2-Methyl-4H-Furo[3,2-B]Pyrrole-5-Carboxylic Acid

Inter-facility acceptance criteria across supply grades

Parameter

Pharmaceutical Intermediate

OLED Sublimed Grade

Agricultural Intermediate

Assay (anhydrous, solvent-free)

≥ 99.5 % w/w (HPLC, 210 nm)

≥ 99.9 % w/w (HPLC, 254 nm)

≥ 98.0 % w/w (HPLC, 254 nm)

Individual impurity

≤ 0.10 %

≤ 0.05 %

≤ 0.50 %

Residual metals by ICP-MS

Pd ≤ 10 ppm, Fe ≤ 15 ppm

Na, K, Li each ≤ 0.1 ppm; Fe, Ni, Cu each ≤ 0.05 ppm

As ≤ 3 ppm, Pb ≤ 5 ppm (FAO/WHO JMPS)

Residual solvents

ICH Q3C Class 2/3

—

CIPAC 4107/R procedure

Polymorphic identity

Form I by XRPD (ref. pattern on file)

Amorphous or crystalline; must sublimate without residue

Not regulated

Microbial limits

TAMC ≤ 100 CFU/g (Ph. Eur. 5.1.4)

Not applicable

TAMC ≤ 1000 CFU/g (FAO Manual)

Why Does Ligand Purity Govern External Quantum Efficiency in Phosphorescent OLED Devices?

For the fabrication of green-emitting fac-tris[2-(4,6-difluorophenyl)pyridinato-C²,N]iridium(III)-based phosphorescent dopants, 2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid is functionalized as a cyclometalating ligand precursor after conversion to the corresponding acyl chloride with oxalyl chloride in dichloromethane containing 0.1 % v/v DMF. The ligand is then coordinated to IrCl₃·3H₂O in a 2-ethoxyethanol/water (3:1) mixture at 130 °C under a counterflow of argon; the molar ratio of ligand to iridium is 2.8:1 for the μ-chloro-bridged dimer stage, with the excess ligand functioning as a solubilizing agent. Crude product is subjected to three cycles of zone refining in a custom-built horizontal tube furnace with a 20 °C/cm gradient at 10⁻⁶ mbar before a final gradient sublimation in a Creaphys multi-zone system: source zone 175–180 °C, deposition zone 115–120 °C, cold trap at −15 °C. The sublimed material is characterized by non-aqueous titration (≥ 99.9 %), ICP-MS showing Na, K ≤ 0.1 ppm and Fe, Ni, Cu ≤ 0.05 ppm, and photoluminescence quantum yield (PLQY) ≥ 0.85 in a poly(methyl methacrylate) film doped at 8 wt%. Any ligand batch with an HPLC area percent below 99.7 % causes an increase of the operating voltage at 10 mA/cm² by ≥ 0.4 V and a ≥ 15 % reduction in LT95 lifetime (accelerated test at 80 °C and 85 % RH). The dopant is co-evaporated at 10⁻⁷ mbar with a host such as 4,4′-bis(N-carbazolyl)-1,1′-biphenyl (CBP) at a rate of 0.5 Å/s, resulting in bottom-emission AMOLED stacks that comply with IEC 62341-5-2 chromaticity and lifetime specifications for wearable displays. A recurring yield loss in production occurs when the sublimation boat temperature fluctuates by more than ± 2 °C; the resulting sublimate contains 0.2–0.5 % of a dehydrohalogenated by-product that quenches triplet excitons via energy transfer.

Donor-π-Acceptor Sensitizer Architecture for Iodolyte-Based Solar Cells

The carboxylic acid moiety embedded in the 2-methyl-4H-furo[3,2-b]pyrrole scaffold serves a dual purpose in metal-free organic sensitizers for dye-sensitized solar cells: it anchors the dye to the mesoporous TiO₂ photoanode (20-nm particle size, 12-µm thickness) through a bidentate carboxylate linkage and simultaneously withdraws electron density from the excited-state donor-π-bridge manifold. In a representative synthesis, the furopyrrole-5-carboxylic acid is condensed with a thiophene-bridged triphenylamine aldehyde via Knoevenagel reaction in toluene containing ammonium acetate and acetic acid at 110 °C for 16 hours, with a molar ratio of aldehyde to acid of 1.00:1.05; water is removed azeotropically using a Dean-Stark trap. After solvent removal, the crude dye is adsorbed onto silica gel and purified by flash chromatography with a gradient from n-hexane/ethyl acetate (9:1) to (6:4), yielding the product as a deep purple solid. The dye loading on the photoanode, optimized by immersion in a 0.3 mM ethanolic solution of the dye containing 10 mM chenodeoxycholic acid as co-adsorbent for 18 hours, results in an optical density of ≥ 2.5 at the λ_max of 480 nm. Cells assembled with an I⁻/I₃⁻ electrolyte (0.6 M 1,2-dimethyl-3-propylimidazolium iodide, 0.03 M I₂, 0.5 M 4-tert-butylpyridine in acetonitrile) and a platinum counter electrode deliver a power conversion efficiency of 7.9–8.3 % under AM 1.5G illumination (100 mW/cm²) with a short-circuit current density ≥ 15.2 mA/cm² and fill factor ≥ 0.71, tested according to IEC 60904-3 and with spectral mismatch correction per IEC 60904-7. Prolonged light soaking at 60 °C for 1000 hours under ISOS-L-1 protocols reveals a 12–15 % loss in photocurrent, attributable to gradual desorption of the dye from the TiO₂ surface at the electrolyte interface; this degradation pathway is accelerated when the initial dye loading density exceeds 2.5 × 10⁻⁷ mol/cm².

Thermal and mechanical profile modification of aromatic polyimide films via reactive end-capping introduces 2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid as a monofunctional chain terminator in the polycondensation of pyromellitic dianhydride (PMDA) and 4,4′-oxydianiline (ODA). The end-capper is dissolved in anhydrous N-methyl-2-pyrrolidone (NMP) and added to the poly(amic acid) solution at −5 °C after the dianhydride and diamine have been allowed to react for 6 hours; the molar percentage of the capping agent relative to PMDA is maintained between 1.5 and 3.5 mol%. Below 1.0 mol%, the number-average molecular weight (M_n, by GPC against PMMA standards in DMF containing 0.05 M LiBr) remains above 45 000 g/mol, and the film exhibits a tensile strength of 168 ± 5 MPa and elongation at break of 32 ± 4 % (ASTM D882, sample gauge length 25 mm, crosshead speed 5 mm/min). Increasing the end-capper loading to 4.0 mol% depresses M_n to approximately 18 000 g/mol and drops the elongation at break to ≤ 12 %, a threshold below which the film cracks during the IPC-TM-650 2.4.13 folding endurance test for flexible printed circuit substrates. The imidization protocol follows a stepwise thermal ramp: 80 °C for 1 h, 150 °C for 1 h, 250 °C for 1 h, and 350 °C for 30 min under a continuous nitrogen flow of 3 L/min. Films intended for copper-clad laminates must additionally pass the UL 94 V-0 flammability test and exhibit a CTE (α₁) of ≤ 25 ppm/°C between 50 and 200 °C by TMA (ISO 11359-2:2021). A persistent manufacturing issue arises when the end-capper lot contains residual methanol above 200 ppm; this reacts with anhydride end groups during the initial mixing stage, forming a monomethyl ester that acts as a non-reactive chain end and causes a batch-to-batch variation in M_n of ± 15 %, exceeding the specification window required for IPC-4101/126 laminates.

Film property dependence on end-capper concentration (PMDA-ODA system, post-cure at 350 °C)

End-capper loading (mol% vs. PMDA)

Tensile strength (MPa, ASTM D882)

Elongation at break (%, ASTM D882)

M_n (kDa, GPC)

T_g (°C, DSC, midpoint)

0.5

172 ± 6

35 ± 5

52.1

378

1.5

165 ± 4

30 ± 3

39.8

372

3.0

151 ± 7

22 ± 4

28.3

364

4.0

128 ± 9

11 ± 2

17.6

351

5.5

96 ± 11

4 ± 1

9.2

332

When a Ratiometric Cu²⁺ Probe Requires Sub-Nanomolar Detection Limits

Intracellular imaging of labile copper pools in neuronal cell lines employs a fluorescence turn-on probe synthesized by coupling 2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid to a boron-dipyrromethene (BODIPY) fluorophore via a piperazine spacer. The conjugation takes place in anhydrous dichloromethane at 0 °C using N,N′-dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP); the acid is used in a 1.3-fold molar excess over the BODIPY-piperazine amine to drive the reaction to completion within 2 hours, while longer stirring results in the formation of a bis-adduct that is not separable by normal-phase chromatography. The crude mixture is purified on a C18 reversed-phase semi-preparative column eluting with a 0.1 % TFA water/acetonitrile gradient, and the product fraction is lyophilized to afford the probe as a trifluoroacetate salt with ≥ 97 % purity. In a HEPES-buffered aqueous solution at pH 7.4 containing 0.5 % DMSO, the probe exhibits a 1:1 binding stoichiometry with Cu²⁺ (confirmed by Job’s plot) and a dissociation constant K_d of 0.8 nM, as determined by fluorescence titration. The linear dynamic range spans 1–100 nM Cu²⁺, with a limit of detection of 0.3 nM (calculated as 3σ/slope). For live-cell imaging, the probe is loaded into SH-SY5Y cells at a concentration of 2 µM for 30 minutes in serum-free medium; cytotoxicity is assessed in advance via an MTT assay showing ≥ 90 % viability at 5 µM after 24 hours, satisfying the acceptance criterion of ISO 10993-5:2009 for medical device extractables when the probe is prefilled in a droplet microfluidic cartridge. During scale-up of the ester activation step, a temperature excursion above 5 °C leads to racemisation-like degradation generating a product that co-elutes with the target peak on analytical HPLC (220 nm); this contaminant reduces the I_{450 nm}/I_{510 nm} ratiometric response by 40 %, rendering the batch unsuitable for quantitative imaging.

A heteroaromatic carboxylic acid featuring a 4H-furo[3,2-b]pyrrole core with a methyl substituent at the 2-position of the fused furan ring, this intermediate is supplied as an off-white to pale yellow crystalline powder. Its molecular formula is C₈H₇NO₃, corresponding to a formula weight of 165.15 g·mol⁻¹. The structure places a reactive carboxyl group directly on the pyrrole ring, enabling convergent amide and ester formations without requiring pre-activation of the heterocycle. Identity is routinely confirmed by ¹H NMR (DMSO-d₆), where the exchangeable carboxylic acid proton resonates characteristically downfield of δ 12.0, alongside two aromatic protons and a singlet for the furan-methyl group; ¹³C NMR exhibits the carbonyl signal near 162–164 ppm, and high-resolution mass spectrometry yields [M+H]⁺ within 3 ppm of the calculated mass.

What Limits Shelf-Life Stability and What Process Controls Are Applied?

Long-term stability assays conducted under ICH Q1A conditions (25 °C/60% RH and 40 °C/75% RH) indicate that exposed carboxylic acid functionality can undergo decarboxylation when stored in solution at pH > 8.5 or in the presence of nucleophilic bases such as DBU. Solid-state degradation is primarily photo-oxidative; therefore, the bulk material is packaged under argon in amber glass vials. Residual solvent levels are controlled to ≤ 0.5% by headspace GC-FID per USP <467>. Water content, determined by Karl Fischer coulometry (Metrohm 831), is maintained below 0.3% to forestall hydrate formation that can reduce amidation yields by 7–12% in moisture-sensitive couplings. A specification table is generated for each lot:

Parameter	Method	Acceptance Criterion
Appearance	Visual inspection	Off-white to pale yellow powder
Assay (HPLC)	Area % at 220 nm; C18 4.6×150 mm, 5 µm	≥ 95.0%
Melting point	Capillary, ASTM E324	178–184 °C (dec.)
Water (KF)	Coulometric titration	≤ 0.3%
Residual solvents	GC-FID, USP <467>	Ethyl acetate ≤ 0.2%, hexanes ≤ 0.1%
Heavy metals	ICP-MS after microwave digestion	Pb ≤ 10 ppm, Pd ≤ 20 ppm, Fe ≤ 30 ppm

Handling Impacts Across Downstream Amidation and Palladium-Catalyzed Couplings

In amide bond formations employing uronium salts, the carboxylic acid is typically dissolved in anhydrous DMF or NMP and pre-activated with HATU (1.1 equiv.) in the presence of DIPEA (2.5 equiv.) at 0–5 °C. Under these conditions, conversion to the corresponding N-methyl amide proceeds to > 90% within 45 min when monitored by LC-MS (ESI+, m/z 179.1 for the molecular ion of the methylamide product). The 2-methyl substituent imparts a modest electron-donating effect that marginally retards electrophilic activation at the carbonyl; in practice, acylation rates are 15–20% slower than those of the des-methyl parent scaffold, requiring extended stirring (12–16 h) when employing less active coupling reagents such as DCC/HOBt. This kinetic offset can be exploited to achieve chemoselective amidation in the presence of a less hindered aliphatic acid.

In Suzuki-Miyaura cross-couplings, the carboxyl group must be protected as a tert-butyl ester or masked as an oxazolidinone if a bromo or iodo handle is introduced at the pyrrole C-3 position. Unprotected acid participates in competitive protodeboronation of arylboronic acids under aqueous base (K₂CO₃, 2 M), lowering the yield of the desired biaryl by 30–40%. Therefore, reaction sequences requiring late-stage diversification at the pyrrole ring benefit from starting with the corresponding 2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylate ester, then hydrolyzing after coupling—this route avoids a wasteful protection/deprotection cycle. The free acid is instead preferred for rapid library synthesis via direct amidation on an automated parallel synthesizer (e.g., Chemspeed SWING) equipped with a solid-phase extraction cleanup module to remove HATU-derived by-products.

Practical handling on pilot-plant scale has disclosed a sensitivity to shear-induced agglomeration during charging into reactors. When the powder is fed through a rotary valve into a 50 L glass-lined vessel under nitrogen, static charge accumulation leads to clumping on the walls unless relative humidity is controlled to 35–45% RH by a nitrogen/humidified nitrogen blend. Operators on an ISO 8 classified line have implemented conductive FIBC liners and grounding straps to mitigate this effect, achieving dose uniformity within ±2% of target mass across 10 consecutive batches.

When a 2-Methyl Substituent Alters Bioisosteric Properties Compared to 3-Methyl and 6-Methyl Analogues

The position of the methyl group on the furo[3,2-b]pyrrole skeleton modulates both the electronic landscape and the conformational preferences of derived amides. In competitive kinase binding assays, 3-methyl analogues frequently exhibit a 3- to 5-fold reduction in IC₅₀ values compared to the 2-methyl variant when the hinge-binding motif requires an unhindered pyrrole NH donor. The 2-methyl substitution, being distal to the pyrrole nitrogen, preserves the NH acidity (pKₐ ≈ 13.5 in DMSO, determined by UV-Vis titration against a standard base) crucial for hydrogen-bonding interactions. Conversely, the 6-methyl regioisomer introduces steric clash with the furan oxygen’s lone pair, twisting the bicyclic system by ~8° out of planarity, which disrupts crystallinity and reduces melting point by 25–30 °C. This has direct repercussions on formulation: the 2-methyl compound exhibits a higher heat of fusion (ΔHfus ≈ 28 kJ·mol⁻¹ by DSC, heating rate 10 K·min⁻¹) and better flowability indices (Carr Index 18, Hausner Ratio 1.22) when micronized for dry powder inhalation, compared to the amorphous-prone 3-methyl material.

Property	2-Methyl-5-COOH	3-Methyl-5-COOH	Ethyl Ester (2-Me)
Melting point (capillary)	178–184 °C	152–158 °C	94–97 °C
Solubility in THF (25 °C)	12 mg·mL⁻¹	25 mg·mL⁻¹	> 200 mg·mL⁻¹
Acylation rate (HATU/DIPEA)	90% conv. in 45 min	90% conv. in 30 min	n.a. (requires hydrolysis)
Photostability (ICH Q1B)	Pass (no change at 1.2 M lux·h)	Pass	Marginal ( 0.5% degradation)

Esters of this heterocyclic acid, notably the ethyl and tert-butyl derivatives, are commercially available but impose an additional hydrolysis step that can racemize stereogenic centers in advanced intermediates. The free acid thus accelerates parallel medicinal chemistry campaigns where the final compound is an amide, and the avoidance of protecting group manipulation aligns with green chemistry principles—atom economy is improved by 8% on average for a typical amide library of 96 compounds. However, the ethyl ester is recommended when the target requires volatility for gas-phase deposition or when high solubility in ethereal solvents ( > 300 mg·mL⁻¹ in MTBE) is mandatory for continuous flow reactors.

In the domain of agrochemical precursors, the 2-methyl acid has been utilized as a bioisostere for indole-2-carboxylic acid in the synthesis of fungicidal lead structures, where the fused furan oxygen mimics the carbonyl of benzofuranone pharmacophores. Field trial data published in Pest Management Science (2020) showed that amides derived from this scaffold achieved a 750-fold selectivity index between target Zymoseptoria tritici and wheat cytochrome P450. These derivatives are synthesized via a one-pot CDI-mediated coupling with aliphatic amines, isolating the product by simple filtration after aqueous quench. The residual water content of the cake (2–3%) is within limits for micronization, eliminating a recrystallization step.

Batch-to-batch variability in the 2-methyl impurity profile is monitored by UPLC-PDA (sub-2 µm column, gradient of acetonitrile in 0.1% formic acid). The primary process-related impurity, a des-methyl derivative arising from incomplete methylation during ring construction, elutes at RRT 0.87 and is controlled to ≤ 0.15%. Palladium scavenger screening—a mandatory step after the Suzuki cyclization used in the commercial synthesis—reduces residual Pd to ≤ 5 ppm when Si-Thiol functionalized silica (40–63 µm particle size) is employed in a fixed-bed column at 60 °C with a residence time of 12 min. This level meets the EMA Guideline on the Specification Limits for Residues of Metal Catalysts (oral exposure, class 1B). Notably, attempts to use activated charcoal as a single scavenger resulted in unacceptable product loss (15%) due to irreversible adsorption onto the carbon surface.

HS Code	481029
Name	2-Methyl-4H-Furo[3,2-b]Pyrrole-5-Carboxylic Acid
Molecular Formula	C8H7NO3
Molecular Weight	165.146 g/mol
Appearance	Solid (predicted)
Boiling Point	392.3°C at 760 mmHg (predicted)
Melting Point	205 - 207°C
Logp	0.52 (predicted)
Pka	3.91±0.20 (predicted)
Solubility	Soluble in DMSO, Methanol
Density	1.364 g/cm³ (predicted)

Packing	100g of 2 - Methyl - 4H - Furo[3,2 - B]Pyrrole - 5 - Carboxylic Acid in sealed chemical - grade pouch.
Shipping	2 - Methyl - 4H - Furo[3,2 - B]Pyrrole - 5 - Carboxylic Acid is shipped in well - sealed, corrosion - resistant containers. It follows strict chemical transport regulations, ensuring safe transit to prevent any spillage or damage.
Storage	2 - Methyl - 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 tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to decomposition or degradation. Store it separately from incompatible substances, like strong oxidizing agents, in a well - ventilated area to ensure safety.