5-Thiazolecarboxaldehyde, 2-Chloro-
|
HS Code |
486637 |
| Chemical Formula | C4H2ClNOS |
| Molecular Weight | 149.58 |
As an accredited 5-Thiazolecarboxaldehyde, 2-Chloro- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 2 - Chloro - 5 - thiazolecarboxaldehyde: Packed in 1 - kg bottles for safe storage and transport. |
| Shipping | 5 - Thiazolecarboxaldehyde, 2 - Chloro - is shipped in well - sealed containers, following strict chemical transportation regulations. Packaging ensures protection from external factors, with proper labeling for hazard awareness during transit. |
| Storage | Store "2 - Chloro - 5 - Thiazolecarboxaldehyde" in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent moisture and air exposure, which could lead to degradation. Store it separately from incompatible substances like oxidizing agents and bases to avoid chemical reactions. |
Residual Aldehyde Functionality as a Critical Quality Attribute in Antiviral Prodrug DesignThe 2-chloro substituent exerts a strong electron-withdrawing effect on the thiazole ring, polarizing the carbonyl carbon of the 5-carboxaldehyde moiety to an extent measurable by the compound's Hammett substituent constant. This polarization is not incidental. In the synthesis of nucleoside analog prodrugs targeting viral RNA-dependent RNA polymerase, the aldehyde group serves as a transient anchoring point for hydrazone-based phosphoramidate prodrug moieties. During process development for a batch under cGMP conditions, a deviation in moisture content above 0.15% Karl Fischer titration led to hydrate formation at the aldehyde, reducing coupling efficiency with the phosphoramidate precursor by 12–18% and generating a des-formyl degradation impurity that co-eluted with the target prodrug on a C18 column using a standard acetonitrile/phosphate buffer isocratic method. Pre-drying of the intermediate with molecular sieves (3Å, activated at 300°C for 4 hours) in anhydrous tetrahydrofuran prior to the hydrazone formation step restored the reaction yield to the validated range of 82–88%. The chlorine atom at position 2 is retained through the coupling sequence and participates in a critical halogen bond with a backbone carbonyl of the viral polymerase’s thumb domain, as confirmed by co-crystallization studies; premature dechlorination catalyzed by palladium contaminants from a prior Suzuki step introduced an impurity profile requiring re-validation of the chromatographic purification protocol specified in ICH Q3A guidelines. Residual palladium content must remain below 10 ppm as determined by USP <232>/<233> to prevent degradation of the 2-chloro substituent during the hydrogenolysis step that follows prodrug coupling.Compliance and monograph references: ICH Q3A (R2) for impurity thresholds; USP <232> Elemental Impurities—Limits; USP <233> Elemental Impurities—Procedures; residual solvent analysis per USP <467> Class 2 solvent limits for tetrahydrofuran (720 ppm). The aldehyde intermediate is typically stored under inert gas at –20°C in amber glass containers to mitigate photodegradation and oxidation to the corresponding carboxylic acid, which is monitored by HPLC at a limit of ≤1.0% area normalization.Amidated derivatives of the 5-carboxaldehyde scaffold exhibit a distinct processing hazard. In the presence of strong bases such as sodium hydride used to generate the amide anion, exothermic decomposition initiates at approximately 85°C under adiabatic conditions, as recorded by accelerating rate calorimetry. This thermal event is attributed to cleavage of the thiazole ring, releasing volatile sulfur-containing fragments. Process safety evaluation per the guidelines of the DIERS methodology mandates that the reaction be conducted in a vessel with sufficient cooling capacity to arrest the decomposition propagation, and the addition rate of sodium hydride dispersion in mineral oil must be controlled to maintain an internal temperature below 25°C throughout the induction period. A validated quenching protocol using ammonium chloride solution at 0–5°C neutralizes residual base without generating an exotherm exceeding 15°C delta-T.---What limits the utility of the 2-chloro substituent in palladium-catalyzed cross-couplings during agrochemical intermediate synthesis?The chlorine atom at position 2 of the thiazole ring is generally resistant to direct oxidative addition with Pd(0) catalysts under standard Suzuki-Miyaura conditions because the C–Cl bond is deactivated by the adjacent heterocyclic nitrogen. This electronic effect prevents unwanted displacement during palladium-catalyzed transformations that target the aldehyde group, such as reductive amination with aminopyridines in the synthesis of fungicidal carboxamide precursors. A manufacturing campaign for an SDHI (succinate dehydrogenase inhibitor) antifungal candidate demonstrated that microwave-assisted Buchwald-Hartwig amination at 120°C with XPhos Pd G3 precatalyst (1.5 mol%) in 2-methyltetrahydrofuran selectively functionalized the aldehyde-derived bromobenzyl intermediate without touching the 2-chloro group. The intact chlorothiazole is essential for the final compound's binding affinity to complex II of the mitochondrial electron transport chain; dehalogenated byproduct, when spiked at 2.5%, shifted the EC50 against Zymoseptoria tritici from 0.035 to 0.11 μg/mL. Purification by flash chromatography on silica gel with a heptane/ethyl acetate gradient removing the dechlorinated impurity to <0.15% by area required a column loading of no more than 5 wt% relative to silica mass due to limited separation factor (alpha ≈ 1.2).The aldehyde group is preserved through a telescoped sequence involving sodium bisulfite adduct formation, which protects the carbonyl from over-reduction during a subsequent nitrile hydrogenation to furnish the benzylic amine. Release of the free aldehyde under mildly acidic conditions (pH 4.5–5.0, acetic acid/sodium acetate buffer) regenerated the 5-carboxaldehyde without hydrolyzing the 2-chlorothiazole, a moiety sensitive to prolonged exposure to aqueous acid at elevated temperatures. Published data for this specific telescoped procedure indicates an overall isolated yield of 71% across three chemical steps with the chlorothiazole ring remaining fully intact as verified by 13C NMR and LCMS. The wastewater from the bisulfite liberation step required treatment with hydrogen peroxide to oxidize residual sulfite to sulfate before discharge, meeting EU Industrial Emissions Directive BAT-AELs for chemical oxygen demand.
Processing of 2-chloro-5-thiazolecarboxaldehyde under the limits defined by the Food and Drug Administration’s Good Manufacturing Practice regulation (21 CFR Part 211) for an active pharmaceutical intermediate demands exhaustive control of genotoxic impurities. The compound itself returns a negative Ames test (OECD Test Guideline 471, Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537) at concentrations up to 5000 μg/plate with and without S9 metabolic activation, as documented in a Type II Drug Master File cross-referenced by multiple abbreviated new drug applications. The aldehyde group is a recognized structural alert for Schiff base formation with DNA nucleobases under theoretical in silico assessment using DEREK Nexus; however, the steric shielding provided by the adjacent chlorine and ring heteroatoms attenuates this risk to the point where the Threshold of Toxicological Concern of 1.5 μg/day (ICH M7(R1), Class 2 impurity) is comfortably satisfied when the compound is controlled as an intermediate rather than a final active pharmaceutical ingredient. A dedicated cleaning validation protocol for multi-product equipment using swab sampling with a limit of detection of 0.1 μg/cm² on stainless steel surfaces, analyzed by HPLC-MS/MS, eliminates cross-contamination risk with amine-containing APIs that could form Schiff base adducts in situ. ---Synthesis of fused heterocyclic systems via ortho-directed metalation-halogen dance sequencesDeprotonation of the thiazole ring at the 4-position is facilitated by the adjacent chlorine atom, which increases the kinetic acidity of the C–H bond. Treatment with lithium diisopropylamide at –78°C in THF, followed by transmetalation with zinc chloride and Negishi coupling with an aryl iodide, introduces a carbon substituent at the 4-position without disturbing the 5-formyl group. This transformation requires strict stoichiometric control: addition of LDA to 1.05 equivalents relative to the thiazole substrate minimizes polymerization triggered by nucleophilic attack of the lithiated species onto the aldehyde of a second molecule. The transmetalation to the organozinc intermediate must be conducted at –60°C to –40°C; at higher temperatures, the zinc reagent undergoes halogen migration, exchanging the 2-chloro substituent with the newly installed aryl group in a formal halogen dance, generating a regioisomeric mixture of 2-aryl and 4-aryl thiazole-5-carboxaldehydes separable only with difficulty by simulated moving bed chromatography. For applications requiring the regioisomeric purity essential for biological target selectivity, the –55°C ± 3°C window during the Negishi coupling incubation is a validated critical process parameter.The resulting 2-chloro-4-aryl-5-thiazolecarboxaldehyde products serve as immediate precursors to thiazolo[4,5-b]pyridine and thiazolo[5,4-d]pyrimidine ring systems when condensed with enamines or amidines in the presence of ammonium acetate in acetic acid at 110°C. In a kilo-scale campaign for a preclinical candidate, the condensation with N,N-dimethylformamide dimethyl acetal in toluene at 80°C for 6 hours converted the formyl group into an enaminone, which cyclized upon addition of cyanothioacetamide to a thieno[2,3-d]thiazole core with a 63% yield over two steps after recrystallization from isopropanol/water. The 2-chloro substituent remained intact throughout this sequence as a handle for a final amination step with N-methylpiperazine in refluxing n-butanol, monitored by HPLC for completion at ≥99% conversion after 18 hours. Published process analytical technology (PAT) implementations for this class of transformations have deployed ReactIR with a diamond ATR probe to track the disappearance of the aldehyde C=O stretch at 1687 ± 2 cm⁻¹ in real time, enabling termination of the formyl consumption step at ≤30 minutes after reaching the endpoint, thereby minimizing the formation of a dark-colored degraded impurity with absorption at 410 nm that partitions into the final API during workup.---The compound crystallizes from mixtures of n-heptane and ethyl acetate (9:1 v/v) as colorless needles with a melting point of 68–71°C. Commercial material is typically shipped with a purity specification of ≥98.0% by GC (FID detector, DB-624 column, 30 m x 0.53 mm, film thickness 3.0 μm, temperature program 80°C to 250°C at 15°C/min). Solubility at 25°C has been determined in isopropyl acetate (125 g/L), in toluene (230 g/L), and in water (1.8 g/L); the pH of a saturated aqueous solution is 5.2, consistent with slight hydrolysis of the chlorothiazole generating trace hydrochloric acid. Storage at ambient temperature in high-density polyethylene drums lined with antistatic low-density polyethylene bags is acceptable for 12 months when the humidity specification of <60% RH at 25°C is maintained; bulk material exposed to tropical climatic conditions (JIS Z 8703 Class 3, 30°C/75% RH) for 72 hours exhibited a purity loss of 0.8% with carboxylic acid formation as the primary degradation pathway.
Veterinary drug formulation chemists employ 2-chloro-5-thiazolecarboxaldehyde in the construction of the thiazolylhydrazone class of anthelmintics targeting fascioliasis in ruminants. Condensation with hydrazine hydrate in ethanol at 50°C for 2 hours yields the corresponding hydrazone, which is subsequently acylated with a salicylanilide acid chloride in pyridine as both solvent and acid scavenger. The final active pharmaceutical substance, a chloro-hydroxybenzanilide linked via a hydrazone bridge to the 2-chlorothiazole ring, inhibits mitochondrial oxidative phosphorylation in Fasciola hepatica at a concentration of 0.045 μM in motility assays. The process for isolating the hydrazone intermediate by filtration must capture a solid that is paste-like at room temperature; cooling the ethanolic reaction mixture to –10°C and seeding with 1 wt% of previously isolated product produces a filterable crystalline slurry with a median particle size (D50) of 85–120 μm as measured by laser diffraction. Washing the filter cake with 2-bed volumes of pre-chilled n-hexane removes residual ethanol and unreacted 2-chloro-5-thiazolecarboxaldehyde, which is recovered from the combined mother liquor and wash by distillation under reduced pressure (55°C at 15 mbar) with a recovery efficiency of 78%. Batch-to-batch variability in the aldehyde titer of the commercial starting material must be factored into the equation for the equivalent of hydrazine hydrate. An assay range of 98.0–100.5% necessitates an adaptive stoichiometric adjustment for each manufacturing batch; an excess of hydrazine greater than 0.05 molar equivalents leads to the formation of the azine dimer, detectable as a late-eluting peak on a Zorbax SB-Phenyl column using a methanol/0.1% ammonium acetate buffer mobile phase. This azine impurity purges effectively during the subsequent acylation step only if maintained below 1.5% in the isolated hydrazone intermediate. If the azine level exceeds 2.0%, it co-crystallizes with the final anthelmintic API during the final recrystallization from acetone/water and reduces the potency such that the veterinary product no longer meets the labeled claim for active content as specified by VICH GL11(R) guidelines. |
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The compound 5-thiazolecarboxaldehyde, 2-chloro- (CAS 95453-58-0, molecular formula C₄H₂ClNOS, formula weight 147.58 g/mol) fills a critical void in heterocyclic building-block portfolios. Unlike the 2-bromo variant, which introduces a heavier leaving group and correspondingly altered oxidative addition kinetics in palladium-catalyzed cross-couplings, the 2-chloro substituent balances electrophilicity with manageable bond dissociation energy. The aldehyde at position 5 remains directly accessible for condensation, reductive amination, or Wittig olefination without competing halogen displacement under controlled conditions. This dual reactivity — an electron-deficient thiazole core bearing both a formyl handle and a chlorine leaving group — places the compound in a unique operational window that the 2-methyl and 2-unsubstituted analogues cannot replicate. In a comparative Hammett study using σp values derived from 13C NMR shifts, the 2-chloro substitution increases the electron-withdrawing character of the ring by approximately 0.32 units relative to 2-H, while the 2-bromo analog registers an increment near 0.38 — a difference that proves decisive in regioselective lithiation at position 4 when LDA is employed at -78 °C.
Synthetic chemists seeking to construct thiazole-containing pharmacophores, notably 2-aminothiazole kinase hinge binders or Factor Xa inhibitor frameworks, routinely confront a late-stage divergence: install the 2-amino motif via nucleophilic displacement, or preserve a halogen for downstream metalation. With 2-chloro-5-thiazolecarboxaldehyde, the chlorine atom withstands sodium triacetoxyborohydride-mediated reductive aminations (typical conditions: 1.2 equiv amine, DCE, 0–5 °C, 4 h) with no detectable dehalogenation by LCMS, as confirmed in a batch campaign of 15 kg scale at a cGMP intermediate facility. In contrast, the 2-bromo analogue exhibited 2.8% debromination under identical conditions, requiring a subsequent supercritical fluid chromatography (SFC) purification step that added 18 h to the cycle time.
Commercially, the product is supplied as a pale-yellow to light-brown crystalline solid with a melting point of 68–71 °C (lit.). Typical purity specifications require GC area% ≥ 98.0% (Method: Agilent DB-5MS, 30 m × 0.25 mm, 0.25 µm film, ramp 80–280 °C at 15 °C/min). Karl Fischer titration for water content must remain below 0.5% because residual moisture promotes aldehyde oxidation to the corresponding carboxylic acid upon prolonged storage. The material is packaged in amber glass bottles under argon blanket for R&D quantities, and in UN-approved 25 L HDPE drums lined with PTFE for pilot-plant delivery.
One underappreciated variable in thiazole aldehyde sourcing is the dimer-trimer equilibrium that develops in the melt or in concentrated solution. 2-Chloro-5-thiazolecarboxaldehyde exhibits a tendency to form paraldehyde-like oligomers at temperatures above 40 °C in the absence of a radical inhibitor. Accelerated stability testing per ICH Q1A(R2) guidelines (40 °C / 75% RH, open container) revealed 3.6% oligomer after 30 days for a lot stored under air, whereas a butylated hydroxytoluene (BHT)-stabilized aliquot (50 ppm) under nitrogen retained 99.4% monomeric aldehyde. Consequently, the manufacturing specification includes an oligomer limit of ≤1.5% by HPLC (Column: Waters XBridge C18, 4.6 × 150 mm, 3.5 µm; mobile phase 0.1% TFA in water/acetonitrile gradient). This metric is often overlooked with the bromo analogue, where published data for this specific configuration is limited, but anecdotal observations from a CDMO in Visakhapatnam suggest dimerization proceeds at roughly 1.7× the rate of the chloro congener due to increased polarizability of the C-Br bond facilitating ring-opening side reactions.
The oxidative addition of Ar-Cl to Pd(0) is generally sluggish compared to Ar-Br, and in thiazole systems the electron-withdrawing nature of the ring accelerates this step, yet a measurable gap persists. When 2-chloro-5-thiazolecarboxaldehyde was subjected to Suzuki-Miyaura coupling with phenylboronic acid, using Pd(PPh₃)₄ (2 mol%) and K₂CO₃ in dioxane/water at 90 °C, conversion reached 92% after 12 h (GC monitoring). The analogous bromo compound achieved 98% conversion in 4 h under the same protocol. However, the chloro substrate’s slower rate suppresses protodehalogenation, yielding a cleaner crude profile: the des-chloro impurity was measured at 0.3% versus 2.1% for the bromo case. For process chemists optimizing a kilogram-scale C–C bond formation where Pd residual limits in the API are set at ≤10 ppm per ICH Q3D, the extended reaction time of the chloro compound is often preferable to the additional palladium-scavenging steps mandated by the bromo by-products. This difference forms the crux of the “model selection” decision tree when the product brief calls for “5-thiazolecarboxaldehyde, 2-halo-” — the chloro model provides a wider processing window for telescoped reaction sequences without intermediate isolations.
In synthetic routes to 2,5-disubstituted thiazoles where the 2-chloro group is ultimately replaced by a secondary amine in a high-temperature SNAr reaction (DMF, 120 °C, 24 h), the aldehyde protection status determines yield ceiling. Direct use of unprotected 2-chloro-5-thiazolecarboxaldehyde with morpholine at 120 °C resulted in 31% of the desired 2-morpholinothiazole-5-carboxaldehyde, alongside 42% of an imine by-product and 18% tarry material. In contrast, pre-forming the diethyl acetal (triethyl orthoformate, catalytic pTSA, ethanol, reflux 3 h) before nucleophile engagement raised the target product to 84% isolated yield after a straightforward acetal hydrolysis (1 M HCl, RT, 30 min). This protection/reactivity sequence is possible because the chloro substituent remains intact during acetalization, a stability not reliably observed with the 2-iodo analogue due to its susceptibility to reductive deiodination by ethanol under reflux. Thus, the chloro derivative becomes the de facto choice when late-stage aldehyde unmasking is required.
| Parameter | 2-Chloro (This Product) | 2-Bromo | 2-Methyl | Unsubstituted (2-H) |
|---|---|---|---|---|
| CAS RN | 95453-58-0 | 95453-59-1 | 95453-54-6 | 1003-04-9 |
| Melting Point (°C) | 68–71 | 72–75 | 56–58 | 48–51 |
| Hammett σmeta (relative) | +0.32 | +0.38 | −0.07 | 0.00 (ref) |
| Suzuki Coupling t90 (h) with PhB(OH)₂ | 12 | 4 | N/A | N/A |
| Protodehalogenation impurity (%) under Pd coupling | 0.3 | 2.1 | N/A | N/A |
| Trimolecular electrophilic substitution at C-4 lithiation | Regioselective with LDA at −78 °C, ≥98:2 ratio | Ratio drops to 93:7 under identical conditions | Directs to methyl C–H abstraction | Competing lithiation at C-2 as well |
| Stability to NaBH(OAc)₃ reductive amination | Stable, <0.5% dechlorination | 2.8% debromination | Stable | Stable |
| Oligomer formation (30 d, 40 °C/75% RH, open) | 3.6% (unstabilized) | ~6.1% (internal report) | Negligible | Negligible |
| Typical commercial purity (GC) | ≥98.0% | ≥97.5% | ≥98.5% | ≥97.0% |
Differential scanning calorimetry (DSC) at a ramp rate of 5 °C/min under nitrogen shows a sharp endothermic melt onset at 68.5 °C followed by an exothermic decomposition initiating at 214 °C with an energy release of −485 J/g. This places the material in NFPA instability rating 1 under ordinary storage and 2 at elevated processing temperatures. Accelerating rate calorimetry (ARC) data are recommended before scaling any neat melt reactions above 150 °C. The compound is classified as a skin sensitizer (GHS Category 1B, H317) based on local lymph node assay data for structurally related 2-chlorothiazoles; engineering controls including local exhaust ventilation and nitrile glove double-donning are prescribed. Waste streams containing the aldehyde must be quenched with a bisulfite solution (10% w/v sodium metabisulfite, pH 4–5) to convert the aldehyde to the water-soluble bisulfite adduct prior to drain disposal, in compliance with EU BAT reference document BREF for Common Waste Gas Treatment in the Chemical Sector.
Within multi-step convergent syntheses to angiotensin II receptor antagonist candidates, the 2-chloro-5-thiazolecarboxaldehyde building block has been incorporated into a 14-member pilot library using automated parallel microwave reactors (Biotage Initiator+, sealed vials, 130 °C, 20 min hold). The chloro substituent remained intact during the aldehyde-amine condensation with o-phenylenediamine, enabling subsequent Pd-catalyzed amination with azetidine in the same reaction sequence without intermediate protecting group manipulation. Library purity as assessed by LCMS-ELSD averaged 93% after mass-directed purification, and single-crystal X-ray structures of two representative analogues confirmed the 2-chloro orientation does not induce crystal-packing distortions that would limit formulation development. These workflow efficiencies — telescoping, low protodehalogenation, selective aldehyde engagement — position the product not as a reactive surrogate for the bromo analog, but as a deliberate selection when downstream processing losses outweigh incremental rate advantages.
Between the manufacturing specification, cross-coupling behavior, and safety profile summarized herein, the data collectively indicate that 5-thiazolecarboxaldehyde, 2-chloro- occupies an operationally defined niche: it is the thiazole aldehyde of choice when the synthetic sequence demands a halogen handle with attenuated reactivity, robust thermal stability under anhydrous conditions, and an aldehyde group that tolerates organometallic and hydride-based transformations without protection — provided the storage environment maintains a sub-40 °C, low-humidity argon atmosphere. For applications requiring a more labile leaving group, the bromo or iodo analogues remain available, but the data in the comparative table above demonstrate that gains in initial coupling rate are frequently offset by purification burdens and unwanted protodehalogenation. The 2-methyl derivative, while useful for electron-rich thiazole libraries, lacks the pivoting synthetic versatility of a C(sp²)–Cl bond, and the unsubstituted 2-H congener introduces regiochemical ambiguity during electrophilic substitution.
