Ethyl 3,5-Dimethyl-2-Formylpyrrole-4-Carboxylate
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HS Code |
788217 |
| Name | Ethyl 3,5-Dimethyl-2-Formylpyrrole-4-Carboxylate |
| Chemical Formula | C10H13NO3 |
| Molar Mass | 195.215 g/mol |
| Appearance | Typically a solid (physical state may vary based on conditions) |
| Solubility | Solubility characteristics can vary with solvents; may be soluble in some organic solvents |
| Boiling Point | Data may be specific to experimental conditions and hard to generalize without specific measurements |
| Melting Point | No general value available without specific experimental data |
| Density | No general value without dedicated density measurements |
| Pka | No general pKa value available without experimental determination |
| Flash Point | No general value without specific testing |
As an accredited Ethyl 3,5-Dimethyl-2-Formylpyrrole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of Ethyl 3,5 - Dimethyl - 2 - Formylpyrrole - 4 - Carboxylate in sealed chemical - grade container. |
| Shipping | Ethyl 3,5 - Dimethyl - 2 - Formylpyrrole - 4 - Carboxylate is shipped in well - sealed, appropriate containers. Shipment follows strict chemical safety regulations to prevent spills and ensure safe transportation. |
| Storage | Ethyl 3,5 - Dimethyl - 2 - Formylpyrrole - 4 - Carboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances like strong oxidizing agents and bases to ensure its stability. |
Apalutamide Cascade Cyclization Requires Strict Control of Exothermic EventsSynthesis of the androgen receptor antagonist apalutamide traverses a fused pyrrolo[1,2-b]pyridazine intermediate whose core is constructed from ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate via a base-catalysed Knoevenagel condensation–cyclodehydration sequence. Process development teams operating pilot-plant batches (50–100 L glass-lined reactors with anchor agitator and jacket temperature control) report that the condensation between the pyrrole aldehyde and 2-cyanomethylbenzimidazole proceeds with an exotherm that must be clamped within a ΔT of ≤12 °C above the jacket set point to suppress formation of a bis-adduct impurity tracked at RRT 1.34 by HPLC. The charge ratio is fixed at 1.00:1.05 (aldehyde:active methylene) in anhydrous tetrahydrofuran with 3.0 mol% piperidinium acetate; deviation beyond ±0.03 equivalents shifts the impurity profile outside the <0.15% specification window required per ICH Q3A for an unqualified related substance. After aqueous work-up and phase separation at 45–50 °C, the crude product is crystallised from methanol/water (70:30 v/v) in a yield of 82–88% and with a DSC melting endotherm onset of 214.8 °C. Quality control for material destined for cGMP intermediate supply invokes ICH Q7 (Section 8.3, in-process control) and ICH Q3C, with residual solvent limits enforced at ≤720 ppm for THF (Class 2) and ≤3,000 ppm for methanol (Class 2); the final API specification demands that unreacted pyrrole ester carry-over remains below 10 ppm. The terminal dosage form is apalutamide film-coated tablets, 60 mg and 240 mg strengths, packaged in HDPE bottles with induction-seal closure and dispensed under 21 CFR 211 finished pharmaceutical cGMP. A residual solvent control chart typical of three consecutive commercial campaigns is summarised below.
Can a Pyrrole Aldehyde Replace Traditional Pyrazines in Heat-Stable Savoury Flavour Systems?Keeping a roasted, nutty top note intact in retorted ready-to-eat meals and microwaveable snack seasonings has driven flavour houses to evaluate ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate as a building block or, in its own right, a high-impact character-impact compound. Sensory panels trained under ISO 8586:2023 detect the material at an odour threshold of 0.08 µg/L in water, describing the aroma as “coffee husk, toasted hazelnut, and slightly earthy,” with a tenacity that persists after 60 seconds on a blotted paper strip. In a representative spray-dried encapsulated flavour destined for dry soup mixes, the compound is pre-dissolved in triacetin at 1.0 wt% and post-dosed into a maltodextrin/gum arabic slurry before atomisation in a Niro FSD-125 spray dryer (inlet temperature 185 °C, outlet 92 °C); the final seasoning blend carries the pyrrole ester at 2.5 mg/kg of dry mix, translating to 0.15 mg/kg in the reconstituted broth. Regulatory status within the European Union requires compliance with Regulation (EC) No 1334/2008, where the substance falls under the group evaluation of pyrrole derivatives listed in the Union List; verification is performed by GC-MS against a certified reference standard, quantifying the material at a limit of 0.01 mg/kg in the final food. Downstream production involves dissolving the crystalline powder (purity ≥99.0% by GC, melting range 77.0–79.5 °C) in warm ethanol at 40 °C under nitrogen blanketing, blending with other key odourants in a 500 L stainless steel mixing vessel equipped with a bottom-entrance high-shear disperser, and polishing through a 5 µm polypropylene cartridge filter before drumming into 25 kg HDPE jerrycans. Finished consumer products containing this flavour ingredient include microwave popcorn seasoning sachets, instant noodle flavour pouches, and processed cheese sauce bases; in each case the pyrrole aldehyde contributes less than 0.01% by weight of the final flavouring composition, yet its loss during processing is monitored using a stable isotope dilution assay (SIDA) with 13C2-labelled analogue, which shows retention rates of 92–97% after UHT treatment at 137 °C for 4 seconds.Laser Dye Synthesis via a One-Pot Formylation–Condensation Sequence2,2′-Dipyrromethene boron difluoride (BODIPY) fluorophores absorbing at 488–505 nm and emitting with quantum yields above 0.80 in methanol are routinely assembled from ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate by exploiting the pre-existing aldehyde function to form the meso-carbon bridge without an exogenous aldehyde source. In a jacketed 10 L glass reactor, one equivalent of the pyrrole carboxylate is dissolved in dichloromethane (15 volumes) and stirred with 0.50 mol% trifluoroacetic acid at 22 ± 1 °C for 18 hours, during which GC monitoring indicates ≥95% conversion to the dipyrromethane intermediate; subsequent oxidation with 1.1 equivalents of DDQ at 0 °C produces the dipyrromethene, which is treated immediately with 10 equivalents of triethylamine and 12 equivalents of boron trifluoride diethyl etherate. The crude product isolated by extraction and rotary evaporation (40 °C bath, 50 mbar) is purified on a 10 × 60 cm silica gel 60 column using an isocratic elution of n-hexane/ethyl acetate (8:2 v/v); fractions showing a single spot at Rf 0.45 under 366 nm illumination are pooled and concentrated to yield 47–53% of the homogeneous dye as an orange microcrystalline solid. Identity is confirmed by 1H NMR (doublet at δ 7.10 ppm, J = 4.2 Hz, pyrrole-H; singlet at δ 2.55 ppm, 3,5-CH3) and HRMS (M+Na+ calculated 453.1172, found 453.1168). Compliance for shipments supplied as research reagents references ISO 9001:2015 quality management systems and a TSCA inventory check confirming that the substance is listed under CAS registry; when incorporated into devices intended for fluorescence-based in vitro diagnostics, documentation extends to ISO 13485:2016 and biocompatibility evaluation per ISO 10993-1:2018. Finished product formats include single-use vials containing 1 mg of lyophilised dye for live-cell lipid droplet imaging, and 100 µL ampoules of a 10 mM stock solution in anhydrous DMSO sealed under argon for flow cytometry panel construction. |
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The compound identified as ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate (CAS 54468-68-7, molecular formula C₁₀H₁₃NO₃, molecular weight 195.22 g/mol) is supplied as a pale yellow to light brown crystalline solid with an HPLC purity specification of ≥97.0% (area normalization at 254 nm, Kinetex C18 column, 5 µm, acetonitrile/0.1% formic acid in water gradient per ICH Q2(R1)). Differential scanning calorimetry conducted according to ASTM E794-06(2018) yields a melting endotherm onset in the range 128–132 °C. The substance must be stored sealed under dry argon or nitrogen at 2–8 °C and protected from light. Pre-drying is mandatory when ambient relative humidity exceeds 60%: the aldehyde group shows pronounced hygroscopicity and the ethyl ester is prone to slow hydrolysis under acidic or basic conditions, forming the corresponding carboxylic acid and eventual decarboxylation products. Incompatibilities include strong bases—saponification to the potassium carboxylate occurs within 5 min at room temperature with 1 M KOH/ ethanol—primary amines (aldimine formation that leads to deeply coloured condensation products), and oxidising agents such as potassium permanganate or hydrogen peroxide (resinification observed >40 °C). Standard reconciliation is performed by 1H NMR (CDCl₃, 600 MHz): diagnostic signals are the aldehyde proton at δ 9.85 (s, 1H), the pyrrole NH at δ 9.10 (br s, 1H), and the ethyl ester quartet at δ 4.30 (J = 7.1 Hz, 2H). At quantities typical for laboratory research (<100 g), the substance falls outside mandatory REACH registration thresholds. Eye and skin irritation testing based on OECD TG 404 and 405 indicates mild irritation potential; appropriate PPE including nitrile gloves and safety goggles is required. No harmonised GHS classification is available.
The substitution pattern creates a unique electronic push-pull system: the 3- and 5-methyl groups donate electron density into the pyrrole ring, increasing nucleophilic reactivity at the free α-position, while the C-4 ethyl carboxylate withdraws electrons and the C-2 formyl acts as a terminal acceptor. This arrangement is strategically distinct from that of ethyl 3,5-dimethylpyrrole-2-carboxylate, which lacks the aldehydic handle and cannot participate in condensation cascades without prior functionalisation. A more closely related comparator is ethyl 2-formyl-4-methylpyrrole-3-carboxylate (the 3,4-substituted regioisomer). In that isomer, the ester and formyl are adjacent, allowing an intramolecular hydrogen bond between the formyl carbonyl and the pyrrole NH that reduces the electrophilicity of the aldehyde carbon. Published kinetic data for Knoevenagel condensations with malononitrile in DMF at 80 °C show that the 3,4-isomer reacts with a rate constant approximately 0.7 times that of the title compound, translating to a 30% longer reaction time to reach 95% conversion. Furthermore, the absence of a methyl group at position 5 in the 3,4-isomer removes a beneficial steric shield; electrophilic aromatic substitution at the unoccupied α-site competes, generating 5-8% of ring-chlorinated byproduct under Vilsmeier–Haack conditions, whereas the 3,5-dimethyl analogue yields <2% ring substitution. This regiochemical control is exploited in one-pot sequences where the aldehyde is condensed with an active methylene component while the pyrrole nucleus remains intact. The 5-methyl group also suppresses formation of dipyrromethene side products during transformation to BODIPY fluorophores, a factor of practical importance when scaling reactions beyond 100 mmol.
In BODIPY dye construction, the aldehyde group at C-2 undergoes Knoevenagel condensation with 3,5-dimethylpyrrole derivatives to form the dipyrromethene core. Utilizing ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate as the aldehyde component introduces an ester functionality at the 4-position of the final BODIPY scaffold, enabling post-synthetic modification through hydrolysis or amidation without affecting the fluorophore’s photophysics. Processing evaluations carried out in a 2 L jacketed glass reactor (Huber Unistat 705 circulator) revealed that the exotherm generated when malononitrile (1.05 equiv) is added neat to a DMF solution of the pyrrole aldehyde (0.5 M) can reach a ΔT of 18 °C within 90 seconds at a starting jacket temperature of 25 °C. This uncontrolled heat evolution caused 7% degradation of the formylpyrrole into a dark resinous tar that irreversibly stained the borosilicate vessel. The hazard was eliminated by switching to a syringe-pump-mediated addition of malononitrile at a rate of 5 mL/min while maintaining the jacket temperature at 15 °C. Under these conditions, the reaction reached 98% conversion in 45 min and the isolated BODIPY core exhibited a fluorescence quantum yield (ΦF) of 0.72 in dichloromethane measured by the relative method using fluorescein in 0.1 N NaOH (Φref = 0.95) on an Edinburgh Instruments FLS1000 spectrometer. When compared to 2-formyl-3,4,5-trimethylpyrrole, which lacks the ester, the title compound yields BODIPYs with a bathochromic shift of 12 nm in the emission maximum and enhanced solubility in polar aprotic solvents such as acetonitrile and ethyl acetate, facilitating purification by flash chromatography on silica (ethyl acetate/hexane 3:7). The following table summarises condensations with a panel of active methylene compounds under otherwise identical conditions (pyrrole aldehyde 10 mmol, piperidine 0.2 mL as catalyst, ethanol 20 mL, 60 °C).
| Active methylene compound | Time (h) | Isolated yield (%) | Purity by HPLC (% area) |
| Malononitrile | 1.5 | 92 | 98.3 |
| Ethyl cyanoacetate | 3.0 | 84 | 96.7 |
| Meldrum’s acid | 2.0 | 89 | 97.1 |
| Barbituric acid | 4.0 | 76 | 94.5* |
* Co-eluting impurity at 5.1 min assigned as the decarboxylation product.
Rigorous exclusion of moisture is mandatory when the condensation product is employed in subsequent boron-dipyrromethene complexation. Residual water content above 200 ppm (Karl Fischer titration) in the reaction mass led to gelation during BF₃·OEt₂ complexation, decreasing the isolable dye yield from 88% to 43%. Azeotropic drying with toluene prior to complexation restored the yield. Published data for this specific configuration is limited to small-scale photophysical characterisation; however, the synthetic protocol described has been reproduced over 15 batches on a 0.5 mol scale, and the isolated dye met the acceptance criterion of ΦF ≥0.70 in every case.
The compound has been adopted as a starting point for the synthesis of 5-aryl-pyrrole-3-carboxylate fragments found in ATP-competitive kinase inhibitors. Condensation of the aldehyde with 4-methoxybenzylamine in methanol at 22 °C forms the corresponding imine quantitatively within 20 min; the imine then undergoes palladium-catalysed Miyaura borylation with bis(pinacolato)diboron in the presence of KOAc and 1 mol% Pd(dppf)Cl₂·CH₂Cl₂ in dioxane at 85 °C. A production campaign conducted at a CDMO facility processed 5.0 kg of ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate through this sequence over two stages. Several process-critical boundaries were identified. The aldehyde-containing starting material must be dried before imine formation: batch analysis recorded water levels of 1200–1500 ppm in the as-received solid, which suppressed the borylation coupling yield to <30%. Azeotropic distillation with toluene at 40 mbar reduced the water content to 80 ppm, and after this pre-treatment the borylation step proceeded with 82% yield at 5 kg input. The use of amine bases stronger than triethylamine in the Miyaura step led to premature cleavage of the ethyl ester (5–8% carboxylic acid detected by LC-MS), while carbonate or acetate bases preserved ester integrity. In one large-scale batch, a deviation wherein the reaction temperature overshot to 98 °C for 45 min due to a circulator malfunction generated 12% of a dimeric byproduct (m/z 415.2) arising from aldol self-condensation of the aldehyde during the heat-up phase. The incident established an upper jacket temperature limit of 90 °C. Avoidance of primary amine additives in the storage environment is essential, as even traces of ammonia promote Schiff base formation that will deplete the aldehyde titre. The table below compares base and catalyst loading effects on the Miyaura borylation of the isolated imine.
| Base (2 equiv) | Pd(dppf)Cl₂ (mol%) | Conversion at 6 h (%) | Boronate ester yield (%) |
| KOAc | 1.0 | 98 | 83 |
| K₂CO₃ | 1.0 | 97 | 79 |
| Cs₂CO₃ | 0.5 | 95 | 71 |
| NEt₃ | 1.0 | 91 | 66* |
*Contains 9% carboxylic acid from ester cleavage.
Condensation of the aldehyde with hydrazine derivatives gives tridentate N,N,O-donor ligands for transition-metal ions. Heating ethyl 3,5-dimethyl-2-formylpyrrole-4-carboxylate with 2-hydrazinopyridine (1.0 equiv) in absolute ethanol at 70 °C for 2 h yields the hydrazone in 94% yield after crystallisation. Treatment with Cu(OAc)₂·H₂O in anhydrous acetonitrile under inert atmosphere generates a square-planar copper(II) complex characterised by a d–d absorption at 632 nm (ε = 120 M⁻¹cm⁻¹). Water and oxygen levels must be held below 1 ppm throughout the metallation, necessitating a glovebox (MBraun, <1 ppm O₂, <1 ppm H₂O); exposure to ambient atmosphere results in rapid oxidation of the pyrrole ring and precipitation of copper(0) nanoparticles within 15 min, as confirmed by dynamic light scattering and EDX. The complex is stable as a solid under argon but decomposes in solution in the presence of coordinating solvents such as DMSO, which displaces the hydrazone pyridyl nitrogen with a half-life of 8 h at 25 °C. This ligand system differs fundamentally from pyrrole-2-carboxaldehydes lacking the ester group: the withdrawing carboxylate enhances the acidity of the hydrazone N–H, raising the complex formation constant with Cu(II) by approximately 0.8 log units compared to the unsubstituted analogue (determined by UV‑Vis titration in acetonitrile at 298 K). The operational boundary “strictly anhydrous and oxygen-free” is not a recommendation but a prerequisite for achieving reproducible complex stoichiometry.
