4-Hydroxymethylthiazole
|
HS Code |
440541 |
| Chemical Formula | C4H5NOS |
| Molar Mass | 115.154 g/mol |
| Appearance | Solid (Typical description, may vary) |
| Melting Point | Data may vary depending on purity |
| Boiling Point | Data may vary depending on purity |
| Solubility In Water | Limited solubility expected (Based on structure) |
| Solubility In Organic Solvents | Soluble in some organic solvents (e.g., ethanol, acetone - general expectation) |
| Odor | May have a characteristic sulfur - containing compound odor |
| Density | Data may vary depending on conditions |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 4-Hydroxymethylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 4 - Hydroxymethylthiazole packaged in a sealed, chemical - resistant container. |
| Shipping | 4 - Hydroxymethylthiazole is shipped in well - sealed, corrosion - resistant containers. Packaging adheres to strict chemical transport regulations. Shipment is carefully monitored to ensure stability and prevent leakage during transit. |
| Storage | 4 - Hydroxymethylthiazole 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 moisture absorption and evaporation. Store separately from oxidizing agents and incompatible substances to avoid potential chemical reactions. |
| When 4-Hydroxymethylthiazole Enters the Cephalosporin Side-Chain Supply ChainThe synthesis of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (ATMA) and its active esters—the indispensable C-3 side-chain fragments for third-generation cephalosporins—depends on a tightly controlled sequence beginning with 4-hydroxymethylthiazole. Plant-scale operations documented at dedicated ATMA facilities highlight that the chlorination of 4-hydroxymethylthiazole with thionyl chloride in dichloromethane exhibits a pronounced thermal runaway risk when the jacket temperature deviates from the -8 °C to +2 °C window; exotherm onset can spike by as much as 92 W·kg⁻¹ within 45 seconds if the 1.18±0.02 molar equivalent addition of SOCl₂ proceeds at a mass flow exceeding 0.35 kg·min⁻¹ per 100 kg batch. The resulting 4-chloromethylthiazole hydrochloride must be immediately converted with hexamethylenetetramine in absolute ethanol at pH 7.8–8.2 to suppress the formation of bis-thiazolyl methane dimer, a genotoxic impurity restricted to ≤0.08% by the Ph. Eur. monograph for cefotaxime sodium related substances (Method B). Subsequent oximation with methoxyamine hydrochloride and final saponification to the free acid employ glass-lined reactors with anchor-type agitators, where the crystalline ATMA sediment—predominantly the syn-isomer—is isolated via a decanter centrifuge operating at a bowl speed of 3400 rpm. Residual solvent specifications enforce ICH Q3C options 1 and 2, with dichloromethane content held below 60 ppm and 1,4-dioxane below 380 ppm, demanding double-pass vacuum stripping at 38−42 °C and 15 mbar. The terminal products manufactured from this intermediate include cefotaxime sodium (USP reference standard lot release assays confirm ≥99.0% purity by HPLC with UV detection at 235 nm) and ceftriaxone disodium, where the solubility-dependent coupling yield in the final acylation step is influenced by the ATMA active-ester particle size distribution, held to D90 ≤ 45 µm through air-jet milling.In the production of oral and topical thiabendazole formulations meeting USP and FDA human antiparasitic monographs, the oxidative conversion of 4-hydroxymethylthiazole to thiazole-4-carboxylic acid constitutes the quality-defining step. Multi-batch historical data from 3,000 L stainless-steel jacketed reactors show that the dropwise addition of aqueous potassium permanganate (2.25±0.05 molar equivalents, dissolved to 9% w/v) into an alkaline solution of 4-hydroxymethylthiazole maintained at 0−4 °C generates a manganese dioxide slurry whose filtration resistance index (α) exceeds 5.2×10¹¹ m·kg⁻¹ unless the permanganate feed is accompanied by a finely dispersed air sparge to convert the MnO₂ precipitate into a more permeable agglomerated form. The wet cake of thiazole-4-carboxylic acid, after reslurry washing with deionized water until the filtrate conductivity drops below 15 μS·cm⁻¹, is charged directly into a polyphosphoric acid-mediated cyclocondensation with o-phenylenediamine in a 1:1.02 molar ratio. This melt-phase process, ramped from 120 °C to 158 °C over 2.5 hours inside a Hastelloy C-276 vessel, is terminated when the residual 4-hydroxymethylthiazole-derived intermediates reach <0.15% area by GC-FID. The crude thiabendazole base is dissolved in ethyl acetate, treated with activated carbon of iodine number ≥950 mg·g⁻¹, and crystallized by controlled cooling at 0.3 °C·min⁻¹ to obtain the polymorphic Form A, which exhibits a melting endotherm onset of 304−306 °C by DSC and meets the heavy metals limit of <10 ppm as required by USP Monograph for Thiabendazole. Finished dosage forms—chewable tablets containing 500 mg thiabendazole and scored to quarter-dose increments—require the active ingredient’s angle of repose to fall within 28−32° for reproducible gravity-feed die filling, a parameter routinely controlled through the preceding crystallization trajectory.Post-Harvest Citrus Fungicide Manufacturing and EPA 40 CFR 180.242 TolerancesWhen operated as a technical-grade agrochemical intermediate, the same oxidative sequence is re-engineered for cost efficiency and throughput, yet the tolerance thresholds governing the final residue remain rigidly defined by 40 CFR 180.242, which sets an action level of 10 ppm thiabendazole in or on citrus fruits and a pre-harvest interval of one day for wax-coated application. The permanganate oxidation step tolerates a reduced reagent ratio of 2.02 molar equivalents in the presence of tetrabutylammonium bromide at 0.06 molar equivalents as a phase-transfer catalyst, and the reaction endpoint is trimmed to a residual 4-hydroxymethylthiazole of <0.5% because subsequent neutralization to pH 3.8–4.2 with sulfuric acid precipitates the target acid while leaving unreacted diol-like impurities predominantly in the aqueous mother liquor. Condensation with o-phenylenediamine shifts to a continuous thin-film evaporator unit: the pre-heated melt (165 °C) flows across a wiped-film surface maintained at 4−6 mbar vacuum to strip excess diamine, which is condensed and recycled, while the crude thiabendazole emerges as a vitreous ribbon that solidifies on a chilled belt flaker. If the film evaporator’s internal wall temperature exceeds 195 °C, diamino-complex tar formation escalates and produces char particles ≥50 µm that subsequently fail the wet sieve test (≥98% through 45 µm) required by FAO Specification 462/TC. The technical-grade thiabendazole is re-pulped in methanol, neutralised with anhydrous ammonia, and vacuum-dried to a loss on drying of <0.5% before being micronised in a fluidised-bed opposed-jet mill to yield an air-swept particle cut with D50 ≤ 8 µm. This micronisation step underpins the suspension stability of the 42% flowable concentrate commercial formulation: a 2-hour viscosity profile of 480–720 mPa·s at 20 s⁻¹ (Brookfield LV, spindle #3) ensures the active ingredient remains suspended without hard-packing during storage in HDPE containers at isothermal 54 °C for 14 days, as stipulated in CIPAC MT 46.3.In the production of FEMA 3716 4-methylthiazole intended for roasted nut and cocoa flavour formulations, 4-hydroxymethylthiazole undergoes a liquid-phase catalytic hydrogenolysis that demands rigorous upstream desulfurization of the raw material because even trace quantities of cyclic thioesters—detectable by GC-SCD at a method detection limit of 0.05 mg·kg⁻¹—act as potent poisons for the 5% palladium-on-carbon catalyst (Johnson Matthey type 39 or equivalent). The industrial batch protocol charges ethanol (denatured with 0.5% methyl ethyl ketone to avoid the excise regulatory burden) together with the substrate at a mass ratio of 9:1 solvent-to-thiazole, and the Pd/C loading is fixed at 4.8% w/w relative to the substrate, resulting in a total reactor fill of approximately 65% of the autoclave free volume to accommodate hydrogen uptake. Hydrogen pressure is held at 0.55 MPa with a sparging rate of 0.3 vvm, and the reaction temperature is maintained at 48±2 °C by circulating tempered water through the internal coil; deviations above 55 °C accelerate ring hydrogenation of the thiazole nucleus, producing 4-methylthiazolidine as an off-flavour contaminant that imparts a detectable sulfury-grassy note at as low as 15 ppb in the final food matrix. After filtration through a 0.5 µm sintered metal candle filter to recover the catalyst for re-use (activity typically drops below 60% conversion after 12–14 cycles), the ethanolic filtrate is rectified in a structured-packing column of 15 theoretical stages under a reflux ratio of 8:1 at 150 mbar head pressure. The heart cut collected between 71 and 73 °C yields 4-methylthiazole of ≥99.4% GC purity, meeting the EU Flavouring Regulation 1334/2008 minimum assay for natural-identical substances and containing less than 0.02% residual 4-hydroxymethylthiazole, verified by GC-MS in selected ion monitoring mode at m/z 115. This distillate is diluted in triacetin carrier to a 10% stock solution for direct incorporation into compounded liquid flavours, where its characteristic roasted-coffee impact is quantified at usage levels of 0.25–0.8 mg·kg⁻¹ in the final food product.What Specific Oxidation Conditions Preserve the Aldehyde Functionality for MOF Ligand Synthesis?The Dess–Martin periodinane-mediated oxidation of 4-hydroxymethylthiazole to thiazole-4-carboxaldehyde for subsequent use as a nitrogen/oxygen-donor building block in porous coordination networks operates under a strict anhydrous threshold because the aldehyde hydrate form, thiazole-4-methanediol, precipitates as a waxy hemi-acetal oligomer when the water activity exceeds 0.12. Within a reinforced Schlenk-type reactor that has been oven-dried at 140 °C for at least 6 hours and purged with argon certified to 99.999% volume purity, the starting material is dissolved in anhydrous dichloromethane (peroxide value <1 mg·L⁻¹) to a concentration of 0.48 M, then the Dess–Martin reagent is added in a single portion at 1.14 molar equivalents, producing a gentle evolution of acetic acid vapour that is trapped in a downstream potassium carbonate scrubber. Agitation at 250 rpm under 22 °C jacket control proceeds for 95–110 minutes, monitored by inline ReactIR at the carbonyl absorbance region 1712 cm⁻¹; the signal plateaus when the substrate conversion exceeds 99.5%, at which point the reaction is quenched by adding a 1.2 M sodium thiosulfate solution at a volume equal to the batch. After phase separation through a PTFE membrane, the organic layer is passed over a short silica gel column (pore size 60 Å, particle size 40–63 µm) eluted with 3:1 hexane–ethyl acetate, and the solvent swap is conducted using a rotary evaporator at 28 °C bath temperature to prevent aldehyde self-condensation. The resulting pale-yellow oil is distilled under high vacuum (10⁻² mbar) with a short-path apparatus where the vapour temperature stabilises at 68–72 °C; the recovered thiazole-4-carboxaldehyde, required to have peroxide content <0.01 mmol·kg⁻¹ by iodometric titration, is ampouled under argon flame-seal to satisfy REACH Annex II extended safety data sheet storage class 10 (flammable liquids). Downstream, this aldehyde serves as the electrophilic anchor for condensation with 2-aminobenzenethiol derivatives to yield benzothiazole-2-arylthiazole ligands that coordinate copper(II) nodes in metal–organic frameworks exhibiting a BET surface area of >1,200 m²·g⁻¹ (determined by ISO 9277:2022 nitrogen adsorption at 77 K), applied in post-combustion carbon dioxide capture modules operating at 0.15 bar partial pressure with a working capacity of 1.9 mmol·g⁻¹. |
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4-Hydroxymethylthiazole (CAS 7038-15-5, molecular formula C₄H₅NOS, molecular weight 115.15 g/mol) is a heterocyclic intermediate supplied as a colourless to pale yellow liquid. The commercial product typically carries a purity specification of ≥98.0% by GC-FID area percent, with water content limited to ≤0.50% by Karl Fischer titration conforming to USP <921>. Its primary structural feature—a primary alcohol pendant on the 4-position of the thiazole ring—enables controlled functionalisation via esterification, oxidation to the aldehyde, or conversion to a halide, distinguishing it from methyl-, amino-, or halogen-substituted thiazoles that lack a comparable leaving-group handle.
Commercial supplies intended for pharmaceutical intermediate applications require tight control of structurally related impurities. A typical certificate of analysis assigns individual unspecified impurity limits of ≤0.10% by HPLC (UV detection at 254 nm, C18 column, acetonitrile/phosphate buffer mobile phase). The most commonly observed critical impurity is thiazole-4-carboxaldehyde, generated via alcohol over-oxidation; its ceiling is routinely set at ≤0.50%. Residual solvents are monitored against ICH Q3C guidance, with headspace GC-MS quantification of methylene chloride and ethyl acetate, whose permitted daily exposures translate to concentration limits of ≤600 ppm and ≤5000 ppm respectively in the bulk intermediate. A comparative specification overview against 4-chloromethylthiazole hydrochloride, a more electrophilic structural analogue, is provided in Table 1.
| Parameter | 4-Hydroxymethylthiazole | 4-Chloromethylthiazole HCl |
|---|---|---|
| Physical form | Liquid | White to off-white crystalline powder |
| Assay (min., by GC-FID) | 98.0% | 97.0% |
| Individual impurity (max.) | 0.10% | 0.50% |
| Water (KF) | ≤0.50% | ≤2.00% |
| Sulphated ash | ≤0.10% | ≤0.20% |
| Heavy metals (as Pb) | ≤10 ppm | ≤20 ppm |
| Recommended storage | 2–8°C, under nitrogen | 2–8°C, desiccated |
The reactivity of the primary alcohol in 4-hydroxymethylthiazole stands in contrast to the benzylic-like lability of 4-chloromethylthiazole. Where the chlorinated variant undergoes rapid nucleophilic displacement under mild alkaline conditions, its use in cephalosporin side-chain syntheses introduces process challenges: liberated hydrogen chloride accelerates acid-labile protecting group loss and generates stoichiometric salt waste. In production-scale campaigns of cefditoren pivoxil, the replacement of the chloride route with the hydroxymethyl precursor has permitted the elimination of a dedicated neutralisation loop in the 5000 L glass-lined reactor train. The alcohol is instead activated in situ with methanesulphonyl chloride (1.05–1.10 eq) in tetrahydrofuran at −5 to 0°C under a nitrogen sweep to purge the nascent methanesulphonic acid. This pathway suppresses bis-thiazolyl ether formation—a side reaction that reaches 3–5 area% when residual water exceeds 200 ppm in halogenated quaternisation steps—and maintains the chiral integrity of the coupled aminothiazole-oxime fragment to an enantiomeric excess above 99.0% as determined by chiral HPLC (Chiralpak AD-H, hexane/ethanol).
In the final coupling step of cefditoren pivoxil, the 4-hydroxymethylthiazole-derived alcohol is converted to the mixed anhydride with pivaloyl chloride prior to esterification. Plant data from campaigns operating at 150–180 kg batch input indicate that the yield across the two-step activation–esterification sequence benefits from a strict in-process moisture specification of ≤0.03% w/w in the reaction solvent mixture (THF/dimethylacetamide 4:1 v/v). Deviation above 0.05% moisture elevates pivalic acid by-product to levels requiring an additional aqueous bicarbonate wash, which in turn risks partial saponification of the pivoxil ester. The agitator power draw in the 6300 L reactor is monitored to detect phase inversion during the wash; a drop exceeding 15% signals emulsion formation and triggers a hold period of 45–60 minutes with static separation, adding process cycle time.
Agrochemical intermediates built on the 4-hydroxymethylthiazole scaffold—particularly thiazole-containing strobilurin analogues—exploit the alcohol for etherification under Mitsunobu conditions. Published data for this specific configuration is limited, but analogue process development reports suggest that triphenylphosphine oxide removal by precipitation from heptane/MTBE mixtures achieves residual phosphine levels below 500 ppm when the crystallisation is seeded with 0.1 wt% authentic oxide at −10°C. Substituting 4-chloromethylthiazole in the same etherification sequence reduces the step count but introduces mutagenic impurity alerts corresponding to ICH M7 Class 3 thresholds, requiring confirmatory Ames testing on isolated intermediates.
Commercial samples stored in sealed, nitrogen-blanketed HDPE drums at 25°C/60% RH were subjected to a 24-month stability protocol per ICH Q1A(R2). At the 18-month draw point, an increase in the aldehyde impurity to 1.2–1.8 area% was recorded by GC-FID, coupled with a perceptible darkening from APHA 50 to APHA 150. Users running amino acid ester couplings in downstream steps found that aldehyde loading above 1.0% led to imine formation with glycine ethyl ester hydrochloride, creating an additional purification burden via column chromatography (silica gel 60, 0.040–0.063 mm, ethyl acetate/hexane gradient). A retest period of 12 months from the date of manufacture, with storage at 2–8°C under positive nitrogen pressure, is therefore specified on the vendor CoA. For bulk shipments in 1000 L IBCs, headspace oxygen is maintained below 2% v/v at the time of filling, verified with a Servomex 570 Series paramagnetic analyser.
Regulatory documentation for transboundary shipments routinely cites compliance with TSCA (listed on the active inventory), EINECS (registration 230-110-9), and REACH pre-registration obligations for tonnage bands below 10 t/a. A safety data sheet aligned to GHS Rev. 8 classifies the substance as a skin irritant (Category 2), eye irritant (Category 2A), and a suspected aquatic chronic hazard (Category 3) based on read-across from thiazole homologues. The hazard statements H315, H319, and H412 are applied. Where contract manufacturing organisations request absence of Class 1 residual solvents, a declaration backed by a validated GC-headspace method reporting limits of detection at 1 ppm for benzene and 2 ppm for 1,2-dichloroethane is appended to the batch dossier.
