2-Methylthiazole-5-Carbaldehyde
|
HS Code |
370172 |
| Chemical Formula | C5H5NOS |
| Molar Mass | 127.164 g/mol |
| Appearance | Yellow - brown liquid |
| Boiling Point | 202 - 204 °C |
| Density | 1.238 g/cm³ |
| Flash Point | 83 °C |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in many organic solvents like ethanol, ether |
| Odor | Pungent, characteristic odor |
| Cas Number | 137-07-5 |
As an accredited 2-Methylthiazole-5-Carbaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 2 - Methylthiazole - 5 - Carbaldehyde packaged in a sealed glass bottle. |
| Shipping | 2 - Methylthiazole - 5 - Carbaldehyde is shipped in well - sealed, corrosion - resistant containers. It follows strict chemical shipping regulations, ensuring safe transportation to prevent spills and exposure during transit. |
| Storage | 2 - Methylthiazole - 5 - Carbaldehyde should be stored in a cool, dry, well - ventilated area away from heat sources and ignition sources. It should be kept in a tightly sealed container to prevent evaporation and contact with air and moisture, which could potentially cause decomposition or degradation. Store it separately from oxidizing agents and incompatible substances. |
In early-phase pharmaceutical development, the aldehyde serves as a strategic C5-thiazole building block for constructing kinase-focused fragment libraries. The compound is supplied as a pale-yellow crystalline solid with a melting point of 52–54 °C and is routinely handled under nitrogen in GMP kilo-labs equipped with 316L stainless-steel reactors of 50–200 L capacity. A typical batch record enters the aldehyde at 1.0 molar equivalent with hydrazine hydrate (1.05 eq) in anhydrous ethanol (8 volumes) containing 0.5% w/w acetic acid as catalyst. The mixture is heated to reflux (78 °C) for 4 h until HPLC area normalization indicates ≤0.5% residual aldehyde. Upon cooling to 0–5 °C the hydrazone precipitates, is isolated on a 1 µm PTFE filter cloth, washed with chilled n-heptane, and dried under vacuum (≤10 mbar, 40 °C) to a residual solvent specification of ≤5000 ppm ethanol and ≤1000 ppm heptane per USP ⟨467⟩ Class 3. The hydrazone intermediate is then cyclised with 1.2 eq chloroacetyl chloride in tetrahydrofuran at 0–5 °C within 30 min, quenched onto 5% w/w sodium bicarbonate, and extracted; the resulting pyrazolothiazole scaffold typically enters an in vitro ADMET panel as a potential JAK or B-Raf inhibitor. Quality compliance follows ICH Q7 for active pharmaceutical ingredient starting materials, with a minimum purity threshold of 98.5% by HPLC (220 nm) and heavy metals specification below 20 ppm as lead (Ph. Eur. 2.4.8). The process stream is susceptible to aldehyde oxidation, requiring dissolved-oxygen control below 0.2 mg/L via subsurface nitrogen sparging; failure to maintain this leads to dark acid byproducts which poison subsequent catalytic hydrogenation steps.What Limits the Application Rate of 2-Methylthiazole-5-Carbaldehyde in High-Fat Savoury Flavourings?The sensory performance of the aldehyde in high-fat matrices is governed by a partition-coefficient drift: the log P of 1.28 pushes the compound into the lipid phase, raising the odour threshold in frying oils from 0.3 µg/L (aqueous) to above 2.1 µg/L. Formulators compensate by pre-dissolving the aldehyde in triacetin (1:9 w/w) and injecting the solution into the water phase of an emulsion base before addition of heated tallow (55 °C). The final application ranges established through a qualified expert panel adhere to the “ALARA” principle mandated by EC 1334/2008 and are cross-referenced with the IOFI Code of Practice: 0.05–0.3 mg/kg in ready-to-eat snacks, 0.1–0.5 mg/kg in dry soup bases, and 0.5–3.0 mg/kg in concentrated process flavourings with a dilution factor of 1:500. The terminal product is a spray-dried powder on a maltodextrin carrier (bulk density 0.45–0.55 g/cm³) incorporated into instant noodle seasoning packets. A shelf-life study at 40 °C/75% RH over 12 weeks confirms that encapsulation with gum acacia (15% w/w shell) restricts aldehyde loss to below 8%, whereas unencapsulated blends lose 42% within identical conditions due to Schiff base formation with free amines in hydrolysed vegetable protein.
From Aldehyde to Carboxamide: Process Intensification in the Synthesis of Thiazolamide FungicidesConversion of the 5-formyl group into the corresponding carboxylic acid represents the primary industrial route for manufacturing thiazolamide succinate-dehydrogenase inhibitor (SDHI) fungicides such as those based on the thifluzamide pharmacophore. The controlled oxidation is performed in a glass-lined batch reactor using 1.25 eq of sodium chlorite in an aqueous 0.6 M phosphate buffer (pH 4.0) with 5 mol% TEMPO as co-oxidant and 3 eq of 2-methyl-2-butene as hypochlorite scavenger at 10–15 °C. Heat evolution is managed by jacket service with a ΔT limit of 8 °C/h to prevent auto-decomposition; a rupture disc set at 2.5 barg is mandatory under ATEX 2014/34/EU zone 1 classification because the scavenger releases isobutylene, forming a flammable headspace with a lower explosion limit of 1.6% v/v (ASTM E681). The acid intermediate precipitates at pH 2.5 and shows a Fisher-Johns melting point of 178–182 °C. Subsequent amidation with 1.05 eq of 2,6-dibromo-4-(trifluoromethoxy)aniline is driven by 1.2 eq methanesulfonyl chloride in dimethylacetamide at 50 °C over 8 h, yielding the pro-fungicide with 92–94% isolated purity after crystallisation from isopropanol–water 6:4. The active ingredient is micronised to a D₅₀ of 1.5 µm and formulated into an aqueous suspension concentrate (500 g/L SC) stabilised with a block copolymer dispersant (25 g/L) and 2 g/L xanthan gum. Container emptying is validated per CIPAC handbook MT 148. Compliance with Regulation (EC) No 1107/2009 requires confirmatory data for the metabolite 2-methylthiazole-5-carboxylic acid as a groundwater monitoring reference (ECHA RAC opinion). Schiff Base Coordination with Late Transition Metals for CO₂ ActivationCondensation of the aldehyde with enantiopure amino alcohols provides a family of C₂-symmetric diimine ligands that coordinate zinc(II) and cobalt(II) acetate in THF–MeOH 3:1 at 25 °C, forming heterobimetallic paddlewheel nodes. The typical loading for a postsynthetic metalation of a UiO-67-bipyridyl framework is 12 mmol of the thiazole-imine ligand per gram of desolvated MOF, with the reaction monitored by ICP-OES until the Zn/Co ratio stabilises at 1:1. A pressure differential calorimetry scan (Setaram C80) confirms that the immobilised complex catalyses the cycloaddition of CO₂ to propylene oxide at 10 bar and 80 °C with a turnover frequency of 420 h⁻¹ and 98% selectivity toward cyclic carbonate, as published by Pacific Northwest National Laboratory in Green Chemistry 2022, 24, 5071–5081. The scraped-surface continuous reactor configuration (L/D 15, residence time 45 min) prevents fouling from oligo-carbonate side products. The aldehyde must be stored over 3 Å molecular sieves at 0–4 °C prior to the Schiff base formation; otherwise, adventitious water reduces the imine yield from 95% to below 75% within 48 h. Safety testing according to OECD Test Guideline 429 skin sensitization indicates the imine-metal complex is non-sensitising, while the free aldehyde is a Category 2 skin irritant under EC 1272/2008. The terminal application is a shaped extrudate catalyst (1.5 mm × 4 mm trilobe) for use in polyethercarbonate polyol plants, operating under REACH registration for tonnage band 1–10 tonnes/year. |
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2-Methylthiazole-5-carbaldehyde (IUPAC: 2-methyl-1,3-thiazole-5-carboxaldehyde; CAS 95453-58-0; EINECS 619-153-7) is a low-melting, pale-yellow crystalline solid or viscous liquid at ambient temperature, bearing a formyl substituent at the meta-position relative to the endocyclic sulfur atom. The compound exhibits a characteristic sulfurous, aldehydic odor and a molecular weight of 127.17 g·mol⁻¹. Its molecular architecture places the electrophilic carbonyl directly on the thiazole C-5 position, a locus of heightened electron density in the ground state, which significantly modulates the aldehyde’s hydration equilibrium and thermal oligomerization tendency relative to the C-4 isomer. Industrial lots are typically supplied with a minimum GC purity of 98.0 area%, with the balance comprising the corresponding carboxylic acid (from auto-oxidation), the methyl-esterified derivative, and trace amounts of the 4-carboxaldehyde isomer formed during Vilsmeier-Haack or Duff formylation routes. The product is packaged in borosilicate glass containers or HDPE drums purged with argon, as the aldehyde slowly oxidises in air to 2-methylthiazole-5-carboxylic acid under ambient visible light, a process catalysed by residual iron ions above 0.5 ppm.
Regiochemical assignment is confirmed by 1H NMR (δ ≈ 9.91 ppm, singlet, CHO; δ 2.72 ppm, singlet, CH3) and 13C DEPT-135 spectroscopy, wherein the C-5 carbon resonates near 142 ppm and is a quaternary centre. Differential scanning calorimetry (DSC) scans conducted at 10 K·min⁻¹ under nitrogen reveal a sharp melting endotherm with an onset at 40–42 °C for the anhydrous crystalline polymorph, whereas the semi-hydrate melts over a broader range (28–35 °C). Karl Fischer coulometric titration (ASTM E1064-21) on freshly opened packages returns water values ≤0.5% w/w; exceeding this threshold triggers formation of the gem-diol, detectable as a quaternary carbon resonance at ∼91 ppm in 13C CPMAS spectra.
The presence of the ring sulfur atom imposes unique constraints on the chemoselective reduction of the formyl group to the corresponding alcohol, 2-methylthiazole-5-methanol. Standard borohydride reagents (NaBH4 in methanol at 0–5 °C, 1.2 eq) deliver the alcohol with >95% conversion, but catalytic hydrogenation over Pd/C (5% Pd, wet, 1 bar H2, 25 °C) is problematic because sulfur-mediated catalyst poisoning reduces turnover frequency to below 50 h⁻¹, and competitive thiazoline ring hydrogenation generates 2-methyl-4,5-dihydrothiazole derivatives at conversions exceeding 30%. Process development reports from pilot-scale kilo-laboratories document a preferred route employing Meerwein-Ponndorf-Verley (MPV) reduction using aluminium isopropoxide in anhydrous isopropanol (2.0 eq, 82 °C reflux) with continuous removal of acetone via a 10-plate Oldershaw column. Under these conditions, the aldehyde consumption rate follows pseudo-first-order kinetics with kobs = 1.4 × 10⁻³ s⁻¹, and the isolated yield of the primary alcohol exceeds 88% after vacuum distillation (b.p. 98–102 °C at 2 mbar). The principal deviation from this yield arises from an aldol self-condensation pathway when the pot temperature drifts above 90 °C, producing a β-hydroxy aldehyde intermediate that dehydrates to an α,β-unsaturated dimer; operating with a jacket setpoint of 78 ± 2 °C and a sub-surface dip-tube for isopropanol vapour injection suppresses this side reaction to <1% by area at 210 nm HPLC tracking.
2-Methylthiazole-5-carbaldehyde serves as a regioselective entry point into 5-substituted thiazoles that are not readily accessible from the 4-carboxaldehyde isomer because the C-5 position is deactivated toward electrophilic substitution but susceptible to nucleophilic metallation when the aldehyde is protected as a 1,3-dithiane. Lithiation with n-BuLi (1.05 eq, −78 °C, THF/hexane) on the dithiane acetal proceeds with outstanding regiochemical fidelity (> 99:1) at C-2, not C-5, as verified by deuterium quenching experiments. Consequently, the aldehyde group’s primary synthetic value lies in condensation chemistries: Knoevenagel condensations with cyanoacetamide or ethyl cyanoacetate (piperidine catalyst, toluene, Dean-Stark trap) deliver 5-(2-cyanovinyl)thiazoles within 4–6 h at 110 °C, with E/Z ratios > 95:5 when the reaction is quenched at 85% conversion. These adducts serve as precursors to 5-(aminopyrimidinyl)thiazoles, a structural motif recurring in investigational kinase inhibitors. Large-scale condensations performed in 200 L glass-lined steel vessels at Reynolds numbers of 1.2 × 10⁴ (anchored paddle impeller, 120 rpm) require a controlled addition profile of the cyanoacetate (0.8 eq·h⁻¹) to avoid exothermic runaway; the observed ΔTadiabatic is approximately 68 K, mandating a jacket temperature not exceeding 105 °C and rupture disc sizing per API 520 for a two-phase relief scenario.
| Parameter | Typical value / Limit | Test method |
|---|---|---|
| Assay (anhydrous, solvent-free) | ≥98.0% (area%) | GC-FID, ASTM D2800-22, column: DB-5 30 m × 0.25 mm, 0.25 µm film |
| Water content | ≤0.5% w/w | Karl Fischer coulometry, ASTM E1064-21 |
| 2-Methylthiazole-5-carboxylic acid | ≤0.8% (HPLC area%, 210 nm) | HPLC-DAD, C18 column, 10 mM phosphate buffer (pH 2.5)/acetonitrile gradient |
| 2-Methylthiazole-4-carbaldehyde (isomer) | ≤0.2% | GC-FID, same conditions as assay |
| Appearance (molten, 45 °C) | Clear pale-yellow to yellow liquid, free of haze | Visual, transmitted light, 50 mm path length |
| Density at 45 °C | 1.18–1.22 g·cm⁻³ | Oscillating U-tube, ASTM D4052-22 |
| Refractive index, nD45 | 1.543–1.548 | Abbe refractometer, sodium D-line, thermostatted |
Batch-to-batch consistency of the molten density is a critical proxy for monitoring oligomeric content, as dimeric aldol species elevate the density by 0.04–0.07 g·cm⁻³ while remaining partially soluble. In one documented production incident at a 500-kg scale campaign, a blocked vacuum-relief line led to a 15-minute temperature excursion to 132 °C inside a wiped-film evaporator during stripping of light ends; the resulting product exhibited an anomalous density of 1.28 g·cm⁻³ and a bimodal GPC trace indicating a high-molecular-weight fraction (Mn ≈ 1,200 Da) from aldehyde polymerization, which rendered the batch unusable for the intended palladium-catalysed direct arylation step.
Storage stability at 5 ± 2 °C under argon in amber glass containers with PTFE-lined caps is confirmed over 24 months through a validated ICH Q1A(R2) stability protocol; nevertheless, once the container headspace is repeatedly breached, dissolved oxygen accumulates in the melt and accelerates the formation of peroxyacid and coloured quinoid-type degradation products absorbing at 420 nm. Headspace oxygen concentrations below 100 ppm v/v are maintained by a positive-pressure argon blanket regulated at 0.2 bar(g). The aldehyde is incompatible with primary and secondary amines, as even catalytic amounts of piperidine or benzylamine initiate an exothermic, autocatalytic aldol polymerisation at temperatures as low as 40 °C, with gelation occurring within 2 h for a 1 w/w% piperidine loading. Storage in 316L stainless steel is permissible for durations not exceeding 72 h when the chromium oxide passive layer is intact; however, pitting corrosion initiated by chloride ions (≥5 ppm) releases ferric species that catalyse oxidative degradation. Consequently, all transfer lines and valve seats are specified in PTFE or Hastelloy C-276 when continuous processing is envisaged.
A comparative evaluation of the two regioisomeric aldehydes—2-methylthiazole-5-carbaldehyde and 2-methylthiazole-4-carbaldehyde (CAS 76426-14-6)—is instructive for route scouting. While both share identical molecular weight and similar GC retention times, their behaviour under C–H activation conditions diverges sharply. The 4-carbaldehyde, when engaged as an N,O-bidentate directing group, facilitates palladium-catalysed C-5 arylation with Pd(OAc)2 (5 mol%) and aryl iodides at 110 °C in DMF, achieving isolated yields in the range 62–78% across a six-substrate scope. In contrast, the 5-carbaldehyde regioisomer directs metallation to the C-4 position (adjacent to sulfur) with substantially reduced efficiency; the lone pair of the sulfur atom competes for palladium coordination and attenuates the ortho-directing effect, resulting in a 3:1 mixture of mono- and di-arylation products and a maximum isolated yield of the target 4-arylated compound of merely 28% under identical conditions. This innate bias dictates that the 5-carbaldehyde be deployed primarily via functional-group interconversion at the aldehyde moiety, rather than as a direct handle for C–H functionalisation on the thiazole ring itself.
| Property | 2-Methylthiazole-5-carbaldehyde | 2-Methylthiazole-4-carbaldehyde |
|---|---|---|
| Gem-diol equilibrium constant (Khyd, D2O, pD 7.0, 25 °C) | 0.48 (±0.03) | 0.12 (±0.02) |
| Melting point (anhydrous, DSC onset) | 40–42 °C | 27–29 °C |
| Boiling point at 15 mbar | 88–91 °C | 79–82 °C |
| Relative rate of NaBH4 reduction (methanol, 0 °C) | 1.0 (reference) | 1.8 |
| Stability in 1,4-dioxane under 100 W halogen lamp | 50% loss after 6 h | 50% loss after 11 h |
The pronounced hydration tendency of the 5-isomer, quantified by the gem-diol equilibrium constant, has practical consequences for reactions requiring strictly anhydrous media; azeotropic distillation of the aldehyde with toluene (20 mL per gram substrate) immediately prior to use reduces water content to below 50 ppm and restores full reactivity in Wittig olefinations. The 4-isomer, by contrast, may be used directly after storage over activated 4 Å molecular sieves without azeotropic drying, provided the sieve activation protocol (ramp to 350 °C under vacuum ≤10⁻² mbar) is followed precisely. These differences, while subtle at the benchtop scale, translate into divergent cost profiles in multi-kilogram production: the drying unit operation for the 5-carbaldehyde adds approximately 8–12 h to the batch cycle time and introduces an additional solvent recovery step that must comply with emission thresholds under Directive 2010/75/EU when toluene is used as the entrainer.
The formylation process used to manufacture the 5-carbaldehyde from 2-methylthiazole involves a Vilsmeier-Haack reagent prepared from phosphoryl chloride and DMF. Quenching the post-reaction mixture with aqueous sodium hydroxide to pH 9–10 must be executed with a jacket temperature not exceeding 15 °C, because localised heating accelerates hydrolysis of the aldehyde back to the parent heterocycle. Quality assurance protocols on production campaigns of 300–800 kg employ at-line ReactIR to monitor the disappearance of the iminium salt intermediate at 1,668 cm⁻¹ and the emergence of the aldehyde carbonyl stretch at 1,702 cm⁻¹. An unexpectedly high residual POCl3 signal (> 0.3% as derived from the 31P NMR of the organic layer) correlates with thiazole-ring chlorination impurities that co-distill during subsequent vacuum rectification, requiring an additional acidic wash with 5% citric acid to avoid off-specification product with elevated total chlorine.
