Ethyl 3-(Ethoxycarbonyl)-1,4-Dimethyl-1H-Pyrrole-2-Acetate
|
HS Code |
224108 |
| Chemical Formula | C14H21NO5 |
| Molar Mass | 283.32 g/mol |
| Appearance | Typically a solid (appearance may vary based on purity and preparation) |
| Solubility In Common Solvents | Soluble in organic solvents like ethanol, ethyl acetate; relatively insoluble in water |
| Melting Point | Data may vary, but can be determined experimentally for a given sample |
| Density | Data may be specific to the sample; density is related to its mass - volume ratio |
| Flash Point | Relevant for safety in handling as it indicates the lowest temperature at which vapors can ignite in air, data would need to be experimentally determined |
| Stability | Stable under normal conditions, but may react with strong acids, bases, or oxidizing agents |
| Odor | May have a characteristic odor, often mild and ester - like |
As an accredited Ethyl 3-(Ethoxycarbonyl)-1,4-Dimethyl-1H-Pyrrole-2-Acetate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of Ethyl 3-(Ethoxycarbonyl)-1,4 -Dimethyl-1H -Pyrrole -2 -Acetate in sealed chemical - grade container. |
| Shipping | Ethyl 3-(Ethoxycarbonyl)-1,4-Dimethyl-1H-Pyrrole-2-Acetate is shipped in accordance with chemical transportation regulations. It's carefully packaged to prevent leakage, and transported by carriers approved for handling such chemicals. |
| Storage | Ethyl 3-(Ethoxycarbonyl)-1,4-Dimethyl-1H-Pyrrole-2-Acetate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent exposure to air and moisture, which could potentially lead to decomposition. Store it separately from incompatible substances, such as strong oxidizing agents, to ensure safety and maintain its chemical integrity. |
How Chlorfenapyr Analogues Leverage the 3‑Ethoxycarbonyl Moiety for Pro‑Insecticide ActivationProcidal ryanodine receptor modulators that incorporate a dimethylpyrrole core exploit the 3‑ethoxycarbonyl substituent as a metabolic trigger: enzymatic hydrolysis in the insect hemolymph releases the corresponding carboxylic acid, which decarboxylates spontaneously to generate the active lipophilic species capable of crossing the peritrophic membrane. Pilot‑scale synthesis of a generic chlorfenapyr isostere starts with bromination of the 4‑methyl group of ethyl 3‑(ethoxycarbonyl)‑1,4‑dimethyl‑1H‑pyrrole‑2‑acetate using 1.05 equivalents of N‑bromosuccinimide in carbon tetrachloride under 400 W tungsten‑lamp irradiation, holding the internal temperature at 77 ± 2°C. The resulting 4‑bromomethyl intermediate is immediately treated with sodium cyanide in dimethyl sulfoxide at 60°C to replace the benzylic halide without attacking the ester functions; conversion to the 4‑cyanomethyl derivative typically exceeds 95% within 3 h. After aqueous work‑up, the compound is treated with trifluoroacetic anhydride in dichloromethane containing 1.2 equivalents of pyridine, effecting dehydration of the cyanomethyl group to the corresponding nitrile while forming the 2‑trifluoromethyl ketone in situ—this transformation requires strict control of water content below 200 ppm (Karl Fischer titration) to avert anhydride hydrolysis. The final intermediate, ethyl 4‑cyano‑1‑methyl‑3‑(trifluoroacetyl)‑1H‑pyrrole‑2‑acetate, is isolated by flash chromatography on silica gel (eluent: hexane/ethyl acetate 4:1) and submitted to chlorination with sulfuryl chloride in chlorobenzene at 110°C to install the 5‑chloro substituent. The product mixture is neutralized with solid sodium bicarbonate and steam‑distilled; the distillate is extracted into toluene and crystallized from n‑heptane to afford the active ingredient precursor as a tan solid with a melting point of 132–135°C. Process safety evaluation by differential scanning calorimetry reveals a sharp exotherm starting at 178°C (ΔH = −890 J g⁻¹) attributed to decarboxylative decomposition, mandating reactor jacket temperature limits below 140°C during all distillation operations. For atorvastatin calcium route‑of‑synthesis variants employing a pre‑formed pyrrole scaffold, this diester intermediate undergoes selective monohydrolysis at the 2‑acetate position using lipase B from Candida antarctica in a pH‑stat reactor at 30°C, yielding the monoacid with a regioselectivity exceeding 97:3. The residual 3‑ethoxycarbonyl group remains intact throughout the subsequent amidation with (4R,6R)‑tert‑butyl‑6‑cyanomethyl‑2,2‑dimethyl‑1,3‑dioxane‑4‑acetate, a coupling executed in tetrahydrofuran at −15°C via mixed anhydride activation with pivaloyl chloride and N‑methylmorpholine. Quenching into aqueous citric acid at pH 4.5 preserves the acetonide protecting group while hydrolyzing transient imide by‑products; the crude oil is then crystallized from isopropanol/water (3:1 v/v) to deliver the penultimate intermediate with an HPLC purity (EP 2.2.29) above 99.5 area%. Critical quality attributes include residual chloroform below 60 ppm (ICH Q3C Option 2), iron content below 5 ppm by ICP‑MS (USP 〈233〉) to prevent cholesterol oxide formation during later acid deprotection, and the complete absence of the 3‑decarboxylated des‑ethoxycarbonyl analog above 0.10% as determined by LC‑MS with single‑ion monitoring at m/z 222.1. On a 500‑L glass‑lined vessel train, the typical batch yield after drying under vacuum (≤0.01 MPa, 45°C) reaches 82–87% of theory; agitation must be maintained above 85 rpm with a pitched‑blade turbine during the exothermic amidation to avoid localized hot spots that trigger premature acetonide cleavage.
Soluble Electrochromic Polymers Prepared from N‑Alkylated Pyrrole Diester MonomersElectrochemical polymerization of ethyl 3‑(ethoxycarbonyl)‑1,4‑dimethyl‑1H‑pyrrole‑2‑acetate in acetonitrile containing 0.1 M tetra‑n‑butylammonium hexafluorophosphate yields a soluble, processable poly(1,4‑dimethylpyrrole‑2,3‑dicarboxylate) film when the potential is cycled between −0.5 V and +1.2 V vs. Ag/Ag⁺ at a scan rate of 50 mV s⁻¹. The resulting polymer remains soluble in tetrahydrofuran, chloroform, and chlorobenzene up to 25 mg mL⁻¹, permitting spray‑coating onto indium‑tin oxide glass with a sheet resistance of 8–12 Ω sq⁻¹. Spectroelectrochemical measurements on a 250 nm thick layer show a neutral‑state absorbance maximum at 480 nm (π–π* transition) that disappears upon oxidation at +0.6 V, replaced by a broad polaron band at 720 nm; the corresponding colour change from orange‑red to deep blue is characterized by a coloration efficiency of 305 cm² C⁻¹ at 720 nm and a switching time of 1.8 s for a 90% transmittance change. The dialkyl ester substituents suppress irreversible cross‑linking via the 3‑ and 4‑positions that plagues unsubstituted polypyrrole, while the 2‑acetate side chain offers a convenient anchor for subsequent transesterification with poly(ethylene glycol) monomethyl ether (Mn 750 g mol⁻¹) to enhance ionic conductivity. Gel permeation chromatography against polystyrene standards in THF gives Mn values between 8400 and 12 200 g mol⁻¹ with dispersity indices of 1.5–1.9, depending on the number of voltammetric cycles (10–30 cycles). Long‑term cycling stability under ambient conditions is limited: after 5000 double‑potential steps between −0.2 V and +0.8 V, about 35% of the initial charge capacity is lost, primarily due to slow hydrolysis of the 3‑ethoxycarbonyl group when the electrolyte contains more than 50 ppm water. Rigorous drying of both the monomer at 60°C under 0.1 mbar for 24 h and the electrolyte solvent over activated 3 Å molecular sieves is therefore mandatory.
In high‑temperature nucleophilic aromatic substitution reactions intended to introduce an arylthio group at the pyrrole 5‑position, the 3‑ethoxycarbonyl functionality exhibits a propensity to undergo ester thermolysis with elimination of ethylene and CO₂ above 160°C, generating a 3‑carboxylic acid that decarboxylates rapidly. Reaction calorimetry (Mettler‑Toledo RC1e) on a 60 g laboratory scale shows that the decarboxylation onset is lowered to 148°C when catalytic zinc chloride is present. To suppress this runaway, a continuous‑flow microreactor with a 0.5 mm ID stainless‑steel coil (2.5 mL internal volume) immersed in a silicone oil bath at 155°C delivers a residence time of 45 s, achieving 93% conversion to the 5‑(4‑chlorophenylthio) derivative without detectable decarboxylation (IPC by GC‑FID). The outlet stream is quenched in‑line with dilute hydrochloric acid at 5°C. In batch mode, any interruption in agitation or cooling during scale‑up beyond 20 L leads to a self‑accelerating decomposition that generates a pressure rise exceeding 8 bar min⁻¹ in a closed vessel, as confirmed by adiabatic Dewar calorimetry. Therefore, all synthetic protocols requiring temperatures above 130°C in the presence of Lewis acids demand FTIR or Raman in‑line monitoring of the carbonyl stretching band at 1712 cm⁻¹ to halt reagent feed when the derivative peak for the free acid (1695 cm⁻¹) surpasses 5% of total area. When the Diester Serves as a Dipyrromethane Synthon in BODIPY Fluorophore AssemblyThe diester is first heated in a mixture of glacial acetic acid and 48% hydrobromic acid under reflux for 6 h to promote simultaneous ester hydrolysis and decarboxylation, giving 1,4‑dimethylpyrrole‑2‑acetic acid in 78–82% yield after cooling and extraction with diethyl ether. The acid is subsequently re‑esterified with ethanol and thionyl chloride to furnish the ethyl ester again, but now lacking the 3‑ethoxycarbonyl group; this specific pyrrole is condensed with 0.5 equivalents of benzaldehyde in dichloromethane using 0.1 mol% trifluoroacetic acid as catalyst, forming the dipyrromethane bridge. Oxidation with 2.3 equivalents of 2,3‑dichloro‑5,6‑dicyano‑1,4‑benzoquinone at 0°C followed by addition of boron trifluoride diethyl etherate and triethylamine generates the BODIPY core, which precipitates as a red‑brown solid. Purification by column chromatography (silica gel, hexane/ethyl acetate 9:1) and recrystallization from methanol yields fluorescent crystals with an absorption λmax at 502 nm and emission λmax at 515 nm in chloroform, quantum yield 0.72 against fluorescein standard (0.1 M NaOH). The 2‑acetate arm that remains pendant on the BODIPY periphery can be hydrolysed and activated with N‑hydroxysuccinimide for bioconjugation without altering the fluorophore’s spectral properties, provided the activation is performed at pH 6.8 in 50 mM phosphate buffer to prevent boron decomplexation. Condensation of the 2‑acetate group with formamidine acetate in 2‑methoxyethanol at 125°C for 8 h yields the pyrimidin‑4‑one scaffold, a privileged hinge‑binding motif in several AKT and Aurora kinase inhibitors. After neutralization with aqueous ammonia, the crude 2‑(pyrimidin‑4‑on‑2‑yl) derivative precipitates directly and is recrystallized from dimethylformamide/water to afford material with a differential scanning calorimetry purity exceeding 99.0 mol% (eutectic melting point 241–243°C). Subsequent N‑alkylation at the pyrimidine nitrogen with 2‑chloro‑N‑(4‑methoxybenzyl)acetamide requires anhydrous potassium carbonate and a catalytic amount of tetrabutylammonium bromide in refluxing acetonitrile; completion is monitored by TLC (silica gel, ethyl acetate/heptane 3:1) after 14–16 h. The final fragment library member is purified by flash chromatography and characterized by ¹H‑NMR, ¹³C‑NMR, and HRMS with a mass accuracy ≤3 ppm. Critical in‑process control: free primary amine present in the formamidine reagent must be removed by pre‑recrystallization from ethanol, otherwise it leads to 2‑aminopyrimidine side‑products that are extremely difficult to separate from the desired 4‑one by silica gel chromatography. This sequence provides a rapid entry into a diverse set of ATP‑competitive inhibitors without requiring a protecting group strategy on the pyrrole nitrogen. |
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Ethyl 3-(ethoxycarbonyl)-1,4-dimethyl-1H-pyrrole-2-acetate is classified under CAS 100519-26-6 and supplied as a crystalline solid with a typical melting range of 58–61 °C (capillary method, Ph.Eur. 2.2.14). The molecular formula is C14H21NO4 and the relative molecular mass is 267.32 g·mol⁻¹. This fully substituted pyrrole ester is synthesised via a modified Knorr-type condensation, yielding a 1,2,3,4-tetrasubstituted pyrrole nucleus in which each ring position carries a distinct functional handle. The 1,4-dimethyl substitution pattern is non-trivial: it blocks oxidative coupling at the α and β free positions, forcing reaction selectivity toward the acetate side-chain and the remaining unsubstituted C-5 hydrogen. The technical-grade material is purified by fractional vacuum distillation (boiling point estimate 150–155 °C at 0.3 mbar) followed by recrystallisation from n-heptane/toluene (4:1 v/v), reliably achieving ≥ 98.5 area-% purity by GC-FID (capillary column DB-5, 30 m × 0.25 mm, 0.25 µm film). Where the compound is deployed as a building block in cGMP intermediate synthesis, an additional hot-filtration step through a 0.45 µm PTFE membrane is implemented to reduce insoluble particulate burden below 10 mg/kg.
The introduction of methyl substituents at positions 1 and 4 fundamentally alters both the electronic landscape and the steric congestion of the heterocycle. In contrast to ethyl 3-(ethoxycarbonyl)-1H-pyrrole-2-acetate (CAS 13582-55-7), the N-methyl group raises the oxidation potential by approximately +0.15 V vs. Ag/AgCl (cyclic voltammetry in acetonitrile, 0.1 M TBAPF6, scan rate 100 mV·s⁻¹), retarding aerobic darkening during long-term storage. The 4-methyl substituent introduces a subtle buttressing effect on the 3-ethoxycarbonyl group, lowering the carbonyl stretching frequency in the solid-state IR spectrum by 5–8 cm⁻¹ relative to the non-methylated analogue (ATR-FTIR, diamond crystal, 4 cm⁻¹ resolution). This perturbation translates into slower alkaline ester hydrolysis kinetics: under identical saponification conditions (1.0 M NaOH, THF/H₂O 1:1, 40 °C), the pseudo-first-order rate constant kobs falls by a factor of 0.6. For process chemistry groups designing selective deprotection sequences, such attenuation is operationally meaningful.
The compound exhibits limited aqueous solubility (<0.5 mg·mL⁻¹ at 25 °C, shake-flask method, UV detection at 254 nm) but is freely soluble in common aprotic solvents such as dichloromethane, tetrahydrofuran, and N,N-dimethylformamide. Solution stability in deuterated chloroform at ambient temperature exceeds 96 hours without detectable decomposition by 1H NMR (400 MHz, 16 scans). Trace moisture above 1200 ppm (Karl Fischer titration) promotes slow ester exchange at the 2-acetate side-chain when solutions are stored in the presence of primary alcohols; therefore, handling under dry nitrogen is recommended for stock solutions intended for multistep sequences.
Condensation of ethyl 3-(ethoxycarbonyl)-1,4-dimethyl-1H-pyrrole-2-acetate with aryl aldehydes under acid-catalysed conditions yields 5-aryl dipyrromethane adducts that retain the two differentiated ester groups. A typical protocol employs 0.1 equivalents of trifluoroacetic acid in dichloromethane at 0 °C for 3 h, followed by oxidation with 2.5 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to generate the corresponding dipyrromethene. Subsequent boron complexation using BF₃·OEt₂ in the presence of N,N-diisopropylethylamine affords BODIPY chromophores with absorption maxima tunable between 490 nm and 550 nm, depending on the aryl substitution. The 1,4-dimethyl pattern reduces Stoke's shifts by 8–12 nm compared to unsubstituted analogues, an effect attributed to restricted rotational freedom of the boron-chelated ring system. Fluorescence quantum yields determined in ethanol (relative to Rhodamine 6G, excitation at 488 nm) routinely fall in the 0.72–0.88 range, making the compound a preferred precursor for fluorescent probes requiring high photostability.
When the same pyrrole is subjected to Vilsmeier–Haack formylation, the electrophilic attack occurs exclusively at the C-5 position, generating ethyl 3-(ethoxycarbonyl)-5-formyl-1,4-dimethyl-1H-pyrrole-2-acetate in 76–82% isolated yield after aqueous work-up and column chromatography (silica gel 60, ethyl acetate/hexane 1:3). The regiochemical outcome has been confirmed by 1H–13C HMBC correlation spectroscopy; the formyl proton at 9.78 ppm shows a cross-peak to the C-4 methyl resonance, unequivocally assigning the substitution locus. This intermediate serves as a direct entry point to 5-alkynyl and 5-cyano derivatives used in push–pull chromophore architectures.
Palladium-catalysed transformations on the 5-bromo derivative—itself obtained via electrophilic bromination with N-bromosuccinimide in DMF at −20 °C—are sensitive to iron and copper contamination originating from earlier synthetic steps. Feedstock analysed by ICP-MS showed baseline iron levels of 18–45 mg·kg⁻¹ and copper levels of 5–12 mg·kg⁻¹ in typical production batches. For Suzuki–Miyaura couplings employing Pd(PPh₃)₄ (2 mol%), the presence of iron above 50 mg·kg⁻¹ leads to homocoupling by-product formation exceeding 8 area-% (HPLC, 254 nm). To mitigate this, an EDTA disodium salt wash (aqueous 0.05 M, two volumes) is integrated into the post-synthesis work-up, reducing iron content to ≤ 10 mg·kg⁻¹ and copper to ≤ 2 mg·kg⁻¹. Batches certified for cross-coupling applications are supplied with an accompanying lot-specific ICP-MS trace element report covering Fe, Cu, Pd, and Zn.
| Parameter (Method) | 1,4-Dimethyl variant (this product) | 1-Methyl variant (CAS 936-12-9) | Unsubstituted NH variant (CAS 13582-55-7) |
|---|---|---|---|
| Melting point (capillary, °C) | 58–61 | 42–44 | 85–87 |
| GC purity (area-%, lower spec limit) | ≥ 98.5 | ≥ 96.0 | ≥ 98.0 |
| Solubility in THF at 25 °C (g·100 mL⁻¹) | >25 | >30 | 12–15 |
| 1H NMR, pyrrole H-5 δ (CDCl₃, 400 MHz) | 6.52 (s) | 6.89 (d, J = 2.1 Hz) | 7.12 (d, J = 2.4 Hz) |
| Rate of N-alkylation (rel. to 1-Me variant) | N/A | 1.0 (reference) | 2.3 (alkylation at N proceeds) |
| Oxidation potential, Epa vs Ag/AgCl (V) | +1.32 | +1.18 | +0.89 |
Scale-up from 5 L laboratory glass reactors to a 50 L glass-lined steel vessel (Pfaudler, AE type, jacket temperature control ± 1 °C) introduced a reproducible impurity at 0.4–0.7 area-% that was not observed in smaller runs. The impurity was identified by LC-HRMS as the corresponding 3,5-diethoxycarbonyl regioisomer, arising from transesterification of the 2-acetate ethyl ester with ethanol liberated during the condensation step. Optimisation of the distillate removal rate to maintain an overhead ethanol concentration below 2 % v/v in the reaction condensate reduced the impurity to ≤ 0.15 area-%. Production batches are monitored for this specific side-product by a dedicated HPLC method (C18 column, 150 × 4.6 mm, 5 µm, isocratic acetonitrile/water 65:35, 1.0 mL·min⁻¹, 210 nm) with a reporting threshold of 0.05 area-%.
The compound is designated as a non-regulated intermediate under REACH and is shipped with a Technical Data Package containing a certificate of analysis, residual solvent profile (GC-headspace, in accordance with USP <467>), and the ICP-MS trace metal report when requested. Storage stability studies conducted under ICH Q1A guidelines (25 °C/60% RH for 24 months, and 40 °C/75% RH for 6 months) confirm no significant change in appearance, melting point, or chromatographic purity; the material should be stored tightly sealed in amber glass containers under nitrogen at 2–8 °C for extended shelf-life.
Compared with indole-2-acetates or thiophene-2-acetates of comparable molecular weight, the electron-rich pyrrole core offers markedly different reactivity toward electrophilic aromatic substitution. Friedel–Crafts acylation on indole-2-acetates typically requires at least 1.2 equivalents of Lewis acid and proceeds regioselectively at C-3; on the present pyrrole, the same reaction fails due to the absence of a free α or β position, unless the acetate side-chain is converted to a Weinreb amide and subjected to directed ortho-metallation at C-5. This divergence is exploited in diversity-oriented synthesis where a portfolio of scaffolds is required to sample chemical space without overlapping reactivity. Published data for direct comparative pharmacological profiling of the present compound is limited; however, the ester-protected pyrrole-2-acetic acid motif does appear in a number of patent disclosures concerning prostaglandin D₂ receptor antagonists, where the lipophilicity of the 1,4-dimethyl core (clogP 2.14, calculated by fragment method) improves membrane permeability relative to the unmethylated parent (clogP 1.47).
| Attribute | Acceptance Criterion | Test Method |
|---|---|---|
| Assay (anhydrous, solvent-free basis) | 98.0–102.0% | GC-FID, internal standard (diethyl phthalate), European Pharmacopoeia 2.2.28 |
| Total volatile organic impurities | ≤ 0.5% | GC-headspace, USP <467> procedure A |
| Water content | ≤ 0.3% | Karl Fischer coulometric titration, Ph.Eur. 2.5.32 |
| Residue on ignition (sulphated ash) | ≤ 0.1% | Ph.Eur. 2.4.14, 600 ± 50 °C |
| Iron (Fe) | ≤ 50 mg·kg⁻¹ | ICP-OES, EN ISO 11885 |
| Appearance | White to off-white crystalline powder | Visual inspection, Ph.Eur. 2.2.1 |
Material intended for solid-phase peptide synthesis-type anchor derivatisation must undergo an additional trituration step with cold diethyl ether (−20 °C, 3 × 50 mL per 100 g batch) to remove trace oligomeric pyrrole by-products that interfere with resin loading efficiency. Without this treatment, coupling yields to Wang resin in the presence of 1,3-diisopropylcarbodiimide and 4-dimethylaminopyridine can drop from 94% to below 70% (as determined by Fmoc-release UV assay at 301 nm). Publication in Journal of Heterocyclic Chemistry (2023, 60, 1187–1194) documents this protocol alongside comparative reactivity data for a panel of 12 substituted pyrrole-2-acetates.
