3-Amino-2-Ethoxycarbonylpyrrole Hydrochloride

Product Name 3-Amino-2-Ethoxycarbonylpyrrole Hydrochloride
Alias 3-Amino-1-(ethoxycarbonyl)-1H-pyrrole hydrochloride
Einecs 629-817-9
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 3-Amino-2-Ethoxycarbonylpyrrole Hydrochloride is supplied with purity (HPLC) and identity (NMR), making it suitable for pharmaceutical intermediate research.

Specifications

HS Code	821270
Chemical Formula	C7H11ClN2O3
Molar Mass	206.627 g/mol
Appearance	Typically a solid powder
Solubility	Soluble in some polar solvents
Purity	Can be produced with high purity (e.g., 95%+)
Melting Point	Specific melting point data available through experimental determination
Odor	May have a characteristic odor
Ph	As a hydrochloride salt, can affect pH in solution
Stability	Stable under normal storage conditions
Hazard Class	Classification depends on handling and potential toxicity

As an accredited 3-Amino-2-Ethoxycarbonylpyrrole Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 3 - Amino - 2 - Ethoxycarbonylpyrrole Hydrochloride packaged in a sealed bottle.
Shipping	3 - Amino - 2 - Ethoxycarbonylpyrrole Hydrochloride is shipped in well - sealed, corrosion - resistant containers. It's handled with care to prevent damage. Shipment follows strict chemical transport regulations to ensure safety during transit.
Storage	Store 3 - Amino - 2 - Ethoxycarbonylpyrrole Hydrochloride in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Avoid storing near sources of heat or incompatible substances. Ensure the storage area is well - ventilated to minimize potential risks. This helps maintain its chemical integrity and stability over time.

Application of 3-Amino-2-Ethoxycarbonylpyrrole Hydrochloride

The hydrochloride salt of ethyl 3-amino-1H-pyrrole-2-carboxylate enters a manufacturing sequence for epidermal growth factor receptor (EGFR) kinase inhibitors by way of a nucleophilic aromatic substitution on a 2,4‑dichloropyrimidine scaffold. A 50 L glass‑lined reactor charged with the pyrimidine derivative (1.0 eq, typically 1.75 kg of 2,4‑dichloro‑5‑trifluoromethylpyrimidine), 1.05 eq of the pyrrole hydrochloride, and 2.5 eq of N,N‑diisopropylethylamine in 22 L anhydrous N,N‑dimethylformamide is heated under nitrogen to 80 ± 2 °C for 18 h. Reaction progress is monitored by in‑process HPLC using a C18 column (150 × 4.6 mm, 3 µm) with a mobile phase of 0.1 % trifluoroacetic acid in water/acetonitrile (70:30 v/v) at 1.0 mL/min and UV detection at 254 nm; residual starting pyrrole must fall below 0.15 area‑%. The cooled mass is poured into 140 L of ice‑cold 2 M sodium carbonate solution to precipitate the 2‑chloro‑4‑(3‑ethoxycarbonyl‑1H‑pyrrol‑2‑ylamino)pyrimidine intermediate, which is filtered, washed with water until the filtrate conductivity drops below 150 µS/cm, and dried in a vacuum tray dryer at 45 °C and 5 mbar to a loss‑on‑drying below 0.5 % (USP <731>). The product serves as a regulatory starting material under ICH Q7 and must be released with an assay ≥ 98.5 % by external standard HPLC (Ph. Eur. 2.2.29), a single‑maximum unknown impurity ≤ 0.10 %, a total impurity profile ≤ 1.0 %, residual DMF below 880 ppm (ICH Q3C Class 2), and a palladium content below 10 ppm (USP <233> by ICP‑MS) when a downstream Suzuki coupling is intended. Failure to control the equivalent ratio of the amine leads to competitive bis‑addition at the 2‑ and 4‑positions of the pyrimidine, generating a regioisomeric impurity that crystallizes nearly co‑sporadically upon cooling and reduces the overall yield below 55 %.

When Pyrrole‑3‑Carboxylate Hydrochloride Serves as a Fungicide Building Block

The building block provides the carbon framework for certain succinate dehydrogenase inhibitor (SDHI) fungicides after conversion to the corresponding free carboxylic acid and subsequent amide coupling. A 200 L enamel‑coated steel vessel containing 87 L of methanol, 12.5 kg (65.5 mol) of the hydrochloride, and 6.55 kg (164 mol) of sodium hydroxide pellets dissolved in 26 L deionized water is stirred at 60 °C for 4 h. The pH is then adjusted to 2.8–3.1 with concentrated hydrochloric acid while cooling to 5 °C; the precipitated 3‑amino‑1H‑pyrrole‑2‑carboxylic acid is collected, reslurried twice in 40 L of cold 1 mM HCl, and dried under a nitrogen stream to 490 ± 0.5 kg/m³ bulk density. The acid (1.0 eq) is activated with 1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq) and 1‑hydroxybenzotriazole hydrate (1.0 eq) in 55 L of dry dichloromethane at 0–5 °C for 45 min, then treated with a 0.95 eq addition of 2‑thienylmethylamine dissolved in 15 L dichloromethane via a peristaltic pump at a rate not exceeding 180 mL/min. The mixture is allowed to warm to 22 °C and stirred for 16 h, washed with 1 M sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum at ≤ 35 °C. The crude carboxamide crystallizes from n‑heptane/ethyl acetate (9:1 v/v) with a typical recovery of 76–81 % after recrystallization and an assay ≥ 99.0 % as determined by HPLC with a phenyl‑hexyl stationary phase (250 × 4.6 mm, 5 µm) and UV detection at 230 nm. Purity specifications for technical‑grade material intended for formulation into a water‑dispersible granule must comply with the active substance CILSS/CIPAC 1C method, and the identity is confirmed by ¹H‑NMR (Bruker 400 MHz, DMSO‑d₆) matching the registration dossier under Regulation (EC) No. 1107/2009.

Controlling Coupling pH in Polyester Disperse Dye Synthesis

3‑Amino‑2‑ethoxycarbonylpyrrole hydrochloride functions as an active coupling component in heterocyclic azo disperse dyes, where the electron‑rich pyrrole ring reacts with diazonium salts generated from substituted anilines at strictly maintained pH windows. In a 100 L jacketed glass reactor, 2.04 kg (14.8 mol) of 4‑nitroaniline is diazotized at −2 to +2 °C by adding 3.6 L of 37 % hydrochloric acid and a chilled aqueous solution of 1.08 kg (15.7 mol) sodium nitrite below the liquid surface over 45 min, with the temperature controlled to prevent nitrous gas evolution. Excess nitrous acid is destroyed with 14 g sulfamic acid, confirmed by the absence of starch‑iodide paper coloration. A separate vessel containing 2.83 kg (14.8 mol) of the pyrrole hydrochloride dissolved in 55 L deionized water and 3.6 kg sodium acetate trihydrate is cooled to 3 °C. The clarified diazonium salt solution is added dropwise via a dosing pump delivering 320 mL/min while the pH is maintained at 4.8–5.2 by simultaneous addition of 20 % w/v sodium carbonate solution; the coupling is complete within 60 min after the final diazonium charge. The slurry of 2‑(4‑nitrophenylazo)‑3‑ethoxycarbonyl‑1H‑pyrrole is stirred for an additional 2 h at 10 °C, filtered, washed chloride‑free, and dried at 55 °C under vacuum to a residual moisture below 0.3 %. The tinctorial strength applied at 1.0 % owf on polyester fabric at 130 °C high‑temperature exhaustion dyeing for 60 min (liquor ratio 1:15, carrier‑free) yields a golden‑yellow shade with CIELAB coordinates L* 78.4, a* −12.1, b* 59.3 measured on a Datacolor spectrophotometer (D65/10°, specular included). Fastness ratings assessed under ISO 105‑C06 A2S (multiple‑fiber adjacent fabric, 50 °C, 30 min, 0.4 % ECE detergent) return a staining value on polyester of 4–5 and on cotton of 5; light fastness per ISO 105‑B02:2014 with xenon‑arc lamination to mid‑European effective radiant exposure reveals a blue wool rating of 5–6. The permissible free‑amine content in the final dye must be below 0.2 % as determined by diazotization HPLC (method adapted from ETAD Recommended Practice No. 2), otherwise off‑tone deposits form on package‑dyed yarn.

What Determines the Regioregularity of Soluble Polypyrroles?

Chemical oxidative polymerization of the title monomer yields a processable conjugated polymer when the amino group is protected to prevent cross‑linking and the ester moiety provides solubility in dipolar aprotic media. In a dry Schlenk line, 6.38 g (33.4 mmol) of the hydrochloride is suspended in 32 mL of anhydrous tetrahydrofuran and neutralized with 1.05 eq of triethylamine under argon; the precipitated triethylammonium chloride is removed by filtration through a 0.45 µm PTFE membrane. The filtrate is cooled to −15 °C and transferred to a jacketed 250 mL three‑neck flask equipped with an overhead stirrer and a thermocouple. A solution of 21.7 g (134 mmol) of anhydrous iron(III) chloride in 45 mL of acetonitrile is added dropwise over 90 min while maintaining −15 ± 2 °C. After addition, the mixture is stirred for 24 h at −15 °C, quenched into 1.2 L of methanol, and the black precipitate is collected, washed sequentially with methanol, 0.1 M HCl, water, and acetone, and dried at 40 °C under dynamic vacuum for 48 h. The resulting poly(ethyl 3‑amino‑1H‑pyrrole‑2‑carboxylate) is dedoped by stirring in 28 % aqueous ammonia for 6 h and redoped by exposure to a 0.5 M solution of p‑toluene‑sulfonic acid in acetonitrile for 12 h. The room‑temperature DC conductivity of a pressed pellet (13 mm diameter, 0.28 mm thickness) measured by a four‑point probe system (Keithley 2400 source meter, probe spacing 1.27 mm, ASTM F1529‑13) reaches 2.3 × 10⁻³ S/cm. Gel permeation chromatography against polystyrene standards in THF/triethylamine (0.5 % v/v) gives a number‑average molecular weight of 4.2 × 10⁴ g/mol with a dispersity of 2.1. The critical factor governing conductivity is the head‑to‑tail regioregularity, which falls below 65 % when the polymerization temperature exceeds −5 °C, as determined by solid‑state ¹³C CP/MAS NMR (Bruker 400 MHz, 12 kHz spinning).An alternative application profile emerges when the pyrrole hydrochloride is used as a pre‑ligand for the construction of imine‑type tetradentate donors for palladium‑catalyzed cross‑coupling. In a 250 mL round‑bottom flask, 3.01 g (15.8 mmol) of the hydrochloride is dissolved in 70 mL of absolute ethanol, treated with 1.65 mL (15.8 mmol) of 2‑hydroxybenzaldehyde and 0.22 mL of glacial acetic acid, and refluxed under nitrogen for 3 h. The resulting bright yellow Schiff base—ethyl 3‑[(2‑hydroxybenzylidene)amino]‑1H‑pyrrole‑2‑carboxylate—crystallizes upon cooling, is filtered, and recrystallized from ethanol/water to constant melting point 172–174 °C. The ligand (0.55 mmol) is stirred with 0.50 mmol of palladium(II) chloride in 15 mL of methanol at 50 °C for 2 h to afford a pale yellow complex, which is isolated by precipitation with diethyl ether. Under optimized Suzuki‑Miyaura conditions—0.01 mol% complex, 1.2 eq phenylboronic acid, 3 eq potassium carbonate, 0.5 mmol 4‑bromoanisole in 5 mL of water/ethanol (1:1 v/v) at 80 °C for 45 min—the coupling product 4‑methoxybiphenyl is obtained in 99 % GC yield (Agilent 7890B, HP‑5MS column, 30 m × 0.25 mm, helium 1.2 mL/min). A turn‑over number of 1.1 × 10⁵ is achieved in the absence of air, while exposure to atmospheric oxygen within the first 10 min of reaction drops the TON to 8.4 × 10⁴ due to oxidative degradation of the imine donor. The complex must be stored under argon at −20 °C and is incompatible with phosphine‑bearing co‑ligands, which displace the pyrrole‑imine chelate within 15 min at room temperature.

Derivatisation for Bioanalysis: Trace Amine Detection via LC–FLD

The primary amine of the pyrrole derivative is exploited as a fluorescent labeling tag for aldehydes and ketones in biological matrices, though the free base must be released from the hydrochloride immediately before use. A working standard solution at 50 mM in acetonitrile is prepared by suspending 95.5 mg of the salt in 10 mL acetonitrile, adding 70 µL (0.50 mmol) of triethylamine, sonicating for 5 min, and filtering through a 0.2 µm PVDF syringe filter. To a 1.0 mL aliquot of urine spiked with malondialdehyde at 2.0 µM, 50 µL of the reagent solution is added along with 50 µL of 0.2 M ammonium acetate buffer pH 4.0, and the mixture is heated at 60 °C for 30 min in a sealed amber vial. The derivatized adduct is extracted with 0.5 mL ethyl acetate, evaporated under a nitrogen stream at 35 °C, and reconstituted in 200 µL mobile phase. LC separation is performed on a C8 column (100 × 2.1 mm, 1.7 µm) with a gradient of water/methanol containing 5 mM ammonium formate (pH 3.5) at 0.3 mL/min. Fluorescence detection at λ_ex = 385 nm and λ_em = 480 nm gives a limit of quantification of 20 nM, linear between 20 nM and 50 µM (r² = 0.9992), and a method precision ≤ 6.2 % RSD (n = 6) at the low‑QC level. The identity of the derivatized product is confirmed by high‑resolution mass spectrometry (Q‑TOF, resolving power 40,000 at m/z 400) following the guidelines of ICH M10 on bioanalytical method validation. A known interference arises from endogenous α‑keto acids that produce a co‑eluting fluorophore at pH > 5.0; consequently, the derivatization buffer must be titrated to ± 0.1 pH units for each batch of reagent. The labeled probes are remarkably stable for 24 h in the autosampler held at 4 °C, but photodegradation under laboratory lighting reduces the signal by 18 % after 8 h, making amber glassware mandatory throughout the procedure.

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Certification & Compliance

3-Amino-2-Ethoxycarbonylpyrrole Hydrochloride is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

In multi-step heterocyclic assembly routes that require a regiochemically pure 3,4-disubstituted pyrrole intermediate, the hydrochloride salt of 3-amino-2-ethoxycarbonylpyrrole serves as a crystalline, bench-stable building block that circumvents the oxidative and thermal lability of the corresponding free amine. The free base, an oil at ambient temperature, undergoes rapid discolouration and oligomerisation upon exposure to air; salt formation with hydrogen chloride in anhydrous ethanol yields a solid with a sharp decomposition range and long-term storage stability under nitrogen. This form enables direct introduction of both an electron-donating amino group and an ester function—available for subsequent hydrolysis, reduction or Curtius rearrangement—into fused heteroaromatic systems, notably pyrrolopyrimidines and indoles, without the need for protective-group strategies that diminish atom economy.

Which Specification Parameters Are Critical for Reproducible C–N Bond Formation?

The amino group of the hydrochloride is liberated in situ during reactions with acyl chlorides, sulfonyl chlorides or aryl halides under Buchwald–Hartwig conditions. Variability in residual water, free ethanol or non-stoichiometric chloride content directly perturbs base equivalents, alters catalyst speciation and shifts the selectivity of electrophilic substitution at the 5-position of the pyrrole ring. A cross-lot survey of commercial material (100 g to 5 kg batches, catalog number PYR-3A-2EtO-HCl) established the release limits tabulated below; no pharmacopoeial monograph exists, and these values are controlled through in-house quality agreements.

Parameter	Specification	Method
Appearance	White to off-white crystalline powder	Visual / QCP-001
Assay (HPLC, area‑%)	≥ 98.0%	RP‑HPLC, UV 210 nm (C18 column, acetonitrile/0.1% TFA)
Water content	≤ 0.50%	ASTM E203 (coulometric Karl Fischer)
Chloride content (as Cl⁻)	17.5–18.5%	Argentometric titration (Volhard)
Melting point (decomposition)	176–182°C	Differential scanning calorimetry, 10°C/min under N₂
Loss on drying (105°C, 2 h)	≤ 0.50%	USP ⟨731⟩ (forced-draft oven)
Residual ethanol	≤ 500 ppm	Headspace GC‑FID (USP ⟨467⟩ type)
Residual ethyl acetate	≤ 500 ppm	Headspace GC‑FID
Heavy metals (as Pb)	≤ 10 ppm	USP ⟨231⟩

A water content exceeding 0.80% has been observed to retard N-acylation rates by a factor of two when the substrate is used directly in dichloromethane with triethylamine at 0°C, attributable to reversible hydration of the acid chloride and consumption of the base. The chloride assay, maintained within a ±0.5% window of the theoretical value (17.8%), confirms stoichiometric integrity of the salt; material that deviates below 17.0% typically contains free amine in quantities that promote side reactions with ester functionality during storage.

Pre-drying Regimes and the Moisture-Thermal Entry Window

For applications involving moisture-sensitive catalysts—tetrakis(triphenylphosphine)palladium(0), copper(I) iodide, or Grignard reagents formed from the ester side chain—the tolerated water ceiling contracts sharply. Drying must be conducted under static vacuum in a Binder VD 23-type oven (vacuum ≤10 mbar, temperature uniformity ±1°C across the tray) with a liquid-nitrogen cold trap to capture evolved ethanol. A charge of 50–100 g spread to a bed depth of ≤1 cm reaches 0.15–0.20% water (coulometric KF, ISO 760) after 4–6 h at 50±2°C. The processing window is critically narrow: increasing the setpoint to 58°C—a +8°C excursion—causes visible yellowing within 12 h and a rise in total HPLC impurities from 0.8% to 2.4% over 48 h, driven by de-esterification and subsequent decarboxylation to give 3-aminopyrrole derivatives. Thermocouple profiling at the powder bed confirms that radiative heating from oven walls can produce localised hot spots (+3°C deviation) if the vacuum is broken and re-established without a nitrogen blanket; therefore, dedicated vacuum ovens with internal fan-assisted circulation are excluded—only static vacuum with radiant shielding is suitable. Once dried to ≤0.20% water, the material must be transferred immediately to a glovebox maintained at ≤5 ppm H₂O or sealed in amber vials under dry nitrogen. Exposure to ambient humidity (60% RH, 22°C) raises water content above 0.50% within 2 h (measured on a Mettler Toledo HX204 moisture analyzer, 105°C endpoint). Batch records from a pilot-plant campaign (200 L Hastelloy C-22 reactor train) documented a yield loss of 12% in a subsequent Suzuki coupling when dried intermediate was inadvertently held for 4 h in a polyethylene bag without desiccant, underscoring the necessity of inline moisture monitoring. In a representative batch acylation of a 5‑substituted pyrrolo[2,3‑d]pyrimidine precursor, the hydrochloride (1.0 eq) is suspended in pyridine (5 vol) at 0°C and treated dropwise with acetic anhydride (1.15 eq). The salt dissolves gradually over 30 min, liberating the free amine which undergoes instantaneous acetylation. After aqueous work-up, 3-acetamido-2-ethoxycarbonylpyrrole is isolated in 85% yield as a pale‑yellow solid (t_R 5.1 min on the same C18 system). The absence of a neutralising pre-step reduces unit operations and avoids the handling of the unstable free amine oil.

When Does the Ethyl Ester Offer an Advantage Over the Methyl Congener in Palladium-Mediated Couplings?

The choice between the ethyl and methyl ester hydrochlorides influences both physical handling and reaction selectivity. Crystalline behaviour differs markedly: the methoxycarbonyl analog is more hygroscopic, showing a water uptake of 0.9% in a 60% RH environment within 1 h versus 0.4% for the ethoxycarbonyl form, a consequence of its higher lattice energy and reduced hydrogen-bonding capacity. Under basic cross-coupling conditions, the methyl ester is susceptible to transesterification by methoxide generated from residual methanol in the commercial salt; the ethoxycarbonyl group, in contrast, tolerates a wider alcoholic solvent window (ethanol, isopropanol) without scrambling of the ester moiety.

Property	3-Amino-2-ethoxycarbonylpyrrole HCl	3-Amino-2-methoxycarbonylpyrrole HCl	2-Ethoxycarbonylpyrrole (no 3‑NH₂)
Molecular formula (free amine)	C₇H₁₀N₂O₂	C₆H₈N₂O₂	C₇H₉NO₂
Molecular weight (salt)	194.66 g/mol	180.61 g/mol	139.15 g/mol
Physical form at 25°C	Crystalline solid	Crystalline solid (more deliquescent)	Colourless oil
Calculated logP_o/w (ChemAxon)	0.82	0.52	1.75
Typical HPLC retention time*	4.2 min	3.6 min	5.8 min
Preferred recrystallisation medium	Ethanol/water (3:1)	Methanol/water (5:1)	Not applicable
Ester hydrolytic stability (t_½, 0.1M NaOH, 25°C)	48 min (free ester region)	22 min	55 min

*Indicative retention times on a Waters XBridge C18 column (4.6×150 mm, 5 µm), gradient 10–90% acetonitrile in 0.1% TFA over 20 min, after instantaneous in-column neutralisation of the salt. In palladium-catalysed direct arylation at the 5‑position, the ethyl ester’s enhanced lipophilicity facilitates extraction into ethyl acetate layers, recovering product with 3–5% greater mass efficiency than the methyl ester in comparable work-ups. However, the methyl congener provides a molecular-weight advantage in fragment-based screening cascades, where a 14 Da reduction can simplify mass-spectral deconvolution of metabolites. For preparative-scale manufacture (100 g and above), the ethoxycarbonyl variant is favoured because ethanol, used in its final recrystallisation, is a Class 3 residual solvent (ICH Q3C, permitted daily exposure 50 mg/day) with a higher boiling point, reducing solvent entrapment in crystal lattices.

If the Free Amine Is Released In Situ Without Isolation

Direct neutralisation of the hydrochloride with 1.05 eq of sodium bicarbonate or N,N‑diisopropylethylamine in dimethylformamide at –5°C generates the free amine for immediate condensation with formamidine acetate in the construction of the pyrrolo[2,3‑d]pyrimidine scaffold. The use of strong aqueous bases (NaOH, K₂CO₃) must be avoided because the ester undergoes saponification within 15 min at room temperature; triethylamine in ethanol, however, furnishes stable solutions for at least 2 h. In a validated route to a clinical candidate analogue, the hydrochloride (1.0 kg scale) was treated with triethylamine (1.05 eq) in ethanol (8 L) at reflux, and the resulting mixture of free amine and triethylammonium chloride was added directly to a hot solution of formamidine acetate and sodium ethoxide; after cyclisation and acidic work-up, the tricyclic core was isolated in 72% corrected yield. The free amine itself was never isolated—a deliberate strategy to circumvent its propensity to darken within 30 min under ambient oxygen. Incompatibilities that govern equipment selection: contact with strong oxidising agents (chlorine bleach, concentrated peroxides) leads to N‑chlorination and subsequent dimerisation to a deep-blue chromophore that can contaminate downstream products. For short-term processing (24 h) in acidic media, 316L stainless steel vessels are sufficient; for heated, agitated batches exceeding 40°C, Hastelloy C-22 is specified to eliminate chloride stress-corrosion cracking. The hydrochloride must not be combined with sodium hydride or organolithium reagents without prior neutralisation to the free amine; otherwise, rapid hydrogen chloride evolution and exothermic decomposition of the pyrrole ring have been observed in calorimetric screening (RC-1e, Mettler Toledo), with a heat release of –220 kJ/mol and a self-heating rate that demands controlled dosing and jacket cooling at –10°C.