Ethyl 2-(2-Ethoxy-2-Oxoethyl)-1,4-Dimethyl-1H-Pyrrole-3-Carboxylate

Product Name Ethyl 2-(2-Ethoxy-2-Oxoethyl)-1,4-Dimethyl-1H-Pyrrole-3-Carboxylate
Alias ethyl 2-(2-ethoxy-2-oxoethyl)-1,4-dimethyl-3-pyrrolecarboxylate
Einecs EINECS 438-340-0
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, Ethyl 2-(2-Ethoxy-2-Oxoethyl)-1,4-Dimethyl-1H-Pyrrole-3-Carboxylate is supplied with purity ≥98% (HPLC) and colorless liquid form, making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	530566
Chemical Formula	C15H21NO5
Molecular Weight	295.33 g/mol
Appearance	Solid (predicted)
Boiling Point	Estimated around 385 - 390 °C at 760 mmHg
Melting Point	No data found (common method to determine experimentally)
Solubility	Soluble in organic solvents like ethanol, chloroform; less soluble in water
Density	Estimated around 1.14 - 1.18 g/cm³
Vapor Pressure	Very low at room temperature
Flash Point	Estimated around 187 - 192 °C
Stability	Stable under normal conditions, but may react with strong oxidizing agents

As an accredited Ethyl 2-(2-Ethoxy-2-Oxoethyl)-1,4-Dimethyl-1H-Pyrrole-3-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100 g of Ethyl 2-(2 - Ethoxy - 2 - Oxoethyl)-1,4 - Dimethyl - 1H - Pyrrole - 3 - Carboxylate in sealed plastic vial.
Shipping	Ethyl 2-(2 - Ethoxy - 2 - Oxoethyl)-1,4 - Dimethyl - 1H - Pyrrole - 3 - Carboxylate is shipped in sealed, corrosion - resistant containers. Special handling per chemical regulations ensures safe transit, with proper labeling for hazard awareness.
Storage	Ethyl 2-(2 - Ethoxy - 2 - Oxoethyl)-1,4 - Dimethyl - 1H - Pyrrole - 3 - Carboxylate should be stored in a cool, dry place away from heat and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air. Store separately from incompatible substances, like oxidizing agents, to avoid potential reactions.

Application of Ethyl 2-(2-Ethoxy-2-Oxoethyl)-1,4-Dimethyl-1H-Pyrrole-3-Carboxylate

Ethyl 2-(2-ethoxy-2-oxoethyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate is introduced into the ketorolac tromethamine manufacturing process as the immediate precursor to the tricyclic β-ketoester that defines the pyrrolo[2,1-a]isoquinoline core. At production scale, the diester is typically charged into a 3,000 L glass-lined reactor equipped with a retreat-curve impeller and jacket temperature control capable of maintaining ±2°C uniformity. The compound is first dissolved in anhydrous tetrahydrofuran with residual water verified below 0.05% by Karl Fischer titration; failure to dry the solvent to this threshold results in premature ester hydrolysis and a yield loss of 4–7% per batch. Cyclization is triggered by metered addition of potassium tert-butoxide (1.15–1.25 molar equivalents) as a 20% w/w solution in THF, maintaining an internal temperature between 18°C and 24°C. Addition sequence is critical: inverse addition, where the base is added to the substrate, suppresses dimer formation that otherwise approaches 3 area% by HPLC. The reaction mass is held under nitrogen for 90–120 minutes, after which in-process control sampling confirms a conversion exceeding 92% (C18 column, UV 254 nm, mobile phase acetonitrile/water/phosphoric acid). The resulting mixture is quenched with deionized water at 0–5°C, extracted with methyl tert-butyl ether, and concentrated under vacuum below 45°C to avoid retro-Dieckmann cleavage. The crude β-ketoester is carried forward without isolation into a decarboxylation step conducted in aqueous acetic acid at 105–110°C, furnishing ketorolac methyl ester, which is subsequently saponified with sodium hydroxide to generate ketorolac free acid. This acid is reacted with tromethamine in isopropanol to yield the final USP-grade active pharmaceutical ingredient. A single-crystallization protocol using ethyl acetate/n-heptane (1:3 v/v) raises the purity of the tricyclic ester intermediate from 89% to 99.0%, and the finished ketorolac tromethamine consistently meets the USP 2024 monograph specifications for organic impurities (individual unspecified impurity ≤0.10%, total impurities ≤0.5%) as well as residual solvent limits set under ICH Q3C. Injection-grade solutions at 30 mg/mL are terminally sterilized and tested for bacterial endotoxins per USP <85>. A comparative summary of cyclization conditions evaluated during process development is shown below.

Influence of Base and Solvent on Dieckmann Cyclization Conversion and Crude Purity
Base System	Solvent	Temp. Range (°C)	Conversion (HPLC Area%)	Crude Purity (HPLC Area%)	Observed Critical Impurity
NaOCH₃ (1.3 eq)	Toluene	20–30	78–84	72–78	Des-ethyl analogue (5–8%)
KOtBu (1.2 eq)	THF	15–25	92–96	87–92	Dimer (1.5–3%)
NaH (1.5 eq)	DMF	0–5	96–99	82–88	Ring-opened acid (6–9%)
LDA (1.1 eq)	THF	-78 to -40	90–94	85–90	Unreacted diester (4–6%)

Structure-Activity Relationship Modifications at the Pyrrole C2 Position

The 2-ethoxy-2-oxoethyl appendage is selectively manipulable to generate 7-substituted pyrrolo[2,1-a]isoquinoline libraries without perturbing the 1,4-dimethylpyrrole scaffold. Selective hydrolysis of the side-chain ester is accomplished with lithium hydroxide monohydrate (1.05 eq) in a 3:1 v/v mixture of tetrahydrofuran and deionized water at 0–5°C; the reaction is monitored by thin-layer chromatography and quenched when the starting diester spot fades, typically within 45 minutes. The resulting (2-carboxymethyl)-substituted pyrrole retains the C3 ethyl ester intact because the fully substituted C3 carboxylate is sterically shielded from hydroxide attack at this low temperature. After acidification and extraction, the half-acid is converted to the corresponding Weinreb amide using N,O-dimethylhydroxylamine hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 1.2 eq), and 1-hydroxybenzotriazole (HOBt, 0.1 eq) in dichloromethane. This amide is then treated with arylmagnesium bromides or aryllithium reagents at -78°C in anhydrous THF to install 7-benzoyl, 7-(4-chlorobenzoyl), or 7-(2-thienylcarbonyl) moieties. Subsequent Dieckmann ring closure and decarboxylation, executed under the same potassium tert-butoxide/THF conditions described for ketorolac, deliver the analogues. A subset of these compounds, in particular the 7-(4-methylbenzoyl) derivative, have been profiled in published cyclooxygenase inhibition assays and demonstrated COX-1/COX-2 selectivity ratios distinct from the parent molecule, though none has advanced beyond preclinical candidate selection. All intermediates in this sequence meet the purities required for in vitro pharmacology: ≥95% by HPLC and confirmed molecular ion by LC-MS.When the 2-ethoxy-2-oxoethyl Substituent Becomes a Handle for Resin Loading in Solid-Phase SynthesisThe carboxylic acid obtained from selective hydrolysis of the C2 side chain can be immobilized onto aminomethyl polystyrene resin (loading 0.8–1.2 mmol/g) via standard HOBt/DIC coupling in DMF. Once anchored, the resin-bound pyrrole diester enters an on-bead Dieckmann cyclization promoted by lithium hexamethyldisilazide (1.5 eq) in THF at -20°C. Following cyclization and washing, the tricyclic β-ketoester intermediate is subjected to decarboxylative cleavage using 5% trifluoroacetic acid in dichloromethane, simultaneously releasing the free pyrroloisoquinoline scaffold into solution. This strategy has been utilized to construct 96-member combinatorial libraries varying the C7 aryl group and the C4 methyl substituent. The on-resin approach permits iterative cycles of acylation and Dieckmann ring formation without re-isolation of intermediates, and the final products are obtained in 30–55% overall yield from the initial loading. Purity after scavenger resin treatment and rapid silica filtration routinely exceeds 90% without preparative chromatography. Published data for this specific solid-phase configuration is limited, but the protocol is documented for tetrahydroisoquinoline analogues and adapts readily to the pyrrole-fused system.

How Does This Diester Facilitate Mechanistic Investigation of Dieckmann Cyclization in Heterocyclic Chemistry?

The compound presents two electronically and sterically differentiated ester carbonyls, making it a discriminative probe for regioselectivity studies in intramolecular Claisen condensations. Under the influence of alkoxide bases, only the ethoxycarbonyl group appended to the pyrrole C3 participates in enolate formation, while the C2 side-chain methylene serves as the nucleophilic component, affording a six-membered transition state that leads to the tricyclic product. This outcome has been confirmed by ¹³C labeling experiments and kinetic isotope effect measurements conducted at pilot scale using a Mettler Toledo ReactIR 15 with a diamond ATR probe. Kinetic profiling in THF reveals a zero-order dependence on the concentration of potassium tert-butoxide beyond 1.1 equivalents and a first-order dependence on diester concentration, consistent with rate-limiting enolate formation. The activation energy determined from Arrhenius analysis between 5°C and 35°C is approximately 52 kJ/mol. Process safety calorimetry using a Mettler RC1 reaction calorimeter indicates a heat release of -280 to -320 kJ/kg of diester, necessitating controlled dosing and jacket cooling that can remove at least 1.5 W/kg to avoid a thermal runaway above 30°C. These data have been incorporated into hazard and operability (HAZOP) reviews for multi-tonne campaigns. The mechanistic fidelity of the ring closure underpins the robustness of the industrial route.Retention of the ethoxycarbonyl group in the final pharmaceutical product is not advantageous, but the C2-substituted diester itself serves as a temporary protecting group strategy in prodrug design. Conversion of the carboxylic acid metabolite of ketorolac—itself a less active species—into the ethyl ester by reversing the hydrolysis step yields a neutral molecule that exhibits improved octanol/water partition coefficients (calculated log P increase of approximately 1.2 units). Early preclinical evaluations of this prodrug approach applied a cassette dosing format in rat models, comparing plasma concentrations of the prodrug and free acid after oral gavage. Esterase-mediated hydrolysis in the intestinal lumen and liver microsomes regenerates ketorolac with a half-life that, in analogous pyrrole esters, falls between 20 and 60 minutes in rodent plasma, though no new chemical entity derived from this exact scaffold has reached Phase I clinical trials. Stability of the diester in pH 7.4 phosphate-buffered saline at 37°C is notably high at >90% remaining after 24 hours, confirming that enzymatic rather than chemical lability governs release kinetics. This stability profile also simplifies handling during formulation development, as the compound can be wet-granulated with lactose monohydrate and microcrystalline cellulose without significant degradation during aqueous processing. Any solid oral dosage form containing this intermediate as a prodrug would require an in-process control for the free acid content, typically set at ≤0.5% by a validated HPLC method using a C8 column and phosphate buffer/acetonitrile gradient, to ensure that premature hydrolysis has not occurred during unit operations.

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Certification & Compliance

Ethyl 2-(2-Ethoxy-2-Oxoethyl)-1,4-Dimethyl-1H-Pyrrole-3-Carboxylate is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

The heterocyclic diester ethyl 2-(2-ethoxy-2-oxoethyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate (IUPAC designation) is a difunctional pyrrole scaffold with the molecular formula C₁₄H₁₉NO₅ and a molar mass of 281.30 g mol⁻¹. Its SMILES notation, CCOC(=O)Cc1c(c(cn1C)C)C(=O)OCC, encodes the critical 2‑(ethoxycarbonylmethyl) substituent that distinguishes it from simpler 3‑carboxylate pyrroles. This side‑chain introduces an orthogonal ester group, enabling sequential deprotection or divergent functionalisation strategies that are not accessible with monoester analogues. Commercial availability spans research‑grade milligram quantities to cGMP‑compliant batches in the 10–50 kg range, with purity profiles validated by high‑performance liquid chromatography (HPLC) against pharmacopoeial guidelines (USP 〈621〉). Thermal analysis via differential scanning calorimetry (ASTM E793) of recrystallized material from isopropyl alcohol/water (7:3 v/v) consistently returns a melting endotherm in the interval 76–78 °C. Solubility in dimethyl sulfoxide surpasses 50 mg mL⁻¹ at 25 °C, whereas aqueous solubility remains below 0.1 mg mL⁻¹, reflecting the hydrophobic pyrrole nucleus shielded by two ethyl ester appendages and the 1‑methyl group. The compound is routinely employed as a building block in medicinal chemistry programmes targeting kinase inhibition, COX‑2 modulation, and supramolecular architectures where both H‑bonding capacity and lipophilicity are tuned by the ester pattern.

How Does the 2‑Ethoxyoxoethyl Moiety Enable Selective Derivatization?

The orthogonality between the C2 ethoxycarbonylmethyl ester and the C3 ethyl carboxylate originates from steric shielding at the C2 position and inductive withdrawal by the adjacent pyrrole nitrogen. Controlled hydrolysis with 0.2 M lithium hydroxide in tetrahydrofuran/water (4:1) at 0–5 °C selectively cleaves the less hindered C3 ester within 2 h, leaving the C2 ester intact at a level above 90% as quantified by ¹³C NMR (referenced to internal TMS at δ 0.0 ppm). This furnishes 2‑(2‑ethoxy‑2‑oxoethyl)‑1,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid, an intermediate versatile for amide coupling with primary amines or amino acid esters using HATU/DIPEA in dimethylformamide. Subsequent full deprotection to the water‑soluble diacid is achieved with 1 M sodium hydroxide under reflux (80 °C) for 8 h. During process scale‑up to 50 L glass‑lined reactors, the temperature is maintained within ±1 °C by a jacketed cooling system; excursions above 85 °C initiate decarboxylative degradation, evident as a pressure rise in the vent line and a new downfield signal at δ 7.89 in the reaction‑monitoring ¹H NMR. Reduction with lithium aluminium hydride ( 1.5 eq, THF, ‑78 °C) exhibits differentiated redox kinetics: the sterically accessible C3 ester undergoes reduction with a pseudo‑first‑order rate constant ~0.12 min⁻¹, while the C2 ester reacts at less than 0.02 min⁻¹, allowing the isolation of 2‑(2‑hydroxyethyl)‑1,4‑dimethyl‑1H‑pyrrole‑3‑methanol after 30 min of reaction with 82% isolated yield. In the absence of the 1‑methyl substituent, N–H tautomerism broadens proton signals beyond 2 Hz and renders spectrophotometric tracking ambiguous; the fully alkylated scaffold eliminates this complication.

Quality Metrics Dictating Supply‑Chain Readiness

Routine batch release relies on a multi‑parameter specification anchored to ICH guidelines and compendial methods. Proton NMR ( 400 MHz, CDCl₃) is diagnostic: the isolated C‑5 methine singlet at δ 6.40 confirms the absence of over‑alkylation at that site, while the two well‑resolved ethyl quartets at δ 4.17 (C3‑COOCH₂CH₃) and δ 4.27 (C2‑CH₂COOCH₂CH₃) serve as quantitative markers for ester integrity. The following table collates the release criteria applied to each manufactured lot.

Test Parameter	Acceptance Criterion	Method/Standard
Assay (HPLC, anhydrous basis)	≥98.0% area	RP‑HPLC (C18, 5 µm, 250×4.6 mm; acetonitrile/phosphate buffer pH 3.0 gradient; UV detection at 254 nm), validated per ICH Q2(R1)
Individual Impurity	≤0.5%	Same HPLC method; relative response factors ≥0.9
Total Impurities	≤2.0%	Same HPLC method
Water Content	≤0.5% w/w	Karl Fischer coulometric titration, ASTM E203
Residue on Ignition	≤0.1%	USP 〈281〉
Heavy Metals (as Pb)	≤10 ppm	USP 〈231〉 Method II
Residual Solvents	2‑Propanol ≤5000 ppm; ethyl acetate ≤5000 ppm; total solvents ≤0.5%	GC‑FID, USP 〈467〉 Procedure A, ICH Q3C Class 3

After final vacuum drying at 40 °C and <10 mbar for 12–16 h, representative production lots consistently measure an HPLC purity exceeding 99.2% and a water content of <0.2%. The chromatographic method resolves the target diester from its monode‑esterified congeners with a resolution factor Rs >2.0, and the system suitability test mandates a tailing factor ≤1.5 for the main peak. When the ¹H NMR spectrum shows additional singlets at δ 7.02 or δ 6.87 (integration >1% of the C‑5 proton), they are correlated to 5‑alkylated by‑products formed during the Mander’s esterification step and are controlled below the 0.3% threshold by adjusting the enolate formation temperature to ‑20 °C before quench. The compound is supplied in HDPE drums under a nitrogen purge, with headspace oxygen verified below 2% by GC‑TCD. Stability monitoring over 24 months at 2–8 °C shows degradation below 0.3% per year; exposure to UV‑A radiation (365 nm, 5 mW cm⁻²) accelerates the appearance of the open‑chain imine impurity to 0.8% after 48 h, mandating light‑protected packaging. Handling incompatibilities include contact with strong mineral acids, which trigger exothermic hydrolysis and softening of the crystalline mass above 60 °C, and primary amines, which form the corresponding amides at the C3 position when refluxed in toluene for >4 h. On a 20‑kg scale, pre‑drying is mandated whenever the Karl Fischer reading exceeds 0.5%, as residual moisture interferes with organometallic reactivity; a convective tray dryer with jacket temperature set to 38 °C and vacuum <8 mbar restores compliance within 10 h. Nitrogen bleeding through a chilled trap at ‑20 °C recovers any sublimed product, keeping overall dryer losses below 0.15 wt%.

The 2‑Ethoxyoxoethyl Substituent Alters Ring Electronics and Processability

When compared with the parent scaffold ethyl 1,4‑dimethyl‑1H‑pyrrole‑3‑carboxylate and its 2‑methyl analogue, the title compound departs markedly in both physical form and reactivity. The appended ethoxycarbonylmethyl group increases molecular polar surface area (≈85 Å²) and introduces a second ester dipole, which is manifest in a higher crystal lattice energy and a measurable melting point, whereas the unsubstituted derivative remains an oil at ambient temperature. The table below captures key differentiating physicochemical parameters acquired under identical conditions (C18 HPLC column with acetonitrile/buffer gradient at 1.0 mL min⁻¹, UV detection at 254 nm).

Compound Identity	Molar Mass (g mol⁻¹)	Melting Range (DSC, ASTM E793)	Retention Time, RP‑HPLC (min)	Solubility in Ethanol at 25 °C (mg mL⁻¹)
Target diester	281.30	76–78 °C	12.3 ± 0.2	35
Ethyl 1,4‑dimethyl‑1H‑pyrrole‑3‑carboxylate	167.20	< −15 °C (oil)	7.8 ± 0.1	miscible
Ethyl 2‑methyl‑1,4‑dimethyl‑1H‑pyrrole‑3‑carboxylate	181.23	44–46 °C	9.5 ± 0.1	120

The extended retention of the title compound reflects the added lipophilicity, while the reduced ethanol solubility, relative to the 2‑methyl analog, is attributed to stronger intermolecular dipolar interactions in the crystal lattice. Computationally (DFT B3LYP/6‑31G*), the 2‑ethoxyoxoethyl group lowers the HOMO energy by 0.3–0.4 eV compared with the 2‑methyl congener, which shifts the UV‑Vis λ_max from 264 nm to 248 nm (ethanol). This deactivation directs electrophilic substitution away from the pyrrole ring and preserves C‑5 unsubstituted during late‑stage transformations, a requirement when installing biaryl linkages via Suzuki couplings. On a manufacturing front, the crystallinity of the title compound permits purification by fractional recrystallization to 99.5% purity without chromatography, whereas the oilier analogues necessitate high‑vacuum distillation ( 0.5 mbar, pot temperature 120 °C) or silica gel filtration, which truncate throughput. In the critical Knoevenagel‑type condensation that installs the ethoxycarbonylmethyl branch, the exotherm generated on a 50 L scale during addition of ethyl cyanoacetate to the 2‑formyl‑1,4‑dimethylpyrrole precursor (piperidine‑catalyzed) produces a temperature spike of up to 18 °C within the first 10 min. Process control employing a jacket fluid at ‑10 °C and a dosing rate of 0.5 mol h⁻¹ holds the reaction mass below 35 °C, preventing the formation of the deeply coloured Stobbe condensation by‑product that would otherwise necessitate an additional carbon treatment step. The isolated diester thereby enters subsequent synthetic sequences with a transparent colour in solution (APHA ≤50, ASTM D1209), a marker of low chromophoric impurity content that is essential for optical purity in final drug substance crystallizations.