1H-Pyrrole-3-Carboxaldehyde, 5-(2-Fluorophenyl)-
|
HS Code |
933444 |
| Chemical Formula | C11H8FNO |
| Molecular Weight | 189.19 |
| Appearance | Solid (predicted) |
| Boiling Point | 343.3°C at 760 mmHg (predicted) |
| Melting Point | 103 - 105°C |
| Density | 1.244 g/cm³ (predicted) |
| Flash Point | 161.4°C (predicted) |
| Solubility | Soluble in organic solvents like DMSO, DMF (predicted) |
| Refractive Index | 1.634 (predicted) |
| Pka | -2.39 (predicted) |
As an accredited 1H-Pyrrole-3-Carboxaldehyde, 5-(2-Fluorophenyl)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5-(2 - Fluorophenyl)-1H - Pyrrole - 3 - Carboxaldehyde in sealed chemical - grade packaging. |
| Shipping | 1H - Pyrrole - 3 - Carboxaldehyde, 5 - (2 - Fluorophenyl) - is shipped in well - sealed, specialized containers. Shipping follows strict chemical safety regulations to prevent any spillage or exposure during transit. |
| Storage | Store "1H - Pyrrole - 3 - Carboxaldehyde, 5 - (2 - Fluorophenyl) -" in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container, preferably in a cabinet dedicated to chemicals. Avoid exposure to moisture and air as it may react. Ensure proper labeling for easy identification and to prevent cross - contamination. |
In current Good Manufacturing Practice–compliant synthesis of a selective ATP‑competitive kinase inhibitor candidate, 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is introduced as a regulatory starting material immediately after the convergent assembly of the indazole hinge‑binder fragment. The batch record defines a stoichiometric window of 1.0:1.05 aldehyde‑to‑activated methylene compound for the base‑catalyzed Knoevenagel condensation with 2‑cyanoacetamide, run in anhydrous tetrahydrofuran at jacket temperature −5 °C ± 2 °C under a nitrogen overlay in a 100‑L glass‑lined reactor equipped with a retreat‑curve impeller. Reaction progress is tracked by inline ReactIR, with the characteristic carbonyl stretch at 1678 cm⁻¹ decaying to <3% peak area before drowning the mixture into ice‑cold purified water. After vacuum filtration through a 0.5‑μm polypropylene cloth and repeated slurry washes with n‑heptane until residual DMF content falls below 720 ppm by GC‑headspace, the wet cake is dried in a double‑cone tumble dryer at 45 °C / 50 mbar to a loss‑on‑drying endpoint of 0.3%. The resulting cyanoacrylamide intermediate is telescoped into a palladium‑catalyzed intramolecular C–H arylation using Pd(OAc)₂/XPhos at 0.5 mol% loading in toluene/water biphasic media at 95 °C, generating the tetracyclic core. Residual palladium is scavenged with Si‑thiol functionalized silica gel to a specification of <10 ppm by ICP‑MS, meeting the ICH Q3D Elemental Impurities guideline for oral administration. Compliance with ICH Q7 Section 7.31 and 11.10 is confirmed through a three‑batch validation campaign where the aldehyde identity is verified by 1H‑NMR (400 MHz) against a certified reference standard, and impurity profile is controlled by a dedicated HPLC method using a C18 column, 1.7 μm particle size, with UV detection at 254 nm; the acceptance criterion for any single unknown impurity is capped at 0.10% area‑%. The terminal dosage form produced from this intermediate is a 25 mg immediate‑release tablet film‑coated with Opadry® II, packed in Alu‑Alu blister strips under 25 °C/ 60% RH stability conditions per ICH Q1A(R2).Field‑Trial Variance as a Function of Residual Boron Content in Arylpyrrole Insecticide Technical ConcentratesWhen 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is utilized for the manufacture of a non‑fumigant, neuronally‑active arylpyrrole insecticide analogous to the chlorfenapyr pharmacophore but with a fluorinated N‑ethoxymethyl side chain, the critical quality attribute that correlates with inconsistent field‑efficacy data across geographically dispersed trial sites is the residual boronic acid level retained from the upstream Suzuki‑Miyaura coupling. The aldehyde is first condensed with hydroxylamine hydrochloride (1.2 eq. relative to aldehyde) in ethanol/water (7:3 v/v) at 50 °C to form the corresponding oxime, which then undergoes a 1,3‑dipolar cycloaddition with ethyl propiolate in the presence of sodium hypochlorite to build the isoxazoline ring. The regulatory framework for the technical grade active ingredient demands compliance with the FAO Specification Manual for Plant Protection Products (March 2022 revision) concerning unidentified impurities and the mandatory submission of a five‑batch analysis for registration under EU Regulation 1107/2009. In the formulation step, the purified technical concentrate (≥98.5% w/w) is dispersed at 120 g L⁻¹ in an aqueous suspension concentrate matrix containing an EO‑PO block copolymer wetting agent and xanthan gum rheology modifier, producing a SC formulation with a particle size Dv90 ≤ 4 μm measured by laser diffraction (ISO 13320). Process-scale preparation occurs in a tandem Sigma‑kneader and basket‑mill circuit where milling media wear metal contamination (ZrO₂ beads, 0.6–0.8 mm diameter) is kept below 15 ppm Fe by magnetic filtration; the resulting suspension is spray‑dried onto water‑dispersible granule cores only for markets requiring reduced operator inhalation risk as per the WHO Hazard Class II classification. The terminal product is deployed as a foliar spray against lepidopteran pests in Brassica crops at a field rate of 50–75 g a.i. ha⁻¹, emptied into the tank via a closed‑transfer system to meet ISO 22475:2022 operator exposure limits, and the commercial unit is a 1 L co‑extruded fluorinated HDPE bottle with a tamper‑evident induction seal.---Thermally evaporated electron‑transport layers in bottom‑emission phosphorescent organic light‑emitting diode stacks frequently suffer from exciplex quenching at the hole‑blocking interface unless the host matrix incorporates a wide‑bandgap component with a deep HOMO level. Vacuum‑sublimed 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, after conversion to a D–π–A chromophore via Knoevenagel condensation with 1,3‑diethyl‑2‑thiobarbituric acid, delivers a neat‑film photoluminescence quantum yield of 0.62 ± 0.03 when deposited on a pre‑cleaned quartz substrate at a rate of 0.3 Å s⁻¹ under base pressure <3 × 10⁻⁷ mbar inside a Kurt J. Lesker SPECTROS system with a six‑pocket e‑beam hearth. The key compliance benchmark for electronic‑grade intermediates is the SEMI C19‑1116 guideline for metal ion contamination; lithium, sodium, and potassium are individually quantified by ion chromatography‑conductivity detection and held below 50 ppb, while chloride and sulfate anions are controlled under 100 ppb to prevent dark spot formation in accelerated shelf‑life tests at 85 °C/ 85 % RH for 500 h. In the device manufacturing protocol, the sublimed fluorophore is co‑deposited with the host material 9‑(3‑(9H‑carbazol‑9‑yl)phenyl)‑9H‑carbazole‑3‑carbonitrile (mCPCN) at a dopant concentration of 8 wt%, controlled by independent quartz crystal microbalances calibrated with a LiNbO₃ reference crystal. The downstream panel fabrication follows a shadow‑mask‑patterned, bottom‑emission architecture on a 6th‑generation (1500 mm × 1850 mm) LTPS backplane; the finished display sub‑pixel array is encapsulated with a multilayer thin‑film barrier of alternating Al₂O₃ and polymer layers deposited by atomic layer deposition, resulting in a smartphone AMOLED module with a luminance decay half‑life exceeding 30,000 h at 1000 cd m⁻² initial brightness, tested per IEC 62341‑5‑2.
When the Aldehyde Moiety Participates as a Griess‑Reactive Capture Probe in Cell‑Free Biosensing MembranesIntegration of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde into a lateral‑flow immunoassay format is achieved through reductive amination with a hydrazide‑decorated cellulose nanocrystal matrix, creating a covalent linkage that resists leaching under the high‑surfactant running buffer conditions typical of whole‑blood separations. The functionalization is performed in a ISO 14644‑1 Class 5 cleanroom laminar‑flow hood on Whatman® CF5 fusion‑membrane strips pre‑activated with 0.2 M sodium periodate for 30 min at 22 °C. The aldehyde‑anchored fluorogenic probe is loaded at 0.8 μg cm⁻² as determined by UV‑visible reflectance densitometry at 360 nm. The relevant quality management standard for the assembled test device is ISO 13485:2016 Section 7.3 on design and development transfer, with the finished membrane strip undergoing accelerated aging at 60 °C in sealed foil pouches containing silica gel desiccant for 42 days to simulate 24‑month refrigerated shelf life. The downstream manufacturing step sheets the rolled membrane into 4.0 mm‑wide lanes using a rotary die‑cutting station, laminates the strips onto 0.010″ clear polyester backing cards, and assembles them into a three‑piece injection‑molded housing fitted with a sample pad and an absorbent sink. The terminal product is a single‑use, visual‑readout dipstick for the semiquantitative detection of nitrite in saliva at a limit of detection of 5 μM, verified by spiked‑recovery experiments against a certified reference material (NIST SRM 3181). Each lot is released only after lot‑to‑lot consistency passes the control‑line intensity ratio tolerance of ±15% (CV) across 30 replicate strips, and any lot with a false‑positive rate exceeding 2% at blank matrix is quarantined for root‑cause analysis per CAPA procedures defined in 21 CFR Part 820.100.
Can Electrografted Poly(5-(2-fluorophenyl)pyrrole) Electrochromic Layers Maintain Optical Contrast After 10⁵ Switching Cycles?The 2‑fluorophenyl substituted pyrrole monomer is electropolymerized directly onto fluorine‑doped tin oxide glass under constant‑potential conditions inside an argon‑atmosphere glovebox (<1 ppm O₂, <1 ppm H₂O) to eliminate parasitic oxygen‑doping that otherwise accelerates electrochromic fatigue. The three‑electrode cell configuration uses a platinum mesh counter electrode and a non‑aqueous Ag/Ag⁺ reference calibrated against the ferrocene/ferrocenium couple; the monomer concentration is held at 0.10 M in anhydrous acetonitrile with 0.10 M lithium perchlorate supporting electrolyte. The formulation addition ratio is defined by the charge passed per geometric area—a deposition charge of 40 mC cm⁻² yields a film thickness of approximately 90 nm as confirmed by stylus profilometry after drying. The electrochromic device is completed by laminating a UV‑curable electrolyte gel containing 1.0 M LiClO₄ in poly(methyl methacrylate) matrix between the working electrode and a counter electrode consisting of bare ITO coated with cerium oxide‑titanium dioxide ion‑storage layer. The terminal product is an automatically dimming exterior rear‑view mirror for passenger vehicles, which must withstand durability testing according to ISO 16750‑4:2023 (clause 5.4) for temperature cycling from -40 °C to +85 °C with a ramp rate of 4 °C min⁻¹. Regulatory compliance regarding substance restrictions is demonstrated by submitting a full‑material declaration per IEC 62474, confirming that the fluorinated polymer layer contains no substances above the reporting thresholds of RoHS Directive 2011/65/EU Annex II, including verification of total bromine content below 900 ppm by combustion ion chromatography. Optical modulation measurements performed on a Minolta CM‑700d integrating sphere spectrophotometer show that the visible‑light contrast ratio at 550 nm between the bleached (+0.2 V) and colored (−0.4 V) states remains above 45% after 1 × 10⁵ square‑wave cycles, a benchmark derived from SAE J 964a reflectivity requirements for Class IV mirrors. |
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5-(2-Fluorophenyl)-1H-pyrrole-3-carboxaldehyde, designated Product Code PFC-301-A and supplied as a pale-yellow crystalline powder, is a formyl-substituted pyrrole bearing an ortho-fluorinated phenyl ring at the 5-position. The compound (IUPAC: 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, molecular formula C₁₁H₈FNO, relative molecular mass 189.18 g·mol⁻¹) is manufactured via a sequential Suzuki coupling of 2-fluorophenylboronic acid with an N-protected 5-bromopyrrole-3-carboxaldehyde, followed by acidic deprotection. The N-protection strategy employs a 2-(trimethylsilyl)ethoxymethyl (SEM) group cleaved with tetra-n-butylammonium fluoride in tetrahydrofuran at 0 °C over 2 h; incomplete deprotection historically generated a persistent SEM-ether impurity at ≈0.3%, eliminated by increasing TBAF concentration from 1.0 M to 1.5 M and extending the ammonium chloride quench time to 30 min. Reaction progress is monitored on an Agilent 1260 Infinity II Prime quaternary LC system equipped with a diode-array detector and a Zorbax Eclipse Plus C18 column (1.8 µm, 2.1 × 50 mm); the target compound typically elutes at retention time 4.62 ± 0.05 min under a gradient of acetonitrile/water containing 0.1% formic acid. LC-UV-MS analysis (Waters ACQUITY QDa) identifies a homocoupling biphenyl side product at 0.1–0.2%, which is minimized by slow, controlled addition of the boronic acid in THF over 4 h at 65 °C. After aqueous work-up, the crude product is isolated by precipitation from n-heptane at −20 °C. A Design of Experiments approach executed on a Mettler Toledo EasyMax 102 automated reactor defined an optimal cooling rate of 0.5 °C/min, a 2 h hold at −20 °C, and a type-A crystal seed loading of 0.5 wt%, yielding a crystalline powder with a median particle size d₅₀ of 18 µm and span (d₉₀−d₁₀)/d₅₀ below 1.2 (Malvern Mastersizer 3000, wet dispersion in Isopar G). Over 12 consecutive production lots manufactured at 500 g scale in a glass-lined Pfaudler reactor (20 L), HPLC purity (λ = 254 nm) ranged from 98.3% to 99.1%, while residual palladium content determined by inductively coupled plasma mass spectrometry (Agilent 7800 ICP-MS) remained below 10 ppm. The aldehyde functionality is moderately air-sensitive; therefore, the product is packaged under argon in amber borosilicate glass vials capped with PTFE-lined phenolic closures, with headspace oxygen content verified below 0.5% by a Dansensor CheckPoint 3 gas analyzer immediately after crimping.
Introducing a fluorine atom at the ortho position of the 5-phenyl ring modifies both electronic and conformational properties of the pyrrole carboxaldehyde scaffold. Single-crystal X-ray diffraction data (Bruker D8 Venture diffractometer, Mo Kα, 100 K) reveal a torsion angle of 42.3° between the pyrrole and the 2-fluorophenyl plane, compared to 38.1° for non-fluorinated 5-phenyl-1H-pyrrole-3-carboxaldehyde (CSD refcode PYRROL01, redetermined under identical conditions). This larger twist reduces π-overlap and slightly elevates the HOMO-LUMO gap observed by UV-Vis, with λmax shifting from 298 nm to 287 nm in acetonitrile. Density functional calculations at the B3LYP-D3/6-311+G(d,p) level predict a LUMO energy of −2.18 eV for the 2-fluorophenyl derivative versus −1.87 eV for the phenyl analog, consistent with enhanced electrophilicity. Pseudo-first-order rate constants for imine formation with p-anisidine in anhydrous tetrahydrofuran at 25.0 °C, measured by stopped-flow UV spectroscopy, are 0.15 L·mol⁻¹·s⁻¹ for the fluorinated species and 0.08 L·mol⁻¹·s⁻¹ for the des-fluoro comparator—a 1.9-fold rate acceleration.
| Property | 5-(2-Fluorophenyl)- derivative | 5-Phenyl- analog |
|---|---|---|
| Molecular weight | 189.18 g·mol⁻¹ | 171.20 g·mol⁻¹ |
| Melting onset (DSC, 10 K/min) | 122–125 °C | 98–101 °C |
| HPLC retention time (method A)* | 4.62 min | 3.95 min |
| LogD₇.₄ (shake-flask, n-octanol/PBS) | 2.14 ± 0.03 | 1.78 ± 0.02 |
| Human liver microsomal half-life (HLM, 1 µM, NADPH) | 47 ± 6 min | 12 ± 3 min |
| Kinetic solubility (µM, pH 7.4 PBS) | 85 ± 5 | 210 ± 15 |
*Method A: Zorbax Eclipse Plus C18, 1.8 µm, 2.1×50 mm, 40 °C, 0.6 mL/min, 5–95% MeCN/0.1% formic acid in 7 min.
The metabolic stability improvement is substantial and consistent with the known effect of ortho-fluorination blocking oxidative metabolism at the phenyl ring. Despite a reduction in intrinsic aqueous solubility, the fluorinated derivative’s moderate LogD and improved microsomal stability often translate into better oral bioavailability in rodent pharmacokinetic studies, although published data for this exact chemical entity remain limited. In a head-to-head comparison of matched molecular pairs synthesized from both aldehydes, the fluorophenyl-pyrrole series exhibited 3- to 5-fold lower intrinsic clearance in cryopreserved rat hepatocyte suspensions.
| Parameter | Method / Instrument | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection | Pale yellow powder |
| Purity (HPLC) | Agilent 1260 Infinity II, Zorbax SB-C18 1.8 µm, 2.1×100 mm, 40 °C, 254 nm, gradient per SOP 7.4.2 | ≥ 98.0% area |
| Single largest impurity | Same as purity method | ≤ 1.0% area |
| Melting range (DSC) | TA Discovery DSC 2500, 10 K/min, crimped Al pan, N₂ 50 mL/min | 122–125 °C |
| Water content | Mettler Toledo C30S Karl Fischer coulometer, oven method 120 °C | ≤ 0.2% w/w |
| Residual Pd (ICP-MS) | Agilent 7800 ICP-MS, microwave digestion in HNO₃/H₂O₂ | < 10 ppm |
| ¹H NMR identity | Bruker AVANCE NEO 400 MHz, DMSO-d₆, δ 9.78 (s, 1H) aldehyde | Conforms to structure |
| Residual solvents (GC-HS) | Agilent 7890B with G1888 headspace sampler, DB-624 30 m×0.32 mm | THF ≤ 0.08%, n-heptane ≤ 0.05% |
All analytical methods are validated in accordance with ICH Q2(R1) guidelines. A stability-indicating HPLC method (same conditions, extended gradient) resolves the carboxylic acid oxidation product (retention time 3.12 min) from the parent aldehyde. Certification of analysis supplied with each lot includes batch-specific 1H NMR integrated against 1,3,5-trimethoxybenzene internal standard, HRMS (Thermo Q Exactive HF-X, ESI+), and elemental analysis (PerkinElmer 2400 Series II CHNS/O, C, H, N within 0.4% of theory).
The 3-formyl group tolerates palladium-catalyzed halogenation at the pyrrole 4-position, enabling orthogonal diversification without protecting group intervention. Treatment of PFC-301-A with 1.05 equivalents of N-bromosuccinimide in anhydrous DMF at 0 °C for 90 min selectively yields 4-bromo-5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde in 83% isolated yield after automated flash chromatography (Biotage Isolera, Sfär silica 25 g column, hexane/EtOAc gradient). During scale-up of this intermediate in a 2 L jacketed reactor, an exotherm of ΔT = 8 °C was observed upon NBS addition; controlled dosing via a J-KEM syringe pump over 15 min kept internal temperature below 5 °C and suppressed dibromination below the 0.1% threshold. The reaction was quenched with 10% w/v aqueous sodium thiosulfate to reduce excess NBS. The resulting bromide undergoes efficient Suzuki-Miyaura cross-coupling with (hetero)aryl boronic acids using the third-generation XPhos palladacycle precatalyst (XPhos Pd G3, 2 mol%) and potassium phosphate tribasic in degassed THF/water (4:1 v/v) at 60 °C. Over 20 coupling partners tested on a Chemspeed Accelerator SLT100 automated parallel synthesizer, isolated yields ranged from 72% to 94%, demonstrating the robustness of this transformation for library production. Electron-deficient and ortho-substituted boronic acids required extended reaction times (18 h) but still delivered product above 70% yield.
The 2-fluorophenyl-pyrrole motif functions as a hinge-region binding element in ATP-mimetic kinase inhibitors. Reductive amination of the aldehyde with primary or secondary amines provides a direct route to 3-aminomethyl analogues. In a representative protocol, the aldehyde (1.0 mmol) and N-Boc-piperazine (1.2 mmol) are stirred in 1,2-dichloroethane (10 mL) with sodium triacetoxyborohydride (1.5 mmol) at ambient temperature for 16 h. Standard aqueous work-up and silica gel chromatography afford the tertiary amine in 85% yield. A focused library of 48 such amides and amines was produced on a 100 µmol scale using an integrated platform comprising a Tecan Freedom EVO liquid handler and a Chemspeed Accelerator workstation; reactions were performed in 4 mL septum-sealed vials under argon with vortex agitation at 800 rpm and temperature control via a Huber CC-505 chiller. Crude products were purified by mass-triggered preparative HPLC (Waters AutoPurification, XBridge C18 OBD 5 µm, 19 × 100 mm, acetonitrile/0.1% NH₄OH) to ≥ 95% purity. The library was screened at 1 µM against a panel of 50 human kinases using the Cisbio HTRF KinEASE format with ATP at Km. The fluorophenyl-containing subset (24 compounds) gave a hit rate of 33% (defined as >50% inhibition) compared to 8% for matched non-fluorinated phenyl analogues. Compound PFC-301-AM17, derived from reductive amination with 1-(2-methoxyethyl)piperazine, exhibited an IC₅₀ of 18 nM against FLT3-ITD in a cellular phospho-STAT5 AlphaLISA assay (PerkinElmer), while the des-fluoro counterpart showed 152 nM, reinforcing the role of the ortho fluorine in target engagement.
Long-term stability studies indicate that the aldehyde undergoes slow autoxidation to the corresponding carboxylic acid when exposed to atmospheric oxygen. At 25 °C and 60% relative humidity, HPLC analysis revealed 5% acid formation after 48 h, whereas material stored under argon at −20 °C ± 5 °C in sealed vials retained >98.5% purity for 18 months. Shipments are made on dry ice with Sensitech TempTale 4 temperature loggers; any excursion above −10 °C for more than 24 h triggers a quality hold pending re-analysis. For routine use, aliquots should be removed under a positive flow of dry nitrogen or argon in a glove bag or glovebox maintaining O₂ below 100 ppm and H₂O below 50 ppm. Solutions in anhydrous DMSO-d₆ for NMR spectroscopy remain spectroscopically unchanged for 72 h at 25 °C; addition of 0.1% (v/v) tert-butylhydroquinone extends solution stability to 7 days. The compound is incompatible with strong oxidizing agents (potassium permanganate, Jones reagent) and must not be stored in proximity to amines or hydrazines to avoid premature imine or hydrazone formation. Thermal hazard assessment by differential scanning calorimetry (DSC, 10 K/min, 30–350 °C, sealed gold-plated pans) shows a single melting endotherm with no exothermic events below 300 °C, confirming safe handling under standard laboratory practice. All stability testing is conducted according to ICH Q1A(R2) guidance, with forced degradation studies under acidic, basic, oxidative, and photolytic conditions documented in the product technical dossier.
