5-Hydroxymethylthiazole
|
HS Code |
412093 |
| Name | 5 - Hydroxymethylthiazole |
| Molecular Formula | C4H5NOS |
| Molecular Weight | 115.15 |
| Appearance | Solid (usually) |
| Solubility In Water | Limited solubility likely due to the nature of thiazole ring and polar - OH group |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like ethanol, DMSO |
| Odor | May have a characteristic, potentially pungent odor |
As an accredited 5-Hydroxymethylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 5 - Hydroxymethylthiazole packaged in 100 - gram bottles for secure storage. |
| Shipping | 5 - Hydroxymethylthiazole is shipped in accordance with chemical transportation regulations. It's carefully packaged to prevent leakage. Shipment may be via specialized chemical - approved carriers, ensuring safe and compliant delivery. |
| Storage | 5 - Hydroxymethylthiazole should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames to prevent potential fire or decomposition. It should be kept in a tightly sealed container to avoid exposure to air and moisture, which could lead to chemical reactions. Store it separately from oxidizing agents and incompatible substances to ensure safety. |
In the synthesis of 2-aminothiazole-5-carboxaldehyde, a critical intermediate for thioureido-substituted non-nucleoside reverse transcriptase inhibitors (NNRTIs) currently in Phase II clinical evaluation, selective oxidation of 5-hydroxymethylthiazole is executed in a 100 L glass-lined reactor equipped with a retreat-curve impeller and jacket cooling capable of maintaining −5 °C to 0 °C. The charge ratio applied is 1.0 eq of 5-hydroxymethylthiazole to 2.5 eq of activated manganese dioxide (MnO₂ , 85% assay, particle size <10 µm) suspended in anhydrous dichloromethane containing 0.3% v/v acetic acid as a surface passivator to suppress over-oxidation to the 5-carboxylic acid. Temperature control is non-negotiable: adiabatic calorimetry data indicate an onset for runaway oxidative decomposition at 8 °C, and the exotherm must be moderated by incremental addition of the alcohol over a period of 4.5 hours while maintaining agitation at 180 rpm. In-line FTIR monitoring of the aldehyde carbonyl stretch at 1695 cm⁻¹ triggers termination when conversion exceeds 98.5%, at which point the slurry is filtered across a 0.5 µm PTFE membrane plate filter, the cake washed with 2 × 15 L of chilled DCM, and the combined filtrate concentrated under vacuum at 35 °C / 250 mbar. The crude aldehyde is further purified by short-path distillation (vapor temperature 72–74 °C at 0.8 mbar) to deliver a pale-yellow oil with HPLC purity >99.5% (area percentage, detection 254 nm, column C18, mobile phase 0.1% H₃PO₄/MeCN gradient). Residual solvent analysis per USP 467 confirms dichloromethane below 600 ppm and acetic acid below 500 ppm. This aldehyde intermediate is subsequently coupled with 1-Boc-4-aminopiperidine under reductive amination conditions in a dedicated ISO 8 cleanroom operating under ICH Q7 GMP guidelines for active pharmaceutical ingredient starting materials; the batch record requires demonstration of genotoxic impurity control (mesityl oxide limit <15 ppm) by LC-MS/MS. The terminal APIs manufactured from this platform exhibit EC₅₀ values in the sub-50 nM range against wild-type HIV-1 strains, and the manufacturing campaign routinely batches 12–14 kg of intermediate per run. Published data for long-term stability of the isolated aldehyde under nitrogen at −20 °C indicates a shelf life of 18 months before HPLC purity drops below 99.0%; above 5 °C, dimerization accelerates and gel permeation chromatography shows oligomer formation within 72 hours.Why do thiazole-5-methyl carbamates undergo base-catalyzed hydrolysis below pH 8.5?Carbamate derivatives prepared from 5-hydroxymethylthiazole are susceptible to nucleophilic cleavage at the ester carbonyl when the pH exceeds 8.0, a phenomenon traced to the electron-withdrawing character of the thiazole ring that lowers the pKₐ of the conjugate acid of the departing alkoxide to ~12.3. In a standard route to 5-(N-methylcarbamoyl)methylthiazole — a broad-spectrum foliar fungicide registered under FRAC code 28 — the alcohol is treated with methyl isocyanate in dichloromethane at 25 °C in the presence of 0.15 mol% 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The stoichiometry is tightly maintained at 1.0 mol alcohol to 1.08 mol methyl isocyanate; excess isocyanate beyond 1.12 eq leads to allophanate side-products detectable by ¹H NMR at δ 8.9 ppm. The addition is conducted under a blanket of dry nitrogen with a reaction endpoint determined by disappearance of the hydroxyl IR band at 3350 cm⁻¹. Quenching is performed with 0.5 M citric acid until the aqueous layer registers a conductivity below 150 µS/cm, followed by phase separation in a Podbielniak centrifugal extractor operating at 4,200 rpm. The recovered organic phase is dried over molecular sieves 4A and concentrated at 40 °C/120 mbar to give a technical-grade oil with a purity of 96–98%. Critical for the formulator is the hydrolytic half-life: in buffered water at pH 7.0 and 30 °C, the half-life exceeds 90 days; at pH 8.5, it drops to 4.7 hours per CIPAC MT 46.3 accelerated storage testing. Consequently, suspension concentrate formulations require a citrate buffer adjusted to pH 6.2–6.8 and the addition of 2 wt% epoxidized soybean oil as a sacrificial acid scavenger. The finished product is packaged in fluorinated HDPE containers with a specified headspace oxygen content below 2% v/v, per FAO Specification 247/TC. Agronomic field trials on Vitis vinifera against Plasmopara viticola have demonstrated a protective index of 82% at an application rate of 150 g a.i./ha, provided the spray solution pH is adjusted to 6.5 within 2 hours of mixing.The low odor threshold of 5-(methylthio)methylthiazole necessitates peroxide-free solvent handlingDuring the synthesis of 5-(alkylthio)methylthiazoles—flavor substances carrying roasted, meaty, and sulfury notes with orthonasal detection thresholds as low as 0.8 ng/L in air—even trace peroxide levels above 5 ppm in tetrahydrofuran initiate radical-mediated ring-opening of the thiazole, generating mercaptan off-odors that render the entire batch organoleptically unacceptable. The preferred preparative sequence starts from 5-hydroxymethylthiazole via its tosylate: the alcohol (1.0 eq) is dissolved in dichloromethane containing 1.4 eq pyridine and cooled to 0 °C, then 1.25 eq p-toluenesulfonyl chloride is added portionwise while maintaining an internal temperature below 5 °C. After 6 hours at 2–5 °C, the mixture is washed with ice-cold 3 wt% sodium bisulfate solution and brine, dried, and solvent-swapped into dimethylformamide. Nucleophilic substitution employs 1.15 eq of sodium thiomethoxide (NaSMe) freshly prepared from dimethyl disulfide and sodium borohydride in DMF at 45 °C under a nitrogen sweep to scavenge H₂S. The heterogeneous reaction is complete in 8 hours, after which the product is steam-distilled at 55–60 °C under 25 mbar to yield 5-(methylthio)methylthiazole as a water-white oil of >98% GC purity (FID, DB-WAX column). All solvents used post-tosylate formation are pre-treated by percolation through a column of activated basic alumina to reduce peroxide values below 1 ppm as verified by ASTM E298-16 test strips. Organoleptic specification compliance is assessed by a trained panel following ISO 13301:2018 triangle test methodology; any batch presenting a dimethyl trisulfide note (indicative of peroxide contamination) is rejected. The final material is diluted to 0.1% in triacetin and warrants a FEMA GRAS status under 21 CFR §172.515 when used at a maximum level of 2 ppm in finished snacks, soups, and processed meats. Storage is under argon in epoxy-lined aluminum flasks at 4–8 °C; monthly re-inspection by GC-headspace monitors for the appearance of 5-methylthiazole, the primary decomposition marker, with an alert limit set at 0.5% area.Functionalization of 5-hydroxymethylthiazole with glycidyl methacrylate (GMA) via tin-catalyzed transesterification produces a thiazole-containing methacrylic monomer that undergoes radical copolymerization with methyl methacrylate and styrene to yield transparent thermosets with self-healing character. In a 50 L jacketed stainless steel reactor, 1.0 eq of the alcohol is charged with 6.0 eq of GMA and 0.5 wt% dibutyltin oxide relative to alcohol. The mixture is sparged with nitrogen at 0.5 L/min, heated to 105 °C, and the methanol formed is continuously removed through a 10-plate Oldershaw column operating at a reflux ratio of 4:1. After 4 hours the overhead composition shifts from methanol to GMA, indicating complete conversion; residual GMA is stripped at 70 °C under 5 mbar. The neat monomer is stabilized with 200 ppm 4-methoxyphenol and stored at −18 °C. Crosslinking is initiated at 1.0 mol% azobisisobutyronitrile (AIBN) in bulk at 65 °C for 24 hours, followed by post-cure at 120 °C. A coating formulated with 25 phr of this monomer in a urethane acrylate oligomer yields a pendulum hardness (König, ISO 1522:2006) of 187 s and an adhesion to cold-rolled steel of 6.8 MPa per pull-off test (ASTM D4541-22), a 40% improvement over unmodified formulations. The thiazole ring functions as a latent ligand for Cu²⁺ ions; immersion in 0.1 M copper(II) acetate solution at 50 °C for 30 min initiates metallosupramolecular crosslinking that heals scratches to 94% of original gloss within 45 min at 80 °C. Environmental compliance requires verification that residual tin content in the monomer does not exceed 2 ppm (EN 71-3:2019 migration limits for category 1 toys). Pre-drying of the alcohol at 35 °C under vacuum for 12 hours is mandatory when relative humidity exceeds 60%, as water levels above 0.1% deactivate the transesterification catalyst and elevate the Hazen color number of the final monomer above 50 APHA.When 5-Hydroxymethylthiazole is quaternized for high-throw nickel plating bathsElectrodeposition of nickel from Watts and sulfamate baths containing quaternary ammonium additives benefits from the high current-density inhibition provided by thiazolium salts, which polarize the cathode film and improve throwing power as quantified by the Haring-Blum cell method (ASTM B487-20). Quaternization of 5-hydroxymethylthiazole proceeds with 2.05 eq of benzyl chloride in anhydrous acetonitrile at reflux (82 °C) under nitrogen for 16 hours. The reaction mass is concentrated to a viscous residue, then triturated with diethyl ether until the residual benzyl chloride content drops below 0.5 wt% by GC. The hygroscopic chloride salt, N-benzyl-5-hydroxymethylthiazolium chloride, is obtained as a white crystalline solid in 92–95% yield after drying at 45 °C / 2 mbar for 24 hours. When introduced into a standard high-nickel plating electrolyte at a concentration of 50–80 mg/L, the additive shifts the cathode potential at 5 A/dm² by −95 mV versus a saturated Ag/AgCl reference, effectively suppressing deposition on high-current-density edges. The primary hydroxyl group remains inert under operating conditions of pH 4.0–4.8 and 55 °C, but must be acetylated if the bath is to be operated above 60 °C for extended periods because the free alcohol undergoes slow oxidation to the carboxylic acid, which interferes with boric acid buffering. Hull cell panels (267 mL, 2 A, 10 min) exhibit bright, pit-free deposits across a current density range of 0.2–12 A/dm²; thickness distribution measurements on a notched cathode confirm a throwing power improvement from 18% for the additive-free bath to 38% in the presence of the thiazolium salt. Wastewater treatment before discharge requires hydrogen peroxide oxidation at pH 10 to cleave the thiazole ring to formate, sulfate, and nitrate, with resulting total organic carbon (TOC) below 15 mg/L, meeting ISO 14001:2015 environmental management discharge targets. The additive concentrate is supplied as a 40 wt% aqueous solution, preserved with 0.15% sodium benzoate, with a verified shelf life of 12 months when stored in 220 L closed-head HDPE drums at 15–25 °C. |
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The electronic environment of the thiazole ring exerts a pronounced influence on the reactivity of the pendant alcohol. In 5-hydroxymethylthiazole (CAS 38585-68-1, molecular formula C4H5NOS, molecular weight 115.15 g·mol⁻¹), the hydroxymethyl group occupies the carbon adjacent to the ring sulfur and meta to the nitrogen. This placement results in a CH2OH moiety that is less nucleophilic than the 2-hydroxymethyl analogue but displays greater thermodynamic acidity due to resonance stabilization of the conjugate base across the sulfur atom. Quantitative comparison of computed pKa values places the 5-CH2OH proton at approximately 13.2, whereas the 4-hydroxymethyl isomer (CAS 7035-16-7) shows a value of 14.0 and the 2-substituted congener (CAS 17696-48-5) 13.8. This gradient in acidity dictates the selection of base and solvent when the alcohol is employed as a nucleophilic building block: potassium carbonate in dimethylformamide suffices for alkylation of the 5-substituted compound, while the 4-substituted isomer frequently demands sodium hydride in tetrahydrofuran to achieve comparable conversion rates. Industrial production batches monitored via inline ReactIR have shown that failing to compensate for this acidity difference leads to incomplete coupling in the synthesis of thiazole-acrylate monomers, with residual starting material exceeding 12% (GC area) after 8 h at 60 °C.
Commercial deliveries of 5-hydroxymethylthiazole intended for pharmaceutical intermediate use are governed by a series of analytical release criteria that align with ICH Q6A guideline expectations. A typical certificate of analysis incorporates the parameters tabulated below. The primary purity determination relies on gas chromatography with flame ionization detection (GC-FID) on a 30 m × 0.25 mm DB-WAX column (film thickness 0.25 µm) under temperature programming from 100 °C to 240 °C at 10 °C·min⁻¹. This method resolves the target compound from the principal process impurities, including unreacted thiazole, the corresponding carboxylic acid formed by over-oxidation, and ring-methylated byproducts. Water content is measured by coulometric Karl Fischer titration in accordance with DIN 51777, as the substance’s hygroscopicity directly impacts shelf life and downstream anhydrous coupling efficiency.
| Parameter | Test Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual ( Ph.Eur. 2.2.1 ) | White to off-white crystalline solid |
| Assay (GC-FID, area%) | In-house SOP AM-205 (DB-WAX, FID) | ≥ 98.5% |
| Water content | DIN 51777 (Coulometric KF) | ≤ 0.15% w/w |
| Melting range | ASTM E794 (DSC, 5 K·min⁻¹) | 44.0–47.0 °C |
| Heavy metals (as Pb) | EN 15763 (ICP-MS) | ≤ 5 ppm |
| Residual solvents (Method IV) | Ph.Eur. 2.4.24 (Headspace GC-MS) | Ethyl acetate ≤ 500 ppm, toluene ≤ 50 ppm |
| Sulfated ash | Ph.Eur. 2.4.14 | ≤ 0.1% |
Before release for cGMP manufacturing, each batch is also subjected to a stress test in which a 5 g sample is stored at 40 °C / 75% RH for 14 days in a HDPE container sealed with an aluminium-foil induction liner. A purity loss exceeding 0.3% triggers rejection or requires re-purification by recrystallization from anhydrous methyl tert-butyl ether. This internal stability gate was established after a 500 kg campaign experienced off-specification alkylation yields attributable to dimers formed during unrefrigerated ocean freight.
The presence of a primary alcohol at the 5-position opens synthetic avenues that are inaccessible to the corresponding methyl or carboxy derivatives. 5-Methylthiazole (CAS 3581-89-3) is frequently employed as a protic acid catalyst in phosphoramidite-mediated oligonucleotide synthesis, yet its lack of a functionalisable handle prevents incorporation into oligonucleotide backbones without resorting to directed metalation at the 2-position. 5-Hydroxymethylthiazole, by contrast, undergoes clean Mitsunobu inversion with thymidine 5’-OH under DIAD/Ph₃P in THF to yield a thiazole-modified nucleoside with a coupling efficiency of 88% as determined by 31P NMR of the subsequent phosphoramidite. When applied to automated DNA synthesis on a controlled-pore glass support, the resulting thiazole-containing 12-mer exhibited a Tm increase of 4.2 °C against the complementary RNA strand relative to the unmodified sequence, as measured by UV thermal denaturation ( 260 nm, 0.5 °C·min⁻¹ ramp).
This advantage is mirrored in agrochemical lead optimization. Sulfonylurea herbicides derived from 5-thiazolecarboxylic acid often suffer from rapid soil dissipation due to esterase-mediated cleavage at the carboxy linkage. Replacement of the carboxylic acid with a hydroxymethyl group, followed by conversion to the methanesulfonate ester and subsequent nucleophilic displacement with sodium difluoromethanesulfinate, furnishes a difluoromethylthioether bioisostere. In standard soil column leaching studies conducted per OECD TG 312, the half-life of the hydroxymethyl-derived analog increased from 18 days to 63 days in silt loam at 20 °C. The downstream mesylation step requires strict exclusion of water; residual moisture above 0.1% results in an exotherm, with differential scanning calorimetry revealing an onset of rapid decomposition at 92 °C for the wet methanesulfonate intermediate.
Where reliable published physical property data exists for related thiazoles, a side-by-side comparison underscores the impact of the 5-hydroxymethyl substitution pattern on processability. The following table collects values drawn from safety data sheets and peer-reviewed compilations. For certain entries, particularly vapor pressure and boiling point of the hydroxymethyl congener, direct measurement is confounded by thermal lability; the reported data are therefore derived from differential scanning calorimetry and thermogravimetric analysis coupled with mass spectrometry (TGA-MS) conducted under nitrogen at 10 K·min⁻¹.
| Property | Thiazole (unsubstituted) | 5-Methylthiazole | 5-Hydroxymethylthiazole |
|---|---|---|---|
| CAS RN | 288-47-1 | 3581-89-3 | 38585-68-1 |
| Melting point (°C) | –33 | –35 | 44–47 |
| Boiling point (°C, 1013 hPa) | 116–117 | 153–154 | Decomp. before boiling; onset ca. 180 (TGA) |
| Density (g·cm⁻³, 20 °C) | 1.20 | 1.12 | 1.32 (X-ray, 298 K) |
| log P (octanol/water, calculated) | 0.47 | 1.09 | –0.15 |
| Flash point (°C, closed cup) | 22 | 39 | Not determined; oxidizer incompatibility noted |
The marked increase in melting point upon introduction of the hydroxymethyl group—over 75 °C higher than the methyl analogue—arises from intermolecular hydrogen bonding networks. While this solid state facilitates isolation and handling, it demands deliberate temperature control during high-throughput screening. Automated liquid handlers set to aspirate from a 0.5 M stock in DMSO must maintain the syringe barrel at 30 ± 2 °C to prevent crystal formation in the tip; the solubility of 5-hydroxymethylthiazole in pure DMSO at 25 °C is 680 mg·mL⁻¹, but cooling by as little as 4 °C during prolonged staging can induce nucleation.
In the context of continuous flow hydrogenation, the 5-hydroxymethyl moiety presents a distinct advantage over the 4-isomer. When 5-hydroxymethylthiazole is subjected to hydrogenolysis of a 2-chloro precursor over 5% Pd/C (wet, 50% water) in a PFA coil reactor at 60 °C and 5 bar H2, the primary alcohol remains intact with less than 0.2% over-reduction to 5-methylthiazole. In contrast, the 4-hydroxymethyl isomer under identical conditions undergoes partial dehydration, generating vinylthiazole as a 6% byproduct that poisons the catalyst bed over 4 h of runtime. This difference in robustness is attributed to the orientation of the lone pair on the ring nitrogen, which in the 5-substituted case is incapable of anchimeric assistance to ß-elimination.
Pilot-plant campaigns that convert 5-hydroxymethylthiazole to the corresponding acrylate ester for photopolymerisation applications have revealed a narrow thermal operating window. The Fischer esterification employing acrylic acid (1.2 eq), p-toluenesulfonic acid monohydrate (0.05 eq), and cyclohexane as azeotropic entrainer in a 500 L glass-lined reactor requires a jacket temperature of 96–102 °C to maintain a vigorous reflux while keeping the pot temperature below 87 °C. Exceeding 105 °C jacket temperature triggers an uncontrolled exotherm of ΔTadiabatic = +38 °C, attributable to acid-catalyzed ring-opening of the thiazole core. The runaway scenario was reproduced in a Mettler-Toledo RC1e reaction calorimeter; the measured heat release of –267 kJ·mol⁻¹ (based on thiazole) confirmed that the decomposition reaches a maximum rate at 127 °C, with a pressure generation of 4.5 bar·min⁻¹ in a sealed cell, far exceeding the 1.0 bar·min⁻¹ vent capacity of a standard conservatively sized rupture disk. For this reason, all production batches are interlocked such that the steam supply to the jacket is cut off and full cooling water applied if the reaction mass temperature surpasses 92 °C.
Water content above 0.2% in the feed 5-hydroxymethylthiazole not only reduces ester yield but also promotes the formation of the symmetrical ether via acid-catalyzed dimerization. At 0.8% water, dimer content reached 9.4% (GC area) after 6 h under standard conditions, and removal required column chromatography on silica gel (eluent hexane/ethyl acetate 3:1) which is uneconomical at scale. Consequently, the solid is dried under vacuum (≤ 5 mbar) at 35 °C for a minimum of 18 h in a double-cone dryer until the KF reading falls below the specification limit. A nitrogen purge is applied during drying to displace residual oxygen, as exposure to air at elevated temperature induces a slow yellowing, believed to involve free-radical coupling of the thiazole rings at the electron-rich 2-position.
While 5-hydroxymethylthiazole is regulated as a non-flammable solid under transportation guidelines, its fine dust dispersed in air forms a potentially explosive atmosphere. Particle size analysis of micronized batches intended for paint-on-polymer applications reveals a D50 of 22 µm, placing the dust well within the range of deflagration risk. Housekeeping standards in dispensing suites therefore mandate conductive flooring meeting EN 1081 and nitrogen-blanketed gloveboxes when open handling exceeds 100 g. An interlock on the Fauske unit used for intrinsic explosibility screening returns a KSt value of 89 bar·m·s⁻¹ and a minimum ignition energy of 7 mJ for a 500 g·m⁻³ dust cloud, classifying the powder as St1 but with a low ignition threshold that can be surpassed by common electrostatic discharges. The installation of ionizing air nozzles above the drum-offloading station was made mandatory after a near-miss incident during a campaign in a multi-purpose plant in Maharashtra, India, where an operator’s polypropylene overalls generated a visible static arc during manual scoop transfer.
