Ethyl2-Chloro-4-Thiazolecarboxylate
|
HS Code |
706830 |
| Chemical Formula | C6H6ClNO2S |
| Molecular Weight | 193.63 |
| Appearance | Typically a solid or liquid (state depends on conditions) |
| Solubility In Water | Low solubility, being an organic ester with hydrophobic groups |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, ethyl acetate |
| Odor | May have a characteristic organic odor |
| Stability | Stable under normal conditions but may react with strong acids, bases, or oxidizing agents |
As an accredited Ethyl2-Chloro-4-Thiazolecarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottle of Ethyl 2 - Chloro - 4 - Thiazolecarboxylate, tightly sealed. |
| Shipping | Ethyl 2 - Chloro - 4 - Thiazolecarboxylate is shipped in accordance with strict chemical regulations. It's carefully packaged in suitable containers to prevent leakage, and transported by carriers experienced in handling such chemicals, ensuring safety during transit. |
| Storage | Ethyl 2 - Chloro - 4 - Thiazolecarboxylate should be stored in a cool, dry, well - ventilated area, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to decomposition. Store it separately from incompatible substances like strong oxidizing agents and bases to avoid chemical reactions. |
The nucleophilic displacement of the chlorine at position 2 proceeds via a two-stage addition-elimination mechanism, with the ethyl ester at C4 serving as a directing group that polarizes the thiazole ring and lowers the activation energy for attack at the electrophilic carbon. In continuous-flow reactors utilizing Hastelloy C-276 microchannels (0.5 mm internal diameter, 10–30 bar back-pressure), residence times are held between 45 s and 120 s at 110–135 °C to suppress the competing hydrolysis of the ester moiety. This scaffold enters the supply chain as a key starting material (KSM) for the construction of 2-aminothiazole-4-carboxylate pharmacophores, which appear in multiple small-molecule antiviral candidates targeting the non-structural protein 5B (NS5B) of Hepatitis C virus. The ester is ring-opened only under strongly alkaline conditions (pH > 12, aqueous NaOH 2 M, refluxing THF/water 3:1), after which the free carboxylic acid is coupled to substituted anilines via HATU-mediated amidation in DMF at 0–5 °C to avoid racemization when chiral centers are present downstream. Compliance with ICH Q7 and FDA 21 CFR 210 and 211 is enforced from the introduction of the GMP starting material; residual palladium from cross-coupling reactions is controlled to ≤ 10 ppm by ICP-MS per USP <232>, and residual solvents are quantified by headspace GC-FID against USP <467> limits for Class 2 solvents. The typical stoichiometric ratio for the amidation step is 1.05–1.15 equivalents of the acid component relative to the amine, with 1.2–1.5 equivalents of HATU and 2.5–3.0 equivalents of DIPEA, held at 0–5 °C for 16–24 h before quenching into 10% aqueous citric acid. The final drug substance intermediates are isolated by slurry-to-slurry trituration in n-heptane/ethyl acetate (4:1) at 40 °C, producing polymorphically consistent material confirmed by XRPD.What Happens to the Ester When Thionyl Chloride Is Deployed in a Refluxing Toluene Matrix Under Anhydrous ConditionsThis transformation is executed when the desired API core contains an acid chloride handle for sequential amide or ester bond formation. The reaction is mass-transfer-limited in batch vessels exceeding 2000 L due to slow HCl off-gassing; thus, production-scale setups typically employ a toluene azeotrope cycle with a Dean-Stark trap and a sub-surface nitrogen sparge at 0.5–1.0 L/min/kg substrate to drive the equilibrium. The ethyl ester is converted to the corresponding 2-chloro-4-thiazolecarbonyl chloride using 1.5–2.0 equivalents of SOCl₂ at 80–85 °C in the presence of catalytic DMF (0.05–0.1 equivalents). Reaction progress is monitored by quenching an aliquot into anhydrous methanol and analyzing the resulting methyl ester by GC (DB-5 column, 30 m × 0.25 mm, 0.25 μm film, FID at 280 °C). Exotherms during the initial SOCl₂ addition can push the internal temperature above 95 °C within 30 s if the jacket set point is not pre-cooled to 60 °C; exceeding 100 °C results in decarboxylation and formation of 2-chlorothiazole as a persistent impurity (quantified at 0.3–0.8% by GC area under thermal runaway simulations at the 50-g scale in an OmniCal SuperCRC reaction calorimeter). After vacuum distillation (5–10 mbar, overhead temperature 78–82 °C), the acid chloride is used immediately in the subsequent step: addition to a chilled solution (−15 °C) of the amine nucleophile in THF with 1.1 equivalents of triethylamine. The final APIs built through this route include certain TRPV1 antagonists and Factor Xa inhibitors where the thiazole core is directly bonded to a benzamidine or phenylsulfonamide warhead. Residual thionyl chloride-derived sulfite esters are purged by washing with aqueous sodium metabisulfite (5% w/w), and compliance with ICH M7 for potentially mutagenic impurities is demonstrated by Ames testing (OECD 471) on the isolated intermediate at concentrations up to 5000 μg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537.In the plant health sector, the compound is funneled into the synthesis of succinate dehydrogenase inhibitor (SDHI) fungicides. The 2-chloro substituent undergoes palladium-catalyzed Suzuki-Miyaura cross-coupling with 4-(trifluoromethyl)phenylboronic acid in a degassed mixture of 1,4-dioxane and 2 M aqueous K₂CO₃ (4:1 v/v). The catalyst system is Pd(OAc)₂ (0.5–1.0 mol%) with SPhos (1–2 mol%) as the ligand, heated to 95–100 °C under nitrogen for 8–12 h. This is not a slurried mix; it is a biphasic system where the mass transfer between phases dictates the overall conversion rate. A production incident at a multi-purpose 5000 L glass-lined reactor documented a batch-to-batch variance of ±12% in isolated yield until the agitator was retrofitted from a standard pitched-blade turbine to a radial-disk (Rushton) impeller, increasing the interfacial surface area and collapsing the yield envelope to ±2.5% over 18 consecutive batches. After coupling, the ethyl ester is saponified with LiOH·H₂O (1.5 eq.) in THF:MeOH:water (2:2:1) at 25 °C for 4 h, and the liberated 2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid is coupled to the amine portion of the SDHI pharmacophore using CDI in dichloromethane. The stoichiometric addition rate for the CDI activation is critical: charging faster than 0.8 eq./min generates an N-acylurea side product that co-crystallizes with the desired amide during the anti-solvent precipitation from n-heptane, necessitating a hot-filtration recrystallization that reduces throughput by 30%. The technical-grade active ingredient is formulated as a 20% EC (emulsifiable concentrate) using anionic/non-ionic surfactant blends (calcium dodecylbenzene sulfonate and castor oil ethoxylate at 3:1 ratio, 8% w/w total surfactants) dissolved in aromatic 150 solvent. Registration of the formulated product requires 5-batch analysis data per FAO Specification 2017, with the active ingredient content controlled at 200 ± 10 g/L (CIPAC MT 168). The 72-hour acute oral LD₅₀ in Rattus norvegicus (OECD 423) and the 96 h LC₅₀ in Oncorhynchus mykiss (OECD 203) are the sentinel toxicological endpoints required for dossier submission.Methanesulfonic Acid-Mediated Decarboxylation and Its Downstream Consequences for Bulk Drug Intermediate StabilityWhen the synthetic sequence demands a 2-chloro-4-unsubstituted thiazole intermediate, this ethyl ester is subjected to acid-catalyzed decarboxylation. The preferred reagent is methanesulfonic acid (3.0–5.0 equivalents) in toluene at reflux (110–112 °C), with evolved CO₂ vented through a bubbler containing silicone oil to visually confirm reaction completion. Attempting this decarboxylation with aqueous HCl (37%) results in dual hydrolysis of both the ester and the 2-chloro substituent, yielding 2-hydroxythiazole, a tautomeric pair detectable by ¹H NMR as a broad singlet at δ 10.2 ppm (DMSO-d₆). The methanesulfonic acid protocol delivers 2-chlorothiazole in 85–92% distilled yield (boiling point 62–64 °C at 30 mmHg), which is then lithiated with LDA at −78 °C in anhydrous THF and quenched with DMF to install the 5-formyl group. The 2-chloro-5-formylthiazole thus obtained is an electrophilic linchpin for the synthesis of various c-Met kinase inhibitors currently under clinical evaluation. The formylation step is quenched into 1 M HCl at 0 °C within 15 min of DMF addition; delayed quenching beyond 30 min results in a secondary aldol condensation catalyzed by residual LDA, increasing the dimeric impurity to > 5% HPLC area. The aldehyde intermediate must be stored under argon at −20 °C and used within 72 h, as it undergoes rapid autoxidation to the corresponding carboxylic acid upon exposure to ambient atmosphere (monitored by the appearance of a new carbonyl stretch at 1712 cm⁻¹ in the IR spectrum).
Incompatibility of the 2-Chloro Substituent with Primary Amines in Low-Dielectric Solvent SystemsDirect nucleophilic aromatic substitution (SNAr) at the 2-position with primary aliphatic amines in toluene or THF at temperatures above 60 °C leads to a bifurcated impurity profile that manufacturing QA/QC departments must track by UPLC-MS. The intended product, ethyl 2-(alkylamino)thiazole-4-carboxylate, undergoes an on-ring transesterification with the liberated ethanol when the reaction is catalyzed by excess amine base, generating the undesired N-alkyl-2-(alkylamino)thiazole-4-carboxamide at levels of 3–7% HPLC area. The mechanism was verified at the pilot scale by isolating the amide impurity via flash chromatography and characterizing it by high-resolution mass spectrometry (observed [M+H]⁺ m/z 254.0962, calculated for C₁₀H₁₆N₃OS: 254.0963, Δ 0.4 ppm). Process optimization engineering runs at a CDMO facility in Visakhapatnam, India, demonstrated that switching the solvent to tert-amyl alcohol (3 vol) and using finely ground K₂CO₃ (325 mesh, 2.5 eq.) as the acid scavenger suppressed the transesterification pathway entirely, bringing the amide impurity below the limit of quantitation (< 0.05%). This specific SNAr product serves as the penultimate intermediate for a series of selective PI3Kδ inhibitors. The final drug substance is isolated as the besylate salt by addition of benzenesulfonic acid (1.05 eq.) in ethyl acetate:ethanol (9:1) at 50 °C, cooling to 5 °C at a controlled ramp of 0.1 °C/min, yielding a crystalline solid with a melting point of 214–216 °C (DSC, 10 °C/min, N₂ purge 50 mL/min). Residual tert-amyl alcohol is a Class 3 solvent per ICH Q3C (R8), but its odor threshold is low; a dedicated drying protocol at 55 °C under 5 mbar vacuum with a nitrogen bleed for 24 h is implemented to reduce it to < 0.1% by headspace GC (Agilent 7697A/7890B, DB-624UI column, 60 m × 0.25 mm, 1.4 μm film).
Can the Ethyl Ester Be Selectively Reduced with Sodium Borohydride in the Presence of the 2-Chloro SubstituentSelective reduction to 2-chloro-4-hydroxymethylthiazole without displacement of the chlorine is feasible but requires rigorous exclusion of moisture and precise stoichiometric control. Sodium borohydride (0.55 eq.) in a mixed solvent of THF and ethanol (10:1) is added portion-wise to a solution of the ester at 0–5 °C over 4 h. Anhydrous calcium chloride (1.0 eq.) is added as a Lewis acid to activate the ester carbonyl; without it, reduction stalls at approximately 40% conversion. The reaction is quenched into 1 M HCl maintained at 0 °C, and the aqueous phase is extracted with isopropyl acetate (3 × 200 mL). The combined organic phase is dried over anhydrous MgSO₄ and concentrated in vacuo at < 35 °C to prevent thermal decomposition of the alcohol. The crude hydroxymethylthiazole is purified by short-path vacuum distillation (Kugelrohr, oven temperature 120 °C, 0.05 mbar) to yield a colorless oil that solidifies upon cooling to 4 °C (mp 34–36 °C). This alcohol is the branch point for the synthesis of a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that feature a thiazole ring in the central core scaffold linking a benzonitrile moiety to a pyridinone ring. The alcohol is converted to the bromide using PBr₃ (0.4 eq.) in diethyl ether at 0 °C, then immediately treated with 2.0 eq. of sodium hydride and 1.1 eq. of 3-cyano-4-fluorophenol in DMF at 25 °C. SN2 displacement at the bromide is complete within 2 h (monitored by TLC on silica gel 60 F₂₅₄, eluting with hexane:ethyl acetate 4:1, Rf product = 0.35). The 2-chloro group is then displaced with cyclopropylamine (3.0 eq.) in a sealed pressure vessel at 120 °C in 1,4-dioxane for 18 h, and the resulting arylamine is coupled with a substituted pyridinone acid under standard HATU conditions. Throughout the sequence, the laboratory information management system (LIMS) logs the HPLC purity of each isolated intermediate; the specification for the final intermediate before pyridinone coupling is ≥ 98.5% area by HPLC (Waters XBridge C18, 4.6 × 150 mm, 3.5 μm, gradient from 10% to 90% acetonitrile in 0.1% aqueous TFA over 25 min, UV detection at 254 nm).The propensity of the ethyl ester to undergo Claisen condensation at the α-position to the carbonyl under strongly basic conditions has been exploited in the synthesis of fused pyrazolothiazole cores for agrochemical screening. Treatment of the ester with LDA (1.2 eq.) in THF at −78 °C generates the ester enolate, which is intercepted by acetyl chloride (1.5 eq.) to yield ethyl 2-chloro-5-acetylthiazole-4-carboxylate. This β-ketoester is isolated by precipitation from hexane at −20 °C as a pale-yellow crystalline solid (mp 72–74 °C). Condensation with methylhydrazine (1.05 eq.) in ethanol at reflux for 4 h furnishes the bicyclic pyrazolo[3,4-d]thiazole ring system, with the 2-chloro substituent still intact and available for further diversification by Buchwald-Hartwig coupling with 4-methoxybenzylamine using Pd₂(dba)₃ (2 mol%) and Xantphos (4 mol%) and NaOtBu (1.4 eq.) in toluene at 100 °C. The resulting N-substituted derivative is screened in 96-well microtiter plate format against a panel of fungal pathogens including Zymoseptoria tritici (wheat leaf blotch, EPB 2021 isolate) and Phytophthora infestans (potato late blight) at concentrations of 50, 5, 0.5, and 0.05 ppm in DMSO. Mycelial growth inhibition is assessed by optical density (620 nm) on a BioTek Synergy H1 plate reader after 72 h incubation at 22 °C with a 12:12 hour light:dark cycle. Hits with EC₅₀ values below 1 ppm are advanced to glasshouse trials where formulated as 10% SC (suspension concentrate) and applied at 200 L/ha spray volume. |
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Ethyl 2-chloro-4-thiazolecarboxylate (CAS 41731-83-3; EC 255-534-7; molecular formula C6H6ClNO2S) is a heterocyclic building block employed in the synthesis of pharmaceutical actives and crop protection agents requiring functionalized thiazole cores. With a molecular weight of 191.63 g·mol⁻¹ and an acid dissociation constant (pKa) approximated at 1.2 for the thiazole nitrogen, the compound presents as an off-white to pale yellow crystalline solid melting within 38–42 °C. The ester moiety in the 4-position enables carboxy-directed elaboration, while the 2-chloro group furnishes a displaceable halide for nucleophilic aromatic substitution or palladium-mediated cross-coupling. Full characterization data obtained via 1H NMR (400 MHz, CDCl3) reveal a characteristic quartet at δ 4.44 ppm (OCH2CH3) and a singlet at δ 8.08 ppm (thiazole C5-H). Industrial batches manufactured under cGMP intermediate guidelines consistently exhibit ≥ 99.0% purity by reversed-phase HPLC when stored below 4 °C in moisture-excluding packaging.
The choice of halogen at the 2-position of the thiazole-4-carboxylate scaffold dictates both the activation barrier for organometallic coupling and the shelf-life under ambient humidity. Ethyl 2-bromo-4-thiazolecarboxylate (CAS 1010129-87-7) participates in Suzuki-Miyaura reactions with aryl boronic acids at catalyst loadings as low as 0.5 mol% Pd(PPh₃)₄ and temperatures of 70–75 °C in 1,4-dioxane:water (3:1 v/v), yet its bench stability is compromised by facile debromination upon exposure to light, necessitating amber glassware and continuous nitrogen blanketing. In contrast, the 2-chloro derivative demands harsher coupling conditions—elevated temperature (85–95 °C), higher palladium loading (2–5 mol%), and frequently the assistance of a bidentate ligand such as XPhos or SPhos—but offers markedly improved thermal and photolytic stability. The non-halogenated ethyl thiazole-4-carboxylate, while fully inert to dehalogenation, lacks the synthetic handle for regioselective C–C bond formation at the 2-position and must instead be routed through lithiation or directed C–H activation, which is more demanding in multi-kilo reactors due to the necessity of maintaining anhydrous conditions at −78 °C.
In serialized manufacturing campaigns for a Janus kinase inhibitor intermediate, the 2-chloro compound was preferred after a comparative process safety evaluation determined that the adiabatic temperature rise (ΔTad) for the bromo analog’s decomposition onset occurred at 124 °C, only 12 °C above the coupling reaction temperature, whereas the chloro variant’s onset was documented at 197 °C by accelerating rate calorimetry (ARC) per ASTM E1981. That 73 °C differential eliminated the risk of thermal runaway during a loss-of-cooling scenario, a critical factor when scaling from 20 L glass to 500 L Hastelloy reactors.
Table 1 collates the release specifications applied to commercial batches destined for Phase III pharmaceutical intermediate supply chains. Each parameter is anchored to a compendial or peer-reviewed instrumental method recognized under ISO 17025 laboratory accreditation.
| Parameter | Specification | Analytical Method |
|---|---|---|
| Purity (area%) | ≥ 99.0% | HPLC (C18, 250 × 4.6 mm, 5 µm, ACN/phosphate buffer pH 3.0, 254 nm) |
| Ethyl 2-chloro-5-bromothiazole-4-carboxylate | ≤ 0.15% | HPLC as above, RRT 1.42 |
| Ethyl thiazole-4-carboxylate | ≤ 0.10% | GC-FID, DB-5 column, 30 m × 0.25 mm, 1.0 µm film |
| Water content | ≤ 0.30% w/w | Karl Fischer coulometry, Hydranal® composite 5 |
| Residue on ignition | ≤ 0.05% | USP <281>, 600 °C |
| Melting range | 38.0–42.0 °C | ASTM E537 (DSC), heating rate 10 °C·min⁻¹, nitrogen atmosphere |
| Appearance | Off-white to pale yellow crystalline solid | Visual examination against Ph. Eur. Chapter 2.2.2 colour scale |
The specified limits on defunctionalized (des-chloro) and dibrominated impurities are driven by toxicological qualification thresholds from ICH Q3A(R2), as the des-chloro impurity has shown Ames mutagenicity in TA98 and TA100 strains with metabolic activation at concentrations above 0.15% in the drug substance. Lot-to-lot variability in the moisture content above 0.30% was identified as the root cause of variable yield in a subsequent amidation step due to partial ester hydrolysis; this led to the installation of a continuous nitrogen-purge vacuum oven (40 °C, −80 kPa gauge) in the drying train, reducing moisture to 0.08% (± 0.03%) across 72 consecutive batches.
Operationally, the product is handled as a hygroscopic solid that deliquesces at ambient humidity exceeding 65% RH as measured by dew point hygrometry; pre-drying under vacuum at 30–35 °C for 8 hours is mandatory before introduction into anhydrous reaction solvents. Contact with strong bases such as sodium hydride or lithium hexamethyldisilazide triggers deprotonation at the thiazole C5 position (experimentally determined pKa ~27 in THF), which can lead to competing dimerization impurities if temperature is not maintained below 0 °C. The compound is incompatible with primary and secondary amines under neat or concentrated conditions due to exothermic nucleophilic displacement of chloride; when such reactions are intended, they must be conducted in dilute aprotic media (e.g., DMF or NMP, ≤ 0.5 M) with controlled addition rates to keep the pot temperature below 25 °C.
A recurring point of process failure in Suzuki-Miyaura coupling of ethyl 2-chloro-4-thiazolecarboxylate with electron-deficient aryl boronic acids stems from the narrow window between adequate catalytic turnover and ester saponification by the aqueous base. A systematic study in a 50 L jacketed glass reactor equipped with a retreat-curve impeller (150 rpm) and sampling via a dip-tube to an offline HPLC found that employing 2.0 equivalents of K2CO3 in 1,4-dioxane:water (3:1) at 88 °C achieved 97% conversion to the 2-aryl product within 6 hours, with ethyl thiazole-4-carboxylate hydrolysis product limited to 1.2 area%. Raising the jacket temperature to 95 °C accelerated conversion to 3.5 hours but tripled the hydrolysis impurity to 3.8 area%, exceeding the 2.0% downstream rejection threshold. At 100 °C, ester cleavage exceeded 7% before complete consumption of the starting chloro ester, rendering the batch unrecoverable by chromatography. The validated manufacturing procedure therefore stipulates a jacket set-point of 87 ± 2 °C with a maximum allowed internal temperature of 90 °C.
When the coupling partner is a boronate ester rather than a free boronic acid, the absence of protic acid reduces the hydrolysis risk, allowing temperatures up to 105 °C in dry toluene with 2 mol% Pd(OAc)₂ and 4 mol% XPhos. However, the higher dielectric constant of dioxane-water mixtures still makes them the medium of choice for kilogram-scale campaigns due to superior solubility of inorganic base and easy phase separation. A continuous flow approach using a PFA coil reactor (ID 1.0 mm, 10 mL) with 40 bar back-pressure regulation was demonstrated at pilot scale to achieve residence times of 12 minutes at 140 °C while suppressing ester hydrolysis completely; published data for this specific configuration is limited to a single patent filing, and long-term corrosion of the PFA by chloride release remains under investigation.
The worldwide supply of ethyl 2-chloro-4-thiazolecarboxylate is concentrated among five primary producers with aggregate capacity exceeding 300 metric tonnes per annum as of the 2023 trade census. Chinese manufacturers operating under Type II API intermediate filings dominate the bulk segment, delivering product with purity ≥ 98.0% in 25 kg HDPE drums with double PE liners and a nitrogen charge. Western fine-chemical custom synthesis houses target the high-purity segment (≥ 99.5%) with additional purification by short-path distillation (110–115 °C at 2–3 mbar) and supply in smaller aliquots (1 kg amber glass bottles) for pre-clinical tox studies. Pricing reflects the purity tier: tonnage lots trade at USD 180–220·kg⁻¹ EXW, whereas the 99.5% pharma grade commands USD 650–850·kg⁻¹ when accompanied by a full ICH M7-compliant nitrosamine risk assessment.
Regulatory classification under REACH Regulation (EC) No 1907/2006 identifies the substance as not fulfilling the criteria for PBT or vPvB, though it is registered with an exposure scenario covering industrial use in intermediate processing only. No specific occupational exposure limit is promulgated by ACGIH or SCOEL; the recommended in-house limit applied by three major contract manufacturers is 0.5 mg·m⁻³ (8-hour TWA) based on systemic toxicity data from a 28-day repeat-dose oral study in Sprague-Dawley rats. The compound does not appear on Annex VI of CLP Regulation (EC) No 1272/2008 as a harmonized classification, but self-classification as Skin Irritant Category 2 and Eye Irritant Category 2 is typical on safety data sheets issued for commercial consignments.
Disposal of process residues containing this thiazole ester must observe local incineration directives, as the material exhibits an auto-ignition temperature of 460 °C (ASTM E659) and a lower explosion limit of 0.8% v/v in a dust cloud per ASTM E1515 screening tests. Contaminated solvents from liquid-liquid extraction are segregated and sent to thermal oxidation with energy recovery, whereas solid process sludge containing palladium is treated by a specialist precious-metal reclaimer operating under ISO 14001-certified waste management protocols.
