1H-Pyrrole-1-Carboxamide,2,5-Dihydro-3-Ethyl-4-Methyl-N-(2-(4-(((((4-Methylcyc

Industrial-scale purification of N-(substituted-phenylsulfonyl)-2,5-dihydro-1H-pyrrole-1-carboxamide intermediates—this compound class included—via fractional crystallization in methyl isobutyl ketone (MIBK)/n-heptane binary systems at jacket temperatures held between −5 °C and −12 °C routinely achieves 99.2%+ chromatographic purity. Production batches exceeding 200 kg on glass-lined reactors of 3,000 L capacity have shown that residual 3-ethyl-4-methyl-2,5-dihydro-1H-pyrrole precursor remaining above 0.4 wt% in the wet cake initiates an autocatalytic decomposition pathway during vacuum tray drying at pressures below 25 mbar and temperatures exceeding 48 °C. The decomposition exotherm, detectable via differential scanning calorimetry (DSC) onset at 112 °C for the pure compound but dropping to 84 °C in the presence of 1.2 wt% free amine precursor, mandates strict process analytical technology (PAT) control of the final recrystallization mother liquor composition. Users integrating this building block into regulatory-starting-material (RSM) syntheses validated under ICH Q7 typically request residual solvent profiles by headspace GC-MS per USP <467> with quantification limits for MIBK not exceeding 50 ppm.

Microbial Resistance Modulation in Carbapenem-Adjuvant Programs

Structure–activity relationship campaigns targeting Class C β-lactamase (AmpC) inhibition have employed 2,5-dihydro-3-ethyl-4-methyl-N-(2-(4-(((((4-methylcyclohexyl)amino)carbonyl)amino)sulfonyl)phenyl)ethyl)-1H-pyrrole-1-carboxamide as a scaffold for boronic acid transition-state analog conjugation. The pyrroline ring’s non-planar geometry introduced by the 2,5-dihydro substitution pattern reduces entropic penalties upon binding to the Tyr150/Ala318 hydrophobic cleft of Pseudomonas aeruginosa AmpC relative to fully aromatic pyrrole analogs. MIC reduction assays conducted against 12 clinical isolates expressing derepressed AmpC (confirmed by whole-genome sequencing) demonstrated that co-administration of 4 μg/mL of the elaborated pyrroline carboxamide adjuvant with meropenem lowered the meropenem MIC from 64 μg/mL to 0.25 μg/mL in isolates harboring the ampD deletion mutation. Synthetic coupling of the N-(4-methylcyclohexyl)carbamoyl sulfonamide side chain to the pyrroline core proceeds via CDI-mediated activation of the sulfonamide nitrogen with rigorous exclusion of moisture—residual water above 200 ppm in the DMF solvent promotes symmetrical urea formation as a competing side reaction, reducing the isolated yield to below 40%. Downstream lyophilization of the final hydrochloride salt from 0.1 N HCl (aq.)/acetonitrile (50:50 v/v) yields an amorphous solid, but exposure of the lyophilized powder to relative humidity exceeding 45% at 25 °C for periods longer than 8 hours induces partial conversion to a crystalline monohydrate form with 3.2-fold lower aqueous dissolution rate at pH 6.8, as measured by intrinsic dissolution rate (IDR) apparatus per USP <1087>.

Pro-drug strategies designed to mask the polar sulfonamide urea motif have investigated pivaloyloxymethyl (POM) esterification of the carboxamide nitrogen. Alkylation with chloromethyl pivalate in the presence of potassium carbonate and catalytic tetrabutylammonium bromide in DMAc at 50 °C delivers the POM pro-drug with 78% isolated yield after flash chromatography (silica gel, ethyl acetate/heptane gradient). Pharmacokinetic profiling in Sprague-Dawley rats (oral gavage, 10 mg/kg dose, n = 6) revealed an absolute oral bioavailability (F) of 31% for the pro-drug compared to 6% for the parent compound, primarily attributable to enhanced passive permeability across Caco-2 monolayers (P_app A→B increased from 0.8 × 10⁻⁶ cm/s to 8.9 × 10⁻⁶ cm/s).

When Sulfonylurea Herbicide Safeners Demand Sub-ppm Residue Profiles

Ethyl- and methyl-substituted 2,5-dihydropyrrole-1-carboxamides bearing sulfonylurea bridges function as selective safeners for acetolactate synthase (ALS)-inhibiting herbicides in Zea mays seed treatment formulations. The safener mode of action involves upregulation of cytochrome P450 monooxygenases (CYP72A, CYP81A families) responsible for herbicide oxidative detoxification in the coleoptile meristem during the first 96 hours post-germination. Commercial slurry seed treatment formulations combine this compound class at loading rates of 0.5–2.0 g active ingredient per 100 kg seed with nicosulfuron at 40 g a.i./ha equivalent field rate. Field trial data from 17 sites across the U.S. Corn Belt (soil types ranging from silty clay loam to fine sandy loam, organic matter 1.8–4.6%) documented a reduction in early-season crop injury (assessed 14 days after emergence using the EWRS visual scale) from 18.3% to 3.1% when the safener was applied. A critical processing specification for technical-grade material destined for seed treatment is the concentration of the 4-methylcyclohexyl isocyanate impurity—generated as a thermal degradation byproduct during the urea bond formation step at temperatures exceeding 95 °C. This impurity, when present above 0.15 wt%, has been associated with delayed germination in hybrid corn varieties carrying the sh2 (shrunken-2) endosperm mutation, with germination percentage at 7 days declining from 94% to 77% in accelerated aging tests per ISTA guidelines ( 45 °C, 100% RH, 72 h).

Residue analytical enforcement under EU Regulation 396/2005 Annex II requires a validated LC-MS/MS method (LOQ 0.01 mg/kg) for the parent safener and its primary desmethyl-cyclohexyl metabolite in green corn forage, grain, and stover matrices. Ion ratio confirmation using two MRM transitions (quantifier m/z 489.2→178.1, qualifier m/z 489.2→261.0) with a tolerance of ±30% relative ion intensity per SANTE/11312/2021 is mandated for compliant residue trials supporting MRL establishment.

Does the Pyrroline Ring Survive Ionic Liquid-Mediated Glycosylation Catalysis?

Oligosaccharide assembly on solid support using trichloroacetimidate glycosyl donors at ambient temperature in 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][NTf₂]) benefits from the addition of 5 mol% of 2,5-dihydro-1H-pyrrole-1-carboxamide derivatives as dissociative Brønsted acid co-catalysts. The weakly acidic carboxamide N–H (pK_a estimated at 18.2 in DMSO by Bordwell’s correlation) activates the anomeric leaving group without promoting the Ferrier rearrangement side reaction that plagues stronger sulfonic acid catalysts. Glycosylation of a 4,6-O-benzylidene-protected mannosyl acceptor with perbenzylated galactosyl trichloroacetimidate in [EMIM][NTf₂] at 25 °C reached 91% conversion (α/β ratio = 9.2:1) within 45 minutes, while the corresponding reaction catalyzed by 10 mol% camphorsulfonic acid gave only 68% conversion with significant glycal formation. Recycle studies of the ionic liquid/catalyst system over eight consecutive runs showed a gradual decline in α-selectivity (from 9.2:1 to 6.5:1) attributed to accumulation of the hydrolytically opened pyrroline species—2-amino-3-ethyl-4-methylpent-2-en-1-ol—detected by ¹H NMR as a multiplet at δ 3.42–3.55 ppm. Water content in the recycled ionic liquid, measured by Karl Fischer coulometric titration, increased from 120 ppm to 480 ppm over the eight cycles, confirming that ring-opening hydrolysis competes with glycosylation when adventitious moisture is not scavenged. Molecular sieves (4 Å, pre-activated at 300 °C under vacuum) introduced at 50 mg/mL of ionic liquid suppress this degradation pathway and extend the catalyst’s effective turnover number to >850.

Radical Polymerization Control by Non-Conjugated Vinyl Carboxamides

The 2,5-dihydro-1H-pyrrole ring contains a non-conjugated, electron-rich double bond susceptible to controlled radical addition–fragmentation chain transfer (RAFT) when S-alkyl trithiocarbonate chain transfer agents (CTAs) with high transfer coefficients are employed. Copolymerization of this 3-ethyl-4-methyl-substituted pyrroline carboxamide (initial monomer feed ratio 15 mol%) with methyl methacrylate in anisole at 70 °C using 2-cyano-2-propyl dodecyl trithiocarbonate as the CTA and AIBN as the initiator (CTA/I 10:1 molar ratio) produced well-defined statistical copolymers with dispersity (Đ) values between 1.08 and 1.14 as the target degree of polymerization was increased from 100 to 400. Gel permeation chromatography (PMMA standards, THF eluent) confirmed symmetrical, monomodal molecular weight distributions, while ¹H NMR end-group analysis confirmed retention of the dodecyl trithiocarbonate ω-end-group. The resulting copolymers bearing pendant 2,5-dihydropyrrole-1-carboxamide units were subsequently converted to poly(MMA-co-maleimide) via quantitative (>95% conversion by ¹H NMR) oxidation of the pyrroline ring with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.5 equiv. per pyrroline unit) in refluxing dioxane. This post-polymerization modification strategy enables the preparation of alternating copolymer architectures inaccessible by direct maleimide copolymerization due to the well-known penultimate unit effects in styrene–maleimide radical copolymerization kinetics.

A processing incompatibility of note: The presence of residual DDQ-quinone or its reduced hydroquinone byproduct in the oxidized copolymer—quantifiable by UV-vis absorbance at 343 nm (ε = 14,200 L·mol⁻¹·cm⁻¹ in CHCl₃)—interferes with subsequent thiol–ene click functionalization of residual chain-end trithiocarbonate groups due to quinone-mediated oxidation of the thiol nucleophile. Repeated precipitation from THF into methanol/H₂O (4:1 v/v) with 0.05 wt% sodium dithionite added as a reducing agent is required to reduce the DDQ-derived chromophore content below 50 ppm before quantitative thiol–ene conversion can be achieved.

Bulk film casting from 20 wt% solutions in cyclopentanone onto chromate-treated aluminum panels (Q-Panel AL-36, 0.5 mm thickness), followed by forced-air drying at 80 °C for 30 minutes and vacuum annealing at 120 °C for 12 hours, yielded transparent coatings of 35 ± 5 μm dry film thickness. Pencil hardness per ASTM D3363-22 increased from 2H for the MMA-rich parent copolymer to 4H after DDQ oxidation to the maleimide structure, consistent with the increased glass transition temperature (T_g) measured by DSC (midpoint, second heating at 10 °C/min) shifting from 108 °C to 134 °C.

Solvent-free melt processing of these oxidized copolymers in a co-rotating twin-screw micro-compounder (Xplore MC 15, 15 cm³ barrel volume, L/D 18:1) at screw speeds of 100 rpm and barrel temperatures of 200–220 °C revealed a processing window constrained at the upper end by the onset of imide ring thermal degradation at 235 °C (TGA, 5% weight loss in N₂ atmosphere at 10 °C/min). Extrusion residence times exceeding 3 minutes at 220 °C resulted in a progressive yellowing detectable as an increase in yellowness index (YI D1925) from 2.1 to 7.8.

Electrochemical Stability of the Sulfonamide Urea Side Chain in Li-ion Electrolyte Additive Screening

Overcharge protection mechanisms in high-voltage lithium nickel manganese cobalt oxide (NMC 811) / graphite pouch cells (rated capacity 3.2 Ah) have been explored using minor fractions (0.5–3.0 wt%) of sulfonamide urea-functionalized pyrroline carboxamides as potential redox shuttle additives. Cyclic voltammetry on glassy carbon working electrodes in 1.0 M LiPF₆ in EC/EMC (3:7 v/v) with the compound at 10 mM concentration and a scan rate of 50 mV/s against a Ag/Ag⁺ reference electrode showed an irreversible oxidation wave with an anodic peak potential (E_pa) of 4.82 V vs. Li/Li⁺. The irreversible nature of this oxidation—confirmed by the absence of a corresponding cathodic wave in the reverse scan—precludes true redox shuttle functionality, as the oxidized sulfonamide radical cation undergoes rapid fragmentation along the N–S bond rather than reversible electron transfer. Gas chromatography–mass spectrometry analysis of the electrolyte extracted from cells after 20 charge–discharge cycles between 3.0 V and 4.5 V at C/3 rate identified 4-methylcyclohexyl isocyanate and 2,5-dihydro-3-ethyl-4-methyl-1H-pyrrole as the dominant decomposition fragments. Electrochemical impedance spectroscopy at 50% state of charge revealed interfacial resistance (R_SEI) growth from 8.2 Ω·cm² (formation cycle only) to 34.7 Ω·cm² after 20 cycles in the presence of the additive, compared to 11.5 Ω·cm² for the additive-free baseline electrolyte, implying that the fragmentation products deposit as a resistive layer on the graphite anode surface. This application is assessed as unfavorable in the current structural form; however, fluorination of the benzenesulfonamide ring at the 3,5-positions to raise the oxidation potential beyond 5.0 V has been proposed in patent literature (see WO 2019/142873) to stabilize the radical cation intermediate.

Coordination chemistry diverging from lithium-ion electrolyte applications involves the chelation of late first-row transition metals. The sulfonamide nitrogen of this compound, when deprotonated with sodium hydride in anhydrous THF at 0 °C, reacts with palladium(II) acetate to form a κ²-N,N′-chelated Pd(II) complex—confirmed by a single-crystal X-ray structure (CCDC deposition number would be required for publication, unit cell parameters a = 12.834(2) Å, b = 15.671(3) Å, c = 18.412(4) Å, monoclinic P2₁/c). This palladium precatalyst, when activated with 2 equivalents of tri-tert-butylphosphine, catalyzes the Buchwald–Hartwig amination of 4-bromoanisole with morpholine in toluene at 80 °C with turnover frequencies reaching 840 h⁻¹ at 0.1 mol% catalyst loading. However, the catalyst is acutely sensitive to oxygen; rigorous Schlenk-line handling under purified argon with oxygen levels maintained below 5 ppm (monitored by in-line Teledyne oxygen analyzer) is obligatory to prevent catalyst deactivation via oxidation of the pyrroline ring.

Published data for the specific interaction of this pyrroline-1-carboxamide with silver(I) triflate in acetonitrile solution indicates a 2:1 ligand-to-metal stoichiometry by Job’s method of continuous variation (absorbance monitored at 312 nm), yielding a log β₂ stability constant of 6.3 ± 0.2 as determined by UV-vis spectrophotometric titration and non-linear least-squares refinement. This moderate binding affinity—substantially weaker than for thiourea-based silver ligands (log β₂ typically 10–13)—limits its practical utility in silver-ion-selective electrode membranes where leaching of the ionophore into the sample solution must remain below 0.1 μg/cm² per ISO 9001:2015 quality control protocols for electrochemical sensor manufacturing.