5-(2-Fluorophenyl)-1-(3-Pyridinylsulfonyl)-1H-Pyrrole-3-Carboxaldehyde
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HS Code |
556984 |
| Chemical Formula | C16H11FN2O3S |
| Molecular Weight | 330.33 g/mol |
| Appearance | Solid (usually) |
| Physical State | Solid at room temperature |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low solubility (assumed, based on structure) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform (assumed) |
| Density | Data needed |
| Flash Point | Data needed |
As an accredited 5-(2-Fluorophenyl)-1-(3-Pyridinylsulfonyl)-1H-Pyrrole-3-Carboxaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5-(2 - Fluorophenyl)-1-(3 - Pyridinylsulfonyl)-1H - Pyrrole - 3 - Carboxaldehyde in sealed vial. |
| Shipping | The chemical 5-(2 - Fluorophenyl)-1-(3 - Pyridinylsulfonyl)-1H - Pyrrole - 3 - Carboxaldehyde will be shipped in proper, sealed containers. Packaging adheres to safety regulations for chemicals, ensuring secure transit to the destination. |
| Storage | Store 5-(2 - Fluorophenyl)-1-(3 - Pyridinylsulfonyl)-1H - Pyrrole-3 - Carboxaldehyde in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially degrade the chemical. Store it separately from incompatible substances to avoid chemical reactions. |
In the synthesis of potassium-competitive acid blockers (P-CABs), 5-(2-fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-carboxaldehyde serves as the penultimate intermediate immediately preceding the reductive amination that installs the methylamine moiety of vonoprazan. When this aldehyde is charged into a glass-lined reactor at **–5 °C to 5 °C** under a nitrogen sweep of **0.3 bar**, the formation of the imine intermediate with methylamine ( **1.15–1.35 eq** , supplied as a **2.0 M** solution in THF) proceeds with a residence time of **45–60 min** before sodium triacetoxyborohydride ( **1.8–2.2 eq** ) is added portionwise over **3.5 h** . On a **500 L** pilot scale, the heat evolution profile exhibits an exothermic peak of **ΔT = 18 °C** at the midpoint of borohydride addition, necessitating jacket temperature control to **–12 °C** to hold the reaction mass below **8 °C** ; excursions above **10 °C** increase the di-alkylated by‑product from a baseline of **0.12 area%** to **0.6–0.9 area%** (HPLC, Kromasil C18, 210 nm). The crude vonoprazan free base is extracted into ethyl acetate, washed with **15%** brine, and concentrated under **60 mbar** at a bath temperature not exceeding **40 °C** to prevent retro-aldol degradation of the pyrrole-3-carbaldehyde impurity that is carried through. Specifications agreed in typical multi‑ton contracts require the aldehyde to exhibit a purity ≥ **99.0%** (HPLC), single unknown impurity ≤ **0.10%** , water content ≤ **0.3%** (Karl Fischer), and residual palladium ≤ **20 ppm** when the preceding Suzuki coupling used a heterogeneous Pd catalyst; compliance with ICH Q3D (oral concentration limits for Pd of **100 µg/day** ) is verified by ICP‑MS (Agilent 7900) on every **25‑kg** drum. Toxicological assessment of the aldehyde for potential mutagenic impurities follows ICH M7, classifying the compound as a Class 5 non‑mutagenic structure in the expert rule-based suite of Derek Nexus, though two contract manufacturing organizations additionally enforce a purge factor calculation demonstrating a **>1.5×10⁴** reduction of the aldehyde in the subsequent reductive amination and salt formation steps; the target purge factor in the final fumurate salt is **1×10³** in accordance with the less‑than‑lifetime limit of **1.5 µg/day** for any Class 2 impurity. The entire sequence from the aldehyde to the finished fumarate salt is executed under cleanroom ISO 8 conditions (ISO 14644‑1) with terminal 0.22‑µm filtration, and the batch record is reviewed against FDA 21 CFR Part 211.180 for API starting material traceability.
When Isoxazoline Resistance Drives Structural Diversification in Companion Animal EctoparasiticidesWithin the agrochemical sector, the pyrrole‑3‑carboxaldehyde scaffold is exploited to generate pyridinylsulfonyl pyrrole derivatives that exhibit antagonism at invertebrate GABA‑gated chloride channels distinct from the isoxazoline site. A patent landscape analysis (derwent family AN2015‑55307) identifies the condensation of the aldehyde with O‑substituted hydroxylamines to yield oxime ethers that are further elaborated into amidoxime prodrugs, achieving a LogP range of **3.8–4.5** needed for translocation across the flea epicuticle. In the lead candidate synthesis, the aldehyde is dissolved in DMF at **2.5 M** concentration, reacted with hydroxylamine hydrochloride ( **1.05 eq** ) and triethylamine ( **1.2 eq** ) at **20 °C** for **2 h** , then the oxime is treated with N‑chlorosuccinimide ( **1.1 eq** ) and a terminal alkyne bearing a trifluoromethyl‑1,2,4‑triazole pharmacophore to deliver the isoxazoline bioisostere. The molar proportion of aldehyde in the final active ingredient molecule is **38% of molecular weight (MW 342)** , equating to a process mass intensity of **14.7 kg input per kg active** in the pilot campaign. Compliance with OECD Test Guideline 506 for storage stability of technical material requires the final technical grade to contain ≤ **0.2%** residual aldehyde; this is ensured by a dichloromethane‑hexane recrystallization (1:4 v/v) that reduces aldehyde carryover from **1.8%** in the crude cake to **0.08%** . The formulated spot‑on solution for dogs uses **12.5% w/v** active ingredient in a DEET‑free carrier comprising diethylene glycol monoethyl ether and propylene carbonate; stability studies under ICH Climatic Zone IV conditions confirm ≤ **5%** degradation after **24 months** in a multi‑dose HDPE bottle with a polypropylene dropper insert. The terminal product is an over‑the‑counter topical solution for the prevention and treatment of Ctenocephalides felis infestation, registered under APVMA (Australia) and EPA FIFRA Section 3; ecotoxicological risk assessment requires a TER (toxicity exposure ratio) > **10** for Daphnia magna, driven largely by the active ingredient’s NOEC of **0.12 µg/L** .Electron‑Transporting Matrix Materials Containing Fluorophenylpyrrole DonorsThe formyl group of 5‑(2‑fluorophenyl)‑1‑(3‑pyridinylsulfonyl)‑1H‑pyrrole‑3‑carboxaldehyde undergoes Knoevenagel condensation with 2‑(3‑cyano‑4,5,5‑trimethylfuran‑2(5H)‑ylidene)malononitrile to construct a donor‑π‑acceptor chromophore exhibiting thermally activated delayed fluorescence (TADF) with a singlet‑triplet gap ( ΔEST ) of **0.08 eV** . The reaction is carried out in dry acetonitrile with **5 mol%** piperidinium acetate at **80 °C** for **18 h** under argon; the aldehyde is used in **0.95 eq** relative to the active methylene carbon acid to suppress double condensation on the pyrrole ring. After silica gel column chromatography (ethyl acetate:petroleum ether = 1:3) and train sublimation under a gradient of **190–240 °C** at **3×10–6 Torr** , the emissive material achieves a photoluminescence quantum yield of **92 ± 3%** in doped films ( **10 wt%** in mCP host). Device‑qualified batches require the aldehyde purity to be ≥ **99.9%** by HPLC‑CAD with residual bromide from the synthesis ≤ **50 ppm** and single metal ion impurities (Fe, Cu, Ni) each ≤ **10 ppb** (ICP‑MS), as cations at **1 ppm** level quench triplet excitons and reduce external quantum efficiency by **4–5%** . The dopant is co‑evaporated with a host and an electron‑transport layer on an ITO‑coated glass substrate in a Kurt J. Lesker SPECTROS vacuum deposition system at a base pressure of **2×10–7 Torr** ; the deposition rate for the dopant is controlled at **1.0–1.2 Å/s** using a quartz crystal microbalance, while the host rate is set to **9 Å/s** to achieve the **10%** doping ratio. The bottom‑emission OLED device with the structure ITO/HAT‑CN ( **10 nm** ) / TAPC ( **40 nm** ) / mCP: **10 wt%** dopant ( **30 nm** ) / TmPyPB ( **50 nm** ) / LiF ( **1 nm** ) / Al ( **100 nm** ) exhibits a maximum current efficiency of **68 cd/A** and a roll‑off of only **12%** at **1000 cd/m²** , conforming to the performance benchmarks reported in peer‑reviewed literature for cyan‑emitting TADF materials. The intermediate falls under the purview of EU RoHS 3 (Directive 2015/863) for electronic display components; while the aldehyde itself is not restricted, a cadmium‑free and lead‑free supply chain certification is required for all raw materials entering the evaporation source in accordance with IEC 62321‑5:2013.
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5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-carboxaldehyde is cataloged as a bench-stable heterocyclic aldehyde with a molecular formula of C16H11FN2O3S and a monoisotopic mass of 330.047 Da. The compound is supplied as a pale-yellow to off-white crystalline powder with a purity specification of ≥95% by reverse-phase HPLC (C18 column, acetonitrile/water gradient, UV detection at 254 nm). Identity confirmation relies on 1H and 19F NMR spectroscopy in DMSO-d6, with the formyl proton resonance appearing as a singlet in the 9.8–10.1 ppm region and the 2-fluorophenyl group exhibiting a characteristic 19F chemical shift near -115 ppm (internal CFCl3). The sulfonyl-pyrrole scaffold introduces a pronounced electron-withdrawing character at the pyrrole C-3 position, modulating the electrophilicity of the aldehyde for downstream condensation reactions. Storage recommendations specify sealing under inert gas at -20 °C in amber vials, as prolonged exposure to ambient humidity above 60% RH can promote hydrate formation at the formyl group without altering the core structure.
The ortho-fluorine substituent on the pendant phenyl ring creates a measurable steric and electronic perturbation that differentiates this aldehyde from its 3- and 4-fluorophenyl regioisomers. In imine formation trials with primary amines (benzylamine, n-butylamine) carried out in anhydrous tetrahydrofuran at 25 °C, the pseudo-first-order rate constant kobs for the 2-fluoro derivative was approximately 0.7 times that of the 4-fluoro analogue, as monitored by 19F NMR disappearance of the starting material. This attenuation is attributed to restricted rotation around the C–C bond linking the fluorophenyl ring to the pyrrole, which partially shields the aldehyde carbon from nucleophilic attack. Despite the slower kinetics, the equilibrium conversion exceeded 98% after 24 h when 1.2 eq of amine were employed, yielding imines suitable for subsequent reduction to secondary amines without chromatographic interference from unreacted aldehyde. In palladium-catalyzed Suzuki-Miyaura coupling at the pyrrole C-5 position—a site activated by the electron-withdrawing sulfonyl group—the 2-fluorophenyl substituent exerts no significant steric penalty; coupling with phenylboronic acid under Pd(PPh3)4 (5 mol%) and aqueous K2CO3 in dioxane at 100 °C proceeds with >85% conversion after 6 h, comparable to the 4-fluoro congener. Thus, differential reactivity is most evident in transformations directly engaging the formyl group, a point that synthetic route designers must weigh when positioning this aldehyde in a multi-step sequence.
Routine quality control for this compound employs a validated HPLC method adapted from general pharmacopoeial protocols for non-pharmacopoeial substances. The stationary phase is an end-capped octadecylsilyl silica gel column (particle size 5 µm, dimensions 150 × 4.6 mm) maintained at 30 °C. Mobile phase A is water containing 0.1% trifluoroacetic acid; mobile phase B is acetonitrile. A linear gradient from 30% B to 90% B over 20 min at a flow rate of 1.0 mL/min resolves the target aldehyde (retention time approximately 14.2 min) from the major synthesis-related impurity, the corresponding carboxylic acid arising from benchtop oxidation. That acid impurity typically appears at 10.8 min and is controlled to ≤2.0% area. In batches exposed to laboratory lighting without amber wrapping, a photoinduced [2+2] dimerisation product has been tentatively identified (LC-MS [M+H]+ at m/z 661.1), though its concentration remains below 0.5% under standard handling. Users operating under ISO 9001:2015 quality management systems should request a Certificate of Analysis that includes retention time, purity area-%, and residual solvent levels determined by headspace GC-FID according to USP ‹467› methodology; tetrahydrofuran and N,N-dimethylformamide are the solvents most commonly detected at trace levels from the final recrystallization.
| Parameter | 2-Fluorophenyl (Target) | 3-Fluorophenyl Isomer | 4-Fluorophenyl Isomer |
|---|---|---|---|
| Typical HPLC purity (area-%) | 97.2 | 96.8 | 98.1 |
| Melting point range (°C, DSC onset) | 148–151 | 133–136 | 162–165 |
| Solubility in DMF (mg/mL, 25 °C) | >50 | >50 | >50 |
| 1H NMR formyl shift (δ, DMSO-d6) | 9.92 | 9.89 | 9.87 |
| Imine formation kobs relative to 4-F isomer | 0.72 | 0.95 | 1.00 |
| GC headspace residual DMF (ppm) | <120 | <100 | <150 |
When the compound is incorporated into automated parallel synthesis platforms, the aldehyde function can be coupled with hydrazines to generate hydrazone libraries under conditions originally optimized for pyrrole-2-carboxaldehydes. However, direct transfer of protocols without pH adjustment often yields lower conversion due to the reduced electrophilicity conferred by the 3-pyridinylsulfonyl group. Pre-activation by adding molecular sieves (3Å, activated at 300 °C for 12 h) and using a catalytic amount of acetic acid (0.1 eq) in methanol at 40 °C restores reactivity, with isolated yields after precipitation typically falling in the 65–78% range for a panel of twelve aliphatic hydrazines. The presence of the pyridine nitrogen on the sulfonamide permits subsequent metal coordination or quaternization, a feature absent in the corresponding benzenesulfonyl-pyrrole aldehydes, and this expands the utility of the scaffold in fragment-based drug discovery where three-dimensional vectors around the sulfonamide are varied.
Dissolution in aprotic dipolar solvents (DMF, DMSO) under ambient atmosphere initiates slow oxidation to the carboxylic acid, with a measured half-life of 34 h in DMSO-d6 exposed to air at 25 °C as determined by sequential 1H NMR integration. This decay pathway becomes operationally relevant during overnight high-throughput experimentation where solutions are prepared in advance. Degassed solvents purged with argon for 30 min prior to use extend the half-life beyond 200 h, making solution stability adequate for robotic liquid handlers operating in an inert atmosphere glovebox (O2 < 5 ppm). The compound should not be pre-dissolved in the presence of N-bromosuccinimide or other radical initiators, as benzylic-type oxidation of the fluorophenyl methylene bridge has been observed in stressed compatibility screens (confirmed via HRMS detection of a ketone intermediate at m/z 344.074). Users performing Vilsmeier-Haack formylation on the parent pyrrole should note that the title aldehyde is already the product of that transformation; additional formylation attempts under POCl3/DMF conditions lead predominantly to decomposition rather than pyrrole ring substitution at C-5, as the sulfonyl substituent deactivates the ring toward electrophilic aromatic substitution. For applications requiring the aldehyde to be reduced to the corresponding alcohol without affecting the fluorine substituent, sodium borohydride in methanol at 0 °C to room temperature provides clean conversion (>95% by TLC, ethyl acetate/hexane 1:1) within 2 h. Lithium aluminum hydride should be avoided; reductive cleavage of the sulfonamide N–S bond occurs at reflux in THF, a side reaction documented for structurally related N-arylsulfonylpyrroles. The alcohol produced is prone to moisture-sensitive gel formation upon concentration and is best used directly in the following Mitsunobu or mesylation step without complete drying. This workflow aligns with process chemistry approaches described in regulatory starting material justification documents following ICH Q11 where late-stage functional group interconversion is preferred over early installation of the fluorophenyl ring.
In material-science explorations where the aldehyde is condensed with diamines to form conjugated polyimines, the 2-fluorophenyl analogue yields thin films exhibiting a bathochromic shift in UV-vis absorption relative to the 4-fluorophenyl polymer (λmax 432 nm vs. 418 nm in chloroform solution). This shift is consistent with a slightly extended conjugation imparted by the ortho-fluorine’s through-space interaction with the pyrrole π-system. The number-average molecular weight (Mn) measured by GPC against polystyrene standards (THF eluent, refractive index detection) reached 8,200 Da with a polydispersity index of 1.9 when the polymerization was performed at equimolar stoichiometry using 1,4-phenylenediamine at 60 °C for 48 h, indicating moderate degrees of polymerization that are comparable to those attained with the 3-fluorophenyl isomer. The pyridinylsulfonyl group, however, increases the glass transition temperature of the resulting polyimine by approximately 12 °C relative to a tosyl-protected analogue, as assessed by differential scanning calorimetry at a heating rate of 10 °C/min under nitrogen. This property may be exploited in applications where enhanced thermal dimensional stability is desired, though published data for this specific configuration is limited, and more extensive thermal aging studies per ASTM E1641-18 would be necessary to establish kinetic parameters for degradation.
| Condition | Matrix | Observation Period | Purity Change (HPLC area-%) | Main Degradant |
|---|---|---|---|---|
| 25 °C, 60% RH, open vial | Neat solid | 14 days | -0.3 | None detected |
| 40 °C, 75% RH, open vial | Neat solid | 7 days | -1.8 | Carboxylic acid (+1.5%) |
| 25 °C, ambient light, amber vial | Neat solid | 30 days | -0.5 | Dimer (+0.3%) |
| 25 °C, air-saturated DMSO | 10 mg/mL solution | 48 h | -8.4 | Carboxylic acid (+7.9%) |
| -20 °C, sealed under argon | Neat solid | 12 months | -0.2 | None detected |
In biological assay contexts, where the aldehyde may be employed as a covalent warhead or reactive fragment, it is imperative to pre-incubate with amine-containing buffers such as Tris only after verifying buffer compatibility. Schiff base formation with Tris at pH 7.4 and 37 °C proceeds with a half-life of 2.3 h, as monitored by LC-MS, which may confound IC50 measurements in biochemical screens unless a non-nucleophilic buffer (e.g., HEPES, pH 7.4) is substituted. The 3-pyridinylsulfonyl moiety, unlike simple benzenesulfonyl groups, exhibits weak coordination to zinc-dependent metalloenzymes in isothermal titration calorimetry experiments, a finding that has been provisionally noted but not fully validated across a panel of isoforms. This chelation potential adds an orthogonal binding element absent in the benzene analog, distinguishing the product in fragment library design where metal-binding pharmacophores are sought.
The compound is manufactured under ISO 9001:2015-certified quality management systems with full traceability to the key raw materials 2-fluorobenzaldehyde and 1-(3-pyridinylsulfonyl)-1H-pyrrole. The supply specification includes a residual ethylene oxide limit of <1 ppm per ISO 10993-7:2008 when the material is streamed toward medical device intermediates, though this is not routinely tested unless requested. For export, a single harmonized system code of 2933.99 is applicable, and the chemical is listed on the TSCA inactive inventory under a generic sulfonyl-pyrrole category; specific PMN review status should be confirmed with the vendor’s regulatory affairs contact. The 2-fluorophenyl characteristic offers a different metabolic profile compared to the chlorophenyl analogue, as the C–F bond resists cytochrome P450-mediated oxidative dehalogenation observed in the C–Cl counterpart, a distinction that metabolic stability assays (human liver microsomes, 1 µM test compound, NADPH regenerating system) have begun to quantify—though comprehensive cross-laboratory data remain unpublished. This halogen-class difference positions the 5-(2-fluorophenyl) variant as a potentially superior scaffold in lead optimization campaigns where metabolic soft spots must be blocked without introducing reactive metabolites flagged under the FDA’s MIST guidance.
The aldehyde’s solubility profile in biorelevant media (FaSSIF, pH 6.5, 37 °C) is 18 µg/mL, classifying it as a BCS low-solubility substance when considered for oral pharmaceutical forms. Milling with a jet mill to a D90 particle size of <10 µm improves the dissolution rate only modestly in USP apparatus II testing (paddle speed 75 rpm, 900 mL media), achieving 42% dissolved after 60 min. Co-micronization with povidone K30 at a 1:1 weight ratio under cryogenic conditions elevates the dissolution extent to 74%, though the physical stability of the amorphous dispersion under ICH storage conditions (25 °C/60% RH and 40 °C/75% RH) requires confirmation via modulated DSC and XRPD, as recrystallization events after 4 weeks have been intermittently observed in small-scale feasibility batches. For discovery purposes, a 10 mM stock solution in DMSO is routinely employed, and repeated freeze-thaw cycles (5 cycles) show no precipitation or precipitate-induced purity drift when the mother solution is kept in amber vials and briefly sonicated before each use.
Transformation into the oxime ether using O-allylhydroxylamine hydrochloride proceeds readily in pyridine at 50 °C, furnishing a product with a distinct mass spectrum that is useful for library encoding. In contrast, the corresponding 2-thienylsulfonyl-protected pyrrole-3-carboxaldehyde forms the oxime at a slower rate due to electronic differences in the sulfonamide N–S bonding; that slower rate has been captured in a small comparative study where the time to 90% conversion was 4.5 h for the pyridinylsulfonyl derivative versus 8 h for the thienylsulfonyl analogue. This rate gap underlines the activating influence of the 3-pyridyl ring and provides a kinetic rationale for selecting the title compound when rapid oxime ligation is of synthetic value.
