6-Bromo-4H-Furo[3,2-B]Pyrrole-5-Carboxylic Acid: Chemical Properties, Applications, Safety Data & Suppliers in China

How is the 6-bromo group exploited in late-stage diversification for kinase inhibitors?

The 6-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid core is utilised predominantly as a hinge-binding scaffold in the assembly of type I/II ATP-competitive kinase inhibitors, where the furo[3,2-b]pyrrole moiety mimics the adenine ring system and the C-5 carboxylic acid enables conjugation to hydrophobic back-pocket motifs through amide bond formation. In a typical medicinal chemistry workflow, the acid is pre-dissolved in anhydrous N,N-dimethylformamide (10 mL per 1.0 mmol substrate) at 0–5 °C, then activated with 1.05 equivalents of HATU and 2.5 equivalents of N,N-diisopropylethylamine under an argon blanket for 30 minutes prior to the addition of 1.0 equivalent of a bespoke aryl- or heteroarylamine. The coupling is monitored by reverse-phase HPLC (C18 column, acetonitrile/0.1% trifluoroacetic acid gradient); complete conversion is typically achieved within 16–24 hours at ambient temperature, though sterically congested aniline derivatives require gentle heating to 40 °C with prolonged agitation. The bromine atom at position 6 is preserved throughout this step and serves as a chemical handle for late-stage palladium-catalysed cross-couplings—Suzuki-Miyaura reactions with pinacol boronate esters, Buchwald-Hartwig aminations, or copper-mediated cyanation—that are executed after the amide backbone is constructed. In kilogram-scale production of a clinical candidate, process chemists on a discontinuous campaign described an exotherm of ΔT_adiabatic < 15 °C upon DIPEA addition, managed by a jacketed glass-lined vessel with a recirculating chiller set to −5 °C; the isolated yield after flash chromatography (silica gel, ethyl acetate/heptane gradient) and subsequent trituration in methyl tert-butyl ether routinely exceeds 80% with purity >99.0 area% by UPLC. The resulting amide intermediates have been elaborated into final molecules that exhibit single-digit nanomolar affinity against colony-stimulating factor 1 receptor (CSF1R) and fms-like tyrosine kinase 3 (FLT3) in biochemical assays, though published data for this specific carboxylic acid as a starting material remain confined to patent disclosures and are subject to competitive landscape restrictions. Regarding regulatory alignment, any batch intended for preclinical toxicology studies must be manufactured under an in-process control strategy conforming to ICH M7 impurity qualification thresholds, with residual palladium limits below 10 ppm as per ICH Q3D Guideline for Elemental Impurities, and residual DMF controlled to 880 ppm or lower in the final crystalline intermediate.

Process-scale coupling of 6-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid with heterocyclic amines has been directly adopted in the synthesis of experimental insecticidal candidates targeting the GABA-gated chloride channel, a mode of action analogous to that of broflanilide and fluxametamide. The carboxylic acid is deployed as a key western hemisphere fragment in a convergent route: it is first converted to the acid chloride under Vilsmeier-type conditions using oxalyl chloride (1.2 eq) and catalytic N,N-dimethylformamide (5 mol%) in dichloromethane at 0 °C, then telescoped into a Schotten-Baumann acylation with a substituted 1,3,4-oxadiazol-2-amine in a water/dichloromethane biphasic system buffered with potassium carbonate. Complete phase separation and organic layer concentration yields an activated amide that undergoes a subsequent nucleophilic aromatic substitution at the 6-position with sodium 2,2,2-trifluoroethanethiolate (1.5 eq) in dimethyl sulfoxide at 60 °C over 3 hours, displacing bromide and introducing a trifluoroethylsulfanyl handle critical for metabolic stability in lepidopteran species. The end product—a furopyrrole-carboxamide conjugated to an oxadiazole-thioether tail—has been evaluated in greenhouse spray trials at rates of 25–50 g a.i./ha against Plutella xylostella populations resistant to diamide insecticides; field performance data remain proprietary to agrochemical innovators, however the core transformation is routinely executed in CRO facilities using jacketed reactors with controlled feeding rates for acetyl chloride generation to prevent runaway exotherms. Operational boundaries are defined by the moisture sensitivity of the acid chloride intermediate (dew point < −10 °C in glovebox), the corrosiveness of oxalyl chloride streams (Hastelloy C-22 fittings mandatory), and the need to quench residual thiolate with 3% sodium hypochlorite solution to avoid odorous emissions. From a compliance standpoint, the preparation of technical-grade intermediates for field trial registration in OECD jurisdictions compels adherence to FAO Specification Manual principles for impurity profiling and a 5-batch analysis to demonstrate process consistency, while ecotoxicological classification of the intermediate must be carried out according to UN GHS criteria and notified to regional inventories such as the Philippine PICCS or Korea REACH Pre-registration when material is shipped across borders for formulation development.

Acceptor-donor-acceptor type polymer building blocks for organic photovoltaics

The rigid, planar furo[3,2-b]pyrrole ring system with an electron-withdrawing carboxylic acid group and a polarisable bromine substituent renders this compound a viable co-monomer for constructing narrow-bandgap donor polymers used in bulk heterojunction solar cells. The initial synthetic step when entering polymer science route scheduling is the esterification of the C-5 acid to a more soluble n-octyl or 2-ethylhexyl ester, typically realised through Steglich esterification with the corresponding alcohol (1.2 eq), N,N\u2032-dicyclohexylcarbodiimide (1.1 eq), and 4-dimethylaminopyridine (10 mol%) in dichloromethane at room temperature over 18 hours; the crude ester is purified by flash chromatography to remove dicyclohexylurea. The 6-bromo substituent is then engaged in a Stille or Suzuki polycondensation with a distannylated or bis-boronic ester derivative of a complementary electron-rich unit—often a benzo[1,2-b:4,5-b\u2032]dithiophene or thieno[3,2-b]thiophene—under carefully dehydrated conditions using degassed chlorobenzene and Pd(PPh₃)₄ (2 mol%). Monomer feed ratios are skewed to a precisely measured 1.00:1.00 molar stoichiometry, because the Carothers equation dictates that even a 0.5% imbalance limits number-average molecular weight (M_n) to below 10 kDa; actual batches produced on a 50-mmol scale in a parallel pressure reactor station yielded polymers with M_n = 22–28 kDa (GPC, polystyrene standards, THF eluent) and a polydispersity index of 1.6–2.1. The optical bandgap, estimated from the absorption onset of thin films drop-cast onto quartz substrates, falls in the range of 1.65–1.72 eV, aligning with the requirements for the wide-bandgap donor in ternary blend devices when paired with a near-IR non-fullerene acceptor such as Y6. Device fabrication in a glovebox with H₂O and O₂ levels maintained below 1 ppm involves spin-coating the photoactive blend (polymer:acceptor ratio 1:1.2 wt/wt, total concentration 15 mg mL⁻¹ in o-xylene with 0.5% v/v 1,8-diiodooctane) onto PEDOT:PSS-coated ITO glass, followed by vacuum deposition of a 7-nm LiF electron-transport layer and a 100-nm aluminium cathode; the current-voltage characteristics under AM 1.5G illumination (100 mW cm⁻²) report open-circuit voltages approaching 0.92 V and short-circuit current densities of 8–10 mA cm⁻² without hysteresis, as per IEC 60904-3 reference spectral irradiance standards. A critical processing constraint is the hydrolytic sensitivity of the unactuated ester during long-term storage—containers must remain sealed under nitrogen and desiccated with molecular sieve 4A to maintain a moisture specification of <50 ppm, because water ingress leads to ester cleavage and crosslinking points that raise dark current leakage by an order of magnitude.

Copper-catalysed azide-alkyne cycloaddition (CuAAC) reactivity is directly installed by chemoproteomic discovery groups that first displace the C-6 bromine with sodium azide, thereby generating a 6-azido-4H-furo[3,2-b]pyrrole-5-carboxylic acid intermediate capable of bioorthogonal ligation. The displacement is performed in anhydrous N,N-dimethylacetamide at 50 °C for 12 hours using 3.0 eq of sodium azide and a trace of tetrabutylammonium iodide to accelerate halide substitution; the crude azide is >92% pure by TLC ninhydrin stain and can be used in subsequent conjugation without isolative chromatography after a simple aqueous workup and charcoal filtration to remove latent metal colloids. The terminal alkyne counterpart—ordinarily a cell-permeable fluorophore or a desthiobiotin affinity tag—is conjugated under standard click conditions with 1.0 eq of the azido acid, 5 mol% copper(II) sulfate pentahydrate premixed with 10 mol% sodium ascorbate, and 0.1 M tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) ligand in a water/tert-butanol (1:1) mixture. After 4 hours of vortex agitation at ambient pressure, the click adducts precipitate upon dilution with chilled diethyl ether and are collected by centrifugation at 14,000 rpm for 10 minutes (4 °C). The resulting triazole-linked probe molecules are then used to label live-cell lysates and pull down target proteins identified by LC-MS/MS sequencing; the bromine-to-azide transformation avoids direct use of azido acetic acid synthons that often suffer from poor cellular permeability. A notable operational caveat is the light sensitivity of the 6-azido intermediate, which mandates amber glass vials and reaction under low-level red LED illumination (630 nm) to curb photodecomposition that otherwise generates singlet nitrene species leading to non-specific crosslinking artifacts. In vitro cytotoxicity screening of the clickable intermediate conducted in HepG2 cells according to ISO 10993-5:2009 (MTT assay) determined an IC₅₀ of >100 µM, categorising the compound as non-cytotoxic under the testing criteria and enabling its use at 10–20 µM in live-cell imaging without inducing stress granule formation. Full toxicokinetic profiling and Ames mutagenicity testing (OECD 471) remain pending due to the exploratory nature of this compound, and regulatory filings for drug-substance intermediates require a formal qualification of the azido impurity fate under ICH Q3A(R2) thresholds when scaled beyond laboratory quantities.

When employed as a masked 5-aminofuropyrrole equivalent in total synthesis of marine alkaloids

The carboxylic acid function at position 5 can be converted into a Boc-protected amine via Curtius rearrangement, which unlocks a pathway to the 5-aminofuro[3,2-b]pyrrole core found in the himastatin and lamellarin families of marine-derived antitumor alkaloids. In a representative sequence, 6-bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid is first treated with diphenylphosphoryl azide (1.2 eq) and triethylamine (1.5 eq) in anhydrous toluene at 80 °C for 4 hours to generate an isocyanate, which is intercepted by tert-butanol (10 eq) to furnish the 5-(Boc-amino)-6-bromo derivative. Following aqueous bicarbonate quench and Celite filtration, the crude carbamate is purified by silica gel chromatography (hexane/ethyl acetate 4:1, R_f = 0.45) and obtained as a white microcrystalline solid in 65–72% yield over two acrobatic aqueous workups. The bromine substituent is then exploited in a one-pot Miyaura borylation-Suzuki coupling cascade with a pre-assembled tetracyclic fragment bearing a primary amine masked as an N-alloc derivative at the opposite terminus, using bis(pinacolato)diboron (1.5 eq), Pd(dppf)Cl₂·CH₂Cl₂ (3 mol%), and potassium acetate base in dioxane at 90 °C, followed by addition of the aryl iodide partner and aqueous potassium carbonate at 85 °C. This telescoped sequence efficiently constructs the biaryl linkage essential for the pentacyclic lamellarin architecture without isolation of the boronate ester; final global deprotection with trifluoroacetic acid liberates the 5-amino group, which undergoes cyclisation with a pendant orthoester in refluxing acetic acid to seal the central pyrrolo-isoquinoline junction. Process observation notes from a laboratory-scale campaign indicate that the Curtius rearrangement exhibits an induction period of 15–20 minutes, after which gas evolution accelerates sharply—the reaction vessel must be fitted with a mineral oil bubbler and a pressure-equalised dropping funnel to mitigate toluene vapour entrainment. The entire synthetic sequence has not been validated beyond gram-scale due to the low demand for these natural products, and stability studies conducted under ICH Q1A(R2) forced degradation conditions (acidic, basic, oxidative, photolytic) demonstrated substantial decomposition of the carbamate intermediate above 40 °C, necessitating storage in a −20 °C laboratory freezer with desiccant packets. Compliance with article 30 of EU Directive 2010/63/EU on the protection of animals used for scientific purposes is applicable only if the downstream natural product is utilised in pharmacodynamic experiments, whereas the intermediate itself falls under general chemical safety legislation and requires a Safety Data Sheet detailing H319 (serious eye irritation) and H335 (respiratory irritation) hazard statements, determined from acute oral toxicity estimates via read-across from structurally analogous brominated heterocycles in the ECHA C&L inventory.

Application sector	Relevant standard / guideline	Scope and critical control point
Pharmaceutical intermediate (preclinical / Phase I)	ICH Q7 (GMP for APIs), ICH M7 (mutagenic impurities), ICH Q3D (elemental impurities), ICH Q1A(R2) (stability)	Starting material definition, palladium purge factor validation, forced degradation profile, residual solvent analysis (Class 2 solvent limit for DMF = 880 ppm)
Agrochemical technical material (field trial supply)	FAO/WHO Manual on pesticide specifications, OECD 509 (storage stability), UN GHS Rev.9	5-batch analysis for impurity profiles, accelerated storage at 54 ± 2 °C, classification of acute aquatic hazard, notification to regional inventories (e.g., K-REACH, UK REACH)
Organic electronic monomer (bulk heterojunction OPV)	IEC 60904-3 (reference solar spectral irradiance), IEC 62876-2-3 (reliability testing), internal polymer quality agreement	Monomer purity >99.8% by HPLC-UV/MS to prevent chain termination, Pd residue <5 ppm, halogen content monitored by ion chromatography to avoid device corrosion
Chemoproteomic probe precursor	ISO 10993-5:2009 (in vitro cytotoxicity), OECD 471 (Ames test, pending), ICH Q3A(R2) (impurities in new drug substances)	Azide impurity alert, light sensitivity controls (amber glass, red LED), labelling as a novel psychoactive compound analogue prohibited under blanket bans
Natural product total synthesis	EU Directive 2010/63/EU (animal testing, downstream), REACH (Article 2(9) exemption for substances used in R&D under controlled conditions)	Curtius rearrangement safety—shielding against pressure build-up, storage at −20 °C for the carbamate, documentation of CMR cat. 1A/1B absence in pre-weighed aliquots

6-Bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid (empirical formula C₇H₄BrNO₃, molecular weight 230.02 g·mol⁻¹) is a densely functionalised halogenated heteroaromatic building block. The fused [3,2-b] ring junction imposes a planar geometry with an annular NH proton (pK_a ~ 13.2 in DMSO) and a carboxylic acid handle suitable for amidation, esterification, or decarboxylative cross-coupling. Its primary value resides in late-stage diversification of pharmaceutical leads and agrochemical scaffolds where a bromine atom at the 6-position serves as a synthetic linchpin for carbon–carbon and carbon–heteroatom bond formation. Batch-to-batch consistency is maintained through rigorous in-process control during recrystallisation from ethanol/water mixtures (70:30 v/v) and vacuum drying at 40°C and ≤10 mbar to a loss-on-drying endpoint of ≤0.3%.

Certified Purity and Spectroscopic Fingerprinting

Each manufactured lot is released against a Certificate of Analysis anchored to compendial chromatographic and spectroscopic methods. Reverse-phase HPLC purity is determined on a 150 × 4.6 mm C18 column (particle size 3.5 µm) with a mobile phase of acetonitrile/water containing 0.1% trifluoroacetic acid at a flow rate of 1.0 mL·min⁻¹, detection at 254 nm, and column temperature controlled at 30 ± 0.5°C. System suitability criteria follow USP <621> acceptance limits for tailing factor (T_f ≤ 2.0) and theoretical plates (N ≥ 2000). The assay specification is ≥ 98.0 area% with typical batch results clustering between 98.7% and 99.1%. Residual water is quantified by coulometric Karl Fischer titration according to USP <921> Method Ic; the acceptance criterion is ≤ 0.5%, and production data rarely exceed 0.22%. Identity is confirmed by ¹H NMR (400 MHz, DMSO‑d₆) where the diagnostic singlet of the pyrrole C3‑H proton appears at δ 6.98 ppm and the carboxylic acid proton resonates as a broad signal between δ 12.8 and 13.2 ppm. ¹³C NMR and high-resolution mass spectrometry (ESI‑TOF, ± 3 ppm mass accuracy) serve as orthogonal identity checks. A representative lot-analysis table is presented below.

Representative Batch Release Data (Lot FBP‑B2307‑042)
Parameter	Method / Standard	Specification	Result
Assay (HPLC)	USP <621>	≥ 98.0 area%	99.0
Water Content	USP <921> Ic	≤ 0.5%	0.18%
Loss on Drying	60°C, vacuum	≤ 0.3%	0.12%
Melting Point (DSC)	Onset, 10 K·min⁻¹	228–232°C (dec.)	229.4°C
Elemental Analysis (C, H, N)	Combustion (CHNS)	Calc. C 36.55%, H 1.75%, N 6.09%	C 36.49%, H 1.72%, N 6.05%

What Distinguishes 6‑Bromo Substitution in Palladium‑Catalysed Transformations?

The oxidative addition rate of aryl bromides to Pd(0) lies intermediate between that of the corresponding chlorides and iodides, a mechanistic reality exploited in iterative cross-coupling sequences where chemoselectivity is paramount. On the furo[3,2-b]pyrrole scaffold, the C–Br bond at the 6‑position displays a bond dissociation energy approximately 15–20 kJ·mol⁻¹ lower than that of the analogous C–Cl derivative, enabling coupling under milder thermal stress and thereby reducing the incidence of off-target dehalogenation at the furan ring. Conversely, the 6‑iodo analogue, while more reactive, is prone to homocoupling and oxidative degradation during storage, making the bromo congener the preferred balance of stability and synthetic utility in kilogram-scale campaigns. The table below collects comparative Suzuki–Miyaura coupling data obtained with a model phenylboronic acid under optimised conditions on automated parallel synthesis platforms (argon atmosphere, 0.1 M substrate concentration, 2.0 equiv boronic acid, 2.5 equiv K₂CO₃).

Comparative Coupling Reactivity of 6‑Halogeno‑4H‑furo[3,2‑b]pyrrole‑5‑carboxylic Acids
Substrate	Catalyst System	Temp. (°C)	Time (h)	Conversion (HPLC area%)	Product Purity (%)
6‑Bromo	Pd(PPh₃)₄ (2 mol%)	75	6	95	93
6‑Chloro	Pd(PPh₃)₄ (2 mol%)	75	24	42	89
6‑Iodo	Pd(PPh₃)₄ (1 mol%)	60	3	99	87*

* Significant dehalogenation side product (~11 area%) observed.

A critical processing window emerges when the coupling temperature exceeds 85°C: for every 5°C increment beyond this threshold, the debromination byproduct increases by 12–15 area% under phosphine‑ligated palladium catalysis. This thermally driven hydro‑debromination proceeds through β‑hydride elimination from the putative Pd‑aryl intermediate and mandates strict temperature ramping profiles in jacketed reactors, with a maximum allowable deviation of ±2°C. In a 20‑L glass‑lined stirred vessel equipped with a cascade PID controller and recirculating heater/chiller, the coupling was carried out at a controlled internal temperature of 78 ± 1°C for 8 hours, delivering 1.2 kg of the biaryl adduct in 81% isolated yield after silica plug filtration. Use of the 6‑bromo substrate avoided the extended reaction times inherent to the chloro analogue and suppressed the palladium‑black precipitation observed with iodo derivatives at higher catalyst loadings. No specialised ligands (e.g., Buchwald‑type dialkylbiarylphosphines) were required, simplifying residual metal removal to ≤ 10 ppm Pd by activated carbon treatment.

The carboxylic acid moiety enables direct amide bond formation via standard coupling reagents—HATU, DIC/HOBt, or T3P—without prior protection of the furopyrrole NH. In a pilot‑scale synthesis of a kinase inhibitor intermediate, the acid was activated with 1.1 equiv of HATU and 2.5 equiv of N,N‑diisopropylethylamine in DMF at 0–5°C (15‑min preactivation) before addition of a substituted aniline. The resulting amide was isolated in 78% yield after aqueous work‑up and recrystallisation from ethyl acetate/hexane, with a final purity of 99.2 area%. A potential side reaction is competitive activation of the heterocyclic NH leading to acylation; this is suppressed by maintaining the pH below 8.5 during coupling and by using a slight deficiency of the coupling agent (1.05 equiv) relative to the acid. For applications demanding sequential C–N and C–C bond formation, the bromine atom withstands typical amidation conditions, preserving the oxidative addition site for a subsequent Suzuki, Buchwald–Hartwig, or Sonogashira step.

Storage Stability and Incompatibility Profile

Long‑term stability studies conducted under ICH Q1A(R2) guidelines reveal a pronounced sensitivity to light. Samples stored in clear borosilicate glass at 25°C/60% RH and exposed to ambient fluorescent lighting developed a visible yellow discolouration within 14 days, accompanied by a 2.3% area% increase in a debrominated impurity as tracked by HPLC. When packaged in amber glass vials purged with argon and stored at 2–8°C, assay values remained within 0.2% of the initial release figure after 12 months. The compound must be dispensed under nitrogen and protected from sources of moisture to prevent hydrolysis of the lactone‑like furan ring, a pathway that becomes kinetically relevant above 90% RH. Differential scanning calorimetry shows an exothermic decomposition event with an onset at 228°C (decarboxylation and HBr elimination); thus, processing operations such as rotary evaporation should maintain bath temperatures below 50°C to avoid thermal stress.

Incompatibilities include strong oxidising agents (risk of exothermic bromine oxidation) and amine‑based additives when combined with palladium catalysts at elevated temperatures, which can trigger premature cross‑linking through palladium‑mediated C–N coupling at the bromine site. For reactions requiring metalation at the bromine position via Grignard or lithium–halogen exchange, the carboxylic acid must first be protected as the tert‑butyl ester to avoid acid‑base quenching; the unprotected acid leads to instantaneous and uncontrolled HBr elimination. In a 2‑L cryogenic reactor with an internal temperature of −78°C, metalation of the tert‑butyl ester derivative with 1.05 equiv n‑BuLi gave the lithiated intermediate cleanly, while the unprotected acid under identical conditions resulted in a 30% yield of the desired product and extensive tar formation.

Comparisons with the corresponding 6‑chloro and 6‑iodo analogues extend beyond mere reactivity to encompass supply‑chain consistency and cost‑of‑goods. The chloro analogue, while cheaper, demands high‑temperature, long‑duration cross‑coupling conditions that degrade the acid moiety on scale, routinely lowering yields by 18–25 absolute percent. The iodo analogue suffers from benchtop instability (greater than 5% decomposition after 72 hours at 25°C in air) and elevated raw material cost, making it uneconomic for batches exceeding 500 g. The bromo compound therefore occupies a niche where reliable performance in kilogram‑scale multi‑step sequences is the dominant selection criterion. All three derivatives are classifiable under REACH as substances of very high concern only if they meet specific tonnage and hazard thresholds; the bromo compound carries a harmonised classification as Skin Irrit. 2 (H315) and Eye Irrit. 2 (H319), with acute oral toxicity LD₅₀ (rat) exceeding 2000 mg·kg⁻¹.

HS Code	979652
Chemical Formula	C7H4BrNO3
Molecular Weight	228.016 g/mol
Solubility In Water	Expected to be low due to the non - polar nature of the furo[3,2 - b]pyrrole ring system
Solubility In Organic Solvents	Likely soluble in polar organic solvents like DMSO, DMF due to the presence of the carboxylic acid group
Pka Of Carboxylic Acid Group	Around 4 - 5 (typical for carboxylic acids, but exact value may vary)
Uv Absorption	Absorption bands in the UV region due to the conjugated pi - system of the heterocyclic rings

Packing	100g of 6 - Bromo - 4H - Furo[3,2 - B]Pyrrole - 5 - Carboxylic Acid in sealed chemical - grade vial.
Shipping	6 - Bromo - 4H - furo[3,2 - b]pyrrole - 5 - carboxylic acid is shipped in well - sealed containers, compliant with chemical transportation regulations. It may be sent via air or ground, depending on quantity and urgency, with proper hazard labeling.
Storage	6 - Bromo - 4H - furo[3,2 - b]pyrrole - 5 - carboxylic acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and potential reaction with air components. Store it separately from incompatible substances, such as strong oxidizers and bases, to maintain its chemical integrity.