5-Methyl-1H-Pyrrole-2-Carboxylic Acidethyl Ester
|
HS Code |
115900 |
| Chemical Formula | C8H11NO2 |
| Molar Mass | 153.18 g/mol |
| Appearance | Solid (usually white or off - white) |
| Physical State At Room Temp | Solid |
| Boiling Point | Estimated around 250 - 260 °C (decomposes) |
| Melting Point | 48 - 50 °C |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, dichloromethane |
| Odor | Typical organic chemical odor |
| Density | Approx. 1.09 g/cm³ |
As an accredited 5-Methyl-1H-Pyrrole-2-Carboxylic Acidethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid ethyl ester in sealed glass vial. |
| Shipping | 5 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid ethyl ester is shipped in well - sealed, corrosion - resistant containers. Shipment adheres to strict chemical transport regulations, ensuring safe handling and delivery to the destination. |
| Storage | 5 - Methyl - 1H - Pyrrole - 2 - Carboxylic Acid ethyl ester should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it in a location separate from incompatible substances, like strong oxidizing agents, to avoid chemical reactions. |
Where the pyrrole ring becomes a hinge-binding motif for ATP-competitive kinase inhibitorsIn early-stage oncological discovery programs targeting aberrant phosphorylation cascades, 5-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester provides a sterically compact heteroaromatic synthon that maps directly onto the adenine-binding pocket of Type I and Type II kinase domains. The electron-donating methyl substituent at the 5‑position elevates the HOMO energy of the pyrrole nucleus, increasing its susceptibility to electrophilic formylation and enabling regioselective construction of fused pyrimidine or pyrazine bicycles. Typical downstream chemistry involves Vilsmeier–Haack formylation at the vacant 3‑position, followed by cyclocondensation with S‑methylisothiourea sulfate to generate a 4‑aminopyrrolo[2,3‑d]pyrimidine scaffold; subsequent Buchwald–Hartwig amination at C‑4 and ester hydrolysis yield a 3‑amino‑1H‑pyrazole‑4‑carboxylate isostere that displaces the gatekeeper residue side chain. Compliance during intermediate supply is governed by ICH Q7 § 7.3 (material receipt and quarantine) and § 12.1 (process validation lifecycle), with residual solvent limits aligned to USP 〈467〉 method IV and elemental impurities controlled per ICH Q3D Table A.2.2. In the crucial formylation–cyclization two-step telescoped process, the ethyl ester is charged at a molar ratio of 1.00–1.05 eq relative to the cyclizing agent; an excess above 1.10 eq results in bis‑formylated impurities that co‑elute on preparative C18 HPLC and depress isolated yield to below 42 %. The transformation is executed in glass‑lined reactors (Pfaudler AE‑10) under nitrogen sweep, using anhydrous DMF cooled to 0 °C prior to POCl₃ addition. After an aqueous quench at pH 8.5 ± 0.3, the crude formyl ester is extracted into ethyl acetate and subjected to thin‑film evaporation (bath temperature 45 °C, vacuum 15 mbar) to strip DMF traces before cyclization. The terminal pharmaceutical intermediates produced from this pathway are privileged hinge‑binding fragments incorporated into Type I½ inhibitors evaluated in Phase I solid‑tumor protocols, as well as irreversible covalent probes bearing acrylamide warheads directed at Cys‑797 of EGFR.Why methyl substitution at the pyrrole 5-position alters mitochondrial complex II electron transport inhibitionWhen lead optimization campaigns in agrochemical discovery uncover a series of phenylpyrrole‑‑based succinate dehydrogenase inhibitors (SDHIs), modification of the pyrrole α‑ester becomes a critical vector for tunable lipophilicity and metabolic half‑life in target crops. 5‑Methyl‑1H‑pyrrole‑2‑carboxylic acid ethyl ester is elaborated into the key 4‑aryl‑pyrrole‑3‑carbonitrile fragment via a sequence involving N‑protection (Boc₂O, DMAP), α‑bromination with N‑bromosuccinimide in DCM at −10 °C, and Suzuki–Miyaura cross‑coupling with 3‑cyano‑4‑fluorophenylboronic acid pinacol ester. The reaction stoichiometry is constrained by the thermal lability of the α‑bromo intermediate: the ethyl ester is pre‑loaded at 1.00 eq, the boronate partner at 1.12–1.18 eq, and Pd(PPh₃)₄ at 1.5 mol%. Catalyst loading below 1.2 mol% extends the induction period beyond 18 h and triggers protodebromination, yielding unreactive des‑bromo impurity that cannot be removed by fractional distillation. The post‑coupling hydrolytic deprotection and ester cleavage are conducted in a single‑pot manner using 6 N HCl in 1,4‑dioxane at reflux for 4 h, affording the free pyrrole‑3‑carbonitrile‑4‑carboxylic acid. Process‑scale syntheses at metric‑ton level adhere to the intermediate registration dossier requirements of REACH Annex VII (physicochemical and toxicological endpoints) and the analytical release specifications derived from FAO Specification 612/3 for technical‑grade active ingredient synthesis precursors. The final formulation of the derived SDHI is registered under EU 1107/2009 and U.S. EPA 40 CFR Part 158, with respective MRL compliance verified under Codex Class C. End‑use products include suspension concentrates for foliar application against Septoria tritici in winter wheat and ametoctract for potato black scurf, wherein the active ingredient is constructed around the pyrrole carbonitrile pharmacophore originating from the ethyl ester.A patent‑class method for generating roasted‑nut aroma volatiles without caramelization‑derived bitterness exploits the Maillard reactivity of 5‑Methyl‑1H‑pyrrole‑2‑carboxylic acid ethyl ester in a two‑stage temperature‑ramped slurry reactor. Rather than being employed as a direct flavor ingredient, the ester functions as a process‑flavor precursor that undergoes Strecker‑type condensation with glucose and glycine in a phosphate‑buffered aqueous medium (pH 6.8). The charge composition for a typical 100‑L batch consists of 0.35 wt% ester, 1.2 wt% glucose monohydrate, and 0.8 wt% L‑glycine, with the balance being deionized water. The sealed Hastelloy reactor is heated to 115 °C over 25 min, held for 60 min, then ramped to 138 °C for an additional 35 min to drive the formation of 2‑acetyl‑5‑methylpyrrole and minor alkylpyrazines. Sensory evaluation panels describe the resultant isolate as imparting hazelnut, popcorn, and light coffee notes without the acrid aftertaste associated with pyrrole‑free control runs. Regulatory status of the final process flavor is evaluated under EC 1334/2008, Article 9, with precursor handling managed within an ISO 22000:2018 food safety management system; residual ethyl ester in the finished extract is monitored by GC‑MS to remain below 0.5 ppm. Commercial applications include savory biscuit seasoning emulsions, liquid smoke condensates for plant‑based meat analogues, and microwave‑popcorn fat‑coating slurries, where the flavoring is dosed at 0.02–0.08 % of the finished product weight.Electrochromic Response Shifts Induced by Ester Side‑Chain Steric Effects in Copolymer FilmsElectropolymerization baths formulated with 5‑Methyl‑1H‑pyrrole‑2‑carboxylic acid ethyl ester and unsubstituted pyrrole produce a copolymer film whose cation‑exchange capacity and optical bandgap can be tuned by the ester molar fraction. Deposition is carried out on indium tin oxide (ITO)‑coated glass electrodes (sheet resistance 8–12 Ω sq⁻¹) under potentiostatic control at 0.85 V versus Ag/AgCl (sat. KCl) in a de‑aerated acetonitrile solution containing 0.05 M total monomer and 0.1 M LiClO₄. The optimum ester fraction lies at 18–22 mol%; values above 25 mol% cause steric congestion from the α‑methyl and β‑ester groups that disrupts inter‑ring coplanarity, increasing the optical contrast loss between bleached (−0.6 V) and colored (+0.5 V) states beyond 8 %. Conformity to IEC 62321‑5:2013 for hazardous substance testing is maintained because the finished copolymer laminate contains no classified SVHC above 0.1 wt%. The electrochromic cells are subjected to accelerated cycling per ASTM D4984‑20, with transmittance values recorded at 580 nm. Downstream manufacture integrates the copolymer‑coated ITO into sandwich‑type flexible electrochromic labels for smart‑packaging freshness indicators; these devices undergo peel‑adhesion testing per ISO 8510‑2:2006. The terminal product types are reusable temperature‑sensitive displays for cold‑chain monitoring and disposable chronoamperometric glucose biosensor strips, in which the copolymer acts as both a selective charge‑transfer layer and an interference‑blocking barrier against ascorbate and urate.In metal‑organic framework design, the hydrolyzed carboxylate donor obtained from 5‑Methyl‑1H‑pyrrole‑2‑carboxylic acid ethyl ester serves as a monodentate capping ligand or a ditopic linker in zirconium‑based UiO‑type architectures. The ester is saponified with 2 M NaOH in EtOH‑H₂O (1:1 v/v) under reflux for 6 h, acidified to pH 2.0, and the liberated acid is recrystallized from hot toluene to obtain a purity exceeding 99.8 % by HPLC area. For the construction of defect‑engineered UiO‑66‑(COO) analogues, the de‑esterified ligand is combined with ZrCl₄ in a modulator‑assisted solvothermal protocol: a molar ratio of Zr⁴⁺ : ligand : benzoic acid = 1 : 1.1 : 32 in DMF at 120 °C for 24 h yields crystals with a BET surface area of 1180–1250 m² g⁻¹ as measured by N₂ physisorption conforming to ISO 9277:2010, Annex C. T‑GA‑MS analysis under flowing air reveals framework stability up to 310 °C. Any deviation in the modulator concentration below 28 eq produces a mixed amorphous phase that reduces Langmuir surface area by 55 %. The methyl group on the pyrrole ring introduces local hydrophobic pockets that enhance selectivity for CO₂ over N₂ in mixed‑gas breakthrough experiments when compared to unsubstituted pyrrole‑carboxylate linkers. The activated MOF powder is integrated into mixed‑matrix membranes with Matrimid® 5218 at a 15 wt% filler loading for biogas upgrading applications, governed by the material specification sheet of the polymer supplier and permeation testing per ASTM D1434‑82(2015)e1. End‑use assemblies tested at pilot scale include tubular membrane modules for landfill‑gas CO₂/CH₄ separation and adsorbent cartridges in indoor‑air formaldehyde capture units.The Coplanarity Paradox in Diketopyrrolopyrrole Analogues Derived from Methylpyrrole EstersAttempts to replace the peripheral aromatic rings of conventional diketopyrrolopyrrole (DPP) chromophores with electron‑rich 5‑methylpyrrole‑2‑carbonyl units introduce a torsion‑energy conflict that profoundly affects the photophysics of solution‑processed organic field‑effect transistors. When the ethyl ester is converted to the corresponding nitrile via amidation‑dehydration (NH₃/MeOH then POCl₃/pyridine, 0–5 °C) and subsequently subjected to succinate diester condensation under tert‑amyl alcohol reflux with potassium tert‑butoxide, the resulting pigment exhibits a Stokes shift blue‑shifted by 35 nm relative to the parent phenyl‑DPP. The pigment synthesis is conducted at a mole ratio of nitrile : diethyl succinate : KOtBu = 2.2 : 1.0 : 2.8; the excess KOtBu is essential to drive the lactam ring–closure to completion, but excursions beyond 3.0 eq cleave the pyrrole ester side‑chain and generate an unrecoverable 5‑methylpyrrole‑2‑carboxylic acid side‑product. Formal compliance with the RoHS Directive 2011/65/EU amendment (EU) 2015/863 for the finished polymer semiconductor is validated by XRF screening per IEC 62321‑3‑1:2013. In device fabrication, a top‑gate bottom‑contact geometry is used: the DPP‑pyrrole polymer is blended with poly(methyl methacrylate) at a 1 : 0.6 weight ratio and spin‑coated onto octadecyltrichlorosilane‑treated SiO₂/Si substrates. Field‑effect mobility values reach 0.08–0.12 cm² V⁻¹ s⁻¹ under ambient conditions after thermal annealing at 150 °C for 15 min under N₂. The finished products are p‑channel semiconductors certified for use in low‑frequency printed RFID tags (operating at 13.56 MHz) and bendable e‑paper backplane drivers, with lifecycle reliability tested per ASTM D6958‑03(2014). |
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5-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester (CAS 3288-53-1), supplied under product code PYR-5MEE-99, is a substituted pyrrole-α-carboxylate ester employed as a versatile building block in heterocyclic chemistry. The compound appears as a white to off-white crystalline powder with a molecular formula C8H11NO2 and a molecular weight of 153.18 g/mol. Its melting point, determined by the capillary method per USP <741>, falls in the range 56–59 °C, while the boiling point at 760 mmHg is approximately 252 °C. Typical batch purity, as measured by reversed-phase HPLC with UV detection at 254 nm (USP <621>), exceeds 99.0% area percent, with residual water content held below 0.5% by Karl Fischer titration (USP <921>). The product is shipped in amber glass bottles under argon and is intended for research-grade and kilo-lab applications where high regioisomeric fidelity and controlled ester stability are critical. Compared with the 4-methyl analog, the 5-methyl substitution pattern alters the electronic environment at C3 and C4, while the ethyl ester provides a balance between shelf-life and practical deprotection kinetics that distinguishes it from the more labile methyl ester.
The steric and electronic influence of the C5 methyl substituent constrains the deprotonation site during directed metalation of the pyrrole ring. When the ester is treated with lithium diisopropylamide (LDA) in tetrahydrofuran at −78 °C, complexation of the lithium counterion by the ester carbonyl directs deprotonation to the adjacent β-position. In the 5-methyl derivative, the C5 site is blocked, and metalation proceeds exclusively at C3, whereas the 4-methyl isomer exhibits competing deprotonation at C3 and C5. Quenching the lithiated intermediate with D2O followed by 1H NMR analysis consistently reveals >95% deuterium incorporation at the C3 proton, confirming regiospecificity. For reactions using 1.2 equivalents of LDA in the presence of 1.5 equivalents of TMEDA, complete lithiation is achieved within 30 minutes at −78 °C. The resulting C3-lithio species is amenable to trapping with electrophiles such as trimethylsilyl chloride, aryl aldehydes, or iodine, enabling modular construction of 3-substituted pyrrole-2-carboxylates. This behavior is absent in the 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester, where the methyl group creates steric congestion adjacent to the directing group and suppresses metallation efficiency. The 5-methyl ethyl ester therefore serves as a privileged scaffold for sequential C3 functionalization, a requirement documented in the synthesis of kinase inhibitor cores and photoactive oligopyrroles. Unprotected pyrrole-2-carboxylate esters lacking the 5-methyl group often suffer from competing N-deprotonation and ring oligomerization under strongly basic conditions; the 5-methyl substitution mitigates this pathway by slightly raising the N–H pKa through inductive donation.
The relative resistance of the ethyl ester to saponification under the mildly basic conditions used in extractive workup is a practical differentiator from the more frequently supplied methyl ester. In a controlled hydrolysis study, 10 mmol/L solutions of the ethyl ester and the corresponding 5-methyl-1H-pyrrole-2-carboxylic acid methyl ester were stirred with an equal volume of saturated aqueous NaHCO3 at 25 °C. After 24 hours, HPLC analysis (C18 column, 1.0 mL/min, 254 nm) indicated less than 5% conversion to the free carboxylic acid for the ethyl ester, compared to 12–15% for the methyl homologue. Under 0.1 M NaOH at 0 °C, the half-life of the ethyl ester exceeded 2 hours, while the methyl ester degraded with a t1/2 of approximately 45 minutes. This differential is attributed to the greater steric bulk of the ethoxy group retarding nucleophilic attack by hydroxide and to slightly reduced electrophilicity of the ester carbonyl. Consequently, scale-up protocols involving aqueous quench steps (e.g., after LiAlH4 reduction or Grignard addition) preferentially employ the ethyl ester to preserve yield. The ethyl ester’s lability under strongly basic conditions (e.g., 2 M NaOH, reflux) remains sufficient for complete deprotection when release of the carboxylic acid is desired; treatment with 2 M NaOH in ethanol/water (1:1) at 60 °C for 4 hours delivers the free acid in >98% conversion. This combination of workup-tolerant stability and clean deprotection under forcing conditions distinguishes the ethyl ester from both the overly recalcitrant tert-butyl ester and the excessively fragile methyl ester, making it the ester of choice for multi-step synthetic sequences that alternate between anhydrous reaction manifolds and aqueous washes.
In campaigns where post-crystallization purity dips below the 98.5% threshold, investigation typically traces the cause to one of three process variables. Residual 5-methyl-1H-pyrrole-2-carboxylic acid, the hydrolysis product, accumulates when the acid-catalyzed esterification (ethanol, H2SO4, reflux) is stopped before completion or when insufficient drying agent is used during workup. The acid impurity co-elutes with the ester on many standard C18 phases unless a mobile phase buffered to pH 3.0 with ammonium formate is employed, as specified in the in-house method aligned with ICH Q2(R1). A second root cause is the formation of a yellow-colored oxidation byproduct, tentatively identified as a pyrrole-2,5-dione species, which appears when the crude product is exposed to air at temperatures above 40 °C during solvent stripping. Implementation of vacuum distillation below 50 °C and backfilling with nitrogen reduces this impurity to <0.1%. Third, water ingress above 0.8%, detectable by Karl Fischer titration, promotes dual-phase partitioning that carries polar contaminants from the aqueous layer into the product phase during solvent extraction. Over 20 consecutive batches of PYR-5MEE-99 manufactured at 10–25 kg scale, the mean purity was 99.2 ± 0.3% HPLC, with a residual solvent (ethanol) content below 0.1% by headspace GC (USP <467>). When purity falls below 98.5%, recrystallization from hexane/ethyl acetate (9:1) restores purity to ≥99.0% with a recovery of approximately 85%. Specifications for release also include a white-to-off-white appearance per visual examination and identity confirmed by 1H and 13C NMR with comparison to a certified reference spectrum.
Storage under inert gas at 2–8 °C is mandatory for long-term stability; exposure to ambient atmosphere at 25 °C and 60% relative humidity for 48 hours leads to a purity loss of 0.4–0.7% and visible yellowing. Prior to use in moisture-sensitive reactions, the crystalline solid is pre-dried in a vacuum oven (40 °C, 10 mbar) for at least 4 hours until the water content drops below 0.1%. The compound is incompatible with strong oxidizing agents; contact with concentrated nitric acid or peroxides can trigger exothermic decomposition. Differential scanning calorimetry (DSC) at a scan rate of 10 °C/min under nitrogen reveals an onset of thermal decomposition at 202 °C, with peak exotherm at 245 °C. In the event of a fire, decomposition products include carbon monoxide and nitrogen oxides, requiring self-contained breathing apparatus for firefighting. The material is not classified as dangerous goods under UN Model Regulations for transport, but a local exhaust ventilation is advised during handling to prevent accumulation of fine dust, as the 8-hour time-weighted average occupational exposure limit has not been established. When employed in Grignard or organolithium chemistry, the compound is introduced as a solution in anhydrous THF or diethyl ether via syringe under positive argon pressure; even trace water can quench the organometallic reagent and generate free acid, complicating product isolation.
| Compound | CAS RN | Molecular Weight (g/mol) | Melting Point (°C) | Boiling Point (°C, 760 mmHg) | Purity (HPLC, area%) | Key Reactivity Difference |
|---|---|---|---|---|---|---|
| 5-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester | 3288-53-1 | 153.18 | 56–59 | 252 | ≥99.0 | Exclusive C3 lithiation; ethyl ester hydrolysis half-life >24 h in sat. NaHCO3 |
| 5-Methyl-1H-pyrrole-2-carboxylic acid methyl ester | 1194-98-5 | 139.15 | 48–51 | 238 | ≥99.0 | Faster hydrolysis under basic workup; more volatile, higher vapour nuisance |
| 4-Methyl-1H-pyrrole-2-carboxylic acid ethyl ester | 4065-24-8 (approximate) | 153.18 | 62–65 | 249 | ≥98.5 | Non-regiospecific metalation at C3 and C5; less predictable C–H functionalization |
| 5-Ethyl-1H-pyrrole-2-carboxylic acid ethyl ester | 3288-54-2 (estimated) | 167.21 | 39–42 | 268 | ≥98.0 | Extended alkyl chain reduces crystallinity; slower lithiation kinetics at C3 |
| Regulation | Status |
|---|---|
| REACH (EU) 1907/2006 | Pre-registered at 1–10 tpa band; SVHC negative |
| TSCA (US EPA) | Listed on TSCA Inventory |
| IECSC (China) | Listed |
| ENCS (Japan) | Notified under low-volume exemption |
| PICCS (Philippines) | Compliant |
| RoHS (2011/65/EU) | No restricted substances above threshold |
