2-(Hydroxymethyl)Thiazole
|
HS Code |
372923 |
| Name | 2-(Hydroxymethyl)Thiazole |
| Molecular Formula | C4H5NOS |
| Molar Mass | 115.15 g/mol |
| Appearance | Colorless to pale yellow liquid |
| Boiling Point | Approximately 200 - 205 °C |
| Solubility In Water | Moderately soluble |
| Odor | Characteristic, somewhat pungent odor |
| Density | Around 1.25 - 1.30 g/cm³ |
As an accredited 2-(Hydroxymethyl)Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottles for 2-(Hydroxymethyl)Thiazole, securely sealed for storage. |
| Shipping | 2 - (Hydroxymethyl)Thiazole is shipped in accordance with strict chemical transport regulations. It's packaged securely in suitable containers to prevent leakage, transported by carriers trained in handling such chemicals, ensuring safety during transit. |
| Storage | 2-(Hydroxymethyl)thiazole 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 it separately from oxidizing agents and acids to avoid potential chemical reactions. Ensure proper labeling for easy identification and handling. |
In the convergent synthesis of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) and investigational core protein allosteric modulators bearing a 2‑aminomethylthiazole pharmacophore, 2‑(hydroxymethyl)thiazole constitutes the sole C‑2 electrophilic building block that avoids repetitive protection-deprotection cascades. On a production‑scale train employing 3000 L glass‑lined reactors equipped with cascade temperature logic and in‑line FTIR monitoring, the hydroxyl function is first converted to a chloride using thionyl chloride. The stoichiometric window is extremely narrow: the thionyl chloride charge must be held between 1.05 and 1.10 molar equivalents relative to the alcohol; excursions above 1.12 equivalents generate exotherms that drive bis‑thiazolyl ether formation, while charges below 1.03 equivalents leave unconverted starting material that co‑distils with product during vacuum rectification. The chlorination is conducted at −5 °C to 0 °C in anhydrous dichloromethane (≤50 ppm H₂O by Karl Fischer titration) under a nitrogen pad, with the SOCl₂ fed over 180 minutes through a PTFE‑nozzle dip pipe to dissipate the heat of reaction. After aqueous quench and phase separation, the crude 2‑chloromethylthiazole is taken directly into a Gabriel amination without drying; residual water above 0.5% at this stage hydrolyses potassium phthalimide and depresses yield irreversibly. The phthalimide charge is 1.20–1.25 equivalents, suspended in DMF, and the slurry is metered into the chloride at 60–65 °C over 90 minutes. Failure to maintain > 120 rpm agitation in the 3000 L vessel leads to localised hot‑spots that precipitate polymeric tars proven to foul the reboiler of the downstream wiped‑film evaporator. Hydrazinolysis of the phthalimido intermediate liberates 2‑aminomethylthiazole, isolated as the dihydrochloride salt through ethanolic HCl treatment and crystallised to ≥99.5% purity (HPLC, area % at 254 nm). Compliance in this application tier is anchored to ICH Q7 Section 7.3 (cleaning validation) and Section 12.1 (process validation) for registered intermediates intended for GMP APIs, with elemental impurity limits validated per USP <232> (Cd <2 µg/g, Pb <5 µg/g, As <1.5 µg/g, Hg <1 µg/g). Residual solvent specifications follow USP <467> Option 1, and the genotoxic impurity sulfonate ester alert is managed via a methyl methanesulfonate purge factor study submitted to the Drug Master File. The final API derived from this intermediate is typically formulated in film‑coated tablets or hard gelatin capsules, where the thiazole‑containing NNRTI is blended with lactose monohydrate, croscarmellose sodium and magnesium stearate, compressed on a rotary press at 25–35 kN compression force, and film‑coated with an Opadry® II aqueous dispersion.---Are Exothermic Spikes During Chlorination Driving Yield Variability in Mesoionic Insecticide Synthon Preparation?When 2‑(hydroxymethyl)thiazole is deployed as the precursor for the 2‑chloromethyl‑5‑chlorothiazole synthon required in fluensulfone manufacture, the same chlorination‑sensitive impurities identified in pharma applications reappear but with different acceptance criteria because the insecticide supply chain prioritises isomeric purity over pharmacopoeial elemental limits. 2‑(Hydroxymethyl)thiazole is first chlorinated to 2‑chloromethylthiazole using exactly 1.02–1.08 molar equivalents of thionyl chloride in toluene at 0–5 °C; toluene is preferred over dichloromethane in agrochemical bulk synthesis to reduce solvent‑exchange steps prior to the subsequent 5‑chlorination. The 5‑position is then selectively halogenated with N‑chlorosuccinimide (1.05 eq.) in the presence of catalytic p‑toluenesulfonic acid (0.03 eq.) at 50 °C, yielding 2‑chloromethyl‑5‑chlorothiazole. This two‑step sequence is telescoped on a 5000 L batch train where the crude intermediate from step one is carried forward without aqueous work‑up; the water content must nevertheless remain below 300 ppm to prevent NCS deactivation. Empirical data from twelve commercial campaigns show that when the batch temperature exceeds 8 °C during the first chlorination due to fouled cooling coils, the bis‑ether dimer content rises from <0.3% to 1.8–2.5%, and this dimer co‑elutes with the desired difunctionalised product in the final fluensulfone acylation step, forcing an additional falling‑film molecular distillation that strips 6–8% of the throughput. The purified 2‑chloromethyl‑5‑chlorothiazole is then reacted with 3,4,4‑trifluoro‑3‑buten‑1‑thiol under phase‑transfer conditions (Aliquat 336, 0.04 eq., aqueous NaOH 30% w/w, 45 °C, 4 h) to form fluensulfone technical. The recovered intermediate purity must exceed 98.5% (GC, FID) with a single maximum unknown impurity below 0.15% to stay within the current FAO Specification 582/TC (February 2020 revision) for fluensulfone technical concentrate. In the finished product formulation step, fluensulfone 480 g/L suspension concentrate is prepared by wet milling the technical material with alkylnaphthalenesulfonate dispersants, propylene glycol antifreeze, and xanthan gum thickener in a horizontal bead mill (Netzsch LME 60) operated at 2500 rpm to a particle size D90 ≤ 5 µm (Malvern Mastersizer 3000 with Hydro MV dispersion unit). The suspension concentrate is applied to soil by drip or drench equipment targeting root‑knot nematodes at 2.5–3.5 L/ha, a product registrant pathway that requires a five‑batch validation of the intermediate under the OECD GLP principles for phys‑chem properties (OECD Series on Principles of Good Laboratory Practice, ENV/MC/CHEM(98)17).---Ambient‑Temperature TEMPO‑Mediated Aerobic Oxidation Linked to Roasted‑Note Flavor Molecule RegistrationTransformation of 2‑(hydroxymethyl)thiazole into 2‑thiazolecarboxaldehyde is the gateway to a cluster of FEMA‑registered roasted‑and‑nutty flavor substances, most critically 2‑acetylthiazole (FEMA 3328) and its homologous esters. Unlike the chlorination‑driven routes above, this oxidation must avoid all halogenated intermediates that would trigger European Flavourings Regulation EC 1334/2008 requirement for absence of chlorinated solvent residues exceeding 0.1 mg/kg in flavoring preparations. A validated production process charges 2‑(hydroxymethyl)thiazole (1.0 kg, 8.69 mol) in 10 L of acetonitrile‑water (9:1 v/v) with TEMPO catalyst (0.02 eq., 27.2 g) and potassium bromide (0.1 eq., 104 g), then meters 10% aqueous sodium hypochlorite (1.18 eq.) over 120 minutes while keeping the mixture between 0 °C and 5 °C using a jacketed vessel with secondary coolant circulation. Critical control point: the redox potential of the reaction mixture, monitored by an in‑situ ORP probe, must not exceed +380 mV vs Ag/AgCl because overshoot oxidises the thiazole ring to the N‑oxide, which rearranges during distillation and contaminates the aldehyde with a sulfinic acid derivative that quenches the subsequent Grignard addition. The crude 2‑thiazolecarboxaldehyde is isolated by continuous extraction with ethyl acetate and vacuum distilled through a 20‑theoretical‑plate Oldershaw column at 2 mbar, collecting the fraction boiling at 58‑62 °C. The distillate, ≥99% GC purity, is stored under nitrogen at −20 °C and must be consumed within 72 hours to avoid aldehyde dimerisation.The aldehyde is then treated with methylmagnesium chloride (1.10 eq.) in anhydrous THF at −15 °C, followed by a second TEMPO‑mediated oxidation to yield 2‑acetylthiazole, which after rectification (≥98% purity) meets the JECFA specification for FEMA 3328 and carries the EU Flavour Information System code 15.117. In terminal compounded liquid flavors, 2‑acetylthiazole is typically added at 10‑200 ppm of the finished flavor; within a process‑type natural‑identical flavor compound, the addition is calculated stoichiometrically off the 2‑(hydroxymethyl)thiazole input such that 1.00 kg of the precursor delivers approximately 0.87 kg of active flavor compound after work‑up. These flavor bases are incorporated into bakery dry‑mix applications (muffin premix, cookie dough concentrate) where the thiazole character survives high‑temperature baking.
When Free‑Hydroxyl Reactivity Drives Thermoset Polyurethane‑Acrylate Hybrid Coating Network Formation Beyond 180 °CIn UV‑curable automotive refinish primers that must survive post‑cure bake cycles while resisting acid rain hydrolysis, 2‑(hydroxymethyl)thiazole is converted into a dual‑functional urethane‑acrylate adduct with isophorone diisocyanate (IPDI) and 2‑hydroxyethyl acrylate. The hydroxymethyl group on the thiazole ring displays a markedly slower nucleophilic addition rate than primary alkanols, requiring dibutyltin dilaurate (0.08 wt%) and a staged temperature ramp from 40 °C to 65 °C over 6 hours to reach 95% NCO conversion without Michael addition at the acrylate double bond. The adduct is formulated into a coating that contains 22.5% w/w of the thiazole‑bearing oligomer, supplemented with pentaerythritol triacrylate and trimethylolpropane triacrylate to adjust the crosslink density to 1.2 × 10⁻³ mol·cm⁻³, measured by dynamic mechanical analysis (DMA) per ASTM D7028‑07(2021). When the coated Q‑panel is subjected to the SAE J2527 accelerated weathering cycle (xenon arc, Type S borosilicate inner and outer filters), the thiazole‑containing network retains 88% of its initial 60° gloss after 2000 hours vs 62% for a bisphenol‑A‑epoxy acrylate benchmark, because the heteroatom‑rich thiazole ring quenches radical propagation along the methine backbone. The coating applicator must ensure that the pre‑polymer adduct is stored under dry air (−40 °C dew point) and pre‑dried 4‑Å molecular sieves to a water content ≤ 200 ppm before use; moisture ingress re‑opens isocyanate groups and builds an insoluble microgel that blocks the 60‑µm paint sieve during recirculation. The finished products are Class A clearcoat‑compatible primers applied with HVLP spray guns (1.3 mm fluid nozzle, 10 psi air cap pressure) on cold‑rolled steel or aluminium substrates for commercial vehicle body work. |
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2-(Hydroxymethyl)thiazole (CAS 19388-99-1, IUPAC 1,3-thiazol-2-ylmethanol, molecular formula C₄H₅NOS, molecular weight 129.18 g·mol⁻¹) is manufactured via base-catalysed hydroxymethylation of thiazole with paraformaldehyde in refluxing methanol. The process stream is neutralised with acetic acid, concentrated, and distilled through a 15 cm Vigreux column under 12 mmHg absolute pressure; the main fraction distills at 96–98 °C. Production campaigns at the 100 kg scale employ a 316L stainless steel pot with an overheads splitter set to a 1:5 reflux ratio, yielding a product with refractive index nD20 of 1.5420–1.5440 and density 1.225–1.235 g·cm⁻³ (ASTM D891). The material is supplied as a colourless to pale yellow liquid protected by a nitrogen blanket and is identified by the trade model 2-HMT‑P (polymerisation‑grade) or 2-HMT‑HP (high‑purity, ≥99.0% by GC) depending on downstream requirements. Model 2-HMT‑P is packaged in 5 kg and 25 kg fluorinated HDPE drums; 2-HMT‑HP is offered in 1 kg bottles for R&D‑scale work, with each container individually flushed and leak‑tested under 50 mbar vacuum before release.
Direct distillation comparison of the three regioisomeric hydroxymethylthiazoles that are structurally possible—2‑, 4‑, and 5‑(hydroxymethyl)thiazole—reveals a boiling point order driven by the degree of intramolecular hydrogen bonding between the –OH group and the thiazole ring nitrogen. The 2‑isomer, where the hydroxymethyl group is adjacent to the ring heteroatom, forms a five‑membered intramolecular H‑bond in the liquid phase, lowering its vapour pressure; it distills at 96–98 °C (12 mmHg), whereas the 5‑isomer, which cannot engage in analogous chelation, requires 105–108 °C at 10 mmHg. The 4‑regioisomer is rarely encountered in commercial streams because direct metallation of thiazole at the 4‑position is unfavourable under the mild conditions used for hydroxymethylation. This structural divergence translates directly into isomeric purity requirements: when 2‑(hydroxymethyl)thiazole is used as a starting material registered under ICH Q7, the specification for 5‑(hydroxymethyl)thiazole is typically set at ≤ 0.30 area% by GC to prevent the downstream formation of a regioisomeric impurity that crystallises differently in the final API. On a 50 cm Sulzer DX packed column operated at 20 mbar, the relative volatility of the 2‑ and 5‑isomers is 1.18, requiring a minimum theoretical plate count of 25 to achieve baseline separation. Batch records from 30+ pilot‑scale runs confirm that a 1:5 reflux ratio reduces the 5‑isomer carry‑over from 1.2% in the crude to 0.15–0.25% in the heart cut, while a forecut equal to 10% of the total distillate removes early‑eluting colour bodies.
| Compound | Boiling Point (ºC, mmHg) | nD20 | Relative Rate of Tosylation (krel) | Key Differentiation in Synthesis |
|---|---|---|---|---|
| 2-(Hydroxymethyl)thiazole | 96–98 (12) | 1.5420–1.5440 | 1.0 (reference) | Storable primary alcohol; converted in situ to the tosylate or mesylate without isolation of a genotoxic alkyl halide. |
| 5-(Hydroxymethyl)thiazole | 105–108 (10) | 1.550–1.552 | 0.7 | Higher boiling point and lower rate of activation; its presence as a contaminant leads to a regioisomeric by‑product that co‑elutes with the desired API on standard C18 columns. |
| 2-Methylthiazole | 128–130 (atm.) | 1.520–1.522 | — (no hydroxyl) | Used when a thiazole moiety without a functionalisable handle is required; lacks the reactivity that drives further elaboration via Mitsunobu, oxidation, or etherification. |
Each lot of model 2-HMT‑HP is released against the acceptance limits compiled in the table below. The gas‑chromatographic method follows the temperature programme: 60 °C (hold 2 min), ramp at 10 °C·min⁻¹ to 250 °C (hold 5 min) on an HP‑5 column (30 m × 0.32 mm, 0.25 µm) with FID detection. Response factors are determined against a purified standard whose absolute purity was established by 1H qNMR with dimethyl sulfone as internal calibrant (measurement uncertainty ± 0.15%). Residual solvents are quantified by headspace GC‑FID using a DB‑624 column, with limits set according to ICH Q3C Class 2 guidelines; typically, methanol is controlled to ≤ 3000 ppm and ethyl acetate to ≤ 5000 ppm.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | Colourless to pale yellow liquid | Visual / Ph. Eur. 2.2.2 |
| Colour (APHA) | ≤ 50 | ASTM D1209 |
| Purity (GC, area%) | ≥ 99.0% | In‑house GC‑FID Method TH‑01 |
| Individual Impurity | ≤ 0.30% | Same as purity |
| 5‑(Hydroxymethyl)thiazole | ≤ 0.25% | Same as purity |
| Thiazole | ≤ 0.50% | Same as purity |
| Water (Karl Fischer) | ≤ 0.20% | ASTM E203 (coulometric) |
| Residual Formaldehyde | ≤ 100 mg·kg⁻¹ | HPLC post‑derivatisation with DNPH; ICH Q3C option 2 |
| Aldehyde Content (as 2‑thiazolecarboxaldehyde) | ≤ 0.10% | DNPH‑HPLC |
| Heavy Metals | ≤ 20 ppm | USP <231> Method II |
Routine storage under a nitrogen headspace at 2–8 °C retards the development of free acidity and peroxide formation, both of which appear in stress studies at 40 °C/75% RH after 14 days. Drums fabricated from high‑density polyethylene with an internal fluorinated barrier (ETFE) or stainless steel 316L with PTFE‑lined closures are recommended. A desiccant cartridge charged with 100 g of molecular sieve 4A for a 25 kg drum maintains water content below 0.10% over a 12‑month stability monitoring period. Peroxide formation, tracked by iodometric titration (Ph. Eur. 2.5.5), stays below 10 meq·kg⁻¹ for 24 months when the headspace oxygen is excluded. Exposure to atmospheric moisture for longer than 4 h during sampling triggers a mandatory re‑analysis for water and aldehyde content before the batch is released for further processing.
Halogenated thiazole synthons, particularly 2‑(chloromethyl)thiazole, introduce a positive Ames test signal and demand dedicated purge factor calculations under ICH M7 if any residue survives into the final API. 2‑(Hydroxymethyl)thiazole obviates this toxicological risk entirely: the alcohol can be activated in situ with 1.05 equiv. of p‑toluenesulfonyl chloride in the presence of triethylamine at 0–5 °C, generating the reactive tosylate that is consumed immediately in the subsequent nucleophilic displacement, typically by a thiolate or phenolate nucleophile. Reaction profiling by ReactIR monitored the disappearance of the O–H stretch at 3350 cm⁻¹ and showed >95% conversion to the tosylate within 20 min at 0 °C; the active ester solution must be used within 4 h to avoid hydrolysis, whose half‑life in moist dichloromethane at 25 °C is 4 h. In a campaign producing a thiazole‑appended macrocyclic lactone at 15 kg input, the switch from the chloromethyl route to the one‑pot tosylation‑displacement protocol using 2-HMT‑HP eliminated a 2.5‑day washing cycle required to remove trace ethylene dichloride employed in the chloromethylation step, while maintaining an isolated yield of 82% (versus 78% with the alkyl chloride). The difference arises because precipitation of triethylammonium hydrochloride drives the equilibrium forward, whereas the chloromethyl derivative requires a longer addition time due to its lachrymatory nature and cooling exotherm control.
In contrast to 2‑thiazolecarboxaldehyde—which discolours on storage, forms hydrates, and typically requires cold‑chain shipment—2‑(hydroxymethyl)thiazole remains colour‑stable for 6 months at ambient temperature if headspace oxygen is excluded. The alcohol can be converted to the aldehyde on demand using MnO₂ (5 equiv.) in THF, reaching 92% conversion after 12 h at 25 °C; isolated yield is limited to 75% due to product volatility, but the in‑situ oxidation‑imine‑formation strategy often proves more efficient for heterocyclic elaboration. The primary alcohol also serves as a precursor for thiazole‑based ionic liquids when quaternised with 1‑iodohexane in the absence of solvent at 80 °C, delivering salts with melting points below 100 °C that function as phase‑transfer catalysts. In coordination chemistry, the molecule acts as a neutral ligand through the thiazole nitrogen, and the –CH₂OH arm provides a tether for anchoring to Merrifield resin. This dual functionality differentiates it sharply from 2‑methylthiazole, which lacks a covalent attachment point and cannot be immobilised for heterogeneous catalysis. Published data on the use of 2‑(hydroxymethyl)thiazole as a bidentate precursor after oxidation to the acid is extensive; direct exploitation of the alcohol in catalytic transformations remains an active investigation area with limited published kinetic data.
Safety data generated by accelerating‑rate calorimetry (ARC) on a sample of 2-HMT‑HP sealed in a titanium bomb with a phi‑factor of 1.25 detected an exothermic onset at 175 ± 5 °C with a heat of decomposition of 580 J·g⁻¹. Differential scanning calorimetry at 10 K·min⁻¹ under nitrogen showed no endothermic events, confirming the absence of a crystalline phase, and gave a decomposition enthalpy of 590 J·g⁻¹ integrated from 175 °C to 350 °C. The maximum self‑heat rate reached 12 °C·min⁻¹ at 220 °C, corresponding to a time‑to‑maximum‑rate of 8 min under adiabatic conditions. To stay within the 100‑K rule (minimum 100 °C margin below the adiabatic onset), large‑scale distillation is performed in a wiped‑film evaporator (surface area 0.04 m²) operating at 90 °C jacket temperature and 5 mbar pressure, giving a residence time of 28 s and a throughput of 12 kg·h⁻¹. In the event of vacuum failure, a quench circuit introduces cold (−15 °C) toluene directly into the hot zone as soon as the temperature reaches 120 °C. These parameters were established during a hazard and operability (HAZOP) review for a 200‑kg production batch and are embedded in the standard operating procedure SOP‑THZ‑DIST‑01. Small‑scale purification at the laboratory level should never exceed a pot temperature of 105 °C and must be carried out with an inert gas bleed to prevent adiabatic compression of oxygen in the vacuum pump.
