3-Aminopyrrolidine

Product Name 3-Aminopyrrolidine
Alias 1,2,3-Tetrahydropyrrole-3-amine
Einecs 629-749-5
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-Aminopyrrolidine is supplied with assay (GC) ≥ 98% and water content (KF) ≤ 0.5%, making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	720808
Name	3 - Aminopyrrolidine
Molecular Formula	C4H10N2
Molar Mass	86.14 g/mol
Appearance	Colorless to light yellow liquid
Boiling Point	160 - 162 °C
Melting Point	N/A
Density	0.992 g/cm³
Solubility In Water	Soluble
Flash Point	62 °C
Pka	10.75
Odor	Ammonia - like odor
Ph	Basic

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

Packing & Storage

Packing	100 - gram bottle of 3 - Aminopyrrolidine, securely sealed for chemical storage.
Shipping	3 - Aminopyrrolidine is shipped in accordance with strict chemical regulations. It is packaged securely in appropriate containers to prevent leakage. Shipments are handled by carriers trained in transporting hazardous chemicals, ensuring safety during transit.
Storage	3 - Aminopyrrolidine should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store it in a tightly sealed container to prevent exposure to air and moisture, which could lead to degradation or unwanted reactions. Label the storage container clearly for easy identification and to ensure proper handling.

Application of 3-Aminopyrrolidine

When the 7-Chloro Substituent Requires Selective Displacement via (S)-3-Aminopyrrolidine in Tosufloxacin Tosylate Production

In the manufacture of tosufloxacin tosilate API, the quinolone carboxylic acid intermediate 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (or its ethyl ester) is condensed with optically active (S)-3-aminopyrrolidine dihydrochloride under strictly anhydrous conditions. The displacement reaction proceeds in dimethyl sulfoxide or dimethylformamide at a temperature maintained between 85°C and 95°C for a duration of 6–8 h, using an excess of amine at a molar ratio of 1.0:1.05–1.10 (core:amine) to compensate for competing hydrolysis of the 7-chloro leaving group. Triethylamine is employed as an acid scavenger, charged at 2.0–2.5 equivalents relative to the core. Post-reaction, the mixture is cooled to 20–25°C and quenched into purified water, where the crude tosufloxacin base precipitates as a crystalline solid; subsequent recrystallization from ethanol/water (v/v 70:30) yields the API with a purity exceeding 99.5% (by HPLC, area normalization). The final tosilate salt formation is carried out in ethanol with p-toluenesulfonic acid monohydrate. Compliance with ICH Q7 Section 12.1 (cleaning validation) and adherence to the European Pharmacopoeia monograph for tosufloxacin tosilate (EP 2204) dictate limits for known impurities, particularly the des-chloro byproduct (≤0.10%) and the N-formyl derivative (≤0.15%), which are monitored using a C18 column at 280 nm. Glass-lined reactors with a jacket temperature uniformity of ±1.5°C are preferred to avoid localized overheating that promotes dimer formation. The terminal dosage form is the oral tosufloxacin tosilate tablet, typically supplied in 150 mg and 200 mg strengths for respiratory and urinary tract infection indications.

In the production route to balofloxacin, the introduction of the (3-aminopyrrolidin-1-yl) group at the C-7 position of the 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid scaffold requires careful management of the 8-methoxy substituent’s steric and electronic effects. Unlike non-methoxylated quinolones, the electron-donating methoxy group retards nucleophilic aromatic substitution; accordingly, the molar ratio of (S)-3-aminopyrrolidine to the quinolone core is raised to 1.0:1.15–1.25 and the reaction is conducted in N-methylpyrrolidone at 100–105°C for 8–10 h under a nitrogen atmosphere. Potassium carbonate (1.5 eq.) replaces triethylamine to enhance deprotonation and to avoid side reactions with the methoxy group. After completion, solvent is removed under reduced pressure (≤50 mbar, bath temperature 60°C), and the residue is recrystallized from isopropanol to obtain balofloxacin with residual N-methylpyrrolidone below 410 ppm in compliance with ICH Q3C guidelines. The process fits within cGMP frameworks per 21 CFR Part 211 and requires in-process control for the des-methoxy impurity (limit ≤0.15%) by HPLC. The terminal dosage form is balofloxacin oral tablets, usually 100 mg strength, as listed in the Japanese Pharmacopoeia (JP 18).

What Limits the Enantiomeric Purity of the (S)-3-Aminopyrrolidine Moiety in Prulifloxacin Precursors?

When synthesizing the prulifloxacin prodrug, the (S)-3-aminopyrrolidine side chain is first incorporated into the quinolone acid intermediate 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-1,4-dihydro-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid. Subsequent acetylation at the pyrrolidine nitrogen furnishes the prodrug, which relies on hepatic esterase activation. Optical purity of the amine fragment is critical because the (R)-enantiomer alters pharmacokinetics; thus, the (S)-3-aminopyrrolidine free base (ee ≥ 99.0%, measured by chiral HPLC with a Chiralpak AD-H column) is used at a precise stoichiometric ratio of 1.00:1.00 to avoid kinetic resolution complications during coupling. The condensation is performed in acetonitrile at reflux (81°C) with 1.0 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene over 12 h, yielding the penultimate intermediate. To meet ICH Q6A specifications, the diastereomeric purity is verified with a detection limit of 0.05% for the R,R isomer. Crystallization from ethyl acetate/hexane (1:3) reduces palladium residues (from a prior hydrogenation step) to <10 ppm, aligning with EMA/CHMP/SWP/4446/2000. The final product is prulifloxacin, a prodrug approved for urinary tract infections in Japan and Italy, subsequently formulated into 600 mg tablets.

Pyrrolidine-based Organocatalyst Assembly — From Amine Monomer to Prolinamide Derivatives

(S)-3-Aminopyrrolidine serves as a chiral building block for prolinamide-type organocatalysts employed in asymmetric aldol and Michael addition reactions. A typical preparation involves amidation of the free amine with tert-butoxycarbonyl-protected L-proline using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole in dichloromethane at 0–5°C, keeping the molar ratio proline:amine at 1.0:0.98 to ensure complete consumption of the valuable amine. After Boc deprotection with trifluoroacetic acid, the catalyst is isolated as a hydrochloride salt. Production-scale batches up to 5 kg in a 50 L jacketed cylindrical reactor with anchor stirrer at 80 rpm achieve a mean yield of 72% after recrystallization from methanol/diethyl ether. These catalysts must meet residual solvent and heavy metal limits consistent with REACH Annex XVII entries and are often further tested for endotoxin levels (<0.25 EU/mg) when the target catalyst is intended for use in a drug substance manufacturing line. The end products are enantiomerically enriched β-hydroxy ketones or nitroalkane Michael adducts, not a commercial API, making the organocatalyst a specialty performance chemical requiring batch-specific identity confirming by polarimetry (specific rotation [α]_D²⁰ checked against a certified reference).

Nitro Reduction Efficiency as a Function of Particle Size in Aminopyrrolidine-mediated Agrochemical Synthesis

In the synthesis of a proprietary insecticide intermediate—5-amino-1-(3-chloropyridin-2-yl)-3-pyrrolidinol—the nitration of a pyridine derivative followed by catalytic reduction using 3-aminopyrrolidine as the hydrogenation substrate for in situ imine formation is an established route. The addition ratio is dictated by the stoichiometry of the condensation between the nitro-pyridine and the primary amine: 1.0:0.95 (nitro intermediate: 3-aminopyrrolidine) under 4.0 bar hydrogen pressure with Raney nickel catalyst (type 2400, 3 wt% loading relative to substrate) in methanol at 40°C. Particle size of the Raney nickel slurry is controlled at D50 20–25 µm to minimize agglomeration and maintain a filtration pressure drop below 0.2 bar during catalyst recovery. The exotherm is managed by a cascade control loop that modulates the hydrogen feed rate, keeping the reactor temperature deviation within ±1.0°C. Purity of the resulting amine intermediate, as determined by GC-MS after derivatization, exceeds 98.5%. The process complies with FAO specification guidelines for pesticide manufacturing (AGP: CP/321) and requires documentation of trace N-nitrosamine levels (<0.05 ppm) under Directive 98/83/EC. The final active ingredient is a pyrrolidine-substituted neonicotinoid analogue, formulated into suspension concentrate or wettable powder end-use products.

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Certification & Compliance

3-Aminopyrrolidine 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

3-Aminopyrrolidine (CAS 79286-79-6 for the racemic mixture; enantiopure designations assigned as (R)- and (S)- under CAS 116183-81-4 and 114715-39-8, respectively) represents a saturated five-membered heterocyclic diamine with one primary amine substituent at the 3-position. Its molecular formula C₄H₁₀N₂ corresponds to a molecular weight of 86.14 g·mol⁻¹. The free base is a clear, water-white to pale yellow liquid with a characteristic amine odor; density at 20 °C typically falls in the range 0.965–0.975 g·mL⁻¹ depending on enantiomeric purity and thermal history. Refractive index n_D²⁰ is recorded at 1.478–1.482. Boiling point exhibits stereochemical sensitivity: racemic material distills between 150–155 °C at 760 mmHg, while (S)-3-aminopyrrolidine shows a boiling point elevation to 162–165 °C under identical pressure. The compound is miscible with water, lower alcohols, and polar aprotic solvents such as dimethylformamide and tetrahydrofuran; solubility in aliphatic hydrocarbons is limited to <1% w/w. Commercial availability spans three purity tiers—technical, pharmaceutical intermediate, and GMP-compliant—with assay specifications driven by the end-use requirements of active pharmaceutical ingredient (API) synthesis and fine chemical manufacturing.

What Differentiates 3-Aminopyrrolidine from Its Positional Isomers in Amide Formation?

The reactivity profile of 3-aminopyrrolidine in acylations and reductive aminations diverges sharply from that of the 2-amino isomer and the parent pyrrolidine. The difference originates in the steric and electronic environment of the primary amine relative to the secondary ring nitrogen. In 2-aminopyrrolidine, the amino group is situated on the carbon adjacent to the ring nitrogen, creating a 1,2-diamine motif that readily participates in intramolecular cyclization to form imidazoline or tetrahydropyrimidine derivatives under mildly acidic conditions. This instability renders the free base of 2-aminopyrrolidine inconvenient for direct use; synthetic operations preferentially employ the hydrochloride salt (mp 138–142 °C) and require strict pH control during workup. In contrast, the 1,3-relationship in 3-aminopyrrolidine precludes formation of five-membered cyclic amidines via simple dehydration; the six-membered cyclization pathway is kinetically disfavored at temperatures below 80 °C, permitting clean N-acylation with chloroformates or activated esters without competing ring closure. The parent pyrrolidine lacks the exocyclic amine entirely, limiting its derivatization to N-functionalization.

Parameter	Pyrrolidine	2-Aminopyrrolidine (free base)	3-Aminopyrrolidine
CAS number	123-75-1	Not isolated as stable free base	79286-79-6 (rac.)
Molecular weight (g·mol⁻¹)	71.12	86.14	86.14
Boiling point (°C, 760 mmHg)	87–88	Decomposes; hydrochloride MP 138–142	150–155 (rac.); 162–165 ((S)-)
pK_a of conjugate acid (ring N, 25 °C, 0.1 M)	11.3 (potentiometric)	Not determined for free base	9.2–9.5 (potentiometric)
Intramolecular cyclization tendency	None	High; imidazoline formation at pH 4–6	Low; six-membered ring closure requires >120 °C in neat
Preferred handling form	Liquid, stored under N₂	Hydrochloride salt, stored desiccated	Free base or hydrochloride; pre-dry if RH >60%

The hydrochloride salt of 3-aminopyrrolidine, obtained by treatment of the free base with anhydrous HCl in diethyl ether, offers improved ambient stability for long-term storage. Moisture uptake studies at 25 °C and 75% relative humidity measured by dynamic vapor sorption (DVS) show that the free base adsorbs 4.2 wt% water within 2 hours, while the hydrochloride salt under identical conditions shows a mass increase limited to 0.8 wt%. Karl Fischer titration according to DIN 51777 on freshly opened containers of free base typically returns water content between 0.3–0.5 wt%; after 30-minute exposure to laboratory air at 55% RH, the water content rises to 1.2–1.8 wt%. For moisture-sensitive transformations such as Grignard additions or lithium amide base formation, the free base is therefore subjected to vacuum drying (10 mbar, 40 °C, 12 h) until Karl Fischer reading ≤200 ppm. Storage recommendation: amber glass bottles under an inert atmosphere (argon or nitrogen), sealed with PTFE-lined caps, and kept at 2–8 °C for long-term stability; under these conditions, re-test of assay by GC after 12 months reveals a purity drop of less than 0.3 area%.

Specification Gradients Across Pharmaceutical and Industrial Tiers

Parameter	Test Method	Technical Grade	Pharmaceutical Intermediate
Assay (GC area%)	In-house GC-FID, DB-5 column, 30 m	≥95.0%	≥99.0%
Water content (KF)	DIN 51777	≤1.0%	≤0.3%
Enantiomeric excess (chiral HPLC)	Chiralpak IA, hexane/EtOH	Not required	≥99.5%
Any single impurity (GC)	Same GC method	≤2.0%	≤0.3%
Appearance	Visual	Pale yellow liquid	Colorless to faint yellow liquid
Chloride content (by ion chromatography)	DIN EN ISO 10304-1	Not specified	≤0.05%

3-Aminopyrrolidine serves as a chiral auxiliary or building block in the synthesis of dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin. In a typical pilot-scale reductive amination of 3-aminopyrrolidine with a trifluorophenyl acetone derivative, the reaction is conducted in a 500 L glass-lined reactor equipped with a retreat-blade impeller and a jacket temperature control system capable of maintaining internal temperature within ±2 °C. The amine (1.1 eq) is charged as a THF solution, followed by dropwise addition of the ketone at 0–5 °C to limit Schiff base hydrolysis; the temperature is then raised to 20 °C and sodium triacetoxyborohydride (1.3 eq) is added in five portions over 60 minutes with vigorous stirring to maintain a Reynolds number > 10,000 in the reactor. Reaction progress is monitored by in-line ReactIR tracking of the acetone carbonyl band at 1715 cm⁻¹ and confirmed by HPLC (C18 column, UV 210 nm). Conversion typically exceeds 97% after 4 h. Critical process parameter: the pH must be kept below 6.5 to suppress dialkylation; addition of acetic acid (0.5 eq relative to amine) is employed as buffer. The crude product is isolated by pH adjustment to 10–11 with 2 M NaOH and extraction with dichloromethane, followed by distillation under reduced pressure (90–95 °C at 15 mbar) to yield the secondary amine intermediate with chemical purity > 98.5% by GC. This procedure, adapted from patent literature and scale-up reports, illustrates the synergy between amine nucleophilicity and the absence of competing N-alkylation at the adjacent position—a distinct advantage over 2-aminopyrrolidine, where amine self-condensation lowers yield to 70–75% under identical conditions. The enantiopure (S)-3-aminopyrrolidine required for sitagliptin synthesis can be obtained via lipase-catalyzed kinetic resolution of the racemic amine. Using immobilized Candida antarctica lipase B (CAL-B, Novozym 435) in 2-methyltetrahydrofuran at 40 °C, with vinyl acetate as the acyl donor, enantioselective acylation preferentially converts the (S)-amine to the corresponding acetamide, leaving (R)-amine unreactive. The reaction is monitored by chiral GC (Chiraldex B-PH column, 30 m) and stopped at 55–60% conversion to maximize enantiomeric excess of the amide. After silica gel chromatography, the acetamide is hydrolyzed with 6 M HCl at reflux to liberate (S)-3-aminopyrrolidine hydrochloride, which upon neutralization and distillation yields the free base with enantiomeric excess >99.0% as determined by chiral HPLC (Chiralpak IA, hexane/ethanol 90:10, 1.0 mL/min). The overall recovery of (S)-amine exceeds 40% of theoretical, a figure that limits this approach to high-value pharmaceutical applications. This contrasts with the 2-aminopyrrolidine system, where the proximity of the amine to the ring nitrogen accelerates spontaneous N→O acyl migration, complicating isolation of enantiopure material.

Why Does the 3-Amino Substituent Resist Cyclization Under Acidic Conditions Relative to the 2-Amino Isomer?

The resistance originates in the ring strain and transition-state geometry required for internal amidine formation. For 2-aminopyrrolidine, conversion to a cyclic imidazoline proceeds through a five-membered transition state with a calculated activation enthalpy (ΔH‡) at the B3LYP/6-31G(d) level of approximately 15 kcal·mol⁻¹, a value that renders the reaction spontaneous at ambient temperature. In 3-aminopyrrolidine, the analogous six-membered ring-forming pathway would require formation of a 1,3-diazacyclohexene skeleton; computation places the barrier above 28 kcal·mol⁻¹. Experimental validation through differential scanning calorimetry (DSC) on the free amine in sealed capsules shows no exotherm up to 200 °C, whereas a sample of 2-aminopyrrolidine hydrochloride exhibits a broad exothermic decomposition starting at 130 °C associated with imidazoline formation. This thermal stability underpins the suitability of 3-aminopyrrolidine for high-temperature amidation reactions in dipolar aprotic solvents such as N-methyl-2-pyrrolidone at 120–140 °C without the need for protecting groups on the ring nitrogen. 3-Aminopyrrolidine is classified as a corrosive amine with an LD50 (oral, rat) reported in safety data sheets as 200–500 mg·kg⁻¹; vapor pressure at 20 °C is approximately 0.5 hPa, necessitating local exhaust ventilation or use of a fume hood. Incompatibilities include strong acids (exothermic neutralization), acid chlorides (violent acylation), and oxidizing agents such as peroxides and nitric acid (risk of explosive nitrosamine formation). Contact with carbon dioxide leads to slow carbamate formation, which may reduce assay after prolonged storage. For waste disposal, incineration in an approved facility with alkaline scrubbing of NOₓ is employed; release to water bodies is prohibited under REACH Annex XVII restrictions on hazardous amines.