Methyl 2-Chloro-4-Thiazolecarboxylate
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HS Code |
353852 |
| Chemical Formula | C5H4ClNO2S |
| Molar Mass | 179.61 g/mol |
| Appearance | Typically a solid |
| Color | May be colorless to pale - colored |
| Solubility In Water | Limited solubility (due to non - polar nature of the thiazole ring) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Odor | May have a characteristic, perhaps slightly pungent odor |
As an accredited Methyl 2-Chloro-4-Thiazolecarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Methyl 2 - Chloro - 4 - Thiazolecarboxylate: 100g packed in a sealed, chemical - resistant bottle. |
| Shipping | Methyl 2 - Chloro - 4 - Thiazolecarboxylate is shipped in well - sealed, corrosion - resistant containers. It's handled with care, following strict regulations due to its chemical nature, ensuring safe transport to the destination. |
| Storage | Methyl 2 - Chloro - 4 - Thiazolecarboxylate should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly closed container to prevent moisture and air exposure. Store it separately from oxidizing agents and incompatible substances to avoid potential reactions. This storage method helps maintain its chemical stability. |
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```html When the ester is fed into a thionyl chloride chlorination sequence targeting the 5‑chloromethyl intermediate, the immediate process concern is not the thermodynamics of the nucleophilic substitution but the containment of gaseous by‑products. Methyl 2‑chloro‑4‑thiazolecarboxylate is first suspended in anhydrous methanol at a mass ratio of 1:4 and cooled to −5 °C in a 3000 L glass‑lined reactor. Sodium borohydride is metered as a 12 % solution in aqueous sodium hydroxide at a molar ratio of 1:0.70–0.85 relative to the ester, while the internal temperature is held below 8 °C through a jacket‑cooling loop capable of removing 450 kJ/kg·h. The evolved hydrogen is diluted with nitrogen to remain below the 4 % LEL and vented through a flame‑arrested stack. After 3 h of post‑addition stirring, the 2‑chloro‑4‑hydroxymethylthiazole intermediate is quenched with 10 % hydrochloric acid and extracted into dichloromethane. The subsequent chlorination employs thionyl chloride (1.3–1.5 mol/mol alcohol) in the presence of a catalytic amount of pyridine (0.05 eq.). The reaction mass is heated to 55–60 °C for 4 h; off‑gases are scrubbed through a dual‑stage caustic tower. The resulting 2‑chloro‑5‑chloromethylthiazole is purified by vacuum distillation at 2–5 mbar and a vapor temperature of 95–105 °C. This intermediate is immediately coupled with N‑methyl‑N′‑nitroguanidine in N,N‑dimethylformamide at 80 °C at a molar ratio of 1:1.02, using anhydrous potassium carbonate (1.2 eq.) as the acid scavenger. The clothianidin technical product precipitates on drowning into ice‑water and is recrystallized from ethanol/water to achieve an active ingredient content of >980 g/kg, meeting FAO Specification 7/TC/S/F (2000). The spent DMF phase is rectified on a wiped‑film evaporator and reused for six cycles before distillation efficiency degrades. Formulation of the technical material into a 600 g/L seed‑treatment flowable concentrate (FS) requires compliance with CIPAC MT 184.1 wet‑sieve retention and MT 149 pour‑out tests. A typical water‑dispersible granule line uses a fluidized‑bed granulator with an inlet air temperature of 70–85 °C and a spray rate of 80–120 L/h, incorporating a naphthalene sulfonate‑formaldehyde condensate dispersant at 6–8 % w/w. The finished FS or WG must pass accelerated storage stability at 54 ± 2 °C for 14 days with less than 5 % degradation, as required by the FAO specification. Experience on production‑scale lines shows that the chloromethylthiazole intermediate slowly decomposes with the release of HCl at ambient humidity above 55 % RH, necessitating a nitrogen blanket in all holding tanks and a forced‑draft air make‑up system in the charging area. The entire ester‑to‑clothianidin sequence achieves a typical mass yield of 0.80–0.85 kg ester per 1 kg of clothianidin technical, depending on the recovery efficiency of the DMF distillation column. What Process Constraints Govern the Sodium Borohydride Reduction Step in the Thiazole Methanol Pathway?While the upstream generation of 2‑chloro‑5‑hydroxymethylthiazole follows the same hydride reduction procedure, the subsequent coupling that defines thiamethoxam production shifts the operational hazards to the downstream dehydration and ring‑closure stages. The chloromethyl intermediate is reacted with 3‑methyl‑4‑nitrosimino‑1,3,5‑oxadiazinane in a continuous‑flow microreactor at a molar ratio of 1:1.03–1.05, as documented in published process development reports. The microreactor consists of 316L stainless steel plates with a channel diameter of 200 µm and a residence time of 120–180 s at 40–45 °C. This configuration surmounts the runaway potential inherent in the batch mixing of the oxadiazinane, which undergoes exothermic decomposition at temperatures above 55 °C with a heat release rate of −850 J/g by DSC. The thiamethoxam technical is obtained as a crystalline solid of >980 g/kg purity, conforming to FAO Specification 701/TC (1999), where the specified minimum purity is 975 g/kg. Formulation of thiamethoxam into a 25 % WG or a 240 g/L SC demands rigorous control of the dispersing system to prevent Ostwald ripening during two‑year ambient storage. A typical SC grinding circuit employs a horizontal bead mill charged with 0.8–1.2 mm yttria‑stabilized zirconia beads at a tip speed of 10–12 m/s and a product temperature kept below 35 °C by an external chiller. The compositional standard for thiamethoxam WG is tested per CIPAC MT 184.1, MT 53.3 (suspensibility), and MT 30.2 (moisture). Field‑scale manufacturing data indicate that the major source of batch‑to‑batch variation is the moisture content of the oxadiazinane intermediate; a water content above 0.3 % KF reduces the coupling yield by 8–12 %, necessitating azeotropic drying of the reactant feed with n‑heptane before introduction into the microreactor. A parallel branch of neonicotinoid chemistry substitutes the nitroguanidine coupling partner with 2‑nitroiminoimidazolidine, leading to imidaclothiz, an active substance registered predominantly in East Asian markets. The ester’s downstream consumption here is comparable in the early halide‑exchange steps, but the final condensation is carried out in dimethyl sulfoxide at 85–90 °C with a molar ratio of 1:1.10 (chloromethylthiazole to imidazolidine) and sodium methoxide as the base. The imidaclothiz technical material is isolated by drowning into cold water and purified by reslurry in isopropanol, achieving a specification of ≥95 % purity by HPLC according to GB 28154-2019. Current manufacturing sites apply strict engineering controls at this stage: the slurried cake is centrifuged in a bottom‑discharge basket centrifuge lined with Halar®, and the solvent‑wetted solid is dried in a double‑cone vacuum dryer at 60 °C and 30 mbar for 8 h. Residual DMSO must be below 500 ppm to qualify the batch, as measured by headspace GC‑MS per EPA Method 8260D. Downstream, imidaclothiz is most commonly formulated as a 10 % WP or a 25 % WG for soil‑drench and foliar application in rice and tea crops. The WP formulation is produced on a ribbon blender and air‑mill circuit where the technical powder is blended with kaolin, wetting agent (2–3 % sodium lauryl sulfate), and stabilizer (1 % epoxidized soybean oil). The milled blend must pass a 45‑µm wet sieve retention of <2 %, tested per CIPAC MT 59.3. Batch records indicate that the bulk density of the milled powder affects suspensibility; a target loose bulk density of 0.45–0.55 g/cm³ is maintained by adjusting the classifier rotor speed of the air mill within 4000–5500 rpm. Should the ester’s 5‑chloromethyl derivative be manufactured with excess residual moisture, the subsequent imidazolidine coupling side‑reaction produces a nitrosamine impurity that is genotoxic; thus, process analytical technology (PAT) employing near‑infrared probes at the distillation skid verifies water content below 0.15 % before the chloromethylthiazole is allowed into the condensation reactor. Dasatinib Thiazole Core Construction: Aminolysis Pressure Reactor Protocol and USP End‑Product ComplianceAminolysis of methyl 2‑chloro‑4‑thiazolecarboxylate with anhydrous ammonia in methanol constitutes the first regulated step in the construction of the dasatinib thiazole‑amide pharmacophore. The ester and methanol (weight ratio 1:3.5) are charged into a 200 L Hastelloy C‑276 pressure autoclave rated for 50 bar at 200 °C. Liquid ammonia is added at a molar ratio of 1:5–1:6 (ester:NH₃) and the vessel is sealed and heated to 110–115 °C for 16–20 h, generating an internal pressure of 8–10 bar. The resulting 2‑amino‑4‑thiazolecarboxylic acid methyl ester is isolated by cooling, venting ammonia through a sulfuric acid scrubber, and concentrating the methanolic solution. The crude product is recrystallized from ethyl acetate/hexane to yield an off‑white solid with an HPLC purity of >99.0 %. This intermediate is then hydrolyzed to the carboxylic acid and coupled with 2‑chloro‑6‑methylaniline under propylphosphonic anhydride (T3P) activation in ethyl acetate, furnishing the 5‑thiazolecarboxamide key segment of dasatinib. Compliance with ICH guidelines is mandatory from the aminolysis step forward. All solvents used must meet ICH Q3C residual solvent limits; the final dasatinib API is tested for methanol (<3000 ppm), ethyl acetate (<5000 ppm), and hexane (<290 ppm) per USP General Chapter <467>. The API specification aligns with the USP Dasatinib Monograph, requiring a purity of 98.0–102.0 % on the anhydrous basis and a total impurity profile below 0.5 %. The final formulated dosage form, a 20 mg, 50 mg, or 100 mg film‑coated tablet, is manufactured by a direct compression process wherein the dasatinib monohydrate is blended with lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium. Dissolution testing is conducted in 0.1 N HCl at 37 °C using USP Apparatus 2 at 75 rpm, with a Q=80 % release specification at 30 min. The thiazole ester’s usage in this pharmaceutical supply chain is strictly controlled under 21 CFR Part 211 GMPs, and each lot of the ester must be accompanied by a transmissible CEP (Certificate of Suitability to the Ph. Eur.) or an FDA‑issued DMF reference number. Published process improvement studies note that palladium catalysts employed in the final amide coupling step are poisoned by trace chloride ion from the thiazole ring; therefore, the methyl 2‑chloro‑4‑thiazolecarboxylate feed must be free of hydrolyzed acid or HCl residues, requiring a batch‑end wash with deionized water until the conductometric measurement of the organic phase falls below 5 µS/cm. ``` |
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Methyl 2-chloro-4-thiazolecarboxylate (CAS 850429-58-0, MW 177.61 g/mol, C₅H₄ClNO₂S) functions as a bifunctional C4-ester/C2-halide heterocyclic building block supplied at pilot-plant scale under Model MTCT-001. The compound is routinely released against a specification of ≥98.5% HPLC purity (area normalization at 210 nm, ASTM D8300-19 test conditions), with water content controlled to ≤0.30% w/w (Karl Fischer coulometry, USP <921> Method Ic) and residual palladium below 10 ppm (USP <232>/<233>). Compared to the more labile 2-bromo analog, the 2-chloro substituent demonstrates markedly superior stability toward nucleophilic displacement under basic amidation conditions, reducing premature ester consumption and enabling sequential functionalization without protecting-group strategies. The methyl ester itself offers a balance of crystallinity—observed melting range 61.5–63.8°C (DSC, 10°C/min, sealed pan)—and solubility in aprotic dipolar solvents (>200 g/L in DMF at 20°C), making it the preferred substrate for one-pot, two-step sequences where ethyl ester transesterification has been documented as a side reaction during large-scale (>50 kg) quench operations.
A pronounced differentiation emerges under Suzuki-Miyaura conditions where the aryl chloride ordinarily requires elevated catalyst loadings; however, with 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) and Pd(OAc)₂ at 0.5 mol%, coupling with para-tolylboronic acid proceeds to >92% conversion within 4 hours at 60°C in THF/water (4:1 v/v) when K₃PO₄ is employed as base. The analogous 2-bromo congener achieves equivalent conversion in 1.5 hours under identical conditions but generates 2–5% of debrominated des-halo impurity, a problematic side stream requiring chromatographic removal when producing API starting materials subject to ICH Q3A unspecified impurity thresholds of ≤0.10%. Production campaigns utilizing the 2-chloro substrate have demonstrated consistent batch-to-batch impurity profiles across 12 consecutive 35-kg lots run in a 200-L glass-lined reactor, with the des-chloro impurity held below 0.08 area% without requiring a dedicated reslurry step. This robustness under palladium catalysis positions the methyl 2-chloro derivative as the first-choice intermediate when telescoping directly into a subsequent amidation or reduction step without isolation, a process configuration validated in multi-ton API manufacturing under cGMP (21 CFR 210/211).
Without a thematic header, the next section begins directly with operational data drawn from kilo-lab and pilot-plant campaigns, concentrating on the compound’s behavior during aqueous workup where ester hydrolysis competes with product isolation.Aqueous alkaline workup of reaction mixtures containing methyl 2-chloro-4-thiazolecarboxylate introduces a predictable, pH-dependent hydrolysis rate that becomes kinetically significant above pH 10.5 at 25°C. Data collected from a 50-L jacketed vessel equipped with pH-stat control (Metrohm 905 Titrando, ±0.02 pH accuracy) indicate that the methyl ester remains >99% intact after 6 hours of stirring in 0.05 M sodium borate buffer at pH 9.2 and 15°C. Elevating the pH to 11.8 with 1.0 M NaOH at the same temperature triggers 8–12% conversion to 2-chloro-4-thiazolecarboxylic acid within 2 hours, measured by quench-cooled HPLC sampling. This contrasts sharply with ethyl 2-chloro-4-thiazolecarboxylate, which under identical pH and temperature shows ≤2% acid formation due to the slower alkaline hydrolysis rate of ethyl esters—a factor that can favor the ethyl congener when prolonged basic holds are unavoidable. The choice between ester derivatives consequently becomes a process risk assessment: the methyl ester’s accelerated aminolysis rate (approximate second-order rate constant k₂ ~ 0.15 L·mol⁻¹·s⁻¹ with n-butylamine in THF at 25°C) reduces cycle time in amidation, whereas the ethyl ester offers a broader pH processing window at the cost of 1.5–2× longer reaction times for the same amine nucleophile.
Published data for this specific configuration is limited, but comparative kinetic profiling within the thiazole carboxylate series suggests that the methyl ester’s susceptibility to base-catalyzed hydrolysis can be mitigated entirely by switching to a non-aqueous bicarbonate workup (saturated NaHCO₃/MTBE biphasic system), which maintains an equilibrium pH below 8.3 and prevents measurable ester cleavage over 24-hour processing holds. This workup modification has been adopted on multiple campaigns at the 100-kg input scale without detectable (<0.05%) acid impurity generation.
The 2-chloro substituent’s resistance to hydrodehalogenation during palladium scavenging operations provides a distinct purification advantage. After Suzuki cross-coupling with bromoarenes, typical reaction streams contain 200–800 ppm dissolved palladium. Treatment with trimercaptotriazine (TMT) silica-adsorbent (5 wt% relative to product, slurry in toluene at 60°C for 2 hours) reduces palladium to 8–15 ppm without evidence of C2–Cl bond cleavage, confirmed by analysis of the organic phase before and after scavenging. The analogous 2-iodo derivative suffers 3–7% deiodination under identical TMT conditions, reintroducing the des-halo impurity at a concentration exceeding ICH Q3D Option 1 oral concentration limits for palladium (10 μg/day at a 10 g/day dose). Multiple 20-kg batches of the chloro ester processed through a charcoal cartridge filtration loop (Pall PSC filter, 0.5 μm nominal, 3M R53SLP carbon media) achieved final palladium levels of 3–5 ppm, fully compliant with the USP <232> elemental impurity limits for drug substances.
| Parameter | Methyl 2-Chloro-4-Thiazolecarboxylate | Ethyl 2-Chloro-4-Thiazolecarboxylate | Test Methodology |
|---|---|---|---|
| CAS Number | 850429-58-0 | 850429-59-1 | — |
| Molecular Formula | C₅H₄ClNO₂S | C₆H₆ClNO₂S | — |
| Molecular Weight (g/mol) | 177.61 | 191.63 | — |
| Melting Range (°C, DSC) | 61.5–63.8 | 52.0–54.5 | DSC, 10°C/min, N₂, sealed pan |
| Assay (HPLC Area%, 210 nm) | ≥98.5% | ≥98.0% | ASTM D8300-19 C18 column |
| Water Content (% w/w) | ≤0.30 | ≤0.50 | USP <921> Method Ic (coulometric KF) |
| Residual Pd (ppm) | ≤10 | ≤15 | ICP-MS, USP <233> digestion |
| Solubility in DMF at 20°C (g/L) | 235 | 280 | Gravimetric, equilibration 24 h |
| Relative Aminolysis Rate (n-BuNH₂, THF, 25°C) | 1.0 (reference) | 0.55 | Pseudo-first-order decay, 1H NMR |
The thiazole ring itself exhibits conditional pH lability, and the 2-chloro electron-withdrawing group modulates ring-opening susceptibility differently than the 2-bromo or unsubstituted analogs. Under strongly acidic conditions (pH < 1.0, 6 M HCl, reflux), both methyl and ethyl esters undergo sequential ester hydrolysis followed by slow ring cleavage to form α-chloro-β-mercaptoacrylic acid derivatives, but the 2-chloro derivative ring-opens approximately 4× slower than the 2-bromo variant based on relative disappearance half-lives at 100°C. This stability margin allows for acid-catalyzed ester deprotection to the free carboxylic acid in 3 M HCl/dioxane at 70°C with <2% ring-degradation products after 8 hours, whereas the bromo analog accumulates 6–9% ring-opened material under the same protocol. For synthetic sequences that demand a late-stage ester hydrolysis while preserving the thiazole core—common in the preparation of 2-chlorothiazole-4-carboxylic acid as a penultimate intermediate for carboxamide APIs—the chloro ester is the only viable choice when the acid lability of the heterocycle governs the overall yield.
In basic media, ring-opening proceeds via nucleophilic attack at the C5 position. Sodium methoxide in methanol at 40°C induces <1% ring degradation of methyl 2-chloro-4-thiazolecarboxylate over 24 hours, verified by LCMS monitoring of the mercaptoacrylate fragment ion at m/z 152 [M-H]⁻. The corresponding ethyl ester shows similar inertness. This contrasts with the documented susceptibility of 2-unsubstituted thiazole-4-carboxylates to methoxide-mediated ring scission, indicating that the 2-chloro substituent provides kinetic protection against nucleophilic ring-opening, likely through inductive depletion of electron density at C5.
A second table consolidates forced-degradation impurity profiles obtained under ICH Q1B photostability conditions, relevant for bulk storage classification.| Impurity Designation | RRT (HPLC) | Initial (Area%) | Post-Exposure (Area%) | Proposed Origin |
|---|---|---|---|---|
| Des-chloro (methyl thiazole-4-carboxylate) | 0.68 | 0.05 | 0.09 | Photolytic dehalogenation |
| 2-Chloro-4-thiazolecarboxylic acid | 0.82 | 0.12 | 0.94 | Photoinduced ester cleavage |
| Dimer impurity (2-chloro-4,4′-bithiazole derivative) | 2.15 | ND | 0.31 | Radical coupling |
| Unknown at RRT 1.34 | 1.34 | 0.04 | 0.22 | — |
The 0.94% acid impurity generated during photostress exceeds the 0.10% unspecified impurity threshold, necessitating storage in amber glass or opaque HDPE drums under nitrogen. Production-scale material is typically packaged in 25-kg HDPE containers with double LDPE liners, vacuum-sealed after nitrogen purge to <0.5% residual oxygen. Accelerated stability data (40°C/75% RH for 6 months) confirm <0.3% total impurity growth under these packaging conditions, supporting a 24-month retest interval when stored at 2–8°C in the original sealed container.
Synthetic access to 2-vinyl-4-thiazolecarboxylate monomers for specialty acrylate copolymers has been documented via Stille coupling of the 2-chloro ester with tributyl(vinyl)tin in the presence of Pd(PPh₃)₄. The use of methyl 2-chloro-4-thiazolecarboxylate here is driven not by reactivity but by the avoidance of β-hydride elimination byproducts observed when the 2-iodo substrate is employed; the chloro leaving group suppresses palladium β-hydride elimination that would generate ethylene and regenerate the starting haloarene, a catalytic shunt that can reduce isolated yields by 15–20%. Comparative trials in a 100-mL Hastelloy Parr reactor at 80°C with 2 mol% Pd loading demonstrated 87% isolated yield of methyl 2-vinylthiazole-4-carboxylate using the chloro ester, versus 71% for the iodo analog and 63% for the bromo. The resultant vinyl monomer, after inhibitor removal by basic alumina filtration, exhibits a polymerization exotherm (DSC, AIBN initiator 1 wt%) with onset at 82°C and peak at 106°C, producing a homopolymer with glass transition temperature of 114°C (DSC midpoint, second heating). Such specialty polymers, functionalized with thiazole side chains, are under evaluation as metal-chelating coatings for corrosive environments; published corrosion inhibition data for thiazole-functionalized polymethacrylates have shown polarization resistance improvements of 2.3–4.1 kΩ·cm² on mild steel in 3.5 wt% NaCl relative to unmodified polymethacrylate controls, though the direct performance of the 2-chloro-4-thiazolecarboxylate-derived polymer requires further published validation.
In contrast, ethyl 2-chloro-4-thiazolecarboxylate remains preferred for applications requiring distillative purification, as its slightly lower melting point and higher boiling point under reduced pressure (~125°C at 0.5 torr, extrapolated from vapor pressure data) permit fractional distillation with less sublimation line clogging than the methyl ester, which sublimes readily at temperatures above 80°C under high vacuum. The methyl ester’s sublimation tendency can complicate drying operations in tray dryers; rotating conical vacuum dryers with scraped walls (e.g., RCA-200 type) operated at 45°C jacket temperature and 10–15 mbar absolute pressure are recommended over static tray systems to mitigate product migration and line blockages.
