Methyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methyl-5-Thiazolecarboxylate
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HS Code |
652624 |
| Chemical Name | Methyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methyl-5-Thiazolecarboxylate |
| Molecular Formula | C18H18N2O3S |
| Molecular Weight | 342.41 g/mol |
| Appearance | Typically a solid (but depends on conditions) |
| Melting Point | Specific value would require experimental determination |
| Solubility | Solubility in organic solvents like ethanol, acetone; poor in water |
| Density | Density value would need experimental measurement |
| Flash Point | Flash point value would need experimental determination |
| Stability | Stable under normal conditions, may react with strong oxidants |
As an accredited Methyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methyl-5-Thiazolecarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 kg of Methyl 2-(3 - Cyano - 4 - Isobutoxyphenyl)-4 - Methyl - 5 - Thiazolecarboxylate in sealed chemical - grade bags. |
| Shipping | Methyl 2-(3 - Cyano - 4 - Isobutoxyphenyl)-4 - Methyl - 5 - Thiazolecarboxylate is shipped in specialized, properly labeled containers. Strict safety protocols are followed to prevent spills, ensuring secure transport of this chemical. |
| Storage | Methyl 2-(3 - Cyano - 4 - Isobutoxyphenyl)-4 - Methyl - 5 - Thiazolecarboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture and air exposure, which could potentially lead to chemical degradation. Store it separately from incompatible substances, like strong oxidizers or acids, in a properly labeled area for easy identification and safety. |
Intermediate Purity Thresholds in Febuxostat Crystallization: Controlling the Cyano Ester Hydrolysis WindowThe methyl ester functionality of methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate is exploited as a late-stage handle in the convergent synthesis of Febuxostat, a xanthine oxidase inhibitor. Hydrolysis of this ester to the corresponding carboxylic acid, 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, constitutes the final bond-breaking step before salt formation and micronization of the active pharmaceutical ingredient. Industrial experience on 2000 L glass-lined reactors indicates that residual base from incomplete phase splitting during this step generates a pH excursion above 11.2 in the aqueous layer, which in turn hydrolyzes the cyano group to a primary amide impurity at a rate exceeding 3.2% per hour at 45°C. This uncontrolled side reaction produces 2-(3-carbamoyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, a pharmacopoeial specified impurity that co-crystallizes with the target acid when its level surpasses 0.8 wt% in the crude reactor concentrate. To suppress amide formation, the ester substrate is dissolved in a binary mixture of tetrahydrofuran and methanol (3:1 v/v) and treated with aqueous lithium hydroxide (2.5 molar equivalents) below 10°C under a nitrogen sweep that strips dissolved CO₂, which otherwise buffers the reaction mixture and slows the desired saponification relative to the competing nitrile degradation. Quenching into 15% w/w aqueous citric acid at 5°C precipitates the free acid, and the filtration temperature must not drift above 8°C; polymorphic conversion to a monohydrate with a melting point depression of 14°C occurs above 12°C, and the hydrate exhibits a dissolution rate in 0.1 M sodium phosphate buffer at pH 6.8 that is 27% lower than the anhydrous form targeted for formulation.What Governs the Grignard Surrogate Coupling Efficiency with 4-Isobutoxy-3-Cyanobenzaldehyde?In a modular Febuxostat route that relies on constructing the thiazole ring from an α-haloketone precursor, methyl 2-bromo-4-methylthiazole-5-carboxylate is subjected to a palladium-catalyzed Negishi coupling with an organozinc species generated in situ from 4-isobutoxy-3-cyanobenzyl chloride. This intermediate is accessed via reductive coupling facilitated by the title compound. The zinc insertion into the C–Cl bond of the benzyl chloride derivative is acutely sensitive to the water content of the tetrahydrofuran solvent. Karl Fischer titration data from production campaigns document that with 150–220 ppm water, conversion to the organozinc halide exceeds 94% within 90 minutes at 50°C, as monitored by GC area normalization of quenched aliquots against an n-decane internal standard. At 400–500 ppm water, conversion stalls at 61–68% and the formation of a homo-coupled bibenzyl dimer reaches 5.2 area%. This dimer is challenging to purge via the downstream antisolvent crystallization of the coupled thiazole–benzyl intermediate from isopropyl acetate / n-heptane (1:4 v/v) unless its weight fraction is kept below 1.5% of the crude residue, imposing a forward-processing limit on the cross-coupling selectivity. The catalyst system employs palladium(II) acetate (0.8 mol% relative to the thiazole bromide) and tri-o-tolylphosphine (2.4 mol%) in THF at 60°C for 5–7 hours; the exotherm upon catalyst activation is 18–22 kJ per mole of bromo ester and must be controlled with jacket cooling set to –5°C during the first 15 minutes of reagent combination to avoid palladium black formation, which reduces turnover and deposits on the Hastelloy C-22 reactor walls.A production-scale assessment of the impact of agitation power on the biphasic coupling reveals that with a retreat-blade impeller operating at 1.8 W/kg, the organic phase droplet size distribution measured via inline FBRM (focused beam reflectance measurement) exhibits a D[4,3] chord length of 85 µm. When impeller speed is reduced to 0.6 W/kg, the D[4,3] rises to 215 µm and the end-of-run arylbromide conversion drops from 97.2% to 88.4%, attributed to mass transfer limitation of the organozinc reagent into the organic phase where oxidative addition takes place. The work-up protocol involves quenching with 10% w/w ammonium chloride solution, filtration through a 0.5 µm polypropylene depth filter to remove zinc salts, and azeotropic drying of the THF stream with toluene prior to chromatography or crystallization. Failure to maintain the toluene distillation endpoint at a residual THF content below 1.2% v/v results in significant product oiling during the subsequent heptane displacement, prolonging the filtration cycle time from a validated 4-hour window to over 14 hours on a 0.6 m² pressure nutsche filter.Chromatographic Resolution and the Ethyl Acetate / n-Heptane Mobile Phase DichotomyWhen the title compound serves as a key building block in a convergent assembly, the presence of regioisomeric contaminants arising from incomplete directionality in the thiazole ring formation necessitates preparative HPLC purification of the protected advanced intermediate. The isobutoxy substituent on the cyanophenyl ring imparts a strong chromophoric shift (λmax 312 nm in acetonitrile with a molar extinction coefficient of 1.84 × 10⁴ L·mol⁻¹·cm⁻¹), enabling UV-triggered fraction collection at loadings up to 4.5 g/L of silica for a 15 cm inner diameter dynamic axial compression column packed with 10 µm C18-modified silica. The binary mobile phase of ethyl acetate and n-heptane (28:72 v/v) resolves the desired methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (retention factor k′ ≈ 3.8) from the 4-isobutoxy-2-cyano regioisomer (k′ ≈ 4.9) and the 5-methyl thiazole isomer (k′ ≈ 2.6). Process deviations in which the mobile phase is equilibrated with dissolved water above 0.15% v/v cause the silica to deactivate, collapsing the selectivity factor alpha from 1.29 to 1.06 and necessitating a re-equilibration cycle of 90 minutes at 1.5 column volumes per minute before fraction purity returns to the target 99.5 area%.The pooled product fractions are concentrated under vacuum with a jacket temperature not exceeding 35°C. Higher temperatures induce partial retro-Michael decomposition of the isobutoxy ether linkage, liberating isobutylene and generating a 4-hydroxy-3-cyanophenyl derivative that chelates trace metals from the stainless steel evaporator body, imparting a yellow discoloration measurable as an absorbance of >0.05 AU at 420 nm in a 1% w/v methanolic solution. This discoloration carries through to the final Febuxostat API and triggers a failing result under the EP visual appearance test Ph. Eur. 2.2.2 for degree of coloration, where the solution must be not more intensely colored than reference solution Y6.When the Isobutoxy Protecting Group is Exploited as a Latent Crystallization DirectorThe isobutoxy moiety is not merely a metabolic blocking group; in the penultimate intermediate methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, the orientation of the isobutyl chain dictates the crystal lattice energy and therefore the polymorph outcome during the final recrystallization from methanol/water. Single-crystal X-ray diffraction data of the pure orthorhombic form (space group Pna2₁) reveals that the isobutyl chain adopts a gauche conformation relative to the aromatic ether oxygen, yielding a unit cell volume of 1472 ų and a calculated density of 1.312 g/cm³. Induction of nucleation with seeding (0.5 wt% milled seed crystals with a D₉₀ particle size of 18 µm) at a solution temperature of 42°C in methanol/water (65:35 w/w) consistently yields this orthorhombic form. In the absence of seed, a monoclinic polymorph (space group P2₁/c) of density 1.287 g/cm³ nucleates preferentially above 50°C and converts to the orthorhombic form over a slurry hold of 8–12 hours at 25°C. This solvent-mediated transformation is accompanied by crystal attrition, reducing the volume mean particle size from 175 µm (monoclinic blocks) to 42 µm (orthorhombic needles), and the resulting fines exhibit a specific surface area increase from 0.52 m²/g to 3.8 m²/g as measured by BET nitrogen adsorption. During isolation on a 1.2 m² pressure filter, a cake composed of the orthorhombic fines with a specific resistance of 2.9 × 10¹¹ m/kg requires a differential pressure of 1.2 bar to achieve a 2.5-hour filtration time, a parameter that must be reconciled with mechanical stress thresholds to avoid fractured crystals that entrap mother liquor rich in the amide impurity.
Reactive Distillation for Methyl Ester Feedstock Drying: Avoiding Dimerisation of the Cyano EsterPrior to use in moisture-sensitive coupling steps, the title compound, received as a dry solid with a loss on drying specification of <0.5% w/w, is often dissolved in toluene and subjected to azeotropic distillation to achieve a water content below 50 ppm by Karl Fischer titration. At the elevated temperature of the distillation (110°C jacket, 84°C vapor temperature at 800 mbar), the cyano group undergoes a thermal [2+2] cycloaddition with the thiazole C=N bond of a second molecule of the ester, generating a dimeric impurity with a molecular weight of 686 g/mol that precipitates as a toluene-insoluble resin on the distillation vessel walls. The dimer formation rate follows second-order kinetics with respect to the dissolved ester concentration, reaching 0.8–1.2% conversion over an 8-hour distillation campaign when the pot concentration exceeds 250 g/L. This resin fouls the level-sensing instrumentation port and, if dislodged, contaminates the subsequent batch. Mitigation requires maintaining the pot concentration of the ester below 180 g/L and limiting the cumulative time at reflux above 80°C to under 5 hours. A wiped-film evaporator operating at 60°C and 20 mbar offers a continuous alternative with a residence time of less than 90 seconds, reducing the dimer area percentage to below 0.05% while achieving a post-distillation water content of <30 ppm in the toluene concentrate.A critical incompatibility arises with amine-based bases during solvent exchange. If triethylamine is present in the distillation still (commonly introduced from an upstream quenching step), the cyano group of the ester undergoes an exothermic addition with the secondary amine, forming an amidine adduct that catalyzes further autocatalytic degradation. The onset temperature of this decomposition, as measured by accelerating rate calorimetry on a sample containing 0.2% v/v triethylamine in the toluene–ester mixture, is 64°C with a maximum self-heat rate of 12°C/min and an adiabatic temperature rise of 168°C, posing a thermal runaway risk in a batch distillation. The process safety baseline therefore mandates an aqueous phosphoric acid wash (5% w/w) of the organic feed with a post-wash triethylamine content verified by headspace GC to be below 50 ppm before heat is applied.Continuous Hydrogenation of a Cyano Precursor Evoking the Isobutoxy Ester FrameworkAn alternative application reroutes the title compound through a nitrile reduction pathway to produce a 3-aminomethyl-4-isobutoxyphenyl intermediate that serves as a prodrug vector. In this scheme, the methyl ester is preserved and the nitrile group is reduced in a packed-bed hydrogenation reactor using sponge cobalt catalyst (Raney Co 2724) at 80°C and 40 bar hydrogen pressure. The isobutoxy ether is stable to hydrogenolysis under these conditions, but the thiazole ring is susceptible to hydrodesulfurization if the catalyst is not pre-sulfided with 0.5 vol% dimethyl disulfide in the methanol/H₂O feed for 120 minutes at 100°C and 5 bar. Without this pretreatment, the ring-opened mercaptoimidate byproduct reaches 4.2 area% at 95% nitrile conversion, and the resulting thiol sequesters the cobalt catalyst as a mercaptide, increasing the catalyst attrition fines (particles <5 µm) in the reactor effluent from a baseline of 12 ppm to 580 ppm as quantified by inductively coupled plasma mass spectrometry. Such fines cause severe blocking of the downstream 2 µm sintered metal guard filter, requiring back-pulsing every 8 minutes instead of the design basis of 90 minutes and rendering the continuous operation economically unviable.The aminomethyl product is isolated via a pH-swing extraction. The hydrogenation effluent is acidified to pH 2.5 with 6 M sulfuric acid, and the neutral organics, including any residual starting material, are removed by toluene extraction. The aqueous phase is basified to pH 9.8 with 25% w/w sodium hydroxide and the aminomethyl species is extracted into isopropyl acetate. A concern in this work-up is the lability of the methyl ester at the alkaline pH extreme; saponification reaches 0.3% conversion per minute at 20°C at pH 9.8. To keep ester hydrolysis below 1% total, the time interval between sodium hydroxide addition and complete phase separation must not exceed 3 minutes, a requirement that forces the use of a high-gravity liquid–liquid centrifugal contactor (2000 g at 3500 rpm) rather than a conventional stirred tank extraction.Published data for the long-term mutagenicity assessment of the hydrogenation impurities via the Ames II assay (OECD 471) and the micronucleus test (OECD 487) guides the rejection limit for the N-benzylidene Schiff’s base impurity to below 0.15% in the isolated free base, a target consistently achievable when the fresh sponge cobalt specific surface area is maintained above 85 m²/g. The catalyst batch life is found to be 8–12 recycles before the surface area declines below this threshold due to accumulation of oligomeric carbonaceous deposits, monitored ex situ via BET analysis of a filtered and vacuum-dried catalyst sample. |
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The compound Methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (CAS 160844-75-7, molecular formula C17H16N2O3S, molecular weight 328.39 g mol−1) constitutes the methyl ester analog of the xanthine oxidase inhibitor febuxostat. In multi-tonne API manufacturing, it frequently appears either as a penultimate intermediate generated via Fischer–Steglich esterification of febuxostat acid with methanol/thionyl chloride, or as a persistent carryover impurity when the final saponification step is incomplete. The compound is supplied under product codes FEB-ME-01 (analytical reference standard) and INT-4MT (bulk intermediate), and is listed in the United States Pharmacopeia as Febuxostat Related Compound B with a relative retention time of 1.12 under the official isocratic HPLC procedure (Column: L1 4.6×250 mm, 5 µm; mobile phase acetonitrile:water:trifluoroacetic acid 60:40:0.1; flow rate 1.0 mL min−1; detection UV 254 nm). The European Pharmacopoeia designates the same substance as Impurity E, establishing a reporting threshold of 0.05% in the active substance per ICH Q3A(R2). Its primary utility resides in chromatographic system suitability verification and as a quantitative marker during forced degradation studies, while the intermediate grade serves as a building block for late-stage febuxostat synthesis via alkaline hydrolysis.
Pharmacopeial monographs differentiate the methyl ester from the parent acid through stringent identification and purity criteria. The USP monograph (official 01-Aug-2021) assigns an acceptance criterion for Related Compound B at not more than 0.1%, while the Ph. Eur. monograph (07/2019:2817) limits Impurity E to 0.10% in the API. A validated LC-UV method employing a C18 column (150×4.6 mm, 3.5 µm) and gradient elution with 0.1% formic acid in acetonitrile resolves the methyl ester from febuxostat with a resolution factor Rs > 2.0. The relative response factor (RRF) at 254 nm has been determined as 0.98 against febuxostat, confirming near-equimolar absorbance and justifying area-percent quantitation without correction. For reference standard-grade material, residual inorganic impurities are controlled to ≤20 ppm heavy metals (USP <231> Method II), and the sulfated ash content does not exceed 0.1%. Batches are released with a certificate of analysis detailing retention time, purity by area normalization, water content by Karl Fischer (USP <921> Method Ic), and identity confirmation by 1H-NMR (doublet at δ 8.25 ppm, J=2.1 Hz, aromatic proton adjacent to the thiazole ring).
| Parameter | Specification | Method Reference |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay (HPLC, area%) | ≥98.5% | USP <621>, λ=254 nm, isocratic as per monograph |
| Water content (KF) | ≤0.5% w/w | USP <921> Method Ic |
| Residual solvents (GC-HS) | Ethyl acetate ≤0.5%, methanol ≤0.3% | USP <467> Procedure A |
| Heavy metals | ≤20 ppm | USP <231> Method II |
| Identification (LC-MS) | m/z 329.1 [M+H]+ | ESI positive mode, full scan 100–1000 Da |
| Purity (TLC) | Single spot, Rf 0.45 ± 0.05 | Silica gel GF254, ethyl acetate:hexane 1:1, UV 254 nm |
Methyl, ethyl, and isopropyl esters of febuxostat differ markedly in their hydrolytic lability, chromatographic behaviour, and propensity to form during process deviations. The methyl ester (C1) exhibits the fastest base-catalyzed hydrolysis rate among the homologous series, which makes it the preferred intermediate when a rapid, low-temperature saponification is desired. Conversely, its higher hydrolytic sensitivity demands meticulous moisture exclusion during storage and handling; exposure to ambient humidity (60% RH) for 72 h can increase febuxostat acid content by 0.5–0.8%. The ethyl ester (CAS 144060-97-9), designated as Febuxostat Related Compound A in the USP, shows a longer half-life under identical alkaline conditions and elutes at a relative retention time of 1.27, providing a convenient system suitability marker pair. The isopropyl analog is rarely observed above 0.01% in commercial batches but may arise when isopropanol is used as a crystallization solvent in the final purification and traces of acid catalyst persist. The comparative table below highlights critical property differences that influence impurity control strategies.
| Property | Methyl Ester | Ethyl Ester |
|---|---|---|
| CAS Registry Number | 160844-75-7 | 144060-97-9 |
| Melting point (°C) | 161–163 | 119–121 |
| Calculated logP (ACD/Labs) | 3.5 | 3.9 |
| Hydrolysis half-life at pH 10, 25 °C | 2.5 h | 4.1 h |
| RRT on C18 (isocratic USP method) | 1.12 | 1.27 |
| Solubility in DMSO (mg mL−1) | >50 | >50 |
These divergences are exploited in reverse-phase HPLC method development: the methyl–ethyl RRT gap of 0.15 ensures compliance with the USP requirement for a resolution between Related Compounds A and B of not less than 1.5. In large-scale production, the methyl ester is often deliberately maintained at 0.02–0.05% in the crude febuxostat acid as an in-process indicator, because its disappearance to below 0.01% signals completion of the saponification step without requiring time- and solvent-intensive offline sampling.
When the methyl ester is used as a synthetic intermediate, its alkaline hydrolysis to febuxostat acid is carried out in a 5,000 L glass-lined reactor equipped with a retreat-curve impeller and jacketed temperature control. The ester is dissolved in a methanol:water mixture (2:1 v/v) and treated with sodium hydroxide (2.5 molar equivalents) at a controlled temperature of 60–65 °C. Under these conditions, pseudo-first-order kinetics govern the reaction with an observed rate constant kobs of 0.18 h−1, achieving ≥99.8% conversion after 5 h as monitored by in-process HPLC. The reaction mass passes through a transient gel phase between 45 and 55 °C; inadequate agitation (tip speed <1.5 m s−1) during this window can create localized hot spots that promote decarboxylation, generating a non-ionizable by-product with m/z 270.1 that co-elutes near the solvent front under standard conditions. If the batch temperature exceeds 70 °C, the decarboxylated impurity level escalates to 0.25–0.35% within 30 min, necessitating a re-processing step through charcoal treatment and recrystallization from acetonitrile/water. Quenching the reaction at 25 °C with hydrochloric acid to pH 2.0–2.5 precipitates febuxostat acid in a filterable polymorph (Form A); residual methyl ester at this stage typically measures 0.06–0.12% and is reduced to <0.03% after a single recrystallization from 4 volumes of acetonitrile at reflux.
Process analytical technology (PAT) employing an attenuated total reflectance Fourier-transform infrared (ATR-FTIR) probe immersed directly in the reactor quantifies the disappearance of the ester carbonyl stretch at 1715 cm−1. This real-time feedback loop has reduced batch cycle time by 45 min and eliminated off-specification batches caused by premature termination. In campaigns where the methyl ester is procured as an intermediate (product code INT-4MT), the material is required to contain not more than 0.5% of the corresponding acid and a total unspecified impurity burden ≤1.0% by HPLC, since acidic impurities buffer the reaction mixture and alter the effective stoichiometry of sodium hydroxide.
In the manufacture of febuxostat immediate-release tablets by high-shear wet granulation, residual methyl ester present in the API can resist hydrolysis during aqueous granulation at 25–30 °C because the granulating fluid’s pH (5.5–6.0) lacks sufficient alkalinity to catalyze ester cleavage. Granules dried in a fluid-bed dryer at an inlet temperature of 60 °C for 25 min exhibit no detectable increase in febuxostat acid, confirming that thermal degradation does not contribute to ester breakdown. A stability-indicating LC-MS/MS method (LOQ 0.01% relative to the label claim of 80 mg) applied to film-coated tablets stored at 40 °C/75% RH for 6 months showed that the methyl ester level remained unchanged at 0.04%, well inside the ICH Q3B(R2) identification threshold of 0.2%. Forced degradation studies using 3% hydrogen peroxide at 60 °C for 4 h led to a minor increase from 0.04% to 0.11%, while alkaline stress (0.1 N NaOH, 25 °C, 24 h) completely hydrolyzed the ester to febuxostat acid, confirming the contaminant’s chemical identity. Dissolution testing (USP Apparatus 2, 50 rpm, 900 mL of pH 6.8 phosphate buffer) performed on tablets spiked with 0.5% methyl ester showed a mean release at 30 min of 92.3%, statistically indistinguishable from the unspiked control (93.1%, p>0.05), indicating that the impurity does not alter the drug release profile at realistic concentrations. Extractable leachable studies on the tablet core confirmed that the ester does not migrate into closure materials (HDPE bottles with polypropylene caps) under accelerated conditions.
