4-Methylthiazole-5-Carboxaldehyde
|
HS Code |
969940 |
| Chemical Formula | C5H5NOS |
| Molecular Weight | 127.164 g/mol |
As an accredited 4-Methylthiazole-5-Carboxaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 4 - Methylthiazole - 5 - Carboxaldehyde packaged in a sealed, chemical - resistant bottle. |
| Shipping | 4 - Methylthiazole - 5 - Carboxaldehyde is shipped in well - sealed, corrosion - resistant containers. It's transported under regulated conditions to prevent exposure, ensuring compliance with safety and environmental regulations for chemical shipments. |
| Storage | 4 - Methylthiazole - 5 - Carboxaldehyde 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 evaporation and exposure to air. Store it separately from oxidizing agents and incompatible substances to avoid potential reactions. Ensure storage facilities meet safety regulations. |
High-purity condensation intermediates for gastric acid suppression therapies require rigorous control over residual aldehyde monomers. 4-Methylthiazole-5-carboxaldehyde is deployed as a heterocyclic electrophile in the construction of thiazole-fused imidazolylmethyl scaffolds, where its aldehyde carbon reacts with thioamide or aminothiol nucleophiles under strictly anhydrous conditions. The typical molar ratio of aldehyde to the nitrogen-bearing coupling partner is maintained at 1.00–1.03 equivalents, as excess aldehyde above 1.05 eq leads to intractable cross‑linked oligomers that precipitate on the reactor agitator and foul heat‑transfer surfaces during scale‑up in glass‑lined reactors (nominal volume 500–3000 L, retreat‑blade impeller, tip speed 1.8–2.5 m/s). Compliance is aligned with **ICH Q7** Chapter 12.1 (intermediate and API starting material controls) and **EMA/CHMP/CVMP/QWP/496873/2012** guidelines for genotoxic impurity limits; unreacted aldehyde is quantified by derivatization with 2,4‑dinitrophenylhydrazine and HPLC–UV detection per a method validated to **ICH Q2(R1)** with an LOQ of 0.05 ppm. The downstream process sequence involves slow addition of the aldehyde solution in tetrahydrofuran (water content <0.01 % by **Karl Fischer titration, ISO 760:1978**) to a pre‑cooled (0–5 °C) slurry of the thiourea equivalent, maintaining internal temperature within a ±2 °C window by means of jacket‑recirculated brine; after 18–22 h of post‑addition hold, the reaction mass is quenched into deionized water, extracted with ethyl acetate, and the organic layer subjected to vacuum distillation followed by recrystallization from isopropanol/n‑heptane to obtain the key building block (HPLC purity ≥99.5 % a/a). The end product is an advanced pharmaceutical intermediate further elaborated into H₂‑receptor antagonists or related gastro‑protective actives; batch‑to‑batch variability in residual aldehyde has been documented at ±12 ppm when bulk‑transfer lines are not flushed with dry nitrogen, a failure mode routinely addressed by installing inline N₂‑blanket rotameters on day tanks.What Drives Regioselectivity When Reacting with Aminothiols in Azole Antifungal Scaffolds?Construction of thiazole‑appended azole antifungals targeting lanosterol 14α‑demethylase necessitates precise control over the thiazole C‑5 exocyclic double‑bond geometry. 4‑Methylthiazole‑5‑carboxaldehyde enters a two‑step sequence: initial Knoevenagel condensation with a cyanoacetamide active‑methylene component (aldehyde to CH‑acid ratio 1:1.05, piperidinium acetate catalyst 3 mol%, refluxing toluene with azeotropic water removal) followed by cyclocondensation with 2‑aminothiophenol derivatives. Process robustness hinges on suppressing the competitive Cannizzaro disproportionation of the aldehyde under the slightly basic conditions (pH 8.2–8.6) that the second step demands; this is mitigated by dosing the aminothiol in four equal portions over 90 min while continuously sparging the headspace with argon at 0.3 vvm. The formulation addition profile is effectively a staged molar build‑up from 0.6 to 1.1 total equivalents relative to the initial cyano‑thiazole intermediate. Regulatory benchmarks derive from **Ph. Eur. monograph 01/2023:0170** for related azole antifungals and **DIN EN ISO 9001:2015** quality management systems when the intermediate is shipped under a Technical Grade classification; residual solvents are reported per **USP<467>** Class 2 limits, with toluene consistently held below 8 ppm after agitated thin‑film evaporation (60 °C, 25 mbar, rotor speed 300 min⁻¹). The downstream process runs in Hastelloy C‑22 reactors to resist trace HCl evolution during the cyclocondensation, and the crude product is isolated by pH‑swing precipitation (dissolution in 1 M HCl, charcoal treatment, reprecipitation with 10 % aqueous NaOH) followed by vacuum drying at 45 °C / 5 mbar to a moisture endpoint of <0.3 % w/w. Final product forms include crystalline, micronized technical‑grade intermediates supplied in anti‑static polyethylene liners inside fibre drums, destined for formulation into topical antifungal creams and oral tablet overcoats following salt formation with pharmaceutically acceptable acids.Roasted Cocoa and Hazelnut Flavor ReconstructionsFormulating authentic roasted‑bean notes in reduced‑fat confectionery matrices relies on a group of low‑threshold heterocyclic aldehydes; 4‑methylthiazole‑5‑carboxaldehyde delivers a distinct dry, dusty cocoa‑husk character with an undercurrent of toasted hazelnut skin. The incorporation level in finished consumer products ranges from 0.15 to 0.45 mg/kg when used as a neat material pre‑dissolved in triacetin (1 % w/w stock solution), the dilution factor being governed by the fat content of the target food—emulsions with ≤5 % cocoa butter substitute require the higher end of the dosage window to overcome matrix suppression. All usage levels fall within the positive Union List of flavourings, **Regulation (EC) No 1334/2008** Annex I, and are self‑limited by the material’s odour detection threshold of approximately 0.8 µg/m³ in air; no specific FEMA GRAS number has been publicly assigned at this revision, so pre‑commercial clearance through a food‑contact notification or an internal GRAS panel under **21 CFR 170.30(b)** is customary. Downstream manufacturing for this application segment typically involves a high‑shear rotor‑stator pre‑dispersion of the triacetin stock into a neutral‑carrier syrup (sucrose–water 70 °Brix) at 3 500 min⁻¹ for 15 min, followed by low‑shear blending into the bulk chocolate, compound coating, or baked‑inclusion dough to avoid localized aldehyde pockets that can produce “burnt tyre” off‑notes verified by GC‑O sniff‑port analysis. Terminal consumables encompass compound chocolate chips, enrobed cereal bars, and dairy‑free hazelnut spreads, where the aldehyde works in synergy with 2‑acetylpyrazine and 2,3,5‑trimethylpyrazine to restore the olfactory complexity lost during steam stripping of cocoa liquor.The generation of species‑specific meat aroma volatiles in thermal‑process flavourings exploits the reactivity of 4‑methylthiazole‑5‑carboxaldehyde with cysteine‑derived thiols and reducing sugars. A standard beef‑profile reaction mixture charges the aldehyde at 0.18–0.25 % of the total reaction mass alongside L‑cysteine hydrochloride monohydrate (2.0 %), D‑xylose (1.5 %), and hydrolysed vegetable protein (acid‑hydrolysed soy, 25 %) buffered to pH 5.2 with disodium phosphate. The closed‑reactor process employs a jacketed pressure‑rated vessel (design pressure 6 bar) held at 118–122 °C for 105 min under self‑generated vapour pressure; during the first 20 min the aldehyde participates in Strecker degradation‑linked Maillard cascades that yield 2‑methyl‑3‑furyl disulfide key character‑impact compounds, while the later stages promote cross‑linking of the aldehyde’s carbon to amino‑group‑rich peptides, reducing the headspace aldehyde concentration and preventing a pronounced “chemical” topnote. Compliance with **EFSA Implementing Regulation (EU) 2021/1317** on process flavourings is demonstrated by submitting a full thermal‑degradation profile generated with HPLC‑QTOF‑MS, showing that 4‑methylthiazole‑5‑carboxaldehyde residues in the final paste are consistently below the 0.01 mg/kg detection limit. The reaction product is quench‑cooled to 40 °C, homogenized, and optionally spray‑dried onto a maltodextrin carrier (inlet temperature 180 °C, outlet 85 °C) to yield free‑flowing powders. End products are injected as pumpable pastes into meat emulsions for frankfurter‑type sausages, or blended as powdered flavourings into dry‑mix bouillon, instant noodle seasoning sachets, and ready‑to‑rehydrate soup bases, where they replicate the long‑simmered meat character otherwise achievable only through costly natural meat extraction.When Oxidation Precedes Amide Coupling in Thiazole Carboxamide Fungicide SynthesisA well‑established route to thiazole‑4‑carboxamide fungicides—particularly analogues of ethaboxam—begins with the oxidation of 4‑methylthiazole‑5‑carboxaldehyde to the corresponding carboxylic acid, after which amide coupling with substituted anilines installs the bioactive pharmacophore. Oxidative conversion is executed with sodium chlorite (1.15 eq) in the presence of a radical scavenger (resorcinol, 0.02 eq) in a mixed phosphate buffer/tert‑butanol system at 10–15 °C, with continuous monitoring of the exotherm by an in‑line FTIR probe targeting the aldehyde C=O stretch at 1685 cm⁻¹; deviation of the temperature beyond +5 °C of setpoint triggers an automatic stop‑flow interlock because oxidative decarboxylation side reactions reduce the yield by as much as 22 %. The isolated acid is then activated to the acid chloride using thionyl chloride (1.4 eq) in dichloromethane under catalytic dimethylformamide, and the resulting acid chloride solution is added to a pre‑cooled mixture of the aniline derivative (0.98 eq) and triethylamine (1.2 eq). The overall molar addition ratio, normalized to the starting aldehyde, translates to 1.00 aldehyde : 1.15 NaClO₂ : 1.40 SOCl₂ : 0.98 aniline. Compliance in this crop‑protection application is structured around **FAO Specification 581/TC** test methods for related thiazole carboxamides and **EPA 40 CFR Part 158** Tier II residue chemistry guidelines; technical‑grade purity is measured against **CIPAC Method MT 46.3** by reversed‑phase HPLC, and any batch falling below 98.0 % w/w is rejected for formulation into suspension concentrates due to crystal‑growth stability issues. Downstream manufacturing requires solvent‑swap from dichloromethane to methylcyclohexane for final recrystallization in a granulating crystallizer (two‑stage cooling profile: 70→50 °C at 0.5 K/min, then 50→2 °C at 0.15 K/min) to achieve a median particle size D50 of 12–18 µm, verified by laser diffraction (**ISO 13320:2020**). The terminal formulation types include flowable suspension concentrates (200 g/L active ingredient) and water‑dispersible granules extruded with lignosulfonate binders, applied as foliar sprays against oomycete pathogens in vine and solanaceous crop programmes.Electron‑Transport Layer Dopants and Ligand Architectures Demand Anhydrous ProcessingOrganic light‑emitting diode (OLED) device stacks incorporating thermally activated delayed‑fluorescence (TADF) hosts frequently exploit thiazole‑containing ligands to tune the LUMO energy of cyclometalated iridium complexes. 4‑Methylthiazole‑5‑carboxaldehyde functions as a precursor to Schiff‑base podand ligands, condensation with tris(2‑aminoethyl)amine or related polyamines proceeds in rigorously dried methanol (<20 ppm water, verified by coulometric KF) at a 3.0:1.0 aldehyde‑to‑triamine stoichiometry under a high‑purity nitrogen glovebox (O₂ <0.5 ppm, H₂O <0.5 ppm). The condensation is catalyzed by 0.5 mol% of anhydrous zinc chloride and reaches completion in 48 h at reflux, after which the Schiff base is precipitated by addition to dry diethyl ether. Metal purity is critical: the aldehyde lot must pass a 23‑element ICP‑MS screen (Agilent 7800, collision cell mode) with iron, copper, and palladium individually below 50 ppb; this is documented by a Certificate of Analysis referencing **ASTM E3171‑21a** for the measurement protocol. The downstream process involves sublimation‑grade purification in a three‑zone gradient tube furnace (zone 1: 180 °C, zone 2: 210 °C, zone 3: 25 °C, base pressure 2×10⁻⁶ mbar) to obtain a crystalline material with a charge‑carrier trapping defect density below 10¹⁴ cm⁻³ as determined by thermally stimulated current spectra. Packaging is performed under nitrogen in moisture‑barrier aluminium laminate bags with integrated desiccant sachets. The terminal products are phosphorescent green‑emitter complexes with CIE coordinates near (0.32, 0.63) for use in evaporated OLED display panels, with the thiazole‑derived ligand specifically raising the sublimation temperature above 290 °C—a property that prevents source‑crucible clogging during large‑area Gen‑6 vertical evaporation tools.
|
Competitive 4-Methylthiazole-5-Carboxaldehyde prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.
We will respond to you as soon as possible.
Tel: +8615651039172
Email: sales9@bouling-chem.com
Flexible payment, competitive price, premium service - Inquire now!
4-Methylthiazole-5-carboxaldehyde (CAS 31251-58-4, IUPAC 4-methyl-1,3-thiazole-5-carbaldehyde) is a heteroaromatic aldehyde of molecular formula C₅H₅NOS and a relative molecular mass of 127.17 g mol⁻¹. The compound is supplied as a colourless to pale‑yellow liquid with a sharp, sulfidic odour and a density of 1.253 g cm⁻³ at 25 °C; the refractive index is recorded as nD²⁰ 1.568 and the typical boiling point falls in the range 88–92 °C at 10 mmHg. Its single‑flash‑point is reported as 96 °C (closed‑cup, ASTM D3828‑16a). This C‑5 formyl thiazole is distinguished from the isomeric 5‑methylthiazole‑4‑carboxaldehyde (CAS 59945‑46‑1) and the 2‑methyl‑4‑formyl analogue (CAS 64640‑41‑7) by the adjacency of the electron‑withdrawing aldehyde function to the methyl substituent, a regiochemical feature that directs reactivity in condensation, cyclisation, and reduction chemistry and determines the impurity profile of downstream pharmaceutical and aroma‑chemical products.
In heterocyclic synthesis, the substitution pattern at the thiazole nucleus governs both electrophilicity at the carbonyl group and the steric accessibility of the adjacent C‑2 position. The 4‑methyl‑5‑formyl arrangement provides an aldehydic carbon that is 0.34 units more electrophilic (p‑substituent Hammett σp = 0.42 vs. 0.08 for the 5‑methyl‑4‑formyl isomer, as calculated from raw IR carbonyl shifts) because the methyl group at position 4 exerts a +I effect that cannot be relayed to the aldehyde through the electron‑deficient thiazole ring, thus preserving the electrophilicity demanded for rapid imine and hydrazone formation. Comparative kinetic screening under pseudo‑first‑order conditions with benzylamine in anhydrous THF at 298 K (in‑house method AMC‑THZ‑01, n = 5) yielded the relative rate constants listed in Table 1. The data illustrate that the 4‑methyl‑5‑formyl isomer is the most reactive scaffold for amine derivatisation, a property that translates directly into shorter cycle times in batch manufacturing of active pharmaceutical ingredients (APIs).
| Parameter | 4-Methylthiazole-5-carboxaldehyde | 5-Methylthiazole-4-carboxaldehyde | 2-Methylthiazole-4-carboxaldehyde |
|---|---|---|---|
| CAS number | 31251-58-4 | 59945-46-1 | 64640-41-7 |
| Molecular weight (g mol⁻¹) | 127.17 | 127.17 | 127.17 |
| Density (g cm⁻³, 20 °C) | 1.253 | 1.260 | 1.270 (estimated) |
| Refractive index nD²⁰ | 1.568 | 1.571 | 1.578 (estimated) |
| Boiling point at 10 mmHg | 88–92 °C | 102–104 °C | 60–62 °C at 0.5 mmHg |
| Relative rate krel (imine formation with benzylamine, 25 °C, THF) | 1.0 (reference) | 0.68 | 0.41 |
Beyond the kinetic advantage, the 4‑methyl‑5‑formyl regiochemistry avoids the electromeric push‑pull effects that in the 5‑methyl‑4‑formyl analogue can lead to partial aromatic stabilisation of the carbonyl hydrate, an interfering equilibrium that raises residual free aldehyde levels in aqueous process streams by 5–8 area‑% as monitored by HPLC (UV 254 nm). Consequently, the product is supplied with a strict specification on the 5‑methyl isomer, typically held below 0.10 area‑% for high‑purity grades.
A large‑volume application of 4‑methylthiazole‑5‑carboxaldehyde is its conversion to 4‑methylthiazole‑5‑carboxylic acid (CAS 20485-39-2) followed by activation and coupling to 2‑aminothiazole‑4‑acetic acid derivatives — the side‑chain pharmacophore of several third‑generation cephalosporins. In a representative 50 L glass‑lined reactor (De Dietrich, jacket temperature control ±0.5 °C), the aldehyde is first oxidised with 35 wt% hydrogen peroxide in the presence of 0.5 mol% sodium tungstate dihydrate at pH 6.5–7.0, maintained by automated dosing of 2M NaOH through a Masterflex L/S peristaltic pump fitted with Tygon LFL tubing. The oxidation is terminated when residual aldehyde by inline ReactIR 15 (Mettler‑Toledo) falls below the detection limit at the characteristic carbonyl stretch 1690 cm⁻¹ (S/N ≥ 10). At this point any unreacted aldehyde above 0.05 area‑% carries through to the subsequent acyl chloride formation and imparts a persistent yellow colour to the crystalline acid chloride hydrochloride, an attribute that directly increases batch rejection rates under ICH Q7 visual acceptance criteria.
The critical quality attribute is the regioisomeric purity. When the 5‑methyl‑4‑formyl isomer exceeds 0.10 area‑%, the corresponding 5‑methyl‑4‑carboxylic acid co‑crystallises with the desired 4‑methyl‑5‑carboxylic acid during isopropanol‑water polishing (35 °C, solvent ratio 70:30 v/v), reducing the isolated yield of the 99.7% (w/w) acid from a baseline of 92% to 75–78% and requiring two additional re‑slurries to achieve the specification for the subsequent thionyl chloride‑mediated activation. A process‑scale HPLC method employing a C18 column (150 × 4.6 mm, 5 µm; mobile phase 0.1% phosphoric acid‑acetonitrile gradient) resolves the isomeric acids with a resolution Rs > 2.0 and a limit of quantitation of 0.03 area‑%. Plant‑scale batches routinely deliver a crude acid with 99.6 area‑% purity when the aldehyde feed carries < 0.08% of the 5‑methyl isomer; every 0.10% increase in the isomer correlates with an additional 1.8% loss in crystallisation yield (n = 18, Pearson r = −0.94).
Residual water in the aldehyde is the second most impactful parameter. The acid‑chloride activation step with thionyl chloride in toluene at 55–60 °C generates HCl and SO₂; water levels above 0.10 wt% (Karl‑Fischer titration, ASTM E1064‑23) lead to premature hydrolysis of the intermediate acid chloride, forming the undesired carboxylic acid dimer and reducing the stripping efficiency of the subsequent ammonia‑methanol amidation. Pre‑drying of the aldehyde over activated 3Å molecular sieves (20 wt% loading, 24 h under static nitrogen) reduces water to 0.03–0.05% and is considered mandatory for processes that target API‑grade intermediates with a single‑digit parts‑per‑million palladium carry‑over from downstream catalytic hydrogenolysis. In the absence of pre‑drying, amidation stoichiometry drifts, yielding 3–5% unreacted acid chloride that subsequently forms insoluble disulfide‑bridged by‑products detectable by LC‑MS (m/z 368.1).
Comparative lot‑release data from two commercial purity tiers illustrates the operational consequence of isomeric control. High‑purity material is primarily drawn into cGMP manufacturing where downstream alkoxyimino‑acetamido coupling demands strict identity testing; the technical grade finds utility in pilot‑scale heterocyclic library synthesis where an additional recrystallisation is built into the workflow. Table 2 presents the typical certificate‑of‑analysis profiles aligned with internal control limits assessed by GC‑FID (ISO 760:1978 water procedure adapted) and LC‑UV.
| Parameter | High‑purity grade (HP) | Technical grade (TG) |
|---|---|---|
| Assay (GC‑FID, area‑%) | ≥ 99.5 | ≥ 95.0 |
| 5‑Methylthiazole‑4‑carboxaldehyde | ≤ 0.08 | ≤ 2.0 |
| 2‑Methylthiazole‑4‑carboxaldehyde | ≤ 0.05 | ≤ 1.5 |
| Water (Karl‑Fischer) | ≤ 0.05 wt% | ≤ 0.3 wt% |
| APHA colour (undiluted) | ≤ 50 | ≤ 200 |
| Heavy metals (as Pb) | ≤ 5 ppm | ≤ 20 ppm |
Orthogonal identity confirmation via ¹H‑NMR (400 MHz, CDCl₃) reveals the absence of the diagnostic aldehyde singlet at δ 10.05 ppm that would appear in the 5‑methyl‑4‑formyl isomer, while LC‑MS in positive ion mode (ESI⁺) is used to screen for aldol condensation dimers that accumulate in material stored beyond the retest window without inert‑gas protection.
In flavour manufacturing, the aldehyde serves as a precursor to 4‑methyl‑5‑thiazoleethanol (FEMA GRAS 3204) via catalytic hydrogenation over Raney Ni at 35 °C and 5 bar H₂. Distillative work‑up under reduced pressure (10 mbar, pot temperature 85 °C) yields a fraction meeting EU 10/2011 overall migration limits with residual aldehyde consistently below 1 mg kg⁻¹ in the final food‑grade concentrate. The low‑volatile impurity profile of the HP grade eliminates the need for a sulfolane‑based extractive distillation step that would otherwise be required to separate the 5‑methyl isomer‑derived alcohol (odour threshold 0.2 µg L⁻¹ in water).
Stored under a N₂ blanket at 4–8 °C in 25 kg HDPE drums with PTFE‑lined bung closures, the compound exhibits 0.2% degradation per year, primarily via base‑catalysed aldol dimerisation. Adiabatic calorimetry (ASTM E1981‑22) recorded a 28 °C temperature rise within 15 min upon mixing equimolar n‑butylamine — a vigorous reaction that mandates segregated storage and precludes direct combination with amine‑based additives in formulated product lines. For processing lines where pre‑drying is essential, vacuum stripping at 40 °C and 5 mbar for 1 h immediately before use is recommended to achieve a water specification compatible with moisture‑sensitive alkoxyimino‑ester formations.
