1H-Pyrrole-3-Methanamine,5-(2-Fluorophenyl)-N-Methyl-1-(3-Pyridinylsulfonyl)

The molecule assigned the systematic name 1H‑Pyrrole‑3‑Methanamine,5‑(2‑fluorophenyl)‑N‑methyl‑1‑(3‑pyridinylsulfonyl) (C₁₇H₁₅FN₄O₂S, monoisotopic mass 358.39 Da) constitutes a fully substituted pyrrole scaffold wherein a secondary amine handle, an electron‑deficient pyridine sulfonamide, and an ortho‑fluorinated phenyl ring converge. The secondary amine emerges as an N‑methylaminomethyl side chain appended at the pyrrole 3‑position, while the 3‑pyridinesulfonyl group occupies the ring nitrogen and the 2‑fluorophenyl substituent is installed at the 5‑position. These structural elements distinguish the compound from the broader class of 3‑aminomethylpyrroles that typically carry a tosyl or phenylsulfonyl protecting group at N1 and lack the simultaneous methylation of the exocyclic amine. The presence of the pyridyl nitrogen introduces a basic site (pKa ~ 4.8 predicted via MarvinSketch 21.17) capable of engaging in hydrogen‑bonding networks, while the ortho‑fluorine on the pendant phenyl ring simultaneously withdraws electron density and sterically shields the biaryl bond, a motif examined in analogue kinase hinge‑binder programs. Identity confirmation at release relies on high‑resolution mass spectrometry (HRMS‑ESI, resolving power ≥ 30 000 FWHM) yielding an [M+H]⁺ ion within ±3.0 ppm mass error, alongside ¹H and ¹³C NMR spectra acquired at 400 MHz (DMSO‑d₆) where the characteristic AB quartet of the pyrrole C4‑H proton (δ 6.52 ppm, J = 2.8 Hz) and the pyridine α‑H singlet (δ 9.08 ppm) serve as orthogonal diagnostic signals.

What Structural Features Differentiate 1H‑Pyrrole‑3‑Methanamine,5‑(2‑Fluorophenyl)‑N‑Methyl‑1‑(3‑Pyridinylsulfonyl) from Analogous Aminomethylpyrroles?

A conspicuous departure from documented 3‑aminomethyl‑1‑arylsulfonylpyrroles is the N‑methyl substitution of the exocyclic amine. In un‑methylated counterparts, the primary amine offers two hydrogen‑bond donors, a property frequently exploited for direct attachment to aza‑heterocycle ATP‑competitive inhibitors. The tertiary amine generated by N‑methylation eliminates donor capacity while retaining acceptor capability and elevates lipophilicity, documented by a measured logP (shake‑flask octanol/water, pH 7.4) of 2.83 for the methyl analogue versus 1.41 for the des‑methyl primary amine processed in triplicate with a standard deviation of 0.08 log units. Another departure lies in the 3‑pyridylsulfonyl group. Replacing the common 4‑methylphenylsulfonyl (tosyl) or unsubstituted phenylsulfonyl substituent with a 3‑pyridylsulfonyl unit inserts a nitrogen atom that can adopt either the protonated or neutral form under physiological conditions, thereby modulating solubility and off‑target binding. Single‑crystal X‑ray structures of 1‑(3‑pyridylsulfonyl)indole analogues (CSD refcode family TIR*) confirm that the pyridine nitrogen routinely intermolecularly hydrogen‑bonds to amide donors, a feature also anticipated here. The 2‑fluorophenyl motif at the pyrrole 5‑position differentiates the product from 5‑phenyl or 5‑(4‑fluorophenyl) variants; the ortho‑fluorine rotates the pendant ring out of planarity (dihedral angle estimated by DFT B3LYP/6‑31G** at 52°) and retards oxidative metabolism at the adjacent carbon, a metabolic shielding pattern observed in vivo for related biaryl systems. Combining these three features into a single molecule yields a chiral‑free, low‑molecular‑weight (358 Da) fragment‑sized ligand with a modulated hydrogen‑bond profile, yet published pharmacological data for this specific configuration remain limited to internal screening databases.

In fragment‑based lead generation and high‑throughput screening campaigns, the compound is routinely provided as a pre‑weighed solid in amber septum‑sealed vials under argon atmosphere. Typical quantities range from 10 mg to 500 mg, accompanied by a certificate of analysis (CoA) that details batch‑specific chromatographic purity, residual solvent profile, and water content. Laboratories initiate dissolution by adding degassed anhydrous dimethyl sulfoxide (DMSO, ≤ 50 ppm H₂O by KF) to a target stock concentration of 10 mM, with sonication at 25 °C for up to 15 min applied when visible particulates persist. Because the sulfonamide linkage is susceptible to base‑catalyzed hydrolysis, dissolution in alkaline buffers (pH > 8.5) is avoided; screening collections dilute the DMSO stock into neutral phosphate buffered saline (PBS, pH 7.4) immediately prior to assay, maintaining final DMSO concentrations below 0.1 % (v/v) to preclude solvent‑induced artifacts. Automated liquid handlers employed in acoustic dispensing (Labcyte Echo 555 series) have been qualified with the compound at 10 mM in DMSO without observation of needle clogging or precipitate formation over a 48‑h stability window at 4 °C, as verified by LC‑UV monitoring at 254 nm.

Stability and Storage Under Ambient Laboratory Conditions

Long‑term archiving of the neat solid is conducted at −20 °C in tightly sealed glass vials under a dry argon blanket, with a secondary container of indicating silica gel (cobalt‑free, orange‑to‑green transition) placed inside the outer bag. Under these conditions, HPLC purity (Symmetry C18 column, 150 × 4.6 mm, 5 µm, 40 °C) of a representative lot remained at 98.8 % after 24 months of storage, with no new impurity exceeding the reporting threshold of 0.05 area%. Exposure to ambient humidity (55–65 % RH at 23 °C) for 4 h resulted in water uptake of 0.8–1.2 wt% as determined by volumetric Karl Fischer titration (Metrohm 831 KF coulometer), indicating a mildly hygroscopic character that necessitates handling under positive nitrogen pressure when the receiver’s relative humidity exceeds 60 %. For preparative use that demands anhydrous material, the solid may be dried under reduced pressure (< 10 mbar) at 40 °C for 6 h with a liquid‑nitrogen trap; post‑drying water content routinely falls below 0.1 wt%. Thermogravimetric analysis coupled with differential scanning calorimetry (TGA‑DSC, Mettler‑Toledo TGA/DSC 3+, 10 K/min under N₂ flow) revealed a single‑stage mass loss of 0.4 % up to 140 °C, followed by an exothermic decomposition event with onset at 168.5 °C and peak at 185.2 °C. No glass transition or melting endotherm is observed prior to decomposition. These data support classification as a Class II combustible solid for transport purposes but do not invoke any special controlled‑temperature shipping requirement.

When Regioselective Aryl Introduction is Critical: Synthetic Access to 5‑(2‑Fluorophenyl)‑3‑(methylaminomethyl)pyrrole Motifs

The regiodefined installation of an aryl group at the pyrrole 5‑position, rather than the thermodynamically favored 2‑position, represents the central challenge in assembling the carbon skeleton. Electrophilic aromatic substitution on unprotected or N‑alkyl pyrroles nearly exclusively delivers 2‑aryl adducts; therefore, the synthetic strategy employs the pre‑installed N‑(3‑pyridylsulfonyl) group as both a steric director and an electronic deactivator that shifts lithiation selectivity to the 5‑position. A validated route (as executed in multi‑gram batches on a ChemGlass Schlenk line) begins with N‑sulfonylation of methyl 1H‑pyrrole‑3‑carboxylate using 3‑pyridinesulfonyl chloride hydrochloride in dichloromethane with triethylamine at 0→20 °C. The resulting ester is reduced by LiAlH₄ (2.5 eq, THF, 0 °C to reflux) to the 3‑hydroxymethyl intermediate, which is converted to the corresponding bromide via Appel reaction (CBr₄, PPh₃, CH₂Cl₂, 0 °C) and subsequently displaced with methylamine (2.0 M in THF, 40 °C, 16 h) to generate the N‑methyl‑3‑aminomethyl moiety in > 90 % crude yield. The key arylation step proceeds by directed lithiation of the pyrrole 5‑position with n‑butyllithium (1.1 eq, −78 °C, THF, 30 min), quenched with triisopropyl borate to deliver the 5‑boronic ester, which is immediately subjected to a Suzuki‑Miyaura cross‑coupling with 2‑fluorophenyl bromide. The coupling is catalyzed by 2 mol% Pd(PPh₃)₄ in a two‑phase toluene/2 M K₂CO₃ system at 90 °C for 8 h, furnishing the target compound after flash chromatography (silica gel 60, heptane/EtOAc 1:1 → 1:4, Rf 0.35) in overall 68–72 % isolated yield across the acylation‑reduction‑amination‑arylation sequence. In‑process HPLC monitoring (C18, acetonitrile/0.1 % TFA gradient) quantified the 2‑aryl regioisomeric impurity at 2.3–3.8 % prior to purification; post‑chromatographic fractions that exceed 1.0 % 2‑isomer are re‑chromatographed. The primary impurity, the des‑fluoro phenyl analogue arising from protodeboronation of the intermediate boronic ester, is controlled to ≤ 0.3 % by ensuring strict anhydrous conditions during borylation.

Residual Palladium, Sulfonate Esters, and ICH Q3D Elemental Impurity Scoping

Although the compound is supplied as a research‑only reagent and not as a pharmaceutical active, analytical specifications align with ICH Q3D Guideline for Elemental Impurities to permit seamless transition into preclinical development. Palladium, classified as a Class 2A element with an oral permitted daily exposure (PDE) of 100 µg/day, is the primary metal of concern from the Suzuki coupling. Sample preparation by closed‑vessel microwave digestion (CEM Mars 6, HNO₃/H₂O₂, 210 °C) followed by ICP‑MS quantification (Agilent 7900, He collision mode) against external calibration standards traceable to NIST SRM 3100 series results in a typical batch value of 8–22 ppm, comfortably below the 100 ppm control threshold applied when the substance is used at a daily dose not exceeding 1 g. Iron, nickel, and chromium are additionally monitored (limits per ICH Q3D Option 1) and non‑detected above their respective reporting limits of 0.5 ppm. The absence of sulfonate ester genotoxins—potential by‑products from reaction of the sulfonyl chloride with alcohols—is confirmed by LC‑MS/MS screening (Sciex 5500 QTRAP, APCI+) targeting methyl, ethyl, and isopropyl 3‑pyridinesulfonate with a limit of detection of 1 ppm; none have been detected across 12 consecutively manufactured lots. Table 1 presents a consolidated release specification derived from batch analysis.

Table 2 compares architectural parameters of the reported compound with two related pyrrole‑3‑methanamine derivatives that have been catalogued in commercial screening libraries.

Handling in a standard fume hood employing nitrile examination gloves (tested to EN 374‑3 against DMSO breakthrough > 480 min) is adequate. No acute toxicity alerts are flagged by in silico QSAR models (Leadscope Model Applier Suite) for this structural class; nonetheless, the compound should be treated as a chemical hazard until occupational exposure limits are established. Incompatibilities include strong oxidizing agents—which can oxidize the pyrrole ring to maleimide derivatives—and strong bases (e.g., NaOH pellets, KOtBu), which cleave the sulfonamide bond at temperatures above 60 °C, generating 3‑pyridinesulfinate and the corresponding free amine. During aqueous work‑up at pH < 3, the pyridyl nitrogen is protonated, significantly increasing water solubility and requiring careful adjustment of extraction solvents; ethyl acetate proved sufficient (partition coefficient > 10) only after neutralization with saturated NaHCO₃. Waste disposal complies with local regulations for nitrogen‑ and fluorine‑containing organic compounds; incineration in a permitted facility equipped with scrubbers for HF and NOx is recommended.