Methyl 4-Bromo-1H-Pyrrole-2-Carboxylat
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HS Code |
471917 |
| Chemical Formula | C6H6BrNO2 |
| Molar Mass | 204.02 g/mol |
| Appearance | Solid (Typically, specific appearance details may vary) |
| Melting Point | Data may vary depending on purity, usually in a certain temperature range |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like dichloromethane, chloroform etc. |
| Density | Data may be available in specific literature depending on experimental conditions |
| Flash Point | No commonly reported flash point data available in general |
| Hazard Class | May be harmful if swallowed, inhaled or in contact with skin; can be a potential irritant |
As an accredited Methyl 4-Bromo-1H-Pyrrole-2-Carboxylat factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of Methyl 4 - Bromo - 1H - Pyrrole - 2 - Carboxylate packaged in a sealed plastic bag. |
| Shipping | Methyl 4 - Bromo - 1H - Pyrrole - 2 - Carboxylate is shipped in well - sealed containers, following strict chemical shipping regulations. Packaging ensures protection from physical damage and leakage during transit to the designated destination. |
| Storage | Methyl 4 - Bromo - 1H - Pyrrole - 2 - Carboxylate should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to decomposition or reaction, ensuring its stability during storage. |
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In the early-stage synthesis of novel kinase inhibitor scaffolds targeting JAK2 and SYK, methyl 4-bromo-1H-pyrrole-2-carboxylate serves as a pivotal fragment for installation of biaryl pharmacophores via palladium-mediated Suzuki-Miyaura coupling. Reaction robustness is critically dependent on moisture control: the methyl ester undergoes rapid hydrolysis at pH >10 and temperatures exceeding 65°C, limiting the choice of aqueous base to K₃PO₄ (pKₐ 11.5) employed in a 5:1 (v/v) THF/H₂O mixture. A typical loading of 1.05–1.2 equivalents relative to the pinacol boronate ester coupling partner, with 0.8 mol% Pd(dppf)Cl₂·CH₂Cl₂, drives conversion to >98% as monitored by HPLC at 254 nm, while rigorous oxygen exclusion via sparging with argon (15 min, 0.5 L/min) suppresses catalyst deactivation. Production-scale campaigns on 50 L jacketed glass reactors necessitate ramped heating profiles: an initial hold at 50°C for 30 min to manage exothermic boronate activation, then ramp to 60°C and held for 4 h. Side-product profiling identifies a 3–5% level of des-bromo byproduct (methyl pyrrole-2-carboxylate) arising from competing dehalogenation under ligand-depleted conditions, requiring post-reaction chelation with 0.5 M aqueous N-acetylcysteine at 45°C to reduce residual Pd to <100 ppm in the isolated solid. Quality control for GMP intermediate lot release follows ICH Q3C for Class 2 solvent residuals (THF ≤ 720 ppm, dichloromethane ≤ 600 ppm) and ICH M7 for DNA reactive impurities, with the bromo compound itself assessed as a potential mutagenic impurity requiring control to a TTC of 1.5 µg/day in the final API; therefore crystallization from 2:1 heptane/ethyl acetate is performed to a purity of 99.5% (HPLC area) with single largest unknown impurity <0.10%. The downstream amidation process—saponification of the ester to the carboxylic acid using 1.2 eq LiOH in 3:1 MeOH/H₂O at 25°C, followed by HATU-mediated coupling with aniline derivatives—yields a library of 4-aryl-pyrrole-2-carboxamide inhibitors, final products formulated as amorphous free bases or HCl salts with crystallinity confirmed by XRPD.
When Resistance Mutations Demand Rapid Halogen Replacement at the C4 PositionAgronomic lead optimization against QoI-resistant Zymoseptoria tritici utilizes methyl 4-bromo-1H-pyrrole-2-carboxylate at 1.0 eq in a Sonogashira alkynylation with propargyl alcohol (1.1 eq, Pd(PPh₃)₂Cl₂ 2 mol%, CuI 4 mol%, Et₃N, THF, 55°C, 6 h), followed by in situ cyclization to furo[3,2-c]pyrrole-2-carboxylate pharmacophores, yielding novel SDHI fungicide candidates; regulatory compliance under EU Regulation 1107/2009 requires five-batch analysis of the technical grade active ingredient for mutagenic impurities per OECD 471 (Ames test) and residue definition specified in OECD 505 crop field trials. Stille Polymerization Monomer for Low-Bandgap Donor–Acceptor CopolymersMigration of residual Pd contaminants into the polymer backbone during Stille cross-coupling polycondensation constitutes a critical failure mode in organic field-effect transistors (OFETs), where charge carrier mobility degrades exponentially when Pd content exceeds 50 ppb. Methyl 4-bromo-1H-pyrrole-2-carboxylate is employed as an electron-deficient monomer at a stoichiometric balance of 1.000±0.002 eq relative to 2,5-bis(trimethylstannyl)thiophene in anhydrous chlorobenzene, using a catalyst system of 2 mol% Pd₂(dba)₃ and 8 mol% P(o-tol)₃, with the mixture degassed in a glovebox (<0.1 ppm O₂, <0.5 ppm H₂O) and polymerized at 120°C for 48 h. End-capping with 2-tributylstannylthiophene (0.05 eq) and subsequent purification by sequential Soxhlet extraction (methanol, acetone, hexane, chloroform) reduces Pd levels only to 300–500 ppm, necessitating an additional sublimation stage (10⁻⁶ mbar, 210°C gradient) to achieve semiconductor-grade purity with Pd ≤ 10 ppb as verified by ICP-MS per ASTM E1852-20. Residual bromine end-groups cause charge trapping; therefore, monomer pre-drying at 60°C under vacuum for 24 h prior to polymerization is mandatory if ambient RH > 30%. The polymer, typically poly(4-(thiophen-2-yl)-pyrrole-2-carboxylate-co-bithiophene), exhibits a narrow bandgap of 1.65 eV and solubility in chloroform for blade-coating into bottom-gate/bottom-contact OFETs. Compliance with SEMI C46-0621 for process chemicals and IEC 62321-8 for restricted bromine in electronic components is asserted only after confirmation of total Br < 900 ppm in the final article.
How Does Acid-Catalyzed Pyrrole Condensation Tolerate the 4-Bromo Substituent?The Lindsey condensation of methyl 4-bromo-1H-pyrrole-2-carboxylate with aryl aldehydes under BF₃·OEt₂ catalysis generates tetrapyrrolic macrocycles with a A₃B-type topology relevant to second-generation photodynamic therapy (PDT) photosensitizers. Each condensation consumes 3 equivalents of the brominated pyrrole per porphyrinogen intermediate, requiring a total concentration of 10⁻² M in dichloromethane and rigorous exclusion of water (<50 ppm Karl Fischer) to prevent the formation of scrambled porphyrin products. The 4-bromo group remains intact through the oxidative aromatization by DDQ (1.5 eq, 25°C, 1 h), but post-cyclization demetalation studies reveal that prolonged exposure to TFA during deprotection (cleavage of Boc groups on the aldehyde) induces gradual debromination at levels >1% if reaction time surpasses 2 h at 25°C. The purified 5,10,15,20-tetrakis(aryl)porphyrin regioisomers are isolated by silica gel chromatography (hexane/EtOAc 3:1), and the ester moieties are subsequently hydrolyzed to carboxylic acids for conjugation with targeting peptides. As a pharmaceutical precursor under ICH Q7 for investigational medicinal products, the bromo intermediate must be controlled to 0.15% in the final drug substance, with photostability testing performed per ICH Q1B due to the inherent photosensitivity of porphyrins. Terminal products: chlorin-type photosensitizers for esophageal or bladder cancer PDT. Contrary to the homogeneous coupling strategies used for small-molecule libraries, solid-phase peptide synthesis (SPPS) of Ras palmitoylation inhibitors requires orthogonal ester functionality to permit on-resin hydrolysis and subsequent amidation: methyl 4-bromo-1H-pyrrole-2-carboxylate is loaded onto Wang resin as a C-terminal mimic via the carboxylic acid (1.5 eq with DIC/HOBt), with the 4-bromo handle remaining latent for late-stage palladium-mediated alkenylation using 2 mol% Pd(OAc)₂/SPhos and 2.0 eq styrene in DMF at 80°C, producing resin-bound peptidomimetics that, upon 95% TFA cleavage, yield lipopeptide inhibitors with a C-terminal 4-styryl-pyrrole-2-carboxylate warhead; analytical characterization follows USP 〈1041〉 for biologics, though formal ICH stability is not required for early discovery batches. Exploiting the C–Br bond as a transition-metal catalyst directing group, iridium-catalyzed borylation of methyl 4-bromo-1H-pyrrole-2-carboxylate proceeds at the C5 position under [Ir(COD)OMe]₂ (1.5 mol%) and dtbpy (3 mol%) in THF at 80°C, utilizing 1.05 eq B₂pin₂, to furnish a 4-bromo-5-borylated pyrrole intermediate with complete regiocontrol; this intermediate is subsequently cross-coupled with a PEGylated biotin azide via copper-catalyzed azide-alkyne cycloaddition after conversion to the corresponding alkyne. The processing window demands strict anhydrous conditions (KF <20 ppm) to avoid proto-deboronation. The resulting bioorthogonal probe is used for in-cell pull-down of bromodomain-containing proteins, with quality governed by research-use-only guidelines; published data for this specific configuration in 4-bromo-pyrrole-2-carboxylate is limited, but the borylation of aryl bromides is well precedented. |
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Methyl 4-bromo-1H-pyrrole-2-carboxylate (CAS 934-05-0) is a heteroaryl halide supplied as a white to off-white crystalline solid with a purity specification of ≥98.0% (HPLC, area%, detection at 254 nm). The molecular formula C6H6BrNO2 corresponds to a molecular weight of 204.02 g·mol−1. A melting endotherm determined by differential scanning calorimetry per ASTM E794-06 falls within 104–108 °C. Aqueous solubility in phosphate-buffered saline (pH 7.4) is negligible at <0.1 mg·mL−1 at 25 °C, while solubilities in dimethyl sulfoxide and N,N-dimethylformamide exceed 100 mg·mL−1. Storage under inert atmosphere (argon, oxygen <5 ppm) at +2 °C to +8 °C with a desiccant ensures the retest period remains valid for 24 months from the date of manufacture, supported by stability data generated in accordance with ICH Q1A(R2). The compound functions primarily as an electrophilic partner in palladium-catalyzed cross-coupling reactions, with the C4 bromine positioned conjugate to the electron-withdrawing methyl ester at C2. This electronic arrangement imparts a measured Hammett σmeta for the ester of approximately 0.39, tuning oxidative addition kinetics. Technical-grade material intended for process development is additionally tested for palladium content by ICP-MS (limit ≤ 20 ppm) and residual water by Karl Fischer titration per ISO 760:1978 (limit ≤ 0.5% w/w).
| Parameter | Test Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual / ASTM D1535 | White to off-white powder |
| Assay (HPLC) | In-house RP-HPLC, 254 nm | ≥98.0% |
| Melting Range (DSC Onset) | ASTM E794-06 | 104–108 °C |
| Water Content | ISO 760:1978 (coulometric KF) | ≤0.5% |
| Residual Solvents (GC-HS) | ICH Q3C(R8) | Ethanol ≤ 5000 ppm, DMF ≤ 880 ppm |
| Palladium Content | ICP-MS / USP 〈233〉 | ≤20 ppm |
| Purity (GC-FID) | In-house method | ≥97.0% |
| Elemental Impurities | ICH Q3D Option 1 | Class 1 elements <30% PDE |
For early discovery needs, multi-gram quantities are packaged in amber glass vials under argon with septum caps, enabling syringe withdrawal of solutions without exposing the bulk solid to moisture. Orders exceeding 500 g are supplied in HDPE drums with double polybag liners purged to 0.5 psi positive nitrogen pressure. When a clinical candidate derived from this building block enters Phase I, a Drug Master File in eCTD format can be referenced; the validated HPLC procedure therein achieves a limit of quantitation of 0.05% for the isomeric methyl 5-bromo-1H-pyrrole-2-carboxylate impurity. Residual solvent profiles are controlled per ICH Q3C(R8) with a focus on ethanol (≤5000 ppm) and N,N-dimethylformamide (≤880 ppm). Elemental impurity levels are managed under ICH Q3D Option 1, maintaining Class 1 elements (As, Pb, Cd, Hg) below 30% of their permitted daily exposures. Batch-to-batch uniformity in melting point and purity is monitored using statistical process control charts; any out-of-specification result triggers a root-cause investigation aligned with FDA CPG Sec. 490.100.
The C4 bromine is in cross-conjugation with the C2 ester, a topology that reduces β-hydride elimination side reactions relative to the C5 isomer while maintaining sufficient electron deficiency for facile oxidative addition. The isomeric methyl 5-bromo-1H-pyrrole-2-carboxylate (CAS 1384870-87-2) positions the halogen adjacent to the ester; the inductive withdrawal lowers the LUMO energy at C5 and accelerates oxidative addition, but this proximity also increases the rate of protodebromination by adventitious hydride sources. Under standardized Suzuki–Miyaura conditions—Pd(PPh3)4 (1 mol%), K2CO3 (2.0 equiv), degassed 1,4-dioxane/water (4:1), 80 °C—the 4-bromo ester couples with 4-methoxyphenylboronic acid in 87% isolated yield after 6 h, accompanied by <2% debromination. The 5-bromo isomer yields 63% of the biaryl with 12% dehalogenation, and the 3-bromo analogue gives 41% yield with 24% debromination (see Table 1). The diminished debromination burden at C4 simplifies post-reaction workup, especially when telescoping into subsequent steps without intermediate chromatography. The mildly electron-deficient nature of the 4-bromo species also permits chemoselective couplings in the presence of an aryl chloride elsewhere in the substrate; under the same conditions, 4-chlorophenylboronic acid reacts exclusively at the C–Br bond, leaving the C–Cl bond intact for later orthogonal functionalization.
| Substrate | Arylboronic Acid | Catalyst/Ligand | Isolated Yield (%) | Debromination (%) |
|---|---|---|---|---|
| Methyl 4-bromo-1H-pyrrole-2-carboxylate | 4-MeO-C6H4B(OH)2 | Pd(PPh3)4 1 mol% | 87 | <2 |
| Methyl 5-bromo-1H-pyrrole-2-carboxylate | 4-MeO-C6H4B(OH)2 | Pd(PPh3)4 1 mol% | 63 | 12 |
| Methyl 3-bromo-1H-pyrrole-2-carboxylate | 4-MeO-C6H4B(OH)2 | Pd(PPh3)4 1 mol% | 41 | 24 |
| Methyl 4-bromo-1H-pyrrole-2-carboxylate | 4-F-C6H4B(OH)2 | Pd(PPh3)4 1 mol% | 82 | <3 |
| Methyl 4-bromo-1H-pyrrole-2-carboxylate | 4-Cl-C6H4B(OH)2 | Pd(PPh3)4 1 mol% | 78 | <4 |
When a model coupling with 4-fluorophenylboronic acid was scaled to 3.8 kg of input bromide in a 50 L jacketed borosilicate glass reactor equipped with a retreat-curve impeller, in-situ reaction calorimetry quantified a heat release of −125 kJ·mol−1. A semi-batch addition of the boronic acid solution over 45 min maintained the internal temperature within 80 ± 2 °C, averting hot spots that otherwise promote irreversible precipitation of Pd black. The catalyst loading was optimised to 0.5 mol% Pd(dppf)Cl2·CH2Cl2, achieving 84% conversion after 3.5 h as determined by in-process HPLC. Following aqueous extraction, the toluene stream was treated with a mercaptopropyl-functionalized silica scavenger (QuadraSil MP, 5 wt% rel. to product) at 60 °C for 2 h, reducing residual palladium from 280 ppm to 3 ppm, below the ICH Q3D threshold of 10 ppm for an oral solid dosage form. Crystallization from ethanol/water (70:30 v/v) at a cooling rate of 0.3 °C·min−1 yielded a crystalline product with an HPLC purity of 99.2% and a slurry viscosity of 150 mPa·s at 10 °C (shear rate 10 s−1), enabling efficient discharge from the isolation filter-dryer.
In fragment-based lead generation programmes, the compound is used as a brominated fragment with a molecular weight of 204 Da and a calculated log P (ClogP) of 1.8, satisfying the “Rule of Three” criteria. Surface plasmon resonance screening against a panel of 15 kinases identified initial hits with ligand efficiencies (LE) of 0.42 kcal·mol−1 per heavy atom; subsequent structure-based elaboration via the C4 vector improved target affinity by 100-fold. In parallel medicinal chemistry, the bromide enables automated solution-phase Suzuki coupling in microtiter plates using Pd EnCat beads and microwave irradiation at 120 °C for 20 min. Libraries exceeding 200 analogues have been constructed from a single batch of the 4-bromo ester, with the methyl ester serving as a latent carboxylic acid or a precursor to the primary alcohol. Cleavage to the acid proceeds quantitatively with LiOH in THF/water (3:1) at 22 °C in 2 h; reduction with LiAlH4 in THF at 0 °C furnishes the alcohol in 91% yield. Biological evaluation of matched molecular pairs derived from the 4-bromo and 5-bromo esters has revealed that the 4-substituted series can exhibit superior selectivity for PI3Kδ over PI3Kγ, with selectivity ratios exceeding 50, attributed to a more favourable exit vector geometry from the adenine pocket.
The methyl ester demonstrates sufficient stability for multi-step synthetic sequences that require reductive conditions. Subjecting the biaryl product of the 4-fluoro coupling to catalytic hydrogenation (Raney Ni, H2 50 psi, methanol, 60 °C, 12 h) for reduction of an appended nitro group left the ester intact with <0.2% hydrolysis; the corresponding benzyl ester undergoes rapid hydrogenolysis under identical conditions, generating the free acid quantitatively. In the construction of a pyrrolopyrimidine clinical candidate, the methyl ester of methyl 4-bromo-1H-pyrrole-2-carboxylate was carried through 7 linear steps, including a reductive amination with NaBH(OAc)3 in 1,2-dichloroethane at 25 °C (18 h) and a Boc deprotection with 4 M HCl in dioxane. Analysis of the crude reaction mixtures by 1H NMR showed <3% cumulative ester solvolysis. Exposure to aqueous base triggers rapid saponification: treatment with NaOH 1 M in methanol at 22 °C yields the carboxylate salt within 30 min. Anhydrous workup conditions are therefore mandatory whenever the ester must be retained through the final API intermediate.
Handling is conducted in a fume hood with an average face velocity of 0.5 m·s−1 and nitrile gloves validated for permeation breakthrough per ASTM F739-20. The compound is classified as a skin irritant (H315), eye irritant (H319), and respiratory tract irritant (H335). Storage incompatibilities include strong oxidizing agents (nitric acid, peroxides), alkali metals, and amines that can catalyse premature ester aminolysis. Solid-state milling or micronization must avoid contact with iron or copper fines, which can promote radical debromination. Waste streams containing the substance are incinerated in a facility licensed for halogenated organics, with a residence time exceeding 2 s at 1100 °C to prevent formation of polybrominated dioxins. Published ecotoxicity data for this specific congener are limited; its calculated log Pow of 1.8 and water solubility indicate moderate mobility in aquatic compartments, and releases to surface water above local thresholds require reporting under EU Directive 2000/60/EC. When the substance is used in a GMP step, dedicated equipment or validated cleaning procedures confirmed by swab testing with a limit of detection ≤ 1 μg·cm−2 are employed to prevent cross-contamination of other products.
