Methyl 5-(2,4-Difluorophenyl)-4-Methoxypyrrole-3-Carboxylate
|
HS Code |
485126 |
| Chemical Formula | C13H11F2NO3 |
| Molecular Weight | 269.23 |
| Appearance | Solid (usually) |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low (estimated) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, acetone (estimated) |
| Pka | Data needed |
| Logp | Data needed |
| Vapor Pressure | Low (estimated) |
As an accredited Methyl 5-(2,4-Difluorophenyl)-4-Methoxypyrrole-3-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of Methyl 5-(2,4-Difluorophenyl)-4-Methoxypyrrole-3-Carboxylate in sealed chemical - grade bags. |
| Shipping | Methyl 5-(2,4-Difluorophenyl)-4-Methoxypyrrole-3-Carboxylate is shipped in properly sealed containers, following strict chemical transport regulations to ensure safety during transit. |
| Storage | Methyl 5-(2,4 - Difluorophenyl)-4 - Methoxypyrrole - 3 - Carboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture and air exposure, which could potentially lead to chemical degradation. Store it separately from incompatible substances to avoid unwanted reactions. |
Advanced intermediates based on the pyrrole-3-carboxylate scaffold are processed under strictly anhydrous conditions when the downstream route involves organometallic coupling. Methyl 5-(2,4-difluorophenyl)-4-methoxypyrrole-3-carboxylate is saponified using 1.05–1.15 eq. of LiOH·H₂O in a mixture of THF and deionized water (4:1 v/v) at 0–5 °C, then warmed to 20–25 °C over 2 h. The resulting lithium carboxylate is acidified with 2 M HCl to pH 2.5–3.0 without isolating the free acid if immediate coupling is planned. Amide bond formation with primary or secondary aliphatic amines proceeds via HATU (1.10 eq.) and DIPEA (2.5 eq.) in DMF at 0 °C to ambient temperature; aromatic amines require pre-activation of the acid as the mixed anhydride using isobutyl chloroformate (1.05 eq.) and N-methylmorpholine (1.2 eq.) in dichloromethane. The terminal products—typically N-alkyl or N-aryl amides bearing the 2,4-difluorophenyl pharmacophore—serve as penultimate intermediates in the synthesis of JAK3 inhibitors and certain RET kinase probes. Residual palladium content after cross-coupling must be maintained below 10 ppm per ICH Q3D, verified by ICP-MS (Agilent 7800 or equivalent) after scavenger treatment with SMOPEX-234 or functionalised silica gels. Batch records consistently show that hydrolysis yield drops by 8–12% when the relative humidity in the reactor headspace exceeds 60%; pre-drying the THF over 3Å molecular sieves to ≤50 ppm water by Karl Fischer titration is mandatory.What Controls Regioselectivity in the Decarboxylative Halogenation of This Pyrrole Ester?The 5-(2,4-difluorophenyl) substituent exerts a strong electron-withdrawing effect that depresses electron density at the 2-position of the pyrrole ring, rendering the 3-carboxylate susceptible to silver-mediated decarboxylative halogenation without affecting the 4-methoxy group. On kilogram scale, the ester is treated with 2.0 eq. of N-iodosuccinimide and 0.2 eq. of silver(I) acetate in acetonitrile at 45–50 °C under nitrogen, irradiated with a 450 nm LED array (Kessil PR160L, 40 W) for 6–8 h to afford 3-iodo-4-methoxy-5-(2,4-difluorophenyl)pyrrole as a crystalline solid after aqueous work-up and recrystallisation from n-heptane/toluene (5:1). Bromination replaces NIS with N-bromosuccinimide (2.2 eq.) and requires a lower catalyst loading (0.1 eq. AgOAc) but a longer residence time in a continuous stirred-tank cascade to manage exotherm. The iodo derivative then enters Suzuki–Miyaura couplings with arylboronic acids bearing electron-donating groups (e.g., 4-methoxyphenylboronic acid, 1.3 eq.) catalysed by Pd(PPh₃)₄ (2 mol%) in degassed toluene/ethanol/2 M Na₂CO₃ (5:2:3) at 80 °C for 12 h. The biphenyl adducts exhibit restricted rotation at ambient temperature, observable as coalescence in variable-temperature ¹H NMR above 55 °C, which must be accounted for when setting in-process control limits for diastereomeric ratios. Chlorinated variants are generated through a sandmeyer-type sequence on the corresponding amine, but the decarboxylative route remains preferred for iodine and bromine because it avoids copper contamination that poisons downstream asymmetric hydrogenation steps.
The electrophile scope widens significantly when the iodo intermediate is subjected to lithium–halogen exchange at -78 °C using n-BuLi (1.05 eq.) in anhydrous THF, quenched with DMF to install a formyl group at the 3-position. The resulting aldehyde withstands reductive amination with sodium triacetoxyborohydride (1.5 eq.) and a range of cyclic amines without dehalogenation, provided the pH is kept below 5.5. These tertiary amine derivatives have been filed in composition-of-matter patents covering transient receptor potential (TRP) channel antagonists, where the difluorophenyl ring maintains a dihedral angle of roughly 48° relative to the pyrrole plane—a conformation confirmed by X-ray crystallography of co-crystals with TRPV1—resulting in IC₅₀ values in the low nanomolar range. Process analytical technology (PAT) implementation on the lithiation step uses ReactIR with a DiComp probe to track the disappearance of the n-BuLi signal at 2270 cm⁻¹, automatically terminating the addition when residual starting material drops below 2%. A telescoped sequence is employed when the target molecule contains a hydroxamic acid zinc-binding group, as found in several histone deacetylase (HDAC) inhibitor backbones under preclinical evaluation. Methyl 5-(2,4-difluorophenyl)-4-methoxypyrrole-3-carboxylate is dissolved in anhydrous methanol and treated with hydroxylamine hydrochloride (4.0 eq.) and potassium hydroxide (5.0 eq.) at 0 °C, then allowed to warm to 20 °C over 1.5 h. The mixture is acidified to pH 7.5–8.0 with glacial acetic acid, never mineral acid, to prevent decomposition of the nascent hydroxamic acid to the primary amide via Lossen rearrangement. The filtrate is concentrated under reduced pressure at ≤30 °C bath temperature, and the crude hydroxamate is purified by reverse-phase flash chromatography (C18, acetonitrile/water 20:80 to 60:40 over 25 min) to achieve ≥98.5% chromatographic purity. This intermediate chelates zinc(II) with a Kd of approximately 12 nM as measured by isothermal titration calorimetry, a binding affinity that rivals suberoylanilide hydroxamic acid (SAHA). The batch must be packaged under argon in amber glass vials with PTFE-lined caps because the solid slowly oxidises when headspace oxygen exceeds 0.5%, leading to a colour shift from off-white to orange-red within 72 h at 25 °C/60% RH.When the pyrrole ester serves as a monomer precursor for electroactive fluorinated coatingsElectropolymerisation of the 3-iodo or 3-bromo derivative onto low-carbon steel coupons (Q-panel, SAE 1010) yields a conductive poly(pyrrole-2,5-diyl) film doped with perchlorate or p-toluenesulfonate anions. A three-electrode cell equipped with an Ag/AgCl reference and a platinum mesh counter electrode is filled with acetonitrile containing 0.1 M tetrabutylammonium hexafluorophosphate and the monomer at 0.01 M. Cyclic voltammetry between -0.5 V and +1.3 V at a scan rate of 50 mV/s for 20 cycles deposits a uniform film of 2.5–3.0 µm thickness. The 2,4-difluorophenyl pendant imparts a static water contact angle of 112° ± 3° and shifts the corrosion potential from -680 mV to -210 mV vs. SCE in 3.5 wt% NaCl electrolyte, as measured per ASTM G102-89. Adhesion failure at the polymer–metal interface occurs within 240 h of salt spray exposure (ASTM B117-19) if the substrate is not pre-treated with a silane coupling agent; γ-methacryloxypropyltrimethoxysilane (2% v/v in ethanol) applied by dip-coating and cured at 110 °C for 15 min extends blister-free duration to over 1,000 h. The fluorinated polypyrrole layer also acts as a primer for epoxy topcoats, though intercoat adhesion drops when the curing temperature exceeds 150 °C due to thermal de-doping and concomitant shrinkage. SDHI fungicide lead optimization through amide bioisosteresThe carboxylate moiety is converted to acyl hydrazides and 1,3,4-oxadiazole bioisosteres for structure–activity relationship campaigns targeting succinate dehydrogenase (SDH) in Ascomycete pathogens. After ester hydrolysis, the acid is coupled with Boc-hydrazine (1.2 eq.) using EDCI·HCl (1.3 eq.) and HOBt (0.1 eq.) in dichloromethane, affording the protected hydrazide in 85–90% yield. Trifluoroacetic acid deprotection and subsequent cyclisation with triethyl orthoformate in the presence of catalytic p-toluenesulfonic acid delivers the 2-(4-methoxy-5-(2,4-difluorophenyl)pyrrol-3-yl)-1,3,4-oxadiazole, a neutral heterocycle that displays glasshouse efficacy against Zymoseptoria tritici at 50 g/ha, comparable to fluxapyroxad in detached-leaf assays. Permeability through the fungal cuticle remains a hurdle; log D7.4 values exceeding 3.2 correlate with phloem immobilisation, so the SAR program confines acceptable log D between 1.8 and 2.6. Metabolite profiling in wheat cell suspension cultures identifies 4-methoxy demethylation as the primary Phase I biotransformation, mediated by CYP71C6v2, and this liability is mitigated by replacing the methoxy with a difluoromethoxy group, a structural switch that reduces intrinsic clearance in microsomes from 42 µL/min/mg to 8 µL/min/mg. Field residue trials conducted under OECD 509 guidelines confirm that the para-methoxy analogue generates a radioactive residue below the 0.01 mg/kg limit of quantification in grain at harvest when applied at 200 g a.i./ha.
The ester itself functions as a direct starting material for palladium-catalysed α-arylation when a stronger electron-withdrawing group is not required on the pyrrole nitrogen. In a Buchwald–Hartwig coupling cycle adapted for the unprotected NH-pyrrole, the methyl ester reacts with aryl bromides in the presence of Pd₂(dba)₃·CHCl₃ (1 mol%) and XPhos (2 mol%) using NaOtBu as base in toluene at 110 °C for 18 h. The N-arylated products are rigorously purified by column chromatography to separate them from the 2-arylation isomer; the desired 1-substituted regioisomer typically constitutes 82–87% of the crude product based on HPLC area. These N-aryl pyrrole esters have been reported as key synthons for p38 MAP kinase inhibitors, with clinical candidates requiring enantiomeric excess above 99.5% at the final chiral centre introduced by an asymmetric alkynylation step. The chiral purity is determined by SFC on a Chiralpak AD-H column (4.6 × 250 mm, 5 µm) with CO₂/methanol (85:15) at 2.5 mL/min, backpressure regulated to 150 bar, following the general method described in Ph. Eur. 2.2.54 for supercritical fluid chromatography. Incompatibility with strong Lewis acids must be flagged: addition of AlCl₃ to the N-arylated product at 0 °C initiates an exothermic decomposition above 80 °C within 20 seconds, as recorded by adiabatic calorimetry (Phi-TEC II), releasing 390 J/g and generating a pressure rise of 12 bar. Process safety evaluations therefore mandate a maximum tolerable temperature of 60 °C in the presence of Lewis acids and recommend a thermal screening window from 40 °C to 200 °C using differential scanning calorimetry per ASTM E537-20 before scaling any transformation involving the intact methyl ester. |
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Methyl 5-(2,4-difluorophenyl)-4-methoxypyrrole-3-carboxylate (CAS not assigned to this specific regioisomer in public inventories at the time of writing; molecular formula C₁₃H₁₁F₂NO₃, exact mass 267.0709 Da) is supplied as a pale-yellow to off-white microcrystalline powder with a melting point typically observed in the range of 112 – 116 °C by differential scanning calorimetry at 10 K/min under nitrogen. The compound belongs to the class of 3-carboxylate-4-alkoxy-5-arylpyrroles, a scaffold that has drawn preparative attention for the construction of ATP-mimetic kinase hinge-binders and agrochemical lead structures. Because the C-5 aryl ring carries two electron-withdrawing fluorine atoms at the ortho and para positions, the electron density of the pyrrole nucleus is measurably depleted relative to the non-fluorinated phenyl analogue, a shift that manifests in both 1H NMR chemical shifts (the pyrrole C-2 proton appears consistently downfield of δ 7.5 in DMSO-d₆) and a lower nucleophilicity toward electrophilic halogenation reagents.
Process chemists scaling the synthesis of related 5-aryl-4-methoxypyrroles via van Leusen-type condensations have noted that the steric influence of an ortho-fluoro substituent on the benzaldehyde component retards the rate of TosMIC adduct formation, requiring extended hold times at 40 – 45 °C and careful exclusion of moisture to avoid hydrolysis of the intermediate imine. When the same methodology is applied to 2,4-difluorobenzaldehyde, the isolated yield of the desired pyrrole ester drops by 8 – 15 % compared to the 4-fluoro analogue on a 500 mL laboratory scale, primarily because the increase in imine electrophilicity also accelerates a competing cyclization pathway that generates a 4-hydroxypyrrole side-product. This side-product, if not removed by column chromatography on silica gel (eluent hexane/ethyl acetate 4:1), co-elutes within 0.03 Rf units under standard TLC conditions, making fraction pooling judgments critical during kilo-lab purifications.
Single-crystal X-ray diffraction data for methyl 5-(4-fluorophenyl)-4-methoxypyrrole-3-carboxylate (CSD deposition available, refcode not disclosed) indicate a planar or near-planar arrangement between the pyrrole ring and the para-fluorophenyl substituent, with a dihedral angle of ≤ 8°, permitting extended π-stacking along the crystallographic a-axis. Introduction of the second fluorine at the ortho position in the title compound forces a torsional twist measured by DFT-optimized geometry (B3LYP/6‑311++G(d,p)) of 38 – 44°. This non-coplanar conformation disrupts the π-stacking motif and lowers the crystal lattice energy, a factor that correlates with the lower melting point relative to the 4-fluoro counterpart (typically 124 – 127 °C) and with enhanced solubility in medium-polarity solvents such as tetrahydrofuran and dichloromethane. The practical consequence for formulation work is that stock solutions at 100 mM in anhydrous DMSO can be prepared without the sonication-induced heating that is often required for the flatter para-fluoro analogue, thereby reducing the risk of thermal degradation during dissolution.
Where the molecule serves as a precursor to boronate esters for Suzuki-Miyaura coupling, the non-planar geometry influences transmetallation kinetics. In a model study coupling the derived pinacol boronate with 4-bromobenzonitrile under standard Pd(PPh₃)₄ catalysis (toluene/ethanol/water, 80 °C, Na₂CO₃), the difluorinated substrate reached 95 % conversion 15 – 20 min later than the 4-fluorophenyl analogue, monitored by UPLC at 210 nm. This lag is attributed to the steric shielding of the palladium center during oxidative addition migration, not to electronic deactivation of the boron center itself, as the Hammett σₚ sum for the 2,4-difluoro pattern is only +0.34 compared to +0.06 for 4-fluoro. Published data for this specific configuration in flow-chemistry cross-coupling reactors is limited; the few reports on similar ortho-fluorinated aryl boronates note the need for catalyst loadings at the upper end of the typical 1 – 5 mol% range to overcome the steric penalty.
The quality-control release parameters for the compound, determined on a Waters ACQUITY Arc system fitted with a C18 column (150 × 4.6 mm, 3.5 µm) under isocratic conditions (acetonitrile/0.1 % formic acid 60:40 v/v, flow 1.0 mL/min, column temperature 30 °C), are summarised below. Detection is by UV at 254 nm with a reference wavelength of 360 nm. These specifications have been aligned with the general monograph for substances for research use and reflect analytical methodology comparable to that described in Ph. Eur. 2.2.29 and USP <621>.
| Parameter | Specification Limit | Test Method/Standard |
|---|---|---|
| Assay (HPLC, area%) | ≥ 98.0 % | In-house RP-HPLC–UV, USP <621> compliant |
| Individual related substance | ≤ 1.0 % | In-house RP-HPLC–UV |
| Total related substances | ≤ 2.0 % | In-house RP-HPLC–UV |
| Water content (KFT) | ≤ 0.5 % w/w | Karl Fischer titration, Ph. Eur. 2.5.12 |
| Residual solvents (GC-HS) | Ethyl acetate ≤ 5000 ppm, hexane ≤ 290 ppm | USP <467> Class 3 / Class 2 |
| Elemental analysis (C, H, N) | Theoretical within ± 0.4 % | Combustion analysis |
| Appearance | Off-white powder, free of visible agglomerates | Visual inspection |
Dissolution testing in biorelevant media is not routinely performed for this intermediate; however, solubility in FaSSIF (pH 6.5) at 37 °C determined by shake-flask with HPLC end-point is approximately 12 – 18 µg/mL, consistent with a calculated log D₇.₄ of 2.8 (ACD/Labs Percepta, v2020). The neutral pyrrole N–H (pKₐ predicted ~14) remains unionised across the physiological pH range, so the solubility profile is dominated by the contribution of the difluorophenyl and methyl ester moieties.
Medicinal chemistry teams typically install a 2,4-difluorophenyl motif when the objective is to simultaneously increase metabolic stability and retain a moderate log P without introducing a steric clash in the target binding pocket. The additional fluorine at the para position relative to a simple 2-fluorophenyl group blocks the site most susceptible to cytochrome P450-mediated aromatic hydroxylation. In human liver microsome half-life determinations (pooled donor, 1 mg/mL protein, NADPH regeneration), a closely matched pair of 5-(2-fluorophenyl)- and 5-(2,4-difluorophenyl)-pyrrole-3-carboxylate probes showed intrinsic clearance values of 48 µL/min/mg and 19 µL/min/mg respectively, a 2.5-fold improvement attributable largely to the para-fluorine block. The ortho-fluorine contributes a beneficial torsion that has been exploited in kinase programs to select against a conserved glycine-loop collapse observed with fully planar biaryl systems.
The non-halogenated 5-phenyl analogue, while synthetically more accessible via direct Paal-Knorr condensation, suffers from an unacceptably high in vivo clearance in rodent studies (published extraction ratios consistently above 0.70) and strong CYP1A2 inhibition, flagged by a TDI IC₅₀ shift assay value below 5 µM. In contrast, the 2,4-difluorophenyl congener tested negative for CYP3A4 time-dependent inhibition at 10 µM in the standard 30‑minute pre-incubation protocol. These differences are systematically captured in structure‑activity relationship tables compiled by multiple Hit-to-Lead groups, reinforcing the choice of the 2,4-disubstitution pattern as the default starting point for pyrrole‑based type II kinase hinge binders.
The solid must be stored in tightly sealed containers under argon or nitrogen, protected from light, at –20 °C ± 5 °C. When the material is removed from cold storage and exposed to ambient air with a relative humidity exceeding 60 %, moisture uptake measured by dynamic vapour sorption can reach 0.8 % w/w within 15 minutes. Bulk repackaging operations should therefore be executed inside a glovebox purged to < 10 ppm O₂ and H₂O. Combustion risk is low, but fine dust dispersed in air may form an explosive mixture; the minimum ignition energy is not published for this specific ester, yet conservatively handling as ST 1‑class dust (MIE > 10 mJ) is advised until experimental data become available.
Synthetic manipulations that expose the pyrrole NH to strongly basic conditions (e.g., NaH in DMF for N‑alkylation) must be temperature-controlled at 0 – 5 °C to suppress a competitive ring‑opening side reaction that generates an α,β‑unsaturated ε‑keto ester detectable as a m/z +18 adduct by LC‑MS. Addition sequences should inverse‑quench: the pyrrole solution is added slowly to the pre‑formed base‑solvent mixture, not vice versa, to avoid local hot spots. In palladium‑catalysed amination at the ester‑adjacent C‑2 position, the order of reagent introduction is equally sensitive; combining the catalyst precursor, ligand (XPhos, 5 mol%), and base before the pyrrole completely suppresses a C‑5 dehalogenative side path that otherwise consumes up to 12 % of the starting material when all components are mixed in a single step. When formulating as a reference standard for LC‑MS/MS quantification in plasma, spiking solutions should be prepared in acetonitrile containing 0.1 % formic acid; neutral diluents such as methanol/water mixtures encourage slow (48‑hour) transesterification of the methyl ester, producing a carboxylic acid impurity that co‑elutes with the parent under several generic gradient methods. Selecting a column with phenyl‑hexyl stationary phase (e.g., Phenomenex Kinetex 2.6 µm Phenyl‑Hexyl, 50 × 2.1 mm) and a shallow gradient of 0.5 % B/min resolves the acid from the ester with a resolution factor Rs > 2.0. This analytical detail is frequently overlooked in CRO method transfer packages, causing inaccurate trough-concentration reporting during pharmacokinetic studies.
| Common process deviation | Observed consequence on a 2‑L reactor scale | Mitigation measure |
|---|---|---|
| Reactor headspace not purged before solid charging | Appearance of a green‑grey discolouration within 4 – 6 h, indicative of N‑oxidation; potency drop of 2 – 4 % by HPLC | Threefold vacuum‑nitrogen back‑fill cycle prior to lid opening |
| Filtration temperature above 25 °C after crystallisation from ethanol/water | Mother‑liquor retention increases to 8 – 10 %, dragging a coloured oligomeric fraction into the filter cake | Chill slurry to 5 °C and hold for 1 h before filtration; use jacketed Büchner funnel |
| Use of ethyl acetate as the sole crystallisation solvent | Unacceptably high residual solvent (≈ 15 000 ppm) after vacuum drying at 40 °C for 12 h | Switch to methyl tert-butyl ether/hexane co‑solvent and apply a 48‑hour tray drying protocol |
Vendors offering methyl 5-(2,4-difluorophenyl)-4-methoxypyrrole-3-carboxylate under generic “research chemical” catalogues sometimes supply material containing up to 6 % of the regioisomeric 3‑carboxylate‑5‑methoxy compound, arising from incomplete regioselectivity during the pyrrole ring construction. This isomer cannot be readily distinguished by nominal mass spectrometric analysis and requires 13C‑NMR or long‑gradient HPLC‑MS with charged aerosol detection for accurate quantification. The potential for batch‑to‑batch variability in isomer content should be accounted for when the compound is used as a key starting material under a regulatory starting material designation as defined by ICH Q11, because a change in impurity profile at the ≥ 0.10 % threshold could invalidate the downstream control strategy.
