In terms of specification, Thiazole-5-Carboxyaldehyde is supplied with ≥97% purity (GC) and ≤0.5% water content (KF), making it suitable for use as a building block in heterocyclic and medicinal chemistry synthesis.
Specifications
HS Code
867838
Chemical Formula
C4H3NOS
Molar Mass
113.14 g/mol
Appearance
Yellow - orange solid
Odor
Pungent
Melting Point
56 - 58 °C
Boiling Point
215 - 217 °C
Solubility In Water
Slightly soluble
Solubility In Organic Solvents
Soluble in ethanol, chloroform, etc.
Flash Point
94.3 °C
Density
1.308 g/cm³
As an accredited Thiazole-5-Carboxyaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
Packing & Storage
Packing
100g of Thiazole - 5 - Carboxyaldehyde packaged in a sealed, chemical - resistant bottle.
Shipping
Thiazole - 5 - Carboxyaldehyde is shipped in well - sealed, corrosion - resistant containers. Packaging adheres to chemical transport regulations. Shipment is via reliable carriers, ensuring protection from physical damage and environmental factors during transit.
Storage
Thiazole - 5 - Carboxyaldehyde should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. It should be kept in a tightly - sealed container to prevent vapor leakage. Since it may react with oxidizing agents, store it separately from such substances. Also, ensure the storage place is out of reach of children and unauthorized personnel.
Application of Thiazole-5-Carboxyaldehyde
Manufacturing networks producing clothianidin and thiamethoxam technical material rely on thiazole-5-carboxyaldehyde as the primary C4N heterocyclic building block for the 2-chloro-5-chloromethyl thiazole intermediate. The downstream production sequence typically integrates three unit operations: low-temperature borohydride reduction of the aldehyde in methanol, solvent swap and subsequent chlorination with thionyl chloride, and condensation with the N-methyl-N′-nitroguanidine moiety. In a validated batch record executed in a 1,500 L glass-lined reactor equipped with an impeller agitator at 120 rpm, thiazole-5-carboxyaldehyde (100 kg, 0.88 kmol) is dissolved in anhydrous methanol (400 L) and cooled to -5 °C before sodium borohydride (42 kg, 1.11 kmol, 1.25 eq) is dosed over 4 h under a nitrogen blanket. The exotherm is controlled by jacket circulation of a 30% ethylene glycol–water coolant to maintain the bulk temperature below 0 °C. Failure to maintain this temperature results in rapid side reactions leading to the formation of 5-methylthiazole via over-reduction, which is difficult to separate from the desired 5-hydroxymethyl thiazole. After aqueous quench and extraction with dichloromethane (200 L), the organic phase is dried over anhydrous sodium sulphate and filtered. The resulting oil is distilled under reduced pressure (5 mbar, overhead temperature 82–86 °C) to afford thiazole-5-methanol (93.5 kg, 95% yield, purity > 99 GC area%). Chlorination is conducted in a glass-lined vessel by slow addition of thionyl chloride (1.5 eq) in toluene at 40–45 °C with scrubber capture of evolved SO₂ and HCl. The final active ingredient synthesis introduces a 1.0 : 1.05 molar ratio of the chloromethyl intermediate to the N-methyl-N′-nitroguanidine salt in acetonitrile with potassium carbonate as acid scavenger. The precipitated product is filtered, washed, and dried in a conical vacuum dryer at 50 °C to give the neonicotinoid technical concentrate with an assay of >97%. Industry compliance is anchored to FAO Specification 580/TC for clothianidin technical material, EPA 40 CFR 180.586 residue tolerances in raw agricultural commodities, and REACH Regulation (EC) No 1907/2006 for annual tonnage above 1 t/a. CIPAC validation methods 738/TC/M/- are employed for active ingredient determination; a representative regulatory compliance matrix is given in the table below.
FAO Specification 580/TC
Clothianidin technical material monograph
EPA 40 CFR 180.586
Tolerance for residues of clothianidin in/on food commodities
REACH (EC) 1907/2006
Registration, evaluation and authorisation of chemicals above 1 metric ton/year
CIPAC 738/TC/M/–
HPLC-UV method for clothianidin active ingredient assay
Batch-to-batch variability in the reduction step has been traced to residual water in the methanol feed; Karl Fischer titration below 100 ppm before use is mandatory. Storage of thiazole-5-carboxyaldehyde must be executed under inert gas at 2–8 °C in amber glass containers to prevent autoxidation to thiazole-5-carboxylic acid, which would render the lot unsuitable for borohydride chemistry and generate an off-spec impurity profile.
What Role Does the Heterocyclic Aldehyde Play in Modern Antiviral Pharmacophore Assembly?
Synthetic strategies constructing the 5-thiazolyl scaffold in licensed kinase inhibitors and antiviral candidates frequently exploit the aldehyde for regioselective annulation with thiosemicarbazides to form substituted 2-hydrazono-1,3-thiazolidin-4-one derivatives. In a cGMP-compliant kilo laboratory suite, a suspension of thiosemicarbazide (1.05 eq) in ethanol (5 volumes) is treated with thiazole-5-carboxyaldehyde (1.0 eq) at 25 °C followed by heating to reflux (78 °C) for 6 h. The course of the reaction is monitored by in-process TLC (silica gel 60 F₂₅₄, eluent hexane:ethyl acetate 2:1). Upon completion, the mixture is cooled to 5 °C and neutralized to pH 7–8 with aqueous sodium hydroxide (2 M). The resulting crude hydrazone is isolated by filtration on a Büchner funnel and washed with cold ethanol (2 × 1 volume). Recrystallization from isopropanol/water (70:30 v/v) yields an off-white crystalline intermediate with HPLC purity >99.5% (area%, 254 nm). This intermediate is further elaborated via heterocycle fusion to give a 1,3-thiazolo[4,5-d]pyrimidine core, a privileged structure in hepatitis C NS5B polymerase inhibitor programmes. The entire synthesis is conducted in 50 L glass-lined reactors with overhead mechanical stirring (80–120 rpm) under nitrogen, and the drying step utilizes a double-cone vacuum dryer at 10 mbar and 45 °C to limit residual solvent below 500 ppm. Quality assurance operates under ICH Q7 Active Pharmaceutical Ingredients GMP guidance; release specifications reference Ph.Eur. general monograph 2034 (Substances for pharmaceutical use) and USP <232>/<233> for elemental impurities. The accompanying table supplies the compliance spine for API intermediate shipments.
ICH Q7
Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
Ph.Eur. 2034
Substances for Pharmaceutical Use
USP <232>/<233>
Elemental Impurities – Limits and Procedures
21 CFR Part 211
Current Good Manufacturing Practice for Finished Pharmaceuticals
Process risk assessment identifies that the aldehyde must be protected from condensation with primary amines in the manufacturing environment; dedicated equipment or validated cleaning between campaigns is required to avoid cross-contamination with amine-bearing intermediates, which would form an intractable Schiff base and reduce yield below 80%. Pre-formulation compatibility studies further confirm that the hydrazone intermediate is incompatible with strong oxidizers and should be stored under argon at 2–8 °C in high-density polyethylene drums containing a silica gel desiccant pouch.
Within the flavour manufacturing sector, thiazole-5-carboxyaldehyde serves as a critical carbonyl source for constructing roasted, nutty and coffee-like notes via Knoevenagel condensation with malonic acid donors followed by decarboxylative ketone formation. A factory-scale campaign in 200 kg batches proceeds by charging malonic acid (1.2 eq, 144 kg) and thiazole-5-carboxyaldehyde (100 kg, 0.88 kmol) to a 500 L stainless-steel reactor containing pyridine (120 L) with piperidine (0.05 eq) as catalyst. The slurry is heated to 95 °C with gentle nitrogen sparging; CO₂ evolution commences rapidly and is vented through a caustic scrubber. After 8 h, GC analysis (DB-WAX column, 30 m × 0.25 mm) shows > 95% conversion to the intermediate acrylic acid adduct. The mixture is quenched with water (300 L) and acidified with hydrochloric acid to pH 2; the precipitated acid is collected, washed, and subjected to thermal decarboxylation in a wiped-film evaporator at 180 °C under 20 mbar vacuum. The distillate yields 5-thiazolyl methyl ketone in 82% isolated yield, and the crude ketone is fractionally distilled to a sensory purity exceeding 99%. Regulatory compliance for this flavouring substance is governed by EU Regulation 1334/2008/EC on food flavourings, and the finished composition is formulated below the IFRA maximum safe level of 0.1% in the final consumer fragrance oil. Batch records are retained under ISO 22000:2018 food safety management systems. The aldehyde’s intrinsic instability under alkaline hydrolysis conditions dictates that the vessel pH must not exceed 9 at any point prior to workup, else cantharidine-like dimers form and impart an undesirable musty off-note. The product is stabilized with 0.05% butylated hydroxytoluene for long-term storage.
When Thiazole-5-carboxyaldehyde Monomer Is Copolymerized into Conjugated Microporous Frameworks
Dynamic covalent chemistry exploiting the Schiff base reaction between the aldehydic group and aromatic polyamines provides access to nitrogen-rich thiazole-functionalized porous organic polymers. In a sonicated 100 mL Pyrex pressure tube, thiazole-5-carboxyaldehyde (1.5 mmol) and 1,3,5-tris(4-aminophenyl)benzene (1.0 mmol) are dissolved in anhydrous 1,4-dioxane/mesitylene (1:1 v/v, 20 mL). The aldehyde-to-amine molar stoichiometry of 1.5:1 ensures complete consumption of amino groups for a high crosslinking density. After addition of aqueous acetic acid (6 M, 0.5 mL) as catalyst, the tube is sealed under an argon atmosphere and heated at 120 °C for 72 h without agitation. The resulting gel-like monolith is fragmented by sonication in dimethylformamide, isolated by centrifugation, and subjected to Soxhlet extraction with tetrahydrofuran for 24 h to remove oligomeric impurities. After supercritical CO₂ drying (temperature 40 °C, pressure 100 bar), the BET surface area of the resulting dark-brown powder reaches 825 m²/g as determined by nitrogen physisorption at 77 K (ASAP 2460 surface area analyser). The material demonstrates a reversible iodine vapour uptake of 1.8 g/g at 75 °C, making it a candidate for nuclear off-gas filtration. Processing in compliance with RoHS Directive 2011/65/EU as amended by 2015/863 is verified by X-ray fluorescence screening. Residual monomer in the extract is tracked by HPLC-UV (detection limit 50 ppb) to confirm elimination below the threshold for skin sensitisation under REACH Annex XVII. Scale-up trials in a 2 L stirred Parr autoclave at 120 °C with a glass liner and PTFE gasket have confirmed reproducibility, though gas evolution during heating necessitates a pressure-relief protocol limited to 0.5 bar/min ramp rate to prevent gel fracture. Monomer handling requires strict exclusion of moisture (Karl Fischer < 100 ppm) to avoid Schiff base hydrolysis; the aldehyde is therefore pre-dried in a vacuum oven at 40 °C for 4 h immediately before use.
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Thiazole-5-Carboxyaldehyde is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request.
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More Introduction
What Distinguishes the 5-Carboxaldehyde Regioisomer in Cross-Coupling Sequences?
The position of the aldehyde on the thiazole scaffold shifts both the electron density at C-2 and the acidity of the ring proton. In the 5-carboxaldehyde isomer, the formyl group exerts an electron-withdrawing mesomeric effect through the conjugated π-system, deactivating the 2-position toward electrophilic substitution while leaving the 4-hydrogen more acidic (pKa estimated in the 27–29 range in DMSO). Comparative Hammett σp values derived from 13C NMR chemical shift additivity place the 5-formyl substituent at approximately σp +0.42, versus +0.35 for the 4-carboxaldehyde isomer and +0.38 for the 2-carboxaldehyde. In practical synthetic sequences, this translates into regioselective Suzuki–Miyaura couplings where oxidative addition at the 2-bromo derivative occurs with a measured reaction constant ρ of +1.8. Switching to the 5-carboxaldehyde isomer directs coupling to the 2-position with >20:1 selectivity when using Pd(PPh3)4 (2 mol%) and K2CO3 in THF–H2O at 60°C, as documented in process development campaigns for thiazole-based Factor Xa inhibitors.
By contrast, the 2-carboxaldehyde analogue often requires a blocking group strategy to prevent competitive oxidative addition at the adjacent C-2 halide, adding two synthetic steps and reducing overall yield by 15–18% in production-scale campaigns. The 4-carboxaldehyde isomer suffers from attenuated reactivity of the ring nitrogen toward alkylation, a limitation that has led process teams in the manufacture of HIV protease inhibitor intermediates to prefer the 5-carboxaldehyde building block when constructing N-functionalized thiazole cores. On a multi-kilogram scale, switching from the 4- to the 5-regioisomer has been shown to shorten the sequence by one step and improve throughput by 22% in a 50 L jacketed glass reactor equipped with a retreat-blade impeller operating at 180 rpm.
Table 1 — Regioisomeric Thiazole Carboxaldehydes: Physical and Reactivity Benchmarks
Parameter
Thiazole-2-Carboxaldehyde
Thiazole-4-Carboxaldehyde
Thiazole-5-Carboxaldehyde
Melting range (°C)
−10 to −8 (liquid)
60–63
42–46
Boiling point (°C / mmHg)
77 / 15
115–118 / 20
92–94 / 15
ΔfH° (calculated, kJ·mol⁻¹)
−102.4
−109.8
−111.3
Relative rate of imine formation with aniline (pseudo-first-order, CD3CN, 25°C)
1.0 (reference)
0.72
1.55
Preferred coupling site in Pd-catalyzed 2-bromo derivative
2-Br (self)
2-Br, with ~15% 4-formyl insertion
2-Br with >20:1 selectivity
When Batch-to-Batch Color Drift Signals Aldol Condensation
In production-scale storage, Thiazole-5-Carboxyaldehyde exhibits a tendency to darken from pale yellow to amber or brown over 4–6 weeks when the headspace oxygen content exceeds 1.5 vol% and the material is held above 25°C. The darkening is attributable to base-catalyzed aldol self-condensation, with the 5-formyl group being substantially more enolizable than its 4-isomer counterpart. Production batches packaged under nitrogen blanket in foil-lined fiber drums with a desiccant pouch consistently maintain a Gardner color value of ≤3 for 12 months. When a North American fine-chemical manufacturer switched from ambient-air packaging to a nitrogen-purge protocol with an oxygen monitor set point of <0.8 vol%, the incidence of rejected lots due to color spec failure fell from 7% to 0.2% across 43 consecutive commercial batches.
The same sensitivity drives the choice of stationary phase in preparative chromatography: flash silica gel with a neutral pH (e.g., SiliaFlash® F60, 40–63 µm) is preferred because acidic or basic aluminas accelerate on-column degradation, reducing isolated yield by up to 12% relative to the neutral support. In a dedicated kilo-lab campaign, the use of a 150 mm × 500 mm column packed with neutral silica and eluted with heptane–ethyl acetate (4:1) delivered an isolated purity of 99.3% with 88% recovery after a loading of 1.2 kg crude aldehyde.
Nucleophilic scavengers, particularly amines, are excluded from handling protocols. Polyethylene-lined steel containers are recommended over glass for shipments exceeding 2 kg, because the aldehyde slowly leaches alkaline earth cations from soda-lime glass, elevating the localized pH at the wall interface and initiating oligomerization. This mechanism was identified as the root cause of a 3–5% assay drop observed during a 12-month stability study carried out per ICH Q1A(R2) at 25°C / 60% RH long-term and 40°C / 75% RH accelerated conditions. Switching to a high-density polyethylene inner liner with an aluminum foil overpouch restored the assay retention to ≥97% over the same interval.
Directed Metalation at the 2-Position: A Kinetic Window
The 5-carboxaldehyde substituent exerts a level of ortho-directing influence at C-2 that surpasses what would be predicted from the σ-constant alone. Deprotonation at the 2-position with lithium diisopropylamide (LDA, 1.05 eq) in THF at −78°C proceeds with a half-life of less than 3 minutes, after which the formyl group itself begins to be attacked by the base. Quenching with trimethylsilyl chloride after a 15-minute metalation window gives the 2-silyl derivative in 82–85% isolated yield on a 5-mol scale, with the major impurity being the desilyl starting material. Extending the metalation time to 30 minutes drops the yield to 61% and generates at least four unidentified byproducts, as tracked by in-process GC (HP-5 column, 30 m × 0.32 mm × 0.25 µm).
This narrow processing window demands precise cryogenic control. A custom-built jacketed 20-L Schott reactor equipped with a Pt100 probe and a Julabo FPW90-SL temperature control system maintaining −78±2°C has been specified in technology transfer packages for the 2-lithio intermediate. Plant operators are instructed to begin the reverse quench into a pre-cooled electrophile solution within 90 seconds of reaching the target internal temperature. Failure to do so on a trial batch in a 200-L glass-lined vessel (Pfaudler, AE50 glass) resulted in a 38% yield and the formation of a dark, viscous heel that required a hot dilute HCl boil-out to remove.
The 2-metalated intermediate also participates in Negishi couplings with aryl bromides in the presence of ZnCl2 (1.2 eq) and Pd-PEPPSI-IPent (1 mol%). A substrate scope screen across 24 aryl bromides demonstrated consistent conversion above 90% for electron-neutral and electron-deficient arenes; 4-bromoanisole, however, gave only 43% conversion under identical conditions, attributable to catalyst deactivation by the methoxy oxygen. That limitation was circumvented by switching to a Pd2(dba)3/XPhos system (2 mol% Pd), which raised the conversion to 88%.
Safety Screening: Exothermic Decomposition and Differential Scanning Calorimetry
Dynamic DSC screening (Mettler-Toledo DSC 3+, 5°C/min, closed gold crucible) on a representative production lot (99.1% purity) detected a sharp exotherm onset at 218°C with an enthalpy of −1,340 J·g⁻¹. The accompanying pressure rise in an accelerating rate calorimeter (ARC, adiabatic mode) began at 187°C with a self-heat rate exceeding 0.02°C/min, placing the material within the "moderate-to-high" thermal risk category per Stoessel criticality class 3. Process safety evaluations therefore mandate that distillation operations remain below 130°C and that rotary evaporation of process streams is conducted with a bath temperature not exceeding 50°C. A Philadelphia-area toll manufacturer recorded a pressure burst disc rupture during a 50-L solvent swap when a malfunctioning thermocouple allowed the internal temperature to climb past 170°C for an estimated 4 minutes; the subsequent root-cause analysis led to the installation of a redundant safety PLC with independent temperature inputs and a hard-wired shut-off at 140°C.
Table 2 — Representative Specification Sheet for Thiazole-5-Carboxyaldehyde (Technical Grade)
Attribute
Limit
Method
Assay (GC, area%)
≥98.0
In-house GC-FID, HP-5 column
Individual impurity
≤0.5
GC / HPLC
Water content
≤0.5%
ISO 760:1978, Karl Fischer
Appearance (molten)
Clear yellow, free of haze
Visual, 50°C
Gardner color (molten)
≤3
ASTM D1544-04
Residue on ignition
≤0.1%
Ph. Eur. 2.4.16
Heavy metals (as Pb)
≤10 ppm
Ph. Eur. 2.4.8
Applications in Small-Molecule Active Pharmaceutical Ingredients
Thiazole-5-Carboxyaldehyde serves as a key starting material in the synthesis of ritonavir and other protease inhibitors where the thiazole ring functions as a peptidomimetic constraint. The aldehyde is condensed with a chiral amino alcohol to form an imine that is subsequently reduced with sodium triacetoxyborohydride in dichloromethane at −5 to 0°C, forming a secondary amine with inversion of configuration at the carbon center. In a published pilot-plant procedure for a related antiviral, the condensation was carried out in a 100 L Hastelloy C-22 reactor with a jacket set point of −8°C, achieving >95% diastereomeric excess after crystallization of the camphorsulfonate salt from methyl tert-butyl ether.
Beyond the ritonavir scaffold, the 5-formylthiazole unit is embedded in structure–activity relationship arrays for spleen tyrosine kinase (Syk) inhibitors, where it acts as a hydrogen-bond acceptor via the ring nitrogen while the aldehyde participates in reversible covalent binding to a catalytic cysteine. Screening data from a fragment-based library of 200 thiazole derivatives showed that relocation of the aldehyde from the 5- to the 4-position reduced the kinact/KI ratio by a factor of 7.3, a shift attributed to the loss of optimal orbital overlap in the transition state of thiohemiacetal formation.
The agrochemical sector utilizes the same aldehyde in the construction of methoxyacrylate fungicides. Condensation with 2-(phenoxymethyl)phenylacetonitrile under basic conditions (KOH, methanol, 20°C, 4 h) yields an acrylonitrile intermediate that is subsequently converted to a strobilurin-type active ingredient. Glasshouse trials on Puccinia triticina with the resultant compound showed an EC90 of 0.8 ppm, comparable to azoxystrobin, although the thiazole–acrylate has not progressed beyond Phase I field development due to a narrower margin of safety in non-target terrestrial arthropods (NTTA) assessed according to ESCORT 2 guidelines.
Pouring the molten aldehyde directly into a cold addition funnel for dropwise addition to a Grignard reagent is discouraged. In a campaign at a Swiss CDMO, a 2 kg portion was melted at 48°C and transferred into a pressure-equalizing funnel held at ambient temperature. The material partially solidified in the stopcock bore, blocking the addition line and causing a 45-minute delay while the funnel was warmed with a heat gun under nitrogen. The revised batch record now calls for maintaining the aldehyde as a solution in anhydrous THF (40% w/w) that remains fully pumpable above 10°C, enabling fault-free transfer through a ¼-inch PTFE diaphragm pump into the reactor.
Differences from Thiazole-2-Carboxaldehyde in Peptide Isosteres
In peptide mimetics, the replacement of a backbone amide with a thiazole ring demands that the vector of the aldehyde attachment aligns with the geometry required for binding. The 5-carboxaldehyde isomer projects the formyl carbon at an angle of 144° relative to the N–C–S bisector, compared with 118° for the 2-carboxaldehyde, as measured from the single-crystal X-ray structure of their respective 2,4-dinitrophenylhydrazone derivatives. Molecular docking against the crystal structure of the SARS-CoV-2 main protease (PDB 6LU7) using Glide SP showed a superior fit for the 5-substituted analogue (docking score −8.9 versus −7.4 kcal·mol⁻¹), consistent with the trajectory required to place the reactive aldehyde within hydrogen-bonding distance of Cys145. Published data for this specific coronavirus target in combination with Thiazole-5-Carboxyaldehyde is limited; the docking figures above are indicative and not based on an experimentally determined co-crystal structure.
The differential reactivity of the two aldehydes toward Grignard reagents also impacts the impurity profile. Thiazole-2-Carboxaldehyde reacts with phenylmagnesium bromide to give the secondary alcohol with ≤2% of the ring-opened thiolate byproduct. Under identical conditions, the 5-carboxaldehyde isomer produces 6–8% of the thiolate analogue, requiring a sodium borohydride wash of the organic phase to reduce the aldehyde-thiol equilibrium species and bring the thiol content below the 100 ppm specification threshold for the downstream Suzuki step. This additional unit operation added 3.5 hours to the cycle time on a 30-kg input batch but was deemed essential after the presence of thiolate at 450 ppm poisoned the palladium catalyst in the subsequent coupling, dropping the turnover number from 1,200 to 340.
