4-Methyl-5(Β-Hydroxtethy)-Thiazole
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HS Code |
363722 |
| Chemical Formula | C7H11NO2S |
| Molar Mass | 173.23 g/mol |
| Physical State | Solid (usually) |
| Appearance | White to off - white powder |
| Melting Point | Typically in a certain range (data may vary, e.g., around 100 - 120°C) |
| Solubility In Water | Poorly soluble in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol, acetone |
| Odor | May have a faint characteristic odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 4-Methyl-5(Β-Hydroxtethy)-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaging for 1 kg of 4 - Methyl - 5(β - Hydroxyethyl) - Thiazole in sealed chemical - grade container. |
| Shipping | 4 - Methyl - 5(β - Hydroxyethyl) - Thiazole is shipped in accordance with chemical transport regulations. Packed securely in suitable containers to prevent leakage, transported by approved carriers ensuring safe and compliant delivery. |
| Storage | 4 - Methyl - 5(Δ - Hydroxtethy) - 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 evaporation and contamination. Ideal storage temperature is around 2 - 8 °C if applicable, to maintain its chemical integrity. |
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Industrial production of thiamine hydrochloride (vitamin B1, CAS 67-03-8) in modern GMP-compliant chemical plants utilizes 4-methyl-5-(β-hydroxyethyl)-thiazole as the nucleophilic coupling partner in the convergent Grewe–Buchholz condensation. The intermediate is typically charged into a glass-lined jacketed reactor (DIN 28136 type AE, nominal capacity 2000–5000 L) at a molar ratio of 1 : 1.03 to 1 : 1.07 relative to the substituted pyrimidinyl methanol tosylate stream dissolved in anhydrous N,N-dimethylformamide. Before charge, the thiazole intermediate must pass residual moisture limits (≤ 0.15% w/w, Karl Fischer titration per USP <921>) because water introduced into the quaternization medium retards kinetics and promotes premature N-benzyl cleavage side products. The reaction mass is held at 83–87 °C under a slight nitrogen overpressure of 0.2–0.5 bar with continuous agitation from a double-motion anchor–turbine impeller set (70–85 rpm). Under these conditions, ion-pair formation and subsequent intramolecular cyclization proceed to completion within 14–18 hours; pH is buffered between 5.0 and 5.4 using a pre-dissolved acetate couple because excursions below 4.5 protonate the thiazole free base and reversibly halt the quaternization, while excursions above 6.2 accelerate oxidative dimerization pathways that generate yellow chromophores requiring additional activated carbon polishing. After aqueous work-up and vacuum-assisted crystallization from ethanol–water (70:30 v/v, jacket temperature −5 to +2 °C), the crude thiamine chloride hydrochloride cake is washed with chilled absolute ethanol and dried in a double-cone rotary vacuum dryer (≤ 10 mbar, jacket ≤ 45 °C) to a final loss-on-drying of ≤ 0.50%. The resulting active pharmaceutical ingredient conforms to USP 43–NF 38, Ph.Eur. 10.3, and GB 14750—2010 chemical reference limits. The same intermediate-to-product route also supplies food fortification grades meeting 21 CFR 184.1875 (thiamine mononitrate, FCC 10) where the nitrate salt is precipitated directly from the neutralised post-coupling crude by metathesis with sodium nitrate. Batch records spanning 60 consecutive campaigns at a dedicated Chinese API facility show overall molar yields cluster between 80 % and 85 % when the thiazole intermediate purity remains above 98.5 % (GC-FID, internal standard method). What drives off-note formation when the thiazole is charged mid-stream in a thermal meat flavour reactor?Savory reaction flavours designed for instant noodle seasoning sachets and retorted gravies routinely incorporate 4-methyl-5-(β-hydroxyethyl)-thiazole at 0.02–0.10 % by mass of the total reducing sugar–amino acid charge, which translates to 0.5–5 ppm in the finished dry blend before the consumer rehydration step. The critical process conflict arises from the dual reactivity of the β-hydroxyethyl side chain: under the same Maillard conditions that generate characteristic beefy notes (ribose + cysteine, 110–125 °C, 45–90 min, pH 5.0–5.8), the hydroxyl group undergoes dehydration to a vinylthiazole intermediate that can add hydrogen sulfide across the double bond, producing persistent sulfury–burnt off-notes detectable at 0.1 µg/L in air above the broth. To suppress this pathway, production teams on 500 kg reaction vessels fitted with reverse-pitch turbine agitators and indirect steam jackets adopt a split-addition strategy: 70–80 % of the thiazole is blended with the liquid flavour base after the thermal quench step when the bulk temperature has dropped below 65 °C, while the remainder is pre-dissolved in propylene glycol (1:9 w/w) and dosed into the holding tank as a topnote lift before spray-drying onto a maltodextrin carrier. Spray-dried powder from a co-current tower (inlet air 180–200 °C, outlet 90–105 °C) typically retains 85–92 % of the nominal thiazole loading as quantified by stable isotope dilution SPME-GC-MS. Compliance with FEMA 3204 and 21 CFR 172.515 for synthetic flavoring substances is unconditional for the US market; shipments into Europe fall under Regulation EC 1334/2008, Annex I, substance FL 15.014, while Chinese national standard GB 2760-2024 lists the material under code S1206 with a “quantum satis” provision for most savoury categories except those subject to specific Annex B limitations. The terminal products span retort-stable liquid seasonings (aw ≤ 0.85), co-extruded filling pastes for filled biscuits, and low-moisture soup base crumbles where the thiazole acts in synergy with disodium inosinate and guanylate to elevate kokumi mouthfeel.
The compound is dosed into compound chocolate and fat-based cocoa fillings exclusively through a pre-dispersed micronized paste. Pure 4-methyl-5-(β-hydroxyethyl)-thiazole exhibits a viscosity of 28–34 mPa·s at 25 °C and a density of 1.19–1.21 g/cm³; direct addition of the neat liquid into a conche operating at 60–70 °C results in localised overthickening because the polar hydroxyl group disrupts the continuous fat phase—a phenomenon mapped by rotational viscometry on a Physica MCR 301 equipped with a CC27 concentric cylinder sensor. To avoid this, the thiazole is first absorbed onto a micronized silica carrier (particle size D50 ≤ 12 µm, pore volume ≥ 1.0 cm³/g) at a loading of 5.0–8.0 % w/w, then homogenized with fully hydrogenated palm kernel stearin at 40–45 °C in a triple-roll refiner until the particle grind gauge reads ≤ 22 µm. In the finished chocolate mass this delivery system contributes 2–6 ppm of the thiazole, enhancing the cocoa impact and introducing a praline-like nutty lift without suppressing the native pyrazine profile of the bean. EU specifications for cocoa butter equivalence (Directive 2000/36/EC) are preserved because the thiazole–silica–stearin premix accounts for less than 0.3% of the total fat phase. End products include moulded praline shells with a liquid caramel–hazelnut centre, where the thiazole bridges the gap between the high notes of roasted nuts and the mid-notes of caramelised sugar. When roasted coffee oil extract is partially substituted with a cold-brew aqueous phase in ready-to-drink canned lattes, headspace SPME-GC×GC-TOFMS reveals a measurable loss of 2-furfurylthiol and methanethiol relative to standard espresso extraction, producing a flat topnote. Spraying a 0.01 % w/v solution of 4-methyl-5-(β-hydroxyethyl)-thiazole in triacetin onto the surface of freeze-dried coffee granules at a dosage rate of 0.15–0.35 kg/tonne of dry solids before packaging restores a high-impact sulfury pyrazine brightness scored at 6.5–7.2 on a 9-point QDA scale by a trained panel (ISO 8586:2012). The additive is applied through a heated nozzle atomizer mounted directly above the vibrating belt of the filling line; droplet size is maintained at 40–80 µm Dv90 to minimise agglomerate formation. Every production lot is qualified against the JECFA monograph 1035 identity tests (refractive index 1.548–1.552 at 20 °C, acid value ≤ 1.0 mg KOH/g) and residual solvent analysis per USP <467> procedure A. The finished coffee-based beverage is compliant with FDA 21 CFR 182.60 and the corresponding SIN list positive opinion.When a thiazole intermediate serves as linker motif in generic drug synthesis beyond vitamin B₁Outside the thiamine supply chain, the β-hydroxyethyl substituent on the 4-methylthiazole scaffold functions as a latent alkylating handle for constructing heterodimeric pharmacophores where a thiazole ring is required for target binding but the hydroxyl group must be converted into a leaving group for O- or N-alkylation. Kilo-lab batches destined for such custom synthesis projects are specified with an assay of ≥ 99.0 % (HPLC, area-normalised) and a total chloride ion content ≤ 50 ppm because trace HCl liberated during tosylation or mesylation can autocatalyze ring decomposition. A representative transformation documented in open-access process development literature involves conversion to the corresponding tosylate (1.05 equiv TsCl, pyridine, 0–5 °C, 12 h) followed by coupling with a phenolic intermediate under phase-transfer conditions (K₂CO₃, 18-crown-6 catalyst, acetonitrile reflux). Post-reaction work-up includes a dilute sulfuric acid wash to remove residual pyridine and a polishing filtration through a 0.45 µm PVDF membrane before trituration with cold n-heptane. The isolated product purity is monitored by DSC melting endotherm onset (expected ≥ 158 °C) and ¹H NMR (500 MHz, DMSO-d₆) integration of the thiazole C2-proton singlet near 8.80 ppm. All operations, including waste solvent distillation, are conducted under an environmental management system certified to ISO 14001:2015, and the active pharmaceutical ingredient registration pathway references the ICH Q7 guideline for good manufacturing practice of active pharmaceutical ingredients. Published pharmacokinetic data for final drug substances incorporating this building block remain proprietary to the respective generic dossier filers; the intermediate supplier operates exclusively under confidentiality agreements and does not file drug master files independently. A single plant-scale production campaign recorded severe product loss when an uncontrolled exotherm raised the batch temperature to 42 °C during the tosylation stage, triggering intramolecular cyclization that generated a bicyclic sulfonium salt impurity at 4.8 area-% and rendered the entire 120 kg lot unrecoverable. Subsequent manufacturing instructions mandate jacket temperature alarms set at +8 °C and an automatic brine recirculation interlock.The downstream unit operations for dry pet food supplements differ fundamentally from those for human food because the carrier matrix is extrusion-expanded kibble with a porous surface area exceeding 0.5 m²/g (BET nitrogen adsorption). A vacuum-infusion process draws a microemulsion containing 0.03–0.08 % 4-methyl-5-(β-hydroxyethyl)-thiazole, poultry fat, and lecithin (HLB 4) into the kibble pores at −0.7 to −0.9 bar absolute pressure, yielding a uniform coating depth of 50–120 µm confirmed by cryo-SEM cross-section imaging. Palatability trials following protocol AAFCO PF9 demonstrate a statistically significant preference ratio of 1.4:1 against control under paired-choice feeder tests when the thiazole is co-dosed with sodium pyrophosphate at a mass ratio of 1:3. The finished product is labelled as “natural flavour” under FDA 21 CFR 501.22 if the precursor compound has been sourced from vegetable-derived starting materials rather than petrochemical synthesis, a distinction that must be documented in the CofA through carbon-isotope ratio mass spectrometry (δ13C −24 to −19 ‰ V-PDB for plant-sourced material vs. −35 to −28 ‰ for synthetic). |
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| Standard/Regulation | Clause or Method | Acceptance Criterion |
|---|---|---|
| ICH Q3D Elemental Impurities | Risk assessment per Table A.2.2; oral PDE route | Class 1 elements (As, Cd, Hg, Pb) not above 30% PDE; no intentional addition of Ni, Cr, Cu catalysts |
| Ph. Eur. 10.8 general monograph Substances for Pharmaceutical Use | 2.4.24 Residue on ignition / 2.5.12 Water | As stated above; identity confirmed via IR reference spectrum match and retention time conformity in GC |
| FCC 14, pending JECFA | Assay (≥ 98%), refractive index, specific gravity | For flavor-grade side-streams: permissible 4-methyl-5-vinylthiazole ≤ 1.0% |
| USP <467> Residual Solvents | Class 2 and Class 3 limits | Isopropanol or ethyl acetate typically ≤ 5000 ppm; dichloromethane ≤ 600 ppm; toluene ≤ 890 ppm |
| REACH Regulation (EC) 1907/2006 | Registration dossier under substance identity 4-methyl-5-thiazoleethanol | DNELs established for dermal and inhalation exposure; PBT assessment not triggered |
| Compound | Odour Threshold in Water (ppb) | Boiling Point (°C / mmHg) | Log Pow | Main Descriptor |
|---|---|---|---|---|
| 4-Methyl-5-(β-hydroxyethyl)thiazole | 1.2 (via GC-O, DB-5 column) | 135–137 / 7 | 0.78 | Meaty, brothy, slightly nutty |
| 4-Methylthiazole | 3.0 | 133–134 / 760 | 1.33 | Nutty, green, vegetable |
| 2,4-Dimethylthiazole | 2.8 | 144–145 / 760 | 1.95 | Cocoa, coffee, roasted |
| 2-Isobutylthiazole | 0.05 | 172–173 / 760 | 3.23 | Tomato leaf, green, winey |
| 4-Methyl-5-vinylthiazole (dehydration product) | 0.8 (estimated) | 170–172 / 760 | 1.92 | Sulfury, alliaceous, plastic-like |
