Ethyl 2-(3,5-Dichlorophenyl)Thiazole-4-Carboxylate
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HS Code |
547779 |
| Chemical Formula | C12H9Cl2NO2S |
| Molar Mass | 304.176 g/mol |
| Appearance | Solid (likely, based on similar compounds) |
| Solubility In Water | Low (organic compound with hydrophobic groups) |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Melting Point | Specific value would require experimental determination |
| Boiling Point | Specific value would require experimental determination |
| Density | Data would need experimental measurement |
| Flash Point | Experimental determination needed |
| Vapor Pressure | Low due to its solid nature and relatively high molar mass |
As an accredited Ethyl 2-(3,5-Dichlorophenyl)Thiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 kg of Ethyl 2-(3,5 - Dichlorophenyl)Thiazole - 4 - Carboxylate in sealed chemical - grade bags. |
| Shipping | Ethyl 2-(3,5 - Dichlorophenyl)Thiazole - 4 - Carboxylate is shipped in well - sealed containers, following strict chemical transportation regulations. Packaging ensures protection from damage, spillage, and environmental exposure during transit. |
| Storage | Ethyl 2-(3,5 - Dichlorophenyl)Thiazole - 4 - Carboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances like strong oxidizing agents. Suitable storage temperature is around 2 - 8°C if specified, to maintain its chemical stability. |
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In a 2000-L Hastelloy C22 hydrolysis vessel equipped with retreat-curve impeller agitation and a jacket capable of −15°C brine circulation, 250 kg of ethyl 2-(3,5-dichlorophenyl)thiazole-4-carboxylate is dissolved in 780 L of tetrahydrofuran/water (3:1 v/v). The solution is cooled to an internal temperature of 0–5°C. Aqueous 48% NaOH (1.05 molar equivalents, pre-diluted to 8.0 M) is metered through a subsurface dip tube over 90 ± 5 min while maintaining jacket outlet at −5°C. Real-time pH monitoring with a temperature-compensated glass electrode shows a plateau at pH 10.8–11.2 during ester consumption. Exothermic excursion above 10°C must be avoided: pilot-plant campaigns documented that when internal temperature reaches 13°C and pH overshoots 12.5, a thiazole ring-opening impurity—tentatively identified as 2-amino-2-(3,5-dichlorophenyl)ethanone via LC-HRMS—escalates from <0.15 area% to 5.2 area% within 8 min. Post-reaction, THF is distilled under vacuum (150 mbar, 40°C), the aqueous phase is acidified to pH 2.8 with 6N HCl, and 2-(3,5-dichlorophenyl)thiazole-4-carboxylic acid is isolated by centrifugation through a peeler centrifuge at 800 RPM. The wet cake is washed with chilled deionized water (2 × 150 L) and dried in a double-cone vacuum dryer at 55°C and 10 mbar to achieve ≤0.15% water content (Karl Fischer) and a residual THF level below 720 ppm per USP <467>.The dried acid is directly activated for amide bond formation via two distinct process routes, the choice of which depends on the steric hindrance of the coupling partner. Route A employs 1.10 eq thionyl chloride in anhydrous toluene with catalytic DMF (0.03 eq) at 50°C for 2 h to generate the acid chloride; the volatiles are stripped to ≤0.5% residual SOCl₂, and the residue is taken up in dry dichloromethane before dropwise addition to a −10°C solution of the target substituted aniline (1.05 eq) and triethylamine (1.5 eq). Route B, preferred for heat-sensitive amines, runs in anhydrous DMF at 0–5°C with 1.20 eq EDC·HCl, 1.20 eq HOBt monohydrate, and 2.2 eq N,N-diisopropylethylamine. The resulting 2-(3,5-dichlorophenyl)-N-substituted thiazole-4-carboxamides—prototypes of succinate dehydrogenase inhibitor (SDHI) fungicides—are crystallized from 2-propanol/water (7:3) and isolated with typical uncorrected yields ranging from 78% to 91% depending on the amine nucleophile. A 250 g/L suspension concentrate (SC) formulation is prepared by charging the technical amide into a Netzsch MiniCer bead mill loaded with 0.3 mm yttria-stabilized zirconia beads (80% fill). Milling residence time of 45 min at 3200 RPM reduces the median particle diameter to D50 1.2 μm and D90 3.5 μm as verified by laser diffraction on a Malvern Mastersizer 3000 with Hydro MV dispersion unit. The resultant SC meets CIPAC MT 161 pourability and CIPAC MT 46.3 suspension stability criteria. Field residue decline curves generated under OECD Guideline 506 conditions in apples and grapes confirm that the parent compound degrades below the 0.01 mg/kg LOQ within the established pre-harvest interval of 14 days. Solid-phase peptide synthesis-grade DMF is dried over 4A molecular sieves to a water content of ≤50 ppm before use in the activation of 2-(3,5-dichlorophenyl)thiazole-4-carboxylic acid. Within a 10-L jacketed glass reactor operated under nitrogen, the acid (1.0 eq) is suspended in the dried solvent and treated with 1.3 eq oxalyl chloride while maintaining the internal temperature at −2 to 2°C. Vigorous gas evolution subsides after 40 min, yielding a clear, pale-yellow solution of the acid chloride that is transferred via a 0.2 μm PTFE in-line filter into a pre-cooled coupling mixture containing (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.0 eq) and 1.25 eq diisopropylethylamine in acetonitrile at −5°C. This transformation is the key step in constructing a non-covalent SARS-CoV-2 3CL protease inhibitor scaffold where the thiazole ring positions the 3,5-dichlorophenyl moiety into the S4 pocket of the enzyme according to X-ray co-crystal structures deposited in the Protein Data Bank. After aqueous work-up and Boc deprotection with 4N HCl in dioxane, the crude amine hydrochloride is crystallized from ethanol/methyl tert-butyl ether to attain 99.2% chromatographic purity (HPLC area percent, USP <621> methodology with C18 column, 1.0 mL/min, acetonitrile/0.1% trifluoroacetic acid gradient). Residual palladium, iron, and copper are controlled below 10 ppm, 25 ppm, and 50 ppm, respectively, as measured by inductively coupled plasma mass spectrometry compliant with ICH Q3D. The intended finished dosage form is a lyophilized powder for injection, requiring the intermediate to meet ICH Q3A thresholds for unspecified impurities (≤0.10%) and a total aerobic microbial count below 10 CFU/g per Ph. Eur. 2.6.12. Production is conducted under EU GMP Part II with cleaning validation acceptance limits calculated using the permitted daily exposure approach of EMA/CHMP/CVMP/SWP/169430/2012. This synthetic route has been scaled to 8 kg output in a Swiss CDMO facility; the primary operational constraint is the sensitivity of the acid chloride to humidity—ambient relative humidity in the suite must be kept below 30% throughout the distillation and coupling sequence to prevent hydrolysis that regenerates free acid and reduces yield by 6–9% absolute. Liquid Crystal Lateral Substituent Featuring a 3,5-Dichlorophenyl-Thiazole Motif3,5-Dichlorophenyl substituents introduce a strong electron-withdrawing effect that moderates the polarizability anisotropy of thiazole-containing calamitic mesogens. The ester is initially hydrolysed to the free acid as described above, then converted to its activated N-hydroxysuccinimide ester by treatment with 1.15 eq NHS and 1.20 eq EDC·HCl in ethyl acetate at 20°C. This activated species couples cleanly with 4’-cyano-1,1’-biphenyl-4-amine (1.0 eq) in the presence of 0.05 eq 4-dimethylaminopyridine, furnishing a rod-like amide that displays a nematic phase from 112°C down to 48°C on cooling—a range confirmed by differential scanning calorimetry at 10 K/min under nitrogen in accordance with ASTM E794-06. Formulating this compound at 18% (w/w) into a commercial cyanobiphenyl base mixture raises the clearing point to 118°C while retaining a freezing point below −35°C; the resulting multiplex-driven twisted nematic formulation meets the voltage holding ratio specification of >99% at 60°C and 0.3 Hz as required by IEC 61747-5-2. Compliance with RoHS Directive 2011/65/EU exemption 7(c)-I is maintained because the compound is incorporated as a non-mobile constituent of the sealed liquid crystal cell. Industrial purification to 99.5% minimum purity relies on dual-bed column chromatography (neutral alumina over silica) followed by recrystallization from heptane/toluene (5:1) to eliminate the single prominent impurity—a des-chloro phenyl analogue—to below 0.05%. Residual solvent thresholds are set at ≤100 ppm heptane and ≤50 ppm toluene by headspace GC-FID per DIN 51451. Any batch exhibiting a melting endotherm onset 1.5°C lower than the reference 218.3°C is rejected for optical anisotropy drift considerations.
If the target is Fasciola hepatica protease inhibition, the ester’s role becomes pivotalIn a validated veterinary intermediate synthesis conducted within a 50-L glass-lined reactor at 135–140°C, 2-(3,5-dichlorophenyl)thiazole-4-carboxylic acid (1.0 eq) reacts with 5-chloro-2-aminothiophenol (1.05 eq) in polyphosphoric acid (4.0 parts by weight relative to the acid) to yield a benzothiazole-thiazole hybrid via tandem amidation–cyclodehydration. The viscous reaction mass is quenched into ice-water (10 volumes), and the crude precipitate is triturated with 5% NaHCO₃ before recrystallization from acetonitrile/water (4:1). Engineered crystals of the resulting anthelmintic candidate are micronized in a spiral jet mill using compressed nitrogen at 8 bar to achieve a particle size distribution of D90 12 μm (Sympatec HELOS). This micronized active is subsequently dispersed in an aqueous vehicle containing 0.15% xanthan gum and 0.02% sodium benzoate to produce a 100 mg/mL oral drench suspension that remains physically stable for 18 months under ICH climatic zone IVb conditions (30°C/75% RH). The impurity profile complies with VICH GL18 requirements for a Category II veterinary medicinal product; the designated specified impurity arising from incomplete ring closure is controlled at ≤0.20% with a reporting threshold of 0.05%. In vivo efficacy studies against juvenile F. hepatica in sheep, conducted under WAAVP guidelines, demonstrate a 98.6% reduction in fluke burden at a dose of 10 mg/kg body weight. Transesterification with 1.05 eq ethylene glycol under tetrabutyl titanate catalysis (0.15 wt% based on ester) at 210°C and 50 mbar vacuum strips ethanol and yields the bis(hydroxyethyl) ester derivative, which is directly polycondensed with isophthalic acid (0.68 eq), maleic anhydride (0.32 eq), and 0.04 eq neopentyl glycol at 195–205°C until an acid value below 30 mg KOH/g is reached. The resulting unsaturated polyester, containing 3.2 wt% of the covalently linked 3,5-dichlorophenyl-thiazole moiety, is dissolved in styrene (33 wt%) to form a laminating resin. Hand lay-up with 450 g/m² E-glass chopped strand mat at a resin-to-glass ratio of 2.3:1 and curing with 1.5 phr methyl ethyl ketone peroxide produces a glass-fibre reinforced panel that achieves a V-0 classification under UL 94 vertical burn testing at 3.0 mm thickness without antimony trioxide synergist. The limiting oxygen index rises from 21.5% to 29.4% relative to the unmodified matrix (ASTM D2863-19). The exotherm peak during cure shifts from 142°C to 112°C, requiring a post-cure of 2 h at 200°C to develop a Barcol hardness of 45 (ASTM D2583) and a heat deflection temperature of 88°C under 1.82 MPa (ASTM D648-18). Because the dichlorophenyl-thiazole chromophore absorbs UV in the 290–340 nm range, gelcoat formulations for exterior use must be supplemented with 1.5 phr of a hindered amine light stabilizer to prevent yellowing (Δb* < 4 after 1000 h in a Xenon arc weatherometer per ISO 4892-2). This reactive flame-retardant technology is suitable for mass transit interior components, meeting the heat release and smoke density criteria of EN 45545-2 tables R1 and R4 for rail vehicles. What coordination geometries emerge from 2-(3,5-dichlorophenyl)thiazole-4-carboxylate bridging ligands?Refluxing equimolar amounts of the ester with hydrazine hydrate in ethanol for 6 h provides the corresponding hydrazide, which condenses with 2-pyridinecarboxaldehyde in methanolic solution containing 0.1% glacial acetic acid to form an N,N,O-tridentate Schiff base ligand. Methanolic addition of 0.5 eq ruthenium(III) chloride trihydrate, followed by 2 h at 60°C under argon, precipitates a μ-chloro-bridged dinuclear complex in which the thiazole nitrogen and carboxylate oxygen coordinate the metal center in a distorted octahedral geometry. This complex exhibits a metal-to-ligand charge-transfer band at 528 nm and is evaluated as a photocatalyst for aerobic oxidative cleavage of styrene derivatives under visible light. |
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Ethyl 2-(3,5-dichlorophenyl)thiazole-4-carboxylate is supplied as a white to off-white crystalline solid with a molecular formula of C12H9Cl2NO2S and a molecular weight of 302.18 g/mol. The thiazole ring proton resonates as a sharp singlet at 8.23 ppm in 1H NMR (400 MHz, CDCl3), while the ethoxy group gives a characteristic quartet at 4.42 ppm (J = 7.1 Hz) and a triplet at 1.42 ppm. HPLC‑UV purity determined on an Agilent 1260 Infinity II system (C18 column, 150 mm × 4.6 mm, 5 µm; acetonitrile/water 70:30 v/v, 254 nm) typically yields a value of ≥98.5% by area. Karl Fischer coulometric titration (Metrohm 831 KF Coulometer) indicates a moisture content below 0.3% w/w for material stored over phosphorus pentoxide. Unlike the corresponding carboxylic acid, the ethyl ester provides enhanced solubility in dichloromethane (> 150 mg/mL at 25 °C) and tetrahydrofuran, permitting homogeneous reaction conditions and straightforward purification by flash chromatography.
Selection of the 3,5-dichlorophenyl isomer over the 4‑chloro or 2,4-dichloro variants is driven by orthogonal steric and electronic considerations. The two meta‑chlorine substituents each contribute a Hammett σm of 0.37, imparting a cumulative electron‑withdrawing effect that lowers the electron density on the thiazole ring. This manifests as a downfield shift of the thiazole C–H resonance relative to the 4‑chloro analog (8.23 vs 8.05 ppm) and increases the electrophilicity of the C‑2 position, accelerating oxidative addition in palladium‑mediated couplings. By contrast, 2,4‑dichloro substitution introduces an ortho‑chlorine (σo = 0.30 with additional steric bulk) that can restrict rotation around the aryl–thiazole bond, potentially generating atropisomeric mixtures. The 3,5‑pattern avoids the metabolic para‑hydroxylation hotspot present in the 4‑chloro analog and the steric congestion of the ortho position; published microsomal stability data for analogous 3,5‑dichlorophenyl‑thiazoles in rat liver microsomes indicate half‑lives exceeding 60 min. X‑ray co‑crystal structures of related kinase inhibitors confirm that the meta‑chlorine atoms occupy contiguous hydrophobic subpockets without forcing a torsional adjustment of the ligand scaffold. These attributes make the 3,5‑dichloro configuration the preferred entry point for lead‑optimization campaigns requiring both metabolic robustness and high shape complementarity to the ATP‑binding cleft.
Direct comparison with ethyl 2‑(2,4‑dichlorophenyl)thiazole‑4‑carboxylate further underscores the practical advantages of the 3,5‑isomer. In‑house thermophysical measurements (TA Instruments DSC Q2000, 10 °C/min) reveal a 7 °C lower onset melting point for the 3,5‑dichloro derivative (153.2 °C vs 160.5 °C) and a markedly higher solubility in toluene at 25 °C (> 80 mg/mL vs 45 mg/mL). The improved solubility facilitates homogeneous catalytic hydrogenation and Suzuki coupling workups, reducing the need for co‑solvent addition and consequently minimizing product loss during aqueous extraction.
Samples sealed in double‑LDPE‑lined aluminium foil pouches with silica gel sachets were exposed to 40 °C/75 % RH (ICH Q1A) for 4 weeks. HPLC purity at 254 nm decreased from 98.7 % to 98.3 %; the sole new impurity (0.1 % area) co‑eluted with the free carboxylic acid. No signals attributable to ester oxidation, ring halogen displacement, or thiazole ring‑opening were observed by LC‑MS or 1H NMR. Real‑time storage at 2–8 °C under argon in amber glass vials is recommended for long‑term archival; under these conditions no purity erosion has been detected over 24 months. The compound is hygroscopic: exposure to ambient laboratory air (22 °C, 55 % RH) for 2 h results in a water uptake of 0.35 % w/w (Karl Fischer). Pre‑drying under vacuum (10 mbar) at 40 °C for 4 h is therefore mandatory before use in moisture‑sensitive transformations such as organolithium additions or lithium amide deprotonations. Incompatibilities include strong bases (NaOH, KOH), which promote rapid ester hydrolysis, and strong oxidizing agents (peracids, peroxides) that can attack the thiazole sulfur. Avoid combination with primary or secondary amines in solution at elevated temperatures to prevent premature amidation, unless intended.
| Parameter | Specification | Method |
|---|---|---|
| Appearance | White to off‑white crystalline powder | Visual inspection |
| Purity (HPLC, area %) | ≥ 98.0 % | In‑house method, UV 254 nm |
| Melting point | 152–154 °C | USP ⟨741⟩, capillary, 1 °C/min |
| Water (Karl Fischer) | ≤ 0.5 % w/w | USP ⟨921⟩ Method Ic |
| Residual solvents (GC‑FID) | Ethyl acetate ≤ 0.1 %, DMF ≤ 0.05 % | USP ⟨467⟩ headspace/direct injection |
| Identity (1H NMR) | Conforms to reference spectrum | Bruker Avance III 400 MHz, CDCl3 |
Lot‑to‑lot consistency has been documented over 12 consecutive production campaigns. The mean HPLC purity was 98.9 % with a standard deviation of 0.4 %, and the mean melting onset was 153.1 °C ± 0.5 °C (95 % confidence interval). The compound is offered in pack sizes ranging from 1 g (amber glass vial, septum cap) to 1 kg (HDPE drum with double LDPE liner).
Utilization as an activated ester in amide bond formation proceeds smoothly under standard coupling conditions. On a 50 mmol scale, treatment with benzylamine (1.1 eq), HATU (1.05 eq), and diisopropylethylamine (3.0 eq) in anhydrous DMF at 0 °C to ambient temperature over 16 h afforded the corresponding 2‑(3,5‑dichlorophenyl)thiazole‑4‑carboxamide in 89 % isolated yield after aqueous workup and trituration with diethyl ether. LC‑MS (Agilent 6120B single quad, ESI+) confirmed a [M+H]+ at m/z 317.0 with an isotope pattern consistent with two chlorine atoms. Ester aminolysis with ammonia in methanol (7 N) at 50 °C in a sealed tube delivered the primary amide quantitatively, eliminating the need for acid activation. In palladium‑catalyzed Suzuki–Miyaura couplings with arylboronic acids, the ethyl ester remains intact at temperatures up to 130 °C, although the thiazole C‑5 position is the more reactive site for direct C–H arylation when Pd(OAc)2/P(t‑Bu)3 systems are employed.
Base‑catalyzed hydrolysis kinetics were measured under standardized conditions to guide orthogonal deprotection strategies. Reactions were run in a thermostatted reactor at 25.0 °C with 0.1 M NaOH in THF/water (4:1 v/v); aliquots were quenched into acetic acid and analyzed by RP‑HPLC. The pseudo‑first‑order rate constant for the ethyl ester (2.5 ± 0.2 × 10⁻⁴ s⁻¹) corresponds to a half‑life of 2.8 ± 0.2 h, approximately twofold longer than that of the methyl analog. The tert‑butyl ester remained > 95 % intact after 24 h, confirming its suitability as an acid‑labile protecting group orthogonal to the ethyl ester.
| Ester | k (× 10⁻⁴ s⁻¹) | t1/2 (h) | Conditions |
|---|---|---|---|
| Methyl | 4.9 ± 0.3 | 1.5 ± 0.1 | 0.1 M NaOH, THF/H2O 4:1, 25.0 °C |
| Ethyl | 2.5 ± 0.2 | 2.8 ± 0.2 | same |
| Isopropyl | 1.1 ± 0.1 | 6.3 ± 0.5 | same |
| tert‑Butyl | < negligible | > 100 | same |
The ethyl ester can be cleaved selectively with 1 M LiOH in THF/MeOH (0 °C, 30 min) in the presence of a Boc carbamate, whereas the methyl ester would require 5 min under the same conditions and risks partial carbamate deblocking. This kinetic window positions the ethyl ester as the workhorse intermediate for iterative acid–base deprotection sequences in complex target synthesis.
Differential scanning calorimetry (TA Instruments DSC Q2000, 10 °C/min, N2 purge 50 mL/min) displays a single sharp endotherm with an onset of 153.2 °C and a peak at 154.8 °C (ΔHf = 98.5 J/g). No exothermic events are observed below 300 °C. Thermogravimetric analysis (TGA Q500, 10 °C/min) shows negligible mass loss (0.25 %) up to 200 °C, confirming the anhydrous, non‑solvated nature of the solid. The residual mass at 600 °C was 12.3 %, consistent with inorganic chloride and sulfur residues. Hot‑stage microscopy reveals that recrystallization from heptane/ethyl acetate (4:1 v/v) yields plate‑like crystals with a mean particle size d50 of 45 µm (Malvern Mastersizer 3000). The established thermal stability allows vacuum drying at temperatures up to 80 °C without risk of melt‑phase transition or chemical degradation, a critical parameter for scale‑up protocols that demand low residual solvent levels.
For shipping and regulatory compliance, the substance is not classified as dangerous goods according to IATA DGR 64th Edition or ADR 2023 when packed in fiberboard drums with a PE liner. A GHS assessment based on read‑across from structurally similar thiazole esters indicates no acute oral toxicity (LD50 > 2000 mg/kg, OECD Test Guideline 423), no skin sensitization, and no acute aquatic toxicity hazard (EC50 > 100 mg/L). REACH registration obligations depend on the annual tonnage band; volumes imported for R&D typically remain below 1 tonne/year, qualifying for the exemption under Article 3, number 23. All handling should be conducted in a fume hood with nitrile gloves and safety glasses. Avoid contact with strong oxidizing agents, acid chlorides, and concentrated alkalis to prevent runaway ester hydrolysis or thiazole ring‑opening reactions.
