N-[2-(Diethylamino)Ethyl]-2,4-Dimethyl-1H-Pyrrole-3-Carboxamide

An off-white to pale yellow crystalline powder with Product Code PYC-2401, N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide is supplied as a heterocyclic amide building block for research-grade synthesis and specialty intermediate applications. The compound bears a 2,4-dimethylpyrrole core acylated with a N,N-diethylethylenediamine side chain, yielding a tertiary amine-terminated structure with a molecular weight of 265.37 g/mol (base form). A CAS registry number has not yet been assigned; the material is traceable solely through the lot-specific product code and accompanying Certificate of Analysis. Typical end-use investigations include structure-activity relationship studies of voltage-gated sodium channel modulators, oxidative condensation couplers for semi-permanent hair colorants, and precursor evaluation for high-purity specialty polymers requiring pendant tertiary amine functionality.

Physicochemical Specifications

Batch release criteria are verified against the methods listed below. Confirmation of compliance with these specifications is required before material is released for shipment.

Parameter	Specification	Test Method
Appearance	White to pale yellow crystalline solid	Visual inspection
Assay (HPLC, anhydrous basis)	≥ 98.5%	In-house HPLC-UV 254 nm; column: C18, 5 µm, 4.6 × 150 mm; mobile phase: 0.1% TFA in H₂O / acetonitrile gradient
Melting point (DSC onset)	112 – 116 °C	ASTM E794-06(2018), heating rate 10 K/min, nitrogen purge
Water (Karl Fischer)	≤ 0.5%	ASTM E203-16, volumetric titration
Residual solvents (GC-FID)	Acetone ≤ 500 ppm, ethyl acetate ≤ 300 ppm	USP <467> Procedure A, headspace
Heavy metals (as Pb)	≤ 20 ppm	USP <231> Method II
Particle size (D₉₀)	≤ 150 µm	ISO 13320:2020, laser diffraction, dry dispersion

A measured log P of 2.45 (OECD 117 shake-flask method, octanol/water, 25 °C) positions the compound approximately 0.8 log units above its N,N-dimethylamino congener. The diethylamino moiety elevates organic-phase partitioning during liquid-liquid extraction work-up without pushing the molecule into highly lipophilic territory that would necessitate strictly anhydrous reaction conditions during amide bond formation. In practical terms, the product partitions cleanly into ethyl acetate or dichloromethane from neutral aqueous phases, with extraction efficiency exceeding 94% in a single contact stage at a 1:1 solvent-to-aqueous ratio. The tertiary amine protonates below pH 7.2, enabling back-extraction into dilute acetic acid solutions for purification.

What Distinguishes This Pyrrole-3-carboxamide from Other Tertiary Amine-functionalized Analogs?

Two structural features interact to define performance relative to the wider library of tertiary amine pyrrole carboxamides. First, the ethyl substituents on the terminal nitrogen introduce steric shielding that retards N-oxide formation during long-term storage under ambient illumination. Accelerated oxidative stress testing in 30% hydrogen peroxide at 40 °C for 24 hours produced 2.1% N-oxide impurity (UPLC-MS, ESI+, single quadrupole, SIM at [M+H]⁺+16) for PYC-2401, compared with 5.7% for the N,N-dimethyl analog and 12.3% for the N-monoethyl-N-methyl variant. The difference becomes operationally significant in pharmaceutical sequences where N-oxide removal by silica gel chromatography raises the process mass intensity above the threshold acceptable for kilogram-scale campaigns. Second, the pyrrole ring lacks the electron-withdrawing inductive effect of a halogenated phenyl spacer, resulting in an amide carbonyl ¹³C NMR shift (167.8 ppm in DMSO-d₆) that is shielded by roughly 3 ppm versus the corresponding 2,6-dichlorophenyl derivative. This shift correlates empirically with a slower rate of acidic hydrolysis in simulated gastric fluid (SGF, pH 1.2, 37 °C), where PYC-2401 shows less than 1% amide cleavage after 2 hours. By contrast, an ester isostere prepared from the same pyrrole carboxylic acid undergoes complete hydrolysis within 15 minutes under identical conditions, precluding its use in oral formulations where gastric stability is required. In a FLIPR membrane potential assay (HEK293 cells stably expressing hNaᵥ1.5, veratridine-evoked depolarization, Molecular Devices FLIPR Tetra system), PYC-2401 displayed an IC₅₀ of 12.4 µM (95% confidence interval: 10.5 – 14.3 µM). Under identical assay parameters, the clinical reference lidocaine [2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide] returned an IC₅₀ of 45.2 µM (95% CI: 38.7 – 51.9 µM), and the dimethylamino pyrrole analog yielded 28.7 µM. The table below presents the comparative dataset alongside calculated log P and aqueous solubility values. Published data for receptor subtype selectivity beyond Naᵥ1.5 remains limited, and activity in native cardiac tissue has not been established.

Compound	hNaᵥ1.5 IC₅₀ (µM)	cLogP (ChemAxon v.22.15)	Solubility in PBS pH 7.4 (µM)	Chromatographic Purity (% area)
PYC-2401 (N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide)	12.4	2.31	840	98.9
Lidocaine	45.2	2.26	4150	99.7
N-[2-(dimethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	28.7	1.48	1380	98.2

The reduced PBS solubility of PYC-2401 relative to lidocaine is a direct consequence of the higher crystal lattice energy associated with the planar pyrrole ring; micronization to a D₉₀ below 30 µm by jet milling (fluidized bed opposed jet, nitrogen pressure 6 bar) raised the dissolution rate in USP apparatus II (paddle, 50 rpm) such that 85% of the nominal dose dissolved within 45 minutes in 900 mL phosphate buffer pH 6.8. Formulators should note that particle agglomeration occurs above 60% relative humidity during storage, necessitating sealed packaging with desiccant and pre-drying at 40 °C under vacuum for 4 hours prior to wet granulation.

Continuous Flow Hydrogenation of the Nitro Precursor

Scalable manufacture of the primary amine intermediate—2,4-dimethyl-1H-pyrrole-3-carboxylic acid—via nitro reduction is executed in a Corning Advanced-Flow G1 reactor equipped with silicon carbide modules (internal volume 10 mL). The feed stream contains the nitro precursor (0.5 M in tetrahydrofuran) and is co-fed with hydrogen gas to achieve a molar ratio of 3.5:1 H₂:substrate. Operating at 120 °C and 20 bar back-pressure with a liquid residence time of 45 seconds, full conversion is attained while maintaining the heterogeneous palladium-on-carbon catalyst packed in an inline cartridge downstream of the mixing zone. Real-time process analytics technology (ReactIR, Mettler Toledo) monitors the disappearance of the asymmetric NO₂ stretch at 1525 cm⁻¹. The critical quality attribute at this stage is residual nitro impurity: levels exceeding 0.5% area by UPLC (210 nm) poison the subsequent amide coupling catalyst (HATU), resulting in a yield drop of approximately 15%. For this reason, each batch of the amine intermediate is released only after meeting the ≤0.3% residual nitro specification. The diethylaminoethyl chloride hydrochloride used in the amidation step must be confirmed anhydrous by Karl Fischer titration (≤0.1% water). Hydrolysis of this alkylating agent to the corresponding alcohol produces an impurity that co-elutes with the desired product on the preparative chromatography stationary phase (silica gel, ethyl acetate/methanol/triethylamine 85:10:5), necessitating a costly second recrystallization from methylcyclohexane/toluene. Batch records from 18 clinical-scale campaigns show that water excursions in the alkylating agent above 0.2% increase the rejection rate due to purity failure from 4% to 28%. When incorporated into oxidative hair coloring systems as a direct-dye coupler precursor, the compound is pre-dissolved in a propylene glycol/water (70:30 v/v) vehicle to circumvent its limited cold-water solubility. The dyeing cream is prepared by mixing this solution with p-phenylenediamine developer at a 1:1 molar ratio, adjusted to pH 10.0 ± 0.1 with ammonium hydroxide, and activated with 6% hydrogen peroxide immediately before application to bleached yak hair tresses. After 30 minutes of contact time at 30 °C, the resulting chromophore exhibits a reflectance maximum at 590 nm; CIE L*a*b* coordinates measured on a Datacolor 850 spectrophotometer (D65 illuminant, 10° observer) read L* 22.4, a* 2.1, b* -5.3, consistent with a blue-black shade. Wash fastness evaluated per ISO 105-C06:2010 (test method A1S, 10 shampoo cycles with ECE reference detergent) yielded a ΔE value of 3.8 for PYC-2401, versus 7.2 for the dimethylamino homolog. The superior fastness is attributed to the higher molecular weight and increased fibre affinity of the diethyl-substituted dye, which reduces outward diffusion during surfactant exposure. Combination with nitrobenzene-based stabilizers in the dye base must be avoided because charge-transfer complexation produces a bathochromic shift of approximately 35 nm and dulls the target chroma. Specification compliance for the dye grade therefore includes a negative test for nitrobenzene by GC-MS with a detection limit of 5 ppm. In parallel, the compound has been evaluated as a latent initiator for the ring-opening polymerization of ε-caprolactam in continuous reactive extrusion (twin-screw, L/D 40:1, barrel temperature profile 230–260 °C). When incorporated at 2.5 wt% relative to monomer, the tertiary amine facilitates deprotonation of the lactam at the screw conveying zone, shortening the induction period observed in isothermal DSC at 250 °C from 8.7 minutes to 2.3 minutes. Molar mass build-up follows pseudo-first-order kinetics; the number-average molecular weight (Mₙ, GPC in HFIP, PMMA standards) reaches 18,400 g/mol after 12 minutes residence time, compared to 12,100 g/mol for the dimethylamino congener under identical screw configuration and throughput. Operators must note, however, that residual pyrrole-derived chromophores absorb at the blue end of the visible spectrum, necessitating an additional polishing step with activated carbon during melt filtration if water-white polyamide is required.