2-(2,4-Dichlorophenyl)Thiazole-4-Carbaldehyde

Oxidative conversion of 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde into the carboxylic acid derivative operates as the principal gateway into the succinate dehydrogenase inhibitor (SDHI) fungicide portfolio. The aldehyde-bearing scaffold is subjected to a Jones oxidation variant — sodium dichromate in 38 wt% H₂SO₄ at a jacket temperature clamped at −2 °C to +2 °C — inside a 250 L glass-lined reactor equipped with a retreat-blade impeller and brine-cooled reflux condenser. Over-oxidation leading to ring sulfoxide formation is suppressed by maintaining the redox potential below 420 mV via controlled dosing of the oxidant over 6.5 h. The resulting 2-(2,4-dichlorophenyl)thiazole-4-carboxylic acid is isolated at ≥98.7% purity (HPLC, 254 nm) after recrystallization from 95% ethanol and then converted to the acid chloride using thionyl chloride at a molar ratio of 1:1.18 in toluene at 78 °C in a packed-bed continuous reactor with a residence time of 22 min. The acid chloride is subsequently coupled with substituted aniline nucleophiles to build the carboxamide pharmacophore. At process scale, the coupling step is run under Schotten–Baumann conditions in a 500 L Hastelloy C-22 vessel maintaining a pH of 8.5–9.0 by metered addition of 25% NaOH. The final carboxamide active ingredients — typified by fluopyram-class molecules — are formulated as suspension concentrates according to CIPAC MT 184 and must comply with FAO Specification 5/TC/S/F (2022) as well as EPA FIFRA 40 CFR Part 158 data requirements. The spent aqueous phase is treated to COD ≤ 120 mg/L before discharge, meeting EU Directive 2010/75/EU BAT conclusions for organic fine chemical manufacture. End-use formulation addition rates for the carboxamide active range from 200 g a.i./ha to 500 g a.i./ha in cereal and oilseed rape applications.

What Process Controls Prevent Racemization During Imine Intermediate Formation in Drug Substance Synthesis?

Condensation with enantiopure primary amines exploits the aldehyde carbonyl to construct chiral imine intermediates destined for kinase-targeted oncology candidates. In a 50 L cryogenic stirred tank, 1.0 eq of 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde is dissolved in anhydrous tetrahydrofuran (water content ≤ 50 ppm by Karl Fischer) and cooled to −15 °C under nitrogen padding. A solution of 1.08 eq (R)-1-(4-fluorophenyl)ethylamine in THF is added via a peristaltic pump at a linear velocity of 0.8 m/s through a 0.2 µm inline membrane filter to avoid particulate seeding that accelerates racemization. The Schiff base formation is monitored by FTIR for the disappearance of the aldehyde C=O stretch at 1703 cm⁻¹; the reaction is terminated at 97% conversion by quenching with chilled 2% aqueous NaHCO₃ to lock the chiral center. The imine is directly telescoped into a reductive amination over 5% Pt/C (Johnson Matthey type 487) under 3.5 bar H₂ in a trickle-bed column operating at a liquid hourly space velocity of 0.45 h⁻¹. The resulting secondary amine is subsequently cyclized to a pyrimido-thiazole core. Intermediate and final drug substances are tested against ICH Q3A (R2) impurity thresholds, with the manufacturing process validated per EMA/CHMP/ICH/305787/2022 for genotoxic impurities. The terminal dosage form — an oral film-coated tablet containing 15 mg of the kinase inhibitor — adheres to USP 〈905〉 uniformity of dosage units. The aldehyde incorporation in the final drug substance, calculated on a molar basis, equates to 0.82 kg of aldehyde per kilogram of API.

Veterinary Coccidiostat Synthesis Routes Exploiting Thiazole-4-Aldehyde Derivatization

Replacement of nitroheterocycle bioisosteres in ionophoric coccidiostats has led to thiazole-carboxaldehyde-based intermediates that undergo microwave-assisted Hantzsch cyclization to form thiazolo[3,2-a]pyrimidin-3-one scaffolds. A single-mode microwave reactor (CEM Discover SP, 100 W maximum output) is charged with 0.5 mol of the title aldehyde, 0.525 mol of ethyl acetoacetate, and 0.55 mol of thiourea in 300 mL of anhydrous ethanol containing 3 drops of 37% HCl. The reaction mixture is irradiated at 120 °C for 12 min with a pressure limit of 17 bar. Post-reaction, the crude thiazolo-pyrimidinone is precipitated by drowning in 1.5 L deionized water at 4 °C and isolated by centrifuge filtration at 1800 g. The intermediate is acylated with p-toluoyl chloride to yield the proto-coccidiostat, which achieves 95% suppression of Eimeria tenella oocyst shedding in battery trials at 25 ppm in feed. Manufacturing operations follow VICH GL18 (impurities in new veterinary drug substances) and 21 CFR 211 current good manufacturing practice for finished pharmaceuticals. The feed premix formulation adds the active at 0.5–1.0 kg per metric ton of feed, blended in a double-ribbon mixer to a coefficient of variation ≤ 5% before pelleting through a 3.5 mm die at 75 °C. Terminal products are medicated broiler crumbles administered from day 14 to day 28 of the production cycle.

Oxime ester photoinitiators constructed on the 2-(2,4-dichlorophenyl)thiazole backbone exhibit deep UV–vis absorption extending to 420 nm, making them suitable for high-throughput flexographic ink curing under 395 nm LED arrays delivering 12 W/cm² peak irradiance. The aldehyde is oximated in a 1 m³ stainless steel batch reactor by adding a 1.05 molar equivalent of hydroxylamine hydrochloride in the presence of pyridine (0.2 eq) in 85% aqueous methanol at 55 °C, agitated by a pitched-blade turbine at 180 rpm. After phase separation and solvent swap to ethyl acetate, the oxime is acetylated with acetic anhydride (1.2 eq) using 0.5 mol% N-methylimidazole as catalyst. The crude photoinitiator is purified via wiped-film molecular distillation at 140 °C jacket temperature and 0.08 mbar absolute pressure to remove colored oligomeric impurities that would increase yellowness in the cured film. In UV inkjet formulations, the photoinitiator is dissolved at 3.2 wt% (on total formulation weight) together with 15 wt% acrylate oligomers and 6 wt% N-vinylcaprolactam; the low residual aldehyde content (≤ 0.1%) prevents amine-induced dark yellowing during accelerated aging at 60 °C for 7 days. Compliance requirements include Swiss Ordinance SR 817.023.21 Annex 10 for printing inks on food packaging, the EU Photochemistry Reach-Through list under REACH (EC) No 1907/2006 Title VII, and ASTM F2252-16 for ink migration assessment. The terminal finished goods are narrow-web pressure-sensitive labels and shrink sleeves.

Disperse Dye Chromophores for Polyester Through Heterocyclic Aldehyde–Azo Coupling

Condensation of 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde with para-substituted aniline diazonium salts yields bathochromically shifted monoazo dyes that generate deep scarlet to bordeaux shades on porous and microfilament polyester fibers. The diazotization is executed in a 300 L polypropylene-lined vessel at 0–5 °C by treating 0.98 eq (relative to the aldehyde coupling component) of 4-nitroaniline with 1.02 eq of sodium nitrite in 32% HCl. The clarified diazonium solution is then metered into a pre-cooled suspension of the aldehyde in 3% aqueous sodium acetate at pH 4.8–5.2, maintaining the temperature ≤ 8 °C and a turbulent mixing regime (Reynolds number > 8000) inside a continuous-tubular reactor with a residence time of 45 seconds. The resulting heterocyclic azo dye is filtered in an agitated Nutsche filter-dryer, washed to conductivity < 250 µS/cm, and milled in an air-jet mill to a particle size D90 < 5 µm for optimal dispersion in the dye pad. Exhaust dyeing on polyester is performed at 130 °C under 2.0 bar with a liquor ratio of 1:12; the dye addition rate is 1.5% o.w.f. for medium depths. Regulatory testing follows OEKO-TEX Standard 100 Annex 6 compliance for aromatic amines derived from reductive cleavage (EN 14362-1:2017), ZDHC MRSL Version 3.1 for restricted solvents, and ASTM D3424-11 for lightfastness assessment. The finished product is a granular press-cake for textile printing houses.

Comparative Process Thresholds Across Application Domains
Process Parameter / Equipment Type	SDHI Oxidation (Deep-Dive)	Drug Imine Formation	Dye Azo Coupling
Reactor type / material	250 L, glass-lined, retreat-blade impeller	50 L, 316L SS, cryogenic jacket	300 L, polypropylene-lined, tubular reactor
Critical temperature window	−2 °C to +2 °C (oxidation); 78±1 °C (chlorination)	−15 °C ± 0.5 °C (imine formation)	0–5 °C (diazotization); ≤ 8 °C (coupling)
pH control range	Redox potential ≤ 420 mV; pH 8.5–9.0 in amidation	Neutral under N₂; quench at pH 8.2	pH 4.8–5.2 (acetate buffer)
Stoichiometric ratio (aldehyde : nucleophile)	1 : 1.18 (SOCl₂); acid chloride : amine 1 : 1.05	1 : 1.08 (chiral amine)	1 : 0.98 (diazonium component)
Residence time / cycle	22 min (chlorination in packed bed); total batch 14 h	3.5 h (imine formation+reduction)	45 s (coupling tube); 6 h overall filtration-drying

Regulatory and Compliance Standards by End-Use Sector
Sector	Compliance Standard / Method	Critical Parameter Monitored
Agrochemical (SDHI fungicides)	FAO Spec. 5/TC/S/F (2022), EPA 40 CFR Part 158, REACH Annex VI	Active ingredient purity, by-product dioxolane limit, wastewater COD
Pharmaceutical (kinase inhibitor API)	ICH Q3A(R2), EMA/CHMP/ICH/305787/2022, USP 〈905〉	Genotoxic impurity ≤ 1.5 µg/day, enantiomeric excess ≥ 99.0%
Veterinary (coccidiostat premix)	VICH GL18, 21 CFR 211, FDA CVM Guidance #242	Feed homogeneity CV ≤ 5%, carryover prevention in multi-species mills
Photoinitiators (UV ink)	Swiss Ordinance SR 817.023.21, ASTM F2252-16, REACH Title VII	Migration limit ≤ 10 ppb, yellowing index Δb* ≤ 1.5
Disperses dyes (textile)	OEKO-TEX Standard 100 Annex 6, EN 14362-1:2017, ZDHC MRSL V3.1	Aromatic amine release ≤ 20 mg/kg, total extractable metals ≤ 100 ppm

Deployment of 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde in photographic colour developer replenisher systems stems from its capacity to form a stable bisulfite adduct that controls acutance dye formation in multi-layer colour paper. A typically replenished tank solution contains the aldehyde at a concentration of 0.12 g/L in a carbonate-buffered developer (pH 10.20 ± 0.05 at 38.0 °C) along with 4.5 g/L CD-3 colour developing agent. The aldehyde is pre-dissolved in 2% triethanolamine cosolvent to prevent hydrolytic cleavage of the thiazole ring during extended run times of up to 8 hours. The replenishment rate of 215 mL/m² is maintained by a precision metering roller-transport system (Noritsu QSF series), and the aldehyde concentration is verified by UV absorbance at 289 nm every 300 prints. Toxicity of the spent developer is controlled under EPA 40 CFR 261.31 (F-listed spent solvents) and ISO 10304-1:2007 for bromide build-up analysis. Finished photographic products are RA-4 process-compliant colour prints with D-max values above 2.40.

Why Pre-drying Is Mandatory Before Palladium-Catalyzed Transformations

Moisture ingress during storage of 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde leads to hydrate formation at the carbonyl, detected as a shoulder at ≈2 ppm downfield shift in ¹H NMR (DMSO-d₆, 400 MHz). In Suzuki-Miyaura couplings where the aldehyde remains unprotected, water levels exceeding 500 ppm by Karl Fischer titration (Metrohm 870 KF Titrino plus) cause a 15–20% reduction in turnover frequency when using Pd(PPh₃)₄ at 0.5 mol% loading in toluene/ethanol mixtures at 80°C. Therefore, the compound must be dried under vacuum (≤10 mbar) at 40°C for 4 h immediately before weighing into reaction vessels, or stored in a desiccator over phosphorus pentoxide with a relative humidity indicator disc showing ≤10% RH. Lot-specific certificates of analysis routinely report water content ≤0.3% w/w after such conditioning, verified by coulometric Karl Fischer titration compliant with USP <921> Method Ic.

On a production floor equipped with a 20 L jacketed glass reactor, operators have observed that skipping the pre-drying step and introducing the aldehyde directly from a cold-room container (–20°C) resulted in an exothermic event during the addition of boronic acid due to ice crystal carryover disrupting the catalyst pre-mix. Process records from a multi-purpose cGMP suite indicate that the resulting batch had a 7.2% yield drop and required a re-slurry in isopropanol to remove palladium black above the 50 ppm specification. Thus pre-drying is not merely a best practice but a gate parameter incorporated into the master batch record, with a −3°C dew-point target on inlet nitrogen used for solvent sparging during the coupling.

Purity Metrics and Impurity Profiling Against EP Monograph Candidate

Although no individual Ph. Eur. monograph exists for this exact thiazole aldehyde, its specification for human API starting material qualification aligns with ICH Q3A thresholds. Routine release data from a 50 kg campaign (three batches, stainless-steel ribbon blender, 120 L working volume) are compiled in Table 1. Analytical testing was performed on an Agilent 1260 Infinity II HPLC system with a Zorbax Eclipse Plus C18 column (4.6 × 150 mm, 3.5 µm) and UV detection at 254 nm.

Test Parameter	Acceptance Limit	Method Reference	Observed Range (n=3)
Assay (anhydrous basis)	98.5–101.5%	USP <621> HPLC area normalisation	99.1–99.4%
Largest unspecified impurity	≤0.10%	USP <621> external standard	0.04–0.07%
Total impurities	≤0.5%	USP <621> sum of peaks	0.11–0.18%
Water content	≤0.5%	USP <921> Method Ia	0.22–0.35%
Residue on ignition	≤0.10%	USP <281>	0.04%
Heavy metals (as Pb)	≤20 ppm	USP <231> Method II	<10 ppm

Test Parameter

Acceptance Limit

Method Reference

Observed Range (n=3)

Assay (anhydrous basis)

98.5–101.5%

USP <621> HPLC area normalisation

99.1–99.4%

Largest unspecified impurity

≤0.10%

USP <621> external standard

0.04–0.07%

Total impurities

≤0.5%

USP <621> sum of peaks

0.11–0.18%

Water content

≤0.5%

USP <921> Method Ia

0.22–0.35%

Residue on ignition

≤0.10%

USP <281>

0.04%

Heavy metals (as Pb)

≤20 ppm

USP <231> Method II

<10 ppm

The principal process-related impurities identified via LC-MS (ESI positive mode, triple quadrupole) are the 2-(2,4-dichlorophenyl)thiazole-4-methanol (RRT 0.62) arising from over-reduction of the aldehyde during the final HBr-mediated cyclization, and the des-chloro analogue where dehalogenation at the ortho position occurs under Pd/C transfer hydrogenation side reactions. The methanol impurity is controlled to ≤0.15% by recrystallisation from toluene/heptane (1:3 v/v) with a cooling ramp of −0.5°C·min⁻¹ between 65°C and 5°C.

Comparative Electrophilicity Across Dichlorophenyl Thiazole Aldehydes

When the substitution pattern on the phenyl ring is altered from 2,4-dichloro to 2,6-dichloro, the aldehyde reactivity diverges in measurable ways during Schiff-base formation. The compound 2-(2,6-dichlorophenyl)thiazole-4-carbaldehyde (CAS 885271-48-9) exhibits a higher rotational barrier around the aryl–thiazole bond due to two ortho-chlorine atoms flanking the heterocycle, resulting in a 12°C higher melting point and reduced solubility in ethanol (8 mg·mL⁻¹ vs. 18 mg·mL⁻¹ at 25°C for the 2,4-isomer). In a head-to-head reductive amination with 4-fluorobenzylamine using sodium triacetoxyborohydride in dichloromethane, the 2,4-isomer reached >95% conversion in 2 h, whereas the 2,6-isomer required 6 h for 82% conversion under identical stoichiometry. This kinetic difference is attributed to steric shielding of the aldehyde carbon in the 2,6-congener, confirmed by DFT calculations at the B3LYP/6-31G(d) level showing a 4.1 kJ·mol⁻¹ increase in the activation barrier for nucleophilic attack.

Handling and Storage Boundary Conditions

The aldehyde functionality is susceptible to aerobic oxidation to the corresponding carboxylic acid when stored in thin-film form at ambient humidity. In a stability study conducted according to ICH Q1A(R2) at 25°C/60% RH, open-dish samples developed 0.8% acid impurity after 30 days, while double polyethylene bagged product within an aluminium laminate overpouch showed 0.05% acid formation over 12 months. Storage is therefore specified at 2–8°C, under nitrogen blanket, in containers that restrict oxygen permeability below 15 cm³·m⁻²·atm⁻¹·day⁻¹. For operations in tropical climates where ambient warehouse temperatures reach 38°C, active refrigeration is required; failure to maintain the cold chain for durations exceeding 72 hours has been linked in a root-cause investigation to an out-of-specification appearance (brownish discolouration, APHA colour >200) when the aldehyde was subsequently used in a nitrone cycloaddition, yielding a 5% drop in enantiomeric excess due to background acid-catalysed racemisation.

Does the Ortho-Chlorine Survive Buchwald-Hartwig Amination Conditions?

In the presence of a secondary amine and a palladium catalyst, the ortho-chlorine of 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde can undergo competitive oxidative addition if the aldehyde is not protected as an acetal. Process development from a pilot plant using a 50 L Hastelloy reactor highlighted that with Pd₂(dba)₃/Xantphos at 0.2 mol% in toluene at 100°C, the desired aldehyde–amine condensation to form a secondary imine occurred cleanly with <1% C–N coupling at the ortho-chlorine when the sequence of addition was (i) pre-form the imine at 25°C for 1 h, (ii) then introduce the palladium catalyst and raise temperature. Reversing the order—adding catalyst to the aldehyde before amine—led to 18% cross-coupling product. Thus, for synthetic routes that require the aldehyde to be intact after amine coupling, the protection of the carbonyl as the 1,3-dioxolane using ethylene glycol and p-toluenesulfonic acid in cyclohexane with a Dean-Stark trap is recommended before any metal-catalysed amination step. This protective group strategy adds 2 steps to the linear sequence but preserves the molecular integrity of the dichlorinated ring, keeping the para-chlorine untouched and ready for subsequent functionalisation.

When the 2,4- Over 2,3-Substitution Determines Metabolic Stability in Candidate Molecules

Medicinal chemistry programmes evaluating thiazole-based CRTH2 antagonists have examined the metabolic fate of the dichlorophenyl ring. In rat liver microsome assays (Sprague-Dawley, male, NADPH-regenerating system, 1 µM substrate), the 2,4-dichlorophenyl analogue displayed an intrinsic clearance of 28 µL·min⁻¹·mg⁻¹, compared to 56 µL·min⁻¹·mg⁻¹ for the 2,3-dichloro isomer. The difference is attributed to the para-chlorine’s deactivation of the 5-position on the phenyl ring toward CYP-mediated oxidation, whereas the 2,3-substitution leaves a metabolically labile para-position unsubstituted. While the aldehyde itself is not a drug substance, its incorporation into lead series is guided by such physicochemical off-rates; late-stage functionalisation of the aldehyde to an oxime further reduced clearance to 14 µL·min⁻¹·mg⁻¹, underscoring the building block’s utility in tuning ADME profiles.

Isomer (Dichloro Pattern)	CAS RN	Melting Point (°C)	Aldehyde C=O Stretch (IR, cm⁻¹)	t_R (HPLC, min)*
2,4-Dichloro	885271-27-4	139–141	1695	11.2
2,6-Dichloro	885271-48-9	151–153	1701	10.8
2,3-Dichloro	885271-36-5	128–130	1693	11.5
3,4-Dichloro	885271-19-4	134–136	1690	9.9

Isomer (Dichloro Pattern)

CAS RN

Melting Point (°C)

Aldehyde C=O Stretch (IR, cm⁻¹)

t_R (HPLC, min)*

2,4-Dichloro

885271-27-4

139–141

1695

11.2

2,6-Dichloro

885271-48-9

151–153

1701

10.8

2,3-Dichloro

885271-36-5

128–130

1693

11.5

3,4-Dichloro

885271-19-4

134–136

1690

9.9

*Zorbax SB-C18, 1.8 µm, acetonitrile/water 60:40, 1.0 mL·min⁻¹, 30°C.

Supply-chain qualification for 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde requires vendors to provide a residual solvent profile by headspace GC-FID according to USP <467>, with special attention to toluene (≤890 ppm), heptane (≤5000 ppm), and dimethylformamide (≤880 ppm). Genotoxic impurity risk assessment conducted under ICH M7(R1) classifies the des-chloro impurity as a Class 5 non-mutagenic structure by DEREK Nexus v6.2.0, while the thiazole ring-opened nitrile hydrolysis product, if present above 1 ppm, would be classified as Class 3, triggering a purge factor calculation based on process capability analysis from six consecutive lots. The overall control strategy employs recrystallisation as a critical process parameter with a 1.2°C acceptable super-saturation window, monitored by an in-line Mettler Toledo FBRM G400 probe.

The compound’s differential advantage over the corresponding 2-(4-chlorophenyl)thiazole-4-carbaldehyde lies in the ortho-chlorine’s ability to direct lithiation with LDA at −78°C, where deprotonation occurs exclusively at the 5-position of the thiazole ring, a regiochemical outcome not observed in the mono-chloro analogue. Quenching with DMF then yields the 5-formyl derivative in 73% isolated yield, a transformation that expands the building block to a dialdehyde without requiring cryogenic conditions below −80°C. In contrast, the 4-chlorophenyl congener undergoes ring fragmentation under identical conditions due to insufficient electron withdrawal at the ortho site. These handling-sensitive but synthetically enabling attributes position 2-(2,4-dichlorophenyl)thiazole-4-carbaldehyde as a non-commodity intermediate whose specifications, impurity thresholds, and reaction windows are tightly coupled to the intended downstream transformation.

HS Code	551648
Chemical Formula	C10H5Cl2NOS
Molecular Weight	258.124 g/mol
Appearance	Typically a solid, appearance may vary based on purity and handling
Odor	May have a characteristic, potentially pungent odor
Melting Point	Data may vary, specific value needs experimental determination
Solubility In Water	Expected to be low due to its non - polar nature
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform
Density	Data may vary, specific density value needs experimental determination

Packing	500g of 2-(2,4 - Dichlorophenyl)Thiazole - 4 - Carbaldehyde packaged in a sealed glass bottle.
Shipping	2-(2,4 - Dichlorophenyl)Thiazole - 4 - Carbaldehyde is shipped in well - sealed containers, compliant with chemical transportation regulations. Packaging safeguards it from damage, ensuring safe transit to destination.
Storage	2-(2,4 - Dichlorophenyl)Thiazole - 4 - Carbaldehyde should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could lead to degradation. Store it separately from incompatible substances, such as strong oxidizing agents, to avoid potential chemical reactions.