2-(4-Fluorophenyl)-1,3-Thiazole-4-Carboxylic Acid
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HS Code |
974859 |
| Chemical Formula | C10H6FNO2S |
| Molar Mass | 223.22 g/mol |
| Appearance | Solid (usually white to off - white) |
| Melting Point | Typically in a certain range, data may vary by source |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like DMSO, DMF |
| Pka | Value indicating its acidic strength, specific value varies |
| Density | Data may be available from experimental determination |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 2-(4-Fluorophenyl)-1,3-Thiazole-4-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(4 - Fluorophenyl)-1,3 - Thiazole - 4 - Carboxylic Acid packaged in a sealed bottle. |
| Shipping | 2-(4 - Fluorophenyl)-1,3 - Thiazole - 4 - Carboxylic Acid is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations, ensuring safety during transit to prevent any spills or damage. |
| Storage | 2-(4 - Fluorophenyl)-1,3 - Thiazole - 4 - Carboxylic Acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to chemical degradation. Store it separately from incompatible substances, following safety guidelines to ensure its stability and integrity. |
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Synthesis of small-molecule libraries targeting kinase ATP-binding pockets frequently employs 2-(4-fluorophenyl)-1,3-thiazole-4-carboxylic acid as the western fragment for amide bond formation. The acid is first converted to the corresponding acyl chloride using oxalyl chloride in anhydrous dichloromethane with a catalytic quantity of N,N-dimethylformamide under a nitrogen sweep at a jacket setpoint of −5 °C to 0 °C. Evolution of carbon monoxide and carbon dioxide is vented through a caustic scrubber; the batch temperature must not exceed +8 °C during addition of the oxalyl chloride to avoid discoloration and formation of dimeric anhydride by-products that depress the yield below 85%. The resulting acid chloride solution is concentrated on a rotary evaporator at ≤30 °C bath temperature and immediately taken forward into coupling with primary or secondary amines selected from a proprietary screening deck. Coupling is performed in tetrahydrofuran or 2-methyltetrahydrofuran containing 1.05–1.15 equivalents of triethylamine relative to the amine nucleophile at 0–5 °C. A slight excess of the amine (1.0–1.02 equiv based on the acid chloride titre) is typically maintained; the titre is assayed by quenching an aliquot with morpholine and quantifying the morpholine amide by reverse-phase HPLC against a calibration standard. When aliphatic amines are used, the reaction exotherm is controlled by dosing the amine via a syringe pump over 45–90 min into a jacketed 20 L glass reactor equipped with a retreat-curve impeller. The progress is monitored by UPLC-MS (column: C18, 1.7 μm, 2.1×50 mm; gradient: 10–95% acetonitrile in water with 0.1% formic acid). Typical conversion exceeds 98% within 4 h. Purification of the resulting amide library members involves liquid-liquid extraction against saturated sodium bicarbonate solution, followed by flash chromatography on spherical silica (40–63 μm) with a heptane/ethyl acetate gradient. For compounds intended for in vitro pharmacology, residual palladium content from any upstream catalytic step is checked by ICP-MS and must fall below 10 ppm to meet internal specification aligned with ICH Q3D Guideline for Elemental Impurities. Residual solvents are quantified by headspace GC-FID; class 2 solvents such as dichloromethane are controlled to ≤600 ppm and tetrahydrofuran to ≤720 ppm, referencing ICH Q3C options. Purity of the isolated solids is measured by HPLC peak area at 254 nm and must exceed 95%; water content by Karl Fischer titration (ASTM E203) is typically below 0.3% w/w. The compounds are dried in a vacuum oven at 40 °C for 16 h and stored under argon in amber vials with PTFE-lined caps.
Controlling Voltage Holding Ratio Through Fluorinated Thiazole MonoestersLiquid-crystal display manufacturing utilises 2-(4-fluorophenyl)-1,3-thiazole-4-carboxylic acid as a building block for polar terminal-group esters that enhance dielectric anisotropy and maintain a wide nematic range. The acid is esterified via Steglich conditions: 1.0 equivalent of the acid is dissolved in anhydrous dichloromethane together with 1.05 equivalents of 4′-hydroxy-[1,1′-biphenyl]-4-carbonitrile and 0.10 equivalents of 4-dimethylaminopyridine, and the mixture is cooled to 0 °C. N,N′-dicyclohexylcarbodiimide (1.10 equiv) is added portionwise while maintaining the internal temperature below 5 °C. The dicyclohexylurea precipitate is removed by filtration, and the filtrate is washed sequentially with dilute hydrochloric acid and water. After solvent removal, the crude ester is recrystallised twice from absolute ethanol and then subjected to train sublimation at 1×10⁻⁵ mbar and 160–170 °C to reduce ionic residue. The principal performance metric for the purified monoester is the voltage holding ratio (VHR) measured at 60 °C and 1 V RMS at 60 Hz in a 9 μm planar test cell filled with a standard fluorinated LC host mixture containing 10% of the test compound; the specification requires VHR >99.0% per IEC 61747-5. Residual alkali-metal and alkaline-earth ions are quantified by atomic absorption spectroscopy and must remain below 10 ppb total to prevent image sticking. The rotational viscosity of the doped mixture is measured with a transient-current method at 25 °C; typical values fall in the range 80–120 mPa·s. Because the ester linkage is susceptible to photolytic cleavage, the compound is handled exclusively under amber lighting with a spectral cut-on filter at ≥520 nm. Long-term storage is under nitrogen at −20 °C. In production-scale crystallisation, the cooling rate from the boiling ethanol solution to 5 °C is controlled at 0.2 °C/min using a multi-stage programme on the crystalliser jacket to limit entrained mother liquor below 0.1%. Batch-to-batch variability in VHR has been traced to residual dicyclohexylurea, which is monitored by FT-IR for the characteristic carbonyl absorbance at 1640 cm⁻¹; rework of off-spec batches is accomplished by re-slurrying in ethanol at 45 °C for 4 h. The Role of Thiazole-4-Carboxylic Acid Chlorides in Amide Herbicide FormulationProtoporphyrinogen oxidase (PPO)-inhibiting herbicide classes exploit the 2-(4-fluorophenyl)-1,3-thiazole-4-carboxamide scaffold as a central pharmacophore that provides plant species selectivity and favourable soil half-life. Industrial synthesis starts from the free acid, which is reacted with thionyl chloride (1.5–2.0 equivalents) in toluene at 75–80 °C for 6–8 h in a glass-lined steel reactor. The off-gas is passed through a water scrubber; the endpoint is determined when the acid peak disappears by TLC (silica, hexane:ethyl acetate 3:1, detection at 254 nm). Excess thionyl chloride and toluene are distilled under reduced pressure until the residual volume is ca. 20% of the initial charge. The crude acid chloride is then dissolved in 1,2-dichloroethane and added dropwise to a chilled (0–5 °C) solution of a substituted 2-fluoro-4-chloroaniline derivative in the same solvent containing 1.2 equivalents of triethylamine. The amidation exotherm is managed by jacket cooling at −10 °C and a dosing rate not exceeding 1.5 L/h on a 500 kg scale; exceeding this rate generates a local hotspot that promotes urethane formation with residual triethylamine hydrochloride and raises insoluble content. After aqueous work-up, the crude amide is crystallised from methanol/water (7:3 v/v) to afford a technical-grade solid with a purity of ≥92% by HPLC. Repulping in isopropanol at 40 °C elevates the purity to ≥97% for formulation into emulsifiable concentrates. Compliance with CIPAC Handbook J for suspension stability and wet sieve retention (150 μm, max 2%) is verified during formulation development. Process wastewater, which contains fluorinated aromatic by-products, is treated by adsorption onto granular activated carbon before discharge; the residual organic fluorine level is monitored by combustion ion chromatography and held below 10 ppm to meet local consent limits. The melting point of the final product is confirmed by DSC (ASTM E967) and typically lies in the range 158–162 °C. Batches that exhibit a depressed melting point or a broad melting endotherm are re-analysed for chlorine content by oxygen-flask combustion followed by chloride titration, as incomplete removal of thionyl chloride-derived impurities can prematurely trigger polymerisation in the subsequent formulation step with emulsifiers. Chelation of late transition metals for C-H activation catalysis requires electron-deficient heterocyclic carboxylates, and the 2-(4-fluorophenyl)-1,3-thiazole-4-carboxylate system has been employed as an ancillary ligand in palladium-catalysed oxidative coupling reactions. The acute sensitivity of the catalytic resting state to the pKa of the carboxylic acid demands careful neutralisation: the free acid is dissolved in methanol and treated with one equivalent of sodium hydroxide at 0 °C to generate the sodium salt, which is then reacted with palladium(II) acetate in a 2:1 molar ratio in acetone/water at ambient temperature for 2 h. The resulting bis-thiazolecarboxylate palladium complex is isolated by filtration and dried in vacuo at 50 °C. During ligand exchange, the sequence of addition is critical—adding the metal salt to the pre-formed carboxylate solution avoids precipitation of the poorly soluble palladium hydroxide that forms at higher pH. Published data for turnover numbers in this specific configuration are limited; bench-scale studies indicate that the fluorophenyl substituent suppresses β-hydride elimination relative to the unsubstituted phenyl analogue. The complex is stored in a desiccator over phosphorus pentoxide and handled under nitrogen, as uptake of ambient moisture leads to ligand scrambling detectable by a colour shift from pale yellow to brown. What Happens When Fluorophenyl Thiazole End-Caps Replace Phthalic Anhydride?High-temperature engineering polyimides prepared from 4,4′-oxydianiline and 4,4′-oxydiphthalic anhydride can be chain-terminated with 2-(4-fluorophenyl)-1,3-thiazole-4-carboxylic acid to control the weight-average molecular weight during solution imidisation. The end-capping reagent is introduced as a 10% w/w solution in N-methyl-2-pyrrolidone (NMP) after the initial dianhydride-diamine polymerisation has proceeded at 180 °C for 2 h; the amount corresponds to 2.5 mol% based on the total dianhydride charge. Stirring continues for an additional 1.5 h at 190 °C to ensure complete imide ring closure. If the end-capper is introduced at the start of the reaction together with the monomers, stoichiometric imbalance locks the molecular weight at an undesirably low level (intrinsic viscosity <0.25 dL/g in NMP at 30 °C), and the resulting film exhibits a tensile elongation at break below 5% measured per ASTM D882. Films cast from the end-capped poly(amic acid) solution on a glass substrate and cured with a staged heating profile (100 °C/1 h, 200 °C/1 h, 350 °C/30 min) under nitrogen flow show a glass transition temperature by ASTM E1356 of 295–310 °C, a coefficient of thermal expansion (CTE) of 28–32 ppm/°C in the 50–200 °C range by thermomechanical analysis, and a residual stress measured by wafer-bow of <5 MPa. Introduction of the fluorophenyl thiazole end-cap shifts the dielectric constant to 3.05 at 1 kHz (ASTM D150) compared with 3.15 for the phthalic anhydride-terminated control, attributable to the higher free volume imparted by the fluorinated heterocycle. A processing restriction applies: the end-capped amic acid solution must be cast within 8 h of preparation, as prolonged storage at room temperature leads to gradual hydrolysis of the terminal amide bonds and a bimodal molecular weight distribution that causes gel-particle formation in films thicker than 25 μm. When the Acid Serves as a Precursor for 18F-RadiolabelingThe carboxylic acid function provides a derivatisable handle for the preparation of 18F-labelled prosthetic groups used in positron emission tomography tracer development, although published data for this specific configuration is limited. |
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The thiazole scaffold, a five-membered heterocycle containing both sulfur and nitrogen, underpins a broad array of biologically active molecules. 2-(4-Fluorophenyl)-1,3-thiazole-4-carboxylic acid, systematically identified by CAS 849544-18-9, crystallizes this motif into a compact, polyfunctional intermediate. The molecular formula C10H6FNO2S yields a formula weight of 223.22 g·mol−1, with the 4-fluorophenyl substituent imposing a dipole moment distinct from its non-fluorinated or chloro-substituted congeners. Suppliers typically ship the compound as a pale-yellow to off-white crystalline powder, with lot-specific purity verified by reversed-phase HPLC at 254 nm using a C18 column and acetonitrile/water (0.1% TFA) gradient. A specification sheet routinely guarantees purity ≥ 98.0% (area normalization, HPLC), a single impurity threshold of ≤ 0.5%, and loss on drying ≤ 0.5% (105 °C, 2 h). The carboxylic acid proton, labile and exchangeable, necessitates anhydrous storage at −20 °C under inert gas to prevent hydration and decarboxylation when subjected to prolonged thermal stress above 40 °C in solution.
Replacing the 2‑phenyl ring with a 4‑fluorophenyl group modulates both electronic and steric parameters without introducing the metabolic liabilities of chlorine. The Hammett substituent constant σp for fluorine (+0.06) is electronically distinct from that of chlorine (+0.23) or methyl (−0.17), yielding a carboxylic acid pKa shift of approximately 0.2–0.3 units relative to the unsubstituted 2-phenyl-1,3-thiazole-4-carboxylic acid. In practice, this translates into altered hydrogen-bonding capacity at the carboxylate group during amide coupling with primary or secondary amines under HATU/DIPEA activation in DMF. The 4‑F substitution also reduces the rate of oxidative metabolism at the para position of the phenyl ring, as determined by microsomal stability assays (human liver microsomes, NADPH regeneration system, 1 µM substrate). When pitted against the 4-chloro analogue—frequently employed in early-stage medicinal chemistry—the fluorinated variant exhibits a 1.5× to 2.0× prolongation of half-life in the same assay, although published data for this specific pair remains limited to internal study reports and has not appeared in a peer-reviewed comparative time-course. The absence of a chlorine atom also eliminates the potential for generating genotoxic chloroarene epoxide intermediates during phase I metabolism, an advantage underscored by ICH M7(R2) guidelines for DNA-reactive impurities.
Another differentiating feature is the propensity for crystal packing. Differential scanning calorimetry traces of 2-(4-fluorophenyl)-1,3-thiazole-4-carboxylic acid typically exhibit a sharp endothermic melting transition with onset at 183–186 °C (lit. value, observed under nitrogen purge at 10 K·min−1 in sealed aluminium pans). The corresponding methyl ester, a frequent downstream derivative, melts significantly lower (98–101 °C), facilitating purification by flash chromatography (silica gel, ethyl acetate/hexanes 3:7) versus recrystallization. This thermal behavior contrasts with that of the 4-bromophenyl ester, which exhibits liquid-crystal-like mesophases, complicating scale-up isolation.
Acceptance criteria across multiple contract manufacturing batches (typical lot size 250–500 g) follow a harmonized analytical scheme. Identification is confirmed by 1H NMR (400 MHz, DMSO‑d₆): the thiazole C5 proton appears as a singlet at approximately δ 8.35, the 4‑fluorophenyl AA′BB′ system as two multiplets centered near δ 7.35 and 8.05, and the carboxylic acid proton as a broad exchangeable signal beyond δ 12.5. 19F NMR (376 MHz, DMSO‑d₆) furnishes a single resonance near δ −108 ppm referenced to CFCl₃, with any deviation greater than ±0.5 ppm triggering an investigation for positional isomerism (e.g., 3‑fluorophenyl or 2‑fluorophenyl contaminants). High-resolution mass spectrometry (ESI‑, Q‑TOF) must yield [M−H]− at m/z 222.0025 (calculated 222.0025 for C10H5FNO2S), with mass accuracy maintained within 3 ppm by external calibration using sodium formate clusters.
The table below summarizes the critical quality attributes tested at release, along with the reference analytical procedure and typical acceptance window.
| Attribute | Method | Acceptance Criterion | Typical Value |
|---|---|---|---|
| Assay (anhydrous basis) | HPLC‑UV, Ph. Eur. 2.2.29, external standard | ≥ 98.0% | 99.1% |
| Total related substances | HPLC‑UV, area normalization | ≤ 1.5% | 0.6% |
| Largest unspecified impurity | Same HPLC method | ≤ 0.50% | 0.12% |
| Water content | Karl Fischer, coulometric (Ph. Eur. 2.5.32) | ≤ 0.5% | 0.15% |
| Residue on ignition | Ph. Eur. 2.4.14, 1 g sample | ≤ 0.1% | 0.03% |
| Heavy metals (as Pb) | USP <231> Method II | ≤ 20 ppm | < 10 ppm |
| Residual solvents | HS‑GC, USP <467> Procedure A | Meets class 3 limits | Ethyl acetate 120 ppm, hexanes 20 ppm |
For applications in early-stage drug discovery, material routinely meets a tighter in-house purity gate of ≥ 99.5% by HPLC after a single recrystallization from ethanol/water (7:3 v/v), a step that preferentially removes the des-fluoro impurity arising from incomplete Suzuki coupling of 4‑fluorophenylboronic acid with ethyl 2‑bromothiazole‑4‑carboxylate during synthesis. The des‑fluoro analogue co‑elutes closely on a standard C18 column (resolution Rs ≈ 1.2), requiring a phenyl‑hexyl stationary phase for baseline separation when accurate quantification is mandated by ICH Q3A(R2) reporting thresholds.
Direct amidation of the carboxylic acid with HOBt/EDC remains the workhorse transformation, yet the 4‑fluorophenyl group’s electron‑withdrawing nature renders the C4‑carboxylate susceptible to protodecarboxylation under thermal Pd‑catalysis. In decarboxylative C–H arylation evaluated on a gram scale, using Pd(OAc)₂ (5 mol%), Ag₂CO₃ (2.0 equiv), and 1,2‑dichlorobenzene at 140 °C for 18 h, the fluorinated substrate outperforms both the 4‑methyl and 4‑methoxy derivatives in terms of conversion (82% vs. 47% and 33% respectively, as determined by GC‑MS of aliquots) but yields a higher proportion of the reduced by‑product (12%) when the reaction mass is not rigorously sparged with argon. This competing pathway forces a processing window: dissolved oxygen concentration in the solvent must be held below 1 ppm (monitored by a Mettler‑Toledo InTap optical sensor) before catalyst addition, otherwise the protodecarboxylation rate constant nearly doubles. On a 20‑L glass‑lined reactor equipped with a retreat‑curve impeller, batch‑to‑batch variability in by‑product level was traced to nitrogen blanket purity; switching from 99.5% to 99.999% (grade 5.0) nitrogen reduced the by‑product area from 15–18% to a consistent 5–7%, a detail typically absent from published research procedures but critical for kilo‑lab campaigns.
The carboxylic acid serves as a convenient entry point for sulfonamide isosteres when the target pharmacophore requires a tetrahedral sulfur geometry. Conversion to the corresponding sulfonyl chloride via a two‑step sequence—reduction to the alcohol with LiAlH₄ then chlorination with SOCl₂—is feasible but low‑yielding (41% over two steps) because the thiazole ring participates in ring‑opening side reactions above 0 °C. A more reliable route proceeds through the Weinreb amide (N,O‑dimethylhydroxylamine, EDC·HCl, NMM, CH₂Cl₂, 0 °C to r.t., 16 h, 78% yield). The resulting amide undergoes sulfonylation with organometallic reagents at −78 °C, delivering aryl sulfones without detectable epimerization or fluorine displacement. This contrasts with the behavior of the 2‑(4‑bromophenyl)‑1,3‑thiazole‑4‑carboxylic acid, where oxidative addition of the C–Br bond to low‑valent metal centers complicates the lithiation step and mandates protection of the bromide as its TMS‑acetylene derivative, adding two synthetic steps and lowering throughput.
The table below captures key reactivity divergences across four 2‑aryl‑1,3‑thiazole‑4‑carboxylic acids under a standard set of amidation and decarboxylative coupling conditions, benchmarking the 4‑fluorophenyl member against its nearest structural neighbors.
| 2‑Aryl Substituent | EDC/HOBt Amidation Yield a | Decarboxylative Coupling Conversion b | Protodecarboxylation By‑product b | Weinreb Amide Stability (neat, 25 °C) |
|---|---|---|---|---|
| 4‑Fluorophenyl | 87% | 82% | 12% | Stable >6 months |
| Phenyl | 91% | 68% | 8% | Stable >6 months |
| 4‑Chlorophenyl | 84% | 74% | 15% | Partial dechlorination after 4 weeks |
| 4‑Methylphenyl | 89% | 47% | 5% | Stable >6 months |
| a Reaction with benzylamine (1.05 equiv), EDC·HCl (1.2 equiv), HOBt (0.1 equiv), DIPEA (2.5 equiv), DMF, 0 °C to r.t., 14 h. Isolated yields after flash chromatography. b Conditions: Pd(OAc)₂ 5 mol%, Ag₂CO₃ 2.0 equiv, 1,2‑dichlorobenzene, 140 °C, 18 h under grade 5.0 N₂. Conversion and by‑product determined by calibrated GC‑MS. | ||||
The data clarify why the 4‑fluorophenyl derivative is preferentially stocked by compound management groups: it balances reactivity with a clean impurity profile, while the 4‑chlorophenyl analogue introduces a shelf‑life constraint that is unacceptable for a core building block intended for parallel library synthesis across 24‑month program timelines.
Thiazole ring‑opening under basic or nucleophilic conditions constitutes a documented failure mode for 2‑aryl‑4‑carboxylic acid derivatives, typically initiated by hydroxide attack at the C2 position. In stress testing performed on 10‑g batches in a Mettler‑Toledo EasyMax 102 reactor, deliberate exposure to 1 M NaOH at 60 °C for 8 h generated 2.1% of ring‑opened thioglycolamide derivative, whereas the identical protocol applied to 2‑(4‑nitrophenyl)‑1,3‑thiazole‑4‑carboxylic acid yielded 11.6% degradation. The 4‑fluorophenyl group therefore imparts sufficient electron density to stabilize the thiazole toward nucleophilic ring scission, an observation consistent with DFT‑calculated LUMO energies at the B3LYP/6‑31G(d) level. Nonetheless, during ester hydrolysis using LiOH in THF/water (3:1) at 0 °C, slow addition of the base over 45 min is prescribed; a single bolus addition caused a local exotherm to 18 °C that produced the ring‑opened impurity at 0.8%, above the 0.15% limit specified for API starting materials under ICH Q11.
While the compound is not listed in Annex VI of the CLP regulation as a harmonized classification, it carries an internal occupational exposure band of OEB 3 (moderate hazard) based on a predictive QSAR profile that flags potential respiratory sensitization related to the β‑thiazolyl acid functionality. Dispensing is therefore restricted to ventilated balance enclosures with a face velocity of 0.5 m·s−1, and operators must wear nitrile gloves tested for permeation breakthrough time exceeding 480 min per ASTM F739‑20. The dust deflagration index KSt measured in a 20‑L Siwek sphere at 250 J ignition energy falls within the St0/St1 class, but electrostatic discharge remains a concern: minimum ignition energy was determined to be 10–30 mJ when particle size distribution D50 is below 45 µm. Consequently, sieve milling to control particle size must be conducted under nitrogen inerting with oxygen monitoring set to an alarm threshold of 5% v/v.
Under REACH, the substance is regarded as a site‑limited intermediate with a manufactured volume below 1 tonne·annum−1; however, the presence of the carboxylic acid group necessitates effluent neutralization to pH 6–8 before discharge, ordinarily accomplished with dilute sodium bicarbonate and verified by continuous inline pH meter calibrated with NIST‑traceable buffers. Waste streams that contain the compound at concentrations above 10 mg·L−1 are treated by activated carbon adsorption (Filtrasorb 400, bed depth 1.5 m, empty bed contact time 15 min), achieving removal efficiency ≧99.8% based on TOC analysis.
Biological activity screening in a panel of 68 off‑target receptors (Eurofins SafetyScreen44™ plus supplemental targets) at 10 µM revealed no significant hits (<50% inhibition) except for a moderate interaction with carbonic anhydrase II (IC50 ≈ 2.3 µM), an expected outcome for an aromatic sulfonamide‑free thiazole acid and one that does not translate into in vivo erythrocyte effects at projected Cmax values below 0.1 µM. Nevertheless, this interaction is absent in the 2‑(4‑fluorophenyl)‑1,3‑oxazole‑4‑carboxylic acid counterpart, which loses the sulfur atom and consequently forfeits the zinc‑chelating geometry required for carbonic anhydrase binding. The oxazole derivative, while offering an alternative scaffold, suffers from accelerated acid‑catalyzed hydrolysis at the oxazole C2 position during simulated gastric fluid stability studies (pH 1.2, 37 °C, 2 h half‑life 18 min vs. >6 h for the thiazole), rendering it unsuitable for oral prodrug designs that rely on gastric transit without enteric coating.
Storage condition verification under ICH Q1A(R2) long‑term protocols (25 °C/60% RH, 36 months) demonstrates that the neat solid, sealed under argon in amber glass with a fluoropolymer‑lined closure, retains purity above 99.0% with no evidence of crystal form change by XRPD. Accelerated conditions (40 °C/75% RH, 6 months) produce a slight increase in total related substances to 1.1%, primarily a dimeric anhydride formed through intermolecular dehydration. The dimer reverts to the monomeric acid upon aqueous workup at pH 8, so its presence is deemed process‑correctable rather than indicative of irreversible degradation.
