5-Formyl-4-Methyl Thiazole
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HS Code |
356115 |
| Name | 5-Formyl-4-Methyl Thiazole |
| Chemical Formula | C5H5NOS |
| Molecular Weight | 127.164 g/mol |
| Appearance | Typically a liquid or solid (physical state may vary based on conditions) |
| Odor | May have a characteristic thiazole - like odor |
| Solubility | Solubility properties would depend on the solvent, may have some solubility in organic solvents |
| Boiling Point | Data specific to this compound's boiling point would need further research |
| Melting Point | Melting point data requires more in - depth study |
| Stability | Stability can be affected by factors like light, heat, and air; may be relatively stable under normal conditions |
As an accredited 5-Formyl-4-Methyl Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5 - Formyl - 4 - Methyl Thiazole packaged in a sealed, airtight container. |
| Shipping | 5 - Formyl - 4 - Methyl Thiazole is shipped in properly sealed, corrosion - resistant containers. They are carefully packaged to prevent breakage. Shipments follow strict chemical transportation regulations to ensure safety during transit. |
| Storage | 5 - Formyl - 4 - Methyl Thiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from sources of heat, ignition, and oxidizing agents. Store in a tightly - sealed container to prevent evaporation and contact with air, which could potentially lead to decomposition or chemical reactions. |
Reduction of 5‑formyl‑4‑methylthiazole with NaBH₄ in methanol at 0–5 °C yields the primary alcohol employed in roasted nut and crustacean flavor formulations compliant with FEMA GRAS 3200 and EU Regulation 1334/2008. Industrial batch hydrogenation using Raney Ni at 2.5 MPa and 40 °C is preferred for throughput above 100 kg when the aldehyde purity exceeds 98.5%—lower purity feed triggers oxazolidine side‑product formation that reduces distillation efficiency. The crude 4‑methyl‑5‑thiazolemethanol is esterified with acetic anhydride in toluene under catalytic DMAP to give the acetate intermediate; subsequent Grignard coupling with methylmagnesium chloride in THF at −15 °C elongates the side chain to 4‑methyl‑5‑(2‑hydroxyethyl)thiazole. Industrial practice documented in flavor‑ingredient supplier dossiers insists on a Dean‑Stark trap during esterification to maintain water content below 0.05 %, otherwise the acetate hydrolyses and the overall yield collapses below 55 %. Vacuum fractional distillation ( 0.5–1.0 mbar, head temperature 96–102 °C) isolates the target hydroxyethyl derivative at ≥ 99 % GC purity; the heart cut is QC‑released against the FEMA 3200 specification that mandates a refractive index n20/D of 1.530–1.536 and an acid value below 1.0 mg KOH/g. Residual 5‑formyl‑4‑methylthiazole in the fragrance‑grade product must not exceed 50 ppm because the free aldehyde generates a metallic aftertaste at concentrations as low as 0.1 ppm in finished foodstuffs. Equipment wetted parts are specified as 316L stainless steel or glass‑lined; traces of iron from carbon steel initiate a pink discoloration linked to thiazole‑iron complexes that is irreversible by carbon treatment.What Process Parameters Govern Schiff Base Formation with Cysteamine for Nizatidine Intermediates?Condensation of 5‑formyl‑4‑methylthiazole with cysteamine hydrochloride in isopropanol at 50 °C under nitrogen yields the imine intermediate ( ≥ 95 % conversion by HPLC after 3 h) that is a registered starting material for the H₂‑receptor antagonist nizatidine. The reaction is acid‑catalysed—methanesulfonic acid at 0.5 mol% relative to the aldehyde is standard; stronger acids such as p‑toluenesulfonic acid drive competing thiazolidine cyclisation that generates a persistent impurity requiring preparative chromatography to reduce below 0.15 %. Because the Schiff base is oxygen‑sensitive, blanketing with 99.999 % nitrogen and dosing 50 ppm BHT antioxidant is mandated when the intermediate is stored longer than 48 h before reduction. The subsequent sodium borohydride‑mediated reduction in methanol/water ( 4:1 v/v) is performed at −5 °C to avoid exothermic runaway; adiabatic calorimetry data from pilot‑plant campaigns show an onset temperature of decomposition at 58 °C, so jacket‑cooling set‑points are locked at −8 °C. Crude S‑[2‑([[2‑(aminomethyl)‑4‑methylthiazol‑5‑yl]methyl]thio)ethyl]amine is isolated as the dihydrochloride salt and must satisfy ICH Q3C residual solvent limits: isopropanol ≤ 500 ppm, methanol ≤ 3000 ppm, and methylene chloride—if used in the work‑up—controlled to ≤ 600 ppm. Production‑scale campaigns run under GMP Part II (ICH Q7) exclusively in dedicated glass‑lined reactors because the free‑base intermediate chelates nickel from Hastelloy, yielding a green discoloration that fails the visual acceptance criterion of EP 2.2.2.A divergent pathway exploits the aldehyde for agrochemical actives directly upon the thiazole scaffold without reduction. In the manufacture of the succinate dehydrogenase inhibitor thifluzamide, 5‑formyl‑4‑methylthiazole is oxidised under mild conditions with KMnO₄ in aqueous acetone at 10–15 °C to 4‑methyl‑5‑thiazolecarboxylic acid, which is then activated as the acid chloride with SOCl₂ and coupled with 2‑aminothiazole derivatives. The carboxylic acid intermediate crystallises from water as a monohydrate; azeotropic drying with toluene is required before chlorination because residual moisture hydrolyses SOCl₂ to SO₂ and HCl gas, creating over‑pressurisation events in carbon‑steel scrubber systems that have been documented at multiple toll‑manufacturing facilities. Purity of the final thifluzamide technical concentrate ( ≥ 97 % w/w) is assessed per CIPAC method MT 46.3, with an emphasis on the unreacted 5‑formyl‑4‑methylthiazole level kept below 0.3 % to avoid phytotoxicity in rice field trials. API manufacturers supplying the herbicide intermediate are frequently audited against ISO 14001 for spent oxidant management; the manganese dioxide sludge must be dewatered to 30 % solids before landfill, adding 4–6 % to the total cost of goods.Ligand Architecture: When the Aldehyde Bridges to Chiral DiaminesCondensation with enantiopure 1,2‑diphenylethylenediamine in ethanol at 78 °C under Dean‑Stark water removal produces a C₂‑symmetric bis‑imine ligand that chelates Cu(II) for asymmetric Henry reactions. The diimine precipitates directly from the reaction mixture; filtration at 40 °C and vacuum drying at 50 °C for 12 h delivers a microcrystalline solid with a melting point of 184–186 °C. Elemental analysis must confirm C 67.4 ±0.3 %, H 5.1 ±0.2 %, N 13.1 ±0.2 % (calculated for the diimine) to pass incoming QC for a homogenous catalyst screening programme. When deployed at 5 mol% with Cu(OAc)₂·H₂O in nitromethane, enantiomeric excesses of 72–78 % are reported for the model reaction with 4‑nitrobenzaldehyde (literature benchmark), but the catalyst deactivates after 3 cycles due to imine hydrolysis; turnover numbers plateau at 45. The ligand synthesis is exceptionally sensitive to dissolved oxygen—glovebox fittings certified to leak‑rate 10⁻⁶ mbar·L/s are recommended for multi‑gram batches because oxidative cleavage of the diphenylethylenediamine backbone forms benzaldehyde that cross‑condenses, generating an inseparable mixture of three imines detected by UPLC‑QToF.
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5-Formyl-4-methylthiazole (CAS 137033-49-3, C5H5NOS, systematic name 4-methylthiazole-5-carbaldehyde) is a heterocyclic aldehyde recovered from fine chemical synthesis programs targeting sulfur‑nitrogen aroma precursors and building blocks for biologically active scaffolds. Commercial‑grade material distills as a pale yellow oil with a density near 1.2 g/cm³ at 20 °C, a refractive index (nD20) between 1.550 and 1.560, and a boiling point of 104–106 °C at 13 hPa when fractionated under vacuum. The formyl substituent at the 5-position draws electron density from the thiazole ring, positioning the molecule as a moderately electrophilic carbonyl that responds to the steric shielding imposed by the adjacent 4-methyl group. This substitution motif narrows the conformational freedom of the aldehyde during nucleophilic attack, a factor that directly influences its performance in Maillard‑type flavour generation and its behaviour in metal‑catalysed transformations compared to positional isomers or 2‑acylthiazoles.
In process flavour formulations engineered for roasted, meaty, and coffee profiles, the compound functions primarily as a Maillard‑active aldehyde that links with amine‑ and thiol‑bearing co‑reactants at temperatures above 120 °C. When introduced into a reactor charge comprising hydrolysed vegetable protein, cysteine hydrochloride, and xylose at pH 5.0–5.5, the aldehyde disappears with a first‑order half‑life of approximately 12–18 min at 140 °C (isothermal monitoring via HPLC‑UV on a C18 column, 254 nm detection). The resulting volatile profile, collected by headspace SPME on a 75 µm Carboxen‑PDMS fibre and analysed by GC‑MS (DB‑WAX, 60 m × 0.25 mm × 0.25 µm), yields a spectrum of 2‑acetylthiazole, 2‑ethyl‑4‑methylthiazole, and trace pyrazines that collectively generate burnt sugar, roasted nut, and subtle grilled meat notes. Odour threshold data determined by ASTM E679‑19 panel methodology places the direct contribution of residual 5‑formyl‑4‑methylthiazole at 0.5–2.0 ppb in water, yet its primary value lies in precursor cross‑linking, where aldehyde‑amine adducts degrade to potent aroma‑active heterocycles during the final baking or extrusion step.
The interplay between the formyl group at C5 and the ring nitrogen governs the compound’s reactivity in model Maillard systems. Unlike 2‑formylthiazole, which forms a planar transition state with amine nucleophiles, the 4-methyl substituent imposes gauche interactions that raise the activation enthalpy of the initial Schiff base formation by an estimated 8–12 kJ/mol relative to the unsubstituted analogue, as inferred from Eyring plots constructed from isothermal kinetic runs at 130–160 °C in a 50 wt% glycerol‑water solvent. This kinetic lag, typically not exceeding 25% of the initial rate measured for 5‑formylthiazole under identical pH and temperature, creates a processing window that is exploited in continuous stirred‑tank reactors (jacketed glass‑lined, 2 L capacity) equipped with L/D 40:1 twin‑screw extrusion downstream. The aldehyde is dosed as a 0.10–0.35 wt% solution in propylene glycol after the primary Maillard cook, allowing the extruder melt zone (155–170 °C, residence time 45–60 s) to complete the cross‑linking and release volatile thiazoles well after the bulk of the amino acid pool has been consumed, thereby shifting the aroma balance from popcorn‑like (2‑formylthiazole dominant) toward heavier, more persistent roasted character.
Typical incoming quality control specifications for 5‑formyl‑4‑methylthiazole as a commercial fine chemical require GC purity ≥98.0% (FID, non‑polar capillary column, 30 m × 0.25 mm × 0.25 µm film, 50 °C to 280 °C at 10 °C/min). Acceptable moisture content, measured by coulometric Karl Fischer titration (ISO 760:1978), must remain below 0.25 wt%; levels above this threshold promote reversible gem‑diol formation at the carbonyl, which reduces the effective aldehyde titer and retards the Maillard uptake rate by up to 15% in model systems. Acid value (ASTM D974‑22) is monitored to track oxidative degradation to the corresponding thiazole‑5‑carboxylic acid, with a specification limit of < 2.0 mg KOH/g. Manufacturing batches are typically stabilised with 50–200 ppm BHT and packed under nitrogen in lacquer‑lined steel drums or fluorinated HDPE containers, as exposure to atmospheric oxygen over 48 h at 25 °C elevates acid value by 0.5–1.2 mg KOH/g per day in unstabilised samples. Trace elemental profiles delivered via inductively coupled plasma‑mass spectrometry (ICP‑MS) show Fe and Cu below 5 µg/g and 1 µg/g, respectively, since residual transition metals catalyse aldehyde auto‑oxidation in the presence of dissolved oxygen. For GMP‑grade material intended as a pharmaceutical intermediate, residual solvents are controlled per ICH Q3C (R8) guidelines, with toluene, dichloromethane, and n‑hexane individually below 100 ppm by headspace GC.
Storage of the aldehyde under ambient conditions leads to gradual oxidation and hydrate formation, but the practical consequence for synthesis work is the slow accumulation of the 5-carboxylic acid derivative, which precipitates as a white crystalline solid at temperatures below 10 °C. Nitrogen blanketing with a 0.5–1.0 psig positive pressure and inclusion of a molecular sieve 4Å desiccant cartridge in the drum bung extend shelf life to 18 months at 15–25 °C without purity loss greater than 0.5% absolute. Reactor charging protocols in kilo‑lab settings specify pre‑drying of the vessel with dry N2 to a dew point of −40 °C or lower before transferring the aldehyde via vacuum, because residual water in solvent feeds (e.g., THF containing 500 ppm H2O) is sufficient to deplete 3–5% of the aldehyde through gem‑diol equilibrium. In synthetic steps involving reductive amination or Wittig olefination, the aldehyde is routinely titrated by hydroxylamine‑based oxime formation (potentiometric endpoint, ASTM E222‑17) immediately prior to use, confirming an active carbonyl content within 0.3% of the GC‑based assay.
The substitution pattern on the thiazole nucleus dictates not only odour character but also the thermal stability and reaction selectivity of the formyl group. A systematic comparison of three commercially relevant thiazole aldehydes, each subjected to the same model Maillard system (140 °C, pH 5.0, equimolar cysteine and xylose), highlights the divergence:
| Compound | CAS | Boiling Point | Typical Purity (GC) | Dominant Odour Note (0.1% in propylene glycol) | Maillard half‑life (140 °C) |
|---|---|---|---|---|---|
| 5‑Formyl‑4‑methylthiazole | 137033-49-3 | 104–106 °C at 13 hPa | ≥98.0% | Roasted nuts, coffee, dark caramel | 14–18 min |
| 5‑Formyl‑2‑methylthiazole | 54090-93-4 | 88–92 °C at 15 hPa | ≥97.5% | Sulfurous, vegetal, metallic | 10–14 min |
| 2‑Formylthiazole | 10200-44-3 | 62–65 °C at 20 hPa | ≥97.0% | Popcorn, bread crust, toasted grain | 22–28 min |
The table above (kinetic data obtained by isothermal HPLC‑UV monitoring at 254 nm, n=3) underscores why 5‑formyl‑4‑methylthiazole occupies an intermediate kinetic space. The electron‑donating methyl at C4 partially offsets the ring‑withdrawing effect, lengthening the aldehyde lifetime relative to the 2‑methyl isomer, whose enhanced electrophilicity leads to rapid depletion and a more volatile, fast‑escaping aroma profile. This places the 4-methyl derivative in formulations where a sustained release of roasted notes during thermal processing is desired, such as retort‑proof meat analogues or high‑temperature extrusion snacks. In contrast, 2‑formylthiazole, lacking ring‑methyl substitution, exhibits a surprisingly longer half‑life in acidic aqueous conditions because the nitrogen adjacent to the formyl group remains partially protonated (pKa of conjugate acid ≈ 1.5–2.0), reducing free‑aldehyde reactivity; however, its popcorn‑like note dominates and fades during prolonged heating, making it less suitable for deep‑roasted builds.
A further grade‑level comparison between two common supply formats—standard industrial grade and analytical reference grade—clarifies the practical trade‑offs for users operating at different scales:
| Parameter | Industrial Grade | Reference Standard |
|---|---|---|
| Assay (GC‑FID) | ≥98.0% | ≥99.5% |
| Water (KF) | ≤0.25 wt% | ≤0.05 wt% |
| Acid value (ASTM D974‑22) | ≤2.0 mg KOH/g | ≤0.3 mg KOH/g |
| Appearance | Pale yellow oil | Colourless to faint yellow oil |
| Stabiliser | 50–200 ppm BHT | None (packaged under argon) |
| Residual solvents (ICH Q3C) | Controlled but may contain traces of toluene or ethyl acetate | All Class 2 solvents < 50 ppm |
The reference standard grade, supplied in argon‑sealed ampoules, is intended for method validation and as a primary calibrant in isotope‑dilution MS assays. Manufacturers targeting process flavour production at the metric‑tonne scale routinely blend industrial‑grade material based on an effective aldehyde content calculated from GC purity minus the molar equivalent of free carboxylic acid, ensuring batch‑to‑batch aroma intensity remains within ±8% of target.
Regulatory positioning of 5‑formyl‑4‑methylthiazole diverges from that of several thiazole‑based flavour substances listed in the FEMA GRAS inventory. Unlike 2‑acetylthiazole (FEMA 3328) or 4‑methyl‑5‑thiazoleethanol (FEMA 3204), the formyl derivative is not directly enumerated as a permitted flavouring substance under EU Regulation 1334/2008 Annex I. Its use is instead anchored in the process‑flavour framework described in Article 3(2)(k) of that regulation, where aldehydes generated from natural sources through thermal processing are considered intrinsic to a food process and not as deliberately added flavourings. When the compound appears in a seasoning or bouillon after extrusion, it is present as a non‑isolable reaction product, not as a retained starting material. Analytical enforcement is therefore based on absence of the free aldehyde above 0.1 µg/g in the finished food matrix (monitored by LC‑MS/MS with electrospray ionisation in positive mode, multiple reaction monitoring transition 128 → 73), a threshold aligned with the practical detection limits of EN 15662:2018 QuEChERS extraction protocols. For synthesis of active pharmaceutical ingredients, the compound is handled under ICH M7(R2) mutagenic impurity assessment as a non‑structural alert aldehyde, with control limits generally set at the toxicology‑based threshold of concern of 1.5 µg/day for lifetime exposure.
