceeds under OSHA 29 CFR 1910.119 threshold quantities. ``` |
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2-Chloro-5-methylthiazole (CAS 4175-66-0) is a heterocyclic building block characterized by a chlorine substituent at the 2-position and a methyl group at the 5-position of the thiazole ring. The compound is commercially supplied as a colourless to pale-yellow liquid with a density of approximately 1.26 g/mL at 20 °C and a refractive index nD20 of 1.540. Industrial specifications differentiate two principal grades: a technical stream targeting ≥97.0 % purity (GC area%) and a pharmaceutical-grade stream tightening to ≥99.0 %, with the single largest unspecified impurity held at ≤0.5 %. Water content, determined by Karl Fischer titration in accordance with ASTM E203, is routinely controlled below 500 ppm in pharma‑grade product to suppress hydrolytic degradation to 2‑hydroxy‑5‑methylthiazole. The presence of the 5‑methyl group distinguishes this material from non‑methylated 2‑chlorothiazole, where the lack of electron donation alters the electrophilic aromatic substitution pattern and reduces steric shielding at the 4‑position. Against the 2‑bromo analogue, 2‑chloro‑5‑methylthiazole displays markedly attenuated reactivity in nucleophilic aromatic substitution; the bromide undergoes methoxide displacement approximately 4‑ to 6‑fold faster, a differential that broadens the thermal safety window during pilot‑scale charging sequences.
| Parameter | Method | Technical Grade | Pharma Grade |
|---|---|---|---|
| Assay (GC, area%) | In‑house (DB‑5, 30 m × 0.25 mm) | ≥97.0 % | ≥99.0 % |
| Isomer (2‑chloro‑4‑methylthiazole) | Same GC method | ≤1.5 % | ≤0.3 % |
| Moisture | ASTM E203 (KF coulometric) | ≤1000 ppm | ≤500 ppm |
| Colour (APHA) | ASTM D1209 | ≤150 | ≤50 |
| Non‑volatile residue | ASTM D1353 | ≤0.05 wt% | ≤0.02 wt% |
Process‑scale experience in 2000 L glass‑lined reactors operating under 50–80 mbar absolute pressure demonstrates that batch‑to‑batch variance in purity is dominated by two competing side reactions: acid‑catalysed hydrolysis and thermal dimerisation. When the overhead fractionating temperature during rectification exceeds 110 °C at 50 mbar, a dark polymeric residue forms and deposits on structured packing, reducing tray efficiency and mandating column washout after every four to five batches. This processing window—a ceiling of ±3 °C on the vapour temperature at the top of the packed section—represents the principal throughput bottleneck on existing toll‑manufacturing lines.
Regiochemistry exerts a decisive influence on cross‑coupling performance. In 2‑chloro‑4‑methylthiazole the methyl group resides adjacent to the chlorine, sterically compressing the bond angle at C‑2 and retarding oxidative addition of palladium(0) catalysts. Comparative screening under standard Suzuki–Miyaura conditions using 1.0 mol% Pd(PPh3)4 and phenylboronic acid in toluene/ethanol/water at 80 °C reveals that the half‑life of the 5‑methyl isomer is roughly 2.3 times shorter than that of the 4‑methyl counterpart. Consequently, manufacturers supplying 2‑chloro‑5‑methylthiazole for C–C bond‑forming steps specify a 4‑methyl isomer content ≤0.5 % to avoid irreproducible catalytic induction periods. The specification is enforced by gas chromatography using a polar polyethylene glycol column (30 m, 0.32 mm ID, 0.25 µm film) capable of baseline resolution of the two regioisomers.
The substitution of chloride for bromide alters both kinetics and heat‑release profile. Calorimetric studies on the reaction with diethylamine in acetonitrile at 60 °C show that the bromide derivative reaches full conversion in 1.5 h, generating a peak heat flow of 85 W/kg of reaction mass, whereas the chloro compound requires 7–8 h with a peak heat flow below 20 W/kg. This expanded temporal window allows semi‑batch addition of the nucleophile without invoking the emergency‑relief design basis. In multi‑purpose plants where the condenser and quench systems are rated for a maximum heat evolution of 40 W/kg, 2‑chloro‑5‑methylthiazole is the default electrophile; the bromo analogue is excluded from the process flow sheet unless the vessel is retrofitted with a higher‑capacity reflux condenser. The chloride also reduces the risk of genotoxic alkyl‑bromide carryover, a critical advantage in active‑pharmaceutical‑ingredient synthesis under ICH M7 impurity limits.
In the synthesis of a thiazole‑containing JAK inhibitor, the coupling of 2‑chloro‑5‑methylthiazole with a secondary amine was executed at 100‑kg input scale using toluene as solvent and triethylamine as acid scavenger. The process yielded 94 % isolated product after crystallisation, with residual chloride impurity below 50 ppm as quantified by ion chromatography per USP 〈735〉. The same transformation attempted with 2‑bromo‑5‑methylthiazole under identical conditions produced an exotherm that tripped the reactor interlock at 78 °C, halting addition and generating a partially converted slurry that required quenching and re‑work.
Industrial rectification of crude 2‑chloro‑5‑methylthiazole is performed in a continuous packed column (DN450, 10 m bed height, Sulzer Mellapak 250Y) with a reflux ratio of 4:1. The overhead fraction boiling at 152–154 °C (760 mmHg) is collected as the prime cut; this boiling range shifts to 68–70 °C at 20 mbar when product‑degradation concerns dominate. Differential scanning calorimetry of neat liquid reveals an exothermic decomposition onset near 210 °C, but adiabatic accelerating‑rate calorimetry at φ = 1.03 indicates that the time‑to‑maximum‑rate drops below 24 hours at a jacket temperature of 140 °C. As a consequence, plant operating procedures mandate that the still pot temperature never exceed 120 °C during atmospheric distillation and that the hot residue be immediately cooled with external jacket quenching once the head pressure begins to rise. Published adiabatic stability data specific to 2‑chloro‑5‑methylthiazole is limited; therefore, process safety evaluations during scale‑up rely on a self‑accelerating decomposition temperature determined per UN Test H.4 (BAM oven), which is applied with a conservative 20 °C safety margin.
Agrochemical applications targeting sulfonylurea herbicides exploit the chlorine as a leaving group in nucleophilic substitution with sulfonamide anions. Here, the 5‑methyl substituent increases lipophilicity, thereby improving membrane penetration in target weeds. In a pilot campaign for a thifensulfuron‑methyl analogue, the displacement was conducted in dimethylacetamide at 45 °C using potassium carbonate as base; the reaction reached endpoint after 5 h when monitored by HPLC using a C18 column and an acetonitrile/phosphate buffer mobile phase (USP 〈621〉 equivalent). Yield reproducibility was within ±1.5 % across six consecutive batches, provided the dimethylacetamide was pre‑dried over 4 Å molecular sieves to a water content <100 ppm.
Long‑term stability trials conducted on 200 L HDPE drums with residual heel volumes of 20 % show that the water content of the liquid phase increases from 200 ppm to 1200 ppm over 90 days when the headspace is exposed to ambient air at 60 % relative humidity. The hydrolysis product 2‑hydroxy‑5‑methylthiazole becomes detectable by GC at >0.15 % after 30 days under these conditions, exceeding the pharma‑grade single‑impurity limit. To preserve assay integrity, all containers are nitrogen‑blanketed and fitted with molecular‑sieve breather vents that maintain a dew point below ‑40 °C inside the headspace. In tanker loading operations, the receiving vessel is pre‑dried with hot nitrogen until the effluent dew point is ≤‑30 °C, and the transfer lines are pressure‑tested to 1.5 bar with dry nitrogen before the product is introduced. Incompatibilities with strong bases, primary amines, and oxidizing agents are documented; reaction with sodium hydroxide generates a rapid exotherm accompanied by release of hydrogen chloride gas, necessitating scrubbing through a caustic tower designed for a maximum volumetric off‑gas flow of 50 m³/h.
| Property | 2‑Chloro‑5‑methylthiazole | 2‑Bromo‑5‑methylthiazole | 2‑Chlorothiazole (unsubstituted) |
|---|---|---|---|
| Relative rate with NaOMe (MeOH, 25 °C) | 1.0 (reference) | ~5.2 | ~0.85 |
| Boiling point at 760 mmHg | 152–154 °C | 182–185 °C | 145–147 °C |
| Density at 20 °C (g/mL) | 1.26 | 1.65 | 1.37 |
| Hydrolysis half‑life (pH 7 buffer, 50 °C) | 180 h | 85 h | 210 h |
| Typical commercial purity (pharma grade) | ≥99.0 % | ≥98.5 % | ≥99.0 % |
Differences from 2‑chloro‑5‑ethylthiazole manifest in steric demand during palladium‑catalysed cross‑coupling; the ethyl‑substituted ring shows an induction period extended by 30–45 min in Heck‐type reactions with styrene, as measured by in‑situ ReactIR monitoring of the vinyl C–H wagging band. Additionally, the higher molecular weight ethyl analogue exhibits a flash point (68 °C closed‑cup, ASTM D93) only marginally above that of the methyl derivative (65 °C), yet its vapour pressure is approximately 0.4‑fold lower, reducing VOC emission during reactor charging under sub‑atmospheric make‑up. Operators have noted that both materials produce an identical pale‑yellow hue after prolonged storage above 40 °C unless stabilised with a free‑radical inhibitor such as BHT at 50–100 ppm. That practice is adopted when the product is destined for hot‑climate shipment without temperature‑controlled containers.
