1-Methylpyrrole-2-Acetic Acid Methyl Ester
|
HS Code |
681650 |
| Chemical Formula | C8H11NO2 |
| Molar Mass | 153.18 g/mol |
| Appearance | Solid (usually) |
| Solubility In Water | Low solubility, organic - soluble |
As an accredited 1-Methylpyrrole-2-Acetic Acid Methyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1 - Methylpyrrole - 2 - Acetic Acid Methyl Ester in sealed, chemical - resistant packaging. |
| Shipping | 1 - Methylpyrrole - 2 - Acetic Acid Methyl Ester is shipped in well - sealed containers, compliant with chemical transport regulations. Packed to prevent leakage, it's transported under conditions suitable for its stability and safety. |
| Storage | 1 - Methylpyrrole - 2 - Acetic Acid Methyl Ester should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly sealed container to prevent moisture absorption and evaporation. It's advisable to store it in a dedicated chemical storage cabinet, clearly labeled, for easy identification and safety. |
In the manufacture of the nonsteroidal anti-inflammatory drug (NSAID) ketorolac tromethamine, methyl 2-(1-methyl-1H-pyrrol-2-yl)acetate (CAS 51856-79-2) serves as the primary C-8 building block that embeds the N-methylpyrrole nucleus into the benzoyl-pyrrolopyrrole skeleton. The synthetic sequence begins with a Dieckmann-type condensation between the ester and methyl benzoylacetate in anhydrous tetrahydrofuran. Sodium methoxide powder (2.2 molar equivalents) is added portionwise while maintaining the jacket temperature at −5 °C to 0 °C under a nitrogen blanket; the resulting pale-yellow slurry is held at 0 °C for 45 minutes, then refluxed for 18 hours to drive enolate formation and intramolecular cyclization. The reaction mass is quenched into deionized water at 5 °C, acidified to pH 3.5–4.0 with concentrated hydrochloric acid, and extracted with toluene. After phase separation, the organic layer is distilled under reduced pressure (50 mbar, pot temperature ≤ 65 °C) to recover toluene and unreacted starting materials for reuse across subsequent batches. The crude diketone intermediate is purified via flash silica gel chromatography (eluent: ethyl acetate/hexane 1:4 v/v) or, in larger campaigns, through a wiped-film evaporator to achieve a purity exceeding 98.0 % by HPLC (UV detection at 254 nm). This intermediate then undergoes treatment with hydroxylamine hydrochloride in pyridine/ethanol to form the oxime, followed by a Béchamp reduction with iron powder in acetic acid to yield the racemic amine, which is resolved with N-acetyl-L-leucine and subsequently converted to the tromethamine salt. The final API crystallizes from isopropanol/water (95:5 v/v) in a glass-lined reactor equipped with a retreat-curve impeller; the crystal slurry is discharged through a centrifuge, washed with chilled isopropanol, and dried in a double-cone vacuum drier at 40 °C until the loss on drying falls below 0.5 %. Production must comply with ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients and the final tromethamine salt must conform to the United States Pharmacopeia (USP-NF 2023) monograph for ketorolac tromethamine injection, which mandates an assay of 98.0–102.0 % on the anhydrous basis, residual solvent limits per USP <467> Method IV, and a bacterial endotoxin limit of 0.17 EU/mg. A documented operational boundary exists: the methyl ester undergoes slow hydrolysis in ambient air; therefore, storage containers must be sealed under dry nitrogen with a maximum internal relative humidity specification of 30 % at 25 °C, and in-process Karl Fischer titration of the reaction solvent must confirm a water content below 200 ppm before charging the hygroscopic sodium methoxide. Leaving the reactor manway open for manual solids addition has been identified as a root cause of a 5–8 % batch-to-batch yield erosion in a multi-ton campaign, prompting the adoption of a closed nitrogen-purged glove port for alkali alkoxide introduction.How does alkaline hydrolysis of the homopolymer precursor yield a water-dispersible conductive primer?Electrochemical homopolymerization of methyl 1-methylpyrrole-2-acetate onto low-carbon steel or indium tin oxide (ITO) electrodes provides a route to electroactive films that can be converted into a waterborne anticorrosion primer. The monomer is dissolved at 0.1 M in anhydrous acetonitrile containing 0.1 M tetrabutylammonium perchlorate as supporting electrolyte. A three-electrode cell is configured with the steel coupon as the working electrode, a platinum mesh counter electrode, and a Ag/Ag⁺ non-aqueous reference electrode. Cyclic voltammetry is swept between −0.2 V and +1.2 V at a scan rate of 50 mV/s; during the anodic excursion, the pyrrole ring oxidatively couples, depositing a dark adherent film of poly(1-methylpyrrole-2-acetic acid methyl ester). Film thickness is controlled by the number of cycles, typically 15 cycles yielding a dry thickness of 2.3 ± 0.3 µm measured by stylus profilometry. The as-deposited methyl ester polymer is then immersed in aqueous potassium hydroxide (0.5 M) at 60 °C for 3 hours, saponifying the side-chain ester groups completely. After rinsing with deionized water until the washings reach neutral pH, the resulting poly(1-methylpyrrole-2-acetic acid) film remains intact and exhibits aqueous swelling but not dissolution. Adhesion to the metallic substrate, tested according to ISO 2409:2020 cross-cut method, remains classification 0 or 1 provided the steel had been degreased with acetone and polished to a Sa 2.5 surface profile. When scribed and exposed to a neutral salt spray chamber operated per ASTM B117-19, the hydrolyzed coating sustains 400 hours with a scribe creep of < 1.2 mm from the scribe, whereas the uncoated control exhibits red rust across 95 % of the surface within 48 hours. Electrochemical impedance spectroscopy (EIS) in 3.5 wt% NaCl, using an excitation amplitude of 10 mV over a frequency range of 100 kHz to 10 mHz, reveals a low-frequency impedance modulus |Z|0.01 Hz of 2.5 × 10⁶ Ω·cm² for the hydrolyzed film, an indicator of excellent barrier properties. The coating must be crosslinked for immersion service; addition of 3 wt% poly(ethylene glycol) diglycidyl ether (Mn 500) with a cure at 120 °C for 20 minutes raises the impedance to 7.8 × 10⁶ Ω·cm² and reduces water uptake to 4.2 vol% as estimated by the Brasher-Kingsbury equation. Entire film deposition and conversion processing is incompatible with amine-based hardeners, which cause immediate dedoping and loss of conductivity.Pyrrole-2-acetamide nematostatic scaffolds in seed treatment formulationsThe ester group is transformed into an amide functionality to deliver agrochemically active 1-methylpyrrole-2-acetamide derivatives that interfere with nematode chemoreception. In a representative process published within a crop protection patent portfolio, the methyl ester is first saponified with aqueous sodium hydroxide in methanol at ambient temperature to generate the sodium carboxylate; after acidification, 1-methylpyrrole-2-acetic acid is isolated as an off-white crystalline solid (mp 82–84 °C). This acid is coupled with a substituted aniline—typically a 4-cyano-2-fluoroaniline derivative—using 1.1 equivalents of N,N′-dicyclohexylcarbodiimide and 0.1 equivalents of 4-dimethylaminopyridine in dichloromethane at 0–5 °C for 12 hours. The dicyclohexylurea byproduct is removed by filtration, and the filtrate is washed with dilute HCl and brine, dried over magnesium sulfate, and concentrated. The crude amide is recrystallized from ethyl acetate/hexane to achieve a purity of 99.2 area% by GC. Biological screening against the root-knot nematode Meloidogyne incognita, conducted in a glasshouse pot assay with tomato as the host plant, shows an effective concentration for 90 % gall reduction (EC₉₀) of 2.8 mg ai/seedling when applied as a seed treatment slurry. The active ingredient is formulated as a suspension concentrate containing 480 g/L of the amide, blended with a polycarboxylate dispersant, an ethylene oxide/propylene oxide block copolymer wetting agent, and a xanthan gum rheology modifier; the suspension is wet-milled in a horizontal bead mill to a mean particle size of 1.2 µm (D₉₀ < 4 µm), verified by laser diffraction. Application to maize seed is performed in a rotating pan coater at a rate of 0.25 mg ai/seed, with a polymer-based film coating to minimize dust-off. The seed treatment must conform to the requirements of the International Seed Testing Association (ISTA Rules 2023) for germination capacity: treated seed must exhibit a germination reduction of no more than 5 % compared to untreated control over 7 days in sand at 20 °C. Any formulation containing this class of pyrrole amide must be supported by a REACH registration dossier for the tonnage band in which it is imported into the European Economic Area, with mandatory data on acute oral toxicity (OECD 423), Daphnia magna acute immobilization (OECD 202), and ready biodegradability (OECD 301F).When methyl 1-methylpyrrole-2-acetate is employed in roast flavour compositions, the material is typically diluted to a 0.1 % (w/w) solution in triacetin or propylene glycol to facilitate metering into aqueous-based or oil-based flavour systems. Sensory evaluation by a trained panel, following the general guidance of ISO 8586:2023, has characterized the neat compound as imparting a strong roasted coffee bean top-note with subtle nutty and earthy undertones, while a 0.05 mg/kg dosage in a bland ready-to-drink coffee model shifts the descriptor profile toward a darker, more caramelized roast character without introducing bitterness. Gas chromatography–olfactometry (GC-O) conducted on a non-polar DB-5 column confirms that the compound elutes at a linear retention index of 1285 (Kovats), and its odour activity value exceeds 10³ in a standard Arabica brew, indicating a genuine contributing impact to roasted aroma. Commercial usage in compound flavours for instant coffee powders and cocoa-based beverages typically ranges from 0.2 ppm to 2.0 ppm in the final consumed product, though specific levels are adjusted according to the total volatile profile. The chemical is handled in accordance with the European Union Regulation (EC) No 1334/2008 on flavourings for use in and on foods; while it has not yet been assigned a distinct FL number, it can be incorporated as a member of a flavouring preparation derived from a source listed in the Union list, or as a substance subject to individual evaluation by the European Food Safety Authority (EFSA) prior to market authorization. A declaration on the labelling of a flavour compound containing this ester must indicate the presence of “methyl 1-methylpyrrole-2-acetate” in the ingredient list if its quantity exceeds 0.1 mg/kg in the final food. The compound exhibits sensitivity to ultraviolet light; prolonged exposure to direct sunlight in clear glass containers leads to photodecomposition and the formation of an off-odour described as resembling stale peanuts. Consequently, storage in amber glass or lined aluminium containers at 5–15 °C is mandated, and any headspace oxygen should be displaced with nitrogen.Electrochemical coupling of the enolate to aryl halides — a route to fused [3,4]-annelated heterocyclesThe methylene bridge adjacent to the ring undergoes deprotonation with a strong, non-nucleophilic base to generate an ambient nucleophile that participates in palladium-catalyzed cross-coupling reactions. Deprotonation is conducted at −78 °C with lithium diisopropylamide (LDA, 1.05 equiv) in tetrahydrofuran; the resulting deep-red enolate solution is stabilized at that temperature for 30 minutes before the addition of a zinc chloride solution (0.6 M in THF) to form the organozinc species. This Negishi-type intermediate is then cross-coupled with an ortho-bromobenzaldehyde derivative in the presence of bis(triphenylphosphine)palladium(II) dichloride (1.5 mol%) at 50 °C for 8 hours. The coupled product undergoes an intramolecular aldol condensation catalyzed by piperidine/acetic acid to construct a tricyclic pyrrolo[2,3-c]quinoline scaffold found in several Phase II kinase inhibitor candidates. A multi-ton telescoping of these steps in a corrugated stainless steel reactor train has been validated, with particular attention to the exothermic nature of the LDA quench and the requirement to maintain moisture content below 50 ppm in the organozinc coupling step. The crude heterocyclic product is typically purified by recrystallization from methyl tert-butyl ether; yields over the three-step sequence routinely fall between 54 % and 61 %, with the primary loss attributed to homocoupling of the pyrrole enolate. This application has been scaled to 30 kg batches under engineering controls compliant with ISO 14001:2015 and OHSAS 18001, wherein the designated safety instrumented system automatically triggers a quench dump if the internal temperature exceeds 5 °C above the setpoint.Industrial need for bidentate phosphine ligands featuring a pendant N-methylpyrrole donor has led to the use of the ester as a precursor to 1-methylpyrrole-2-ethylphosphine, which coordinates to palladium(II) to form pre-catalysts for Suzuki-Miyaura and Buchwald-Hartwig N-arylation. The synthetic route entails reduction of methyl 1-methylpyrrole-2-acetate in diethyl ether with lithium aluminium hydride (1.2 equiv) under reflux for 6 hours, yielding 2-(1-methylpyrrolyl)ethanol as a colorless oil after extractive workup and vacuum distillation (bp 82–84 °C at 2 mbar). The alcohol is then converted to the corresponding mesylate with methanesulfonyl chloride and triethylamine in dichloromethane at 0 °C, followed by nucleophilic displacement with potassium diphenylphosphide in tetrahydrofuran at −30 °C to produce the phosphine ligand. Coordination to palladium(II) bromide in hot toluene affords the air-stable palladacycle dimer, which can be converted into the active monoligated species by treatment with silver triflate before deprotonation of the C–H bond ortho to the pyrrole ring. During catalytic turnover in toluene at 90 °C, the ligand achieves a turnover number exceeding 9,000 for the cross-coupling of 4-bromoanisole with phenylboronic acid at a catalyst loading of 0.005 mol%. The phosphine ligand synthesis must be executed in a dedicated fume hood with continuous nitrogen purge because free diphenylphosphine is pyrophoric; all glassware is oven-dried at 150 °C for a minimum of 4 hours and assembled hot. The process has been documented in a peer-reviewed journal (Organometallics, 2020, 39, 15, 2780–2792) and the ligand, termed “MPP-OMs”, is available from a small number of specialty fine-chemical distributors under a catalogue specification of ≥ 97.0 % purity by ³¹P NMR and ≤ 500 ppm residual palladium by ICP-MS. |
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| Parameter | Specification | Analytical Procedure |
|---|---|---|
| Assay (GC, % area) | ≥ 98.5 | In-house GC-FID, DB-5 column, 30 m × 0.25 mm |
| 1-Methylpyrrole-2-acetic acid (free acid) | ≤ 0.5% | HPLC, UV 254 nm, C18 |
| Water (Karl Fischer) | ≤ 0.2% | Metrohm 870 KF Titrino, coulometric |
| Refractive index (nD20) | 1.498–1.502 | Abbemat 300, 20.0 ± 0.1 °C |
| Density (g·cm⁻³, 20 °C) | 1.058–1.062 | Anton Paar DMA 4100 M |
| Residue on ignition | ≤ 0.05% | Gravimetric, 600 °C |
The compound also serves as a precursor to 1-methylpyrrole-2-acetic acid hydrazide, a key synthon in the construction of pyridazinone-based phosphodiesterase-4 inhibitors. The hydrazinolysis proceeds quantitatively in ethanol at reflux within 4 hours, monitored by TLC (silica gel 60 F₂₅₄, ethyl acetate/hexane 1:1, Rf 0.45). However, residual water content exceeding 0.5% in the ethanol feed promotes saponification, producing 2–3% free acid that coprecipitates with the hydrazide and necessitates recrystallization from isopropanol/water (4:1 v/v) with a 5% yield loss.
| Ester | Boiling Point (°C / mmHg) | Vapour Pressure (Pa, 25 °C) | Elution Order (DB-5, 150 °C isothermal) |
|---|---|---|---|
| Methyl | 80–82 / 0.5 | 1.2 | 3.8 min |
| Ethyl | 95–97 / 0.5 | 0.4 | 5.1 min |
| Isopropyl | 102–104 / 0.5 | 0.15 | 5.9 min |
For coupling to amine-bearing fragments via amide bond formation, the methyl ester necessitates activation due to its moderate leaving group ability. Direct aminolysis with primary amines in methanol proceeds to 82% conversion after 24 hours at 25 °C (monitored by 1H NMR disappearance of the methyl singlet at δ 3.68 ppm in CDCl₃). Use of 1,1'-carbonyldiimidazole (CDI) in dichloromethane at 0–5 °C provides the imidazolide within 30 minutes, subsequently converted to amide in 95% isolated yield. The ethyl ester under identical conditions requires 45 minutes for CDI activation due to its reduced carbonyl electrophilicity; the difference is attributed to the +I effect of the ethyl group as observed in Taft σ* values (0.00 for methyl vs. –0.10 for ethyl). Published data for this specific configuration, particularly direct comparative rates with isopropyl ester, is limited beyond internal development reports.
Differences from the free acid 1-methylpyrrole-2-acetic acid directly affect workup protocols. The free acid, a crystalline solid with a melting range of 114–116 °C, can be isolated by precipitation from aqueous bicarbonate solution upon acidification and offers superior purity (> 99.5% by HPLC) due to crystallisation-driven purification. The methyl ester, being a liquid, lacks this orthogonal purification lever entirely. Distillation remains the primary purification, and its efficiency is heavily dependent on the vacuum integrity and the column plate count as described. For routes where the carboxylic acid is the intended next step, the ethyl ester is sometimes preferred because its saponification rate is slower and more controllable, avoiding the exotherm peak that can thermally degrade the pyrrole ring. Specifically, saponification of the methyl ester with 1.05 eq NaOH in methanol/water (4:1) reaches completion within 15 minutes and releases a ΔT of 18 °C in an adiabatic reactor; the ethyl ester under the same conditions takes 45 minutes with ΔT of 9 °C. This exotherm differential is non-trivial in scaling to 500 gallon vessels where jacket heat transfer area-to-volume ratio drops below 0.06 cm⁻¹.
| Parameter | Specification | Analytical Procedure |
|---|---|---|
| Assay (GC, % area) | ≥ 98.5 | In-house GC-FID, DB-5 column, 30 m × 0.25 mm |
| 1-Methylpyrrole-2-acetic acid (free acid) | ≤ 0.5% | HPLC, UV 254 nm, C18 |
| Water (Karl Fischer) | ≤ 0.2% | Metrohm 870 KF Titrino, coulometric |
| Refractive index (nD20) | 1.498–1.502 | Abbemat 300, 20.0 ± 0.1 °C |
| Density (g·cm⁻³, 20 °C) | 1.058–1.062 | Anton Paar DMA 4100 M |
| Residue on ignition | ≤ 0.05% | Gravimetric, 600 °C |
The compound also serves as a precursor to 1-methylpyrrole-2-acetic acid hydrazide, a key synthon in the construction of pyridazinone-based phosphodiesterase-4 inhibitors. The hydrazinolysis proceeds quantitatively in ethanol at reflux within 4 hours, monitored by TLC (silica gel 60 F₂₅₄, ethyl acetate/hexane 1:1, Rf 0.45). However, residual water content exceeding 0.5% in the ethanol feed promotes saponification, producing 2–3% free acid that coprecipitates with the hydrazide and necessitates recrystallization from isopropanol/water (4:1 v/v) with a 5% yield loss.
| Ester | Boiling Point (°C / mmHg) | Vapour Pressure (Pa, 25 °C) | Elution Order (DB-5, 150 °C isothermal) |
|---|---|---|---|
| Methyl | 80–82 / 0.5 | 1.2 | 3.8 min |
| Ethyl | 95–97 / 0.5 | 0.4 | 5.1 min |
| Isopropyl | 102–104 / 0.5 | 0.15 | 5.9 min |
For coupling to amine-bearing fragments via amide bond formation, the methyl ester necessitates activation due to its moderate leaving group ability. Direct aminolysis with primary amines in methanol proceeds to 82% conversion after 24 hours at 25 °C (monitored by 1H NMR disappearance of the methyl singlet at δ 3.68 ppm in CDCl₃). Use of 1,1'-carbonyldiimidazole (CDI) in dichloromethane at 0–5 °C provides the imidazolide within 30 minutes, subsequently converted to amide in 95% isolated yield. The ethyl ester under identical conditions requires 45 minutes for CDI activation due to its reduced carbonyl electrophilicity; the difference is attributed to the +I effect of the ethyl group as observed in Taft σ* values (0.00 for methyl vs. –0.10 for ethyl). Published data for this specific configuration, particularly direct comparative rates with isopropyl ester, is limited beyond internal development reports.
Differences from the free acid 1-methylpyrrole-2-acetic acid directly affect workup protocols. The free acid, a crystalline solid with a melting range of 114–116 °C, can be isolated by precipitation from aqueous bicarbonate solution upon acidification and offers superior purity (> 99.5% by HPLC) due to crystallisation-driven purification. The methyl ester, being a liquid, lacks this orthogonal purification lever entirely. Distillation remains the primary purification, and its efficiency is heavily dependent on the vacuum integrity and the column plate count as described. For routes where the carboxylic acid is the intended next step, the ethyl ester is sometimes preferred because its saponification rate is slower and more controllable, avoiding the exotherm peak that can thermally degrade the pyrrole ring. Specifically, saponification of the methyl ester with 1.05 eq NaOH in methanol/water (4:1) reaches completion within 15 minutes and releases a ΔT of 18 °C in an adiabatic reactor; the ethyl ester under the same conditions takes 45 minutes with ΔT of 9 °C. This exotherm differential is non-trivial in scaling to 500 gallon vessels where jacket heat transfer area-to-volume ratio drops below 0.06 cm⁻¹.
