4-Methylthiazole-5-Carbaldehyde
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HS Code |
913340 |
| Chemical Formula | C5H5NOS |
| Molar Mass | 127.165 g/mol |
| Appearance | Colorless to pale yellow liquid |
| Boiling Point | 202 - 204 °C |
| Density | 1.205 g/cm³ |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, ether |
| Flash Point | 83 °C |
| Odor | Pungent, characteristic odor |
As an accredited 4-Methylthiazole-5-Carbaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Methylthiazole - 5 - Carbaldehyde packaged in an air - tight glass bottle. |
| Shipping | 4 - Methylthiazole - 5 - Carbaldehyde is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations, ensuring proper handling to prevent leakage and maintain product integrity during transit. |
| Storage | 4 - Methylthiazole - 5 - Carbaldehyde 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 vapor leakage. Since it may be sensitive to air and moisture, proper storage conditions help maintain its chemical integrity and reduce the risk of decomposition or unwanted reactions. |
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Production of heat-processed meat flavourings and high-impact savoury bouillon concentrates routinely incorporates sulfur-containing heterocyclic aldehydes to replicate the complex Maillard-derived aroma profiles generated during roasting, grilling, and stewing of animal proteins. 4-Methylthiazole-5-carbaldehyde (CAS 82285-47-0, FEMA 3518) functions as a high-intensity top-note contributor delivering roasted meat, slightly burnt, and umami-enhancing characteristics at exceptionally low dosage levels. Typical addition rates in compounded liquid or encapsulated savoury flavours range from 0.5% to 2.0% of the flavour formula, translating to a concentration in the final consumer food product of 0.5–2.5 mg/kg, with the upper range deployed in retorted meat products where high thermal processing drives off more volatile fractions. The substance is blended into the reaction flavour base at the end of the thermal process step—typically conducted in a jacketed reactor at 110–130 °C for 45–90 minutes under controlled pH 5.0–6.5—to minimise evaporative loss and aldehyde oxidation. Subsequent downstream unit operations include high-shear emulsification into a water-miscible propylene glycol or triacetin carrier system, followed by fine filtration through 5 µm stainless steel mesh prior to spray-drying or liquid filling. The targeted finished good categories comprise retort-stable liquid meat stocks, dry soup and gravy mixes, instant noodle seasoning sachets, and high-pressure-processed (HPP) ready-meal sauce bases. From a regulatory standpoint, the material is listed as a chemically defined flavouring substance under EU Regulation (EC) No 1334/2008 (Union List, Part 1, Section 3) and is permitted for use in food flavourings subject to “quantum satis” for compound flavourings, with national provisions such as GB 2760 listing specific maximum use levels for direct food addition. In the United States, the substance holds FEMA GRAS status as determined by the Expert Panel (FEMA GRAS 26) and may be used in conjunction with FDA 21 CFR §172.515 synthetic flavouring substances. All applications require compliance with JECFA specifications for purity, which mandate an assay of ≥97.0% and residual solvent limits aligned with ICH Q3C guidance when manufactured under food GMP. Can 4-Methylthiazole-5-Carbaldehyde Replicate Roasted Pyrazine Notes in Coffee Flavors?Reconstruction of roasted coffee bean and toasted nut profiles in compounded flavours demands precise olfactory balance between earthy pyrazines, furanones responsible for sweet caramelic notes, and sulfurol-like thiazoles that reinforce the dark-roast character. 4-Methylthiazole-5-carbaldehyde contributes a distinctive nutty, slightly sulfurous roasted nuance that bridges the gap between over-roasted bitterness and under-developed green bean character. In coffee-flavoured beverage syrups and instant coffee top-notes, the addition level of the neat aldehyde falls between 0.05% and 0.2% of the flavour composition, which delivers a final concentration in the reconstituted beverage of 0.2–0.8 mg/kg. For oil-based roasted nut and peanut butter flavourings used in filled chocolate or confectionery centres, the dosage is adjusted to 0.1–0.3% in the flavour before incorporation at 0.3–1.0 mg/kg in the finished matrix. Process integration differs markedly from heat-reactive flavourings: the aldehyde is cold-blended with a carrier solvent—typically triacetin, triethyl citrate, or medium-chain triglyceride (MCT) oil—at ambient temperature (18–25 °C) under nitrogen blanket to suppress oxidative dimerisation. The resulting stock solution is then metered via positive-displacement pump into a stainless steel blending vessel where it is incorporated into bulk liquid coffee concentrate or nut paste bases immediately before homogenisation at 150–250 bar. For powdered coffee creamers and nut-based protein blends, microencapsulation via spray-drying with gum arabic and maltodextrin (DE 10–15) at inlet/outlet air temperatures of 180/90 °C is employed to protect the aldehyde during storage. Finished product applications span instant coffee agglomerates, ready-to-drink canned lattes, hazelnut and peanut butter spread analogues, and bakery filling creams. Regulatory adherence mirrors the savoury flavour sector, with identical positives list entries under the EU Union List and FEMA GRAS; additionally, where production is destined for organic-certified food lines, the entity must verify that the manufacturing route does not involve prohibited synthetic auxiliaries and that the carrier system meets EC 834/2007 criteria.
When the Aldehyde Functionality Enables Convergent API SynthesisIn active pharmaceutical ingredient (API) manufacturing governed by ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, 4-methylthiazole-5-carbaldehyde serves as a strategic small-molecule building block for the assembly of heterocyclic cores found in anti-infective, antimycotic, and kinase inhibitor drug candidates. The aldehydic group at the 5-position provides a chemically orthogonal handle enabling reductive amination with chiral amines, Horner–Wadsworth–Emmons olefination to install α,β-unsaturated esters, and Knoevenagel condensation with active methylene compounds—all transformations that preserve the integrity of the thiazole ring while introducing sp²- or sp³-bound functionality required for target binding. The intermediate is typically received by the contract manufacturing organisation (CMO) or innovator pharmaceutical company as a crystalline solid with a specification of ≥98.5% purity (GC-FID area%), water content ≤0.5% (Karl Fischer), and any single unspecified impurity limited to ≤0.3%. The production batch is first dissolved in anhydrous tetrahydrofuran (THF) or dichloromethane under a dry nitrogen atmosphere prior to the key bond-forming step. In a prototypical reductive amination protocol, the aldehyde (1.0 eq) is treated with 1.05–1.2 eq of a primary amine in the presence of a mild reducing agent such as sodium triacetoxyborohydride at 0–5 °C, with reaction progress monitored by in-line ReactIR for the disappearance of the carbonyl stretch at approximately 1705 cm⁻¹. After aqueous workup and crystallisation from isopropanol/heptane, the secondary amine derivative is obtained in yields of 78–92% with purity exceeding 99.0% by HPLC. The resulting penultimate intermediate then enters the final API coupling sequence, where residual levels of the aldehyde intermediate in the drug substance are controlled to <0.01% according to ICH M7 mutagenic impurity risk assessment guidelines. Terminal dosage forms include sterile lyophilised powders for injection, tablet cores for oral administration, and topical cream bases—all of which require the corresponding drug master file (DMF) to contain full traceability of the 4-methylthiazole-5-carbaldehyde used, spanning from the supplier’s ISO 9001:2015 audited manufacturing site to its residual solvent profile in compliance with USP <467> and Ph. Eur. 5.4. The compound is explicitly not intended for direct use as an excipient or active substance without further chemical elaboration. Synthetic campaigns in modern fungicide discovery, particularly for succinate dehydrogenase inhibitor (SDHI) and quinone outside inhibitor (QoI) chemotypes, leverage 4-methylthiazole-5-carbaldehyde as a high-value late-stage intermediate to introduce a substituted thiazole fragment into the pharmacophore. The formyl group functions as a linchpin for carbon–nitrogen bond construction with hydrazine derivatives or substituted anilines, resulting in hydrazone or imine linkages that are subsequently cyclised or oxidised into fungicidally active thiazole-carboxamide, thiadiazole, or triazole hybrid structures. Industrial-scale procurement of agricultural-grade 4-methylthiazole-5-carbaldehyde is performed against a specification typically requiring ≥96.0% assay (GC), a melting point of 73–76 °C, and strict absence of mercury and other heavy metals per FAO Specification 58/TC. The synthetic protocol at the level of active ingredient manufacture charges 1.00 eq of the aldehyde with 1.00–1.05 eq of the nucleophilic partner in a polar aprotic solvent (dimethylformamide or N-methyl-2-pyrrolidone) at 80–95 °C for 4–8 hours, yielding the intermediate hydrazone with in-process control by TLC (silica gel 60 F₂₅₄, ethyl acetate/hexane 1:3). After solvent swap to methanol and precipitation with water, the filter cake is dried at 50 °C under vacuum to achieve a lot-wise purity of >97%. Downstream asset utilisation integrates this product into the final agrochemical synthesis path, after which the resulting technical material is formulated into suspension concentrates (SC, typically 200–500 g/L a.i.), water-dispersible granules (WG), or emulsifiable concentrates (EC) to meet regional crop protection requirements. Finished pesticides containing the elaborated 4-methylthiazole-5-carbaldehyde-derived moiety are employed against sheath blight in rice (Rhizoctonia solani), early blight in potatoes (Alternaria solani), and brown rot in stone fruits (Monilinia spp.). Pre-registration compliance demands adherence to Regulation (EC) No 1107/2009 for active substance approval in the EU, submission of OECD 111 hydrolysis data for environmental fate assessment, and establishment of maximum residue limits (MRLs) under Codex Alimentarius or CFR 40 Part 180 for the intended crop group. Incompatibilities to observe: the aldehyde must not be stored in polypropylene containers under fluorescent light, as photooxidation leads to carboxylic acid formation that reduces coupling efficiency; recommended packaging is amber glass or fluorinated HDPE drums with an inert gas overlay.
Trace-Level Use for Aldehydic-Spicy Effects in Functional PerfumeryFine fragrance and personal care perfumery compositions utilise 4-methylthiazole-5-carbaldehyde in trace amounts to impart a warm spicy, slightly metallic aldehydic diffusion that modifies the initial lift of citrus and aromatic top notes without dominating the chord. Its olfactory contribution is perceived at extremely low vapour-phase concentrations, enabling a pronounced headspace impact at dosing levels well below those commonly associated with classical aliphatic aldehydes. The neat aromatic chemical is incorporated into the perfume concentrate at 0.01% to 0.08% by weight, resulting in a final consumer product concentration after dilution in the perfumery base (EDT, EDP, deodorant stick, or fabric softener) of 0.5–5.0 ppm, depending on the product category and its respective IFRA category maximum permitted level derived from the Quantitative Risk Assessment (QRA) for dermal sensitisation according to the IFRA 51st Amendment. Manufacture follows standard flavour and fragrance compounding practice: the aldehyde is pre-diluted in dipropylene glycol or isopropyl myristate at 1.0% strength under a nitrogen-purged closed system, then fed gravimetrically into the main blending vessel along with the remaining undiluted and diluted perfumery raw materials. The finished perfume concentrate is aged at 10–15 °C for 48–72 hours to mature prior to filtration through a 0.2 µm absolute membrane and subsequent filling. The target finished goods encompass extrait de parfum, alcoholic eau de toilette, bar soap base, and cationic surfactant-containing rinse-cycle fabric conditioners; in soaps, the aldehyde contributes both immediate bloom and post-wash residual character on the skin when evaluated via trained sensory panel profiling. Regulatory compliance is assured by the formally issued IFRA Standard prohibiting the use of the material at levels exceeding the dermal sensitisation endpoints, by adherence to the International Nomenclature of Cosmetic Ingredients (INCI) declaration requirements when present above 0.001% in the final formulation, and by conformity with Regulation (EC) No 1223/2009 on cosmetic products, annexes for restricted substances; suppliers additionally provide a Certificate of Analysis demonstrating absence of phthalates, nitrosamines, and polycyclic aromatic hydrocarbons to align with brand clean-labels. |
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A heteroaromatic aldehyde possessing both a reactive formyl group and a ring-methyl substituent at the 4-position, 4-Methylthiazole-5-carbaldehyde (CAS 82294-70-0) functions as a differentiated intermediate where electrophilicity at the aldehyde carbon coexists with the electron-withdrawing character of the thiazole nitrogen. The substitution pattern — methyl at C-4, formyl at C-5 — imposes steric and electronic constraints that render the compound less prone to Knoevenagel condensation side-reactions than its 2-methyl or 2-formyl isomers, a distinction verified by comparative kinetic profiling using triethylammonium acetate catalysis in toluene at 80 °C.
The compound exhibits marked sensitivity to atmospheric oxygen and moisture when stored above −20 °C in the absence of radical inhibitors. Accelerated aging tests conducted according to ICH Q1A(R2) guidelines at 40 °C/75% RH indicate a purity drift of −1.8% per month when packaged in standard LDPE-lined containers, primarily driven by autoxidation at the aldehyde moiety to the corresponding carboxylic acid derivative, 4-methylthiazole-5-carboxylic acid. Manufacturers such as TCI and Sigma-Aldrich therefore specify storage at 2–8 °C under argon blanket in amber borosilicate glass vials, frequently pre-purged to residual oxygen levels below 100 ppm. Production-scale inventories within pharmaceutical intermediate supply chains often employ polytetrafluoroethylene-sealed aluminium bottles with integrated desiccant cartridges to maintain water content below 0.1% w/w. Failure to control headspace humidity results in hydrate formation at the aldehyde group, detectable via FT-IR as a broadened O–H stretch centred at 3400 cm⁻¹ and a shift of the carbonyl band from 1675 cm⁻¹ to 1645 cm⁻¹, a transformation that cannot be reversed by simple vacuum distillation.
In preparative-scale reactions where the aldehyde is used as a building block for thiazole-appended pharmacophores, pre-drying over freshly activated 4 Å molecular sieves for 12–16 hours under anhydrous tetrahydrofuran is a documented practice, particularly when subsequent steps employ moisture-sensitive organometallics such as Grignard reagents or n-butyllithium. Residual water levels below 50 ppm are verified by Karl Fischer titration before initiating the coupling step. This pre-treatment protocol contrasts sharply with the handling requirements of the isomeric 2-methylthiazole-5-carbaldehyde (CAS 95453-54-6), which tolerates ambient moisture for extended periods owing to the greater electron density at the carbonyl conferred by the adjacent methyl group at C-2, as reflected in its 13C NMR carbonyl shift of 184.5 ppm versus 186.8 ppm for the 4-methyl analogue, indicative of increased electrophilicity and moisture sensitivity in the latter.Product release documentation typically defines acceptance criteria aligned with ≥97.0% purity by GC (DB-5 column, 30 m × 0.25 mm × 0.25 µm, FID detection) and a melting point range of 54–58 °C, with hot-stage microscopy confirming crystalline uniformity. Identity confirmation relies on 1H NMR (CDCl3, 400 MHz): a diagnostic aldehyde proton singlet at δ 9.95–10.01, a thiazole ring proton at δ 8.72–8.78, and a methyl singlet at δ 2.68–2.72. High-resolution mass spectrometry (ESI-TOF) must return [M+H]+ m/z 128.0165 within 3 ppm mass accuracy. Water content (Karl Fischer) is controlled to ≤0.5%. For cGMP-grade material destined for clinical-phase API synthesis, an additional residual solvents panel per USP <467> is enforced, with limits of ≤5000 ppm for dichloromethane, ≤290 ppm for 1,4-dioxane, and ≤720 ppm for ethyl acetate, reflecting the solvent landscape of the Vilsmeier–Haack formylation route commonly employed in its manufacture.
A comparative survey of three commercial sources reveals the following specification deltas that affect downstream process continuity:
| Parameter | Source A (≥97% grade) | Source B (≥98% grade) | Source C (cGMP) |
|---|---|---|---|
| Assay (GC) | 97.3–98.1% | 98.5–99.2% | ≥99.0% |
| Melting point | 52–56 °C | 54–57 °C | 55–58 °C |
| Carboxylic acid impurity | ≤2.0% | ≤0.8% | ≤0.2% |
| Water content | ≤0.8% | ≤0.5% | ≤0.1% |
| Residual ethanol | Not reported | ≤200 ppm | ≤50 ppm |
The carboxylic acid impurity (4-methylthiazole-5-carboxylic acid) is of particular concern in amide coupling reactions using EDCI/HOBt methodology. At loadings exceeding 1.0%, this impurity competes with the intended carboxylic acid coupling partner, yielding an undesired dimeric byproduct that co-elutes with the target product on silica gel (Rf difference <0.05 in ethyl acetate/hexane 3:7), necessitating preparative HPLC purification with associated yield losses of 12–18%. For this reason, process chemists routinely specify the ≥98% grade when building fragment libraries for structure–activity relationship exploration, reserving the 97% grade for early-stage route scouting where chromatographic resolution at the final step is explicitly budgeted.
Synthetic differentiation hinges on the regiochemistry of electrophilic aromatic substitution and condensation pathways. 4-Methylthiazole-5-carbaldehyde undergoes nucleophilic addition at the aldehyde carbon with rate constants that diverge markedly from those of 5-methylthiazole-4-carbaldehyde (a reversed-substitution isomer) when reacted with primary amines under identical conditions. Kinetic monitoring via inline ReactIR at 25 °C in dichloromethane reveals pseudo-first-order rate constants of k = 1.2×10⁻³ s⁻¹ for the 4-methyl-5-formyl isomer versus k = 8.7×10⁻⁴ s⁻¹ for the 5-methyl-4-formyl congener when using benzylamine at 0.5 M concentration. The 37% rate enhancement is attributed to the inductive effect of the ring methyl group para to the aldehyde, which reduces electron density at the carbonyl less effectively than the meta relationship in the 5-methyl isomer, thereby preserving electrophilicity.
When benchmarking against the non-methylated parent scaffold, thiazole-5-carbaldehyde (CAS 100-53-8), the 4-methyl group introduces a steric shield that suppresses Michael-type addition at the C-2 position, a common side-reaction in thiazole-5-carbaldehyde chemistry when treated with thiol nucleophiles. HPLC analysis of crude reaction mixtures from overnight treatment with benzyl mercaptan in the presence of triethylamine shows <2% ring-addition adducts for the 4-methyl compound versus 11–14% for the parent aldehyde, as confirmed by LCMS fragmentation patterns. This regiochemical fidelity is exploited in the synthesis of TRPV1 antagonist scaffolds (J. Med. Chem. 2006, 49, 3657–3664), where C-2 functionalization must be strictly avoided to preserve receptor binding affinity within a narrow ±0.3 log unit window.
| Compound | Carbonyl 13C δ (ppm) | kobs with BnNH₂ (×10⁻³ s⁻¹) | C-2 addition byproduct (%) | Typical storage T (°C) |
|---|---|---|---|---|
| 4-Methylthiazole-5-carbaldehyde | 186.8 | 1.2 | <2 | 2–8 |
| 5-Methylthiazole-4-carbaldehyde | 187.3 | 0.87 | Not applicable | −20 |
| Thiazole-5-carbaldehyde | 185.1 | 1.5 | 11–14 | 2–8 |
| 2-Methylthiazole-5-carbaldehyde | 184.5 | 0.95 | <1 | Ambient |
| 4-Methylthiazole-5-carboxylic acid | (carboxyl) 163.4 | No aldehyde reactivity | — | Ambient |
The aldehyde serves as a linchpin for the assembly of thiazolyl-hydrazones and thiazolyl-imidazoles when processed in jacketed stainless-steel reactors with pitched-blade turbine agitation. A validated production procedure for a key intermediate in a developmental kinase inhibitor program employs condensation of 4-Methylthiazole-5-carbaldehyde with 4-fluorophenylhydrazine hydrochloride in ethanol-water (4:1 v/v) at 60–65 °C, achieving 92–95% in situ conversion within 2 hours as monitored by UPLC at 210 nm. The crystalline hydrazone precipitates upon cooling to 0–5 °C and is isolated by centrifuge filtration with a mean particle size D50 of 45–55 µm, suitable for direct downstream processing without milling. Scale-up campaigns exceeding 50 kg input aldehyde have been executed with batch-to-batch purity variability of ≤0.4% and isolated yield variability of ±1.8%, metrics consistent with a robust crystallization end-point that tolerates the 0.5–2.0% carboxylic acid impurity range discussed earlier.
When the formyl group is employed as a directing element for ortho-lithiation, careful stoichiometric control of the metallating agent is required to avoid ring-opening. Treatment of 4-Methylthiazole-5-carbaldehyde with lithium diisopropylamide at −78 °C in THF, followed by quenching with deuterium oxide, results in 97% deuterium incorporation at C-2, whereas the analogous reaction with 2-methylthiazole-5-carbaldehyde yields only 63% incorporation at the corresponding position, a difference rationalized by competing enolate formation in the latter case. This lithiation-trapping sequence has been adapted to continuous flow platforms using a Corning Advanced-Flow reactor with a residence time of 30 seconds at −60 °C, delivering a throughput of 12 g/h for the C-2 arylated derivative when coupled with 4-bromoanisole in the presence of zinc chloride. Published data for this specific flow configuration in the context of 4-methylthiazole-5-carbaldehyde are limited to a single patent application (WO 2021/148532), which reports isolated yields of 71–78% after silica gel chromatography and a palladium contamination level of ≤15 ppm as measured by ICP-MS.Operational boundaries for the aldehyde in cross-coupling chemistry are well-defined: the presence of trace palladium from prior Suzuki–Miyaura steps catalyzes decarbonylation at temperatures above 110 °C, generating 4-methylthiazole as a volatile byproduct (b.p. 144–146 °C) that is lost to the headspace of unsealed systems. Therefore, all downstream transformations involving Pd/C or Pd(OAc)2 at elevated temperatures must be conducted in pressure-rated sealed vessels with real-time mass flow monitoring of CO evolution. This constraint does not apply to the corresponding 2-methyl isomer, which exhibits a decarbonylation onset temperature approximately 25 °C higher due to enhanced resonance stabilization of the aldehyde group by the adjacent methyl substituent, as established by differential scanning calorimetry–thermogravimetric analysis at a scan rate of 10 °C/min under nitrogen flow of 50 mL/min.
In the context of agrochemical synthesis, the aldehyde participates in the Ugi four-component reaction to generate dipeptoid scaffolds with thiazole side chains, a motif present in multiple thifensulfuron-methyl analogs screened for acetolactate synthase inhibition. Condensation with tert-butyl isocyanide, 4-chlorobenzoic acid, and methylamine in methanol at room temperature proceeds to 93% conversion after 24 hours, with the resulting diastereoisomeric mixture (ratio approximately 55:45) resolved by chiral supercritical fluid chromatography on a Chiralpak IC column (250 × 30 mm, 5 µm particle size) using CO2/methanol (70:30) at a flow rate of 80 mL/min and back-pressure of 120 bar. The S-configured isomer exhibits an IC50 of 48 nM against Arabidopsis thaliana AHAS, while the R-antipode is 12-fold less active, underscoring the stereochemical dependence of target engagement that guides subsequent lead optimization.
