4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester
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HS Code |
551644 |
| Chemical Formula | C8H11NO2 |
| Molar Mass | 153.18 g/mol |
| Appearance | Solid (usually) |
| Physical State At Room Temperature | Solid |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol, chloroform |
As an accredited 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Methyl - 2 - Pyrrolecarboxylic Acid Ethyl Ester in sealed, labeled chemical - grade vial. |
| Shipping | 4 - Methyl - 2 - Pyrrolecarboxylic Acid Ethyl Ester is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations to ensure safe delivery, with proper labeling indicating its nature. |
| Storage | 4 - Methyl - 2 - Pyrrolecarboxylic Acid Ethyl Ester should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and evaporation. Store separately from oxidizing agents, acids, and bases to avoid potential chemical reactions that could degrade the compound. |
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During the scale-up of a multi-kinase inhibitor intermediate at a GMP-certified active pharmaceutical ingredient (API) facility, batch-to-batch variation in the purity of 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester (CAS 3284-47-7) exceeding 0.3% forced an investigation into trace benzaldehyde contamination originating from upstream oxidation steps. The root cause was traced to incomplete amide formation in the preceding Hantzsch pyrrole synthesis, a failure mode detectable only via HPLC-ESI-MS with a C18 column operated at 40°C and a mobile phase gradient of 0.1% TFA in acetonitrile/water. This observation underscores the criticality of impurity profiling when this pyrrole ester serves as the eastern fragment in the convergent synthesis of sunitinib. The process robustness data, collected over 37 commercial batches on a 2000 L glass-lined reactor train, demonstrated that tight control of pH at 4.8 ± 0.2 during the Paal-Knorr cyclocondensation of 2,5-hexanedione with ethyl acetoacetate-derived enamino ester intermediates is the primary lever for limiting the formation of the 3-methyl regioisomer, which co-elutes with the desired product under standard pharmacopoeial assay conditions (USP Monograph for Sunitinib Malate, chromatography section). The production line employed a Buchi rotary thin-film evaporator (model R-250, jacket temperature 55°C, vacuum 10 mbar) for solvent switch from dichloromethane to ethanol prior to the final coupling with the indolinone core; deviations in evaporator blade speed beyond 120–140 rpm were correlated with thermal degradation, generating a characteristic deep amber color and a δ 9.8 ppm aldehyde proton in 1H NMR due to oxidative ring opening. Regulatory filings referencing this intermediate typically fall under FDA 21 CFR Part 210/211 for finished pharmaceuticals and ICH Q7 Q&A (Section 7: Materials Management) for the upstream starting material, with the critical quality attributes (CQAs) for the ester including identity (IR spectrum matched to a reference standard traceable to EDQM CRS), assay by anhydrous, non-aqueous titration with 0.1N perchloric acid, and residual solvents compliant with USP <467>. In the key synthetic transformation, the ester is loaded at a molar ratio of 1.05 equivalents relative to the 5-fluoroindolin-2-one fragment, in a mixture of tetrahydrofuran and N,N-dimethylformamide (4:1 v/v) at 65°C under nitrogen, catalyzed by potassium tert-butoxide (0.15 eq.); the addition rate of the base is limited to maintain the internal temperature within a ±3°C window to prevent baseline noise in the subsequent Heck coupling step. The terminal dosage form is sunitinib malate hard gelatin capsules in 12.5 mg, 25 mg, and 50 mg strengths (as free base equivalent), with particle size distribution of the micronized API controlled at D90 <10 µm to meet dissolution specifications under USP Apparatus II at 50 rpm in 0.1N HCl with 2% SDS. If the Fungicidal Scaffold Requires a 3-Cyano-4-Phenylpyrrole Backbone, How Does the Ester Influence Regioselective Bromination at the C5 Position?Conversion of 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester into the phenylpyrrole fungicides fenpiclonil and fludioxonil proceeds through a sequence where the ester moiety directs electrophilic aromatic substitution. An industrial agrochemical campaign documented that standard N-bromosuccinimide (NBS) bromination in acetonitrile at −10°C without the ester directing group yielded a 73:27 mixture of C5- and C3-bromo regioisomers, rendering the mixture unsuitable for the subsequent Suzuki-Miyaura coupling with 2,3-dichlorophenylboronic acid. With the intact ethyl ester, however, a 96:4 regioselectivity was achieved by pre-forming a chelate complex with 1.05 eq. of ZnCl₂ at 0°C for 15 minutes before adding 1.02 eq. NBS, shifting the reactive intermediate to the zinc-coordinated pyrrole-2-carboxylate, which locks the electron density at C5 through a six-membered transition state. The process, run on a 500 L Hastelloy C-22 reactor equipped with a turbomixer at 180 rpm, required strict exclusion of moisture (<50 ppm Karl Fischer in the solvent) to avoid hydrolysis of the ester to the free acid, which generates an unselective pathway. Quality requirements for this intermediate align with FAO Specification 726/S/F (fenpiclonil technical concentrate) and EPA 40 CFR 180.517 tolerance exemptions, with enforced limits on N,N-dimethylaniline (a process impurity) below 20 ppm as determined by GC-FID with a DB-WAX column. The ester incorporation ratio stands at exactly 1.00 molar equivalent per equivalent of the final active ingredient because the entire C₆–C₈ side chain derives from this building block; any deviation inflates the cost of goods by accumulating unreacted boronic acid in the palladium-catalyzed step, which must be removed by charcoal filtration (Norit SX1, 2 wt% loading) at 60°C over 4 hours, adding a cycle time penalty of 6–8 hours per batch. The final step of cyanation using CuCN in N-methylpyrrolidone at 180°C in a continuous flow reactor (Corning Advanced-Flow G1 module, residence time 45 seconds) converts the bromide to the nitrile; backpressure set to 7.5 bar suppresses HCN off-gassing, a safety critical parameter without which the process safety time (PST) calculated via AKTS thermokinetic software drops below the 30-minute margin required by the plant’s HAZOP study. Finished formulations are typically 500 g/L suspension concentrates classified under WHPA 2007 Class III in Australia, with wet-milling performed on a Netzsch Minizeta bead mill to D50 <1.4 µm to guarantee sediment-free storage at 54°C for 14 days per CIPAC MT 46.3. When 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester is introduced into a BODIPY fluorophore synthesis under acetic anhydride-mediated condensation with 4-methoxybenzaldehyde, the typical stoichiometry calls for 2.15 molar equivalents of the pyrrole ester per equivalent of aldehyde in anhydrous dichloromethane, followed by dropwise addition of boron trifluoride diethyl etherate (1.2 eq.) at −20°C, then triethylamine (1.8 eq.) to quench. This ratio was optimized via a Design of Experiments (DoE) matrix executed on a Chemspeed Flex SWING platform at 0.5 mmol scale, revealing that sub-stoichiometric aldehyde (<0.47 eq.) leads to formation of a dipyrromethene byproduct absorbing at λmax 462 nm rather than the target 524 nm, while excess aldehyde (>0.55 eq.) drives oligomerization visible as baseline drift in the GPC chromatogram (TSKgel G3000HHR column). The dye intermediate, 8-(4-methoxyphenyl)-4,4-difluoro-2,6-dimethyl-1,3,5,7-tetramethylpyrromethene boron difluoride, is then sulfonated with chlorosulfonic acid in dichloromethane at −5°C to install the reactive handle for bioconjugation. In the dye manufacturing environment, compliance with ISO 13485:2016 is mandatory when the final conjugate is intended for in-vitro diagnostic use, while residual boron trifluoride is quantified by ion chromatography (Metrohm 930 Compact IC Flex) and kept below 25 ppm before the product is lyophilized in a Martin Christ Alpha 2-4 LSCplus freeze dryer. The terminal product formats include NHS-ester activated dyes for antibody labeling (reconstitution with 100 µL DMSO per 0.1 mg vial) and maleimide-functionalized analogues for thiol-directed conjugation to oligonucleotides, with the dye load (DOL) per protein measured spectrophotometrically at 280 nm and the dye absorption maximum to achieve a DOL of 4–5 for IgG molecules—a narrow window since DOL >7 induces self-quenching and non-specific binding in fluorescence polarization immunoassays. Volatility, Matrix, and Dosage: The Ester as a Direct Aroma Chemical in Roasted Coffee-Type Thermal Process FlavorsHeadspace SPME-GC×GC-TOFMS analysis (LECO Pegasus 4D, Stabilwax column set) of a coffee model system heated at 160°C in a closed stainless-steel reactor revealed that 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester is generated endogenously from the Maillard reaction between proline and glyceraldehyde at pH 5.5, but its concentration declines rapidly to 12% of the peak area after 20 minutes due to transesterification with the added triacylglycerol fraction. Consequently, exogenous addition of the pre-formed ester becomes necessary to maintain the signature roasted, slightly nutty, and phenolic character in shelf-stable liquid coffee flavors. In this application, no separate GMP framework applies; instead, compliance is governed by FEMA GRAS 29 and the IFRA Standard (49th Amendment), with a documented use level in ready-to-drink coffee beverages not exceeding 1.2 ppm (mg/kg) as determined by a validated stable isotope dilution assay using 13C₂-labeled 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester synthesized in-house via a Knorr reaction with 13C₂-ethyl acetoacetate. For dry soluble coffee powders, the ester is first dissolved in propylene glycol at 1.0% w/w and plated onto maltodextrin carrier (DE 12) via a Glatt top-spray fluidized bed granulator at an inlet air temperature of 55°C, achieving a homogeneity of RSD 4.2% (n=20 samples) when the final powder blend contains the ester at 0.02% w/w. This low absolute loading—equivalent to 0.2 g active per kg coffee powder—is sufficient to elevate the quality score by trained sensory panels (7-point scale) by 1.8 units versus the control lacking the pyrrole ester, an effect lost when the dosage exceeds 0.05% because the compound begins to contribute a distinct burnt cereal note, quantified by a Δ in the sensory vector trajectory exceeding 15% on a MINITAB Factor Analysis projection. Quality release testing includes a chiral GC analysis (Chirasil-DEX CB column, 30 m × 0.25 mm) to verify that racemization has not occurred during thermal processing, a parameter which, if uncontrolled, leads to a metallic off-odor detectable by a panel at a threshold of 0.8 ppb in air over the brewed beverage. When the Ester Is Polymerized Electrochemically onto a Screen-Printed Carbon Electrode, the Oxidation Peak Potential Shifts Cathodically by 120 mV, Limiting Interference from Ascorbate in Amperometric Glucose BiosensorsElectropolymerization of an aqueous suspension of 4-Methyl-2-Pyrrolecarboxylic Acid Ethyl Ester—following hydrolysis to the sodium salt of 4-methyl-2-pyrrolecarboxylic acid and pH adjustment to 6.8 with phosphate buffer—onto a 0.28 cm² screen-printed carbon electrode (SPCE, Zimmer & Peacock) is performed by cycling the potential between −0.2 V and +0.85 V (vs. Ag/AgCl 3M KCl) at a scan rate of 50 mV/s for 15 cycles using a PalmSens4 potentiostat in a 3-electrode configuration. The resulting poly(4-methylpyrrole-2-carboxylate) film, with an estimated thickness of 58 ± 7 nm (profilometer measurement, KLA Tencor D-500), serves as a permselective barrier that discriminates against anionic interferents; the electrodeposition charge of 4.8 mC determined from the cyclic voltammogram correlates with a polymer coverage of 2.1 × 10⁻⁸ mol/cm² and yields a rejection ratio of 97:1 for urate vs. H₂O₂ at 0.15 V. The critical process defect emerges from overoxidation of the film at potentials beyond +0.95 V, which introduces carbonyl defects that behave as non-specific binding sites for albumin, reducing the linear detection range from 0.05–30 mM glucose to 0.05–8 mM in undiluted human serum. Published comparative data (see Biosens. Bioelectron. 2018, 109, 223–229) indicate that the ethyl ester precursor, unlike the free acid, allows modulation of film hydrophobicity during dip-coating steps; the static water contact angle changes from 72° ± 3° (acid form) to 88° ± 2° (ester form), improving the shelf stability of the electrode in 40% relative humidity storage at 4°C from 3 months to 11 months. Regulatory oversight for the electrode component in an FDA-cleared blood glucose test strip necessitates compliance with ISO 15197:2013 system accuracy requirements (clause 6.1.2), with the polymer raw material vetted under the strip manufacturer’s supplier quality agreement requiring full disclosure of residual monomer levels <100 ppb as verified by LC-MS/MS on a Waters Xevo TQ-XS, because unpolymerized monomer can leach and deactivate glucose oxidase via Schiff base formation with surface lysine residues. The terminal product is an integrated glucose test strip with a haematocrit range of 20–60%, calibrated against the YSI 2300 STAT Plus reference analyzer, where the methyl substituent on the pyrrole ring enhances π-π stacking with the carbon electrode, reducing the electron transfer resistance (Rct) derived from electrochemical impedance spectroscopy at 0.1 Hz from 12.4 kΩ (unmodified SPCE) to 2.1 kΩ. |
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A heteroaromatic building block increasingly specified for C–C and C–N bond-forming sequences, 4‑Methyl‑2‑pyrrolecarboxylic acid ethyl ester (CAS 2199‑49‑7; IUPAC name ethyl 4‑methyl‑1H‑pyrrole‑2‑carboxylate; molecular formula C8H11NO2, Mr 153.18 g·mol⁻¹) is routinely stocked by global chemical suppliers under catalogue designators such as SY‑E4MP‑025 for the 25‑g research pack and P‑E4MP‑1K for the 1‑kg pilot‑scale container. The off‑white to pale‑yellow crystalline mass exhibits a melting point of 38–42 °C, a boiling range of 90–94 °C at 0.6 mmHg (Kugelrohr distillation), and a refractive index nD20 of 1.5040. At 25 °C the compound is freely soluble in dichloromethane, tetrahydrofuran, and ethyl acetate, sparingly soluble in hexane, and displays a water solubility of < 0.1 mg·mL⁻¹ (shake‑flask measurement, 72‑h equilibration).
Direct Comparison with the Free Acid Derivative
In contrast to the parent 4‑methyl‑2‑pyrrolecarboxylic acid (CAS 18711‑58‑1), the ethyl ester circumvents the problematic gelation and high‑viscosity behaviour that the acid exhibits in amide‑bond‑forming solvents such as dimethylformamide. The acid form requires pre‑dissolution at 60 °C and still yields a turbid mixture that clogs inline filters of a standard syringe pump; the ester remains a clear, homogeneous solution at concentrations up to 2.0 M in anhydrous DMF at 22 °C. This rheological advantage translates directly into greater batch‑to‑batch reproducibility on automated flow‑chemistry platforms (e.g., Vapourtec R‑Series with a 10 mL PFA reactor coil) where pressure deviations exceeding 0.5 bar are frequently observed with the acid but not with the ester.
| Property | Ethyl 4‑methyl‑pyrrole‑2‑carboxylate (CAS 2199‑49‑7) | Ethyl pyrrole‑2‑carboxylate (CAS 2199‑43‑1) | Ethyl 3‑methyl‑pyrrole‑2‑carboxylate (CAS 2199‑50‑0) | Ethyl 5‑methyl‑pyrrole‑2‑carboxylate (CAS 3284‑51‑3) |
|---|---|---|---|---|
| Melting range (DSC onset, °C) | 38–42 | 39–41 | 34–36 | 43–45 |
| Boiling point (°C at reduced pressure) | 90–94 / 0.6 mmHg | 80–82 / 0.5 mmHg | 78–81 / 0.4 mmHg | 95–98 / 0.6 mmHg |
| Solubility in DMF at 25 °C (g·mL⁻¹) | 0.9 | 1.2 | 1.0 | 0.8 |
| Pyrrole N–H δ (1H NMR, CDCl3, ppm) | 9.23 | 9.40 | 9.05 | 9.18 |
Gas‑chromatographic purity, as determined on an Agilent 7890B instrument equipped with a 30 m × 0.25 mm HP‑5MS column (film thickness 0.25 µm) and flame‑ionisation detection, consistently exceeds 98.5% when the crude ester is purified by flash chromatography on a Teledyne ISCO Combiflash EZ Prep system using a RediSep 120 g silica cartridge and a gradient of ethyl acetate in heptane. The main impurity—ethyl 4‑methyl‑3‑bromopyrrole‑2‑carboxylate—is held below 0.8% by limiting the bromination‑quench time to 2 min post‑addition of sodium thiosulfate.
The electron‑donating methyl group at the 4‑position raises the energy of the pyrrole HOMO by approximately 0.18 eV relative to the unsubstituted ethyl ester (DFT calculation at the B3LYP/6‑31G* level in gas phase), with the HOMO coefficient localised predominantly at C‑5. This orbital perturbation increases the second‑order rate constant for Vilsmeier–Haack formylation by a factor of 1.7 compared with ethyl pyrrole‑2‑carboxylate when measured in 1,2‑dichloroethane at 0 °C (POCl3/DMF conditions). The resulting 5‑formyl intermediate is obtained in 82–87% isolated yield after 4‑h reaction, whereas the unsubstituted analogue requires 6 h for 75% conversion. However, the same methyl group introduces steric hindrance at the adjacent 5‑position, which becomes critical when bulky electrophiles are deployed. Acylation with 2,4,6‑trimethylbenzoyl chloride (MesCOCl) under AlCl3 catalysis proceeds to only 34% completion after 24 h at ambient temperature, whereas the 3‑methyl isomer (methyl remote from the reactive site) achieves 78% conversion under identical conditions. This electronic activation/steric occlusion dichotomy must be factored into route selection whenever a late‑stage diversification at the 5‑position is planned.
| Parameter | Acceptance Limit | Analytical Technique | Reference Standard |
|---|---|---|---|
| Assay (anhydrous, solvent‑free basis) | ≥ 98.5% | HPLC‑DAD, C18, 254 nm | USP 〈621〉, PhEur 2.2.29 |
| Water (Karl Fischer) | ≤ 0.5% w/w | Volumetric KF, Metrohm 870 Titrino plus | USP 〈921〉 Method Ia |
| Residual solvents (GC‑HS) | Heptane ≤ 0.1%, EtOAc ≤ 0.3% | DB‑624, 30 m column, FID | ICH Q3C (R8) |
| Individual unspecified impurity | ≤ 0.3% | HPLC area%, RRT 1.15–2.20 | ICH Q3A(R2) |
| Heavy metals (as Pb) | ≤ 10 ppm | ICP‑OES, microwave digestion | USP 〈233〉 |
For the quantitative NMR purity assay, a 400 MHz Bruker Avance III HD spectrometer is used with 25.0 mg of sample dissolved in 0.7 mL CDCl3 containing 0.03% v/v TMS. The integral of the pyrrole C‑H resonances (δ 6.72 and 6.45 ppm) is referenced against a certified calibrator (dimethyl sulfone, TraceCERT®, Lot BCBW2625). The method yields an expanded measurement uncertainty of ± 0.4% (k=2), compliant with ISO/IEC 17025:2017.
In the synthesis of pyrrole‑based β‑turn mimetics and neurotensin receptor antagonists, the ethyl ester is converted to the corresponding 4‑methyl‑2‑pyrrolecarboxylic acid via saponification and then coupled to amine‑terminated peptide moieties using HATU/DIPEA activation in DMF. This two‑step sequence—hydrolysis followed by amide bond formation—avoids the direct aminolysis of the ester, which under thermal or high‑pressure conditions can generate traces of the pyrrole‑2‑amide alongside N‑ethylated by‑products caused by ethanol‑catalysed transesterification. Process‑scale hydrolysis is conducted in a 5‑L jacketed glass reactor fitted with an overhead stirrer (IKA Eurostar 60 control) and a Cryo‑Compact Circulator set to 0 °C. A 1.0 M aqueous solution of lithium hydroxide (1.05 equiv.) is added dropwise to a solution of the ester in THF/water (3:1 v/v) over 40 min, keeping the internal temperature ≤ 5 °C. Above 10 °C, the decarboxylation half‑life drops below 2 h as tracked by in‑situ ReactIR (Mettler Toledo, diamond probe, 1700 cm⁻¹ band). After quenching with saturated ammonium chloride, the acid is isolated in 93–96% yield with a purity > 99% by HPLC. The subsequent coupling with H‑Gly‑OMe·HCl using HATU (1.05 equiv.) and DIPEA (3.0 equiv.) in anhydrous DMF at 0 °C to room temperature furnishes the dipeptide isostere in 85 % yield after flash chromatography. Failure to pre‑dry the DMF over 4 Å molecular sieves (48 h) reduces the coupling yield by 12–18 % due to competing ester hydrolysis.
Storage of bulk material in amber glass bottles under argon, sealed with PTFE‑faced butyl septa and stored at 2–8 °C, preserves the initial purity for a minimum of 24 months. After that period, a slow increase in the acid number (determined by non‑aqueous titration, modified ASTM D974‑21) from < 0.5 mg KOH·g⁻¹ to 1.8 mg KOH·g⁻¹ signals the onset of atmospheric moisture‑induced ester cleavage. An induction‑coupled argon‑blanketing system on the storage cabinet reduces the hydrolysis rate to below 0.02% per week at 4 °C. Contact with primary or secondary amines must be avoided because even ppm‑level contamination can catalyse aminolysis within hours at ambient temperature, generating the corresponding amide that co‑crystallises with the ester and necessitates a reslurrying step in cold heptane for removal.
The 4‑methyl‑2‑pyrrolecarboxylic acid ethyl ester is routinely brominated at the 5‑position to generate the versatile building block ethyl 5‑bromo‑4‑methyl‑1H‑pyrrole‑2‑carboxylate, a precursor for Suzuki–Miyaura cross‑couplings that install aryl and heteroaryl substituents in kinase inhibitor scaffolds. The bromination is performed with N‑bromosuccinimide (NBS, recrystallised from water, dried 24 h over P2O5) in anhydrous DMF at cryogenic temperature. A 1.0 M stock of the ester in DMF is cooled to –5 °C using a Julabo FP50‑MC refrigerated/heating circulator connected to a 250‑mL double‑walled glass reactor equipped with a PTFE paddle stirrer. NBS (1.02 equiv.) is added portion‑wise over 1 h while the internal temperature is maintained at –5 ± 2 °C. Exotherms are dampened by a 30‑s pause between each portion; exceeding 0 °C for more than 3 min results in dibromination at the 3‑position, as evidenced by the appearance of a distinct singlet at δ 6.33 in the 1H NMR of the crude mixture. The 5‑bromo product is obtained in 78 % isolated yield after aqueous workup and silica‑gel chromatography (CombiFlash EZ Prep, gradient 0–15% EtOAc in heptane). The regioisomeric ratio 5‑Br/3‑Br exceeds 15:1 under these conditions; for the unsubstituted ethyl pyrrole‑2‑carboxylate, the ratio is typically 9:1, and for the 5‑methyl isomer it drops to 6:1 because the methyl group directs bromination toward the 3‑site. Thus, the 4‑methyl substitution pattern not only accelerates electrophilic substitution but, through a combination of electronic activation and steric shielding of the 3‑position, reduces over‑bromination, a critical advantage in milligram‑ to kilogram‑scale preparations where chromatographic separation of dibromo by‑products can consume up to 40% of the total processing time when those by‑products are formed in > 10% abundance.
