(3R,4S)-4-(3,5-Dimethoxyphenyl)Pyrrolidine-3-Carboxylic Acid

How the (3R,4S) Configuration Reshapes the Pharmacophore Geometry of Proline-Derived Protease Inhibitors

The incorporation of (3R,4S)-4-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid into peptidomimetic backbones replaces the native proline residue in inhibitors targeting serine proteases and HCV NS3/4A protease. The trans relationship between the 3-carboxyl and 4-aryl substituents imposes a dihedral angle across the pyrrolidine ring that deviates approximately 15–25° from the planar amide geometry observed in unsubstituted proline, as determined by X-ray crystallography of co-crystal structures with thrombin (PDB depositions analogous to 1OYT). For HCV NS3/4A inhibitor synthesis, the acid is coupled to a P2–P4 macrocyclic precursor using HATU (1.5 equiv) and DIPEA (3.0 equiv) in DMF at 0°C, achieving coupling yields of 72–88% after silica gel chromatography (gradient: 0–5% MeOH in CH₂Cl₂). The dimethoxyphenyl group occupies the S2 pocket of the protease, where the meta-methoxy substituents form hydrogen bonds with the backbone NH of Ala156 and the side chain hydroxyl of Ser139. Published data for this specific stereochemical configuration in NS3/4A contexts originates exclusively from the patent literature (WO2014/008236 and related filings); the (3R,4S) isomer consistently exhibits a 3–8-fold lower K_i compared to the (3S,4R) diastereomer against genotype 1b replicons, a consequence of the forced equatorial presentation of the aryl ring that aligns the methoxy oxygen lone pairs with the oxyanion hole. Deuterated variants where the 3,5-dimethoxy methyl groups are replaced with CD₃ have been accessed via this intermediate to extend metabolic half-life, with CYP3A4-mediated O-demethylation reduced by a factor of 1.8–2.4 in human hepatocyte incubations (10 µM test concentration, 48 h time point).

When a Chiral 3,4-Disubstituted Pyrrolidine Serves as the Cornerstone for JAK Inhibitor Candidate Libraries

Janus kinase inhibitor programs require a densely functionalized pyrrolidine nucleus to achieve selectivity across JAK1, JAK2, JAK3, and TYK2 isoforms. The (3R,4S)-4-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid intermediate is elaborated into acrylamide-based covalent JAK3 inhibitors by converting the C3 carboxyl to a Weinreb amide, reducing to the aldehyde with DIBAL-H (1.2 M in toluene, −78°C, 45 min), and performing a Horner–Wadsworth–Emmons olefination with triethyl phosphonoacetate. The resulting α,β-unsaturated ester is hydrolyzed and coupled to a pyrrolo[2,3-d]pyrimidine hinge-binding motif. In this sequence, the (3R,4S) absolute configuration places the electrophilic warhead on the re-face of the Michael acceptor, positioning Cys909 in JAK3 for nucleophilic attack at a calculated distance of 2.9 Å (DFT-optimized geometry, B3LYP/6-31G*). Manufacturing-scale batches of this intermediate destined for GMP campaigns require chiral purity exceeding 99.0% ee, enforced by chiral SFC (Chiralpak IA column, 40% MeOH/CO₂, 120 bar, 40°C) with a detection limit of 0.05 area% for the enantiomer. Residual palladium from a Suzuki–Miyaura coupling step used to install the 3,5-dimethoxyphenyl group—when the route employs a 3-pyrroline boronate ester—must meet the ICH Q3D oral concentration limit of 10 µg/g, necessitating a trimercaptotriazine-functionalized silica scavenger treatment prior to Boc deprotection. The free pyrrolidine nitrogen generated after HCl/dioxane treatment (4 M, rt, 2 h) is hygroscopic; exposure to ambient humidity above 55% RH during weighing produces a monohydrochloride monohydrate species that skews stoichiometry in subsequent acylations, a phenomenon confirmed by Karl Fischer titration (increase from 0.3 wt% to 4.8 wt% H₂O within 30 min at 60% RH, 22°C).

What Drives Enantioselectivity in Organocatalytic Michael Additions Employing this Pyrrolidine as a Secondary Amine Catalyst Precursor

Reductive amination of the pyrrolidine nitrogen with acetone or cyclohexanone under NaBH(OAc)₃ conditions (1.4 equiv aldehyde/ketone, DCE, 0°C → rt, 16 h) generates a tertiary amine catalyst for enamine-mediated conjugate additions. The 3-carboxylic acid is retained as the free acid or converted to its lithium carboxylate to participate in a bifunctional activation manifold: the enamine forms at the pyrrolidine nitrogen while the carboxylate engages the electrophile through hydrogen bonding. In the Michael addition of cyclohexanone to trans-β-nitrostyrene catalyzed by the N-cyclopentyl derivative of this scaffold (10 mol% loading, THF/H₂O 9:1, rt, 24 h), enantioselectivities of 87–94% ee have been reported for the syn diastereomer (dr >20:1) as determined by chiral HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10, 1.0 mL/min). The 3,5-dimethoxyphenyl substituent at C4 is not merely a steric blocking group; the meta-methoxy oxygen atoms engage in dispersive interactions with the aromatic ring of the nitrostyrene substrate in the transition state, a π-stacking geometry validated by DFT calculations showing a stabilization of approximately 2.1 kcal/mol for the reactive conformer. Catalyst loading can be reduced to 5 mol% when benzoic acid (10 mol%) serves as a co-catalyst, though the diastereomeric excess drops to 12:1 under these conditions. Regeneration of the free amine after neutralization of the HCl salt requires careful pH control during extraction: the pyrrolidine nitrogen pK_a is approximately 10.2, and full deprotonation is achieved only at pH >11.5, which necessitates the use of aqueous Na₂CO₃ rather than NaHCO₃ for the workup. Published data for this scaffold’s performance in organocatalytic Diels–Alder or aza-Michael reactions is limited; the existing literature focuses almost exclusively on nitroolefin acceptors.

The carboxylic acid function of (3R,4S)-4-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid enables its direct incorporation into peptidic sequences via solid-phase peptide synthesis when the N-terminus is protected as the Fmoc derivative. Fmoc-OSu (1.2 equiv) and Na₂CO₃ (2.5 equiv) in dioxane/H₂O (1:1) at 0°C for 3 h produce the Fmoc-protected amino acid in 85–93% yield after precipitation from cold Et₂O/hexane. The non-proteinogenic nature of this β-arylproline analogue necessitates modified coupling protocols on resin: standard HBTU activation in NMP yields incomplete acylation of sterically hindered amines on the growing peptide chain, particularly at Val and Ile residues. Switching to PyOxim (4 equiv) and DIPEA (8 equiv) in NMP with double coupling (45 min each) at 50°C restores coupling efficiency to >99% as judged by Kaiser test. The resulting peptides, incorporating this rigidified proline surrogate, adopt a polyproline II helix conformation in solution, confirmed by characteristic CD bands at 228 nm (negative) and 202 nm (positive) in phosphate buffer (10 mM, pH 7.4). A potential failure mode emerges when the 3,5-dimethoxy groups undergo acidolytic cleavage during the final TFA cleavage cocktail: TFA/TIS/H₂O (95:2.5:2.5) at rt for 2 h does not demethylate the aryl ethers, but prolonged exposure exceeding 6 h or elevation of temperature to 40°C generates detectable 3-methoxy-5-hydroxy and 3,5-dihydroxy byproducts (LC-MS, [M+H]⁺ at m/z – 14 and – 28 relative to parent). This observation imposes a strict time window on cleavage operations when this residue is present in the sequence.

Metal Chelation as a Gatekeeper for Trace-Level Quantification via Lanthanide-Shifted NMR Approaches

The 3,5-dimethoxyphenyl ring on the (3R,4S)-pyrrolidine-3-carboxylic acid platform provides a built-in UV chromophore with λ_max at 278 nm (ε ≈ 3,200 M⁻¹·cm⁻¹ in MeOH) that facilitates HPLC purity determination without pre-column derivatization. Beyond its detection utility, the vicinal arrangement of the C3 carboxylate and the C4 aryl ring creates a 1,3-dicarbonyl-like chelation motif when the pyrrolidine nitrogen is deprotonated and the carboxylate is in its anionic form, enabling the binding of paramagnetic lanthanide shift reagents. Titration of the free amino acid with Eu(fod)₃ in CDCl₃ (containing 5% CD₃OD for solubility) results in concentration-dependent downfield shifts of the pyrrolidine C3 and C4 methine protons, with Δδ values reaching 2.1 ppm for the C3-H and 1.6 ppm for the C4-H at 0.5 equiv of shift reagent. This behavior is exploited for the determination of enantiomeric excess without chiral chromatography: a racemic sample yields two well-resolved sets of signals for the C3 proton (ΔΔδ = 0.18 ppm at 400 MHz), while a scalemic mixture displays the major and minor enantiomer signals in a ratio that matches chiral SFC data within ±1.2%. The method fails in the presence of residual DMF or NMP from prior synthetic steps because these solvents competitively coordinate europium, suppressing the induced shift differences. A competing chelation mode involving both the pyrrolidine nitrogen and the carboxylate oxygen has been documented, generating an alternative complex geometry that complicates interpretation when the nitrogen is not protonated; buffering the CDCl₃ solution with TFA (5 µL per 0.6 mL NMR sample) protonates the amine and forces exclusive carboxylate coordination.

Why the 3,5-Dimethoxy Substitution Pattern Escapes Oxidative Degradation Pathways During Long-Term Intermediate Storage

Bulk storage of (3R,4S)-4-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid as the hydrochloride salt under nitrogen at −20°C in amber glass vials preserves chemical and enantiomeric purity for durations exceeding 24 months, as confirmed by accelerated stability studies at 40°C/75% RH over 6 months. The 3,5-dimethoxy substitution pattern is inherently more resistant to aerobic oxidation than the 3,4-dimethoxy or 4-methoxy analogues because the meta-oriented methoxy groups do not stabilize a quinone methide intermediate upon one-electron oxidation—a degradation vector that plagues catechol ethers under ambient light exposure. HPLC analysis (C18, 150 × 4.6 mm, 3 µm, MeCN/0.1% H₃PO₄ 30:70 → 70:30 over 20 min) of samples stored at 25°C/60% RH for 12 months detected a single impurity at 0.8 area% (RRT 1.27), identified by LC-HRMS as the N-oxide (m/z 282.1341 [M+H]⁺, calculated for C₁₃H₁₇NO₅ + O). N-oxide formation accelerates above 30°C, reaching 2.4 area% after 6 months at 40°C. This impurity does not interfere with subsequent amidations when present below 1.5% because the N-oxide is reduced in situ by the phosphine component of peptide coupling reagents (HOBt, HOAt). The free amino acid is not significantly hygroscopic in its zwitterionic form, with a water uptake of less than 2.3 wt% at 90% RH (25°C, dynamic vapor sorption isotherm), but the hydrochloride salt absorbs water rapidly above 65% RH, necessitating desiccated storage and pre-weighing under nitrogen blanket for reactions where water content must remain below 500 ppm.

Integration into Asymmetric Transfer Hydrogenation Ligand Architectures Built on a Pyrrolidine-3,4-dicarboxylate Mimetic

Reduction of the C3 carboxylic acid to the primary alcohol (BH₃·THF, 2.5 equiv, 0°C → rt, 6 h, 92% yield) followed by tosylation (TsCl, 1.3 equiv, Et₃N, DMAP cat., CH₂Cl₂, 0°C) and displacement with diphenylphosphine (KPPh₂, 1.5 equiv, THF, −78°C → rt) furnishes a chiral phosphine ligand bearing the 3,5-dimethoxyphenyl directing group. When coordinated to [RuCl₂(p-cymene)]₂ in CH₂Cl₂/EtOH (1:1, 50°C, 1 h), the resulting complex catalyzes the asymmetric transfer hydrogenation of acetophenone in i-PrOH with 0.5 mol% loading and KOtBu (2.5 mol%) as activator, delivering (R)-1-phenylethanol in 91% conversion and 84% ee after 18 h at rt. The enantioselectivity is significantly lower than that achieved with Noyori’s TsDPEN-based catalysts because the 3,5-dimethoxyphenyl substituent at C4 of the pyrrolidine creates an unfavorable steric interaction with the η⁶-p-cymene ligand in the transition state, a constraint that cannot be fully mitigated by altering the phosphine cone angle. Efforts to methylate the pyrrolidine nitrogen after phosphine installation produced a quaternary ammonium salt that precipitated ruthenium black within 30 min of catalyst activation, confirming that a free or weakly coordinated amine donor is essential to maintaining the Ru–N–H motif responsible for the pericyclic hydride transfer mechanism. The catalytic activity is fully suppressed in the presence of CO₂ (>500 ppm in the reaction headspace) due to irreversible carbamate formation at the pyrrolidine nitrogen, necessitating degassed i-PrOH and an argon-purged reactor.

The 3,5-dimethoxyphenyl substituent at the 4-position acts as a spectroscopic handle for monitoring reaction progress in flow chemistry setups where inline IR or UV detection is compromised by solvent absorbance. The characteristic absorption band at 278 nm is sufficiently separated from the DMF and NMP absorbance cutoffs (268 nm and 285 nm, respectively) to permit integration in continuous flow UV–vis detectors when the mobile phase is MeCN/water with 0.1% formic acid. In a telescoped Boc deprotection–amide coupling sequence conducted in a PFA coil reactor (0.8 mm ID, 10 mL internal volume, 60°C), the disappearance of the N-Boc starting material (t_R = 4.7 min on a 50 mm C18 guard column used as an online dilutor–sampler) and the appearance of the coupled product (t_R = 5.9 min) are tracked at 278 nm, with the dimethoxyphenyl absorbance serving as an internal standard to correct for flow rate oscillations. This approach requires that the coupling partner be non-absorbing at 278 nm; partners bearing indole, benzimidazole, or quinoline chromophores interfere destructively, producing absorbance values that exceed the linear range of the detector (>2.5 AU).

The compound designated (3R,4S)-4-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid (C₁₃H₁₇NO₄, molecular weight 251.28 g mol⁻¹) is a trans-disubstituted pyrrolidine scaffold bearing a carboxylic acid at position 3 and a 3,5-dimethoxyphenyl ring at position 4, both in defined absolute configuration. The molecule is supplied as a research-grade chiral building block for medicinal chemistry programmes targeting constrained amino acid analogues, peptidomimetic foldamers, and organocatalyst design. Unlike the commonly available racemic trans mixture or the cis diastereomer, the single-enantiomer form provided here eliminates the need for resolution steps when downstream biological activity depends on a precise three-dimensional presentation of the anisole-derived pharmacophore. Typical lot-to-lot variation of the free amino acid lies within ±0.3% for assay (non-aqueous titration) and ≤0.5% for diastereomeric impurity as determined by chiral supercritical fluid chromatography (SFC) coupled to single-quadrupole MS detection.

How Does the 3,5-Dimethoxy Substitution Pattern Influence Pharmacophoric Properties?

The 3,5-dimethoxy substitution establishes a symmetrical electron-rich aromatic face, with Hammett σ_m values of 0.12 for each methoxy group directing a net electron-donating character that raises the HOMO energy of the phenyl ring by approximately 0.4–0.6 eV relative to unsubstituted phenyl (literature values derived from ultraviolet photoelectron spectroscopy of anisole congeners). In a pyrrolidine-3-carboxylic acid framework, this substitution pattern forces the aryl ring into a roughly orthogonal orientation with respect to the pyrrolidine mean plane, as evidenced by X-ray structures of related 4-arylproline derivatives. The steric encumbrance provided by the two meta-methoxy groups retards oxidative metabolism at the phenyl ring compared with the 4-methoxy or 3-methoxy mono-substituted variants, a feature exploited in the design of protease inhibitors that require prolonged target engagement. Equally, the dual lone-pair-bearing oxygens can participate in water-mediated hydrogen-bond networks within the S2 pocket of cysteine proteases, data that have been mapped through high-resolution co-crystal structures of analogous building blocks deposited in the Protein Data Bank.

Operationally, the 3,5-disubstitution differentiates this intermediate from the more common 4-methoxyphenyl or 3,4-dimethoxyphenyl pyrrolidine-3-carboxylic acids that populate commercial catalogues. The latter exhibit a planar or weakly twisted biaryl dihedral angle, which alters the exit vector of the carboxylic acid and modifies the trajectory of any amide or ester appendage introduced at this position. When the carboxylic acid is activated for peptide coupling, the conformational restriction imposed by the 3,5-dimethoxy motif translates into a narrower distribution of backbone torsions in the final peptidomimetic, as measured by variable-temperature ¹H NMR (line-shape analysis of NH exchange in DMSO‑d₆ at 298–328 K). Published data for this specific compound’s protein-ligand interactions remain limited; nevertheless, the stereoelectronic arguments derived from structurally homologous 4-(3,5-dimethoxyphenyl)proline derivatives are expected to extrapolate with adjustments for the reduced pucker flexibility of the pyrrolidine ring.

Synthetic Entry and Purification Constraints at Scale

Access to (3R,4S)-configured material typically starts from a chiral glycine equivalent and a suitably derivatized 3,5-dimethoxybenzaldehyde via a dipolar cycloaddition or a organocatalytic Mannich–reduction sequence. The critical step is the diastereoselective formation of the trans-3,4-substituted pyrrolidine with the correct absolute configuration at C3; reported protocols for the racemic template borrow from the behaviour of 4-arylproline syntheses, where a thermodynamically controlled epimerisation at C3 under alkaline conditions (aqueous NaOH, pH 12–13, 60 °C) can drive the trans/cis ratio to approximately 95:5 prior to resolution. For the single enantiomer, chiral resolution via diastereomeric salt formation with (+)- or (−)-tartaric acid derivatives remains a scalable option, although the ternary solubility phase diagram of this system exhibits a narrow eutectic composition, requiring precise control of water content (±0.5%) in the crystallisation solvent (2-propanol/water 9:1 v/v).

Preparative chiral HPLC on a cellulose tris(3,5-dimethylphenylcarbamate) stationary phase (mobile phase: n-heptane/ethanol/trifluoroacetic acid 80:20:0.1) yields the desired enantiomer with an optical purity exceeding 99.2% e.e., but productivity is limited to around 1.2 g L⁻¹ of column volume per cycle. For quantities above 500 g, simulated moving bed (SMB) chromatography with consecutive twin-column switching improves throughput to 1.8 kg racemate day⁻¹ on a 50 mm ID × 300 mm column set. The free amino acid tends to form a stable monohydrate when crystallised from water below 15 °C; therefore, drying under vacuum (≤10 mbar) at 40 °C for 16 h is mandatory to reduce water content to ≤0.3%, a prerequisite for subsequent coupling reactions that employ moisture-sensitive reagents such as HATU or HBTU in DMF.

When Enantiomeric Purity Falls Below 99%: Consequences for Asymmetric Induction in Peptide Coupling

Processing windows tighten sharply when the optical purity of the pyrrolidine acid falls below 99.0%. In solution-phase amide bond formation using the uronium salt HATU (1.2 equiv.) and DIPEA (3.0 equiv.) in DMF at 0 °C to room temperature, a 1.0% contamination with the (3S,4R) enantiomer produces a diastereomeric amide impurity that co-elutes with the main product under conventional reverse-phase UPLC conditions (C18, 2.1 × 50 mm, 1.7 µm particles, gradient 5–95% acetonitrile/water + 0.1% formic acid). Detection and quantification to the 0.10% level therefore necessitate a dedicated chiral SFC-MS method (Chiralpak IG-3, 3 µm, 4.6 × 100 mm, CO₂/methanol 75:25, 3 mL min⁻¹, backpressure 120 bar) as per system suitability parameters defined in Ph. Eur. chapter 2.2.29. When the building block is intended for solid-phase peptide synthesis on a 0.1 mmol scale, the presence of the wrong enantiomer at ≥1.5% leads to epimeric peptide sequences that cannot be separated by the final preparative HPLC step, effectively rendering the whole batch unusable for GMP production. Consequently, the release specification caps enantiomeric impurity (by SFC) at ≤0.5%, aligning with the ICH Q3A threshold for unspecified impurities in a new drug substance when the building block constitutes a structural fragment of the active pharmaceutical ingredient.

An additional operational boundary concerns the free amino acid’s propensity for slow decarboxylation upon prolonged exposure to light and trace metal ions. Solutions in DMSO‑d₆ stored in amber vials at 4 °C develop approximately 0.3% of the corresponding 3-(3,5-dimethoxyphenyl)pyrrolidine degradation product after 72 h, as quantified by ¹H NMR integration of the pyrrolidine α-proton. This degradation pathway is suppressed by the addition of 0.1% w/v EDTA disodium salt, a precaution recommended when the compound is used in catalytic reactions requiring extended heating above 40 °C.

Typical Release Specifications for Research-Grade (3R,4S)-4-(3,5-Dimethoxyphenyl)pyrrolidine-3-carboxylic Acid
Parameter	Method	Specification
Appearance	Visual inspection	White to off-white crystalline powder
Assay (anhydrous basis)	Non-aqueous titration (HClO₄), Ph. Eur. 2.2.20	≥98.0%
Enantiomeric purity	Chiral SFC-UV (254 nm), Ph. Eur. 2.2.29	≥99.0% e.e.
Diastereomeric impurity (cis isomer)	Reverse-phase UPLC, 210 nm	≤0.5%
Specific optical rotation (c = 1.0, MeOH, 20 °C)	Polarimetry, Ph. Eur. 2.2.7	[α]_D²⁰ = −38° to −42°
Water content	Karl Fischer coulometry, Ph. Eur. 2.5.12	≤0.5%
Residual solvents	Headspace GC-FID, ICH Q3C Table 2	2-Propanol ≤ 5000 ppm, n-heptane ≤ 500 ppm
Heavy metals	Ph. Eur. method 2.4.8 (Class I)	Pb ≤ 10 ppm, Cd ≤ 5 ppm

Differential scanning calorimetry (DSC) of the anhydrous form at a heating rate of 10 K min⁻¹ under nitrogen reveals a single endothermic melting onset at 187.2 °C (ΔH_f = 135 J g⁻¹), with no glass transition or cold crystallisation events. The monohydrate exhibits an additional broad endotherm between 60 °C and 90 °C corresponding to dehydration. Storage at −20 °C under argon in sealed LDPE-lined aluminium pouches maintains enantiomeric integrity for at least 36 months as validated by real-time stability protocols conducted in accordance with ICH Q1A. Once opened, the material should be stored over P₂O₅ desiccant at 2–8 °C and used within 30 days to prevent moisture-induced racemisation.

The behaviour of the single (3R,4S) enantiomer diverges significantly from that of the racemic trans mixture when deployed as a chiral ligand precursor for asymmetric catalysis. In a prototypical test, the lithium salt of (3R,4S)-4-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid was complexed with Cu(I) thiophene-2-carboxylate and screened in the enantioselective Henry reaction between nitromethane and 4-chlorobenzaldehyde. The single enantiomer produced (R)-1-(4-chlorophenyl)-2-nitroethanol in 84% e.e., whereas the racemic trans ligand gave the product in only 12% e.e., with both catalysts generating comparable conversion (78–82% after 24 h at 25 °C). This disparity stems from the formation of a heterochiral dimeric copper complex when both enantiomers are present, which attenuates the enantiofacial discrimination at the metal centre. The (3S,4R) enantiomer alone furnishes the opposite product enantiomer in 82% e.e., confirming that the stereochemical course is dominated by the pyrrolidine absolute configuration rather than by the achiral dimethoxyphenyl substituent. Researchers focused on the construction of β^2,3-homophenylalanine analogues also note that the (3R,4S) diastereomer gives rise to a right-handed turn conformation in solid-phase-bound tetramers, whereas the (3S,4R) analogue enforces a left-handed screw sense, as probed by circular dichroism spectroscopy (far-UV band at 218 nm). Published data for direct comparison with the cis-configured (3R,4R) and (3S,4S) diastereomers are sparse, but preliminary molecular mechanics simulations (OPLS4 force field, water implicit solvent) indicate a 3.2 kcal mol⁻¹ preference for trans geometry in the pyrrolidine ring, suggesting that cis isomers would introduce substantial ring strain and a different projection of the carboxylic acid onto the binding surface.

Incompatibilities merit explicit mention: combination with amine-based bases beyond sterically hindered tertiary amines (e.g., 2,6-lutidine) should be avoided during amide bond formation, as the pyrolidine NH can undergo competitive acylation under standard HOBt/EDC protocols to yield a lactam impurity detectable at 0.2% by LC-MS. This side reaction is negligible when HATU/DIPEA coupling in DMF is conducted strictly at 0–5 °C for the first 30 min, but becomes significant at ambient temperature beyond 2 h. Additionally, halogenated solvent streams, particularly dichloromethane containing trace HCl, have been observed to catalyse epimerisation at C3 if the free acid is stored in solution for longer than 12 h; the recommended workaround is to handle the compound as its hydrochloride salt (isolated by lyophilisation from 0.1 M HCl) when prolonged exposure to chlorinated media is anticipated.

HS Code	811082
Chemical Formula	C15H21NO5
Molecular Weight	295.33 g/mol
Iupac Name	(3R,4S)-4-(3,5 - Dimethoxyphenyl)pyrrolidine - 3 - carboxylic acid
Appearance	Solid (usually white to off - white)
Solubility	Soluble in some organic solvents like DMSO, less soluble in water
Chirality	Chiral, has (3R,4S) configuration
Functional Groups	Pyrrolidine ring, carboxylic acid group, two methoxy groups on phenyl ring

Packing	100 - gram vial containing (3R,4S)-4-(3,5 - Dimethoxyphenyl)pyrrolidine - 3 - carboxylic acid.
Shipping	The chemical (3R,4S)-4-(3,5 -Dimethoxyphenyl)Pyrrolidine -3 -Carboxylic Acid will be shipped in sealed, specialized containers, ensuring compliance with chemical transportation regulations to safeguard its integrity during transit.
Storage	(3R,4S)-4-(3,5 - Dimethoxyphenyl)pyrrolidine - 3 - carboxylic acid should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store in a well - ventilated area, away from incompatible substances to avoid chemical reactions.