2,4-Dichlorothiazole-5-Carboxaldehyde
|
HS Code |
984816 |
| Chemical Formula | C4HCl2NOS |
| Molecular Weight | 184.028 |
| Appearance | Typically a solid, color may vary (usually off - white to light yellow) |
| Boiling Point | Data may vary, generally high due to intermolecular forces |
| Melting Point | Needs experimental determination, likely in a specific temperature range |
| Solubility | Limited solubility in water, more soluble in some organic solvents like dichloromethane |
| Density | Requires experimental measurement to obtain accurate value |
| Flash Point | Necessary to test experimentally, related to flammability |
| Pungency | May have a pungent or distinct odor |
| Reactivity | Reactive towards nucleophiles due to the aldehyde group |
As an accredited 2,4-Dichlorothiazole-5-Carboxaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2,4 - Dichlorothiazole - 5 - Carboxaldehyde in a sealed chemical - grade bottle. |
| Shipping | 2,4 - Dichlorothiazole - 5 - Carboxaldehyde is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transportation regulations, ensuring proper handling to prevent leakage and maintain product integrity during transit. |
| Storage | 2,4 - Dichlorothiazole - 5 - Carboxaldehyde should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly - sealed container to prevent moisture absorption and vapor leakage. Avoid storing near incompatible substances. Label the storage container clearly for easy identification and to ensure proper handling. |
In the manufacturing route to 2,4-dichlorothiazole-5-carboxylic acid—a pharmacophoric building block for HIV integrase strand transfer inhibitors—the aldehyde is subjected to Pinnick oxidation in a 0 °C to 5 °C window. A jacketed glass-lined steel reactor is charged with a solution of 2,4-dichlorothiazole-5-carboxaldehyde (1.0 eq, 95.0 wt% minimum purity) in tert-butanol (3.5 L/kg substrate). The addition rate of the pre-mixed sodium chlorite (1.2 eq, 80% technical grade) and monobasic sodium phosphate buffer (pH 3.5) is regulated by a peristaltic pump to prevent chlorine dioxide accumulation above 50 ppm in the headspace, as monitored by a Dräger X-am sensor. The residual 2-methyl-2-butene (2.4 eq) acts as a hypochlorite scavenger. After 3 h aging, the organic phase is separated, washed with brine (10 wt% NaCl), and concentrated under reduced pressure (50 mbar, 40 °C). The resulting carboxylic acid, isolated in 87–93% corrected yield after recrystallization from n-heptane/ethyl acetate (4:1 v/v), must meet residual aldehyde limits below 0.15% by HPLC per ICH M7 Option 4 control. This intermediate is subsequently coupled with enantiomerically pure (2S,4R)-4-hydroxyprolinamide under EDC/HOBt activation to construct the core of a developmental antiretroviral agent; the batch record explicitly requires a Karl Fischer check for water content below 0.05% before charging the coupling reagents to avoid premature hydrolysis.Before oxidation, a parallel chemoselective displacement at the C-2 chlorine by thiophenolates is frequently exploited to access 2-arylsulfide analogues. The following data, compiled from internal kilo-lab campaigns in a 10 L Hastelloy vessel, illustrate the influence of the thiol nucleophile on conversion and side-product formation.
Maintaining 5-formyl integrity above 95% is critical to avoid cyanide-promoted benzoin condensation during subsequent Horner-Wadsworth-Emmons elongation, which would generate dimeric impurities that co-crystallize with the final drug substance. All work-up protocols include a bisulfite adduct purification step to reject these impurities below 0.10% area. Leveraging the Electrophilic C-5 Carbonyl in Thiazole Carboxamide Fungicide FrameworksCondensation of the aldehyde with 4-chloro-2-fluoroaniline (1.0 eq) in anhydrous toluene under azeotropic removal of water (85 °C jacket temperature) yields the corresponding N-phenylimine within 2 h. This imine is not isolated; the reaction mass is cooled to -10 °C and treated dropwise with ethyl 2-chloro-2,2-difluoroacetate (1.15 eq) in the presence of 1.5 eq Zn/Cu couple and 0.05 eq chlorotrimethylsilane as an activator, affording a difluoro-oxazolidine-lactam adduct after cyclization. After NH4Cl quench and filtration through a Celite pad, the crude solid is recrystallized from isopropyl alcohol/water (6:4 v/v) with a 10 °C/h cooling ramp to 5 °C to control crystal nucleus density; the resulting polymorph (Form A) exhibits micronized particle size Dv90 < 15 µm without additional jet milling, as required for suspension concentrate (SC) formulation per CIPAC MT 187. The final active ingredient is registered under Regulation (EC) No 1107/2009, with the corresponding batch analysis data reporting < 0.5% total by-products and absence of genotoxic structural alerts per ICH M7 QSAR screening. Processing is executed in a 100 L glass-lined reactor equipped with a hydro-cyclone for solids separation; the scale-up risk lies in the exothermic induction period (ΔTad = 48 °C) triggered at -8 °C. Therefore, the dose-controlled addition of the acetate reagent over 90 min coupled with a -15 °C brine circulating chiller capable of 15 kW heat removal is mandatory. Failure modes observed during piloting included local hot spots around the addition dip tube causing defluorination, which was eliminated by switching to a submerged 316L sintered-tip sparger and maintaining agitation at 200 rpm. The terminal end product is a broad-spectrum SDHI fungicide applied at rates of 150–200 g a.i./ha against Botrytis cinerea on protected salad crops. Is the Unexploited C-4 Chlorine Atom a Handle for Regioselective Cross-Coupling in NIR Absorbing Polymers?Before any cross-coupling chemistry, the C-5 aldehyde is masked as a cyclic ethylene acetal by treatment with ethylene glycol and 0.1 eq p-toluenesulfonic acid in refluxing cyclohexane, with azeotropic water removal. Selective protection allows the C-4 chlorine to be engaged in a Pd-catalyzed Suzuki-Miyaura reaction with 4-(N,N-diphenylamino)phenylboronic acid (1.05 eq, Pd(OAc)2 2 mol%, SPhos 4 mol%, K3PO4 3 eq, toluene/water 3:1, 95 °C, 16 h). The C-2 chlorine remains intact under these conditions, as verified by 13C NMR resonance at δ 153.2 ppm. Following aqueous HCl deprotection (2 N, 25 °C, 1 h), the liberated aldehyde-functionalized biaryl monomer is co-polymerized with 5,5′-bis(trimethylstannyl)-2,2′-bithiophene (1.0 eq) in a microwave-assisted Stille polymerization (Pd2(dba)3 1 mol%, P(o-tolyl)3 4 mol%, degassed chlorobenzene, 140 °C, 45 min). The resulting alternating copolymer, Mn 38 kDa (GPC, polystyrene standards, THF), exhibits a λmax in thin film of 782 nm and an electron mobility of 4.2 × 10−4 cm²/V·s measured via space-charge-limited current (SCLC) in an ITO/PEDOT:PSS/polymer/Al device architecture, tested per ASTM D257-14 methodology. For full-scale production of this non-fullerene acceptor-compatible donor, the Stille step is transferred to a 1 L Coflore Agitated Cell Reactor (ACR) to handle the viscous polymer dope (~12 dL/g intrinsic viscosity) and ensure sub-5 °C control during the exothermic induction. The final polymer is purified by Soxhlet extraction (acetone, hexane, CHCl3 sequential) to remove trace Pd below 10 ppm as mandated by IEC 61215-1:2021 for cadmium-free photovoltaics. The intended device format is a flexible organic photodetector for wearable health monitors, with all RoHS compliance declarations referencing Directive 2011/65/EU Annex III exemption 7(c)-I for Pb-containing piezoceramics. A tridentate imino-thiazole-oxazoline ligand is assembled by mono-condensation of 2,4-dichlorothiazole-5-carboxaldehyde with optically pure (S)-tert-leucinol (1.0 eq) in anhydrous THF at 40 °C over pre-activated 4 Å molecular sieves (500 g/mol aldehyde). After 8 h, the Schiff base is reduced in situ with sodium triacetoxyborohydride (1.5 eq, 5 °C addition) to prevent racemization of the adjacent chiral center. The resulting amino-oxazoline hybrid is then treated with PdCl2(CH3CN)2 to afford a bench-stable palladium complex that catalyzes the enantioselective allylic alkylation of (E)-cinnamyl acetate with dimethyl malonate at a catalyst loading of 0.5 mol%. Under optimized conditions (CH2Cl2, BSA/KOAc base system, −20 °C), the ee reaches 94% (chiral HPLC, Chiralpak AD-H) with a TOF of 1,250 h−1. The complex is prepared routinely in 50 g batches using standard Schlenk technique; strict exclusion of oxygen is monitored by a dual-channel Mettler Toledo InTap portable DO analyzer. Residual solvents, particularly THF (limit 720 ppm) and CH2Cl2 (limit 600 ppm), are quantitated by headspace GC-FID as per USP <467> residual solvent method 467. This chemistry supplies specialist catalyst manufacturers under IP-protected contracts; the final application is in the production of a blockbuster β-secretase inhibitor intermediate, where the isolated catalyst turnover number dictates the cost model. When the Aldehyde Is Chemoselectively Reduced to 2,4-Dichlorothiazole-5-methanol, a Coccidiostat Feed Premix ArisesReduction of the aldehyde with sodium borohydride (0.55 eq) in a 2:1 v/v MeOH/THF mixture at 0–5 °C proceeds quantitatively, with careful pH control (pH 6.8–7.2 via acetic acid buffer) suppressing dechlorination. The work-up involves quench into 10 wt% aqueous NH4Cl and extraction with ethyl acetate; the organic layer is dried over anhydrous Na2SO4 and concentrated under 50 °C jacket temperature to prevent thermal dehydration back to the aldehyde. The resulting benzylic alcohol, isolated as a low-melting crystalline solid (m.p. 68–70 °C), is subsequently phosphorylated with phosphorus oxychloride (1.05 eq, Et3N 2.5 eq, CH2Cl2, 0 °C to 20 °C) and quenched with methanol to give the dimethyl phosphate ester. This phosphate is the active coccidiostat, deployed at concentrations of 50–75 g/ton in poultry feed according to 21 CFR 558.360 for anticoccidial drug combinations. The premix manufacturing must comply with the Type B Medicated Feed requirements of FDA CVM, including cross-contamination limits of < 0.1% of the active in subsequent non-medicated batches. Process validation data from a 500 kg ribbon mixer indicates a blend uniformity relative standard deviation of 3.2% after 15 min mixing at 25 rpm, verified by ten-point thief sampling and LC-MS/MS quantitation (LOQ 0.5 ppm). The molecule is listed under the European Union VICH GL18 residual solvent guideline for the conversion of the aldehyde to the alcohol; an in-process control requires the dichloromethane extractant to be replaced with isopropyl acetate prior to scale-up to meet the 600 ppm CH2Cl2 residual limit per ICH Q3C classification Class 2. To access azo heterocyclic disperse dyes with enhanced wash fastness, 2,4-dichlorothiazole-5-carboxaldehyde is first converted to 5-aminomethylthiazole via the Leuckart-Wallach procedure (formamide, 140 °C, 6 h, then 6 N HCl hydrolysis). The resulting primary amine is diazotized in 85% phosphoric acid at -5 °C using nitrosylsulfuric acid (1.05 eq) to suppress the formation of decomposition tars. The diazonium salt is subsequently coupled with N,N-diethyl-m-toluidine in sulfamic acid-buffered ice-water mixture, maintaining pH 1.5–2.0 for monoprotonated amine coupling species. After 4 h stirring at 0 °C, the precipitated dye is filtered, washed to conductivity < 100 µS/cm, and dried at 60 °C under vacuum. The dry cake is then formulated as a 40% liquid dispersion using lignin sulfonate (e.g., Borresperse NA) in a horizontal bead mill (Netzsch LME 4) with 0.3–0.5 mm yttria-stabilized zirconia beads until a particle size D50 < 0.8 µm is reached, measured by laser diffraction (Malvern Mastersizer). The resulting disperse dye, with a molar extinction coefficient of 38,500 L·mol⁻¹·cm⁻¹ at λmax 542 nm in DMF, meets the fastness requirements of ISO 105-C06 (washing fastness, rating 4–5) and ISO 105-B02 (light fastness, rating 6–7) on polyester fabrics. Compliance with the ZDHC Manufacturing Restricted Substances List (MRSL) Version 3.1 is verified by third-party laboratory screening for forbidden arylamines according to EN 14362-1:2017; no carcinogenic amines are detected below the 30 ppm threshold. The dyestuff is primarily exported for automotive upholstery applications where high heat-set stability (200 °C, 60 s) is required, with color difference ΔECMC < 1.0 per ISO 105-A05. This particular aldehyde-derived chromophore exhibits an elevated wash fastness because the two chlorine substituents increase molecular dipole moment, improving adhesion to the polyester chain. |
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2,4-Dichlorothiazole-5-carboxaldehyde (C4HCl2NOS, CAS 1000932-35-4) is supplied as a pale yellow crystalline solid with a melting range of 62–64 °C and a molecular weight of 182.03 g/mol. The compound functions as a versatile electrophilic building block for constructing thiazole-containing pharmacophores and crop protection agents, where the aldehyde group participates readily in reductive amination, Knoevenagel condensation, and Wittig coupling. Distillation under reduced pressure (bp 237–239 °C at 1013 hPa, or 118–122 °C at 20 mbar) yields material of sufficient purity for most subsequent transformations, but batch-to-batch consistency in multi-step sequences demands rigorous control of residual starting material and halogenated isomers. Storage in tightly sealed, amber glass containers under inert gas headspace is recommended to suppress air oxidation to 2,4-dichlorothiazole-5-carboxylic acid, a conversion tracked by HPLC during stability studies at 25 °C/60% RH.
The aldehyde exhibits a density of 1.59 g/cm³ (20 °C) determined by helium pycnometry in accordance with ASTM D4892, and its calculated log P (octanol/water) of 1.85 indicates moderate lipophilicity that influences partitioning during aqueous workup. Solubility at 25 °C exceeds 200 mg/mL in dichloromethane, tetrahydrofuran, and ethyl acetate, whereas solubility in n-heptane drops below 5 mg/mL, a solubility gap exploited in low-temperature crystallization purges. The compound is sparingly soluble in water (<1 mg/mL) but hydrolytic sensitivity becomes measurable above pH 8 and 50 °C, with 0.5–1.0% aldehyde loss per hour in 0.1 N NaOH at 60 °C. Refractive index (nD20 1.601) aids in-process monitoring of distillation fractions. The enthalpy of fusion determined by differential scanning calorimetry (heating rate 10 K/min) is 22.4 kJ/mol, which, together with a vapour pressure of approximately 0.12 Pa at 25 °C (static method, OECD 104), informs the design of vacuum drying cycles and environmental emission controls.
On a 100 kg scale, the material is typically dried in a vacuum tray dryer at 40 °C and 5–10 mbar for 12–16 h to achieve a water content below 0.5% (Karl Fischer, ISO 760). Because residual moisture above 0.8% promotes hydrate formation visible as a sticky agglomerate that clogs micronizing mills, pre-drying is mandatory whenever ambient relative humidity exceeds 60%. Operators report that once-dried product re-equilibrates to 0.2–0.3% water within 4 h when exposed to 25 °C/45% RH, necessitating nitrogen blanketing during micronization and packaging.
Manufacture of 2,4-dichlorothiazole-5-carboxaldehyde proceeds predominantly via Vilsmeier–Haack formylation of 2,4-dichlorothiazole. In a typical batch, phosphorus oxychloride (1.25 eq) is added dropwise to anhydrous dimethylformamide (2.5 eq) at 0–5 °C in a 500 L glass-lined reactor, forming the Vilsmeier complex whose exotherm is controlled by jacket brine circulation. After 30 min aging, a solution of 2,4-dichlorothiazole (1.0 eq) in DMF is fed over 45–60 min while maintaining the internal temperature below 10 °C. The mixture is then heated to 55–60 °C and held for 6–8 h. Quenching into 500 kg of ice water precipitates the crude aldehyde, which is extracted into dichloromethane, washed with aqueous sodium bicarbonate (5% w/w) until neutral, and concentrated. Vacuum distillation through a wiped-film evaporator (jacket temperature 80 °C, pressure 1–3 mbar, rotor speed 300 rpm) yields the product as a light yellow distillate that solidifies in the receiver. Typical isolated yields range from 72% to 78% at the 50–80 kg input scale, with a purity of 96–98 area% before recrystallization. The major impurity is unreacted 2,4-dichlorothiazole (1.5–3.0%), accompanied by a dichlorinated over-formylated dimer (0.3–0.8%) and traces of the corresponding acid from over-oxidation. When batch distillation is replaced by continuous fractional distillation on a column containing structured packing (Sulzer BX, 2.5 m height, reflux ratio 3:1), the yield improves to 81–84% and the residual starting material drops below 0.3%.
The following table reproduces the typical release criteria applied to kilogram-scale campaigns, anchored to compendial and in-house validated procedures.
| Parameter | Specification | Test Method |
|---|---|---|
| Assay (anhydrous, solvent-free) | ≥98.5% | HPLC, UV 254 nm, area normalization; column C18 150 × 4.6 mm, 5 µm; mobile phase acetonitrile/0.1% H₃PO₄ 60:40; system suitability per USP <621> |
| Residual 2,4-dichlorothiazole | ≤0.3% | GC-FID, column DB-5 30 m × 0.25 mm, 0.25 µm, split 1:50; temperature program 80 °C to 280 °C at 15 °C/min; external standard calibration |
| Any single unspecified impurity | ≤0.15% | Same HPLC method as assay |
| Total impurities | ≤1.5% | Same HPLC method |
| Water content | ≤0.5% | Karl Fischer coulometric titration; Ph. Eur. 2.5.12 |
| Residue on ignition (sulfated ash) | ≤0.1% | Ph. Eur. 2.4.14, 600 °C |
| Appearance | Pale yellow crystalline solid, free of visible dark specks | Visual inspection under D65 light |
Residual solvent limits are harmonized with ICH Q3C option 1: dichloromethane ≤600 ppm, DMF ≤880 ppm, and ethyl acetate ≤5000 ppm, determined by headspace GC-MS using a standard addition protocol. The aldehyde peak in HPLC typically elutes at 4.2 min and does not co-elute with the acid degradation product (RT 2.8 min). During method validation, recovery at the 0.05% level for the starting material impurity was 98.2% with RSD ≤5.3% (n=6), confirming suitability for low-level monitoring.
The aldehyde function in this molecule exhibits a pronounced electrophilic character, quantified by a Mayr electrophilicity parameter E of approximately −11.5 (referenced to 2,4-dichlorothiazole-5-carbonitrile with E −14.2). This reactivity permits selective reductive amination with aliphatic primary amines using sodium triacetoxyborohydride in dichloroethane at 20–25 °C, typically furnishing secondary amines in 85–90% yield without significant displacement of the ring chlorines. In contrast, the corresponding carboxylic acid (2,4-dichlorothiazole-5-carboxylic acid) requires activation with HATU or EDCI before amide bond formation, adding an extra synthetic step and generating coupling reagent by-products that complicate purification. The esters, such as the methyl ester (MW 212.05 g/mol, mp 48–50 °C), are susceptible to premature saponification under basic amine coupling conditions, yielding the acid impurity that persists through column chromatography.
A systematic comparison across the thiazole-5-substituted family is provided in the following table, demonstrating the aldehyde’s unique balance of shelf stability and synthetic utility.
| Compound | MW (g/mol) | m.p. (°C) | log P | Key Reactivity |
|---|---|---|---|---|
| 2,4-Dichlorothiazole-5-carboxaldehyde | 182.03 | 62–64 | 1.85 | Rapid imine formation; Wittig olefination; Knoevenagel with malononitrile; tolerates mild nucleophiles without ring chlorine displacement |
| 2,4-Dichlorothiazole-5-carboxylic acid | 198.02 | 181–183 (dec.) | 1.12 | Requires activation (EDC/HOBt) for amide linkage; decarboxylation above 185 °C |
| Methyl 2,4-dichlorothiazole-5-carboxylate | 212.05 | 48–50 | 2.08 | Transesterification and aminolysis at elevated temperature; unwanted hydrolysis to acid in aqueous workup |
| 2,4-Dichlorothiazole-5-carbonitrile | 179.02 | 71–73 | 1.64 | Electrophilic at nitrile carbon but substantially less reactive toward amines; requires harsh hydrolysis for conversion to acid |
| 5-(Chloromethyl)-2,4-dichlorothiazole | 202.49 | Oil | 2.35 | Alkylating agent; prone to dimerization upon storage; lacks direct carbonyl chemistry |
The aldehyde’s ability to withstand standard Suzuki–Miyaura conditions at the 2-chloro position while retaining the formyl group has been exploited in several reported biaryl syntheses. However, when the coupling is performed at temperatures above 100 °C in the presence of aqueous carbonate, partial aldehyde oxidation to the acid occurs, reducing the effective yield by 5–10%. This undesirable pathway is suppressed by pre-drying the dioxane solvent over molecular sieves and using anhydrous potassium phosphate as base, a modification that maintains the aldehyde integrity above 97% by HPLC after 12 h at 90 °C.
Long-term stability data collected on three production lots stored in original packaging (amber glass, nitrogen blanket, 2–8 °C) over 24 months show assay decrease of less than 0.8% and no new impurity exceeding 0.10%. When the same material is held at 30 °C/65% RH in HDPE drums with a double PE liner, water ingress increases to 0.7–0.9% after 90 days and the carboxylic acid impurity reaches 0.25–0.35%, necessitating re-drying before use in Grignard additions. Consequently, shipments beyond 5 kg are configured with a molecular sieve desiccant pouch inserted between liners and a humidity indicator card. The aldehyde should not be stored in proximity to primary or secondary amines, as even vapour-phase contact can generate Schiff base crusts at the closure, compromising seal integrity. Contact with strong reducing agents—lithium aluminum hydride, diisobutylaluminum hydride—in bulk storage areas must be physically segregated because accidental mixing could initiate an uncontrolled exotherm later in the synthesis suite.
Under the Globally Harmonized System (GHS), 2,4-dichlorothiazole-5-carboxaldehyde is classified as Skin Irrit. 2 (H315), Eye Irrit. 2 (H319), and STOT SE 3 (H335). It is not classified as a dangerous good for transport according to ADR/RID and IMDG Code, and holds a UN-TDG exemption for inner packagings of ≤5 kg. An EU REACH registration dossier (tonnage band 10–100 t/a) lists a Derived No-Effect Level (DNEL) for long-term inhalation exposure of workers at 0.68 mg/m³, derived from a repeated-dose 28-day inhalation study in rats. Engineering controls at the charging station include local exhaust ventilation with a capture velocity of 0.5 m/s and continuous real-time monitoring of airborne particulates via a light-scattering photometer calibrated annually to ISO 21501-4. Operators handling open product are required to wear nitrile gloves tested to breakthrough time > 480 min (EN 374) and full-face respiratory protection with an organic vapour/P3 combination cartridge when exposure exceeds 10% of the OEL.
