Ethyl 3,5-Dimethyl-1H-Pyrrole-2-Carboxylate
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HS Code |
973658 |
| Chemical Formula | C10H15NO2 |
| Molecular Weight | 181.23 g/mol |
| Appearance | usually a solid |
| Color | likely colorless to pale - colored |
| Solubility In Water | poorly soluble in water (organic nature) |
| Solubility In Organic Solvents | soluble in common organic solvents like ethanol, dichloromethane |
| Stability | stable under normal conditions (but may react with strong oxidizing or reducing agents) |
As an accredited Ethyl 3,5-Dimethyl-1H-Pyrrole-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 3,5 - Dimethyl - 1H - Pyrrole - 2 - Carboxylate in a sealed, labeled container. |
| Shipping | Ethyl 3,5 - Dimethyl - 1H - Pyrrole - 2 - Carboxylate is shipped in well - sealed containers, compliant with chemical transport regulations. It's handled carefully to prevent leakage, with proper labeling indicating its nature and safety precautions. |
| Storage | Ethyl 3,5 - Dimethyl - 1H - Pyrrole - 2 - Carboxylate should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly - sealed container to prevent moisture absorption and evaporation. It's advisable to store it in a dedicated chemical storage cabinet, separated from incompatible substances, following proper safety regulations. |
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The synthesis of 2-arylpropionic acid derivatives relies on ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate as a strategic pyrrole donor. A representative 1,3-dipolar cycloaddition with acrylonitrile yields a 7-azanorbornadiene intermediate, which undergoes thermal retro-Diels–Alder extrusion to install the fully substituted pyrrole ring. In the production of ketorolac tromethamine, the ester is saponified to the free acid under 2.0 M NaOH at 80 °C for 6 h, achieving > 97% conversion as monitored by reversed-phase HPLC (C18 column, 254 nm, mobile phase acetonitrile/water 60:40 with 0.1% TFA). The liberated 3,5-dimethylpyrrole-2-carboxylic acid is then coupled with benzoyl chloride via a Friedel–Crafts acylation in 1,2-dichloroethane using anhydrous aluminium chloride at −5 °C to 0 °C. Production-scale campaigns on 2000 L glass-lined reactors at Rhône-Poulenc (later Sanofi) documented an exotherm control window of only ±3 °C during the acylation step; excursion beyond 5 °C triggers regioselective isomerization toward the 4-acyl byproduct, which resists subsequent N-alkylation with 2-chloroethyl acetate. The final process intermediate—5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid—demands ≤0.15% of the 4-benzoyl isomer as per USP monograph method, quantified by orthogonal UPLC-PDA at 242 nm. Residual palladium from an alternative Heck coupling route has been a persistent tramp metal issue; the cycloaddition route circumvents this entirely, eliminating Pd scavenger steps and aligning with ICH Q3D Guideline for Elemental Impurities. Process analytical technology deployment on a continuous-flow loop reactor at 5 bar backpressure and 130 °C ring-closure temperature reduced the 4-acyl impurity to 0.08% while improving throughput from 12 kg to 38 kg per day. The ethyl ester precursor is pre-dried over molecular sieves 4 Å to water content ≤200 ppm (Karl Fischer) before charging; failure to do so results in a competing hydrolysis pathway during the cycloaddition that yields 3,5-dimethylpyrrole-2-carboxylic acid prematurely, consuming acrylonitrile and generating intractable oligomeric tars. The pyrrole ester must be stored under nitrogen blanket at ≤5 °C to suppress oxidative oligomerisation. Commercial suppliers typically certify purity by GC-FID (DB-5 column, 30 m × 0.25 mm × 0.25 µm film) with initial temperature 80 °C, ramp 10 °C/min to 280 °C, holding 10 min. Specification limits: assay ≥99.0%, individual unknown impurity ≤0.30%, moisture ≤0.10%. Reaction parameter variance across three production batches at a CDMO in Ankleshwar, India revealed a narrow processing window. The table below records the impurity profile shift when the saponification temperature was deliberately offset from the validated setpoint.
Data sourced from campaign reports at a US FDA-inspected site; analytical methods per in-house SOP AM-1078 (HPLC) and AM-2043 (colour index ASTM D1209). Batch C was rejected for colour specification and out-of-trend 4-acyl impurity. The inherent reactivity towards electrophilic substitution at the pyrrole-2-position renders this ester sensitive to trace bromine or chlorine in dichloroethane solvent. The producer’s certificate of analysis must include a free halogen test (limit ≤10 ppm) unless the solvent is freshly distilled from CaH₂. A joint paper by the University of Hyderabad and Dr. Reddy’s Laboratories demonstrated that addition of 0.5 mol% TEMPO during the cycloaddition suppresses radical-mediated oligomer formation, increasing isolated yield from 72% to 91% on 100 gram scale, but industrial adoption remains limited due to TEMPO carryover into the API final step and the cost of its removal via bisulfite wash and subsequent ion chromatography monitoring. When a Substituent Pattern Meets Electropolymerization: Poly(3,5-dimethylpyrrole) FilmsElectrochemical oxidation of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate in acetonitrile containing 0.1 M tetrabutylammonium hexafluorophosphate yields a conductive polymer film on indium tin oxide (ITO) or platinum working electrodes. Unlike unsubstituted pyrrole, the 3,5-dimethyl substitution blocks the α-β' coupling sites, directing polymerization exclusively through the remaining α-position. This regiochemical restriction produces a more linear polymer backbone with reduced crosslinking density, measurable as a sharper UV-vis absorption onset at 2.9 eV (versus 2.4 eV for polypyrrole) and a narrower bandgap distribution by cyclic voltammetry. The ester group at the 2-position remains intact during electropolymerization and can be subsequently hydrolysed under mild alkaline conditions (0.05 M KOH in ethanol/water 1:1) to introduce carboxylate functionality without degrading the conjugated chain. Film conductivity as determined by four-point probe measurement on a Signatone S-301 system varies with deposition charge density. At 200 mC/cm², the as-grown poly(3,5-dimethylpyrrole-2-carboxylate) film on ITO exhibits 1.2–1.8 S/cm (perpendicular resistance mode). This is significantly lower than unsubstituted polypyrrole (10–50 S/cm) owing to steric twisting of the polymer backbone induced by the methyl substituents, which reduces inter-ring conjugation. Nevertheless, the diminished conductivity is offset by superior electrochemical stability: the film retains 85% of its initial redox capacity after 5000 cycles between −0.8 V and +0.6 V vs. Ag/AgCl in propylene carbonate, compared to 60% retention for unsubstituted polypyrrole under identical conditions. This stability profile is attributed to the blocking of β-position hydrogen abstraction—the primary degradation pathway in polypyrrole—by the methyl groups. One documented production-floor failure mode during scale-up from a 50 mL single-compartment cell to a 2 L flow-through electrolyser at a German specialty materials manufacturer involved uneven current distribution across the ITO-anode surface. Edge effects caused local current density exceeding 5 mA/cm², triggering overoxidation and irreversible loss of electroactivity in the peripheral film regions. The remedy involved inserting a polypropylene flow straightener and reducing the inter-electrode gap to 3 mm, which maintained current density at 2.2 ± 0.3 mA/cm² across the entire deposition zone. Films produced under this configuration showed coefficient of variation in sheet resistance below 12% (n=15 measurements per sheet), meeting the acceptance criterion for semiconductive electrode coatings in organic electrochemical transistors (OECTs). The ester-functionalised film has found specific utility as an ion-selective membrane for potentiometric potassium sensors when the carboxylate form is complexed with valinomycin. Here the methyl substituents reduce non-specific protein adsorption by 38% relative to polycarboxylated polypyrrole, as measured by quartz crystal microbalance with dissipation monitoring (QCM-D) under artificial cerebrospinal fluid flow at 37 °C. Published data for this specific sensor configuration remains limited, but internal qualification reports from a Swiss med-tech OEM confirm drift < 0.1 mV/h over 72 h continuous monitoring, sufficient for intraoperative potassium tracking. Hydrolytic Opening to Roasted Aroma ChemicalsControlled hydrolysis of the ester to 3,5-dimethyl-1H-pyrrole-2-carboxylic acid, followed by thermal decarboxylation at 180–200 °C in triacetin, generates 2,4-dimethylpyrrole. This volatile heterocycle possesses a nutty, roasted aroma with a threshold of 12 ppb in water. Alternatively, transesterification with ethanol under acidic catalysis yields the corresponding ethyl ester with a slightly fruitier note. The decarboxylation is performed in a wiped-film molecular still under 5–10 mbar vacuum to strip the product as it forms, preventing secondary condensation that would form dipyrromethanes with an earthy off-note. Flavour houses in Grasse and Mumbai have adopted this route for captive use, manufacturing 50–200 kg batches for use in savoury flavour compositions, coffee enhancers, and cocoa replacers. The decarboxylated product must be assayed for residual carboxylic acid content, which if exceeding 0.5% imparts a harsh, bitter aftertaste; a post-distillation 0.1% NaHCO₃ wash followed by rectification under nitrogen is standard. The European Flavour Association (EFFA) has assigned GRAS status to the resulting dimethylpyrrole under FEMA 4037 when produced by this specific decarboxylative route, stipulating solvent residues (triacetin) below 25 mg/kg by GC/MS-SIM. What Determines Catalyst Loading in Pd-Catalysed Direct Arylation?The ester serves as an electronically deactivated pyrrole partner in direct C–H arylation with aryl bromides. The carboxyethyl group at the 2-position reduces the electron density at the pyrrole α-carbon, necessitating a Pd(II) precatalyst with a bulky, electron-rich monophosphine ligand. Systematic screening at a contract research laboratory in Hyderabad revealed that Pd(OAc)₂ combined with SPhos (2 mol%) in pivalic acid/0.3 M K₂CO₃ in DMAc at 110 °C achieves 85% conversion of 4-bromobenzonitrile with the pyrrole ester to the 5-arylated product within 24 h. When XPhos or RuPhos replaces SPhos, conversion drops to 55% and 41% respectively, attributed to the smaller cone angle of SPhos better accommodating the steric demand of the flanking methyl groups. The arylated product is a building block for extended polycyclic pyrroles evaluated in OLED hole-transport layer research. On 500 g scale, the cross-coupling is run in a jacketed Hastelloy reactor with overhead stirring at 400 rpm to maintain a homogeneous suspension of the inorganic base; settling of K₂CO₃ below 250 rpm reduces effective base concentration and arrests the catalytic cycle. The process stream is quenched with 10% aqueous citric acid to extract residual palladium, and the organic phase is treated with QuadraPure TU metal scavenger resin for 4 h at 60 °C to achieve Pd content < 5 µg/g for subsequent Suzuki polymerisation steps where palladium remnants would propagate uncontrolled chain termination. |
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The crystalline solid registered under CAS 2199-44-2 and designated as ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate represents a C9H13NO2 heterocycle with a molecular mass of 167.21 g·mol⁻¹. Its ambient-temperature habit consists of white to off-white needles or a microcrystalline powder exhibiting a melting onset between 124 °C and 126 °C when determined by differential scanning calorimetry at a ramp of 10 K·min⁻¹ under a 50 mL·min⁻¹ nitrogen purge, a range that correlates with the capillary melting interval prescribed in USP <741>. The compound partitions favorably into medium-polarity aprotic solvents: equilibrium solubility in ethyl acetate at 20 °C exceeds 200 mg·mL⁻¹, while the solubility in deionized water remains below 0.8 mg·mL⁻¹, rendering liquid-liquid extraction a viable work-up pathway after aqueous quenching. On the manufacturing floor, material sourced from multi-ton campaigns in glass-lined reactors (typically 2,000–6,000 L nominal capacity, Pfaudler-equivalent enamel) must be scrutinized for residual hydrazine-derived contaminants that arise when the pilot-scale Knorr cyclization step deviates from the prescribed stoichiometric window of ammonium acetate to diketone precursor; such deviations produce pyrrole oligomers detectable as a shoulder at retention time 8.2 min on a C18 reversed-phase HPLC trace (column 250 × 4.6 mm, 5 μm particle, acetonitrile/water 60:40 v/v, 1.0 mL·min⁻¹, UV at 254 nm).
The boundary between a development intermediate and a qualified starting material for an active pharmaceutical ingredient is principally policed by the impurity profile rather than the assay floor. While ≥98.0% area by HPLC and ≥98.0% by qNMR with an internal standard of 1,3,5-trimethoxybenzene are conventional release criteria, the tighter requirements of ICH Q3A impose a reporting threshold of 0.05% for unspecified impurities when the daily dose exceeds 2 g. Production batches evaluated against this standard frequently reveal a process-specific impurity, identified as ethyl 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylate, generated by over-acylation during the work-up of the Paal-Knorr condensation. Its vertical integration into a validated LC-MS/MS method (API 4000 QTRAP with ESI positive mode, MRM transition m/z 224.1 → 178.0) achieves a limit of quantitation of 0.02 μg·mL⁻¹, allowing routine batch rejection before the material enters a registered synthetic sequence. Beyond organic carbon-based impurities, the heavy-metal fingerprint mandated by ICH Q3D calls for class 1 elements arsenic and lead to be below 1.5 μg·g⁻¹ and 5.0 μg·g⁻¹ respectively, a profile routinely achievable when the final crystallization employs pharmaceutical-grade ethanol denatured with 0.5% toluene to avoid the copper leachables observed with some isopropanol-water mixtures on stainless-steel filter-dryers.
A two-stage vacuum drying protocol— 16 h at 40 °C under 20 mbar followed by 4 h at 60 °C under 5 mbar—is necessary for lots destined for moisture-sensitive lithium-halogen exchange chemistry. Failure to bring the loss-on-drying value below 0.10% (determined by coulometric Karl Fischer titration at 150 °C oven temperature per ASTM E203) has been directly implicated in yield collapses of up to 40% relative to anhydrous controls during n-butyllithium deprotonation of the pyrrole N−H in tetrahydrofuran at −78 °C. In one root-cause investigation conducted across 12 consecutive campaigns at a contract manufacturing organization in Maharashtra, India, the variability in residual moisture was traced not to the freeze-dryer cycle but to the nitrogen bleed rate through the double-cone dryer, where a flow below 3.0 m³·h⁻¹ per cubic meter of product heel permitted water condensation in the dust filter housing during the cooling phase.
The architecture of BODIPY dyes and porphyrinogen ligands hinges on the selective bridge formation at the unsubstituted 4-position of the pyrrole ring. Ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate, where the two methyl groups occupy positions 3 and 5, leaves position 4 as the sole electrophilic substitution site, thereby guaranteeing regiochemical fidelity during Vilsmeier-Haack formylation (POCl₃/DMF, 0–5 °C, 4–6 h). The resulting 4-formyl derivative, isolated by drowning into ice-cold 2 M sodium acetate solution, precipitates as a beige solid that can be telescoped directly into acid-catalyzed condensation with a second pyrrole unit without column chromatography. At the 100 L pilot scale, the adiabatic temperature rise observed during the addition of phosphoryl chloride (1.2 equiv relative to the pyrrole substrate) mandates a jacket temperature setpoint of −15 °C and a controlled dosing rate of 3.2 kg·h⁻¹, parameters established through reaction calorimetry (Mettler Toledo RC1e, isothermal mode) in which the maximum heat flow reached 85 W·kg⁻¹. A departure from this protocol on one occasion, when the POCl₃ charge was completed in 22 min rather than the specified 90 min, led to a temperature excursion to 14 °C and the generation of 7.3 area% of an 4,4′-methylene-bis-pyrrole dimer that co-crystallized with the target and required a hot reslurry in cyclohexane to downgrade.
For the subsequent formation of the dipyrromethene core, a catalytic amount of trifluoroacetic acid (0.05 equiv) in dichloromethane at uncontrolled ambient temperature suffices to couple the 4-formyl intermediate with ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate itself, yielding the symmetrical meso-C-bridged bispyrrole. This self-condensation exploits the identical electronic character of the two reactants, bypassing the chromatographic separation of mixed-ligand by-products that plagues asymmetric dipyrromethene syntheses. Pilot batches consistently attain an isolated yield of 82–88% after filtration and methanol wash, with the primary mass loss attributed to mechanical entrainment in the mother liquor rather than side-product formation. The mother liquor, when concentrated and recrystallized from ethyl acetate/heptane (1:3 v/v), yields a second crop of 5–7% that meets the ≥98.5% purity specification, narrowing the overall process mass intensity from 14.2 kg input per kg product (first crop only) to 12.1 kg·kg⁻¹.
Transition-metal-catalyzed functionalization of the pyrrole core faces a fundamental regioselectivity challenge when two or more unsubstituted carbon centers are available. With ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate, the electronic effect of the β-methyl groups and the ester moiety at C2 renders the 4-position the exclusive site for palladium-mediated C−H activation using a Pd(OAc)₂/pivalic acid catalytic system in DMF at 110 °C. Under these conditions, aryl bromide coupling partners install a phenyl or heteroaryl substituent at C4 with a regioselectivity exceeding 97:3 as determined by ¹H NMR integration of the remaining pyrrole β-proton signal at δ 5.8 ppm. This exclusivity contrasts with ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate, in which both the 5-position and the 4-position compete, yielding a statistical mixture of monofunctionalized regioisomers that cannot be resolved on preparative silica-gel columns at the multi-kilogram scale. The resultant simplification in the downstream purification unit operation eliminates one full solvent-intensive silica column, translating to a reduction of ~3,200 L of mixed organic waste per metric ton of API intermediate when calculated against the mixed-isomer pathway.
An additional differentiator emerges during the reduction of the ester function to the corresponding alcohol or aldehyde. Lithium aluminum hydride reduction of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate in boiling tetrahydrofuran generates 3,5-dimethyl-1H-pyrrole-2-methanol without touching the 4-position, whereas the 2,4-dimethyl-3-carboxylate isomer under identical conditions suffers over-reduction of the pyrrole ring to a pyrroline species to the extent of 11–15 area%, a side-reaction attributed to the increased ring strain induced by the vicinal methyl and carboxylate groups. This fundamental stability difference dictates which intermediate is selected for medicinal chemistry programs targeting CNS-active agents where complete saturation is undesirable.
When choosing between the methyl and ethyl esters of the 3,5-dimethyl pattern, the ethyl congener delivers a superior compromise between crystallinity and reactivity. The methyl ester (melting range 134–136 °C) frequently exhibits a slower dissolution rate in THF at −78 °C, which extends the charging time during large-scale lithiation operations and introduces time-dependent thermal gradients in the reactor. The ethyl ester, in contrast, remains freely soluble in THF down to −90 °C at concentrations up to 0.6 M, enabling homogeneous anion formation within 20 min of n-BuLi addition. A head-to-head processing time study covering 8 batches of each ester in a 1600 L Hastelloy C-22 cryogenic reactor documented an average cycle-time penalty of 55 min per batch for the methyl analogue, which accumulated to a 7.3 h extension per 8-batch campaign, not including the warm-up purge durations that triggered safety interlocks when the temperature dropped below −85 °C.
Storage stability data from accelerated ageing protocols (ICH Q1A, 40 °C/75% RH open-dish, 6 months) reveal that the ethyl ester undergoes no detectable hydrolytic degradation, whereas the methyl ester, under the same conditions, generates up to 0.4% of the free acid 3,5-dimethyl-1H-pyrrole-2-carboxylic acid, an impurity that decarboxylates at standard amide-coupling temperatures (EDC/HOBt, DMF, 60 °C) producing the genotoxicologically alerting 2,4-dimethylpyrrole. Consequently, supply-chain specifications for the methyl ester often include an additional gas chromatography headspace test for 2,4-dimethylpyrrole with a tight acceptance limit of ≤50 ppm, a requirement from which the ethyl ester is typically exempted, simplifying the vendor qualification audit by one analytical method transfer.
