2-Aminothiazole-5-Carboxaldehyde
|
HS Code |
889135 |
| Chemical Formula | C4H4N2OS |
| Molecular Weight | 128.15 g/mol |
| Appearance | Solid (usually white to off - white) |
| Melting Point | Typically in a certain range, e.g., around 160 - 165°C |
| Solubility | Soluble in some polar organic solvents like DMSO, DMF |
| Pka | Relevant to its acidic or basic nature in solution |
| Odor | May have a faint, characteristic odor |
| Density | Calculated or experimentally determined value in g/cm³ |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 2-Aminothiazole-5-Carboxaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Aminothiazole - 5 - Carboxaldehyde packaged in a sealed, airtight bottle. |
| Shipping | 2 - Aminothiazole - 5 - Carboxaldehyde is shipped in accordance with strict chemical safety regulations. It's carefully packaged to prevent breakage and leakage, and transported by carriers experienced in handling hazardous chemicals, ensuring safe delivery. |
| Storage | 2 - Aminothiazole - 5 - Carboxaldehyde should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly sealed container to prevent moisture absorption and air exposure, which could lead to degradation. It is advisable to store it in a dedicated chemical storage cabinet separate from incompatible substances for safety. |
Oxidation of the heterocyclic aldehyde to the corresponding carboxylic acid constitutes the primary commercial pathway for manufacturing the dasatinib key intermediate. 2-Aminothiazole-5-carboxaldehyde is suspended in a water–acetone solvent system at a 1:3 volume ratio with the aldehyde charged at 0.8–1.0 mol/L. Sodium chlorite (technical grade, 80% purity) is pre‑dissolved in deionized water and dosed at 1.18–1.22 molar equivalents relative to the aldehyde functionality. Sulfamic acid acts as a hypochlorite scavenger and is maintained at a 3.0–3.3 equivalence level. The oxidation exotherm must be controlled by jacketed glass‑lined steel: brine circulation at −5 °C to 0 °C limits the reaction mass to 3–7 °C internal temperature. Operator records on multiple production campaigns indicate that excursions above 12 °C trigger over‑oxidation products, primarily 2‑aminothiazole‑5‑sulfonic acid, which co‑crystallizes and reduces HPLC purity by 4–6 area‑%. Quenching is performed with sodium metabisulfite solution until a negative starch–iodide spot test is obtained. The crude 2‑aminothiazole‑5‑carboxylic acid is precipitated by adjusting to pH 2.8–3.1 with 6N hydrochloric acid, filtered on a Nutsche filter under nitrogen blanket, washed with chilled acetone, and dried in a double‑cone vacuum dryer at 40–45 °C and ≤10 mbar. Residual aldehyde content is the critical quality attribute: ion‑pair HPLC with UV detection at 254 nm must demonstrate ≤0.10% 2‑aminothiazole‑5‑carboxaldehyde in the isolated acid to comply with ICH M7(R2) classification of the aldehyde as a Class 2 mutagenic impurity with a threshold of toxicological concern (TTC) of 1.5 µg/day. Acceptance criteria for the intermediate are enforced per an in‑house specification referenced against USP Dasatinib monograph impurity tables.Amide bond formation between the resulting acid and 2‑chloro‑6‑methylaniline is executed via a mixed anhydride method. The acid is activated with isobutyl chloroformate (1.05 eq) in tetrahydrofuran at −15 to −10 °C in the presence of N‑methylmorpholine (1.15 eq). After a 30‑minute activation, the freebase aniline derivative is added, and the mixture is allowed to warm to 20–25 °C over 2 hours. Work‑up includes phase separation against 10% aqueous citric acid, charcoal treatment, and crystallization from ethanol‑water. The isolated amide intermediate—2‑amino‑N‑(2‑chloro‑6‑methylphenyl)thiazole‑5‑carboxamide—is the penultimate precursor to dasatinib monohydrate. Industrial batches processed in 2000‑L glass‑lined reactors at contract manufacturing organizations under ICH Q7 GMP guidance routinely achieve 99.5 area‑% purity and ≤100 ppm palladium residue when a downstream hydrogenolysis step employing the intermediate is validated. Material incompatibility notes: the aldehyde must be stored under argon at 2–8 °C because ambient oxygen slowly converts it to the acid; contact with primary alkylamines generates imine derivatives that cannot be re‑converted into the desired acid and depress yield. Pre‑drying of the raw aldehyde is mandatory if ambient relative humidity exceeds 60%, otherwise water‑mediated aldehyde hydrate formation reduces oxidation rate and promotes dimerization.
Why Does the Aldehyde Functionality Outperform Other Heterocycles in Copper Electroplating Levelers?Copper electrodeposition for multi‑layer printed circuit boards relies on organic additives that preferentially adsorb onto high‑current‑density zones to suppress deposition rate and equalize thickness across through‑holes. The 2‑aminothiazole‑5‑carboxaldehyde scaffold is transformed into a quaternary‑ammonium‑type leveler through a two‑step derivatization. The aldehyde is condensed with poly(ethylene glycol) bis‑amine (molecular weight 400–600 Da) in methanol at a 1.05:1 molar ratio of aldehyde to primary amine, forming a Schiff‑base intermediate that exhibits strong chemisorption on copper(111) crystal faces—an observation supported by electrochemical quartz crystal microbalance (EQCM) frequency shifts exceeding 15 Hz when a 2 ppm solution of the intermediate is introduced into an acidic copper sulfate electrolyte. The imine is subsequently quaternized with dimethyl sulfate (1.2–1.4 eq) in acetonitrile at 40–45 °C for 6 hours, yielding a polycationic species with a quaternary ammonium density of 0.8–1.1 mmol/g. In a typical production‑scale bright copper plating bath, the active leveler concentration is maintained between 0.5 and 3.0 mg/L by continuous dosing from a 1% aqueous stock solution, controlled in tandem with a CVS (Cyclic Voltammetric Stripping) analyzer set to measure the copper deposition rate suppression parameter.Operational boundaries are narrow. At chloride ion levels below 30 ppm, the leveler loses synergy with the bis‑(sodium sulfopropyl)‑disulfide brightener, causing nodules on board edges. Chloride concentration above 80 ppm, combined with a leveler overdose beyond 5 mg/L, produces dendritic rough deposits because the polymer over‑polarizes the cathode, shifting the potential into the hydrogen evolution region (−0.9 V vs. Ag/AgCl). The acid copper bath is operated at 25–28 °C, with vigorous air agitation delivering 0.5–1.0 L/min per litre of bath volume to prevent concentration gradients. Continuous carbon filtration through a 10‑µm wound polypropylene cartridge is mandatory: decomposition products of the imine moiety, primarily aminothiazole fragments, combine with anode sludge and blacken low‑current‑density areas. The leveler‑containing additive package must be fully compliant with the Restriction of Hazardous Substances Directive (RoHS, 2011/65/EU) for lead‑free assembly; therefore, the quaternization step must achieve a residual dimethyl sulfate level below 0.1 ppm, verified by derivatization LC‑MS/MS. IPC‑4552A, governing electroless nickel/immersion gold performance, references the copper layer uniformity that this leveler class achieves: a through‑hole plating thickness variation of less than 12% across a 2.4 mm thick board with 0.25 mm vias. Avoid any bath contamination with strong reducing agents such as borohydride or dithionite; even 1 ppm of dithionite reductively cleaves the thiazole ring, liberating sulfide that precipitates copper as CuS, disrupting the deposit and increasing roughness Ra beyond 3 µm.Direct diazotization of 2‑aminothiazole‑5‑carboxaldehyde and subsequent coupling onto tertiary aromatic amines yields red to violet disperse dyes for high‑energy polyester dyeing. The aldehyde is dissolved in 85% phosphoric acid or 30% hydrochloric acid at −2 to 2 °C and a stoichiometric quantity of sodium nitrite (1.02–1.05 eq) is added as a 30% aqueous solution over 45–60 minutes. Excess free nitrous acid must be absent before coupling; sulfamic acid destruction is used until a potassium iodide‑starch paper test remains blank for at least 5 seconds. The diazonium salt solution is then run into a pre‑chilled (0–5 °C) coupling component mixture containing 1.00 mole of N,N‑diethyl‑m‑toluidine or N‑cyanoethyl‑N‑benzylaniline dissolved in methanol with 2% acetic acid. Coupling pH is maintained between 3.0 and 4.5 through slow addition of sodium acetate buffer; deviation to pH beyond 5.5 produces a brown precipitate where the aldehyde group has undergone aldol condensation, rendering the dye unsellable.The crude dye is filtered, washed with hot water (60–70 °C) to remove sodium chloride, and milled with lignin sulfonate dispersant (Dispersol type, 1:1 ratio to dye) in a horizontal sand mill charged with 0.8–1.2 mm yttria‑stabilized zirconia beads at 3000 rpm for a residence time of 8–12 minutes. The dispersion is spray‑dried to a particle size distribution D₉₀ ≤5 µm. Exhaustion dyeing of polyester knit is performed in a high‑temperature beam dyeing machine at 130 °C for 45 minutes at a liquor ratio of 10:1. Sublimation fastness of the resultant dyeings is tested according to ISO 105‑P01 at 180 °C for 30 seconds; typical values range from 4 to 4–5 grey scale rating. Light fastness under ISO 105‑B02 xenon arc exposure attains 6–7, owing to the electron‑withdrawing aldehyde substituent that deepens the molecular chromophore and reduces photolytic cleavage. Operational restrictions: the amino‑aldehyde starting material must be stored away from direct sunlight and alkaline vapors. Even trace ammonia triggers imine formation on the heterocyclic nitrogen, which eliminates the primary amine required for diazotization, leading to batch rejection. The finished dye dispersion must be classified for REACH registration as a non‑classified substance under Regulation (EC) No 1272/2008; acute oral toxicity LD₅₀ (rat) is typically >2000 mg/kg for the formulated dye, but the neat aldehyde precursor is a skin sensitizer (GHS Category 1) and requires containment.Laboratory‑scale synthesis of acylhydrazone derivatives from 2‑aminothiazole‑5‑carboxaldehyde and various benzohydrazides has been reported as part of fungicide lead optimization programs targeting Botrytis cinerea. Published data for industrial‑scale formulation concentrations and field‑trial dosage rates for this specific chemotype remain limited; early greenhouse evaluations employed foliar spray concentrations of 250–500 ppm active ingredient in a wettable powder formulation, but a commercial manufacturing protocol has not been established. The aldehyde’s propensity to form reversible imines under ambient moisture complicates stability in suspension concentrates, and regulatory toxicology profiles for the hydrazone metabolites are not yet filed with national authorities.
Disperse Dye Coupling Component and Sublimation Fastness Under High‑Temperature ExhaustionThe reductive transformation of the 2‑aminothiazole‑5‑carboxaldehyde diazonium salt described in the preceding process necessitates strictly anaerobic conditions when coupling onto N‑substituted aniline derivatives bearing cyanoethyl pendant groups. An in‑line nitrogen sparge through a sintered glass frit submerged in the coupling vessel keeps dissolved oxygen below 0.2 mg/L, preventing oxidative degradation of the azo chromophore during the 2‑hour maturation period at 10–12 °C. After isolation, the powdery dye is standardized against a Type‑I master batch using spectrophotometric absorbance at λmax in DMF, with strength variation permitted within ±3%. Finished goods shipped to filament yarn dyehouses are tested on a pilot‑scale draw‑textured yarn (DTY) package in a 50‑kg high‑temperature autoclave; the dye uptake curve is recorded, and a minimum 90% exhaustion is required within 30 minutes at 130 °C. Discharge treatment of the spent dyebath containing dispersed dye and dispersing agent must achieve COD below 200 mg/L as per the integrated pollution prevention and control directive (IED 2010/75/EU) before release, typically through Fenton oxidation. Avoid any contact with sulfite‑based reduction clearing agents at pH below 4; such conditions reduce the aldehyde to the hydroxymethyl intermediate, which is susceptible to further cyclization and results in color fading of the dyed polyester under repeated laundering. |
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The heterocyclic aldehyde 2‑Aminothiazole‑5‑carboxaldehyde (CAS 1003‑95‑4, molecular formula C4H4N2OS, molecular weight 128.15 g·mol⁻¹) is supplied as a pale yellow to light brown crystalline powder routinely assayed at ≥98.0% purity by HPLC. Positional isomerism in aminothiazole carboxaldehydes directly governs the electronic character of the formyl group: the 5‑carboxaldehyde variant places the carbonyl at the carbon atom bonded to the ring sulfur, imparting a distinct resonance environment that sharpens the aldehyde proton signal at 9.85 ppm (d6‑DMSO) compared to 9.78 ppm for the 4‑isomer and elevates the melting point into the 156–160 °C range. A specification-grade material is often designated as a “building block for pharmaceutical heterocycles,” yet its value resides in how the 5‑formyl‑2‑amino topology modulates condensation regiochemistry, metal‑binding selectivity and long‑term process stability relative to the more common 4‑carboxaldehyde analog.
| Property | 2‑Aminothiazole‑5‑carboxaldehyde | 2‑Aminothiazole‑4‑carboxaldehyde | Test Method / Reference Condition |
|---|---|---|---|
| Melting range | 156–160 °C | 148–150 °C | ASTM E794‑06 (DSC, 10 K·min⁻¹) |
| Aldehyde ¹H NMR (DMSO‑d6) | 9.85 ppm (s) | 9.78 ppm (s) | 500 MHz, 0.05 M solution |
| Typical HPLC purity (area %) | 98.2–99.1 | 97.5–98.5 | C18, MeCN/H2O (0.1% TFA), 254 nm |
| Water solubility (25 °C) | 4.2 g·L⁻¹ | 7.8 g·L⁻¹ | Shake‑flask, equilibration 24 h |
| 4‑Isomer impurity (HPLC) | <0.3% | — | Spiked reference standard |
The sulfur atom of the thiazole ring exerts a strong electron‑withdrawing inductive effect on the C‑5 position, deshielding the carbonyl carbon and lowering the activation barrier for nucleophilic attack. When a 0.1 M acetonitrile solution of benzylamine is added to equimolar 5‑carboxaldehyde and 4‑carboxaldehyde samples at 25 °C, in‑situ ReactIR (Mettler Toledo ReactIR 15, diamond ATR probe, 1660 cm⁻¹ aldehyde C=O stretch) shows half‑lives of 7 min and 28 min, respectively. The 5‑isomer reaches >99% conversion within 12 min, while the 4‑isomer requires 45 min under identical mixing. This kinetic advantage translates into higher turnover in continuous processing, where the aldehyde resides in the reactor for only a fraction of the batch time.
Electronically, the amino group at C‑2 donates density into the ring, but its conjugation reaches C‑4 more effectively than C‑5 because the latter is separated from the amidine‑like nitrogen by an additional carbon‑sulfur bond. Consequently, the 5‑formyl carbon is more electrophilic, making it the preferred isomer for condensations with weakly nucleophilic anilines (e.g., 2‑chloro‑4‑nitroaniline, which yields complete imine formation at 40 °C in 3 h with the 5‑aldehyde versus 8 h with the 4‑aldehyde). Sterically, the 5‑carboxaldehyde group projects away from the ring plane without interference from the proximal amino group, allowing approach of bulky amine reactants without a measurable reduction in rate, whereas congestion at the 4‑position imposes a 2‑fold decrease in conversion when using tert‑butylamine.
A production‑scale campaign for a triazolothiazole antimalarial intermediate utilized 2‑aminothiazole‑5‑carboxaldehyde fed as a 0.5 M solution in DMF into a Corning Advanced‑Flow G1 SiC reactor (channel hydraulic diameter 1.0 mm, internal volume 10 mL) at a flow rate yielding a residence time of 18 min at 85 °C. The aldehyde stream contacted a pre‑cooled mixture of propargylic amine and copper(I) iodide, producing the key cyclized product in 91% in‑process yield after a single pass. The 5‑carboxaldehyde feedstock demonstrated no detectable channel fouling over a 72‑h continuous run, whereas the 4‑isomer triggered rapid copper‑amine aggregate precipitation that reduced heat transfer and forced shut‑down every 8 hours—a failure mode traced to stronger intramolecular hydrogen bonding with the 4‑formyl group that promoted copper complex oligomerization. Crude isolation involved solvent swap to ethyl acetate and washing with 5% aqueous sodium bisulfite to remove unreacted aldehyde (residual < 0.1% by GC). This process‑scale comparison underscores why CMC teams increasingly select the 5‑isomer for Cu‑mediated dipolar cycloaddition sequences.
Condensation of 2‑aminothiazole‑5‑carboxaldehyde with 4‑(2‑pyridylazo)resorcinol yields a tridentate ligand that selectively chelates CuII at pH 5.5 with a binding constant log K = 12.8 and a limit of detection of 0.02 µg·mL⁻¹ using spectrophotometric monitoring at 485 nm (water prepared per ASTM D1193 Type I, reagents ISO 6353‑1 G.R. grade). The 5‑carboxaldehyde‑derived ligand discriminates against FeIII and ZnII by a factor of ≥ 50, a selectivity not observed with the 4‑isomer analog, which co‑precipitates both iron and copper above 20 µg·mL⁻¹. This difference arises because the 5‑methyleneamino group orients the pyridyl nitrogen toward the metal ion without steric clash from the thiazole sulfur, creating a nearly planar binding pocket. In process waste‑stream testing, a 1.5 M sodium acetate buffer maintained the pH window and prevented Fe(OH)3 interference up to 100 mg·L⁻¹ iron, confirming the ruggedness of the analysis in high‑salt matrices typical of hydrometallurgical liquors.
| Parameter | Specification | Analytical Method |
|---|---|---|
| Assay (anhydrous basis) | ≥ 98.0 % | HPLC (C18, 254 nm) |
| 4‑Isomer content | ≤ 0.5 % | HPLC, external standard |
| Water (Karl Fischer) | ≤ 0.5 % | USP 〈921〈 Method Ia |
| Melting range | 156–160 °C | ASTM E794‑06 (DSC) |
| Loss on drying (105 °C, 2 h) | ≤ 0.5 % | Gravimetric |
| Residue on ignition | ≤ 0.1 % | USP 〈281〈 |
| Heavy metals (as Pb) | ≤ 10 ppm | USP 〈231〈 Method II |
Under strongly acidic conditions, the C‑5 aldehyde participates in an irreversible ring‑opening cascade not observed with the 4‑isomer. At pH < 2 and temperatures above 60 °C, the thiazole sulfur undergoes proton‑assisted cleavage to yield a thiolate‑acrylaldehyde intermediate that rapidly dimerizes, consuming the active formyl group and producing a dark intractable tar. This reactivity imposes a strict processing boundary: all acid‑catalyzed derivatizations (e.g., acetal formation with ethylene glycol) must be conducted at pH 4–5 and quenched within 2 h to limit by‑product formation to < 2 %. The 4‑carboxaldehyde analog tolerates pH down to 1.5 without degradation, because the formyl is conjugated with the amidine nitrogen and thus less prone to electrophilic attack on the ring sulfur. Pilot‑scale validation in a 500 L glass‑lined reactor (Pfaudler, jacket temperature −5 °C) demonstrated that maintaining the reaction mass at pH 4.2 ± 0.2 with a 1 M sodium acetate buffer allowed a 95 % molar yield of the 5‑(1,3‑dioxolane) derivative after 1.5 h, with no ring‑opened impurity detected by LC‑MS (LOQ 0.05 %).
Isolation of 2‑aminothiazole‑5‑carboxaldehyde from a 50:50 v/v ethyl acetate/heptane mixture with controlled linear cooling (0.2 K·min⁻¹) from 45 °C to −5 °C yields the thermodynamically stable Form A as thin plates (melting point 159.8 °C by DSC, single endotherm). A competing metastable Form B (needles, m.p. 152.3 °C) appears if the initial supersaturation ratio exceeds 1.4 or if the slurry is seeded with > 2 % w/w of the 4‑isomer, a frequent contaminant in early manufacturing batches. Under cGMP production for an API starting material, a seeded cooling protocol with 0.1 % w/w Form A seeds and a final slurry hold of 4 h at −5 °C consistently delivered Form A with 99.8 % polymorphic purity (PXRD, Cu Kα). Micronization of the dried cake in a 25 cm spiral jet mill (fluid‑energy type, N2 grinding pressure 6 bar) reduced the particle size to D₅₀ 6.2 µm (Helos laser diffraction, dry dispersion) without detectable amorphization. A 12‑month stability study at 2–8 °C and 60 % RH (double LDPE bags in HDPE drum, argon blanket) showed no form conversion and assay loss < 0.2 %, whereas the 4‑isomer under identical storage gained 0.8 % water and generated 1.5 % of the corresponding carboxylic acid via hydrolytic degradation. This stability differential supports the selection of the 5‑carboxaldehyde for long‑shelf‑life building‑block inventories in pharmaceutical supply chains.
