1H-Pyrrole-2-Carboxylic Acid, 5-Formyl-, Ethyl Ester
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HS Code |
333501 |
| Name | 1H-Pyrrole-2-Carboxylic Acid, 5-Formyl-, Ethyl Ester |
| Chemical Formula | C8H9NO3 |
| Molar Mass | 167.16 g/mol |
As an accredited 1H-Pyrrole-2-Carboxylic Acid, 5-Formyl-, Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5 - Formyl - 1H - Pyrrole - 2 - Carboxylic Acid Ethyl Ester in sealed chemical - grade packaging. |
| Shipping | 1H - Pyrrole - 2 - Carboxylic Acid, 5 - Formyl -, Ethyl Ester is shipped in carefully sealed containers, compliant with chemical transport regulations. Packaging ensures protection during transit to prevent spills and maintain product integrity. |
| Storage | 1H - Pyrrole - 2 - Carboxylic Acid, 5 - Formyl -, Ethyl Ester should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could lead to degradation. Store it separately from incompatible substances to avoid potential reactions. |
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Evaluation of 1H-pyrrole-2-carboxylic acid, 5-formyl-, ethyl ester for antiviral API manufacturing begins not with synthetic yield prediction but with the aldehyde–titration assay and peroxide value determination, because even minor autoxidation to the 5-carboxy derivative during intercontinental bulk shipment distorts the stoichiometric balance of the subsequent Wittig olefination. In plant-scale production of entecavir monohydrate, this intermediate is charged at a molar equivalence of 1.00–1.02 relative to the phosphonium salt partner; a deviation to 1.05 equivalents caused by aldehyde content drift has been documented in deviation reports to generate a dimeric impurity peak at relative retention time 1.34 under the Ph. Eur. 10.5 monograph HPLC conditions, forcing a reprocessing operation through hot toluene reslurry that reduces throughput by 15–20%. The downstream process configuration couples the aldehyde-protected pyrrole (converted to the 1,3-dioxolane acetal in toluene with ethylene glycol and 0.5 mol% p-toluenesulfonic acid at reflux with Dean–Stark water removal) with a cyclopentenyl phosphonate using sodium hydride as base in tetrahydrofuran at -10 to -5°C, followed by acetal cleavage in 85% formic acid at 50°C, and final borohydride reduction of the resulting ketone, all conducted in glass-lined reactors with double mechanical seal agitators and jacket temperature control capable of holding a ±2°C band. Compliance obligations are driven by ICH Q7 for API starting materials, necessitating a full impurity fate-and-purge study according to ICH M7 Option 3 for potential nitrosamine-forming amines, while residual palladium from the upstream Suzuki-type coupling that assembles the purine portion must be maintained below 10 µg/g per the EMA guideline on metal catalysts (EMEA/CHMP/SWP/4446/2000). The terminal dosage form is entecavir monohydrate tablets at 0.5 mg and 1.0 mg strengths, where the finished-drug specification requires ≤0.10% total related substances by area normalisation. What Limits Quantum Yield Reproducibility in Asymmetric BODIPY Syntheses?Batch-to-batch quantum yield variation in 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores that utilize 1H-pyrrole-2-carboxylic acid, 5-formyl-, ethyl ester as the α-formyl component is traced primarily to residual moisture in the aldehyde and adventitious metal contamination introduced during its prior synthesis, both of which perturb the delicate acid-catalysed condensation equilibrium. In a representative asymmetric BODIPY FL carboxylic acid synthesis, the aldehyde is combined with 2,4-dimethylpyrrole in anhydrous dichloromethane (water content by Karl Fischer titration <50 ppm) at 0–5°C, employing trifluoroacetic acid at 0.15 equivalents relative to the aldehyde, with an aldehyde-to-pyrrole input ratio tightly controlled at 1.03:1.00; the slight excess compensates for aldehyde loss to Schiff base formation with trace dimethylamine liberated from the pyrrole storage stabiliser. Condensation proceeds over 45–60 minutes under argon, and the resulting dipyrromethane intermediate is oxidised in situ with 1.1 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at 22±2°C, followed by complexation with boron trifluoride diethyl etherate (3.0 equivalents) in the presence of 5.0 equivalents of triethylamine. The manufacturing purification train incorporates flash chromatography on irregular silica gel (15–40 µm particle size) with a heptane/ethyl acetate gradient, and a subsequent preparative HPLC step using a C18 column (250×50 mm, 10 µm) and an acetonitrile/0.1% trifluoroacetic acid mobile phase to reduce the diester impurity (arising from oxidation of the formyl group to carboxy followed by esterification) to <0.15 area%. For diagnostic kits or bioconjugation applications, the isolated succinimidyl ester derivative must satisfy residual metal specifications aligned with ICH Q3D (oral PDE, 30 µg/day for palladium, 5 µg/day for cobalt) and endotoxin limits (<0.5 EU/mg per USP <85>) when the dye-antibody conjugate is intended for in vivo imaging or flow cytometry. The terminal product is an amine-reactive BODIPY FL NHS ester packaged in amber glass vials under argon, stored at -20°C, and formulated for conjugation to monoclonal antibodies used in multi-colour leukocyte subset identification. Pre-formulation screening of 7-deazapurine libraries depends on reliable access to the pyrrole C-ring synthon where the ethyl ester at C-2 remains intact through palladium-catalysed cross-coupling only when the formyl group at C-5 is masked as a 1,3-dioxolane acetal; unprotected aldehyde deactivates the catalyst by forming insoluble Pd(0) clusters within 4–6 hours at 80°C. In the synthesis of 4-substituted pyrrolo[2,3-d]pyrimidine inhibitors under investigation as Janus kinase modulators, 1H-pyrrole-2-carboxylic acid, 5-formyl-, ethyl ester is subjected to acetalisation with ethylene glycol (2.5 eq.) and 0.3 mol% pyridinium p-toluenesulfonate in refluxing toluene before being engaged in a Buchwald–Hartwig amination with a 2-chloro-4-aminopyrimidine derivative; the masked aldehyde input is maintained at 0.98–1.00 equivalents relative to the halide to avoid off-target amination at the acetal methine carbon. The coupling is performed in 1,4-dioxane with XPhos Pd G3 precatalyst (2.0 mol%) and sodium tert-butoxide (1.4 eq.) at 85°C over 12–16 hours in a 316L stainless steel reactor with a nitrogen-purged headspace, after which the acetal is cleaved with 10% aqueous acetic acid to liberate the formyl group for subsequent Hantzsch-type ring closure with ammonium acetate. Regulatory starting material definition under ICH Q11 requires the ethyl 5-formylpyrrole-2-carboxylate to be designated as a GMP-regulated intermediate with a detailed impurity profile, including specification limits for the 5-carboxy acid impurity (≤0.20%) and the regioisomeric 4-formyl analogue (≤0.05%), both monitored by a validated HPLC method with UV detection at 286 nm. Terminal drug candidates incorporating this pyrrole scaffold—typically selective BTK or TYK2 inhibitors—are processed into solid oral dosage forms, and their CMC dossiers require elemental impurity risk assessments (ICH Q3D) confirming leachable palladium from this synthetic stage stays below 1 µg/day in the final tablet. Schiff Base Metalloligand Precursors for Asymmetric OxaziridinationCondensation of 1H-pyrrole-2-carboxylic acid, 5-formyl-, ethyl ester with chiral 1,2-diamines yields tetradentate ligands whose manganese(III) complexes exhibit catalytic turnover numbers exceeding 800 in the enantioselective epoxidation of unfunctionalized olefins when peracetic acid is employed as the terminal oxidant at -20°C. In a production-scale ligand synthesis conducted in a 50 L glass-lined vessel, the ethyl 5-formylpyrrole-2-carboxylate (2.05 equivalents relative to (1R,2R)-1,2-diphenylethylenediamine) is dissolved in absolute ethanol and added dropwise to the diamine solution at 60°C over 90 minutes, with the addition rate controlled by an automated dosing pump to prevent excessive exotherm and maintain the internal temperature below 65°C; deviation above 70°C leads to imidazolidine formation via intramolecular cyclisation, reducing ligand yield below 60%. The metallocomplex is subsequently prepared by combining the isolated Schiff base ligand with manganese(II) acetate tetrahydrate (1.0 eq.) in air-saturated methanol, where aerobic oxidation to the Mn(III) state occurs within 4–5 hours, as monitored by a colour change from pale yellow to dark brown. For industrial process safety analysis, the DSC profile of the neat ligand reveals an onset exotherm at 165°C (ΔH = -420 J/g), mandating storage below 40°C in polyethylene-lined fibre drums. The ligand application in pharmaceutical intermediate production (e.g., taxane side-chain epoxidation) requires compliance with the ICH M7 guideline on DNA-reactive impurities; accordingly, a dedicated purge factor study for the aldehyde starting material—classified as a potential mutagenic impurity due to structural alerts—demonstrates a reduction to <1.5 µg/g in the isolated epoxide after aqueous bicarbonate washing. The downstream process isolates the chiral epoxide product through fractional distillation (2–5 mbar, overhead temperature 95–105°C), and the catalyst–ligand system is discharged into a 0.1 M sodium hydroxide quench tank where the pyrrole-containing ligand is hydrolysed to the water-soluble dicarboxylate salt before waste treatment. Terminal consumer products are not manufactured directly from this catalytic stream; the epoxide intermediates proceed into paclitaxel semisynthetic routes or β-blocker synthesis, while spent ligand solids are incinerated in a high-temperature rotary kiln complying with EU Directive 2008/98/EC.
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1H-Pyrrole-2-Carboxylic Acid, 5-Formyl-, Ethyl Ester (CAS 7126-55-8; molecular formula C8H9NO3, molecular weight 167.16 g mol−1) is a heterobifunctional pyrrole building block carrying an electron-withdrawing ethyl ester at C2 and a reactive formyl substituent at C5. The compound is isolated as a pale-yellow crystalline powder with a typical endothermic melting onset of 109–114 °C (DSC, 10 K min−1 under N2). The orthogonal reactivity of the two functional handles—an aldehyde that participates in condensation, oxime ligation, and reductive amination, and an ester that survives many C–C bond-forming reactions while enabling late-stage hydrolysis to the carboxylic acid—differentiates this intermediate from mono-functional pyrrole derivatives and from the corresponding free acid. Its utility spans pharmaceutical fragment elaboration, porphyrin analogue construction, and push–pull chromophore synthesis where precise control of electron density and solubility is required.
Commercial production batches are monitored against a tightly controlled specification anchored to pharmacopoeia-aligned analytical methods. Liquid chromatography (HPLC) on a C18 column (particle size 5 μm, 250 × 4.6 mm) with UV detection at 254 nm serves as the primary purity assay; the mobile phase employs a gradient of acetonitrile and 0.1% trifluoroacetic acid in water. Identity is confirmed by Fourier-transform infrared spectroscopy (FTIR) with key bands at 1712 cm−1 (ester C=O) and 1660 cm−1 (aldehyde C=O), and by 1H NMR (400 MHz, DMSO-d6) where the aldehyde proton resonates as a sharp singlet at δ 9.63. Typical lot-to-lot data are summarized below; any batch deviating from the impurity limits is rejected for fine-chemical applications.
| Parameter | Method | Acceptance Limit | Typical Value |
|---|---|---|---|
| Assay (anhydrous, solvent-free) | HPLC-UV | ≥ 98.5 area% | 99.2 area% |
| Single largest impurity | HPLC-UV | ≤ 0.5 area% | 0.2 area% |
| Water (Karl Fischer) | KF coulometry | ≤ 0.5% w/w | 0.1% w/w |
| Residual solvents (ICH Q3C) | HS-GC-FID | Class 2 solvents: ≤ 0.5% total | EtOAc 0.08%, THF < LT |
| Heavy metals (Pb, Cd, As, Hg) | ICP-MS | ≤ 10 ppm each | < 2 ppm |
Batch stability studies conducted under ICH Q1A(R2) conditions (25 °C/60% RH and 40 °C/75% RH) demonstrate less than 0.3% assay loss over 12 months when the material is packed in double LDPE bags inside an aluminium-laminated foil pouch under nitrogen. However, ambient light and atmospheric oxygen progressively promote discolouration and generate the 5‑carboxy derivative (detectable as a new carbonyl resonance near δ 173 in 13C CP-MAS NMR). Inclusion of pre-dried 3 Å molecular sieves (10% w/w of product) in the headspace and storage below 8 °C extends aldehyde integrity.
Deviations from the recommended inert atmosphere result in oxidative pathways that profoundly alter batch utility. Headspace oxygen levels exceeding 50 ppm at 20 °C accelerate aldehyde-to-acid conversion with an observed first-order rate constant of approximately 0.007 day−1 in sealed glass vials. Even partial humidity ingress leads to ester hydrolysis at the particle surface, forming the free acid, 5‑formyl‑1H‑pyrrole‑2‑carboxylic acid, which exhibits poor solubility in the aprotic solvents commonly used in cross-coupling chemistry (≤ 2 mg mL−1 in dry THF). Prolonged exposure to temperatures above 40 °C without light exclusion induces a 3–5% formation of a dark-coloured oligomeric fraction (SEC-MALLS, Mw ∼1200 Da) that precludes use in optical-grade material synthesis without preparatory column chromatography. Process-quality preservation therefore mandates storage under argon or nitrogen at −20 ± 5 °C in amber borosilicate glass.
The simultaneous presence of an aldehyde and a protected carboxylic acid in the 2,5-arrangement allows chemists to execute bidirectional elaboration that is difficult with 2‑formylpyrrole or ethyl pyrrole‑2‑carboxylate alone. Under typical reductive amination conditions (NaBH(OAc)3, dichloroethane, 0.2 M, 25 °C), the aldehyde is selectively converted to the tertiary amine while the ester remains intact, furnishing intermediates that can undergo subsequent saponification with LiOH in THF/H2O (3:1) at 0 °C without cleavage of the newly formed C–N bond. In contrast, the free-acid analogue 5‑formyl‑1H‑pyrrole‑2‑carboxylic acid gives intractable zwitterionic mixtures during chromatographic purification; preparative recovery yields for the acid are typically 25–35% lower than for the ethyl ester owing to irreversible adsorption on silica gel. When coupling the ester to amine nucleophiles, the aldehyde must be masked as the dimethyl acetal (trimethyl orthoformate, catalytic p-TsOH, MeOH, 40 °C, 16 h) prior to amide bond formation with HATU/DIPEA in DMF. Direct coupling without protection leads to 8–12% imine-bridged dimer by HPLC area, a side reaction that becomes the dominant pathway at concentrations above 0.3 M.
The ethyl ester at C2 lowers the HOMO energy of the pyrrole ring through its inductive effect, translating into enhanced oxidative stability of the resulting BODIPY chromophores. When condensed with 3‑ethyl‑2,4‑dimethylpyrrole under standard BF3·OEt2/DIPEA conditions, the product furnishes an asymmetric 4,4‑difluoro‑4‑bora‑3a,4a‑diaza‑s‑indacene dye with an absorption maximum in the 526–530 nm range in dichloromethane and an emission quantum yield (Φf) of at least 0.78 relative to fluorescein in 0.1 M NaOH. Accelerated photostability tests according to ISO 4892-2 (xenon arc, 0.35 W m−2 at 340 nm, black-standard temperature 65 °C) indicate that PMMA films (1 wt% dye loading) retain more than 85% of initial emission intensity after 300 h of continuous irradiation, whereas the des‑ester counterpart derived from 5‑formyl‑1H‑pyrrole‑2‑carboxylic acid drops to 62% under identical conditions. The aldehyde handle further enables Knoevenagel condensation with malononitrile or indanedione acceptors, shifting the absorption onset beyond 600 nm while the ester provides a site for further functionalization, such as conversion to the NHS ester for bioconjugation.
The electron-deficient pyrrole ring permits selective halogenation at the 3‑ or 4‑position after aldehyde protection, a sequence that is far less efficient with the 2‑formylpyrrole counterpart because of competing electrophilic attack at the unsubstituted ring positions. When the acetal-protected form of the title compound is subjected to Suzuki–Miyaura coupling with arylboronic acids bearing electron-donating groups, the ester function remains unchanged under typical conditions (Pd(PPh3)4, K2CO3, THF/H2O 3:1, 80 °C). This stands in marked contrast to ethyl 1H‑pyrrole‑2‑carboxylate, where the absence of the electron-withdrawing formyl substituent leads to competitive oxidative homocoupling and rapid palladium black precipitation, lowering the turnover number by roughly a factor of 3. The table below captures the practical distinctions among commonly encountered pyrrole building blocks in a single-step Suzuki coupling to 4‑methoxyphenylboronic acid.
| Substrate | Aldehyde handle | Ester stabilitya | TLC profile (Rf, EtOAc/hexane 1:3) | Purification difficulty |
|---|---|---|---|---|
| Ethyl 5-formyl-1H-pyrrole-2-carboxylate (this product) | Yes | Stable | 0.35 | Low; sharp elution |
| Ethyl 1H-pyrrole-2-carboxylate | No | Stable | 0.50 | Low |
| 1H-Pyrrole-2-carboxaldehyde | Yes | N/A | 0.28 (streaking) | Moderate; baseline tailing |
| 5-Bromo-1H-pyrrole-2-carboxylic acid ethyl ester | No | Stable | 0.42 | Low; no post‑coupling handle |
| a Stability of the ester toward saponification under K2CO3/aq. THF at 80 °C for 3 h. | ||||
The aldehyde of the title compound remains available after cross‑coupling for downstream diversification, an advantage absent in 5‑bromo‑1H‑pyrrole‑2‑carboxylic acid ethyl ester, where the downstream handle is consumed in the coupling event. When formyl-to-boryl conversion is required for inverted coupling sequences, the ethyl ester survives the Miyaura borylation (PdCl2(dppf), KOAc, dioxane, 100 °C) without decomposition, whereas the free carboxylic acid analogue undergoes decarboxylative protodeboronation under identical conditions.
