4-Bromo-1H-Pyrrole-2-Carboxylic Acid Ethyl Ester
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HS Code |
323379 |
| Name | 4-Bromo-1H-pyrrole-2-carboxylic acid ethyl ester |
| Chemical Formula | C7H8BrNO2 |
| Molar Mass | 218.05 g/mol |
| Appearance | Solid (usually) |
| Cas Number | 10200-03-8 |
| Melting Point | 74 - 77 °C |
| Boiling Point | 283.7 °C at 760 mmHg |
| Density | 1.554 g/cm³ |
| Solubility | Slightly soluble in water, soluble in organic solvents like ethanol, dichloromethane |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 4-Bromo-1H-Pyrrole-2-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Bromo - 1H - Pyrrole - 2 - Carboxylic Acid Ethyl Ester in sealed chemical - grade vial. |
| Shipping | 4 - Bromo - 1H - Pyrrole - 2 - Carboxylic Acid Ethyl Ester is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations, ensuring safety during transit to prevent any leakage or damage. |
| Storage | 4 - Bromo - 1H - Pyrrole - 2 - Carboxylic Acid Ethyl Ester should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store it separately from oxidizing agents and incompatible substances in a storage area with proper ventilation to ensure safety. |
In the production of the miticidal active ingredient chlorfenapyr, ethyl 4-bromo-1H-pyrrole-2-carboxylate functions as the vector for installing the 4-aryl substituent prior to C5 trifluoromethylation. A validated kilo-lab protocol charges 1.0 eq of the bromoester, 1.25 eq of 4-chlorophenylboronic acid, and 2.5 eq of anhydrous potassium carbonate into a degassed mixture of toluene, ethanol, and water (5:1:1 v/v). Tetrakis(triphenylphosphine)palladium(0) is added at 0.8 mol% relative to the limiting substrate. The jacket is set to 82 °C and the biphasic slurry is agitated at 350 rpm under nitrogen for 14 h. IPC by HPLC (C18, 254 nm) must show < 0.5 area% residual bromide before the batch is cooled to 25 °C and filtered through a Celite pad topped with 3 wt% activated carbon to scavenge colloidal palladium. The organic phase is washed with 10% brine, dried over MgSO₄, and concentrated to a crude that solidifies upon standing. Recrystallization from n-heptane/ethyl acetate (4:1) delivers 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate as off-white needles in 81–84% yield with HPLC purity exceeding 99.3%. Residual palladium by ICP-MS is controlled down to < 8 ppm to meet ICH Q3D oral limits. This intermediate is subsequently N-ethoxymethylated and the ester group is converted to a CF₃ moiety using a methyl chlorodifluoroacetate / CuI / KF system in sulfolane at 135–140 °C in a PTFE-lined pressure vessel — a step where precise moisture exclusion (KF < 50 ppm in solvent) directly determines whether the decarboxylative coupling succeeds or generates intractable tar.How Is the 3-Cyano Motif in Fludioxonil Congeners Constructed from a 4-Bromo-2-Ester Pyrrole?Fludioxonil and its structural analogues require a 4-aryl-1H-pyrrole-3-carbonitrile backbone, a connectivity that can be accessed by repurposing the ester group as a directing group for a regioselective C3 halogenation followed by cyanation. The bromide atom at C4 is retained for a late-stage Suzuki coupling, while the 2-ester is first saponified with 1.1 eq of LiOH in THF/water (3:1) at 0–5 °C over 2 h to avoid decarboxylation. The resulting 4-bromo-1H-pyrrole-2-carboxylic acid is treated with N-bromosuccinimide (1.05 eq) in DMF at 25 °C shielded from light; bromination occurs exclusively at the C3 position, driven by the electron-withdrawing carboxylate. After quenching, the acid is converted to the primary amide via the mixed anhydride method and dehydrated with POCl₃ in acetonitrile at 60 °C to yield 3,4-dibromo-1H-pyrrole-2-carbonitrile. A subsequent chemoselective Suzuki coupling is conducted with 1.0 eq of 2,2-difluoro-1,3-benzodioxole-4-boronic acid pinacol ester, PdCl₂(dppf)•CH₂Cl₂ (1.5 mol%), and aqueous K₃PO₄ (1.8 M) in 1,4-dioxane at 90 °C. The C4 bromide reacts preferentially because the C3-Br is deactivated by the adjacent nitrile group. After workup, the mono-coupled 4-aryl-3-bromo-1H-pyrrole-2-carbonitrile is subjected to a hydrogenolysis with Pd/C (5%, 50 psi H₂) in ethanol with triethylamine to remove the C3 bromine, furnishing the fludioxonil core scaffold with an overall yield of 48–55% from the ester. Limits for genotoxic impurities (potential nitrile epoxides) are validated below 1.5 µg/day per ICH M7(R2).Downstream synthesis of biaryl pyrrole carboxamides serving as NS5A replication complex inhibitors hinges on a strictly anhydrous amidation sequence. After a standard Suzuki coupling on the C4 bromide with a heteroaryl boronate ester to install a biphenyl-like motif, the ethyl ester is hydrolysed to the acid in 99% conversion using 6 N HCl in dioxane at 50 °C for 5 h. The wet cake is dried under vacuum (P < 50 mbar) at 45 °C until KF titration reads < 0.2% water. The acid (1.0 eq) is activated with EDC•HCl (1.15 eq) and HOBt (0.95 eq) in anhydrous DMF at 0 °C for 40 min, then a secondary amine-containing caprolactam fragment (1.05 eq) is added and the mixture is stirred for 18 h while warming to ambient. The product is precipitated by drowning into 10 volumes of ice-cold 5% NaHCO₃, filtered, and re-slurried in isopropanol at 70 °C to remove DMF-solvate. Final purity by qNMR (Bruker 400 MHz, internal standard 1,3,5-trimethoxybenzene) typically exceeds 98.0 wt%, with enantiomeric excess controlled to > 99.5% via the pre-qualified chiral caprolactam input. The powder is micronized to D₉₀ < 10 µm using a spiral jet mill to meet dissolution specification.BODIPY Photosensitizer Assembly via Acid-Catalysed Condensation of 4-Bromopyrrole-2-CarboxylateA meso-aryl BODIPY core functionalised at the β-pyrrole position for bioconjugation can be constructed in a two-pot sequence where the ethyl ester remains inert until the final activation. 2.0 eq of the 4-bromo ester are condensed with 1.0 eq of 4-formylbenzoic acid in anhydrous CH₂Cl₂ under argon; one drop of trifluoroacetic acid (< 0.05 eq) initiates dipyrromethane formation, monitored by disappearance of the aldehyde stretch at 1702 cm⁻¹ via inline FTIR. The dipyrromethane is immediately oxidised with 2.3 eq of DDQ at 0 °C for 30 min, followed by complexation with BF₃•OEt₂ (4.0 eq) and diisopropylethylamine (6.0 eq) at 25 °C for 4 h. Crude material purified over a short silica plug (hexane:EtOAc 7:3) yields the dibromo-BODIPY bis-ester. The C4 bromines on the pyrrole rings are subsequently substituted via Pd-catalysed borylation using bis(pinacolato)diboron (2.2 eq), KOAc, Pd(dppf)Cl₂ (3 mol%) in dioxane at 100 °C, enabling attachment of targeting peptides through Suzuki–Miyaura cross-coupling in aqueous media. The ester groups are finally hydrolysed with LiOH in THF/H₂O and converted to NHS esters for bioligation. Quantum yield of the final conjugate measured in PBS (pH 7.4) under ASTM E1266-22 conditions is not a direct function of the intermediate quality but demands removal of free heavy metals to < 1 ppm, as Cu²⁺ ions quench fluorescence emission at 525 nm.When a 4-bromopyrrole core is coupled to 3,5-disubstituted phenyl boronic acids to interrogate Type II RAF kinase inhibitor scaffolds, the ethyl ester is retained to occupy a lipophilic sub-pocket identified in co-crystal structures. A representative route charges 1.0 eq of the bromoester, 1.3 eq of 3-(trifluoromethyl)-4-methoxyphenylboronic acid, and Pd(OAc)₂ (1 mol%) with XPhos (2.2 mol%) as the ligand system. The solvent is n-propanol/water (4:1), degassed by three vacuum-nitrogen purge cycles to ensure O₂ < 5 ppm. K₂CO₃ (2.5 eq) is charged and the reactor is held at 85 °C for 8 h. Aqueous workup employs a 5% L-cysteine solution at 50 °C for 1 h to sequester soluble palladium residues. After phase separation and solvent switch to methylcyclohexane, the product crystallises upon cooling to −5 °C over 6 h. Single-crystal XRD (Mo-Kα, 100 K) confirms the dihedral angle between the pyrrole and phenyl rings is 42.3°, matching the torsional profile required for binding to the DFG-out conformation. The ester is isolated in 87% yield and can be directly N-alkylated in the next step. A process safety finding from adiabatic calorimetry (ARC, ASTM E1981-21) dictates that the N-alkylation with ethyl iodide and NaH in THF must be maintained below 30 °C; the onset of a rapid exotherm is detected at 34 °C with a ΔTad of 138 K, so a jacket setpoint of 15 °C and slow dosing are mandatory.
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4-Bromo-1H-pyrrole-2-carboxylic acid ethyl ester, C₇H₈BrNO₂, molecular weight 218.05 g/mol, is supplied as a pale yellow crystalline powder with a purity of ≥98% (HPLC, area%) and residual water content controlled to ≤0.5% (Karl Fischer). The ester group can be hydrolysed under alkaline conditions to the free acid or directly converted to amides via peptide coupling reagents, while the 4-bromo substituent serves as a robust handle for palladium-catalysed cross-coupling, nucleophilic aromatic substitution, and lithiation-mediated functionalization. This heterocyclic building block is manufactured under cGMP guidelines per FDA 21 CFR Part 211 and conforms to residual solvent limits defined in ICH Q3C. Typical batch release specifications are summarised in the table below.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | Pale yellow to off-white crystalline powder | Visual |
| Assay (anhydrous basis) | ≥98.0% | HPLC (area%) |
| Water content | ≤0.5% | Karl Fischer coulometry |
| Melting point | 80–84 °C | DSC, endothermic peak onset |
| Residual ethyl acetate | ≤500 ppm | GC headspace |
| Residual DMF | ≤200 ppm | GC headspace |
| Any single unknown impurity | ≤0.3% | HPLC |
The electron-donating character of the pyrrole ring retards oxidative addition of the C–Br bond to palladium(0). Therefore, maintaining a tight processing window is critical for achieving high conversion without generating protodebrominated by-product. In a typical reaction with arylboronic acid (1.05 equiv), Na₂CO₃ (1.5 equiv) as base, and Pd(OAc)₂ (0.5–1.0 mol%) in the presence of SPhos (2:1 L:Pd), the mixture is heated in degassed THF/water (3:1 v/v) at 78±3 °C. At temperatures above 85 °C debromination becomes kinetically competitive, with detectable levels of the des-bromo impurity appearing within 2 h. Conversely, below 72 °C oxidative addition is slow and catalyst deactivation via aggregation predominates.
In a 20 L glass-lined jacketed reactor equipped with a PID temperature controller and an external circulation heater, the temperature setpoint is maintained at 80 °C with an allowable overshoot of ±1.5 °C. The reactor headspace is purged with high-purity nitrogen (O₂ < 10 ppm) for a minimum of 30 min before catalyst injection. Residual oxygen above 20 ppm promotes oxidation of the electron-rich phosphine ligand, leading to palladium black precipitation and a sudden drop in turnover number. Under these controlled conditions, the coupling normally reaches >95% conversion within 6–8 h; however, published data for this specific substrate combination is limited, and results from analogous 4-bromopyrrole systems suggest that prolonged reaction times beyond 12 h increase the formation of homocoupled biaryl dimers to 2–4% by HPLC. The use of K₃PO₄ instead of Na₂CO₃, while beneficial for some electron-deficient bromides, elevates the local pH near the ester function and accelerates saponification, leading to a loss of the ethyl ester group of 3–5% after 8 h at 80 °C.
Direct amidation of the ethyl ester without prior hydrolysis is frequently executed via a HATU‑mediated coupling. The ester (1.0 equiv) is dissolved in anhydrous DMF (dried over 4 Å molecular sieves to <50 ppm water) and treated with HATU (1.1 equiv), DIPEA (3.0 equiv), and the amine (1.2 equiv) at 0–5 °C, then allowed to warm to room temperature over 16 h. The reaction is quenched into ice‑water and extracted with ethyl acetate. Residual DMF is removed by azeotropic distillation with heptane. When anhydrous ammonia gas is bubbled through a methanolic solution of the ester at 0 °C, the primary amide precipitates directly, and is isolated by filtration and washed with cold methanol to deliver a purity of >97% without chromatography. This method avoids hydrolysis of the bromo substituent but demands strict exclusion of moisture, because the ester is susceptible to saponification at pH > 10 even at 5 °C. Therefore, reactions performed at relative humidity above 60% must be conducted under a nitrogen blanket with pre‑dried glassware.
On multi-kilogram campaigns, the 4‑bromo derivative is often selected over the corresponding iodo analogue for three main reasons: cost, stability under ambient light, and a lower tendency to form homocoupling side products. The 4‑iodo ethyl ester, though roughly 4–5‑fold more reactive in oxidative addition with Pd(PPh₃)₄, undergoes measurable photolytic deiodination when exposed to standard fluorescent lighting over a 24 h shift, necessitating amber‑coated reactors and darkened transfer lines. The bromo compound remains unchanged after 72 h of bench‑top light exposure, provided the solid is stored in a closed LDPE liner. At −20 °C under argon, the shelf life of the bromo ester exceeds 12 months with no detectable degradation by HPLC, whereas the iodo analogue frequently develops a purple tint indicative of iodine release after 6 months even under these conditions.
In Buchwald‑Hartwig aminations with sterically demanding secondary amines, the bromo ester typically requires the Xantphos ligand and a Pd source such as Pd₂(dba)₃ at 100 °C in toluene to achieve full conversion in 20–24 h. The iodo ester completes the same transformation in 6–8 h, but the crude product profile contains 5–10% of the dehalogenated pyrrole, which is difficult to purge by recrystallization. The bromo ester gives a cleaner crude (de‑Br impurity <1%), which reduces the number of purification steps and overall solvent consumption. During the scale‑up of a 50 L C‑276 Hastelloy reactor batch, failure to maintain the nitrogen blanket during a Suzuki step resulted in a 15% yield loss attributed to pyrrole ring oxidation, a failure mode that was traced to a leaking sight‑glass gasket and corrected by switching to a PTFE‑encapsulated Viton seal. The bromide‑ion‑induced pitting corrosion observed in a previous 316L stainless steel reactor after extended exposure to the aqueous reaction phase motivated the permanent switch to Hastelloy construction for all post‑reaction hold‑up vessels.
The following table offers a qualitative comparison based on industrial experience and literature trends for analogous heteroaryl halides. Absolute kinetic values vary with the specific coupling partner and ligand set, but the relative rankings are preserved across multiple palladium-catalysed transformations.
| 4-Substituent | Relative Oxidative Addition Rate (Br = 1) | Typical Pd Loading (mol%) | Primary Side Reaction | Ambient Light Stability |
|---|---|---|---|---|
| Fluorine | <0.01 | Not applicable under standard conditions | No coupling; unreactive | Stable |
| Chlorine | 0.1–0.3 | 2–5 | Protodechlorination at high T | Stable |
| Bromine | 1 (reference) | 0.5–1.0 | Protodebromination above 85 °C; homocoupling <2% | Stable for 12 months at −20 °C |
| Iodine | 3–5 | 0.1–0.5 | Photolytic deiodination; homocoupling 5–10% | Discolouration after 6 months; must be stored in the dark |
For all halogenated congeners, the ethyl ester group is susceptible to base‑catalysed hydrolysis, with the rate increasing approximately 3‑fold for each 10 °C rise above 25 °C in the presence of 0.1 N NaOH. Consequently, any aqueous processing during work‑up should be conducted at <10 °C with ≤0.05 N bicarbonate solution. The 4‑chloro analogue, while the most economical, demands substantially higher catalyst loadings and often fails in couplings with sterically hindered boronic acids, whereas the 4‑iodo compound gives rapid conversions but introduces a costly purification burden. The 4‑bromo ethyl ester occupies a commercially advantageous midpoint: sufficient reactivity to keep catalyst loading and cycle time low, yet enough robustness to prevent the runaway light sensitivity and homocoupling that complicate kilo‑lab operations.
