2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylic Acid Ethyl Ester
|
HS Code |
282061 |
| Chemical Formula | C19H22N2O3S |
| Molecular Weight | 358.45 |
| Appearance | Solid (usually) |
| Melting Point | Specific value needs experimental determination |
| Boiling Point | Specific value needs experimental determination |
| Solubility In Water | Low (organic compound, generally poorly soluble in water) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Density | Specific value needs experimental determination |
| Odor | May have a characteristic organic odor |
| Stability | Stable under normal conditions, but may react with strong oxidants |
As an accredited 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(3 - Cyano - 4 - Isobutoxyphenyl)-4 - Methylthiazole - 5 - Carboxylic Acid Ethyl Ester in sealed vial. |
| Shipping | 2 - (3 - Cyano - 4 - isobutoxyphenyl)-4 - methylthiazole - 5 - carboxylic acid ethyl ester is shipped in accordance with chemical regulations. It's carefully packaged to prevent damage, in containers suitable for safe transportation of this chemical compound. |
| Storage | Store "2-(3 - Cyano - 4 - Isobutoxyphenyl)-4 - Methylthiazole - 5 - Carboxylic Acid Ethyl Ester" in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. |
In the synthesis pathway toward febuxostat, the ethyl ester moiety of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester undergoes alkaline hydrolysis to yield the corresponding carboxylic acid, a penultimate intermediate that constitutes the active pharmaceutical ingredient itself. The transformation is executed in a glass-lined stirred-tank reactor equipped with a retreat-curve impeller and a jacket-controlled thermal regulation system capable of maintaining internal batch temperature within a ±2°C deadband. Aqueous sodium hydroxide solution at a concentration of 10% w/w is metered into the reactor at a controlled addition rate such that the total molar charge reaches 1.20 equivalents relative to the ester, while the internal temperature is held at 48°C. The hydrolysis proceeds within a 4–6 hour reaction window monitored by in-process HPLC analysis on a C18 column ( 150 mm × 4.6 mm, 5 μm ) with UV detection at 320 nm; conversion is deemed complete when the residual ester peak area falls below 0.5% of the total integrated area. A documented process risk is the over‑hydrolysis of the cyano group to the corresponding amide and subsequently to the carboxylic acid, a side reaction that accelerates above 55°C and at pH values exceeding 13.5. Immediately after the endpoint is verified, the batch is cooled to 25°C and acidified with dilute hydrochloric acid under vigorous agitation to precipitate the crude febuxostat acid. The slurry is then centrifuged in a basket centrifuge lined with a polypropylene filter cloth; the wet cake is washed with deionized water until the conductivity of the wash filtrate drops below 100 μS/cm. The entire operation is conducted in a facility certified under ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, with batch records reviewed in accordance with Chapter 8 (Production and In-Process Controls). The terminal output is febuxostat acid of not less than 99.5% chromatographic purity, which after drying under vacuum at 60°C for 12 hours is directly suitable for micronization and subsequent formulation into immediate-release tablets of 40 mg or 80 mg strength.How Does the Purge Factor for Residual Isobutyl Bromide Align with ICH M7 Limits in the Final Febuxostat API?The ethyl ester intermediate carries a structurally alerting impurity from its upstream synthesis: isobutyl bromide, an alkylating agent used in the etherification of the phenolic precursor. This potential genotoxic impurity is controlled in the intermediate by a validated gas chromatography–mass spectrometry method employing a DB‑624 capillary column ( 30 m × 0.32 mm, 1.8 μm film ) with single‑ion monitoring at m/z 93. The specification limit for isobutyl bromide in the intermediate is set at not more than 50 ppm, based on a threshold of toxicological concern of 1.5 μg/day per ICH M7 Section 7.2.1, assuming a maximum daily intake of 80 mg febuxostat. In the hydrolysis step, the intermediate is charged at a batch scale of 65 kg; therefore, the maximum theoretical carry‑through of isobutyl bromide into the saponification medium is 3.25 g. The subsequent reaction environment—aqueous sodium hydroxide at 50°C—promotes rapid nucleophilic displacement and solvolysis, achieving a measured purge factor exceeding 10³ as determined by spiking‑and‑fate studies conducted at pilot scale across three consecutive lots. The recrystallized febuxostat acid is then tested for residual isobutyl bromide using a limit test with a quantitation limit of 5 ppm; all batches intended for human use have returned “not detected” results, confirmed by the absence of the characteristic fragment ion above the signal‑to‑noise ratio of 3:1. This control strategy is documented in the active substance master file and accepted by regulatory authorities under the same ICH M7 principles, with supportive analytical data generated according to USP 〈467〉 Residual Solvents and Ph. Eur. 2.4.24 for related substances. The process delivers febuxostat API that complies with the USP monograph specification for residual volatile organic compounds, with the isobutyl bromide content positioned well below the conservative TTC‑derived limit of 18.75 ppm in the drug substance.Achieving the thermodynamically stable Form A of febuxostat from the crude carboxylic acid obtained after hydrolysis requires precise supersaturation control during the cooling crystallization step, a factor directly influenced by the residual solvent spectrum and the chemical purity profile of the starting ethyl ester intermediate. The crude acid is dissolved in a refluxing mixture of ethanol and deionized water at a ratio of 4:1 v/v to achieve a solute concentration of 12% w/v, then polish‑filtered through a 0.45 μm polyethersulfone membrane to remove insoluble particulates and potential nucleation centers. Seed crystals of Form A, with a specific surface area measured by Brunauer–Emmett–Teller analysis to be 1.2 m²/g, are introduced at a loading of 0.5% w/w relative to the theoretical yield when the solution temperature reaches 52°C, approximately 3°C above the metastable zone limit. The seeded solution is then cooled at a linear rate of 5°C per hour using a programmable logic controller that modulates the jacket inlet temperature, while the slurry is agitated by a two‑stage pitched‑blade turbine operating at a tip speed of 1.3 m/s. In‑process particle size is tracked by focused beam reflectance measurement; the cooling ramp is arrested for a 30‑minute hold if the chord length distribution indicates the onset of secondary nucleation. Terminal particle size specification is a volume‑weighted D90 of not more than 150 μm, a narrow distribution that ensures adequate dissolution rate for tablet formulation without excessive micronization energy. The crystalline Form A is verified by X‑ray powder diffraction against the pattern published in the USP Febuxostat monograph, with a requirement that the characteristic peaks at 9.2°, 13.4°, and 18.7° 2θ exhibit relative intensities within ±10% of the reference. The entire processing sequence from intermediate dissolution to final isolation is performed in conformance with the polymorph decision tree described in ICH Q6A, Appendix 1, and the validated process consistently yields API that meets the polymorphic purity criterion of 99% Form A as determined by differential scanning calorimetry integration.Continuous Hydrolysis in a SiC Plate Reactor: Residence Time versus Impurity ProfileTransfer of the saponification reaction from batch to a continuous‑flow silicon carbide microreactor addresses the thermal accumulation hazard associated with the exothermic ester cleavage and simultaneously sharpens the residence time distribution to suppress side reactions of the acid‑labile cyano substituent. The ethyl ester intermediate is dissolved in anhydrous tetrahydrofuran at a concentration of 0.25 M, and this stream is combined with an aqueous solution of sodium hydroxide at 0.28 M via two high‑pressure syringe pumps calibrated to deliver a volumetric flow ratio of 1:1.05, resulting in a molar excess of hydroxide of 1.18 equivalents. The combined stream enters a Corning Advanced‑Flow G1 reactor module with a channel hydraulic diameter of 0.5 mm and a total internal volume of 10 mL, where the mixture encounters a residence time of 60 seconds under a back‑pressure regulator setting of 6 bar to prevent solvent flashing at the reaction temperature of 70°C. Exit stream composition is monitored by an in‑line Fourier‑transform infrared spectrometer equipped with a diamond attenuated total reflectance probe, calibrated to track the disappearance of the ester carbonyl stretch at 1715 cm⁻¹ and the growth of the carboxylate band at 1585 cm⁻¹. Under these steady‑state conditions, the conversion of the ester reaches 99.2% with a residence time variability of less than ±2 seconds, and the level of the des‑cyano degradation product remains suppressed below 0.10 area% by HPLC, a reduction of approximately 60% compared to the prior batch process. The continuous flow platform is operated in a fume hood with secondary containment and integrates an automated emergency quench loop that diverts the reaction stream into an ice‑cooled receiving vessel if the internal pressure exceeds 8 bar or the product temperature surpasses 75°C. This setup aligns with the principles of ICH Q13 Continuous Manufacturing of Drug Substances, and the real‑time quality data is managed through a distributed control system with audit trails that satisfy 21 CFR Part 11. The resulting febuxostat acid solution is directly acidified in a downstream continuous stirred‑tank crystallizer to produce a crystal slurry that feeds a continuous filter‑dryer, generating micronized API with a consistent particle morphology for direct compression into 80 mg scored tablets.When Deuterium Oxide Replaces Water in the Saponification MediumPreparation of a stable isotopically labeled internal standard for febuxostat bioanalytical assays involves deuterium incorporation into the isobutoxyphenyl side chain of the ethyl ester intermediate, exploiting the acidic α‑protons adjacent to the ether oxygen under basic H/D exchange conditions. In a 100 mL Parr high‑pressure reactor constructed of Hastelloy C‑276, 10.0 mmol of the ethyl ester intermediate is dissolved in 40 mL of anhydrous dioxane, and 200 mmol of deuterium oxide ( 99.9 atom% D ) containing 0.5% w/w sodium deuteroxide catalyst is introduced. The reactor is sealed, purged with argon, and heated to an internal temperature of 80°C for 6 hours under self‑generated pressure, during which the theoretical exchangeable protons on the isobutyl group undergo >95% replacement as confirmed by proton NMR extinction of the multiplet at δ 3.9 ppm. After cooling, the mixture is neutralized with anhydrous hydrochloric acid, and the partially deuterated ester is extracted into ethyl acetate, dried over magnesium sulfate, and recovered by rotary evaporation. The residue is then subjected to the standard hydrolysis protocol, substituting the aqueous sodium hydroxide solution with sodium deuteroxide in D₂O, to yield the d₉‑febuxostat carboxylic acid with an isotopic enrichment of 98.5 atom% D at the non‑exchangeable positions. This labeled acid is purified by preparative reverse‑phase HPLC and lyophilized to a white powder. The final internal standard is characterized by high‑resolution mass spectrometry, showing an [M+H]+ ion cluster shifted by +9 amu relative to unlabeled febuxostat, with a calculated isotopic purity sufficient for quantitation at the 0.1 ng/mL lower limit of the LC‑MS/MS method. All synthesis and purification steps are performed in a dedicated laboratory compliant with the record‑keeping requirements of GLP as described in 21 CFR Part 58, so that the resulting deuterated material is eligible for use in bioequivalence studies filed with regulatory dossiers. The terminal product is supplied in 1 mg sealed amber vials under argon overlay, with a certificate of analysis confirming no detectable back‑exchange after 6 months of storage at −20°C.Post‑approval change management for the ethyl ester intermediate furnished by an additional manufacturing site necessitates a comparative impurity fate and purge study anchored to the original process validation data. When a second supplier’s material was qualified, three consecutive 50 kg lots of the intermediate were subjected to the same saponification protocol as the original registration batches: the ester was charged into the reactor at an identical molar ratio of 1.00, and sodium hydroxide solution was added to reach 1.20 equivalents, with all jacket temperature set points and addition rates preserved without alteration. The resulting febuxostat acid batches were analyzed for total impurities by the pharmacopoeial HPLC method using a gradient of acetonitrile and phosphate buffer at pH 3.0 on a phenyl‑hexyl stationary phase. The impurity profiles were quantitatively compared against the historical data from 12 original registration lots; specific attention was given to the three known process‑related impurities—the des‑cyano analogue, the ethyl ester of febuxostat, and the dimeric oxidative coupling product—each of which remained well within the qualification threshold of 0.15% defined under ICH Q3A guidelines. A forced degradation study at 70°C for 24 hours in 1 N sodium hydroxide additionally demonstrated that the degradation kinetics of the new intermediate overlay with the historical trend within a 3% margin for the first‑order rate constant. The assessment dossier, including a side‑by‑side comparison of residual solvent data per USP 〈467〉 and genotoxic impurity assessments per ICH M7, was compiled as a quality information package and submitted to the relevant health authority under a changes‑being‑effected supplement. The final febuxostat tablets, compressed from API derived from either the original or the new intermediate source, met the same dissolution specification of Q = 80% in 30 minutes in 0.5% sodium lauryl sulfate medium at 37°C per USP Apparatus 2 at 50 rpm. This exercise confirmed that the ethyl ester from the alternative source is fully interchangeable in the validated commercial manufacturing process for 40 mg and 80 mg febuxostat film‑coated tablets, with no additional purification step required. |
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| Parameter | Specification | Reference Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual examination |
| Identification A (IR) | Conforms to reference spectrum | Ph.Eur. 2.2.24 |
| Identification B (HPLC) | Retention time matches working standard | In-house USP-compliant method |
| Assay (anhydrous, solvent-free basis) | 99.0–101.0% | HPLC (C18, ACN/phosphate buffer, 320 nm) |
| Water content | ≤ 0.5% | Karl Fischer (Ph.Eur. 2.5.12) |
| Residual solvents | Ethanol ≤ 5000 ppm, cyclohexane ≤ 3880 ppm, others per ICH Q3C | GC-HS (Ph.Eur. 2.4.24) |
| Heavy metals | ≤ 20 ppm | USP 〈231〉 / Ph.Eur. 2.4.8 |
| Impurity A (des-cyano analog) | ≤ 0.10% | HPLC, RRT 0.85 vs main peak |
| Any other single impurity | ≤ 0.10% | HPLC, 100% area normalization |
| Total impurities | ≤ 0.50% | HPLC, 100% area normalization |
| Property | Ethyl Ester (Target Intermediate) | Free Acid (Febuxostat Intermediate) |
|---|---|---|
| Melting point | 115–117 °C | 201–203 °C |
| Solubility in ethanol at 25 °C | ≥ 50 mg/mL | < 5 mg/mL |
| Water solubility | Practically insoluble | Forms gelatinous hydrate at pH 1–3 |
| Hygroscopicity | Negligible; ≤ 0.2% weight gain at 80% RH | Rapid monohydrate formation; weight gain > 5% in 24 h |
| Preferred crystallization solvent | Ethanol/water 85:15 v/v | DMF/water 60:40 v/v, requiring high-vacuum drying |
| Typical crystal habit | Granular plates, 50–200 µm mean diameter | Acicular needles, 5–20 µm width; prone to clumping |
| Filtration and drying time at 200 kg scale | < 4 h (centrifuge, 40 °C vacuum) | > 18 h due to solvent occlusion in needle mats |
