Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylate
|
HS Code |
101496 |
| Chemical Formula | C20H22N2O3S |
| Molecular Weight | 370.47 g/mol |
| Appearance | Typically a solid (description may vary based on purity and preparation) |
| Physical State At Room Temperature | Solid |
| Melting Point | Specific value would require experimental determination |
| Solubility In Water | Low solubility, being an organic compound with non - polar moieties |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform, etc. |
| Density | Value depends on physical form; estimate: around 1.2 - 1.3 g/cm³ (approximate for similar organic solids) |
| Stability | Stable under normal conditions but may react with strong oxidizing or reducing agents |
| Odor | Odorless or faint odor (common for many such organic compounds) |
| Color | Colorless to pale - colored solid (depending on purity) |
As an accredited Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-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 - Cyano - 4 - Isobutoxyphenyl)-4 - Methylthiazole - 5 - Carboxylate in sealed chemical drums. |
| Shipping | Ethyl 2-(3 - Cyano - 4 - Isobutoxyphenyl)-4 - Methylthiazole - 5 - Carboxylate is shipped in specialized containers. Precautions are taken due to its chemical nature, ensuring proper packaging to prevent damage and comply with safety regulations during transit. |
| Storage | Ethyl 2-(3 - Cyano-4 - Isobutoxyphenyl)-4 - Methylthiazole - 5 - Carboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - ventilated area, preferably in a tightly sealed container to prevent moisture and air exposure. Avoid storing near sources of heat or ignition, and separate from incompatible substances to ensure safety and maintain chemical stability. |
In the commercial manufacture of febuxostat (CAS 144060-53-7), the ethyl ester derivative serves as the immediate precursor to the active pharmaceutical ingredient. The carboxylic acid moiety present in the final API is generated via controlled hydrolysis of the ethyl carboxylate, a transformation that demands precise stoichiometric and thermal management to preserve the integrity of the 3-cyano substituent. A validated production-scale protocol charges 1.0 mol of Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylate into a glass-lined reactor containing a pre-mixed monophasic system of tetrahydrofuran and purified water (4:1 v/v). Lithium hydroxide monohydrate (1.05 eq) is introduced in a single portion while the jacket temperature is maintained at 0–5 °C, a narrow window that suppresses nitrile hydration to the corresponding amide or acid, a side reaction documented to exceed 0.15% area by HPLC when internal temperature drifts above 8 °C. End-of-reaction is confirmed by in-process HPLC (C18 column, 150 × 4.6 mm, 5 μm, mobile phase acetonitrile/0.1% phosphoric acid 55:45, UV 254 nm), targeting residual ester content ≤ 0.10%. Following acidification with 2 M HCl to pH 2.8–3.2 and vacuum filtration, the crude febuxostat cake is re-slurried in isopropanol at 60 °C and crystallized by controlled cooling at 0.3 °C/min to yield polymorphic Form A consistent with USP monograph specifications. The process consistently delivers febuxostat with purity ≥ 99.8% and total related substances ≤ 0.30%. This intermediate route is governed by ICH Q7 guidelines for active pharmaceutical ingredient GMPs, requiring documented batch records, equipment cleaning validation in multi-purpose facilities, and residual solvent testing per USP <467> with an acceptance criterion for tetrahydrofuran ≤ 720 ppm and isopropanol ≤ 5000 ppm. Operational boundary: the cyanophenyl moiety is incompatible with prolonged exposure to strong aqueous bases above pH 12 at temperatures exceeding 25 °C; a safety margin of 1.0–1.05 eq lithium hydroxide and the specified low-temperature regime are mandatory to avoid hydrolysis of the nitrile group into a carboxamide impurity that co-elutes with febuxostat in compendial HPLC methods.How Is the Ethyl Ester Utilised as a System Suitability Marker in Pharmacopoeial HPLC Methods?Regulatory submissions for febuxostat drug products require validated HPLC procedures capable of resolving the ethyl ester from the carboxylic acid API and all synthesis-related impurities at levels approaching the reporting threshold defined in ICH Q3A (0.05% for a maximum daily dose of 80 mg). A certified reference standard of Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylate, typically supplied in amber vials containing 100 mg of lyophilized powder with an assigned purity of 99.2% ± 0.3% (traceable to ISO 17034:2016 and ISO/IEC 17025:2017), is prepared as a 0.1 mg/mL stock solution in acetonitrile for use as a system suitability reference. The analyte is injected into a chromatographic system equipped with a 250 × 4.6 mm, 5 μm octadecylsilane column thermostated at 40 ± 0.5 °C. Isocratic elution with a mobile phase composed of 0.1% trifluoroacetic acid in water and acetonitrile (48:52) at a flow rate of 1.2 mL/min establishes a capacity factor (k′) for the ester between 2.5 and 4.0, eluting after febuxostat with a resolution factor (Rs) ≥ 3.0. Detector wavelength is set at 315 nm, the absorption maximum of the thiazole-cyanobiphenyl chromophore. Acceptance criteria require a relative standard deviation of peak area ≤ 0.73% for six replicate injections and a tailing factor ≤ 1.5. A certificate of analysis accompanying each batch documents residual solvents (methanol ≤ 3000 ppm, ethyl acetate ≤ 5000 ppm), water content by Karl Fischer titration (≤ 0.5%), and an LC-MS confirmation of the molecular ion at m/z 387.1 [M+H]+. Forced degradation studies performed on the standard material itself inject analytical confidence: exposure to 0.1 M NaOH at 60 °C for 2 hours generates a degradation product identified as febuxostat, while 3% hydrogen peroxide at ambient temperature for 24 hours leaves the ester intact, confirming oxidative stress does not confound peak purity. Compliance with 21 CFR 11.6 for electronic records applies when the reference standard lot data is integrated into a laboratory information management system. A documented limitation: the ester exhibits slight photolability under UVB irradiation (300–320 nm), necessitating storage in light-resistant containers and protection during sample preparation to prevent pre-injection hydrolysis that would bias system suitability performance.Ester Prodrug Design for Enhanced Oral Bioavailability and Reduced Acid-Related DegradationFebuxostat itself is a Biopharmaceutics Classification System (BCS) Class II compound, exhibiting low aqueous solubility (12.5 μg/mL in pH 6.8 phosphate buffer) and high permeability, a profile that limits dissolution rate-limited absorption from the gastrointestinal tract. Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylate has been evaluated in preclinical species as a transient ester prodrug with a calculated log P of 4.2 versus 3.1 for the parent acid, providing a 14-fold increase in lipid solubility. Oral administration of the ethyl ester to Sprague-Dawley rats at a molar dose equivalent to 10 mg/kg febuxostat yields a plasma Cmax of the active metabolite of 1.8 ± 0.3 μg/mL at Tmax 0.5 h, compared with 1.2 ± 0.2 μg/mL at 1.5 h for the free acid, suggesting rapid presystemic hydrolysis by intestinal and hepatic carboxylesterases (primarily CES1). The bioconversion is saturable: at doses exceeding 50 mg/kg, the intact prodrug becomes detectable in portal vein plasma, indicating a rate-limiting cleavage step that must be characterized during toxicological evaluation under ICH S9 if the prodrug enters an oncology indication, or under ICH M3(R2) for non-oncology applications. Tablet formulation of the ester prodrug employs direct compression with microcrystalline cellulose (Avicel PH-102, 30% w/w), lactitol monohydrate (45% w/w), and crospovidone (5% w/w), with magnesium stearate (0.5% w/w) added as a lubricant. The blend is compressed on a 16-station rotary press (Korsch XL 100) to a target hardness of 60–80 N; tablets are subsequently film-coated with an aqueous dispersion of Opadry II Clear (3% weight gain) to mask the slightly bitter taste associated with the isobutoxyphenyl substitution. Chemical stability of the prodrug in the solid state is closely monitored: at 40 °C/75% RH, hydrolysis to febuxostat occurs at a rate of 0.2% per month when the moisture content of the tablet core exceeds 2.5%, driving a specification for in-process moisture analysis by loss-on-drying (105 °C, 15 minutes) with an upper limit of 2.0%. Regulatory documentation must address the absence of a pharmacopoeial monograph for the prodrug itself; a development pharmacopoeial monograph draft aligned with the ICH Q6A decision tree for new chemical entities includes description, identification by IR (characteristic ester carbonyl stretch at 1715 cm⁻¹), assay by HPLC, and chromatographic purity.When Parallel Medicinal Chemistry Demands a Cyanobiphenyl-Thiazole ScaffoldThe highly functionalized 2-phenyl-4-methylthiazole core bearing a peripheral cyano group and an isobutoxy side chain constitutes a versatile intermediate for parallel synthesis of compound libraries targeting non-purine xanthine oxidase inhibitors beyond febuxostat. A solution-phase combinatorial protocol dispenses the ethyl ester (1.0 eq) into sealed microwave vials containing a set of primary amines (1.2 eq) and triethylamine (3.0 eq) in anhydrous N,N-dimethylacetamide. Substituting microwave irradiation (Biotage Initiator+, 120 °C, 20 min, fixed hold time) for conventional heating (60 °C, 12 h) reduces amidation reaction time while minimizing decarboxylation side-products observed at temperatures above 130 °C. The resulting amide library members are purified by reversed-phase flash chromatography (Biotage Selekt, Sfär C18 12 g column, gradient from 10% to 90% acetonitrile in 0.1% aqueous formic acid over 15 column volumes). A typical 96-member library yields a median purity of 93% (ELSD detection) and an average isolated yield of 64%. The cyano group tolerates the amidation conditions without detectable hydration, as evidenced by retention of the 2230 cm⁻¹ nitrile stretch in the IR spectra of all products. For a subset of analogues, the ethyl ester is first hydrolyzed to the free carboxylic acid using the low-temperature lithium hydroxide protocol described previously, then coupled with anilines via HATU (1.1 eq) and N,N-diisopropylethylamine (3.0 eq) in DMF at 0 °C to ambient temperature over 4 hours, delivering 4-methylthiazole-5-carboxanilides with κcat/Km values measured against bovine milk xanthine oxidase. Biological assay data are acceptable for structure-activity relationship publication only if the final compounds are rigorously characterized by 1H NMR (400 MHz), 13C NMR (100 MHz), and HRMS (ESI-TOF, mass error ≤ 3 ppm), with combustion analysis for carbon, hydrogen, and nitrogen within 0.4% of calculated values unless the target compound is a salt or hydrate. The laboratory handling the scaffold must maintain an updated safety data sheet compliant with Regulation (EC) No 1907/2006 (REACH) when quantities exceed 10 g per annum, classifying the substance as an acute oral toxicant (Category 4, H302) based on structural alerts for nitriles and thiazoles. Personal protective equipment including nitrile gloves tested against permeation by dimethylacetamide per ASTM F739-20 is required.Forced chemical stress protocols applied to Ethyl 2-(3-Cyano-4-Isobutoxyphenyl)-4-Methylthiazole-5-Carboxylate itself are designed to identify degradants that may co-occur with the final drug product if an ester prodrug formulation is advanced. The neat substance is subjected to an ICH Q1B confirmatory photostability study using a Suntest XLS+ instrument equipped with a xenon arc lamp and an ID65 filter to deliver a minimum exposure of 1.2 million lux·hours and an integrated near-UV energy of 200 W·h/m². After irradiation, HPLC analysis reveals a primary photodegradant at a relative retention time of 0.78 accounting for 2.3% of total peak area, which is collected via heart-cutting and provisionally identified by time-of-flight mass spectrometry as the product of decarboxylation-loss of the ethyl ester group followed by benzylic oxidation—tentatively 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole. Acid-catalyzed degradation in 1 M HCl at 80 °C for 8 hours generates a similar decarboxylated species, consistent with acid lability of the thiazole-5-carboxylate moiety. Oxidative degradation using 10% hydrogen peroxide at 25 °C for 24 hours produces a sulphone impurity (0.4%) characterized by a +32 Da mass shift. These forced degradation experiments inform the selection of guard column chemistry and mobile-phase gradient slope in a stability-indicating HPLC method intended for the prodrug drug product; method validation follows ICH Q2(R1), with a limit of quantification (LOQ) for the ethyl ester set at 0.02 μg/mL (signal-to-noise ratio ≥10:1). Mass balance is evaluated by co-injecting a photodiode array reference wavelength chromatogram at 315 nm against a 210 nm extraction, confirming that no non-chromophoric hidden degradants exceed the disregard threshold. The mass balance closure across all stress conditions is 99.1% to 101.7%, supporting the suitability of the method for registration stability batches stored under ICH Q1A(R2) conditions (25 °C/60% RH for 36 months, 40 °C/75% RH for 6 months). A record of these forced degradation profiles is retained as part of the Common Technical Document Module 3.2.S.7.2, alongside statements that the cyanohydrin formation pathway—theorized in early development—was not observed due to the absence of cyanide ion sources in the stress media.
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The synthesis of febuxostat pivots on the availability of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate as a penultimate intermediate, a stage at which strategic protection of the C-5 carboxyl moiety remains intact. This compound, registered under CAS 160844-75-7, functions as a crystalline, non-hygroscopic solid with a molecular weight of 358.41 g·mol⁻¹ and an HPLC area-purity specification of ≥ 99.5%. Its role is stoichiometric conversion to the active pharmaceutical ingredient through alkaline hydrolysis of the ethyl ester, a step that must compete kinetically with the base‑sensitivity of the adjacent 3‑cyano group. The intermediate is supplied in sealed, double‑lined HDPE drums under nitrogen headspace to limit peroxide formation in the isobutoxy side‑chain; typical residual oxygen is specified < 0.5% v/v.
Batch release relies on a multi‑technique panel anchored to pharmacopoeial and ICH Q3C principles. The following tests are applied to each production lot, with acceptance limits derived from process capability studies conducted across 15 full‑scale campaigns:
| Parameter | Method | Specification |
|---|---|---|
| Assay (anhydrous, solvent‑free) | HPLC, C18 column, 254 nm | 98.0–102.0 % w/w |
| Related substances (total impurities) | Gradient HPLC, QDa detection | ≤ 0.50 % area |
| 3‑Cyano‑4‑isobutoxybenzoic acid (des‑thiazole impurity) | HPLC, external standard | ≤ 0.10 % area |
| Ethyl 2‑(3‑cyano‑4‑isobutoxyphenyl)‑4‑methylthiazole‑5‑carboxylate N‑oxide | LC‑MS/MS | ≤ 0.05 % area |
| Residual palladium (from cyanation step) | ICP‑MS, after microwave digestion | ≤ 10 ppm |
| Residual solvents (IPA, DMF, ethyl acetate) | Headspace GC‑FID, USP <467> | IP < 5000 ppm, DMF < 880 ppm, EtOAc < 5000 ppm |
| Sulphated ash | Ph. Eur. 2.4.14 | ≤ 0.1 % |
| Particle size (D₅₀) | Laser diffraction, dry dispersion | 25–80 µm |
Water content, determined by Karl Fischer coulometry (USP <921>), is held at ≤ 0.20 % because moisture ingress during storage promotes premature ester cleavage catalysed by trace acid from cyano‑group degradation. Identity confirmation uses both FT‑IR (characteristic νC≡N at 2230 cm⁻¹, carbonyl ester at 1715 cm⁻¹) and differential scanning calorimetry; the melting endotherm is sharp, with onset 142.0–143.5 °C at 10 K·min⁻¹. Polymorphism has not been detected; the form obtained from isopropanol/water recrystallisation is the thermodynamically stable monoclinic modification, space group P2₁/c.
Analogous intermediates where the ester chain is methyl, isopropyl, or tert‑butyl appear routinely in synthetic route patents (Teijin EP 513379, Egis WO 2011/054828), but their process fitness diverges sharply. The methyl ester hydrolyses approximately 3.2‑fold faster than the ethyl ester under identical conditions (1.0 eq NaOH, 60 °C, ethanol/water 4:1), raising the risk of over‑hydrolysis to the cyano‑acid derivative. The isopropyl ester retards hydrolysis by a factor of 0.45 relative to the ethyl substrate, extending the required dwell time in a subsequent low‑pH hold that accelerates N‑oxide formation. The ethyl ester therefore occupies a kinetic window that allows completion within 4–5 hours at 60–65 °C while keeping the cyano‑hydrolysis side‑product below 0.15%. Additionally, the ethyl ester’s melting point falls within a solvent‑compatible range for slurry washing without agglomeration; the methyl congener melts at 167–169 °C, complicating solvent‑exchange filtration due to plate‑like crystal habit.
When the intermediate is incorporated into pre‑formulation studies as a surrogate for febuxostat in dissolution‑profiling exercises, the material is routinely subjected to high‑shear mixing using a Diosna P1/6 granulator equipped with a 2 L bowl and a chopper speed of 1500 rpm. No amorphisation is observed by XRPD after 10 minutes of dry mixing with microcrystalline cellulose and croscarmellose sodium, provided the jacket temperature remains below 35 °C. Above 40 °C, however, a solid‑state reaction with sodium starch glycolate generates trace ethanol vapour through transesterification, detectable by photoionisation detector readings exceeding 2 ppm at the granulator exhaust. This finding, replicated across 3 manufacturing sites, mandates cold‑water jacket operation during any tribological stress study involving the neat powder.
Bulk stability under ICH Q1A conditions (25 °C/60 % RH, 30 °C/65 % RH, 40 °C/75 % RH) demonstrates no significant change in assay or total impurities over 36 months when the primary container remains sealed. Once opened, equilibrium moisture uptake at 60 % RH reaches 0.08 % w/w within 4 hours; extended exposure beyond 24 hours gives rise to a hydrolytic degradation peak at relative retention time 0.71, identified as the free carboxylic acid. For this reason, any fraction left after dispensing is blanketed with argon and the overpack is re‑sealed with a fresh desiccant sachet containing 20 g of molecular sieve 4A per 500 g of material.
Conversion of the ethyl ester to febuxostat is performed in a jacketed glass‑lined reactor (Pfaudler AE 160 series) with an anchor agitator running at 80–90 rpm. Hydrolysis initiation relies on 1.05 equivalents of aqueous sodium hydroxide (30 % w/w) fed at a constant rate over 30 minutes into a stirred suspension of the ester in 5 volumes of ethanol at 55 °C. The heat of reaction (−112 kJ·mol⁻¹, determined by reaction calorimetry) necessitates a jacket temperature ramp‑down of 3 K·min⁻¹ during the first 20 % of the addition to keep the bulk below 63 °C. Beyond 64 °C, the cyano‑hydrolysis pathway accelerates with an apparent activation energy of 87 kJ·mol⁻¹, producing 3‑carbamoyl‑4‑isobutoxybenzoic acid as a difficult‑to‑purge impurity (solubility in the crystallisation solvent 6.2 mg·mL⁻¹ at 20 °C, compared to 0.3 mg·mL⁻¹ for febuxostat). Process analytical technology (PAT) monitoring via in‑line Raman (785 nm excitation, probe immersed) tracks the disappearance of the ester carbonyl band at 1715 cm⁻¹; the endpoint is called when the univariate intensity falls below 2 % of the starting value, typically at 4.5 hours. Post‑hydrolysis, pH is adjusted from 13.2 to 4.8 with 6 M hydrochloric acid added over 45 minutes, inducing crystallisation of febuxostat with a yield of 92–93 % after vacuum drying at 50 °C (10 mbar).
Differences from alternative intermediates emerge most clearly in this work‑up sequence. The methyl ester, hydrolysing too rapidly, leaves a narrow process window (≤ ±3 °C) to avoid cyano‑hydrolysis, resulting in batch failure rates of 7–10 % at production scale according to data shared by two contract manufacturing organisations. The isopropyl ester requires 7–8 hours for complete conversion, extending the vessel occupancy and reducing annual throughput by an estimated 15 %. The ethyl ester thus reconciles conversion rate with impurity control, and its saponification rejects are removed by a straightforward water‑ethanol azeotropic polish, whereas the methyl ester generates methanol‑containing distillates that must be segregated under local VOC emission directives.
| Property | Ethyl Ester (CAS 160844-75-7) | Methyl Ester | Isopropyl Ester |
|---|---|---|---|
| Melting point (°C) | 142–144 | 167–169 | 121–123 |
| Relative hydrolysis rate (NaOH 1.0 eq, 60 °C) | 1.00 (reference) | 3.2 | 0.45 |
| Cyano‑byproduct at endpoint (%, area) | ≤ 0.15 | 0.4–0.8 | ≤ 0.10 |
| Drying time (vacuum, 50 °C) after hydrolysis cake | 6 h to LOD < 0.5 % | 4 h | 9 h |
| Residual solvent class (ICH Q3C) | Ethanol (Class 3) | Methanol (Class 2, limit 3000 ppm) | Isopropanol (Class 3) |
Regulatory starting material designation under ICH Q11 is often assigned to the cyano‑aldehyde precursor; therefore the ethyl ester sits one step downstream, qualifying as an intermediate where mutagenic impurity risk assessments must address the possibility of alkyl‑sulfonate carryover. A dedicated purge factor study (Teasdale et al., 2013 methodology) confirms a purge factor of 1.2 × 10⁴ for ethyl methanesulfonate in the ethanol‑water recrystallisation, well above the ICH M7 threshold of toxicological concern.
In a minority of synthetic protocols where direct acid‑chloride coupling is attempted with thioacetamide, the ethyl ester is isolated as a hydrobromide salt to improve handling. That salt form (CAS 161799-80-8) is deliquescent above 55 % RH and must not be stored alongside the free base; dedicated segregated storage was instituted after a December 2021 incident at a Polish API plant in which cross‑contaminated HBr drums caused a 12 % assay drop in the free ester inventory within three weeks. No such incompatibility affects the free ethyl ester, which remains chemically inert toward standard excipient mixtures used in tablet core feasibility batches, including mannitol, pregelatinised starch, and hydroxypropyl cellulose of substitution type LH‑11.
