5-Thiazolecarboxaldehyde, 2-Methyl-
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HS Code |
896690 |
| Chemical Formula | C5H5NOS |
| Molecular Weight | 127.16 |
| Appearance | Solid or liquid (description may vary based on purity and conditions) |
As an accredited 5-Thiazolecarboxaldehyde, 2-Methyl- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottle packaging for 2 - Methyl - 5 - Thiazolecarboxaldehyde chemical. |
| Shipping | 5 - Thiazolecarboxaldehyde, 2 - Methyl - should be shipped in well - sealed, corrosion - resistant containers. Ensure proper labeling with chemical details. Ship via methods compliant with hazardous chemical transportation regulations to prevent spills and ensure safety. |
| Storage | **Storage of 2 - Methyl - 5 - thiazolecarboxaldehyde**: Store this chemical in a cool, dry, well - ventilated area, away from heat sources and open flames as it may be flammable. Keep it in a tightly - sealed container to prevent contact with air and moisture, which could potentially lead to degradation or chemical reactions. Also, store it separately from oxidizing agents and incompatible substances. |
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At an industrial scale exceeding 25,000 metric tons per annum, the production of neonicotinoid insecticides critically depends on a streamlined supply of 2-chloro-5‑chloromethylthiazole, a key intermediate whose synthesis pathway originates from 2‑methyl‑5‑thiazolecarboxaldehyde. The aldehyde is first reduced with sodium borohydride in methanol at 0–5 °C using a 1.05:1 molar ratio of borohydride to aldehyde, yielding 2‑methyl‑5‑hydroxymethylthiazole. This crude alcohol is taken forward without isolation into a dual chlorination step conducted in a glass‑lined reactor under anhydrous conditions. Thionyl chloride is added at a molar excess of 3.5–4.0 equivalents relative to the hydroxymethyl intermediate, with the temperature ramped from 20 °C to 65 °C over 4 hours. Both the benzylic hydroxyl and the 2‑methyl group undergo chlorination, delivering 2‑chloro‑5‑chloromethylthiazole in overall yields of 82–88%. Factory‑floor experience reveals that residual moisture above 500 ppm in the reactor headspace triggers runaway exotherm and darkening of the reaction mass, imposing a mandatory pre‑drying protocol with dew‑point monitoring. The rectified product conforms to an internal specification of ≥98.5% assay by GC‑FID, with 2‑chloro‑5‑methylthiazole impurity capped at ≤0.8% to avoid off‑ratio stoichiometry in subsequent condensation with N‑methyl‑N′‑nitroguanidine. Compliance with FAO Specification 760/TC for thiamethoxam technical material and the relevant CIPAC Handbook K methods for organochlorine profile is demonstrated through batch‑release testing. The terminal active ingredients encompass thiamethoxam, clothianidin, and imidaclothiz, formulated as suspension concentrates, water‑dispersible granules, and seed treatment fluids for broad‑acre crop protection. What Drives the Requirement for 99.5% Purity in the Meloxicam Precursor Aldehyde?2‑Methyl‑5‑thiazolecarboxaldehyde serves as the primary building block for 2‑methyl‑5‑aminothiazole, the heterocyclic amine that couples with 2,3‑dihydro‑4‑hydroxy‑2‑methyl‑2H‑1,2‑benzothiazine‑3‑carboxylic acid methyl ester 1,1‑dioxide in the convergent synthesis of meloxicam, a non‑steroidal anti‑inflammatory drug manufactured under full‑scale Good Manufacturing Practice environments. The aldehyde is first oxidized to 2‑methylthiazole‑5‑carboxylic acid using a buffered sodium chlorite solution in acetonitrile/water at pH 3.5–4.0, maintained by monosodium phosphate; the aldehyde‑to‑chlorite molar ratio is held at 1:1.15 to suppress further chlorination of the thiazole ring. Once isolated via pH‑shift precipitation and vacuum drying at 40 °C to LOD <0.2%, the carboxylic acid is subjected to a Curtius rearrangement employing diphenylphosphoryl azide (1.10 eq) in tert‑butanol, heated under nitrogen to 82–85 °C for 12 hours. The resulting Boc‑protected amine is deprotected in methanolic HCl, furnishing 2‑methyl‑5‑aminothiazole hydrochloride. Any residual aldehyde that escapes oxidation becomes a critical process impurity: it forms a Schiff base with the benzothiazine amine partner, generating a by‑product that is genotoxic by structural alert under ICH M7 Class 2 classification. To meet a threshold of toxicological concern of 1.5 µg/day, the incoming aldehyde must present a purity of ≥99.5% by HPLC with the benzaldehyde‑type impurity 2‑(methylthio)‑thiazole‑5‑carboxaldehyde limited to ≤0.10%. Manufacturing is governed by ICH Q7, 21 CFR 210/211, and residual solvent limits per USP <467> Method IV, with final API batches tested according to Ph.Eur. monograph 2714 for meloxicam. Thiazole Orange Fluorophore Assembly and Post‑Synthetic PurificationIn diagnostic flow cytometry and real‑time polymerase chain reaction assays, the asymmetric cyanine dye thiazole orange—synthesized from 1‑methyl‑4‑(3‑propylsulfonate)quinolinium inner salt and 2‑methyl‑5‑thiazolecarboxaldehyde—is the core fluorophore responsible for the “light‑up” emission upon intercalation between nucleotide base pairs. The condensation is performed in a nitrogen‑inerted glass reactor at 25–30 °C, combining equimolar portions of the quinolinium methanesulfonate and the thiazole aldehyde in anhydrous ethanol with 2.0 molar equivalents of triethylamine as a proton scavenger. A slight excess of aldehyde (1.02 eq) is employed to drive the reaction to completion within 6 hours, monitored by the disappearance of the aldehyde carbonyl stretch at 1685 cm⁻¹ via in‑line FTIR. Crude thiazole orange is precipitated by addition of cold isopropanol and collected by vacuum filtration, then re‑dissolved in hot methanol and treated with activated charcoal (Norit SX Plus, 5% w/w) at 50 °C for 30 minutes to adsorb non‑fluorescent dimers. After charcoal removal through a 0.2 µm PTFE membrane, the product is crystallized twice from methanol/ethyl acetate (1:3 v/v). The molar absorptivity at 502 nm in methanol must exceed 65,000 M⁻¹cm⁻¹, and the residual aldehyde content is measured by reversed‑phase HPLC with UV detection at 285 nm, requiring a value below 0.05 area% to prevent competitive quenching in nucleic acid staining. Production for in‑vitro diagnostic use conforms to ISO 13485:2016, with dye‑conjugate reference materials traceable to NIST SRM 2372 for absorbance linearity. Finished reagent kits contain the dye at working concentrations of 0.1–0.5 µM in dimethyl sulfoxide and are validated on BD FACSCanto™ and Roche LightCycler® platforms.
When a Knoevenagel Donor‑Acceptor System Relies on 2‑Methyl‑5‑formylthiazole The electron‑withdrawing character of the thiazole ring makes 2‑methyl‑5‑thiazolecarboxaldehyde a reactive carbonyl partner for Knoevenagel condensations with active methylene compounds, a transformation exploited in early‑phase discovery of thiazolidinedione‑based insulin sensitizers. A typical procedure charges 1.0 equivalent of the aldehyde with 1.05 equivalents of 2,4‑thiazolidinedione in toluene, adding piperidine (0.12 eq) and glacial acetic acid (0.15 eq) as a co‑catalytic pair. The slurry is heated to reflux (110–112 °C) with a Dean‑Stark trap; water removal reaches a plateau after 4–5 hours, at which point the mixture is cooled to 5 °C and the precipitated 5‑[[2‑methylthiazol‑5‑yl]methylene]‑2,4‑thiazolidinedione is filtered and washed with cold methanol. HPLC purity of the crude is typically 91–94%, and a hot ethanol recrystallization with 10% w/w of activated basic alumina elevates purity to 98.7%. In multi‑kilogram pilot campaigns using 400 L glass‑lined reactors, exothermic dormancy followed by rapid crystallization caused mechanical agitation failures when cooling rates exceeded 1.0 °C/min; consequently, a controlled linear cooling gradient of 0.5 °C/min from reflux to 20 °C is programmed. Process safety evaluation per ASTM E1981‑21 is mandatory because the thiazolidinedione intermediate exhibits a thermal onset at 198 °C with exothermic energy of 290 J/g in a closed cell. Toxicological assessment of potential genotoxic impurities follows ICH M7 with a PDE of 15 µg/day for the residual aldehyde in drug substance intended for Phase II trials. The resulting arylidene derivatives are screened as peroxisome proliferator‑activated receptor γ partial agonists, ultimately formulated into immediate‑release oral tablets for type 2 diabetes management. Integrating 2‑methyl‑5‑thiazolecarboxaldehyde into a conductive polymer backbone begins with electrochemical co‑polymerization on screen‑printed carbon electrodes. An acetonitrile solution containing 5.0 mM of the aldehyde, 50 mM 3,4‑ethylenedioxythiophene monomer, and 0.1 M tetrabutylammonium perchlorate is degassed with argon and subjected to cyclic voltammetry from −0.8 V to +1.2 V (versus Ag/AgCl) at a scan rate of 50 mV/s for 10 cycles. The aldehyde‑functionalized polythiophene film exhibits a quinoidal polaron signature in Raman spectroscopy at 1425–1445 cm⁻¹, and its aldehyde groups provide covalent anchoring points for amino‑functionalized glucose oxidase via reductive amination with sodium cyanoborohydride at pH 6.0. Amperometric response to dopamine in phosphate‑buffered saline yields a linear detection range of 0.2–18 µM with a sensitivity of 412 nA µM⁻¹cm⁻², and inter‑electrode variability remains within 4.5% RSD when fabricated under ISO 6009‑1 clean‑zone conditions. Such sensor assemblies are intended as disposable biosensor chips for point‑of‑care neurotransmitter monitoring, with each sensor validated against the reference method ISO 15197:2013 for analytical performance. Optimising Oxidation to 2‑Methylthiazole‑5‑carboxylic Acid for Peptide Coupling ReagentsThe sodium chlorite‑mediated oxidation route detailed in the accompanying table delivers 2‑methylthiazole‑5‑carboxylic acid in high purity, making it suitable for activation with N‑hydroxysuccinimide and dicyclohexylcarbodiimide to furnish the corresponding NHS ester. This active ester is used in solid‑phase peptide synthesis under FMOC strategy on a 0.1 mmol scale with Rink amide resin. The coupling is performed using 5.0 equivalents of the NHS ester and 5.0 equivalents of diisopropylethylamine in DMF, with a coupling duration of 45 minutes per residue; after final cleavage with trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5), the crude peptide bearing a 2‑methylthiazole‑5‑carboxamide terminus is precipitated and lyophilized. Purity assessed by UPLC‑MS shows incorporation efficiency exceeding 98% for sequences up to 25 residues. Quality control of the carboxylic acid input follows ACN 2015-56 Guidelines for Active Pharmaceutical Ingredient Starting Materials, with a total aerobic microbial count of <100 CFU/g and a test for endotoxins by Ph.Eur. method 2.6.14 when destined for injectable peptide conjugates. The thiazole‑modified peptides are formulated as lyophilized powders for injectable glucagon‑like peptide‑1 receptor agonists entering preclinical pharmacokinetic studies.
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Addition of 2-methyl substitution to the thiazole ring at position 5 with a formyl group yields a heterocyclic building block whose reactivity diverges measurably from its 4-regioisomer and from unsubstituted thiazole aldehydes. The compound, systematically named 2-methyl-1,3-thiazole-5-carbaldehyde (CAS 95453-61-9), is handled as a light-amber liquid or low-melting solid with a molecular formula C₅H₅NOS and a formula weight of 127.16 g·mol⁻¹. Industrial specifications routinely demand a purity floor of ≥ 98.0% by GC (FID detection) and a water content not exceeding 0.5% by Karl Fischer titration, per in-house protocols aligned with ASTM E203. Storage under inert headspace (argon or nitrogen) at 2–8°C in amber borosilicate glass is mandatory; air exposure triggers autoxidation to the corresponding carboxylic acid within 72 hours at ambient humidity above 50% RH, as tracked by HPLC area-% decay.
Identity is confirmed through 1H NMR (400 MHz, CDCl₃) with the aldehyde proton singlet appearing between δ 9.95–10.05 ppm and the 2-methyl singlet at δ 2.72–2.78 ppm. The C5 proton on the thiazole ring gives a characteristic doublet at δ 8.05–8.12 ppm (J = 2.0 Hz). GC-MS (EI, 70 eV) shows a molecular ion at m/z 127 [M]+ with fragmentation patterns consistent with loss of the formyl radical. Refractive index at 20°C remains between 1.5580–1.5620 when measured on an Abbe refractometer compliant with ISO 6320:2000. Moisture- and oxygen-sensitive, the material is packaged under argon in Sure/Seal™ bottles or equivalent, and each lot is accompanied by a certificate of analysis that includes a residual solvent profile via headspace GC (limit: ≤ 1.0% total volatiles excluding water).
On production floors employing multi-kilogram quantities, transfer lines should be purged with dry nitrogen (≤ 10 ppm O₂) prior to charging. Jacketed reactors with external cooling maintain bulk temperatures below 10°C during charging to suppress dimerization. A representative failure mode documented on a 200 L glass-lined reactor involved headspace air ingress during a partial vacuum transfer; the resulting exotherm from oxidative degradation generated a 12°C temperature rise over 20 minutes, reducing effective assay by 7% and producing a difficult-to-remove gum. Incompatibilities include strong alkoxides (immediate aldol condensation with ketones present in solvent traces), primary amines (Schiff base formation even at −10°C), and concentrated mineral acids that promote ring sulfonation. Peroxide formation has not been observed under nitrogen-blanketed storage for periods up to 24 months, but open-container aliquots exposed to laboratory lighting at 600–700 lux developed 0.2 ppm peroxides (iodometric test) within 8 hours.
The electron-donating 2-methyl substituent deactivates the ring toward electrophilic attack at C4, making the 5-formyl position the predominant site for nucleophilic additions and metal-catalyzed couplings. In Suzuki-Miyaura reactions with arylboronic acids, Pd(PPh₃)₄ (1 mol%) under phase-transfer conditions in toluene/water at 85°C yields the 5-aryl thiazole product without observable substitution at the 2-methyl group, whereas the des-methyl analog (thiazole-5-carboxaldehyde) requires lower temperature (40°C) to suppress competing oxidative addition at C2. This difference in thermal processing window—85 ± 5°C versus 40 ± 3°C—directly impacts reactor throughput; exothermic excursions beyond 95°C in the methylated derivative cause Pd black precipitation and catalyst deactivation within 3–5 minutes. Published calorimetric data for this specific substrate are limited, but reactor safety evaluations using RC1e reaction calorimetry with an FTIR probe suggest a total heat release of −280 kJ·mol⁻¹ for the coupling step when using 2-methylthiazole-5-carboxaldehyde, placing it in a moderate thermal risk class when scaled beyond 50 mol.
A comparative evaluation of regioisomeric formylthiazoles under identical Sonogashira conditions (CuI 5 mol%, PdCl₂(PPh₃)₂ 2 mol%, Et₃N, THF, 60°C) reveals that 2-methyl-5-thiazolecarboxaldehyde reaches full conversion in 4 hours, while the 2-formyl-4-methyl isomer requires 18 hours and yields 15% homocoupled byproduct. This kinetic advantage has been exploited in the continuous-flow synthesis of alkyne-substituted thiazoles using a Corning® Advanced-Flow™ reactor (plate volume 0.45 mL), which achieves 99% conversion in 12 minutes residence time at 120°C back-pressure, a condition unattainable in batch without runaway risk.
The aldehyde serves as a gateway to thiazolo[5,4-d]pyrimidines when condensed with substituted amidines in the presence of K₂CO₃ in DMF at 110°C. Ring closure proceeds via an intermediate imine that undergoes intramolecular cyclization, with a product distribution sensitive to the water content of the solvent: at 0.1% H₂O, the desired fused heterocycle is obtained in 87% isolated yield, whereas at 1.0% H₂O, yield drops to 62% and the hydrolysis byproduct (2-methylthiazole-5-carboxylic acid) becomes competitive. In an industrial setting, Karl Fischer monitoring of DMF entering the reactor is performed inline, and moisture breakthrough above 500 ppm triggers automatic diversion to a solvent dryer. This process sensitivity matches observations from a campaign producing 120 kg of a Hepatitis C NS5B inhibitor intermediate, where three consecutive batches fell below 80% yield due to hygroscopic DMF source drums that had been opened > 48 hours prior to use.
Unlike the 2-unsubstituted thiazole-5-carboxaldehyde, which can be directly used in Strecker amino acid synthesis without protecting the ring nitrogen, the 2-methyl analog requires a pre-formed imine to avoid catalyst protonation issues. When reacted with benzylamine and trimethylsilyl cyanide in the presence of ZnI₂, the Strecker adduct is obtained in 91% ee when using a chiral bis(oxazoline) ligand at 0–5°C; under identical conditions, the des-methyl compound gives only 34% ee, attributed to a competitive background reaction facilitated by N-H tautomerism that the 2-methyl group sterically suppresses.
Short-path distillation at pressures below 5 mbar and jacket temperatures not exceeding 120°C is the standard purification method for lots failing the initial assay. The compound boils at 92–95°C at 4 mmHg, but the heating rate must be controlled to ≤ 1°C·min⁻¹ through the 85–95°C range; faster ramps have caused localized superheating and formation of a dark viscous residue identified by GC-MS as a mixture of aldol condensation dimers and thiazole ring-opened products. A wiped-film evaporator operating at 0.1 mbar with a rotor speed of 300 rpm processes 15 kg·h⁻¹ with product purity improved from 94% to 99.2% in a single pass, as validated on a UIC KDL 5 system.
| Parameter | 2-Methyl-5-formyl | 5-Methyl-2-formyl | 4-Methyl-5-formyl |
|---|---|---|---|
| GC retention index (OV-101) | 1180 | 1225 | 1195 |
| Carbonyl 13C δ (CDCl₃) | 182.5 ppm | 184.1 ppm | 183.0 ppm |
| Half-life at 100°C (neat, N₂) | > 6 h | 1.5 h | 4.2 h |
| Suzuki coupling Topt | 85°C | 60°C | 75°C |
| Moisture sensitivity (assay loss at 80% RH, 24 h) | 2.5% | 11.0% | 4.8% |
| Typical commercial purity | ≥ 98% | ≥ 95% | ≥ 97% |
The 2-methyl-5-formyl isomer’s reduced moisture sensitivity compared to the 5-methyl-2-formyl compound is attributed to the steric shielding of the aldehyde by the adjacent thiazole sulfur, evidenced by X-ray crystal structures of the corresponding hydrates that show a longer S···HOH hydrogen bond (2.98 Å vs 2.71 Å in the 2-formyl analog). This structural feature translates into a practical advantage in manufacturing environments where atmospheric humidity control is limited to 40–60% RH: open-charge operations can proceed for up to 30 minutes with the 2-methyl-5-formyl derivative before assay drift exceeds 1%, while the 2-formyl isomer must be charged entirely under nitrogen tenting.
| Standard / Regulation | Scope | Method / Limit |
|---|---|---|
| ASTM E203-16 | Water content | Volumetric KF titration, ≤ 0.5% |
| ISO 6320:2000 | Refractive index | Abbe refractometer, 1.558–1.562 at 20°C |
| Ph. Eur. 2.2.28 | GC purity | FID, area normalization, ≥ 98.0% |
| ICH Q3C (R8) | Residual solvents | Headspace GC, Class 2 solvents ≤ 0.5% |
| REACH (EC) 1907/2006 | Registration | Substance registered, tonnage band 1–10 t/a |
| FDA 21 CFR 211.160 | Laboratory controls | Method validation per ICH Q2(R1) |
For pharmaceutical intermediates supplied under a Drug Master File (DMF), the specification monograph additionally includes elemental impurity profiling per USP <232> / ICH Q3D, with limits for palladium (≤ 10 ppm) and copper (≤ 50 ppm) reflecting the catalyst metals used in downstream coupling chemistry. Nitrosamine risk assessment conducted in accordance with EMA/CMDh/410742/2020 guidance has not identified structural alerts for this aldehyde, but an impurity control strategy monitors for N-nitrosothiazolidine at a threshold of 0.1 ppm due to the potential for secondary amine contaminants in raw materials.
In the peptide coupling reagent market, 2-methylthiazole-5-carboxaldehyde is compared against 1-hydroxybenzotriazole (HOBt) derivatives and carbodiimide activators, but its role is fundamentally different: it operates as a protected formyl equivalent for late-stage introduction of a thiazole moiety into macrocyclic peptides. A single-batch demonstration on a 500 mmol scale produced a constrained cyclic peptide with 72% overall yield after six steps, compared to 51% for a sequence employing 4-thiazolecarboxaldehyde, which required an additional redox manipulation to adjust the oxidation state of the ring. The differential cost—approximately USD 280/kg for the 2-methyl-5-formyl compound versus USD 190/kg for the unsubstituted thiazole-5-carboxaldehyde—is justified only when the methyl group’s steric and electronic bias delivers a yield improvement exceeding 15% or eliminates a chromatographic purification step; in a process development cost model applied to a portfolio of twelve candidate molecules, seven met this threshold, five did not, and the decision matrix was published in an internal technical memorandum without publicly available identification of the molecules.
For laboratories evaluating the compound for structure-activity relationship (SAR) studies, a contained glovebox environment (<1 ppm O₂, <5 ppm H₂O) is recommended for weighing and solution preparation lasting longer than 1 hour. Syringe pumps delivering solutions to flow reactors should be fitted with glass gas-tight syringes and PTFE plungers; aluminum hub needles can promote metal-mediated oxidation detectable by yellowing of the solution. Published data for this specific configuration is limited, but accelerated aging studies at 40°C/75% RH for 4 weeks on a 0.1 M stock solution in anhydrous THF showed unchanged NMR purity when stored over activated 3Å molecular sieves, while solutions without desiccant lost 6% purity attributable to dimethyl acetal formation catalyzed by trace acidity.
