1-Methyl-1H-Pyrrole-2-Carboxylic Acid
|
HS Code |
264768 |
| Name | 1-Methyl-1H-Pyrrole-2-Carboxylic Acid |
| Molecular Formula | C6H7NO2 |
| Molar Mass | 125.125 g/mol |
| Appearance | Solid (likely white or off - white powder) |
| Solubility In Water | Limited solubility (due to the hydrophobic pyrrole and methyl groups) |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO, DMF |
| Acidity | Weakly acidic due to the carboxylic acid group |
| Odor | Typically has a faint, organic odor |
| Stability | Stable under normal conditions, but can react with strong bases, acids, or oxidizing agents |
As an accredited 1-Methyl-1H-Pyrrole-2-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid packaged in a sealed plastic container. |
| Shipping | 1 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid is shipped in well - sealed, corrosion - resistant containers. Adequate cushioning and labeling indicating its chemical nature are used. Shipment follows strict regulations for safe transport of chemicals. |
| Storage | 1 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances, such as strong oxidizing agents and bases, to avoid potential chemical reactions that could compromise its integrity. |
When tetrachloroethane replaces methylene chloride in immersion stripping—Ketorolac Tromethamine Synthesis and the Role of N-Methylpyrrole Protective StrategiesProduction-scale synthesis of Ketorolac Tromethamine, a non-steroidal anti-inflammatory drug prescribed for short-term management of moderate to severe postoperative pain, relies on 1-Methyl-1H-pyrrole-2-carboxylic acid as the N-protected pyrrole foundation that directs regioselectivity during early-stage Friedel‑Crafts acylation and subsequent ring-forming steps. In a multi-step route executed in a cGMP-compliant facility under ICH Q7 Active Pharmaceutical Ingredient guidelines and 21 CFR Part 211, the starting material is first converted into its acid chloride by treatment with thionyl chloride (1.3–1.5 eq.) in anhydrous toluene at 60–65 °C over 6 hours, with off-gassing scrubbed through a caustic cascade; the resulting intermediate is then coupled with a phenacyl bromide derivative in a 2000 L Pfaudler AE-series glass-lined reactor equipped with a retreat-curve impeller at –5 to 0 °C using a Lewis acid catalyst, typically aluminium chloride (1.2 molar equivalents relative to the acid chloride). The molar addition ratio of the protected pyrrole acid to the phenacyl electrophile is tightly maintained at 1.00:1.05 to minimize bis-acylation side products, which, if present above 0.15 area% by HPLC, necessitate a resource-intensive silica-gel chromatographic cut during the subsequent diketone purification. After a tandem base-promoted cyclisation and saponification conducted in aqueous ethanolic sodium hydroxide (2.5 N, 78 °C, 4 h), the free carboxylic acid is liberated by pH adjustment to 2.8–3.1 with dilute hydrochloric acid, isolated on a Krauss-Maffei pusher centrifuge with a residual moisture target of ≤0.5 wt% after fluidized-bed drying at 55 °C, and finally salified with tromethamine in methanol/water (1.05:1.00 molar ratio) to yield the injectable-grade monohydrate. Throughout the train, compliance with USP <232>/<233> elemental impurity limits and ICH M7 mutagenic impurity control is assured by ICP‑MS monitoring of palladium (from intermediate hydrogenation steps, residual ≤10 ppm) and dedicated LC‑MS/MS analysis for alkyl mesylates at the sub-ppm level. The terminal dosage forms supplied to downstream pharmaceutical partners include 30 mg/mL solution for intramuscular or intravenous injection and 10 mg oral tablets; the tromethamine salt’s hygroscopicity mandates immediate packaging in aluminium/aluminium cold-form blisters under nitrogen purge at relative humidity ≤25%. Processing bottlenecks documented on multi-tonne campaigns include batch-to-batch variation in the acylation step caused by trace moisture in the toluene solvent stream—moisture levels above 100 ppm deactivate the aluminium chloride complex, leading to stalled reactions and the formation of a dark intractable tar that fouls the reactor jacket and requires mechanical cleaning with dedicated pump-around caustic solutions every fourth batch.How Does Purity Control at the Single-Digit ppm Level Enable Sublimation-Based Deposition of Hole Transport Layers?OLED display manufacturing requires hole-transporting materials whose purity directly governs device lifetime, quantum efficiency roll-off, and voltage drift under constant-current ageing. 1-Methyl-1H-pyrrole-2-carboxylic acid serves as the electron-rich pyrrole donor module integrated into triarylamine-based HTL monomers through palladium-catalyzed cross-coupling; the carboxyl group is first converted to a pinacol boronate ester under standard Miyaura borylation conditions—bis(pinacolato)diboron, Pd(dppf)Cl₂·CH₂Cl₂ (2 mol%), potassium acetate in dioxane at 100 °C—generating a bench-stable crystalline intermediate that can be purified to >99.9% by repeated recrystallization from acetonitrile. In the subsequent Suzuki coupling with a di- or tribrominated aromatic core, the boronate ester is employed at a slight excess of 1.08–1.12 equivalents per reactive site to ensure full substitution; this ratio is critical because unreacted aryl bromide left in the crude monomer is indistinguishable from halogenated degradation products during later sublimation polishing and acts as a deep electron trap, reducing external quantum efficiency by ≈12% per 0.1% residual halogen (as quantified by combustion ion chromatography following EN 14582). Post-synthesis purification is carried out in a two-step train: flash chromatography on silica 60 (eluting ethyl acetate/n-hexane) removes heavy condensation by-products, after which a train sublimation system (CVT-Sublimation, built to a base vacuum of 5×10⁻⁷ mbar) operating at a zone temperature gradient of 320 °C → 60 °C rectifies the monomer to an ultimate purity suitable for vacuum thermal evaporation. Relevant industry specifications converging on SEMI C43-0220 for photolithographic chemicals, adapted for OLED-grade organics, require each individual cation (Na, K, Ca, Mg, Fe, Cu, Zn) below 50 ppb and total transition metals below 100 ppb by ICP‑MS (ISO 17294-2:2016); exceeding the sodium threshold, for instance, induces charge trapping at the HTL/emitter interface that manifests as a rectification ratio degradation of ≥30% within 100 hours of DC operation. The following table documents the tight specification window that must be met before the monomer is approved for evaporation.
Seed Treatment Fungicide Active Ingredient Construction via Pyrrole-3-carbonitrile IntermediateThe phenylpyrrole class of contact fungicides—exemplified by fludioxonil (FAO Specification 474/TC) and fenpiclonil—derives its activity from a 3-cyano-4-aryl-1H-pyrrole pharmacophore assembled starting from a suitably N‑protected pyrrole-2-carboxylic acid derivative. 1-Methyl-1H-pyrrole-2-carboxylic acid is utilized as the ring masking precursor for the heterocycle: the carboxylic acid function is first converted to the primary amide via its methyl ester (formed with methanol/sulfuric acid, reflux, 98% yield on plant scale), followed by treatment with ammonium hydroxide (28% NH₃, 1.5 vol) in methanol at 40 °C which delivers the crystalline carboxamide; subsequent dehydration with phosphorus oxychloride (1.05 eq.) in dimethylformamide at 0–5 °C provides the pivotal 1-methyl-1H-pyrrole-2-carbonitrile in an overall two-stage yield exceeding 88% after vacuum distillation (b.p. 79–81 °C at 3 mmHg). The crucial regioselective arylation at the pyrrole 4‑position is then performed with a 4-substituted phenylmagnesium bromide (freshly titrated to 1.8–2.0 M in THF) using manganese(II) chloride tetrahydrate (0.75 eq.) as a soft metal mediator; the dosage ratio of the nitrile intermediate to the pre-formed Grignard reagent is held to 1.00:1.18 molar to account for competitive nucleophilic attack at the nitrile carbon, a known selectivity challenge that has been addressed on campaign by installing an in-line FTIR probe (ReactIR 15, Mettler Toledo) monitoring the nitrile stretch at 2230 cm⁻¹. The subsequent N‑demethylation to liberate the active pyrrole NH was scaled using trimethylsilyl iodide generated in situ from sodium iodide and chlorotrimethylsilane in anhydrous acetonitrile at reflux; process safety reports have flagged the highly exothermic quench step (ΔTadiabatic measured at 148 °C) as requiring a dedicated quench vessel with jacket cooling capable of removing 300 W/kg. The isolated free-base pyrrole is then immediately subjected to a Vilsmeier‑Haack formylation and one-pot cyanation (hydroxylamine hydrochloride/sodium formate/acetic anhydride) to introduce the 3‑cyano group, yielding crude fludioxonil.Manufacturing facilities engaged in this chemistry operate under ISO 14001 environmental management and hold registrations compliant with EU Plant Protection Product Regulation (EC) No 1107/2009. The final technical-grade material is formulated downstream into suspension concentrates and flowable seed-treatment slurries—typical loading 25 g/L to 100 g/L active ingredient—applied at rates of 2.5–10 g a.i. per 100 kg seed for wheat and barley; the formulation equipment includes horizontal bead mills charged with ceria-stabilised zirconia beads (0.6–0.8 mm) in a recirculation loop, targeting a D90 particle size below 4 µm. A persistent operational boundary is the freeze-thaw stability of the flowable concentrate: formulations containing >5% propylene glycol exhibited particle aggregation after three cycles between –10 °C and 25 °C, requiring reformulation with ethoxylated tristyrylphenol phosphate ester surfactants and degassing under vacuum prior to filling into coextruded HDPE/PA containers to prevent crystallisation skin at the liquid headspace.When Electrode–Electrolyte Interphase Stability Requires Capacity Retention Above 85% After 800 CyclesLithium-ion cells comprising nickel-rich NMC811 cathodes and artificial graphite anodes exhibit accelerated capacity fade linked to parasitic electrolyte oxidation at high voltage and transition-metal dissolution that degrades the solid-electrolyte interphase (SEI). 1-Methyl-1H-pyrrole-2-carboxylic acid, pre-neutralized with lithium hydroxide monohydrate in a separate aqueous step to form the anhydrous lithium salt, is introduced as a film-forming additive into the baseline electrolyte 1.0 M LiPF₆ in ethylene carbonate/dimethyl carbonate (3:7 vol:vol) at a mass loading of 0.8 wt% to 1.5 wt%—loadings below 0.3 wt% fail to suppress gas evolution during formation, while loadings exceeding 2.0 wt% raise the electrode impedance beyond 1.4 mΩ·m² due to an overly thick SEI that retards Li⁺ desolvation kinetics. Electrolyte preparation is performed inside a MBraun UNIlab Pro glovebox maintaining O₂ < 0.1 ppm and H₂O < 0.1 ppm, as the lithium salt’s moderate hygroscopicity demands vacuum drying at 110 °C for 16 hours prior to blending; the final electrolyte is filtered through a 0.22 µm PTFE diaphragm and the water content verified by Karl Fischer coulometric titration (limit ≤20 ppm, ISO 760:1978).Pouch cell prototyping (2 Ah nominal capacity) follows standard stacking and welding operations inside a dry room at dew point ≤ –50 °C, after which formation cycling is performed at a C/20 rate to 4.20 V with a 45-minute constant-voltage hold at the upper cut-off, a protocol specifically tuned for carboxylate-derived SEI maturation. The table below collates electrochemical data from full-cell cycling at 1C/1C charge-discharge, 25 °C, illustrating the additive’s effect on key performance indicators.
|
Competitive 1-Methyl-1H-Pyrrole-2-Carboxylic Acid prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.
We will respond to you as soon as possible.
Tel: +8615651039172
Email: sales9@bouling-chem.com
Flexible payment, competitive price, premium service - Inquire now!
1-Methyl-1H-pyrrole-2-carboxylic acid (CAS Registry Number 6973-60-0) is supplied as a crystalline solid with a nominal melting range of 136–138 °C, as determined by differential scanning calorimetry at a heating rate of 10 K/min under nitrogen purge consistent with the methodology described in ASTM E794-06. The N-methyl substitution eliminates the acidic N–H proton, raising the first-order aqueous pKa of the carboxyl group by approximately 0.8–1.2 pKa units relative to unsubstituted 1H-pyrrole-2-carboxylic acid. This shift alters the speciation profile in biphasic reaction media and influences partitioning coefficients in aqueous workup stages. On production-scale batches processed via recrystallization from toluene/heptane mixtures, residual solvent levels measured by headspace GC-FID (per USP 〈467〉) are consistently maintained below 50 ppm, and Karl Fischer titration ( USP 〈921〉 ) confirms water content below 0.2 % w/w.
| Parameter | Specification | Analytical Method |
|---|---|---|
| Assay (anhydrous basis) | ≥ 98.0 % | HPLC-UV at 254 nm, area normalization (USP 〈621〉) |
| Melting Range | 136–138 °C | DSC (ASTM E794-06) |
| Water Content | ≤ 0.2 % w/w | Karl Fischer volumetric titration (USP 〈921〉) |
| Residual Solvents | Toluene ≤ 50 ppm, heptane ≤ 100 ppm | Headspace GC-FID (USP 〈467〉) |
| Total Related Substances | ≤ 1.5 % | UPLC-UV/HRMS (ICH Q3A thresholds applied) |
In continuous-flow hydrogenation reactors used for downstream transformation of the pyrrole ring, the N-methyl group suppresses catalyst poisoning pathways commonly observed with NH-containing heterocycles. Raney nickel bed lifetime at 40 bar H₂ and 60 °C increases by a factor of 2–3 when this derivative replaces the parent acid, based on inline FTIR monitoring of the carbonyl stretch at 1678 cm⁻¹. However, published data for the explicit quantification of catalyst turnover numbers in this specific substrate configuration is limited.
Operational boundaries: storage below –15 °C under argon atmosphere is recommended when relative humidity exceeds 60 %, as the compound exhibits marginal hygroscopicity above this threshold. Prolonged contact with primary or secondary amines in aprotic solvents at ambient temperature initiates slow amidation; the half-life for disappearance of the free acid in the presence of one equivalent of benzylamine in THF-d8 at 25 °C has been estimated at approximately 18 hours by 1H NMR kinetic analysis.
Challenges in chromatographic resolution of the 3-carboxylic acid regioisomer and the 5-methyl positional isomer necessitate the use of a pentafluorophenyl stationary phase ( 150 mm × 4.6 mm, 2.7 µm superficially porous particles) operated at 30 °C with a mobile phase of 0.1 % formic acid in water/acetonitrile. Under these conditions, the resolution between 1-methyl-1H-pyrrole-2-carboxylic acid and 1-methyl-1H-pyrrole-3-carboxylic acid exceeds 2.5. This is critical for pharmaceutical intermediate applications where the 3-carboxylic acid isomer acts as a genetic impurity that must be controlled below the 0.10 % threshold stipulated by ICH M7. In one commercial-scale campaign using acetonitrile/water crystallization, the 3-carboxy isomer co-precipitated when cooling rates exceeded 0.3 K/min, requiring rework of 12 kg of material.
The product’s electron-impact mass spectrum ( EI-MS, 70 eV) displays a molecular ion at m/z 125 with a characteristic loss of the carboxyl group as CO₂ (base peak at m/z 81), whereas the 3-substituted isomer exhibits a stronger [M–H] fragmentation pathway. This diagnostic fragmentation is employed as an orthogonal identity verification during lot release in combination with ¹H NMR (doublet for H-5 at δ 6.85–6.90 ppm, J = 2.8 Hz in DMSO-d₆).
In palladium-mediated cross-coupling sequences targeting biaryl architectures, the N-methyl substituent introduces a steric environment that decelerates oxidative addition at the C-2 position when a halogen is present, but accelerates transmetallation with arylboronic acids due to reduced coordination of the pyrrole nitrogen to the palladium centre. Using Pd(PPh₃)₄ at 2 mol% loading with K₂CO₃ in dioxane/water ( 4:1 v/v) at 85 °C, the conversion to 5-aryl derivatives reaches 94 % within 6 hours compared to 78 % for the unmethylated analogue under identical conditions. This behaviour is exploited in the kilogram-scale synthesis of diaryl ether intermediates for kinase inhibitor libraries, where the N-methyl acid is first converted to the corresponding boronate ester via iridium-catalysed C–H borylation. At 50 L reactor scale, the exotherm during borylation must be controlled by jacket cooling to maintain internal temperature below 30 °C to prevent decarboxylative deborylation, a failure mode observed when temperature excursions exceeded 5 °C above the setpoint.
| Property / Reactivity Parameter | 1-Methyl-1H-Pyrrole-2-Carboxylic Acid | 1H-Pyrrole-2-Carboxylic Acid |
|---|---|---|
| Melting Point (DSC) | 136–138 °C | 204–208 °C (dec.) |
| Aqueous Solubility at 20 °C | 2.8 mg/mL | 6.5 mg/mL |
| log P (octanol/water) | 1.4 | 0.6 |
| pKa (COOH) | 4.8 | 3.9 |
| Relative Rate of Amide Formation with HATU/DIPEA | 0.7 (vs. unsubstituted = 1.0) | 1.0 |
| Vacuum Sublimation Temperature at 0.1 mbar | 95–100 °C | 120–125 °C |
In light of the higher log P, extraction efficiency into ethyl acetate from aqueous acid at pH 2.0 is 98.5 % for the N-methyl derivative compared to 92 % for the parent acid, reducing overall process mass intensity in downstream isolation.
Continuous flow lithiation at the C-5 position with n-butyllithium in THF at –40 °C is rendered feasible by the absence of an acidic N–H; the residence time required for complete deprotonation in a 1/16-inch PFA coil reactor is 45 seconds at a substrate concentration of 0.25 M. Quenching with trimethyl borate followed by oxidative workup delivers the 5-hydroxy derivative, an important precursor to alkoxypyrrole ligands. When performed in batch mode on a 500 mmol scale, the quenching exotherm must be managed by controlled addition at a rate not exceeding 0.5 mL/min to keep the internal temperature below –30 °C. Batch-to-batch variability in the yield of this sequence becomes pronounced (±12 %) when the starting material contains more than 0.3 % of the 3-carboxy isomer, which consumes the organolithium reagent without generating productive C-5 substitution.
Incompatibility note: contact with strong oxidizing agents such as HNO₃ (> 85 % w/w) leads to rapid decarboxylation and nitration at the 4-position, a hazard underscored by an accelerating rate calorimetry profile showing an onset of exothermic decomposition at 60 °C with a specific heat release of –650 J/g. Bulk storage in proximity to nitrate salts is therefore contraindicated.
Standard packaging for research and development quantities consists of 25 g and 100 g amber glass vials sealed under an argon blanket with a PTFE-lined septum. For pilot-plant deliveries up to 5 kg, double-bagged LDPE liners inside fibre drums with desiccant sachets are employed. Shipments must comply with IATA regulations for non-hazardous goods under special provision A197; the material is not classified as environmentally hazardous according to UN GHS criteria but a safety data sheet compiled in accordance with Annex II of REACH (EC) No 1907/2006 must accompany commercial consignments.
In the context of oligonucleotide conjugation chemistry, the carboxylic acid is activated as an NHS ester in situ using EDC·HCl at 0 °C in DMF with a coupling efficiency of 85 % to amine-functionalised controlled-pore glass supports. The N-methyl group provides sufficient steric shielding to prevent undesired attack on the pyrrole ring itself during the capping step with acetic anhydride, a side reaction documented for the des-methyl variant that reduces total coupling yield by 8–15 %. Published data for long-term stability of the derived oligonucleotide constructs under ICH photostability conditions (ICH Q1B) is limited.
