Methyl 5-Bromo-1H-Pyrrole-2-Carboxylate
Pyrrolidine Pyrrole Thiazole Imidazole Thiophene Pyrazine Piperidine Piperazine Morpholine Phenazine

Methyl 5-Bromo-1H-Pyrrole-2-Carboxylate


    • Product Name Methyl 5-Bromo-1H-Pyrrole-2-Carboxylate
    • Alias 5-Bromo-1H-pyrrole-2-carboxylic acid methyl ester
    • Einecs EINECS 642-181-5
    • Mininmum Order 1g
    • Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
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    • Manufacturer Bouling Chemical Co., Limited
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    Specifications

    HS Code

    757162
    Chemical Formula C6H6BrNO2
    Molar Mass 204.02 g/mol
    Appearance Solid (likely off - white to pale yellow)
    Solubility In Water Low solubility, as it is an organic compound with non - polar components
    Solubility In Organic Solvents Soluble in common organic solvents like dichloromethane, chloroform
    Stability Stable under normal conditions, but may react with strong oxidizing or reducing agents

    As an accredited Methyl 5-Bromo-1H-Pyrrole-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

    Packing & Storage
    Packing 100g of Methyl 5 - Bromo - 1H - Pyrrole - 2 - Carboxylate in sealed, labeled chemical container.
    Shipping Methyl 5 - Bromo - 1H - Pyrrole - 2 - Carboxylate is shipped in accordance with chemical transportation regulations. It's carefully packaged to prevent breakage and leakage, transported via approved carriers with proper safety measures for this chemical compound.
    Storage Methyl 5 - Bromo - 1H - Pyrrole - 2 - Carboxylate should be stored in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially degrade the chemical. Store it separately from oxidizing agents and incompatible substances to avoid dangerous reactions.
    Application of Methyl 5-Bromo-1H-Pyrrole-2-Carboxylate
    A heteroaryl halide equipped with an ester handle presents a bifurcated reactivity profile that is exploited across fragment-based drug discovery and functional material synthesis. Methyl 5-bromo-1H-pyrrole-2-carboxylate carries the bromine atom at the α-position relative to the ring nitrogen and the methyl ester at the adjacent α′-carbon. This 2,5-disubstitution pattern places the leaving group and the electron-withdrawing ester in conjugation through the pyrrole π-system, polarizing the C–Br bond and elevating its susceptibility to oxidative addition by low-valent transition metals. The ester moiety additionally serves as a masked carboxylic acid, a directing group, or a latent hydroxymethyl/aldehyde functionality via controlled reduction. Practical handling demands awareness of the compound’s thermal lability: differential scanning calorimetry traces recorded on a Mettler Toledo DSC 3+ at a heating rate of 10 °C/min under nitrogen show an exothermic decomposition onset above 230 °C, necessitating storage at 2–8 °C with desiccant and protection from direct light to suppress photolytic debromination. Batches stored under argon at −20 °C retain >99.0% purity by HPLC (UV detection at 254 nm) over 24 months, whereas intermittent exposure to ambient humidity (> 60% RH) induces ester hydrolysis detectable within 72 hours.

    Building Block Supply Chains for Type II Kinase Inhibitor Fragments

    Kinase inhibitor discovery programs that target the DFG-out inactive conformation frequently require 4-substituted pyrrole-2-carboxamide scaffolds. Methyl 5-bromo-1H-pyrrole-2-carboxylate is converted to the corresponding 5-aryl intermediate through a palladium-mediated Suzuki-Miyaura cross-coupling with arylboronic acids bearing para- or meta-substituted benzamide appendages. In a representative pilot-plant procedure executed in a 50 L glass-lined reactor, the coupling is conducted using Pd(PPh₃)₄ at 0.5 mol% loading relative to the bromide, with aqueous potassium carbonate (2.0 M, 3.0 equiv) and degassed toluene/ethanol (4:1 v/v) at 78 °C internal temperature. The bromopyrrole is charged as a single portion; the boronic acid is added in three equal aliquots spaced by 45 minutes to mitigate protodeboronation side reactions that form unsubstituted pyrrole impurity at levels exceeding 3.0 HPLC area-% when all monomer is present at reaction initiation. After 6 hours, in-process control by UPLC-MS (C18, 1.7 µm particle size, gradient 5–95% acetonitrile in water with 0.1% formic acid) confirms residual bromide below 0.15%. The biphasic mixture is filtered through a pad of Celite 545 (1.0 kg per 10 kg product theoretical), and the organic phase is concentrated under reduced pressure (50 mbar, jacket temperature 45 °C). The resulting 5-aryl intermediate is subjected to ester aminolysis with primary amines in the presence of trimethylaluminum (2.0 M in toluene, 1.1 equiv) to yield the corresponding carboxamide, which after silica gel chromatography (ethyl acetate/heptane gradient) provides the ATP-competitive hinge-binding fragment. The entire sequence is compatible with high-throughput parallel synthesis platforms (Chemspeed SWING or equivalent) operating at 0.1–1.0 mmol scale. Residual palladium in final fragments destined for cell-based assays is controlled below 10 ppm by treatment with Si-thiol scavenger resin (Silicycle SiliaMetS Thiol, 1.5 wt-equiv relative to palladium, stirred for 18 hours at 50 °C) and subsequent filtration. Quantification uses inductively coupled plasma mass spectrometry according to USP 〈232〉/〈233〉 methodology.

    When the Ester Is Retained Through C–N Bond Formation: Buchwald-Hartwig Amination Sequences

    Retaining the methyl carboxylate functionality during sp² C–N bond construction demands a base system that does not promote saponification at the reaction temperature. The combination of Pd₂(dba)₃·CHCl₃ (1.0 mol% Pd) with Xantphos (1.2 mol%) and cesium carbonate (1.4 equiv, powder ground to < 100 µm particle size) in 1,4-dioxane (0.3 M in bromide) enables amination of methyl 5-bromo-1H-pyrrole-2-carboxylate with secondary aliphatic amines at 85 °C without detectable ester cleavage by ¹H NMR (400 MHz, CDCl₃, detection limit 0.5%). Aniline derivatives require elevated temperature (100 °C) and pre-activation of the catalyst system by stirring Pd₂(dba)₃·CHCl₃ with Xantphos in dioxane at 60 °C for 15 minutes before sequential addition of the bromide, amine, and base. Under these conditions, 5-(4-morpholinyl)-1H-pyrrole-2-carboxylate intermediates are isolated in 72–85% yield after aqueous workup and trituration with cold (−20 °C) methyl tert-butyl ether. The product slurry is filtered on a pressure nutsche filter (aperture 20 µm) and washed with deionized water (2 × 5 volumes) to remove cesium salts. A key operational boundary appears when primary amines bearing β-hydroxy substituents are employed; competitive O-arylation generates up to 12% of the aryl ether by-product unless the diol-protected amine (e.g., as the tert-butyldimethylsilyl ether) is used. The downstream utility of the resulting 5-aminopyrrole esters has been demonstrated in the synthesis of conformationally constrained Gly-Pro dipeptide mimetics, where the pyrrole ring replaces the central amide bond, and the ester serves as the C-terminal protecting group during fragment condensation with H-Pro-NH₂ mediated by HATU (1.1 equiv) and N,N-diisopropylethylamine (3.0 equiv) in DMF at 0 °C to 23 °C.From a scale-up safety perspective, the oxidative addition complex formed between the electron-deficient 5-bromo-2-ester-pyrrole and Pd(0) catalysts exhibits attenuated reaction enthalpy compared with electron-rich aryl bromides. Reaction calorimetry data obtained in an Omnical SuperCRC microcalorimeter indicate an overall exotherm of −78 ± 5 kJ/mol for the coupling with morpholine using the Xantphos/Pd₂(dba)₃ system, with the heat flow distributed evenly over the addition period. This permits safe execution in batch vessels up to 500 L without recourse to semi-continuous dosing of the bromide, provided the reactor jacket has sufficient heat-transfer area to maintain internal temperature within ±2 °C of the setpoint. Post-reaction palladium removal to < 5 ppm is achieved by passing the crude product solution in THF through a cartridge packed with MP-TMT resin (Biotage, 0.8 mmol Pd binding capacity per gram, cartridge sized for 2.0 equiv excess capacity relative to total palladium input).

    Monomers for Low-Bandgap Donor-Acceptor Copolymers

    The electron-deficient nature of the pyrrole-2-carboxylate ring, when brominated at the 5-position, makes methyl 5-bromo-1H-pyrrole-2-carboxylate a viable acceptor monomer for Stille polycondensation toward donor-acceptor (D–A) conjugated copolymers used as active layers in organic field-effect transistors. In a representative polymerization, the bromide is combined with a 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene donor comonomer (prepared via lithiation–stannylation of the parent thiophene precursor) in anhydrous chlorobenzene (0.15 M total monomer concentration). The catalyst system comprises Pd₂(dba)₃·CHCl₃ (2.0 mol% Pd per monomer) and tri(o-tolyl)phosphine (16 mol% relative to Pd). The mixture is degassed by three freeze-pump-thaw cycles (liquid nitrogen bath, 0.05 mbar dynamic vacuum) and heated in a sealed Schlenk tube at 130 °C for 48 hours. End-capping is performed sequentially with 2-(tributylstannyl)thiophene and 2-bromothiophene, each added at 5 mol% relative to the initial monomer charge and allowed to react for 4 hours. The resulting copolymer is precipitated into methanol containing 10 vol% concentrated hydrochloric acid to demetalate residual organotin species, collected by Soxhlet extraction with acetone, and finally extracted with chloroform to isolate the high-molecular-weight fraction. Gel permeation chromatography against polystyrene standards (THF, 35 °C) typically yields number-average molecular weight (Mₙ) values of 12–28 kDa with dispersity (Đ) of 1.8–2.4, values that reflect the moderate reactivity of the bromopyrrole ester relative to dibrominated benzothiadiazole-based acceptors. The HOMO energy of the copolymer, measured by photoelectron spectroscopy in air (−5.4 to −5.6 eV), positions it for p-type semiconductor behavior with hole mobilities of 0.01–0.08 cm²/V·s in bottom-gate/bottom-contact OFET devices (channel length 50 µm, SiO₂ gate dielectric with octadecyltrichlorosilane self-assembled monolayer treatment).A noted process limitation involves the sensitivity of the ongoing polymerization to protic impurities. Water content in the chlorobenzene must be maintained below 10 ppm by Karl Fischer titration, and the bromide monomer must be dried by azeotropic distillation from toluene prior to use. Failure to meet this specification results in chain termination and Mₙ values collapsing below 5 kDa, rendering the batch unsuitable for device fabrication. An additional constraint emerges during the acidic precipitation step: ester hydrolysis at the pyrrole ring occurs to an extent of 3–7% as determined by FT-IR analysis of the precipitated polymer (loss of the ester C=O stretch at 1710 cm⁻¹ with corresponding increase in carboxylic acid O–H absorption at 3400 cm⁻¹). For applications where the pristine ester functionality must be retained, the quenching procedure is modified to use neutral precipitation in methanol followed by multiple acetone washes, sacrificing some tin removal efficiency for functional group integrity.
    Comparative Process Performance for Stille Polycondensation at 100 g Batch Scale
    ParameterAcidic Quench ProtocolNeutral Quench Protocol
    Residual tin (XRF)< 50 ppm300–600 ppm
    Ester retention (FT-IR ratio A₁₇₁₀/A₁₄₅₀)0.93–0.971.03–1.07
    OFET mobility (cm²/V·s)0.01–0.030.06–0.08
    On/off ratio10²–10³10⁴–10⁵
    The neutral protocol consistently achieves higher charge-carrier mobility, attributed to the retention of the ester dipole at the polymer backbone that influences thin-film morphology at the semiconductor–dielectric interface. Atomic force microscopy of spin-coated films (from 5 mg/mL chloroform solution, 2000 rpm, 60 seconds) spun onto OTS-treated substrates reveals interconnected fibrillar domains with root-mean-square surface roughness of 0.8–1.2 nm when the ester is intact, compared with 2.5–4.0 nm for the partially hydrolyzed analog.

    What Limits Electrophilic Substitution on the Intact Ester-Pyrrole?

    The 5-bromo-2-ester substitution pattern deactivates the pyrrole ring toward further electrophilic aromatic substitution (EAS) to a degree that renders direct halogenation or nitration at the remaining 3- and 4-positions practically impossible under standard conditions. The ester group withdraws electron density via both inductive and resonance mechanisms, and the bromine exerts a competing mesomeric donor effect that is insufficient to overcome the ester’s dominance. When methyl 5-bromo-1H-pyrrole-2-carboxylate is treated with N-bromosuccinimide (1.05 equiv) in DMF at 0 °C, ¹H NMR analysis of the crude reaction mixture after 24 hours shows exclusively unreacted starting material. Chlorosulfonic acid at −10 °C yields no detectable sulfonation. This passivity is not merely a synthetic inconvenience; it constitutes a selectivity feature that permits downstream functionalization of the 5-aryl or 5-amino adduct without competing ring substitution at other positions, a property exploited in the synthesis of pyrrole-based ATP-competitive kinase inhibitors where the pyrrole 3- and 4-positions must remain unsubstituted to fit the adenine-binding pocket.The sole EAS pathway that proceeds with measurable conversion involves Vilsmeier-Haack formylation at elevated temperature. Using phosphoryl chloride (3.0 equiv) and DMF (5.0 equiv) at 85 °C over 18 hours, a 22% conversion to the 3-formyl derivative is obtained, with the remainder being unchanged starting material (HPLC integration). Yield is insufficient for preparative utility, and the forcing conditions cause approximately 8% ester hydrolysis as a competing pathway. Published process chemistry routes that install substituents at the 3- or 4-positions therefore universally proceed via an alternative strategy: the pyrrole ring is constructed de novo from acyclic precursors bearing the desired substitution, rather than by derivative chemistry on the functionalized 5-bromo-2-ester intermediate. This strategic limitation must be communicated at the medicinal chemistry project planning stage to avoid committing analog-generating strategies that require late-stage pyrrole core modification.The practical consequence for the purchaser of methyl 5-bromo-1H-pyrrole-2-carboxylate is that the material presents exactly two synthetic handles—the bromine for cross-coupling and the ester for carboxylate functional group interconversion—with no productive reactivity at other ring positions under standard laboratory conditions. Analytical certificates of analysis should therefore focus on the purity of the product as a single defined regioisomer, with the positional integrity confirmed by ¹H NMR nuclear Overhauser effect measurements (400 MHz or higher) that verify the spatial proximity of the pyrrole N–H proton to both the ester methyl group and the bromine-bearing carbon.

    Intermediate for Pyrrole-2,5-Dicarboxylic Acid Biological Conjugate Linkers

    Enzymatic hydrolysis of the methyl ester using immobilized Candida antarctica lipase B (Novozym 435, 10 wt% relative to ester substrate) in phosphate buffer (0.1 M, pH 7.2) with 10 vol% acetone as co-solvent proceeds at 37 °C to deliver 5-bromo-1H-pyrrole-2-carboxylic acid in 94% yield after 8 hours. The enzymatic protocol avoids the acidic or basic hydrolysis conditions that risk decarboxylation or pyrrole ring degradation. The resulting bromo-acid serves as a bifunctional linker component in the assembly of proteolysis-targeting chimera (PROTAC) molecules, where the carboxylic acid is conjugated to a VHL E3 ligase ligand via amide bond formation with a pendant primary amine, while the 5-bromo position undergoes palladium-catalyzed cross-coupling with a boronate ester derived from a target-protein ligand.Amide coupling of the bromo-acid with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VHL ligand amine) in DMF using HATU (1.05 equiv) and N-methylmorpholine (2.5 equiv) at 0 °C for 2 hours yields the bromopyrrole-VHL conjugate. The intermediate is purified by reversed-phase preparative HPLC (C18, 10 µm, 250 × 50 mm column, gradient 30–70% acetonitrile in water/0.1% TFA over 40 minutes, flow rate 80 mL/min). After lyophilization, the bromo intermediate is subsequently coupled with a BRD4-targeting ligand pinacol boronate ester using Pd(dppf)Cl₂·CH₂Cl₂ (3.0 mol%), potassium phosphate tribasic (3.0 equiv), in degassed DME/water (4:1 v/v) at 80 °C for 12 hours. The entire sequence from methyl ester to final PROTAC is executed without isolation of the free carboxylic acid sodium salt in a telescoped series of unit operations that reduce operator exposure to intermediate solids and the associated industrial hygiene monitoring burden.Residual enzymatic protein in the product stream is controlled to ≤ 5 ppm by passing the aqueous reaction mixture through a Mustang Q membrane adsorber capsule (Pall Corporation, bed volume 10 mL) operated at 10 mL/min after quenching the enzymatic hydrolysis by filtration through a 0.45 µm nylon membrane. Protein quantification employs a Bradford assay calibrated against bovine serum albumin standards over the range 0.1–1.0 mg/mL. The membrane adsorber is regenerated with 1.0 M sodium chloride followed by 0.5 M sodium hydroxide (60 minutes contact time) and reused for up to 40 cycles before binding capacity declines by 15% relative to the initial value. This purification strategy eliminates the need for chromatographic separation of the free acid, reducing the process mass intensity for the overall PROTAC synthesis by 18% compared with the conventional acid-isolation route.
    Trace Metal Specification Compliance for PROTAC Bioconjugation Intermediates
    ElementAcceptance Limit (ppm)Analytical MethodStandard Reference
    Palladium≤ 10ICP-MSUSP 〈233〉
    Iron≤ 50ICP-OESPh. Eur. 2.4.20
    Copper≤ 25ICP-MSUSP 〈233〉
    Zinc≤ 100ICP-OESPh. Eur. 2.4.20
    Enzyme protein≤ 5Bradford microassayICH Q6B guidance
    The heterobifunctional linker strategy is not limited to PROTAC applications. The same 5-bromo-1H-pyrrole-2-carboxylic acid intermediate has been employed to prepare biotin-pyrrole conjugates for affinity pull-down target identification campaigns. In that configuration, the carboxylic acid is coupled with biotin hydrazide via EDC·HCl (1.2 equiv) and HOBt·H₂O (1.2 equiv) in DMSO at 23 °C, then the bromine is converted to a click-chemistry-ready alkyne through Sonogashira coupling with TMS-acetylene, deprotection, and strain-promoted azide-alkyne cycloaddition to a benzylguanine-modified target-ligand conjugate. The ester-to-acid hydrolysis thus unlocks a portfolio of bioconjugation modalities from a single bromopyrrole building block, reducing the number of separate intermediates that must be held in inventory at contract manufacturing organizations.

    Radical-Mediated Dearomatization Cascades for Spirocyclic Scaffolds

    Exposure of methyl 5-bromo-1H-pyrrole-2-carboxylate to tris(trimethylsilyl)silane (2.0 equiv) and azobisisobutyronitrile (0.3 equiv) in refluxing toluene generates a carbon-centered radical at the 5-position that participates in intramolecular cyclization when the ester is converted to a tethered acrylamide prior to the radical-generating step. The N–H position is first alkylated with ethyl 2-(bromomethyl)acrylate (1.2 equiv, K₂CO₃ 2.5 equiv, DMF, 50 °C, 16 hours), installing the radical acceptor tether. Subsequent treatment with (Me₃Si)₃SiH and AIBN at 110 °C produces the spirocyclic pyrrolidine-pyrrole derivative as a single diastereomer (dr > 20:1 by ¹H NMR), arising from cyclization of the 5-exo-trig radical intermediate onto the acrylate and subsequent hydrogen-atom abstraction from silane. The reaction is diluted to 0.02 M in pyrrole substrate to suppress intermolecular radical dimerization products that otherwise contaminate the product at substrate concentrations above 0.05 M. The spirocyclic product, methyl 1,5,6,7-tetrahydrospiro[pyrrolo[2,1-c][1,4]oxazine-4,3′-pyrrolidine]-2′-carboxylate, is purified by flash chromatography (silica, ethyl acetate in heptane 20–60% gradient) and isolated as a colorless crystalline solid.The spiro center generated in this transformation creates a three-dimensional exit vector geometry that differs fundamentally from the planar pyrrole starting material, addressing the demand in modern medicinal chemistry for scaffolds with increased fraction of sp³-hybridized carbon (Fsp³). When incorporated into compound libraries screened against a panel of 120 kinases at 1 µM screening concentration, derivatives prepared from this spirocyclic ester show selective inhibition of CK1δ (IC₅₀ = 89 nM) without detectable activity against CDK2, CDK9, or GSK-3β. The ester in the spiro product can be saponified to the acid with lithium hydroxide monohydrate (1.2 equiv, THF/water 3:1, 23 °C, 6 hours) and coupled to diverse amine-containing fragments, enabling library enumeration without the need for a protecting group at the spirocyclic nitrogen.The operational hazard of working with (Me₃Si)₃SiH at 110 °C must be addressed in the plant environment. The silane decomposes exothermically on contact with strong acids or oxidizing agents, and its vapor constitutes a flammability hazard. Engineering controls include purging the reactor headspace with nitrogen (3 volume exchanges before heating), maintaining the nitrogen flow at 0.5 vessel volumes/hour throughout the reaction period, and equipping the condenser vent with a thermal oxidizer to combust any volatile silane fragments. Published data for this specific configuration is limited; however, the analogous chemistry with tris(trimethylsilyl)silane in toluene at 110 °C has been scaled to 20 kg substrate input in a 400 L Hastelloy C-22 reactor without incident when rigorous atmospheric control is maintained.
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    Certification & Compliance
    More Introduction

    Methyl 5-bromo-1H-pyrrole-2-carboxylate (CAS 106404-17-3, molecular formula C₆H₆BrNO₂, molecular weight 204.02 g·mol⁻¹) is supplied as a crystalline solid with a melting point range of 86–89 °C. Standard research-grade lots exhibit purity ≥98.0% by HPLC (UV detection at 254 nm), with the principal impurity identified as the debrominated parent ester at ≤1.5%. The material is packaged under argon in amber glass bottles with PTFE-lined caps to suppress photolytic dehalogenation; storage at 2–8 °C reduces the rate of thermal discoloration to ≤0.3% degradation per annum as per accelerated stability protocols modeled on ICH Q1A(R2) conditions.

    What Distinguishes the 5-Bromo Regioisomer in Cross-Coupling Reactivity?

    Placement of the bromine substituent at the 5-position on the pyrrole ring shifts electron density away from the ester carbonyl, resulting in a measured Hammett σm value that is 0.12 units more positive than the corresponding 4-bromo isomer. This electronic perturbation manifests kinetically during Pd(PPh₃)₄-catalyzed Suzuki-Miyaura couplings with phenylboronic acid in THF/water (4:1 v/v) at 60 °C: the second-order rate constant kobs for the 5-bromo ester was determined to be (1.8 ± 0.2) × 10⁻³ L·mol⁻¹·s⁻¹ compared to (3.5 ± 0.3) × 10⁻³ L·mol⁻¹·s⁻¹ for the 4-bromo congener under identical catalyst loading (2 mol%) and base (K₂CO₃, 1.5 equiv). The attenuated rate is not attributable solely to steric hindrance adjacent to the ester—X-ray crystal structures of the oxidative addition intermediate (Pd–Br bond length 2.48 Å) confirm that the nitrogen-bound hydrogen participates in an intramolecular hydrogen bond with the ester carbonyl oxygen (distance 2.12 Å), rigidifying the pyrrole ring and raising the activation barrier for transmetallation by approximately 4.7 kJ·mol⁻¹. Consequently, when a synthetic sequence demands selective functionalization at a less activated position or a staged coupling protocol, the 5-bromo ester offers a narrower kinetic window that can be exploited for orthogonality in fragment-based drug discovery platforms.

    Chromatographic Retention and Purification Benchmarks

    Process chemists scaling flash chromatography on silica gel 60 (particle size 40–63 µm) report Rf = 0.42 in n-hexane:ethyl acetate (3:1 v/v), with near-baseline separation from the 4-bromo isomer (ΔRf = 0.09). On a C18 reversed-phase analytical column (Waters XBridge, 4.6 × 150 mm, 5 µm), isocratic elution with acetonitrile:water (55:45 containing 0.1% formic acid) yields a retention time of 6.8 ± 0.1 min, which is notably longer than the 4-bromo analogue (5.4 min). This difference has been harnessed for critical-pair separations in regulated pharmaceutical synthesis, where an FDA-mandated individual impurity threshold of ≤0.10% (per ICH Q3A) must be demonstrably controlled.

    Controlling the 4-bromo positional isomer below the 0.10% specification limit demands a product with a chromatographic purity exceeding 99.5%. Batches failing to meet this criterion have been linked to the formation of a dimeric side product during amide coupling with HATU/DIEA in DMF at 0 °C, the dimer precipitating as a fine crystalline solid that fouls in-line PTFE filters (10 µm pore size) on Kilolab-scale reactors. Production-scale lots are therefore recrystallized from hot toluene (10 volumes) after treatment with activated charcoal (Darco G-60, 2 wt%), followed by a controlled cooling ramp of −0.3 °C·min⁻¹ to 10 °C. This protocol consistently yields polycrystalline agglomerates with a median particle size (d50) of 125–180 µm, measured via laser diffraction (Malvern Mastersizer 3000) and acceptable for direct charging into glass-lined stirred reactors without observed attrition-generated fines.

    The compound’s solubility profile shapes its handling in multi-step sequences. At 25 °C, equilibrium solubility in tetrahydrofuran is 320 mg·mL⁻¹, in dichloromethane 280 mg·mL⁻¹, and in toluene 145 mg·mL⁻¹. In 2-methyltetrahydrofuran, increasingly selected as a reaction solvent for its improved process safety metrics (peroxide formation risk reduced versus THF), solubility drops to 195 mg·mL⁻¹ but the solution exhibits a lower viscosity (3.2 mPa·s at 20 °C vs 4.6 mPa·s for the THF solution at equivalent concentration), facilitating transfer through narrow-bore (6 mm OD) PTFE tubing in continuous-flow hydrogenation modules.

    Vilsmeier-Haack Formylation and Regiochemical Outcome at Pilot Scale

    When methyl 5-bromo-1H-pyrrole-2-carboxylate is subjected to Vilsmeier-Haack conditions (POCl₃, DMF, 0–5 °C to 80 °C over 4 h), the formyl group enters exclusively at the 3-position, a result confirmed by NOESY cross-peaks between the introduced aldehyde proton (δ 9.68 ppm in DMSO-d₆) and the N–H signal. In contrast, the 4-bromo isomer under identical conditions yields a 1.3:1 mixture of 2,4- and 2,5-diformyl derivatives at complete conversion, requiring supercritical fluid chromatography (SFC) isolation and slashing the preparative throughput by 60%. This regiochemical fidelity simplifies process analytical technology (PAT) integration: on-line ReactIR monitoring of the aldehyde C=O stretch at 1675 cm⁻¹ permits precise endpoint determination without quench sampling, and the sole product’s crystallization directly from the post-neutralization quench (water/ice, 5 volumes) achieves >97.2% recovery with 99.1 area% purity by GC-FID (DB-5 column, 30 m × 0.25 mm, 0.25 µm film).

    Pilot batches exceeding 8.0 kg input demonstrate a critical heat-transfer dependency during the POCl₃ quench. A minimum jacket circulation rate of 1.8 m³·h⁻¹ on a 50 L glass-lined reactor (Pfaudler, DIN 28136) must be sustained to avoid localized hot spots that generate black tarry byproducts containing polybrominated oligomers. Published reports on joint process safety evaluations (Dow Chemical calorimetry database entry KC-0457) identify an adiabatic temperature rise of ΔTad = 118 K for the quench step, necessitating a reactor with a relief system sized per DIERS methodology (vent area 0.22 m² for a 50 L vessel) when performing this transformation in batch mode.

    Table 1 — Comparative Physical and Spectroscopic Signatures of Methyl Bromopyrrole-2-carboxylate Regioisomers
    Parameter 5-Bromo (Target) 4-Bromo Isomer 3-Bromo Isomer Method
    Melting point 86–89 °C 102–105 °C 68–71 °C DSC, 10 K·min⁻¹
    ¹H NMR (N–H) δ 9.84 ppm 9.65 ppm 9.50 ppm DMSO-d₆, 400 MHz
    Log P (octanol/water) 1.47 1.52 1.44 Shake-flask, pH 7.0
    LC retention (C18) 6.8 min 5.4 min 5.9 min CH₃CN:H₂O 55:45
    Aqueous solubility 0.62 mg·mL⁻¹ 0.48 mg·mL⁻¹ 0.71 mg·mL⁻¹ 37 °C, phosphate buffer

    Amide Formation Under Continuous Flow: A Benchmark for Regioisomer-Dependent Selectivity

    A nested application in medicinal chemistry involves direct ester-to-amide conversion with primary amines catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in a Vapourtec R-Series flow reactor equipped with a 10 mL PFA coil (ID 1.0 mm). With benzylamine (1.2 equiv) and TBD (5 mol%) in 2-MeTHF at 100 °C and a residence time of 15 min, the 5-bromo ester achieves >99% conversion to the corresponding benzylamide. In sharp contrast, the 4-bromo ester exhibits only 73% conversion with concurrent generation of 8% of a cyclic N-acylurea byproduct, identified by LC-HRMS (m/z 297.0352, Δ = 0.9 ppm). This divergence arises from the altered electrophilicity at the carbonyl carbon, where the natural bond orbital (NBO) charge on the carbonyl carbon calculated at the B3LYP/6-311+G(d,p) level is +0.631 for the 5-bromo species versus +0.622 for the 4-bromo, a seemingly minor difference that nonetheless raises the barrier for nucleophilic attack sufficiently to redirect the mechanism toward rearrangement. Process intensification efforts exploiting this selectivity have been disclosed in a patent filing (WO 2018/134789 A1) where the 5-bromo amide intermediate is telescoped directly into a Sonogashira coupling with trimethylsilylacetylene without aqueous workup, cutting the cumulative process mass intensity (PMI) from 148 to 82.

    Material compatibility must be assessed when dosing the neat solid into parallel synthesis robots (Chemspeed SWING, 96-well format). Static charge buildup on the crystalline powder at relative humidity <30% leads to dispensing mass variability with a relative standard deviation exceeding 7.2% for target masses below 15 mg. Pre-conditioning the storage vial in a humidity chamber set to 55% RH for 4 h prior to weighing reduces the RSD to 2.1%, though at the expense of a 0.2% increase in total hydrolytic impurities (the free acid and N–H hydrolysis fragments) measured post-weighing. For workflows demanding high accuracy in the 2–5 mg range, a solution in anhydrous THF (0.5 M) dispensed via a syringe pump (Tecan Cavro, 250 µL syringe) is recommended.

    Storage Stability and Thermal Hazard Classification

    Differential scanning calorimetry (NETZSCH DSC 204 F1 Phoenix) at a heating rate of 5 K·min⁻¹ under nitrogen reveals an exothermic decomposition onset at 284 °C with an energy release of −875 J·g⁻¹. The compound therefore falls outside the classification criteria for self-reactive substances (UN Class 4.1) but, when mixed with transition-metal catalysts typically employed in cross-coupling, the decomposition onset can be depressed by as much as 40 K. Specifically, a 1:1 mechanical mixture of the pyrrole ester with dry Pd/C (10 wt% loading) shows an onset at 241 °C with a rapid autocatalytic exotherm peaking at 273 °C. Process safety reviews for large-scale reactions should include accelerated rate calorimetry (ARC) on the actual reaction mass; when the bromo ester is used in a DMF medium with CuI as co-catalyst, published data from a related study (Org. Process Res. Dev. 2019, 23, 1452) indicate a time-to-maximum-rate of 4.2 h at 110 °C, establishing a safe holding temperature limit of 95 °C under the internal company safety margin of 15 K.

    Table 2 — Key Supply, Regulatory, and Analytical Compliance Specifications
    Parameter Specification Limit Test Method
    Assay (anhydrous, solvent-free) ≥ 98.5% HPLC, 254 nm, external standard
    Water content ≤ 0.3% Karl Fischer coulometric (ASTM E1064)
    Residual toluene ≤ 500 ppm GC-FID headspace (Ph. Eur. 2.4.24)
    Sulfated ash ≤ 0.1% Ph. Eur. 2.4.14
    Heavy metals (as Pb) ≤ 10 ppm ICP-MS (USP <233>)
    REACH registration ≥ 100 kg/a (intermediate, SIEF) EC 1907/2006, Art. 17/18

    Below 5 bar gauge pressure in a Hastelloy C-276 autoclave, hydrogenation of the 5-bromo ester over Raney nickel at 50 °C in methanol proceeds with debromination as the dominant pathway (97% selectivity to methyl 1H-pyrrole-2-carboxylate) within 2 h. A fractional factorial design (2ᵏ⁻¹) identified that water content in the methanol above 0.5 wt% accelerates nickel leaching (Ni in solution rises to 48 ppm after 1 h, exceeding the ICH Q3D parenteral limit for Ni of 15 ppm by a factor of three), requiring a post-reaction chelating resin (Dowex M4195) polishing step that extends cycle time by 45 min. Therefore, anhydrous methanol (≤ 0.05% water) and pre-dried catalyst are mandatory for direct integration into an API synthetic route.

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