3-Methyl-1H-Pyrrole-2-Carboxylic Acid
|
HS Code |
385703 |
| Name | 3-Methyl-1H-pyrrole-2-carboxylic acid |
| Molecular Formula | C6H7NO2 |
| Molecular Weight | 125.13 g/mol |
| Appearance | Solid |
| Melting Point | 186 - 189 °C |
| Solubility In Water | Slightly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, methanol |
| Pka | Around 3.99 |
| Boiling Point | Decomposes before boiling |
| Odor | Odorless |
| Density | 1.25 g/cm³ |
As an accredited 3-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 | 500g of 3 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid packaged in air - tight plastic bags. |
| Shipping | 3 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid is shipped in sealed, corrosion - resistant containers. Adequate cushioning is used to prevent breakage. Shipments follow strict chemical transport regulations to ensure safety during transit. |
| Storage | 3 - Methyl - 1H - pyrrole - 2 - carboxylic acid 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 contact with air, which could potentially lead to degradation. Store it separately from incompatible substances like strong oxidizing agents or bases to ensure its chemical integrity. |
In validated commercial batches of a JAK2-selective inhibitor intermediate, 3-Methyl-1H-pyrrole-2-carboxylic acid is charged at 0.98–1.03 mol eq relative to the amine component after the substrate has undergone azeotropic drying with toluene in a 2000 L glass-lined reactor equipped with a retreat-curve impeller and a jacket capable of holding ±1.5 °C during activation. The acid is dissolved in anhydrous tetrahydrofuran (≤0.005 % H₂O by Karl Fischer) and pre-cooled to -10 °C before isobutyl chloroformate (1.05 eq) and N-methylmorpholine (1.10 eq) are metered in under nitrogen at a rate that maintains internal temperature below -5 °C; this mixed anhydride stream is held for 35–45 min with in-process FTIR monitoring to confirm the 1822 cm⁻¹ carbonyl shift before the amine component is fed over 60 min. Downstream workup involves quenching into chilled 10 % citric acid, phase separation at 15 °C, and subsequent crystallisation from 2-propanol/water (3:1 v/v) to deliver a pyrrole-2-carboxamide intermediate with ≥99.2 % chromatographic purity (HPLC, USP <621>) and residual palladium below 10 ppm as required by ICH Q3D. The entire sequence operates under ICH Q7 cGMP, with the final amide intermediate shipped to registered API sites where it undergoes Vilsmeier formylation and cyclocondensation with guanidine carbonate to assemble the tetra-substituted pyrrolo[2,3-d]pyrimidine scaffold characteristic of the target JAK2 inhibitor drug substance.How pH and Solvent Choice Dictate Amide Coupling Efficiency in Peptide Isostere SynthesisWhen the acid is deployed as a Pro surrogate in peptidomimetic HCV protease inhibitor fragments, the coupling step is uniquely sensitive to the protonation state of the pyrrole NH. The acid–amine pair is combined using HATU (1.03 eq) and 2,4,6-collidine (2.5 eq) in N-methyl-2-pyrrolidone at 0–3 °C; pH measured via a Mettler Toledo InLab Science probe in a mock aqueous dilution must remain between 5.8 and 6.2 to avoid racemisation of the adjacent Cα stereocenter. Under these conditions, epimerisation levels measured by chiral SFC (column: Chiralpak IG-3, modifier: 25 % methanol with 0.1% diethylamine) are held below 0.3 %. Scale-up on a 500 L Hastelloy C-22 reactor with a Hüber Unistat temperature control loop is preferred because the corrosion rate of 316L stainless steel increases measurably above 0.05 mm/year when the post-reaction solution is acidulated with 6 N HCl to pH 2.5 for extraction. The process stream is then concentrated on a wiped-film evaporator (Pope Scientific, jacket 40 °C, vacuum 8 mbar) to a residue that is used directly in the next step — reductive amination with a phenylglycine derivative — without isolation; failure to remove residual NMP below 5000 ppm at this stage causes a 40 % drop in imine formation rate in the subsequent batch. The final peptidomimetic active pharmaceutical ingredient meets residual solvent limits per USP <467> and is packaged under argon for storage at -20 °C.In chemical mechanical planarisation slurries designed for Cu barrier removal at the 14 nm technology node, 3-Methyl-1H-pyrrole-2-carboxylic acid functions as a transient organic passivating agent at 0.15–0.35 wt% loading relative to the total slurry mass. The slurry formulation — a colloidal silica dispersion of 4.5–5.5 pH, 0.8 % H₂O₂, and 0.05 % benzotriazole — is spiked with the acid dissolved in a 1:1 water–isopropanol co-solvent system immediately before point-of-use delivery on a MIRRA Mesa™ CMP tool. Addition is controlled by a mass-flow meter to hold the concentration within ±0.01 % of target; excursions beyond 0.40 wt% shift the static etch rate to > 12 Å/min and induce severe dishing on 100 μm × 100 μm copper pads, as measured by stylus profilometry (VEECO Dektak XT, 2 μm tip). The acid’s pKa₁ of ～4.3 (determined by potentiometric titration in 0.1 M KCl) ensures that the pyrrole carboxylate binds to Cu(I) oxide surfaces without decomposing the peroxide oxidiser, maintaining a Cu:Ta removal selectivity ratio > 70:1 across 120 seconds of polishing. Process qualification is performed against SEMI C35 guidelines for oxidiser-laden slurries, and the acid is supplied with a certificate of analysis listing metals by ICP-MS as per SEMI C1-90.1 with Fe, Na, and K each below 50 ppb.When a Pyrazole Alternative Fails: Introducing the Acid as a Ligand Backbone in Cu(I)-Catalyzed Azide–Alkyne Cycloaddition (CuAAC)The acid scaffold is converted to a tris(triazolyl) ligand library via SOCl₂-mediated chlorination in toluene at 55–60 °C followed by Huisgen cycloaddition with propargylamine in the presence of CuI (5 mol %). The synthesis is executed in a 100 L glass pressure-rated reactor (Büchi Glas Uster, -1.0 to +0.5 barg) because the initial exotherm releases HCl gas that must be scrubbed through a packed column of 10 % NaOH at 5 m³/h nitrogen sweep. The acyl chloride batch requires a Dean–Stark trap charged with cyclohexane to maintain ≤200 ppm water during conversion; Karl Fischer monitoring every 20 min is mandatory. After cycloaddition and subsequent hydrolysis, the crude ligand is purified by flash chromatography on silica gel 60 Å (eluent: ethyl acetate/hexane 1:1) to yield a white powder that coordinates Cu(I) with a stability constant log β > 14.6 (determined via spectrophotometric titration in acetonitrile). The ligand is then used at 0.5–2 mol % in the final CuAAC-based polymer crosslinking step on a production line applying ASTM D7982-15 for process monitoring; terminal product is a biocompatible hydrogel dressing sterilised by 25 kGy gamma irradiation per ISO 11137-1.Pyrrole Carboxylic Acid-Accelerated Dicyandiamide Epoxy Systems: A Curing Profile Crosslink CliffThermoset formulators utilising diglycidyl ether of bisphenol A (DGEBA, EEW 188–192 g/eq) with dicyandiamide hardener (8 phr) incorporate 3-Methyl-1H-pyrrole-2-carboxylic acid as a latent accelerator at 2.0–3.5 phr. Differential scanning calorimetry (TA Instruments Q2000, 10 °C/min ramp, aluminium hermetic pans) reveals that the onset of cure shifts from 178 °C (unaccelerated) to 124 °C at 3.0 phr loading, but a loading exceeding 3.8 phr creates a multi-modal exotherm with a low-temperature shoulder at 97 °C that corresponds to premature carboxyl-epoxy esterification, leading to a drop in lap shear strength (ASTM D1002-10, single-lap joint, 1.6 mm bondline, 2024-T3 aluminium adherends) from 18.7 MPa to 9.2 MPa after thermal aging at 150 °C for 500 h. Production batches are compounded on a co-rotating twin-screw extruder (Coperion ZSK 26 Mc18, L/D 40, screw speed 350 rpm, barrel zones 40–65 °C) with the acid premixed into a fraction of the DGEBA to prevent agglomerate-induced hot spots. The final single-component paste passes outgassing criteria per ASTM E595-15 (<1.0 % TML, <0.1 % CVCM) and is qualified for potting aerospace connectors under RTCA DO-160G thermal shock with 500 cycles from -55 °C to +125 °C.Decarboxylative distillation of 3-Methyl-1H-pyrrole-2-carboxylic acid to produce electronic-grade 3-methylpyrrole monomer is routinely performed in a 200 L stainless steel reactor connected to a 6 m² thin-film evaporator (VTA VK 70-6) under 15–28 mbar absolute pressure with Dowtherm™ A as the heating fluid at 220–235 °C. The acid is slurried in 2.5 parts of heavy mineral oil with copper chromite catalyst (0.15 wt%) and fed at 4.0 L/h to achieve a residency time of 42–50 seconds; off-gas CO₂ is monitored by a nondispersive infrared analyser (Siemens ULTRAMAT 23) to confirm conversion > 99.5 %. Distillate collected in a -15 °C condenser is immediately stabilised with 50 ppm butylated hydroxytoluene and purified further through a 20-tray Oldershaw column under 50 mbar reflux ratio 5:1, yielding 3-methylpyrrole of 99.9+ % purity with water content below 30 ppm (Karl Fischer coulometric). Strict compliance with SEMI G53-1105 for photochemical solvent quality prevents quinoid by-product formation during subsequent electropolymerisation on indium tin oxide substrates. The electropolymerised film — applied as the cathode in aluminium solid electrolytic capacitors — undergoes a forming step at 1.2 V in 0.1 M tetraethylammonium tetrafluoroborate/acetonitrile to yield a capacitance density of 4.2 μF/cm² at 120 Hz as per IEC 60384-4. |
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3-Methyl-1H-pyrrole-2-carboxylic acid (CAS 131013-97-7, molecular formula C6H7NO2, molecular weight 125.13 g·mol⁻¹) is a crystalline pyrrole building block supplied as a white to off-white powder. The compound serves as a synthetic intermediate in the preparation of pyrrolo[2,3-d]pyrimidine kinase inhibitor libraries, conformationally constrained amino acid mimetics, and fluorescent probes where vinylogous amide reactivity must be preserved. The melting point, determined by capillary method per USP <741>, falls within 130–134 °C. Purity is routinely ≥ 98.0 % by reverse-phase HPLC with UV detection at 254 nm (area normalisation), a threshold validated against a two-point calibration using reference material of certified purity (ISO Guide 35). The carboxylic acid moiety at position 2 activates electrophilic substitution at the remaining α-position (C-5), while the electron-donating methyl group at C-3 modulates the ring’s HOMO level without steric interference at the carboxyl conjugation site. As a consequence, Vilsmeier–Haack formylation and N-bromosuccinimide-mediated bromination proceed with a regioselectivity exceeding 95 : 5 in favour of the 5-substituted isomer.
Batch-specific analytical data are released with each lot. The table below summarises the typical specification sheet issued under a quality management system certified to ISO 9001:2015.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | White to pale cream crystalline powder | Visual (Ph. Eur. 2.2.1) |
| Identification | FT-IR spectrum conforms to reference (C=O stretch 1658 cm⁻¹, NH stretch 3305 cm⁻¹) | ATR-FTIR (4000–450 cm⁻¹) |
| Purity (HPLC) | ≥ 98.0 % | RP-18 column, H2O/MeCN + 0.1 % TFA, 1.0 mL/min, 254 nm |
| Melting range | 130–134 °C | USP <741> (capillary) |
| Loss on drying | ≤ 0.5 % (60 °C, vacuum, 4 h) | USP <731> |
| Heavy metals | ≤ 20 ppm (as Pb) | USP <231> Method II |
The compound is packaged under argon in amber glass vials with PTFE-lined caps. Storage below −20 °C is recommended for long-term stability exceeding 24 months; short-term storage at 2–8 °C in a desiccator containing silica gel and 4 Å molecular sieves is acceptable. When the ambient relative humidity rises above 60 % at 25 °C, the container headspace must be purged with dry nitrogen immediately after each withdrawal, as the pyrrole ring is susceptible to ring-opening hydrolysis upon exposure to condensed moisture. No incompatibility with common laboratory solvents (DMSO, DMF, THF, dichloromethane) has been observed at concentrations below 0.5 M and temperatures not exceeding 40 °C; however, solutions in DMSO stored at room temperature for more than 48 hours should be avoided due to gradual decarboxylation catalysed by trace moisture.
The position of the methyl group relative to the carboxylic acid function dictates both the electronic character of the heterocycle and its behaviour in downstream transformations. When the methyl substituent resides at C-3, the carboxylic acid at C-2 benefits from a resonance-permissive geometry: the ortho-methyl group exerts an inductive electron-donating effect (σm ≈ −0.07) that raises the acid dissociation constant by approximately 0.3–0.5 pKa units relative to the parent pyrrole-2-carboxylic acid (pKa4.47 in water at 25 °C, determined by potentiometric titration). In contrast, 2-methyl-1H-pyrrole-3-carboxylic acid (CAS 56458-27-2) suffers from a steric inhibition of conjugation: the C-2 methyl group twists the carboxyl plane, reducing π-overlap and elevating the pKa by a further 0.8–1.2 units. This electronic divergence translates into measurable differences in amide coupling efficiency. Standard HATU/DIEA-mediated activation ( 1.1 eq HATU, 3 eq DIPEA, DMF, 0 °C → rt) of the 3-methyl-2-acid routinely yields isolated amide product in 88–92 % after 16 h, whereas the 3-carboxy isomer requires 2.5 eq of activating agent and extended reaction times to approach comparable conversion. The table below collates the relevant physicochemical and handling data for three commercially available isomers and the unsubstituted reference acid.
| Compound | CAS | Molecular Weight (g·mol⁻¹) | Melting Range (°C) | pKa (calc./est.) | Notable Synthetic Difference |
|---|---|---|---|---|---|
| Pyrrole-2-carboxylic acid | 14530-59-2 | 111.10 | 204–208 (dec.) | 4.47 | Baseline: rapid decarboxylation above 200 °C in DMSO |
| 3-Methyl-1H-pyrrole-2-carboxylic acid | 131013-97-7 | 125.13 | 130–134 | ≈ 4.8–5.0 | Retains α-C-5 reactivity; no steric hindrance at C-2 acid |
| 2-Methyl-1H-pyrrole-3-carboxylic acid | 56458-27-2 | 125.13 | 180–183 (dec.) | ≈ 5.5–5.7 | Slower amidation; C-5 electrophilic substitution still accessible |
| 2,4-Dimethyl-1H-pyrrole-3-carboxylic acid | 19814-56-3 | 139.15 | 193–196 | ≈ 5.8–6.0 | Both α-positions blocked; used primarily for decarboxylative cross-coupling |
The compound is classified under the Globally Harmonized System as a skin and eye irritant; powder handling should be performed in a fume hood equipped with HEPA-filtered exhaust, and nitrile gloves (≥ 0.18 mm thickness) are required during weighing. Moisture ingress poses the greatest risk to long-term integrity. When a bulk container is opened in an atmosphere with a dew point above −5 °C, the hygroscopic nature of the crystalline solid leads to surface hydration that, over repeated cycles, can reduce free-flowing character and foster agglomeration. The material that has absorbed moisture exhibits a broad endotherm in DSC between 45 °C and 65 °C corresponding to water loss, followed by the sharp melt at 132 °C. Therefore, pre-drying is mandatory before any acylation or metal-catalysed coupling: the powder is spread in a glass dish and held at 40 °C under vacuum ( < 10 mbar) for 18–24 hours, with a nitrogen bleed. The residual water content after this protocol is typically below 0.2 % by Karl-Fischer titration (USP <921>, Method Ia).
Amine-based reagents, particularly primary aliphatic amines and ammonia, must be rigorously excluded from the storage environment. Contact with concentrated aqueous ammonia leads to irreversible formation of the ammonium salt and subsequent darkening within 48 hours. Similarly, exposure to strong oxidising agents (e.g., HNO₃, CrO₃) must be prevented because the methyl-substituted pyrrole ring undergoes rapid oxidative cleavage. The compound may be subjected to ethylene oxide sterilisation without measurable degradation when the cycle temperature does not exceed 38 °C and the relative humidity plateau remains below 50 %.
Heterocycle fusion strategies that exploit the remaining α-C-5 position have been examined under parallel-synthesis conditions. Replacing 2-carboxy-4-methylpyrrole (CAS 73672-11-0) with the 3-methyl-2-carboxylic acid isomer in a one-pot pyrrolo[2,3-d]pyrimidine annulation alters the vector of the methyl group from a bay region to a proximal position adjacent to the fused pyrimidine ring. In the reaction with N-cyanoformamide and acetic anhydride (120 °C, 6 h), the 3-methyl derivative affords the desired 9H-pyrrolo[2,3-d]pyrimidine core in 62 % isolated yield after flash chromatography, while the 4-methyl congener reaches only 34 % under identical conditions because of steric compression between the C-4 methyl and the incoming electrophile. This regiochemical influence was also observed during Buchwald–Hartwig N-arylations with 2,4-dichloropyrimidine (Pd2(dba)3 0.025 eq, Xantphos 0.075 eq, Cs2CO3 1.5 eq, dioxane, 100 °C): the C-3 methyl group, being ortho to the pyrrole nitrogen, imposes a dihedral angle that minimises steric clash with the pyrimidine C-5 substituent and delivers the coupled product in 79 % yield ( 1H NMR purity ≥ 95 %).
The isomer’s behaviour under decarboxylative C–H functionalisation has been explored to a limited extent. Preliminary thermal gravimetric analysis (TGA) in flowing nitrogen (10 °C·min⁻¹) shows an onset of mass loss at 181 °C, followed by a steady weight decrease of 35.1 % by 250 °C, consistent with decarboxylation and subsequent volatilisation of the resulting 3-methylpyrrole. Published data for direct kinetic comparison with the 2-methyl-3-carboxylic acid under identical conditions remain scarce; however, the lower decarboxylation temperature of the 2-carboxy series is qualitatively consistent with the greater resonance stabilisation of the incipient pyrrolyl anion at C-2. Users targeting protodecarboxylative coupling (e.g., with aryl iodides using Cu2O 0.1 eq, K2CO3 2 eq, DMF, 160 °C under microwave irradiation) report complete consumption of the starting acid within 30 min, generating the 3-methyl-substituted biaryl in 65–73 % yield, whereas the 3-carboxy isomer requires 60 min under otherwise identical parameters to reach 60 % conversion.
