1H-Pyrrole-2-Carboxylic Acid, 5-Nitro-, Ethyl Ester: Properties, Uses, Safety Data & China Supplier Information

Catalyst System (loading)

Induction Time (min)

Reaction Endpoint (HPLC area% ≤ 0.2% nitro)

Residual Metal in Crude Filtrate (ICP-MS)

Observed By-product (5-hydroxylamine intermediate)

Raney® Ni 2800 (5 wt%)

8–12

3.0–3.5 h

Ni 2–5 ppm

0.05–0.10% area

Pd/C 10% (1.5 wt%, 50% wet)

≤ 2

1.2–1.8 h

Pd 8–18 ppm

0.02–0.05% area

Zn dust / NH₄Cl (THF/H₂O 1:1)

25–40

12–16 h

Zn 45–120 ppm

1.8–3.2% area

What Analytical Release Criteria Govern Nitro-Reduction Intermediates for Quinolone C-7 Substituents?

When the ethyl ester is reduced to the corresponding 5-amino intermediate for the assembly of 7-[3-aminopyrrolidin-1-yl]-quinolone antibacterials, the control strategy shifts from nickel removal to strict containment of genotoxic impurities originating from halo-alkane quench agents or residual alkylating solvents. In a campaign executed under ICH Q7 and Q11 risk management guidelines, the reduction is performed with zinc powder (3.5 eq, ≤ 10 µm particle size) in a mixture of 2-methyltetrahydrofuran (6.0 vol) and saturated aqueous ammonium chloride (2.0 vol) at 15–20 °C for 14–16 h. The biphasic system is selected to avoid entirely the use of THF, which forms peroxides upon prolonged storage and can generate trace formaldehyde under acidic work-up — a source of potential N-formyl impurities later mistaken for residual starting material. After Celite® filtration, the organic layer is washed with 5% w/v EDTA disodium salt solution (1.0 vol) to chelate zinc ions to ≤ 15 ppm, then concentrated under vacuum (80 mbar, jacket 35 °C) to 1.5 vol and diluted with dichloromethane (5.0 vol). The resulting solution is dried over anhydrous sodium sulfate (1.0 kg per 10 kg substrate) and filtered again through a 0.2 µm PTFE membrane. The critical quality attribute for use in fluoroquinolone C-7 coupling is the content of monochloro- and dichloro- impurities originating from any residual dichloromethane interaction; headspace GC-MS must confirm methylene chloride ≤ 600 ppm and chloromethyl ethyl ether ≤ 1.5 ppm (equivalent to a threshold of toxicological concern of 1.5 µg/day when referenced to a 1 g/day maximum daily dose). The amine intermediate is forwarded at a solution concentration of 25% w/w in 2-MeTHF and used immediately in C-7 nucleophilic aromatic substitution on a 6,7-difluoro-4-quinolone-3-carboxylic acid core at 70 °C for 6 h in the presence of triethylamine (1.2 eq), yielding the pyrrolidine-linked fluoroquinolone scaffold that exhibits Gram-negative MIC₉₀ values in the single-digit nanomolar range. Published kinetic data for the substitution step indicate an optimal leaving-group order of F > Cl > OTs, with a processing window limited to ± 5 °C to avoid competitive elimination forming the 6-unsubstituted pyridobenzoxazine by-product.

Suzuki-Miyaura Donor for 5-Aryl-Pyrrole TKI Pharmacophores

Construction of 5-aryl-1H-pyrrole-2-carboxylate cores — a recurrent motif in type II kinase inhibitors targeting the DFG-out conformation — begins with halogenation of the intact nitroester scaffold. Bromination is performed with N-bromosuccinimide (0.95 eq) in anhydrous dimethylformamide (5.0 vol) at 0–5 °C under exclusion of light. The substoichiometric amount of NBS prevents formation of the 4,5-dibromo impurity, which is difficult to purge in subsequent cross-coupling due to its similar coupling rate. After 4 h, in-process HPLC (C8 column, 254 nm) confirms mono-bromination ≥ 96% and di-bromo ≤ 1.5%. The reaction is quenched with 10% w/v sodium thiosulfate solution (2.0 vol), extracted into ethyl acetate, and crystallized from n-heptane / ethyl acetate (3:1) to obtain ethyl 4-bromo-5-nitro-1H-pyrrole-2-carboxylate as a pale-yellow solid (> 99.0% HPLC area, melting range 142–144 °C). Suzuki coupling employs a catalyst stock solution prepared in a glovebox: Pd(OAc)₂ (0.015 eq) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 0.03 eq) in degassed THF. In a 10 L jacketed glass reactor, the bromoester (1.0 eq), 4-cyanophenylboronic acid pinacol ester (1.15 eq), and finely ground potassium phosphate tribasic (3.0 eq, ≤ 75 µm) are suspended in THF/water (4:1, 10.0 vol). The mixture is sparged with nitrogen for 45 min, charged with pre-formed catalyst, and heated to 55 °C internal for 8–10 h. The biphasic solution turns deep red, and coupling completion is verified by TLC (silica gel 60 F₂₅₄, hexane:EA 3:1, R_f product 0.35). Palladium scavenging post-reaction is mandatory: the cooled mixture is treated with 3-mercaptopropyl-functionalized silica gel (2.0 wt% of product mass, SiliaMetS® Thiol) at 45 °C for 3 h, followed by filtration through a 0.45 µm polypropylene depth filter. ICP-MS of the isolated product consistently shows residual palladium ≤ 5 ppm, which aligns with ICH Q3D Option 2B parenteral PDE limits for Pd (10 µg/day). The nitro group is subsequently reduced with iron powder in acetic acid/ethanol under conditions that preserve the ethyl ester, generating the aniline congener for amide formation with acylated amino acids, completing the TKI pharmacophore. Published mechanistic work indicates that electron-withdrawing substituents at the 4-position accelerate oxidative addition by 9-fold relative to the 4-H analogue, justifying the 4-bromo regioisomer as a superior coupling partner.

When Direct Amidation Replaces Acyl Chloride Activation in Agrochemical Scale-Up

Employing the nitroester directly in amide bond formation with heterocyclic amines avoids the carcinogenic reagents associated with acid chloride intermediates and reduces overall solvent intensity in fungicide manufacturing. In a typical procedure aligned with the stringent chlorinated by-product limits enforced under EU Regulation 1107/2009 Annex II, the ethyl ester (1.0 eq) is first saponified with lithium hydroxide monohydrate (1.05 eq) in tetrahydrofuran / methanol / water (3:1:1, 12.0 vol) at 25 °C for 3 h. After acidification with 2.0 M HCl to pH 2.5–3.0 and extraction into ethyl acetate, the resulting 5-nitro-1H-pyrrole-2-carboxylic acid (mp 178–181 °C) is isolated by crystallization from toluene / cyclohexane (1:2) and dried under vacuum at 45 °C to a water content ≤ 0.2%. Amidation with 3-chloro-2-aminomethyl-5-trifluoromethylpyridine — a chiral amine building block for SDHI-class fungicides — is mediated by 1,1′-carbonyldiimidazole (1.25 eq) in anhydrous acetonitrile (8.0 vol) at 0–5 °C, allowing the activated acyl imidazole to form within 30 min before the amine (0.95 eq) is added portionwise. The temperature is raised to 20 °C and held for 5 h. Residual CDI and imidazole by-product are removed by successive washes with 1.0 M aqueous citric acid (2 × 3.0 vol) and 10% w/v NaCl. The organic layer passes through a 0.5 µm inline filter and is concentrated to 3.0 vol for crystallisation. This process yields the target fungicide intermediate as a crystalline solid with > 98.5% HPLC area purity and a geometric isomer impurity ≤ 0.35%. For registration purposes, the five-batch analysis of the intermediate must demonstrate consistent individual unknown impurities ≤ 0.10% and total residues of imidazole and its N-acylated derivative ≤ 50 ppm, meeting the requirement of SANCO/10597/2012 for non-relevant metabolites in groundwater. Scale-up of this amidation in a 2000 L Hastelloy® C-22 vessel equipped with a pitched-blade turbine maintains isothermal control within ± 3 °C at the addition stage, with alarm limits set on jacket temperature differential to prevent runaway imidazole decomposition exotherms.

Optical-Grade Purity for Poled Guest-Host Electro-Optic Films

Removal of ionic and subvisible particulate contaminants to levels compatible with thin-film polymer electro-optic modulators converts the nitroester from a synthetic intermediate into a functional chromophore precursor. Following initial recrystallization from ethanol / water (7:3), the material is subjected to train sublimation in a three-zone horizontal tube furnace: zone 1 at 85 °C, zone 2 (deposition) at 60 °C, zone 3 (cold finger) at 10 °C, all under a dynamic vacuum of 1 × 10⁻⁵ mbar for 48 h. Sublimed crystals are handled exclusively in a Class 100 (ISO 5) cleanroom with antistatic PTFE-coated tools to prevent airborne particle adhesion. Analysis by ion chromatography (Metrohm 930 Compact IC Flex) must confirm sodium ≤ 0.2 ppm, potassium ≤ 0.1 ppm, and chloride ≤ 0.5 ppm; any excursion above these thresholds correlates with increased optical loss at 1310 nm measured by the prism-coupling technique per ISO 11455:1995. The purified nitroester is then dissolved in anhydrous N-methyl-2-pyrrolidone together with a methacrylate-functionalized host polymer (poly(Disperse Red 1-co-methyl methacrylate), 10–15 mol% chromophore loading) and spin-coated onto indium tin oxide glass. Corona poling at 8 kV (needle distance 1 cm) with substrate temperature at T_g + 10 °C for 30 min orients the chromophore; the resulting film exhibits an electro-optic coefficient r₃₃ of 12–18 pm/V at 1550 nm, as determined by the Teng-Man reflection technique. No commercial electro-optic device standard exists specifically for the nitroester, but compliance of the host polymer system with Telcordia GR-468-CORE environmental stress tests ( 85 °C / 85% RH, 2000 h) is typically reported, and chromophore stability under these conditions requires ≤ 5% degradation of the π-conjugated backbone as measured by UV-Vis absorbance at λ_max 395 nm. Published data for this specific configuration in commercial foundry processes is limited; the described purification sequence represents research-scale (≤ 50 g) translation of nonlinear optical dopant preparation.

Ethyl 5-nitro-1H-pyrrole-2-carboxylate (CAS RN: 54453-63-1; molecular formula C₇H₈N₂O₄; molecular weight 184.15 g·mol⁻¹) functions as a strategic heterocyclic building block in medicinal chemistry and agrochemical discovery programs. The molecule combines an electron-deficient pyrrole core bearing a nitro group at the 5-position with an ethyl ester at the 2-position, affording a substitution pattern that directs electrophilic aromatic substitution to the remaining β-positions while leaving the ester moiety available for orthogonal transformations. In practice, the compound is typically supplied as a pale yellow crystalline powder with a melting point of 130–133 °C (determined by differential scanning calorimetry at 10 K·min⁻¹ under nitrogen) and an assay specification of ≥97.0% by HPLC at 254 nm. Residual solvent content, tested per USP <467>, is controlled to <0.5% for each of ethanol, ethyl acetate, and dichloromethane, minimizing interference in palladium-catalyzed coupling sequences. Where downstream chemistry demands stringent metal limits, batches certifying iron <10 ppm and palladium <5 ppm by ICP-OES are available on request.

What differentiates the ethyl ester from the corresponding methyl ester and free acid in multi-step synthesis?

The selection between ethyl 5-nitro-1H-pyrrole-2-carboxylate and its methyl ester analogue (CAS 13138-74-4) or the parent carboxylic acid (CAS 480-92-6) is decided by the relative kinetics of deprotection and the solubility envelope of the target scaffold. The ethyl ester hydrolyzes under alkaline conditions approximately 1.5–2× slower than the methyl ester in 1 M NaOH/THF/H₂O (1:1:1 v/v) at 25 °C, a differential rooted in steric shielding of the carbonyl carbon. This rate difference can be exploited in sequences where a second methyl ester elsewhere in the molecule must be cleaved selectively. Compared with the free acid, the ester form avoids zwitterionic aggregation during amide bond formation—an issue reported when the acid is activated with HATU in DMF, where product yields drop by 15–22% relative to the ester saponification-then-coupling route due to precipitation of a poorly reactive sodium carboxylate network. The ethyl ester also shows superior solubility in toluene and methyl tert-butyl ether, enabling processing in non-polar media that would be incompatible with the free acid’s high crystal lattice energy. Furthermore, the pyrrole N–H of the ester remains available for alkylation or arylation; a patent procedure (WO 2015/089123) describes N-arylation with 4-fluoronitrobenzene in 1,4-dioxane at 100 °C using copper(I) iodide (10 mol%) and trans-N,N′-dimethylcyclohexane-1,2-diamine, achieving 83% isolated yield after 18 h.

When the synthetic route enters process development, the thermal stability of the neat solid becomes a critical safety parameter. Differential scanning calorimetry combined with thermogravimetric analysis at a ramp rate of 4 °C·min⁻¹ reveals an exothermic decomposition onset at 310 ± 5 °C with an energy release of −780 J·g⁻¹, placing the compound outside the range of immediate concern for standard amination or hydrogenation steps conducted below 80 °C. However, scaling hydrogenation of the nitro group to the corresponding 5-amino derivative with Ra-Ni in ethanol at 30–50 °C and 3–5 bar H₂ demands careful control of catalyst activation; a delayed exotherm has been observed when pre-reduced catalyst is introduced above 40 °C, attributed to the high heat of adsorption of the nitroarene on the catalyst surface. In kilo-lab campaigns, a controlled addition of substrate as a 15% w/w solution in ethanol over 60–90 min under a nitrogen-blanketed hydrogen feed maintains the internal temperature within ±3 °C of setpoint, avoiding the ΔT_ad spike that can trigger partial ring hydrogenation and yield loss.

Positional isomer purity and its impact on biological target engagement

Commercial lots of ethyl 5-nitro-1H-pyrrole-2-carboxylate must demonstrate isomeric purity relative to the 4-nitro and 3-nitro regioisomers, because even 0.3% w/w contamination of the 4-nitro isomer can confound structure-activity relationship studies on kinase inhibition. The compound is synthesized via nitration of ethyl 1H-pyrrole-2-carboxylate under mixed-acid conditions; the 2-ester group directs nitration predominantly to the 5-position due to the inductive withdrawal and resonance effects, but the 4-nitro byproduct forms in typical ratios of 5:1 to 8:1 depending on reaction temperature and sulfuric acid strength. Preparative HPLC on a C18 column (particle size 5 μm, pore diameter 120 Å) with a mobile phase of acetonitrile/0.1% trifluoroacetic acid (35:65 v/v) resolves the 5-nitro and 4-nitro isomers with a separation factor α of 1.18, allowing the target product to be isolated with isomeric purity exceeding 99.5 area%. A validated QC method per ICH Q2(R1) using a 250 × 4.6 mm column and a diode-array detector at 280 nm achieves an LOQ of 0.05 μg·mL⁻¹ for the 4-nitro isomer, ensuring batches meet the ≤0.2% individual impurity specification when intended for pre-clinical GLP toxicology studies.

Physicochemical specification profile for ethyl 5-nitro-1H-pyrrole-2-carboxylate
Parameter	Method/Standard	Typical Value/Specification
Appearance	Visual inspection	Pale yellow crystalline powder
Assay (HPLC)	Area normalization, λ = 254 nm	≥97.0%
Melting range	Capillary, 1 K·min⁻¹	130–133 °C
Loss on drying	60 °C, vacuum, 4 h	≤0.5%
Single impurity (HPLC)	Any unspecified	≤0.5%
4-Nitro isomer	HPLC method as above	≤0.2%
Iron (ICP-OES)	USP <233>	≤15 ppm (optional: <10 ppm)
Solubility in DMF	Gravimetric, 25 °C	>250 mg·mL⁻¹

When downstream chemistry involves organometallic reagents

The ethyl ester group remains intact under palladium-catalyzed Suzuki-Miyaura cross-coupling conditions that target the 3- or 4-position of the pyrrole after bromination. Bromination of ethyl 5-nitro-1H-pyrrole-2-carboxylate with N-bromosuccinimide in DMF at 0–5 °C proceeds selectively at the 4-position to give ethyl 4-bromo-5-nitro-1H-pyrrole-2-carboxylate in multi-kilogram campaigns with 88–92% yield after crystallization from isopropanol/water. Subsequent coupling with arylboronic acids using Pd(dppf)Cl₂ (2 mol%) and potassium phosphate in 1,4-dioxane at 85 °C for 6 h tolerates the nitro group without reduction, as confirmed by post-reaction ion chromatography that shows less than 0.1% of the derived aniline. In contrast, attempts to perform Negishi couplings with organozinc reagents directly on the 5-nitro-2-ethyl ester substrate require transmetalation protocols that avoid acidic workups—any residual trifluoroacetic acid from HPLC purification will protonate the pyrrole N–H, forming an inhibitory complex with zinc that drops catalytic turnover frequency below 50 h⁻¹.

A practical bottleneck encountered in the large-scale synthesis of this ester is the tendency of the crude nitration product to retain entrained sulfuric acid, which leads to gradual decomposition during drying if the cake is not adequately washed. Washing the filter cake with water until the effluent pH exceeds 5.0, followed by a displacement wash with 0.5% sodium bicarbonate solution and then water again, reduces sulfate residue to <100 ppm. Drying is then conducted in a double-cone dryer under vacuum (<50 mbar) at 50 °C for 16 h, with a slow nitrogen sweep to prevent localized overheating. Batches dried without the nitrogen sweep have shown discoloration to brown, coincident with an increase in peroxide value from <1 meq/kg to 12–15 meq/kg, indicating autoxidation of the pyrrole ring in contact with residual acid and air at elevated temperature.

Nitro group reduction selectivity windows

Selective reduction of the nitro group to the corresponding 5-amino-1H-pyrrole-2-carboxylic acid ethyl ester is the gateway to a library of amide, sulfonamide, and urea derivatives. Catalytic hydrogenation over 5% Pd/C (wet, 50% water) in ethanol at 25 °C and 2.5 bar hydrogen completes within 3–4 h with a catalyst loading of 1% w/w relative to substrate, but the resulting aniline is prone to rapid oxidation upon exposure to air; therefore, transfer hydrogenation with ammonium formate and Pd/C in methanol at 60 °C is often preferred because the aniline precipitates as a formate salt, improving storage stability for up to 72 h at 2–8 °C under argon. A completely non-hydrogenolytic alternative employs tin(II) chloride dihydrate in ethyl acetate at reflux, but the laborious removal of tin residues via precipitation with aqueous potassium fluoride makes this route unattractive beyond 100 g scale. When the ester must remain unchanged, the use of sodium dithionite in water/THF at pH 7–8 is contraindicated because the alkaline conditions promote partial saponification—approximately 7% of the free acid is generated within 2 h at pH 7.5.

The nitro compound also serves as a precursor to nitrene intermediates via deoxygenation with triphenylphosphine at 110 °C in o-dichlorobenzene, a method applied in constructing fused pyrrolo-benzimidazole scaffolds. Here, the ethyl ester is retained until the penultimate step, where alkaline hydrolysis followed by decarboxylative cross-coupling completes the target molecule. The robustness of the ester toward thermal rearrangement has been confirmed by differential scanning calorimetry isothermal age studies at 120 °C for 24 h, showing less than 0.5% decomposition by HPLC.

Regulatory starting material status and supply chain considerations

Ethyl 5-nitro-1H-pyrrole-2-carboxylate can be classified as a regulatory starting material under ICH Q11 when the nitration step is performed at a dedicated manufacturing site and the compound is introduced into the active pharmaceutical ingredient synthesis at a point where enough synthetic steps remain to purge potential genotoxic impurities. The nitration precursor, ethyl 1H-pyrrole-2-carboxylate, and the mixed acid reagents are commercially procured with full REACH registrations. The product itself requires a hazard classification as a skin and eye irritant (EUH066, H315, H319) under Regulation (EC) No 1272/2008. Long-term storage stability data ( 25 °C/60% RH, 36 months ) indicate no significant change in assay or impurity profile when the material is packaged in double low-density polyethylene bags inside a fiber drum with a desiccant pouch. No photodegradation above 0.1% is detected under ICH Q1B Option 2 visible and UV exposure, confirming the suitability of standard amber glass containers for laboratory-scale distribution.

Comparative reactivity of selected pyrrole-2-carboxylate derivatives under standard amidation conditions^a
Substrate	Amine (1.2 eq)	Coupling System	Conversion at 18 h	Product Purity (AUC)
Ethyl 5-nitro-1H-pyrrole-2-carboxylate	Benzylamine	Ti(OiPr)₄ (10 mol%), toluene, 80 °C	94%	98.5%
Methyl 5-nitro-1H-pyrrole-2-carboxylate	Benzylamine	Ti(OiPr)₄ (10 mol%), toluene, 80 °C	96%	97.8%
5-Nitro-1H-pyrrole-2-carboxylic acid	Benzylamine	HATU, DIPEA, DMF, 0–25 °C	88%	94.2%
Ethyl 1H-pyrrole-2-carboxylate (no nitro)	Benzylamine	Ti(OiPr)₄ (10 mol%), toluene, 80 °C	82%	96.0%
^a Reactions conducted at 0.5 M substrate concentration under argon. Conversion and purity determined by HPLC-UV at 254 nm.

Transition-metal-catalyzed decarboxylative cross-coupling of the corresponding free acid, which can be obtained from the ester by hydrolysis, represents an area where the ethyl ester provides a distinct operational advantage. The ester is hydrolyzed quantitatively with 2 M NaOH in ethanol at 60 °C for 1 h, and the resulting sodium carboxylate can be protonated and used directly without isolation as a stock solution in DMSO. This two-step sequence avoids the adsorption losses that occur during crystallization of the nitro acid, which tends to form fine needles that retain up to 8% mother liquor and are difficult to filter. In contrast, the methyl ester is prone to the formation of a partially hydrolyzed half-ester adduct and can require chromatographic purification if the reaction time extends beyond the necessary endpoint.

HS Code	452981
Chemical Formula	C7H8N2O4
Molecular Weight	184.15 g/mol
Appearance	Typically a solid (physical state can vary based on purity and conditions)
Melting Point	Data may vary, needs experimental determination
Boiling Point	Data may vary, needs experimental determination
Solubility In Water	Low solubility, being an organic ester with a nitro group
Solubility In Organic Solvents	Soluble in common organic solvents like ethanol, dichloromethane
Flash Point	Data may vary, needs experimental determination
Pka	No direct pKa data as it's an ester, but the nitro group can influence acidity in relevant reactions
Odor	Odor likely faint and characteristic of organic nitro - containing esters

Packing	100g of 5 - Nitro - 1H - pyrrole - 2 - carboxylic acid ethyl ester in sealed chemical - grade packaging.
Shipping	1H - Pyrrole - 2 - Carboxylic Acid, 5 - Nitro -, Ethyl Ester is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations to ensure safe transit, with proper labeling for hazard identification.
Storage	1H - Pyrrole - 2 - Carboxylic Acid, 5 - Nitro -, Ethyl Ester should be stored in a cool, dry place away from heat sources and open flames. Keep it in a tightly - sealed container to prevent exposure to moisture and air, which could potentially lead to decomposition. Store it separately from incompatible substances like oxidizing agents and bases to ensure its stability and safety.

1H-Pyrrole-2-Carboxylic Acid, 5-Nitro-, Ethyl Ester