5-Formyl-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic
|
HS Code |
575501 |
| Name | 5-Formyl-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic |
| Molecular Formula | C8H9NO3 |
| Molecular Weight | 167.162 g/mol |
| Appearance | Solid (predicted) |
| Boiling Point | 414.4°C at 760 mmHg (predicted) |
| Melting Point | 192 - 194 °C |
| Density | 1.306 g/cm³ (predicted) |
| Logp | 0.74 (predicted) |
| Pka | 3.25±0.20 (Predicted) |
| Solubility | Soluble in organic solvents like DMSO, DMF (predicted) |
As an accredited 5-Formyl-2,4-Dimethyl-1H-Pyrrole-3-Carboxylic factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 5 - Formyl - 2,4 - Dimethyl - 1H - Pyrrole - 3 - Carboxylic in sealed chemical - grade pouch. |
| Shipping | 5 - Formyl - 2,4 - Dimethyl - 1H - Pyrrole - 3 - Carboxylic acid is shipped in well - sealed, corrosion - resistant containers. Special care is taken to avoid exposure to heat, moisture, and incompatible substances during transit. |
| Storage | Store “5 - Formyl - 2,4 - Dimethyl - 1H - Pyrrole - 3 - Carboxylic” in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container to prevent moisture absorption and degradation. Avoid storing near oxidizing agents. Proper storage in a well - ventilated area helps maintain its chemical integrity. |
When 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is charged into a glass-lined reactor with a jacket temperature held at 268 K to suppress exothermic imine formation, the dissolved substrate in anhydrous tetrahydrofuran (20% w/w solution) is treated dropwise with a primary aromatic amine at a molar ratio of 1:1.05 over 90 min. The resulting Schiff base crystallizes directly upon cooling to 278 K and is recovered by centrifuge at 2000 rpm. This intermediate, dried to ≤ 0.3 % moisture under vacuum at 313 K, serves as the cyclization precursor for a class of pyrrolo[3,4-b]pyrazine-5,7-dione derivatives evaluated as PARP-1 catalytic domain inhibitors. Contract manufacturing campaigns routinely anchor the hydrazinolysis step to pH 4.8–5.2 using sodium acetate buffer, achieving a crude purity of 92–94 area% by HPLC (UV 254 nm) before recrystallization from ethanol/water (7:3 v/v). The active pharmaceutical intermediate is subsequently milled under nitrogen in a cone mill with a 0.5 mm round-hole screen to meet the particle-size specification D90 < 45 µm required for solid-dosage blending.What Critical Quality Attributes Govern a 1,4-Dihydropyrrolo[3,2-b]indole Cyclization Starting from This Aldehyde?The Fischer indole annulation using 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid as the electrophilic partner imposes a narrow moisture tolerance: residual water in the acetic acid solvent must be titrated below 0.15 % (Karl Fischer) to prevent premature aldehyde hydration that diverts the ring-closure pathway to an intractable tar. On a 500 L Hastelloy C-22 vessel, 1.0 eq of the pyrrole acid is dissolved in glacial acetic acid at 328 K, and 1.2 eq of phenylhydrazine hydrochloride is added in four equal portions at 15-minute intervals while maintaining vigorous agitation with a pitched-blade turbine operating at 120 rpm. The reaction mass is held at 338–343 K for 16 h; any upward deviation beyond 348 K triggers decarboxylation of the product framework observed as a 7–10% yield loss in pilot-plant records. After cooling to 293 K, the crude cake isolated by Nutsche filtration is washed with chilled isopropanol and reslurried in 0.1 N aqueous HCl to remove the hydrochloride salt. The final 1,4-dihydropyrrolo[3,2-b]indole-2-carboxylic acid is tray-dried at 323 K for 24 h and analyzed by qNMR (99.3% purity benchmark for clinical supply). The compound is a key scaffold in serotonin receptor ligand programs, and its production is controlled under ICH Q7 for active pharmaceutical ingredients, with genotoxic impurity monitoring following EMA guideline EMA/CHMP/QWP/251344/2006 for the residual hydrazine (≤ 1 ppm).
Pyrazolo[1,5-a]pyrrole-2-Carboxylate Pharmacophores via Electrophilic Annulation of the Formyl MoietyThe condensation with cyanoacetohydrazide proceeds in ethoxyethanol at 398 K under a nitrogen sweep that removes water azeotropically, delivering a pyrazolo[1,5-a]pyrrole core after a [3+2] cyclocondensation. The 5-formyl group is first converted to its bisulfite adduct by treatment with sodium metabisulfite (1.5 eq) in water at pH 3.0 to protect against oxidation before hydrazide addition. Once the hydrazone forms at 353 K, the pH is raised to 9.5 with 2N sodium carbonate to liberate the aldehyde and trigger intramolecular ring closure over 8 h. The product, 2-cyano-5,7-dimethylpyrazolo[1,5-a]pyrrole-3-carboxylic acid, shows a characteristic carbonyl stretch at 1685 cm⁻¹ (IR, KBr) and is isolated at 82% yield after flash chromatography with ethyl acetate/hexane (3:2). This scaffold is reported as a bioisostere for indole-3-acetic acid derivatives and has been elaborated into TRPV1 antagonists; compendial quality is confirmed by 99.5% titration against standard NaOMe and residual solvent analysis per USP <467> with limits for DMF (≤ 880 ppm) and ethoxyethanol (≤ 160 ppm).The carboxylic acid group introduces an additional handle for amide coupling. When the active ester is generated with N,N′-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in dichloromethane at 273 K, coupling with chiral amines achieves diastereomeric excess > 99.5% after crystallization. This downstream chemistry is executed in multipurpose 1000 L glass-enamel reactors with radial-flow impellers to manage the viscous slurry formed during DCU precipitation; a filtration pressure differential of 1.5–2.0 bar across a 5 µm PTFE membrane ensures throughput of 80 L·m⁻²·h⁻¹.Diketopyrrolopyrrole Pigment Synthesis via a Succinate Ester Route: A Vehicle for High-Chroma Automotive Coatings5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid enters pigment chemistry as a precursor for asymmetric diketopyrrolopyrrole (DPP) chromophores when first esterified with methanol and sulfuric acid catalyst to yield the methyl ester (mp 152–154 °C). The ester is then condensed with diethyl succinate in the presence of sodium tert-amylate (2.5 eq) in tert-amyl alcohol at 373 K under rigorously anhydrous conditions (glovebox dew point ≤ –55 °C). After 18 h, the deep-red suspension is quenched with methanol/water and the pigmentary crude is filtered, washed with hot dimethylformamide to remove low-molecular-weight oligomers, and kneaded in a 700 L Z-blade mixer with sodium chloride and diethylene glycol at 408 K for crystal-phase adjustment. The β-phase polymorph, confirmed by X-ray powder diffraction with a characteristic peak at 2θ = 7.2°, provides a hue angle of 28.5° (CIELAB, D65/10° illuminant) and a chroma C* of 82.3 in a high-solid polyester-melamine clearcoat system. The pigment paste is dispersed on a triple-roll mill to a fineness of < 5 µm per ISO 1524:2020, and the resulting coating achieves lightfastness rating 4–5 on the Blue Wool Scale under ISO 105-B02:2014 accelerated weathering. Automotive OEM specifications require a heat-fastness test at 160 °C for 30 min, where color difference ΔE*ab must remain below 1.0. Heavy-metal analysis per EN 71-3:2019 confirms lead and cadmium are < 10 ppm migrateable, enabling classification under EU Directive 2009/48/EC for toy coatings.Agrochemical Pro-insecticide Activation Engineered via the α-Formyl MotifWithin the diamide insecticide class, the formyl-pyrrole acid is employed as a synthetic equivalent of a masked anthranilic acid surrogate. In a patented route, the compound is subjected to a Vilsmeier-Haack formylation on the pyrrole C-5 position, followed by sodium chlorite oxidation of the aldehyde to generate a mixed chlorinated diacid; however, the native formyl group can be engaged directly in a reductive amination with 2-amino-5-chloro-N,3-dimethylbenzamide in the presence of sodium triacetoxyborohydride (1.8 eq) and acetic acid (0.5 eq) in dichloromethane at 293 K. The resulting secondary amine is then acylated with 2-fluoro-3-nitrobenzoyl chloride under Schotten-Baumann conditions (aqueous potassium carbonate, tetrahydrofuran, 278 K), and the nitro intermediate is reduced with hydrogen over Raney nickel (3 bar, 323 K) in methanol to unlock the pharmacophore. The route circumvents genotoxic nitrosoamine formation by holding the reduction temperature below 333 K and maintaining a hydrogen stoichiometry not exceeding 4.0 eq. The final cyantraniliprole analog achieves 98.1% purity by HPLC (210 nm) and is formulated as a 200 g/L suspension concentrate with a droplet size D50 of 2.8 µm after bead milling (Eiger Mill, 0.8 mm yttria-stabilized zirconia beads, 3000 rpm). Accelerated storage stability at 54 ± 2 °C for 14 days per CIPAC MT 46.3 must show decomposition < 5 % and a dispersion-stability re-emulsification time < 60 s. Field trials indicate control of Spodoptera frugiperda at 75 g a.i./ha when applied with a 150 µm flat-fan nozzle delivering 150 L/ha, with a pre-harvest interval of 7 days set under EU Regulation 396/2005 MRL compliance.What Conditions Render the Pyrrole Aldehyde Operable as a Luminescent Metal-Organic Framework Linker?The bifunctional characteristic (carboxylate anchor and aldehyde post-synthetic modification site) enables incorporation into UiO-66-type frameworks where zirconium oxo-clusters are formed in dimethylformamide with formic acid modulator (30 equiv relative to ZrCl₄). A solvothermal synthesis at 393 K for 24 h yields an octahedral crystalline powder with BET surface area 1120 m²·g⁻¹ (N₂ adsorption at 77 K, pore diameter 18 Å by NLDFT). Post-synthetic oxidation of the formyl groups with sodium chlorite and sulfamic acid transforms the aldehydes to carboxylates, doubling the charge density and enabling selective Cd²⁺ adsorption capacity of 178 mg·g⁻¹ from aqueous solution at pH 5.8. The fluorescence quantum yield of the aldehyde-capped framework, Φ = 0.11 (integrating sphere method, excitation 365 nm), undergoes a 3-fold enhancement upon imine conjugation with 4-aminobenzo-15-crown-5, enabling ratiometric potassium sensing in serum with a limit of detection 0.8 µM. The linker loading is determined by digestion 1H NMR using D₂SO₄/DMSO-d₆ digestion, showing 94% incorporation efficiency. Long-term suspension stability in phosphate-buffered saline (pH 7.4) is maintained for 72 h without aggregation as confirmed by dynamic light scattering (Z-average < 250 nm).Formyl-Pyrrole Acid as a Polysiloxane Crosslinking Modifier for Condensation-Cure RTV SystemsIn room-temperature vulcanizing silicone sealants, the 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid functions as a latent crosslinker additive that remains inert during storage and activates upon moisture exposure. It is pre-dispersed in the polydimethylsiloxane base polymer at a loading of 0.8–1.2 phr using a planetary mixer (60 rpm revolution, 900 rpm dispersion) under vacuum (–0.095 MPa). The aldehyde groups slowly condense with amino-functional silanes in the formulation, forming imine bonds that rearrange upon humidity uptake to release the carboxyl functionality, which then coordinates with tin catalysts to accelerate the condensation cure. As a result, the tack-free time can be reduced from 28 min to 14 min at 50% RH and 296 K, while the tensile strength, measured per ISO 8339:2005, increases from 1.8 MPa to 2.4 MPa. A notable processing constraint is the requirement to dry the filler (fumed silica, BET 200 m²·g⁻¹) to moisture content < 0.05 % before incorporating the acid, because adsorbed water can initiate premature imine hydrolysis and viscosity build-up within 2 h of compounding. The cured sealant passes joint-movement capability to ± 25% without cohesive failure and maintains adhesion on glass and anodized aluminum after 1000 h of QUV-B exposure per ISO 11600 class 25LM. Extractable organic carbon after cure is < 0.5% as per EN 12873-1, qualifying the system for potable water contact applications.The pyrrole scaffold’s inherent UV absorption (λmax 288 nm, molar extinction coefficient 8900 M⁻¹·cm⁻¹ in ethanol) confers additional photostabilization to the silicone network, reducing the yellowing index increase to ΔYI = 3.2 after 500 h in a xenon arc Weather-Ometer (ISO 4892-2:2013, Method A) compared to ΔYI = 9.7 for the unmodified control. Production-scale twin-screw extrusion (L/D 48:1) requires barrel temperature zones set at 303/308/313/318/323 K from feed to die to avoid thermal decarboxylation, which is observed at screw speeds above 300 rpm causing localized hot spots. |
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5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, typically supplied as an off-white crystalline powder with a purity specification of ≥97% determined by reversed-phase HPLC at 254 nm, functions as a heterobifunctional pyrrole scaffold carrying three distinct reactive centres: a nucleophilic N–H capable of participating in electrophilic substitution, a carboxylic acid residue accessible to amide coupling, and an aromatic aldehyde suited for condensation, Wittig, and reductive amination sequences. Release certificates issued with production batches reference a differential scanning calorimetry melting endotherm onset of 207–210 °C (ASTM E2550-21, sealed aluminium pan, purge gas N₂ at 50 mL/min, heating rate 10 K/min), a water content not exceeding 0.5 wt% by coulometric Karl Fischer titration (USP <921>, Method Ic), and a residual solvent profile controlled to below 500 ppm for each Class 3 solvent (USP <467> Procedure A, headspace GC-FID). The bulk material is dispensed into amber borosilicate glass containers purged with argon to an overpressure of 0.2 bar and heat-sealed to suppress aldehyde autoxidation and hydrate formation during ambient transit.
When the compound is deployed in palladium-catalysed C–C bond formations, the formyl substituent competes effectively with the carboxylic acid proton as a directing group for ortho-metallation. Using Pd(OAc)₂ (5 mol%) and SPhos ligand (10 mol%) in anhydrous DMF at 80 °C, selective C–H arylation at the position adjacent to the formyl unit proceeds with isolated yields of 58–63%, whereas the corresponding 2,4-dimethyl-1H-pyrrole-3-carboxylic acid—lacking the aldehyde—exhibits no reactivity under identical conditions, based on in‑situ ReactIR monitoring of the C–O stretching region. The presence of the electron‑withdrawing formyl group polarises the adjacent C–H bond, lowering its pKa by approximately 2.4 units relative to the aldehyde‑free congener and facilitating deprotonation by a carboxylate base. This characteristic circumvents the pre‑installation of a halide or pseudohalide that is mandatory with 5‑bromo‑2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid (CAS 160129‑45‑3), thereby shortening synthetic routes by two steps when diversification is required late in a medicinal chemistry program.
The electronic perturbation introduced by the 5‑formyl group red-shifts the UV‑vis absorption maximum from 262 nm to 284 nm (MeCN, 10 µM, 1 cm path length) and raises the molar attenuation coefficient by approximately 35%. More critically, the aldehyde enables a suite of condensation chemistries that are entirely inaccessible to the non‑formylated analogue. Schiff‑base formation with aliphatic primary amines proceeds quantitatively in ethanol at 25 °C within 30 min, as confirmed by 1H NMR disappearance of the aldehydic proton at δ 9.78 ppm (500 MHz, DMSO‑d6). The resulting imines can be reduced in situ with NaBH(OAc)3 (1.5 eq) to give the corresponding aminomethyl derivatives, providing a molecular‑ruler strategy for conjugating the pyrrole‑3‑carboxylic acid handle to primary‑amine‑bearing biomolecules through a two‑carbon spacer arm. By contrast, 2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid (CAS 17106‑13‑7) requires prior electrophilic formylation under Vilsmeier–Haack conditions (POCl₃/DMF, 0 °C → 80 °C) to install the aldehyde; the attendant aqueous quench and neutralisation steps cause partial decarboxylation (7–12%) and necessitate additional chromatographic purification, reducing overall mass recovery to 51% from an initial lot of the parent acid.
When 5‑formyl‑2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid is condensed with 2,4‑dimethylpyrrole in anhydrous dichloromethane under catalysis by BF₃·OEt₂ (1.2 eq, dropwise addition over 10 min at ‑5 °C, then warming to 22 °C), a meso‑unsubstituted BODIPY core bearing a single carboxylic acid at the β‑pyrrolic position precipitates within 45 min. Isolation by vacuum filtration through a 0.45 µm PTFE membrane yields a dark‑orange solid that records an m/z of 345.14 [M+H]+ (ESI‑TOF, positive mode, resolution >40 000 FWHM). The free acid can be activated with EDC·HCl (1.1 eq) and NHS (1.1 eq) in anhydrous DMSO at 20 °C for 4 h to generate the NHS ester in situ; direct treatment with an amine‑terminated oligonucleotide (15‑mer, 0.5 mM in carbonate buffer, pH 8.5) proceeds to 94% conjugation efficiency as determined by analytical RP‑HPLC (C4 column, 5 µm, 150 × 4.6 mm, gradient 5→95% MeCN in 0.1 M TEAA over 20 min). Parallel coupling trials with the methyl ester analogue—5‑formyl‑2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylate—require prior saponification with LiOH (THF/H₂O, 3:1, 0 °C, 2 h), which induces 15–20% aggregate formation in the final bioconjugate as measured by dynamic light scattering (Z‑average diameter shift from 4.2 nm to 38 nm). The availability of the native acid therefore eliminates a deprotection step that is detrimental to dispersion stability in aqueous labelling workflows.
The simultaneous presence of the carboxylic acid and formyl moieties permits the construction of imine‑bonded covalent organic frameworks (COFs) via solvothermal condensation with ditopic amines. A representative protocol utilises p‑phenylenediamine (0.3 mmol) and 5‑formyl‑2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid (0.2 mmol) in a sealed Pyrex tube containing 1,4‑dioxane/mesitylene (1:1 v/v, 2.0 mL) and acetic acid 6 M (0.2 mL) as catalyst. Heating at 120 °C for 72 h affords a dark‑brown microcrystalline solid. Nitrogen adsorption isotherms recorded at 77 K on a Micromeritics ASAP 2420 analyser after activation at 100 °C under dynamic vacuum (10‑6 bar, 12 h) yield a Brunauer–Emmett–Teller surface area of 820 m²/g (ISO 9277:2010, p/p0 range 0.05–0.30) and a total pore volume of 0.48 cm³/g at p/p0 = 0.99. Thermogravimetric analysis reveals a sharp mass loss of 8.7% commencing at 215 °C, assigned to decarboxylation of the framework‑anchored acid groups; this onset temperature falls substantially below the melt‑processing window of imine‑based thermoplastics, ruling out extrusion compounding in a co‑rotating twin‑screw extruder (L/D 40:1, screw diameter 25 mm) operated at barrel temperatures above 200 °C. The N‑methyl analogue—5‑formyl‑1,2,4‑trimethyl‑1H‑pyrrole‑3‑carboxylic acid—undergoes framework collapse at 180 °C during solvothermal synthesis, producing an amorphous polymer with a BET surface area of only 310 m²/g, an outcome attributed to steric hindrance from the N‑methyl group inhibiting the layered stacking required for long‑range crystallinity. For applications demanding high‑temperature post‑synthetic modification of the framework, the acid moisture sensitivity (see below) remains the primary handling constraint rather than thermal decomposition of the imine linkage, provided the temperature is held at or below 150 °C under inert gas flow.
Storage at 25 °C and 60% relative humidity converts the anhydrous crystalline form to a monohydrate within 6 h, as quantified by a mass increase of 8.2% in a TGA isothermal experiment (nitrogen purge, sample mass 12.3 mg). Hydrate formation broadens the aldehyde 1H NMR signal to a half‑width of 8 Hz and reduces coupling efficiency in EDC‑mediated amidation by approximately 22%, because water competes with the amine nucleophile for the activated ester. Consequently, vials stored at bench conditions for longer than 2 h must be dried in a vacuum oven set to 40 °C and 10 mbar for 12 h before use. Decarboxylation is catalysed by strong bases: exposure to DBU (1.0 eq) in anhydrous THF at 0 °C results in complete conversion to 5‑formyl‑2,4‑dimethyl‑1H‑pyrrole (m/z 124.08) within 5 min, as tracked by UPLC‑MS (ESI+, Acquity BEH C18, 1.7 µm). The degradation pathway is suppressed by using 2,6‑lutidine (2.0 eq) as a hindered Brønsted‑base surrogate, which does not deprotonate the carboxylate to the CO₂‑releasing carbanion at reaction‑relevant temperatures. These incompatibilities distinguish the free acid from the corresponding tert‑butyl ester, which withstands DBU treatment but requires trifluoroacetic acid‑mediated deprotection (95:5 TFA/H₂O, 2 h) accompanied by a 12% loss of the formyl group through acid‑catalysed hydrate formation, adding a mandatory re‑oxidation step with PhI(OAc)2 and TEMPO (5 mol%) in dichloromethane at 22 °C.
| Compound | CAS / Reference | mp (°C) ASTM E2550‑21 | Purity (HPLC Area‑% @ 254 nm) | Formyl Present | Carboxylic Acid | Water Solubility (g/L, 25 °C) | Key Application Differentiator |
|---|---|---|---|---|---|---|---|
| 5‑Formyl‑2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid | Batch‑specific COA (Product Code PCL‑FDMP‑001) | 207–210 | ≥97 | Yes | Yes | 1.8 | One‑step bioconjugation via free acid; direct imine‑COF formation |
| 2,4‑Dimethyl‑1H‑pyrrole‑3‑carboxylic acid | 17106‑13‑7 | 185–187 | 98 | No | Yes | 2.5 | Requires Vilsmeier formylation prior to condensation |
| 5‑Bromo‑2,4‑dimethyl‑1H‑pyrrole‑3‑carboxylic acid | 160129‑45‑3 | 192–195 | ≥97 | No | Yes | 0.9 | Suzuki coupling partner; no aldehyde‑mediated derivatisation |
| 5‑Formyl‑1,2,4‑trimethyl‑1H‑pyrrole‑3‑carboxylic acid | Pilot‑plant isolate, not catalogued | 163–167 (dec.) | 94 | Yes | Yes | 3.1 | N‑methylation reduces COF crystallinity; reduced thermal stability |
| Test Parameter | Method | Instrument | Acceptance Criterion |
|---|---|---|---|
| Appearance | Visual inspection | Colour assessment cabinet, D65 | Off‑white crystalline powder, free of visible foreign matter |
| Identification | USP <197K> | FTIR, diamond ATR, 4000–400 cm‑1 | Matches reference spectrum; carbonyl bands at 1665 cm‑1 (formyl) and 1690 cm‑1 (COOH) |
| Assay | USP <621> | HPLC‑UV, C18 (5 µm, 150 × 4.6 mm), ACN/H₂O (70:30) + 0.1% TFA, 1.0 mL/min, 25 °C | ≥97.0% area (retention time 4.2 min) |
| Melting point | ASTM E2550‑21 | DSC, sealed pan, purge N₂ 50 mL/min, 10 K/min | Onset 207–210 °C |
| Water content | USP <921> Method Ic | Coulometric KF titrator, oven temp 140 °C | ≤0.5 wt% |
| Residual solvents | USP <467> Procedure A | GC‑HS, DB‑624 column (30 m × 0.32 mm, 1.8 µm) | Class 3 each ≤500 ppm; total ≤1000 ppm |
| Heavy metals | USP <233> | ICP‑MS, digested in HNO₃/H₂O₂ | Pb ≤5 ppm, Cd ≤2 ppm, As ≤3 ppm, Hg ≤1 ppm, total others ≤20 ppm |
