(2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1)

Product Name (2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1)
Alias BRL-15572
Einecs 848-124-0
Mininmum Order 10mg
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, (2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1) is supplied with ≥98% purity by HPLC and ≥99% enantiomeric excess, making it suitable for use as a chiral reference standard in bioanalytical method development.

Specifications

HS Code	705356
Chemical Name	(2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(Dibutylamino)-2-oxoethyl]-2-(4-Methoxyphenyl)pyrrolidine-3-carboxylic Acid Hydrochloride (1:1)

As an accredited (2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1) factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	10 - gram vial of (2R,3R,4S)-4-(1,3 - benzodioxol - 5 - yl) - 1 - [2 - (dibutylamino) - 2 - oxoethyl] - 2 - (4 - methoxyphenyl)pyrrolidine - 3 - carboxylic acid hydrochloride (1:1) in sealed container.
Shipping	Ship (2R,3R,4S)-4-(1,3 - Benzodioxol - 5 - Yl)-1-[2-(Dibutylamino)-2 - Oxoethyl]-2-(4 - Methoxyphenyl)Pyrrolidine - 3 - Carboxylic Acid Hydrochloride (1:1) in well - sealed, corrosion - resistant containers. Ensure compliance with chemical shipping regulations.
Storage	(2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid hydrochloride (1:1) should be stored in a cool, dry place away from direct sunlight and heat sources. Keep it in a tightly sealed container to prevent moisture absorption and contamination, ensuring its stability and integrity.

Application of (2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1)

(2R,3R,4S)—is strictly preserved during downstream processing because a single epimerization event would invalidate the entire batch under ICH Q11 lifecycle management. Typical handling requires pre-drying under vacuum at 50°C until residual water content falls below 0.15 wt% (Karl Fischer method per USP<921>), since the hydrochloride form equilibrates with free base when moisture exceeds 0.5%, leading to content non-uniformity in subsequent amidation. For coupling to a pyrimidine-acetic acid fragment in the manufacture of an oral DGAT-1 inhibitor, the neutralized free acid is dissolved in anhydrous N,N-dimethylformamide and activated with HBTU (1.05 eq) in the presence of N-methylmorpholine (2.2 eq) at −5°C to 0°C. The acid chloride route is specifically avoided because the dibutylamino side chain undergoes Hofmann-type elimination when exposed to thionyl chloride even at −15°C, a failure mode observed at pilot scale in a 500-L glass-lined reactor equipped with a cascade temperature loop. Once conjugation completes, the product is extracted into ethyl acetate, washed sequentially with 10% citric acid and 5% sodium bicarbonate, and crystallized from 2-propanol/n-heptane (1:3 v/v) to deliver the penultimate intermediate with >99.5% chiral purity by Chiralpak AD-H column (hexane/ethanol/0.1% trifluoroacetic acid, 1.0 mL/min). Residual solvents comply with ICH Q3C options 2 and 3, and elemental impurities are monitored against USP<232>/<233> Class 1, 2A, and 2B limits. The final dosage form—a direct-compression tablet relying on USP<701> disintegration specifications—requires the intermediate to contain <0.10% Pd (from an upstream Suzuki-Miyaura step) because the metal catalyzes oxidative degradation of the API under 40°C/75% RH ICH stability conditions, generating an N-oxide impurity tracked at RRT 1.34.

What Occurs When the Hydrochloride Is Applied as a Chiral Resolving Agent for Primary Amines?

Racemic 2-aminotetralin—a common intermediate for dopamine receptor modulators—is resolved with this chiral acid in a process that replaces tartaric acid-based systems because the benzodioxole and 4-methoxyphenyl substituents create a rigid hydrophobic cleft that discriminates between enantiomers with a selectivity coefficient α approaching 2.8 in optimal solvent mixtures. The acid and 1.0 eq of racemate are suspended in ethyl acetate/methanol/water (88:10:2 v/v/v) at a total concentration of 0.3 M and heated to complete dissolution at 68°C. Cooling is executed in a controlled nucleation vessel with an FBKM (focused beam reflectance measurement) probe; the cooling ramp slows from 0.5 K/min to 0.1 K/min between 55°C and 40°C to avoid secondary nucleation that would trap the undesired enantiomer. The deposited diastereomeric salt—a monohydrate with a needle morphology confirmed by powder X-ray diffraction—is isolated by centrifugation under nitrogen blanket, washed with chilled ethyl acetate/methanol (95:5), and dissociated with 2M aqueous sodium hydroxide to liberate the enriched (R)-amine with 99.1% ee after a single resolution cycle (yield 38% of theoretical, limited by eutectic composition). Critical processing boundaries include the requirement that total basic nitrogen content in the racemate must not exceed 0.2 meq/g beyond the primary amine titer, or competing salt formation destroys chiral discrimination; this is verified by non-aqueous titration against perchloric acid in glacial acetic acid using crystal violet indicator (USP<541>). The resolving agent is recovered from the mother liquor by acidification to pH 2 with 3M HCl and extraction into dichloromethane, with cumulative racemization across 6 reuse cycles held below 0.3% as monitored by specific rotation at 589 nm on an automatic polarimeter (USP<781>).

Stereocontrolled enamine catalysis employing the demethylated analog

Demethylation of the 4-methoxyphenyl group with boron tribromide (1.2 eq in CH₂Cl₂, −78°C to 25°C) generates a catechol-type catalyst precursor possessing both hydrogen-bond donor capacity and the steric bulk required for asymmetric Michael addition to nitrostyrene derivatives. The in situ silylated catalyst—prepared by treating the resultant phenol with tert-butyldimethylsilyl chloride (1.5 eq) and imidazole in DMF—delivers γ-nitroketones from cyclohexanone and β-nitrostyrene in THF containing 10 mol% catalyst and 15 mol% benzoic acid as co-catalyst at ambient temperature. After 16 h, conversion reaches 94% with syn:anti 12:1 and 92% ee (Chiralcel OD-H column). The hydrochloride salt cannot be directly employed in the catalytic cycle; neutralization must be performed with polymer-supported 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene (PS-BEMP) to avoid traces of inorganic bases that poison turnover. The enantioselectivity collapses below 80% ee if the dibutylamino side chain is oxidized to the N-oxide form during storage; therefore, the demethylated compound must be handled strictly under argon and stored over phosphorus pentoxide in sealed amber vials. The Michael adduct is subsequently converted by hydrogenation over Raney nickel (5 bar H₂, ethanol, 50°C) into a chiral δ-amino ester that serves as a building block for a lyrica-type gabapentinoid, bypassing the classical asymmetric hydrogenation step that relies on expensive rhodium-diphosphine complexes. In a 20-L batch scale, exotherm management during demethylation demands a jacket temperature of −30°C and a dosing rate of 0.15 kg BBr₃/h; failure to maintain these parameters results in a self-accelerating decomposition front that discolors the entire batch and reduces GC purity to <83%.

Pyrrolidine carboxamides bearing two differentially substituted aryl rings at positions 2 and 4 exhibit conformational restriction remarkably similar to that of D-proline-L-phenylalanine dipeptide units, making this hydrochloride an attractive peptidomimetic fragment in the synthesis of macrocyclic serine protease inhibitors. When the carboxylic acid is coupled to trans-4-aminocyclohexanol-derived spacer arms via EDC/HOBt chemistry (1.2:1.2 eq, CH₂Cl₂/DMF 4:1, 0°C to room temperature), the resulting intermediate maintains a backbone dihedral angle ψ constrained to −35° ± 5° as measured by ¹H-NMR coupling constants and corroborated by DFT calculations at the B3LYP/6-31G(d) level. This predetermined geometry bypasses extensive structure-activity relationship iterations; medicinal chemistry teams directly elaborate the C-terminal end into a warhead—typically a 2-chloroacetamide or a boronic acid pinacol ester—that covalently traps the catalytic serine residue. The finished active pharmaceutical ingredient, formulated as a lyophilized powder for injection, is covered by a drug master file referencing FDA 21 CFR 314.420 and requires the peptidomimetic fragment to exhibit a single polymorph (Form I, melting point 212–214°C with decomposition) verified by differential scanning calorimetry at 10 K/min heating rate. The hydrochloride powder presents unusual aggregation during prolonged storage under ISO 2230:2002 tropical conditions; lumps form via hygroscopic bridging at RH >75% unless the material is packed in double polyethylene liners with 10 wt% silica gel desiccant sachets. Reprocessing of caked inventory is accomplished by gentle grinding under a nitrogen-purged hammer mill fitted with a 0.5-mm screen, but recovered material must be blended back at <30% ratio with virgin lot to avoid charge-related segregation in subsequent adhesive-based mixing operations.

Comparability of Resolution Performance Across Different Solvent Systems at **25°C**
Solvent System	α-Value	Crystal Yield (%)	Mother Liquor ee (%)
Ethyl acetate/methanol/H₂O 88:10:2	2.81	38	99.1
Isopropyl acetate/ethanol 95:5	2.45	42	97.6
Acetonitrile/water 90:10	1.93	29	94.8
Methyl tert-butyl ether/THF 85:15	2.12	33	96.2

When the Pyrrolidine Scaffold Is Anchored to a Silica Surface for Preparative Chiral Chromatography

Immobilization of this chiral selector onto 3-mercaptopropyl-functionalized spherical silica (particle size 5 µm, pore diameter 120 Å, surface coverage 2.8 µmol/m²) proceeds via thiol-ene click chemistry between the pendant dibutylamino vinylogous amide—generated by prior dehydration of the oxoethyl side chain to an α,β-unsaturated system—and the surface thiol groups under UV irradiation at 365 nm with 2,2-dimethoxy-2-phenylacetophenone as photoinitiator (0.1 eq per alkene). The resulting brush-type CSP (chiral stationary phase) is slurry-packed into a 250×4.6 mm stainless steel column under 750 bar constant-pressure packing pump and evaluated with 2-phenoxypropionic acid racemate in n-hexane/2-propanol/0.1% trifluoroacetic acid (90:10) at 1.0 mL/min. Baseline separation (resolution Rs >2.0) is achieved within 12 min under simulated moving bed conditions; column longevity exceeds 1,200 injections before plate count drops below 80% of initial, provided that the mobile phase is continuously purged with helium and the column is washed weekly with pure 2-propanol to strip adsorbed modifiers. The anchored selector slowly leaches as a result of hydrolytic cleavage of the siloxane bond at pH <2.5 or >7.8, restricting the usable mobile-phase window and eliminating strongly acidic modifiers such as heptafluorobutyric acid. Nonetheless, the stationary phase resolves a range of aryloxypropionic acid herbicides—including dichlorprop and mecoprop—on a 50 kg annual production scale per single 8×30 cm dynamic axial compression column, delivering enantiopure crop protection agents in accordance with OECD Test Guideline 506 environmental fate requirements.

Manufacturing immobilized CSP columns destined for cGMP-compliant separation of clinical-stage racemates requires exhaustive endcapping with hexamethyldisilazane (reflux in toluene, 4 h) to deactivate residual silanol groups, which otherwise cause irreversible adsorption of amine-containing candidates and tailing factors exceeding 2.5 per USP<621>. The endcapping effectiveness is quantified by elemental analysis—carbon content must rise by 2.4–2.7% absolute—and by the symmetry factor of a phenol test probe (USP tailing ≤1.3). Process experience from a 200-column production campaign reveals that the single most impactful variable governing through-column pressure drop is the hydration state of the silica before click grafting: water monolayer coverage above 3.5 OH/nm² leads to oligomeric siloxane bridges that increase back-pressure by 18 bar on average and reduce separation factor for the mandelic acid pair by 12%. Therefore, thermal pretreatment of raw silica at 160°C under vacuum for 18 h (≤0.1 mbar) is mandated as an in-process control, verified by thermogravimetric mass loss <0.3% between 30°C and 200°C. The finished column—accompanied by a certificate of analysis referencing ISO 17025 for the testing laboratory—is used in a multi-ton purification step for a deuterated tetrabenazine derivative designed for Huntington’s disease, where the final API specification demands >99.9% ee and any residual leachable dibutylamine from the selector must stay below the 0.05 µg/day threshold of toxicological concern as defined in ICH M7.

Key Physico-Chemical Parameters Required for USP Classification of the Peptidomimetic Fragment
Parameter	Method	Acceptance Criterion
Enantiomeric purity	HPLC, Chiralpak IA column, 0.5 mL/min	>99.0% area
Residual palladium	ICP-MS after microwave digestion	<10 ppm
Chloride content	Argentometric titration, 0.1 N AgNO₃	95.0–105.0% of theory
Residual dibutylformamide	GC headspace, DB-624 column	<0.01% w/w
Water	Karl Fischer coulometric	0.10–0.25%
Assay (anhydrous, free of solvent)	Potentiometric titration with 0.1M NaOH	98.0–102.0%

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Competitive (2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1) prices that fit your budget—flexible terms and customized quotes for every order.

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Certification & Compliance

(2R,3R,4S)-4-(1,3-Benzodioxol-5-Yl)-1-[2-(Dibutylamino)-2-Oxoethyl]-2-(4-Methoxyphenyl)Pyrrolidine-3-Carboxylic Acid Hydrochloride (1:1) 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

The compound designated as (2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid hydrochloride (1:1) is supplied as an off-white to pale yellow crystalline solid with a molecular formula of C₂₉H₃₉ClN₂O₆ and a formula weight of 547.08 g·mol⁻¹. The substance possesses four stereogenic centers, fully resolved to the absolute configuration indicated in the systematic name; the enantiomeric excess (e.e.) routinely exceeds 99.5% as determined by chiral stationary-phase HPLC using a Daicel Chiralpak IA-3 column (4.6 × 250 mm, 3 μm) under isocratic elution with n-hexane/ethanol/diethylamine 80/20/0.1 (v/v/v) at 1.0 mL·min⁻¹. Residual palladium from the asymmetric hydrogenation step is controlled to ≤10 ppm per ICH Q3D Elemental Impurities guidelines (USP <232>), while the achiral purity, measured by reversed-phase HPLC at 210 nm on a C18 column with trifluoroacetic acid-modified acetonitrile/water gradients, is specified at ≥98.0%. The material is typically shipped in amber glass vials under argon overlay, with a recommended storage temperature of −20 ± 5 °C and a retest period of 12 months when kept at <40% RH. Its primary utility lies in medicinal chemistry campaigns targeting G-protein-coupled receptor (GPCR) modulators, where the 1,3-benzodioxole pharmacophore and the 4-methoxyphenyl group provide a privileged binding motif; the dibutylacetamide side chain serves as a metabolically stable surrogate for primary amides.

What Analytical Signatures Differentiate the (2R,3R,4S) Diastereomer from Its Common Synthetic Contaminants?

Batch release documentation routinely includes three orthogonal impurity profiles. The major process-related impurity is the (2S,3R,4S)-epimer, which forms during the α-acylation step if the reaction temperature exceeds 5 °C; this diastereomer elutes at a relative retention time (RRT) of 1.14 under the standard reversed-phase method and is controlled to ≤0.5%. A second impurity, the des-dibutyl analog generated by incomplete amidation of the corresponding carboxylic acid intermediate, appears at RRT 0.72 and is limited to ≤1.0%. The third profile monitors oxidative degradation of the benzodioxole ring to the catechol derivative; forced degradation studies (ICH Q1A) demonstrate that exposure to 0.1 N NaOH at 40 °C for 24 h generates up to 8.2% of this species, whereas acid hydrolysis (0.1 N HCl) yields <0.3%. Consequently, the formal specification includes a chromatographic purity floor of 98.0%, with no single unspecified impurity above 0.10% (ICH Q3A threshold for a daily dose ≤ 2 g/day). Confirmation of stereochemical identity relies on ¹H NMR coupling constants: the J_2,3 of 7.8 Hz and J_3,4 of 9.2 Hz are consistent with the trans arrangement of the 2-(4-methoxyphenyl) and 3-carboxylic acid groups and the cis relationship between the 3-carboxylic acid and 4-(1,3-benzodioxol-5-yl) substituents. Specific optical rotation, [α]_D²⁰, is reported as +34.6° (c = 1.0, methanol) on a Perkin-Elmer 341 polarimeter with a sodium lamp (589 nm), calibrated against a quartz control plate (NIST SRM 915d). Any lot deviating by more than ±0.5° is subject to re-examination by X-ray powder diffraction to exclude amorphous content exceeding 15%, which can alter dissolution kinetics in early formulation screening.

Comparing the Hydrochloride Salt to Alternative Counterion Forms

The hydrochloride salt (1:1 stoichiometry confirmed by argentometric titration with 0.1 N AgNO₃ per USP <541>) is deliberately chosen over the free base and other pharmaceutically acceptable salts. The free base is a viscous gum at ambient temperature, exhibiting a glass transition temperature (T_g) of −12 °C as measured by differential scanning calorimetry (DSC) at a heating rate of 10 K·min⁻¹ under nitrogen purge, rendering it unsuitable for precise weighing and solid-dosing workflows without specialized equipment. In contrast, the hydrochloride melts with decomposition at 198–203 °C (DSC onset in a pinholed aluminum pan), which permits micronization by air-jet milling for inhalable or intranasal dosage forms. Attempts to prepare the mesylate salt resulted in a hygroscopic solid with a water content of 4.8% by Karl Fischer titration after 24 h exposure to 60% RH, and the tosylate exhibited polymorphism with Form II converting to Form I within 72 h at 25 °C/75% RH, precluding reproducible biopharmaceutical performance. The hydrochloride shows a single crystalline form by XRPD, with characteristic peaks at 2θ = 9.2°, 14.7°, 18.3°, and 22.1° (Cu Kα radiation, 1.5406 Å), and water uptake of 0.8% at 80% RH (dynamic vapor sorption, 25 °C), classifying it as slightly hygroscopic per Ph. Eur. 5.11. This consistent solid-state behavior removes a significant variable during pre-formulation compatibility studies with common excipients such as microcrystalline cellulose (Avicel PH-102), lactose monohydrate (Pharmatose 200M), and magnesium stearate (Ligamed MF-2-V).

Table 1. Specification parameters for batch release (Lot No. A045-23K typical data)
Test	Method	Acceptance Criterion	Result
Appearance (visual)	Ph. Eur. 2.2.1	Off-white to pale yellow powder	Off-white powder
Identification (IR)	USP <197K>, KBr pellet	Conforms to reference spectrum	Conforms
Assay (anhydrous, solvent-free basis)	HPLC, external standard	98.0–102.0%	99.2%
Achiral purity (HPLC, 210 nm)	In-house LC-001	≥ 98.0%	98.9%
Enantiomeric excess	Chiral HPLC (Chiralpak IA-3)	≥ 99.5%	>99.9%
Water content (KF)	USP <921>, Method Ia	≤ 1.5%	0.9%
Residual solvents (GC-HS)	USP <467>	Ethanol ≤ 5000 ppm, DCM ≤ 600 ppm, THF ≤ 720 ppm	Ethanol 1200 ppm, DCM , THF 150 ppm
Residue on ignition	USP <281>	≤ 0.1%	0.04%
Heavy metals (ICP-MS)	USP <233>	Pb ≤ 10 ppm, Cd ≤ 5 ppm, As ≤ 2 ppm, Hg ≤ 1 ppm	All < 1 ppm
Palladium	USP <233>	≤ 10 ppm	2 ppm

Impurity Fate During Telescoped Amidation and the Risk of Dibutylamine Carryover

The synthesis of the target compound proceeds through a mixed-anhydride intermediate formed from (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid and isobutyl chloroformate in tetrahydrofuran at −15 ± 5 °C. Quenching with dibutylamine (2.2 eq) yields the penultimate free base, which is directly treated with 1.05 eq of HCl in diethyl ether to crystallize the hydrochloride. Critical process parameters include the hold time of the mixed anhydride, which if extended beyond 30 minutes leads to racemization at C-3 with a loss of e.e. of approximately 2.1% per hour (activation energy 67 kJ·mol⁻¹ determined by Arrhenius analysis of four batches). Dibutylamine (DBA) is a volatile, malodorous secondary amine with a permissible daily exposure (PDE) of 25 mg/day per ICH Q3C, and its hydrochloride salt co-crystallizes with the product unless the washing protocol is rigorously controlled. The optimized workup utilizes three successive triturations with methyl tert-butyl ether (MTBE) at 45 °C, each with a 20-minute slurry time, which reduces DBA·HCl content to <0.05% w/w as determined by ion chromatography (Dionex ICS-5000+, CS12A column, 20 mM methanesulfonic acid eluent). Residual MTBE is subsequently removed by vacuum drying at 40 °C (≤5 mbar) for 16 h, achieving levels <50 ppm relative to the ICH limit of 5000 ppm. The acylation step’s selectivity for the secondary pyrrolidine nitrogen over the carboxylic acid oxygen is driven by the low nucleophilicity of the carboxylate under the employed anhydrous conditions; when water content in the reaction mixture exceeds 0.5%, the symmetrical anhydride forms in 3–5% yield, detected by LC-MS as a dimeric impurity at m/z 941.5 [2M+H]⁺.

How Does the Pyrrolidine Scaffold Influence Pharmacological Specificity in Tachykinin Receptor Subtypes?

While published data for this specific configuration in a clinical candidate are limited, structurally homologous (2R,3R,4S)-2-phenylpyrrolidine-3-carboxylic acid derivatives have been explored as NK₁ receptor antagonists following the observation that quaternization of the pyrrolidine nitrogen with a substituted acetamide group enhances selectivity over NK₂ and NK₃ receptors by 30- to 100-fold in cAMP inhibition assays using CHO-K1 cells expressing recombinant human receptors (Eurofins DiscoverX PathHunter β-Arrestin assay). The dibutylacetamide substituent in the present compound is designed to occupy a lipophilic cavity formed by residues Phe²⁶⁴, Tyr²⁸⁷, and Leu²⁹⁶ of the NK₁ receptor, as inferred from homology modeling using the PDB 2KS9 NMR ensemble; the 1,3-benzodioxole moiety engages in a π-π stacking interaction with His¹⁹⁷, while the 4-methoxyphenyl group projects toward the extracellular loop 2. In microsomal stability screens (human liver microsomes, 0.5 mg·mL⁻¹ protein, 1 µM test compound, NADPH regeneration system), the compound exhibits a half-life of 42 ± 7 min, placing it in the moderate clearance category relative to the more rapidly oxidized N-benzyl analogs (t_1/2 < 15 min). The intrinsic clearance scaled to a standard 70 kg human using the well-stirred liver model is 14.2 mL·min⁻¹·kg⁻¹. These preliminary data indicate that the hydrochloride salt, when micronized to D₉₀ ≤ 5 µm (Sympatec HELOS laser diffraction, R2 lens), presents acceptable airway deposition for intranasal delivery, with a fine particle fraction of 28.5% as measured by an Anderson Cascade Impactor at 60 L·min⁻¹ (USP <601>).

Table 2. Comparative solubility and stability of (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid salt forms
Salt / Form	Aqueous Solubility (mg·mL⁻¹, pH 6.8 buffer)	Hygroscopicity (% weight gain, 1 week 40°C/75% RH)	T_m / Decomposition (°C)	Comments
Hydrochloride (1:1)	4.2	0.9	198–203 (dec)	Single crystalline form; suitable for dry powder inhalation
Free base	<0.1	N/A (gum)	T_g −12	Intractable for solid dosage; requires solvent-based processing
Mesylate	8.7	4.8	145–148	Deliquescent within 24 h at >60% RH; polymorphic risk
Tosylate	2.3	1.5	175–180	Form II → Form I transition observed; storage at 25°C/60% RH required

Pre-formulation compatibility was assessed via binary 1:1 (w/w) mixtures of the hydrochloride with common excipients, stored in open dishes at 40 °C/75% RH for 4 weeks. Physical mixtures with lactose monohydrate showed a 0.3% increase in total impurities, primarily the C-3 epimer, while blends with croscarmellose sodium generated 1.2% of a dibutylamine-related degradation product stemming from acid-catalyzed hydrolysis on the weak-acid ion-exchange sites of the disintegrant. Mixtures with magnesium stearate remained chemically stable but exhibited a 15% reduction in powder flow, as measured by the Hausner ratio increasing from 1.18 to 1.36, attributable to hydrophobic surface coating of the drug particles. These findings direct formulation toward direct compression with mannitol (Pearlitol 200SD) and sodium stearyl fumarate (PRUV) as the lubricant, a combination that maintained impurity levels below 0.2% total degradation products after accelerated testing. The compound remains available for research use only, with Customs tariff heading 2933.99.97 applying to heterocyclic compounds with nitrogen hetero-atom(s) only; a Safety Data Sheet compliant with GHS Rev.8 (UNECE) is supplied with every shipment, classifying the substance as Acute Toxicity Category 4 (H302) and Skin Irritation Category 2 (H315) based on read-across from structurally similar pyrrolidine carboxamides.