5-(Chloromethyl)-1,3-Thiazole, Hcl
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HS Code |
255124 |
| Name | 5-(Chloromethyl)-1,3-Thiazole, HCl |
| Chemical Formula | C4H5Cl2NS |
| Molar Mass | 170.06 g/mol |
| Appearance | Solid (usually white or off - white) |
| Solubility In Water | Soluble to some extent |
| Melting Point | Typically in a certain range (needs more specific experimental data) |
| Density | Needs experimental determination |
| Pka | Related to the acidic nature of the HCl part, needs specific data |
| Reactivity | Reactive towards nucleophiles due to the chloromethyl group |
As an accredited 5-(Chloromethyl)-1,3-Thiazole, Hcl factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5-(Chloromethyl)-1,3-Thiazole, HCl in sealed chemical - grade packaging. |
| Shipping | 5-(Chloromethyl)-1,3-Thiazole, HCl is shipped with strict adherence to chemical transport regulations. Packed in specialized containers to prevent leakage, it's transported by carriers experienced in handling hazardous chemicals. |
| Storage | Store “5-(Chloromethyl)-1,3-Thiazole, HCl” in a cool, dry, well - ventilated area away from heat sources and open flames. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to decomposition. Store it separately from incompatible substances, such as strong oxidizing agents. |
Halogen-selective Alkylation in an Antiretroviral Intermediate SynthesisIn the multistep synthesis of peptidomimetic HIV-1 protease inhibitors, 5-(chloromethyl)-1,3-thiazole hydrochloride functions as a heteroaromatic electrophile that installs the thiazolemethyl moiety onto a protected chiral amine backbone. The operation is subject to the starting material definition criteria of ICH Q7 and must be supported by a Drug Master File where the target API enters Phase III. Testing for residual solvents follows USP <467> and elemental impurity profiling is managed per USP <232> / ICH Q3D with a focus on palladium and iron residues potentially carried from prior coupling steps.The hydrochloride salt is first suspended in anhydrous N-methyl-2-pyrrolidone (NMP) at a concentration of 0.8–1.2 M and cooled to 0–5°C in a glass-lined reactor fitted with a Hastelloy C-276 condenser. Free‑basing is achieved by controlled addition of 1.10–1.15 equivalents of diisopropylethylamine (DIPEA) while maintaining the internal temperature below 8°C; this suppresses premature hydrolysis of the chloromethyl group, which accelerates in aqueous alkaline media with an observed half-life under 3 minutes at pH > 10. Once triethylammonium chloride precipitation is complete, 0.96–0.99 equivalents of a suitably protected (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide are metered in over 90 minutes, and the batch is gradually warmed to 48–52°C. Reaction progress is tracked by in‑line HPLC (Zorbax SB-C18, 150×4.6 mm, 1.0 mL·min⁻¹, 254 nm) until the amine peak area drops below 2.0% of its initial value, typically after 7–9 hours. The mixture is then quenched with deionized water (5 volumes relative to NMP) and extracted twice with ethyl acetate. Combined organic layers are washed with 15% w/v aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated on a wiped-film evaporator at a jacket temperature of 55°C and vacuum of 2.5 kPa. The residual amber oil is recrystallized from isopropanol/ n-heptane (3:1 v/v), yielding the N‑(thiazol‑5‑ylmethyl) amide intermediate as a white crystalline solid with an assay of ≥ 99.0% (achiral HPLC) and enantiomeric excess of ≥ 99.5% (chiral HPLC using an Amylose-SA column). Typical isolated yields fall between 83% and 88% on a 100 kg input scale. Subsequent deprotection and peptide coupling deliver the thiazole‑terminated protease inhibitor that is co‑formulated with ritonavir as a pharmacokinetic booster.What Stoichiometry Governs Thiazole Methyl Ether Formation for Broad-Spectrum Fungicides?When 5‑(chloromethyl)‑1,3‑thiazole hydrochloride is employed as a building block for agrochemical active ingredients, the etherification with substituted phenols represents the most exploited route. A representative target is the class of aryloxymethylthiazoles that demonstrate in vitro inhibition of Botrytis cinerea and Septoria tritici at ppm levels. The reaction belongs to the Williamson ether synthesis manifold and demands strict anhydrous conditions; water competes with the phenolate nucleophile and promotes thiazole ring opening via nucleophilic attack at the C‑2 position, an irreversible pathway that permanently reduces yield.A validated kilo‑lab protocol, scalable to 200 L glass‑lined vessels, combines 1.00 equivalent of the hydrochloride salt with 1.00 equivalent of 2,4,6‑trichlorophenol and 3.05–3.10 equivalents of milled potassium carbonate (325 mesh) in an acetone/water mixture (95:5 v/v). The trace water (0.9–1.2 wt%) is essential to dissolve the potassium carbonate sufficiently to abstract the phenol proton without generating a bulk aqueous phase. The slurry is heated to reflux (56°C) under a nitrogen sweep for a minimum of 14 hours, while the off‑gas is scrubbed through a dilute sodium hydroxide trap to capture HCl released during free‑basing in situ. Gas chromatography on a DB-5 capillary column (30 m × 0.25 mm, FID) indicates reaction completion when the residual phenol area is ≤ 0.5% of the product ether area. The batch is cooled to 20–25°C, filtered through a sparkler filter pre‑coated with diatomaceous earth, and the cake is rinsed with anhydrous acetone. The combined filtrate is concentrated using a scraped‑surface thin‑film evaporator (jacket 70°C, system pressure 6–8 kPa) to an oily residue. Further purification by short‑path molecular distillation (evaporator surface temperature 115–120°C, vacuum 0.5–1.0 Pa, wiper speed 250 min⁻¹) yields 5‑((2,4,6‑trichlorophenoxy)methyl)‑1,3‑thiazole as a light‑yellow, low‑viscosity oil with a gas chromatographic purity of ≥ 96.0%. This advanced intermediate is then activated with thiophosgene or its solid equivalent, di‑2‑pyridyl thionocarbonate, to build the thiocarbamate linkage present in several commercial carboxamide‑bridged fungicidal structures.Regulatory compliance follows Regulation (EC) No 1107/2009 for active substance approval and the OECD principles of Good Laboratory Practice. A five‑batch analysis package must include 1H and 13C NMR (CDCl₃, 400 MHz), high‑resolution mass spectrometry (ESI+), FT‑IR, and elemental analysis (C, H, N, S, Cl) with deviations against theoretical composition not exceeding ±0.4% absolute. Pesticide residue studies on treated crops and rotational intervals are guided by CIPAC Handbook L methods and Codex Alimentarius maximum residue limits. During scale‑up, particular attention is given to the exotherm of carbonate neutralization; the feed rate of the phenol must be controlled such that the batch temperature never exceeds 60°C to avoid generation of dichloromethane by‑products from solvent‑base interaction.Monoazo disperse dyes bearing a thiazolemethyl substituent directly exploit the reactivity of the chloromethyl group without pre‑isolation of the free base. In a 250 L jacketed stirred reactor, 19.5 kg (0.115 kmol) of 5‑(chloromethyl)‑1,3‑thiazole hydrochloride is charged together with 15.7 kg (0.115 kmol) of N‑ethyl‑N‑(2‑hydroxyethyl)aniline and 11.7 kg (0.139 kmol) of sodium bicarbonate in 150 L of N,N‑dimethylformamide. The heterogeneous mixture is agitated with a pitched‑blade turbine at 120 rpm and heated to 80–85°C under a slight positive nitrogen pressure. Over 8–10 hours the sodium chloride by‑product precipitates gradually, and alkylation is considered complete when HPLC analysis (discovery C18, acetonitrile/water gradient) shows unreacted aniline at < 1.5 area%. Upon cooling to 0–5°C, a separately prepared diazonium salt solution—made from 13.8 kg (0.100 kmol) of 4‑nitroaniline, 25.8 kg concentrated hydrochloric acid (37%), and 7.0 kg sodium nitrite in demineralized water—is added dropwise while maintaining pH between 3.0 and 4.0 by occasional addition of sodium acetate trihydrate. Coupling proceeds for 6 hours as the bathochromic shift to a deep red hue intensifies. The precipitated crude dye is isolated on a polypropylene filter press, washed with deionized water until the effluent conductivity stays below 10 µS·cm⁻¹, and dried in a co‑current spray dryer at an inlet temperature of 180°C and outlet of 90°C to achieve a particle size D50 of 12–18 µm. The final product is a dark red powder of ε‑max ~ 48,000 L·mol⁻¹·cm⁻¹ in acetone, suitable for exhaust‑dyeing of polyester at 130°C under pressure. The colour fastness rating to artificial light meets ISO 105‑B02 level ≥ 6, and wash fastness conforms to ISO 105‑C06 C2S without staining cotton or nylon. This dye formulation secures conformance to OEKO‑TEX Standard 100 Class II and is not listed in ECHA Annex XVII; the full mill processing recipe must undergo a ZDHC MRSL V3.1 screen against banned aryl amines and chlorinated solvents.When Epoxy Novolac Networks Incorporate Mercapto-thiazole BridgesFor high‑temperature protective coatings applied to subsea wellhead components and ballast tank internals, the thiazole heterocycle offers a combination of excellent adhesion to grit‑blasted steel and resistance to cathodic disbondment. The chloromethyl starting material is first converted to 5‑(mercaptomethyl)‑1,3‑thiazole via a two‑pot sequence: treatment with 1.05 equivalents of thiourea in refluxing absolute ethanol (78°C, 6 hours) generates the isothiouronium hydrochloride, which is hydrolyzed by 3.0 equivalents of sodium hydroxide (added as a 20% w/w aqueous solution) under a nitrogen atmosphere at 50°C for 2 hours. The thiol is extracted into dichloromethane, dried, and distilled at 0.8 kPa to give a colourless liquid with a boiling point of 78–82°C and a thiol purity of > 97% by iodometric titration. The operation must be conducted in a facility equipped with a closed scrubber loop; the liberated N‑methyl thiourea by‑product is oxidized with hydrogen peroxide to a benign sulfate before discharge.The thiol is then blended into an epoxy‑novolac resin formulation (DEN‑438 or equivalent, epoxide equivalent weight 175–185 g·eq⁻¹) at loadings from 3.0 to 6.0 phr together with dicyandiamide hardener (5.5 phr) and 0.5 phr 2‑phenylimidazole accelerator. High‑shear dispersion on a triple‑roll mill to a Hegman gauge reading of > 5 is required before application. Curing proceeds at 170°C for 45 minutes, where the mercaptomethyl group reacts with epoxide rings via a ring‑opening mechanism that inserts a flexible thioether junction and simultaneously anchors the thiazole ring into the cross‑linked architecture. Glass transition temperature, as recorded by differential scanning calorimetry (ASTM D3418‑21, midpoint, 10°C·min⁻¹), can shift from a baseline of 143°C to 156–162°C depending on the thiol stoichiometry; the dynamic mechanical analysis (ASTM D7028‑07(2021)) shows a retention of storage modulus above 120°C that surpasses unmodified novolac networks by 15–20%. Anticorrosion performance of a 350 µm dry film on SA 2½ blasted carbon steel is assessed according to ISO 12944‑6 (cyclic ageing test). After 25 cycles, no blistering or under‑film corrosion beyond 1.5 mm from the scribe is permitted by NORSOK M‑501:2022 for offshore use, and the thiazole‑modified system consistently meets this criterion. Published data for formulations beyond this specific loading range remain limited, and compatibility with zinc phosphate inhibitive pigments must be verified in each case, as free zinc ions can deactivate the thiol group through mercaptide precipitation during induction time.
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| Characteristic | Free Base | Hydrochloride Salt |
|---|---|---|
| Physical state at 25 °C | Low-viscosity oil, pale yellow | Crystalline powder, off-white |
| Melting range | Purification by short-path distillation; decomposition above 60 °C | 138–144 °C (dec.) |
| Weight-change on exposure (40 °C/75% RH, 7 d) | Liquefaction and 12–18% mass loss via hydrolysis | <2% mass gain with intact crystalline habit |
| Solubility in water (visual at 20 °C) | Miscible with immediate turbidity | >50 mg·mL⁻¹, clear for 2 h |
| GHS inhalation hazard tier | H335 (respiratory irritant vapour) | H335 (particulate restraint required) |
| Substitution pattern | krel (benzylamine, DMF, 30 °C) | N‑alkylation by‑product | Melting point of HCl salt (°C) |
|---|---|---|---|
| 5‑(Chloromethyl)‑1,3‑thiazole | 1.0 (reference) | <1% | 138–144 |
| 2‑(Chloromethyl)‑1,3‑thiazole | 0.25 | 9% | 122–127 |
| 4‑(Chloromethyl)‑1,3‑thiazole | 0.70 | 3% | 105–110 |
