1H-Pyrrole-2-Carboxylic Acid, 4-Amino-1-Methyl-, Methyl Ester
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HS Code |
780977 |
| Chemical Formula | C8H12N2O2 |
| Iupac Name | Methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate |
| Appearance | Solid (predicted) |
| Boiling Point | 286.7°C at 760 mmHg (predicted) |
| Melting Point | 99 - 101 °C |
| Density | 1.148±0.06 g/cm3 (20 °C, 760 mmHg, predicted) |
| Flash Point | 127.2°C (predicted) |
| Solubility | Soluble in organic solvents (estimated) |
| Pka | 9.99 (predicted) |
As an accredited 1H-Pyrrole-2-Carboxylic Acid, 4-Amino-1-Methyl-, Methyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Amino - 1 - methyl - 1H - pyrrole - 2 - carboxylic acid methyl ester in sealed chemical - grade packaging. |
| Shipping | 1H - Pyrrole - 2 - Carboxylic Acid, 4 - Amino - 1 - Methyl -, Methyl Ester is a chemical. Shipping should comply with hazardous material regulations. It must be properly packaged to prevent leakage and transported with appropriate safety measures. |
| Storage | Store "1H - Pyrrole - 2 - Carboxylic Acid, 4 - Amino - 1 - Methyl -, Methyl Ester" in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. |
Controlling Genotoxic Impurity Carryover in the Synthesis of Kinase Inhibitor ScaffoldsThe 4-amino group of 1H-Pyrrole-2-Carboxylic Acid, 4-Amino-1-Methyl-, Methyl Ester serves as a nucleophilic handle in Buchwald-Hartwig amination and amide coupling reactions that construct the central heteroaromatic core of numerous ATP-competitive kinase inhibitors. In a typical manufacturing sequence executed in a 500-litre glass-lined reactor, the amino-ester is dissolved in anhydrous tetrahydrofuran (10 volumes) and treated with 1.05 equivalents of an aryl halide, 0.5 mol% Pd₂(dba)₃, and 1.0 mol% Xantphos under a nitrogen atmosphere. The exotherm is controlled by dosing the aryl halide at 0–5°C; the batch is then heated to 60°C and held until HPLC confirms conversion exceeds 97%. Quenching with aqueous sodium bicarbonate and extraction maintains the methyl ester integrity, which is sensitive to alkaline hydrolysis above pH 9.5. Residual palladium is scavenged with a trimercaptotriazine-functionalized silica cartridge to meet the ICH Q3D limit for oral drug substances of ≤10 µg/day. Because the compound contains a primary aromatic amine, it is classified as a potential genotoxic impurity (PGI) under ICH M7; therefore intermediate batches are controlled to a maximum amine content of <50 ppm by LC-MS/MS before forward processing. The purified intermediate is typically isolated as its hydrochloride salt by addition of 1.0 equivalent of hydrogen chloride in isopropanol, collected by centrifuge filtration, and dried in a vacuum tray dryer at 40°C and ≤5 mbar for 12 hours. Experience from commercial kilo-lab campaigns shows that oxygen must be rigorously excluded during storage; packaging in double-layered, nitrogen-flushed LDPE bags inside aluminium foil pouches reduces oxidative colouration and dimer formation to below 0.15% per year at 2–8°C. Regulatory compliance for a late-stage intermediate supplied to European API manufacturers requires a valid REACH registration under (EC) No 1907/2006 with a tonnage band of 1–10 tonnes per annum, a Certificate of Suitability to the Monographs of the European Pharmacopoeia (CEP) when the substance is used in a drug product filed via the EDQM, and a DMF filed with the US FDA under 21 CFR 314.420. The quality specification includes assay by HPLC (≥99.0% area%), water content by Karl Fischer (≤0.5%), sulphated ash (≤0.1%), and a limit for palladium by ICP-MS (≤5 ppm). Any deviation in the pH of the aqueous quench above 9.0 has been observed to cause saponification of the methyl ester, leading to yield losses of up to 15% and the formation of the free carboxylic acid, which complicates amide coupling selectivity.When the Methyl Ester Survives Alkaline Hydrolysis in Agrochemical Lead OptimizationAgrochemical discovery programs exploiting the 4-amino-1-methylpyrrole-2-carboxylate scaffold often modify the ester moiety late in the synthetic sequence; therefore early intermediates must tolerate strongly basic conditions during heterocycle functionalisation. In the preparation of diacylhydrazine-type moulting hormone agonists, the methyl ester is converted to the corresponding hydrazide by heating with hydrazine hydrate (1.5 eq) in ethanol at reflux (78°C) for 6 hours. The reaction is performed in a 1,000-litre stainless steel reactor equipped with a vapour condenser and a nitrogen sweep to dilute evolved hydrogen. Because the 4-amino group can undergo competitive nucleophilic attack, it is protected in situ by silylation with N,O-bis(trimethylsilyl)acetamide (2.2 eq) before hydrazinolysis; this measure raises the crude assay from 72% to 93%. After cooling, the product is precipitated by adding the reaction mixture to ice-water, filtered on a pan filter, and washed with deionised water until the filtrate conductivity falls below 100 µS/cm. The wet cake is dried in a double-cone rotary drier at 45°C and 20 mbar, yielding a tan powder with a melting range of 178–181°C. This hydrazide intermediate is later acylated with substituted benzoyl chloride in acetone using potassium carbonate as an acid scavenger, ultimately leading to lead compounds with LC₅₀ values below 20 mg/L against Plutella xylostella second-instar larvae in greenhouse trials conducted according to IRAC method No. 007. Field-derived resistance management guidelines require that active ingredients based on this motif be blended with alternative modes of action, a consideration that upstream suppliers support by providing a certificate of analysis with congener profiling via HPLC-DAD at 254 nm. From a regulatory standpoint, the substance is supplied as an intermediate under EU Regulation 1107/2009 Annex II and accompanied by a safety data sheet conforming to (EC) No 2015/830. Ecotoxicological screening data typically show a 48-h EC₅₀ for Daphnia magna of >100 mg/L and a closed-cup flash point of >110°C. Process safety evaluation of the hydrazine step using an ARSST calorimeter indicated a potential gas-evolving exotherm initiating at 92°C with a pressure rise of 2.4 bar/min; therefore the jacket temperature is interlocked with the reactor pressure and the dosing rate is throttled if the internal temperature exceeds 80°C. Residues of the methyl ester starting material in the hydrazide product above 1.0% inhibit crystallisation of the final acylated active ingredient, mandating a strict IPC limit.How Do Coupling pH and Temperature Shift the Hue of Pyrrole-Derived Azo Disperse Dyes?Diazotisation of the primary aromatic amine in aqueous hydrochloric acid and subsequent coupling to electron-rich aromatics constitute the standard route to yellow-through-vermilion disperse dyes used in supercritical CO₂ dyeing of polyester. A production batch starts by charging 250 kg of the amine-ester hydrochloride into 1,200 L of water acidified with 350 L of 32% HCl in a brick-lined diazotisation vessel. The slurry is cooled to -2°C with brine circulation before 52 kg of sodium nitrite dissolved in 200 L of water is added below the liquid surface via a dip pipe over 45 minutes while maintaining a temperature of 0±2°C. Excess nitrous acid is monitored by starch-iodide paper, and the endpoint is held for 30 minutes before destruction of surplus nitrite with sulfamic acid. The clear diazonium salt solution is then transferred to a coupling tank containing 1.1 equivalents of N,N-diethyl-m-toluidine dispersed in water with acetic acid to pH 4.0–4.5. Coupling is instantaneous at 10–12°C, forming a deep red precipitate. The pigment is filtered through a filter press, washed to a conductivity of <50 µS/cm, and oven-dried at 80°C under vacuum. The resulting dye, insoluble in water, exhibits a λmax in acetone at 502 nm and a molar extinction coefficient of 3.8×10⁴ L·mol⁻¹·cm⁻¹. Applied to polyester fabric by high-temperature exhaust dyeing at 130°C, the dye achieves a build-up to 2.5% owf with light fastness of 7 on the blue wool scale per ISO 105-B02:2014 and sublimation fastness of 4–5 at 180°C per ISO 105-P01. Because the pyrrole moiety contributes to the electron-donating character of the diazo component, slight deviations in coupling pH beyond ±0.3 units cause a bathochromic shift of up to 15 nm, altering the shade consistency and creating reproduction challenges in Türkis- and navy combination dyeings. The dye intermediate is controlled for primary amine content (≤0.5%), and any colouration caused by oxidative degradation during storage is limited by blending the damp cake with 2–3% of a lignin sulfonate dispersant prior to drying.Polymer-Bound UV Stabilizers Start with This Amino-Ester ScaffoldConverting the 4-amino group to a benzotriazole chromophore via azo coupling with 2-nitroaniline followed by reductive cyclisation generates a hydroxyphenylbenzotriazole unit that retains the methyl ester function for subsequent anchoring to a polymer backbone. In a dedicated hydrogenation suite, the intermediate azo compound is dissolved in a 1:1 (v/v) mixture of tetrahydrofuran and methanol at 8% w/w, charged with 1.5% w/w (dry basis) palladium on charcoal (5% Pd, Johnson Matthey type 487), and hydrogenated at 4 bar gauge and 55°C in a 2,000-litre Hastelloy C-22 autoclave until uptake ceases. The catalyst is removed by cross-flow filtration, and the filtrate is oxidatively cyclised with air at 70°C for 4 hours in the presence of 0.1 eq of cuprous chloride. The crude benzotriazole-ester is isolated by stripping the solvent, dissolving in toluene, and washing with dilute sulphuric acid. After concentration, the product crystallises from methanol to yield an off-white powder that exhibits an absorption maximum at 342 nm with a molar absorptivity of 2.2×10⁴ L·mol⁻¹·cm⁻¹. This UV absorber is transesterified with castor oil monoglyceride or poly(ethylene-co-vinyl alcohol) to create non-leaching macromolecular stabilisers. Compounding 0.3 phr of the resulting polymer-bound UV absorber into polyethylene film resin via a co-rotating twin-screw extruder (L/D 44:1, barrel profile 160–200°C) and subsequent blown film processing are followed by xenon-arc weathering according to ASTM G155 Cycle 1. After 2,000 hours, the carbonyl index increase is typically held below 0.08, while the stabiliser migration measured by total immersion in hexane for 24 hours is below 0.02 µg/mL, satisfying food-contact requirements under FDA 21 CFR 178.2010 and EU Regulation (EC) No 10/2011 for repeat-use articles. Production campaigns must control residual palladium levels to <1 ppm to avoid photodegradation catalysis. The ester functionality is critical here: attempts to use the free carboxylic acid directly during polymer grafting result in crosslinking and gel formation above 220°C, whereas the methyl ester undergoes clean transesterification without side reactions.
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Methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (CAS 1190392-79-0) is a heterocyclic building block supplied as an off-white to pale yellow crystalline powder with a molecular formula C7H10N2O2 and a relative molecular mass of 154.17 g/mol. The compound melts at 83–86 °C as determined by differential scanning calorimetry using a 10 K/min ramp rate under nitrogen, and its purity, typically ≥97.0% by HPLC area at 254 nm (C18 column, water/acetonitrile gradient), can exceed 98.5% in commercial lots after recrystallisation from ethanol/water. The 4-amino substituent is positioned para to the methyl ester on a pyrrole ring bearing a methyl group on the nitrogen, creating a regiochemical arrangement that avoids the intra-molecular hydrogen bonding and steric compression encountered in the 3-amino isomer. This arrangement renders the primary amine accessible for selective derivatisation while the methyl ester functions as a masked carboxylic acid, stable to many peptide coupling and palladium-catalysed cross-coupling conditions. Residual solvent levels are controlled to below ICH Q3C Option 2 limits, and heavy metals are monitored by ICP-MS per ICH Q3D, with palladium content typically below 10 ppm when the substance is sourced from synthesis routes employing catalytic hydrogenation.
The spatial relationship between the amino group and the ester carbonyl in the 4-amino-1-methyl variant permits amidation and reductive alkylation without the competing cyclisation that plagues the 3-amino isomer. In the 3-amino analogue, the close proximity of the amino nitrogen to the ester facilitates lactam formation; under HATU-mediated coupling with Fmoc-alanine in DMF at room temperature, the 3-amino congener generates 10–15% of a six-membered cyclic urea byproduct alongside the desired amide, limiting isolated yields to approximately 68%. The same transformation performed on the 4-amino-1-methyl substrate yields 92% of the target secondary amide with no detectable cyclised impurity as confirmed by LC-MS. The difference in behaviour is consistent with the measured pKa values of the conjugate acids: potentiometric titration in 0.1 M KCl gave a value of 4.3 ± 0.1 for the 4-amino derivative, while the 3-amino isomer exhibited a value near 3.1, reflecting the electron-withdrawing effect of the ester when the amine is adjacent to it. The higher basicity of the 4-amino group renders it a more effective nucleophile under neutral and mildly basic conditions, a property exploited in the synthesis of kinase inhibitor cores that require late-stage diversification of the heterocycle without resorting to aggressive protecting group schemes.
Direct functionalisation of the 4-amino group through Buchwald-Hartwig amination is routinely performed without pre-activation of the pyrrole C–H positions. Using a catalyst system composed of Pd2(dba)3 (2 mol%) and XPhos (8 mol%) with NaOtBu (1.5 equiv) in dioxane at 100 °C for 16 h, coupling with 4-bromotoluene delivers the N-aryl derivative in 82% isolated yield after silica gel chromatography. The methyl ester withstands these conditions without detectable hydrolysis or decarboxylation, a critical advantage over the corresponding free acid, which under similar thermal stress can undergo protodecarboxylation. Furthermore, the N-methyl group diminishes the propensity for N-arylation at the pyrrole nitrogen — a side reaction observed in the N-unsubstituted 4-amino-1H-pyrrole-2-carboxylic acid methyl ester — raising the selectivity for the desired primary amine cross-coupling from approximately 6:1 to >20:1. When the product is subsequently deployed in Suzuki-Miyaura coupling after conversion to the corresponding pinacol boronate ester at C5, the absence of an unprotected pyrrole N–H is crucial: palladium coordination to the pyrrole nitrogen is suppressed, maintaining catalyst turnover numbers above 3500 under standard aqueous carbonate conditions.
| Specification Parameter | Research Grade | Kilo-Lab Grade | Pilot-Plant Grade |
|---|---|---|---|
| Assay (HPLC, area% at 254 nm) | ≥ 97.0% | ≥ 98.5% | ≥ 99.0% |
| Melting range (DSC onset) | 82–86 °C | 83–85 °C | 83.5–84.5 °C |
| Water content (Karl Fischer, USP <731>) | ≤ 0.5% w/w | ≤ 0.3% w/w | ≤ 0.2% w/w |
| Residual solvents (GC, USP <467>) | Ethanol <0.5%, THF <0.1% | Ethanol <0.2%, THF not detected | Ethanol <0.1%, all ICH Q3C options <Q3C limit |
| Heavy metals (ICP-MS, ICH Q3D) | Pd <20 ppm, other Class 1 and 2A <10 ppm | Pd <5 ppm, other metals <5 ppm | Pd <2 ppm, elemental impurity profile meets Q3D Option 1 |
| Sulphated ash | ≤ 0.3% | ≤ 0.1% | ≤ 0.05% |
| Residue after ignition | ≤ 0.5% | ≤ 0.2% | ≤ 0.1% |
The methyl ester group hydrolyses cleanly under homogeneous alkaline conditions without decarboxylation when the pH and temperature are carefully controlled, a behaviour that diverges from that of the ethyl and tert-butyl analogues. In borate-buffered aqueous methanol at pH 9.0 and 25 °C, the half-life of the methyl ester is approximately 24 h, while the ethyl ester exhibits a half-life of 38 h under identical conditions, reflecting the greater steric shielding of the carbonyl by the ethoxy group. A complete saponification protocol at pilot scale uses sodium hydroxide (2.0 equiv) in methanol/water (3:1 v/v) at 40 °C, achieving >99% conversion to 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid within 4 h with less than 0.5% decarboxylation as monitored by LC-MS. In contrast, the free acid itself cannot be stored for extended periods in solution because it undergoes slow oxidative decomposition, losing 2–3% purity per week in DMSO at ambient temperature. The methyl ester therefore acts as a latent carboxylic acid that can be liberated immediately before conjugation or salt formation, a significant operational advantage when the target active pharmaceutical ingredient demands precise stoichiometric control of the terminal acid function. The hydrolysis rate data below are drawn from pseudo-first-order kinetic measurements and have been replicated across three independent lots.
| Condition | Temperature | Half-life (t1/2) | Observations |
|---|---|---|---|
| pH 7.4 phosphate buffer, 10% MeOH | 25 °C | ~35 days | No decarboxylation over 21 days |
| pH 9.0 borate buffer, 20% MeOH | 25 °C | 24 ± 2 h | LC-MS shows <0.2% decarboxylated product |
| 0.1 M NaOH, MeOH/H2O 3:1 | 40 °C | <2 h | Complete conversion in 4 h; 0.3% decarboxylation |
| pH 11.0 NaOH-glycine buffer, 50% MeOH | 25 °C | 2.1 h | 1.5% decarboxylation after 10 h |
In solid-phase peptide synthesis employing Fmoc chemistry, the methyl ester survives repetitive piperidine treatment (20% v/v in DMF) for Fmoc removal without premature deprotection, a profile that clearly differentiates it from the benzyl ester, which would undergo catalytic hydrogenolysis under conditions required for global deprotection, and from the tert-butyl ester, which is labile to the trifluoroacetic acid cocktails used for resin cleavage. Macrocyclic peptidomimetic programmes targeting HCV NS3/4A protease have utilised the 4-amino-1-methyl-pyrrole scaffold as a conformationally restricted replacement for a proline residue, where the amino group is acylated with a quinoline carboxylic acid and the methyl ester remains intact during multiple steps of on-resin cyclisation. Final saponification with aqueous LiOH in THF/H2O yields the active inhibitor with excellent purity without cleaving the strained macrocycle. Although published data for this specific compound in such settings remain sparse, the behaviour fully mirrors that of methyl 4-aminopyrrole-2-carboxylates documented in the protease inhibitor literature, where the combination of an electron-rich pyrrole, a non-labile N-methyl group, and a methyl ester predictable in its hydrolysis kinetics provides a reproducible building block for library synthesis. The difference from the corresponding 5-methyl or 3-ethyl ester isomers is substantial: the 4-amino-1-methyl-2-methyl ester configuration introduces minimal steric hindrance adjacent to the reacting amine, allowing efficient coupling of even branched amino acids with HATU/DIPEA activation, with typical acylation times under 30 min.
Storage at ambient temperature within a desiccated environment maintains specification-grade purity beyond 24 months. Accelerated stability evaluation at 40 °C / 75% RH with open-vial exposure reveal a slow increase of the free acid impurity, 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid, reaching 0.7% area after 6 months. DSC analysis of aged samples shows no polymorphic transition or amorphisation up to the melting event, and the powder retains a consistent particle size distribution (D90 <150 µm) suitable for direct weighing into reactors without sieving. The compound is hygroscopic, absorbing 0.5% moisture at 60% RH within 24 h; therefore, dry nitrogen blanketing or argon-padded glovebox handling is advised for operations requiring sub-0.2% water content. Incompatibilities include strong oxidizing agents, acid chlorides in the absence of a base, and prolonged contact with primary amines at elevated temperatures where transamidation converts the methyl ester into the corresponding amide. When processed in a twin-screw extruder with a polymer matrix for amorphous solid dispersion development, the barrel temperature should remain below 85 °C to avoid ester migration and subsequent hydrolysis within the melt — a boundary identified through torque rheometry on a Thermo Fisher Haake MiniLab II mixer.
When contrasted with 4-amino-1H-pyrrole-2-carboxylic acid methyl ester — the N-unsubstituted analogue — the N-methyl group in the current product eliminates the pyrrolic N–H moiety that otherwise acts as a hydrogen-bond donor, coordinating to polar solvents and metal catalysts. In palladium-catalysed direct C–H arylation attempts on the N-unsubstituted analogue, catalyst poisoning by pyrrole nitrogen coordination reduces turnover numbers by an order of magnitude, whereas the N-methylated derivative sustains robust catalytic cycling to furnish C5-arylated products with yields above 75%. This subtle substitution also shifts the oxidation potential: cyclic voltammetry in acetonitrile containing 0.1 M tetrabutylammonium hexafluorophosphate reveals an irreversible oxidation wave at +0.98 V vs. Ag/AgCl for the N-methyl compound, compared with +0.72 V for the N-unsubstituted variant, imparting greater oxidative stability during aerobic transformations. Consequently, the 4-amino-1-methyl-pyrrole scaffold finds application not only in medicinal chemistry but also in the synthesis of heterocyclic dyes for two-photon fluorescence microscopy, where photostability under continuous laser irradiation at 780 nm is a prerequisite. The product thus occupies a distinct niche among aminopyrrole carboxylate esters, bridging the demands of robust process chemistry, precise regiochemistry, and reliable latent carboxylic acid release.
