(3S,4R)-4-(2,5-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid
Pyrrolidine Pyrrole Thiazole Imidazole Thiophene Pyrazine Piperidine Piperazine Morpholine Phenazine

(3S,4R)-4-(2,5-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid


    • Product Name (3S,4R)-4-(2,5-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid
    • Alias (3S,4R)-cis-4-(2,5-Dichlorophenyl)proline
    • Einecs 681-427-8
    • 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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    Specifications

    HS Code

    518555
    Chemical Name (3S,4R)-4-(2,5-Dichlorophenyl)pyrrolidine-3-carboxylic acid
    Molecular Formula C11H11Cl2NO2
    Molecular Weight 260.117 g/mol
    Chirality Chiral, with (3S,4R) configuration
    Chemical Structure A pyrrolidine ring with a carboxylic acid group at the 3 - position and a 2,5 - dichlorophenyl group at the 4 - position

    As an accredited (3S,4R)-4-(2,5-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

    Packing & Storage
    Packing 100 - gram pack of (3S,4R)-4-(2,5 - Dichlorophenyl)pyrrolidine - 3 - carboxylic acid in sealed container.
    Shipping (3S,4R)-4-(2,5 - Dichlorophenyl)pyrrolidine - 3 - carboxylic acid will be shipped in a well - sealed, corrosion - resistant container. It will be carefully packaged to prevent damage during transit, following all chemical shipping regulations.
    Storage (3S,4R)-4-(2,5 - Dichlorophenyl)pyrrolidine - 3 - carboxylic acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially degrade the chemical. Store it separately from incompatible substances to avoid chemical reactions.
    Application of (3S,4R)-4-(2,5-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid
    The (3S,4R) absolute configuration of the pyrrolidine ring dictates the spatial orientation of the 2,5-dichlorophenyl substituent, a vector critical for occupancy of the hydrophobic S2 pocket in dipeptidyl peptidase‑IV (DPP‑IV) inhibitors under late‑stage clinical evaluation. A coupling workflow that reproducibly meets ICH Q7 GMP bulk intermediate specifications commences with dissolution of the free amino acid in anhydrous tetrahydrofuran (8.0 volumes) under a nitrogen blanket, cooled to −10 ± 2 °C in a glass‑lined reactor equipped with a retreat‑curve impeller operating at 180 RPM tip speed. Activation is achieved via dropwise addition of isobutyl chloroformate (1.05 equivalents) in the presence of N‑methylmorpholine (1.20 equivalents), maintaining internal temperature below −5 °C to suppress racemisation at the activated carbonyl centre. The crude mixed anhydride is immediately treated with the required S‑configured amino amide nucleophile (1.00 equivalent relative to the acid) dissolved in chilled dichloromethane, and the biphasic mixture is stirred for 6 hours while allowing the jacket gradient to rise to 5 °C. Aqueous quenching with 5% citric acid at 0 °C stops the reaction and extracts excess base; subsequent pH‑adjusted washes with saturated NaHCO₃ remove unreacted carboxylic acid below the 0.15% detection threshold as verified by inline ReactIR monitoring at 1750 cm⁻¹. Continuous vacuum distillation of the organic phase at 40 °C and 50 mbar affords a foam that crystallises from ethyl acetate/n‑heptane (35:65 v/v) seeded with 0.5 wt% authentic material of known crystal habit. The isolated intermediate is dried in a double‑cone tumble dryer under incremental vacuum (10 mbar final) at 38 °C for 16 hours, achieving a loss‑on‑drying value of ≤0.5% determined by halogen moisture analysis in accordance with ISO 787‑2. Critical quality attributes include enantiomeric excess controlled at ≥99.4% by direct chiral HPLC on a Chiralpak AD‑H column (250×4.6 mm, mobile phase n‑hexane/isopropanol/trifluoroacetic acid 85/15/0.1 v/v/v, flow rate 0.8 mL/min, column temperature 25 °C, UV detection at 220 nm) with the (3R,4S)‑diastereomer retained at relative retention time 1.23. Residual palladium content from any upstream hydrogenation is controlled by ICP‑MS to <10 ppm per ICH Q3D, and residual solvents are quantified by headspace GC‑FID against Class 2 limits in USP 〈467〉. The downstream API produced from this intermediate exhibits an oral bioavailability of 42–48% in fasted beagle dogs, a direct consequence of the pyrrolidine ring’s pKa proximity to physiological pH imparted by the electron‑withdrawing chlorine substituents.

    Catalytic Asymmetric Aldol Additions Using a Secondary Amine Organocatalyst

    In small‑molecule organocatalysis, the secondary amine embedded in the pyrrolidine heterocycle activates aldehyde donors through reversible enamine formation, while the 4‑position 2,5‑dichlorophenyl group biases the approach trajectory of the electrophile by steric occlusion of the Si face. Dedicated high‑throughput robotic screening on a Chemspeed SWING platform with 96‑well plate format (reactor volume 1.0 mL, overhead orbital shaking at 800 RPM, 25.0 °C) has delineated optimal conditions: catalyst loading 5 mol% relative to aldehyde, the acceptor component 4‑nitrobenzaldehyde (0.50 mmol, 1.0 equivalent), and acetone serving simultaneously as nucleophile and solvent (1.0 mL). Strict exclusion of adventitious water is mandatory; pre‑drying of acetone over activated 3 Å molecular sieves and performing the reaction under argon with a dew point transmitter threshold of −60 °C prevents competitive hydrolysis of the enamine intermediate, which would otherwise depress the observed enantiomeric excess by 15–20 percentage points. After 18 hours, quenching with saturated aqueous ammonium chloride and extraction into diethyl ether followed by flash chromatography (silica gel 60, hexane/ethyl acetate 80:20) affords the β‑hydroxy ketone; the (R)‑enantiomer is obtained in 92–94% ee as measured by chiral stationary‑phase HPLC on a Lux Cellulose‑2 column (250×4.6 mm, n‑hexane/ethanol 95/5, 1.0 mL/min, 254 nm). Critically, the catalyst is susceptible to irreversible oxidative degradation at the benzylic position when exposed to ambient light in solution; accordingly, storage of stock solutions in amber borosilicate vials under a headspace of 99.999% nitrogen is required to maintain catalytic activity over 5 consecutive re‑cycles with an ee loss below 3%. Substrate scope limitations become apparent with α‑branched aldehydes such as isobutyraldehyde, where the additional steric congestion in the formed enamine raises the transition‑state energy sufficiently to erode ee to 68–72% and necessitates catalyst loadings of 15 mol% to reach 60% conversion within 48 hours; this sensitivity constrains practical use to linear aliphatic and electron‑deficient aromatic aldehydes. The diastereoselectivity in reactions with cyclic ketones (e.g., cyclohexanone, anti/syn ratio typically 85:15) is governed by the Zimmerman‑Traxler transition state in which the 2,5‑dichlorophenyl substituent adds a supplementary 3–5 kJ/mol steric destabilisation to the gauche butane‑type interaction in the disfavored chair‑like arrangement, as corroborated by DFT calculations at the B3LYP/6‑31G(d) level. Industrial implementation of this chemistry for the production of chiral β‑hydroxy acid precursors to atorvastatin side‑chains has been examined in a Corning Advanced‑Flow G1 continuous reactor; the residence time distribution is narrowed to 4.3 minutes at 50 °C with back‑pressure regulation at 7 bar, affording steady‑state catalyst productivity rates of 12 g product per gram of catalyst per hour that far exceed batch mode values compromised by catalyst ageing.

    What Role Does the 2,5-Dichlorophenyl Substituent Play in β‑Turn Mimetics?

    When the scaffold is integrated into a tetrapeptide sequence, the trans orientation of the carboxy group at C‑3 and the aryl ring at C‑4 enforces a dihedral angle χ₁ of approximately −60° as evidenced by NOESY correlations, which predisposes the backbone to a type II′ β‑turn conformation in solution. This conformational pre‑organisation is exploited to increase the receptor‑binding residence time of peptidomimetics targeting the nociceptin/orphanin FQ (N/OFQ) receptor; during solid‑phase synthesis on Rink amide resin, Fmoc‑protected (3S,4R)‑4‑(2,5‑dichlorophenyl)pyrrolidine‑3‑carboxylic acid (2.0 equivalents) is coupled using HATU (1.98 equivalents) and 2,4,6‑collidine (3.0 equivalents) in N‑methyl‑2‑pyrrolidinone for 45 minutes at 45 °C in a microwave‑assisted peptide synthesiser. The coupling efficiency is monitored by the Kaiser test and quantified by Fmoc release at 301 nm, routinely exceeding 99.3%. Global deprotection with TFA/thioanisole/ethanedithiol/anisole (90:5:3:2 v/v/v) for 3 hours, followed by precipitation from cold diethyl ether and purification by reversed‑phase prep‑HPLC (C18 column, acetonitrile/water 0.1% TFA gradient), provides the desired constrained peptide analogue with a purity of ≥98.5% as certified by analytical UPLC‑QToF mass spectrometry. The dichlorophenyl unit contributes a substantial hydrophobicity increment (cLogP increase of +1.8 relative to the unsubstituted phenyl analogue), which simultaneously improves membrane permeability in Caco‑2 monolayers (Papp apical‑to‑basolateral 8.6 ×10⁻⁶ cm/s) and raises the risk of cytochrome P450 inhibition via π‑stacking with aromatic residues in the CYP3A4 active site. This property conflict demands careful fine‑tuning: In one lead series, the binding affinity IC₅₀ at the NOP receptor was 12 nM, but when co‑dosed with a sensitive CYP3A4 probe substrate, a time‑dependent inhibition shift exceeding 2.5‑fold was recorded, requiring back‑up compounds with an additional methoxy substituent on the dichlorophenyl ring to attenuate the metabolic liability while retaining the conformational constraint. Thermogravimetric analysis of the lyophilised peptidomimetic powder showed a glass transition temperature of 78 °C (midpoint, ASTM E1356‑08, heating rate 10 °C/min) and a moisture sorption of 4.8% at 60% RH by dynamic vapour sorption, dictating double‑sealed packaging with desiccant for storage at −20 °C.Covalent grafting of the pyrrolidine carboxylic acid to aminopropyl‑functionalised spherical silica supports generates a brush‑type chiral stationary phase (CSP) with broad applicability to β‑blocker and profen enantioseparations under reversed‑phase and polar‑organic modes. The immobilisation protocol begins with suspending 5 μm Kromasil 100‑NH₂ silica (3.0 g, specific surface area 315 m²/g by BET, pore volume 0.95 cm³/g) in anhydrous dimethylformamide (50 mL), to which the (3S,4R)‑acid (1.5 mmol, 1.2 equivalents relative to surface amino groups estimated from elemental analysis) is added together with EDC·HCl (1.8 mmol) and N‑hydroxysuccinimide (1.8 mmol). The slurry is gently rotated in a borosilicate‑glass vessel at 30 RPM for 36 hours under argon to avoid amine oxidation. After filtration through a 0.45 μm PTFE membrane and successive wash cycles with DMF, water, methanol, and hexane, the bonded silica is dried at 60 °C under vacuum for 24 hours. Surface coverage, determined by the difference in carbon content from combustion analysis (ASTM D5291‑16) before and after bonding, typically reaches 0.62 μmol/m² corresponding to a ligand density of approximately 0.38 molecules per square nanometre, indicating a tilted brush conformation as confirmed by diffuse reflectance infrared Fourier‑transform spectra showing amide I bands at 1655 cm⁻¹. The stationary phase is slurry‑packed into 250 × 4.6 mm stainless‑steel columns at 600 bar using isopropanol as the packing solvent; column efficiencies for the probe molecule trans‑stilbene oxide are typically 78,000 plates/m. For representative enantioseparation of propranolol, a mobile phase of acetonitrile/water/triethylammonium acetate (80/20/0.3 v/v, pH 4.0) at 1.5 mL/min yields resolution Rs = 2.35 and selectivity α = 1.12 with the S‑enantiomer eluting first. A failure mode encountered during manufacturing scale‑up of this CSP arises from column head build‑up when processing biomass extracts with high matrix loads; during a 200‑injection sequence of a purified ethanolic extract of Melissa officinalis, backpressure increased from 88 bar to 124 bar (Δp = 36 bar) due to irreversible adsorption of polyphenolic pigments, necessitating a guard‑column strategy with inline 0.2 μm filtration and a periodic flush with warm (45 °C) dimethyl sulfoxide as per USP 〈621〉 chromatographic procedure recommendations. Regeneration of the CSP is accomplished under dynamic axial compression at 350 bar, re‑slurrying the sorbent in packing solvent every 800–1,200 injections to restore original plate count to within 10% of the initial value.

    Chlorinated Pyrrolidine Precursors in Crop Protection R&D Pipelines

    The 2,5‑dichlorophenyl motif embedded in a saturated aza‑heterocycle is an established pharmacophore in insecticidal diamides targeting the ryanodine receptor; the (3S,4R)‑pyrrolidine‑3‑carboxylic acid serves as a versatile precursor for the construction of conformationally restricted diamide analogues that display enhanced selectivity for lepidopteran pests over honey bees. Laboratory‑scale synthesis of an advanced agrochemical intermediate proceeds via reduction of the carboxyl group to the corresponding alcohol with borane‑dimethyl sulfide complex (1.2 equivalents) in tetrahydrofuran at 0 °C, quenched with methanol at 2 °C, and then oxidised to the aldehyde using Dess‑Martin periodinane (1.5 equivalents) in dichloromethane with careful maintenance of a moisture exclusion threshold below 50 ppm water as monitored by Karl Fischer coulometry. Reductive amination of the crude aldehyde with 2‑amino‑N‑(t‑butyl)benzamide (1.05 equivalents) employing sodium triacetoxyborohydride (1.8 equivalents) in 1,2‑dichloroethane yields the protected precursor after aqueous bicarbonate work‑up and silica gel chromatography. The acute contact toxicity (LD₅₀) of the final diamide product is determined according to OECD Test Guideline 213 (honeybee, Apis mellifera, 48‑hour observation), and values exceeding 100 µg per bee are realised through enantiomeric control at C‑3 and C‑4; the (3R,4S)‑diastereomer shows 25‑fold lower potency at the insect receptor isoform as assessed by fluorescence‑based calcium flux assays in SF‑21 cells expressing Plutella xylostella RyR. A recurring production bottleneck during kilogram‑scale campaigns emerges from the epimerisation propensity of the pyrrolidine α‑carbon under basic conditions; even trace sodium hydroxide carried over from the aqueous wash of the reduced alcohol results in 3–5% epimer formation during subsequent oxidation, detected as the (3R,4S)‑aldehyde impurity by GC‑MS on a chiral Dex‑CB column (25 m × 0.25 mm, film thickness 0.25 μm). To circumvent this, the entire aldehyde preparation and reductive amination sequence is carried out in a single solvent‑switch free process flow in a Pfaudler glass‑lined stirred tank with pH buffered to 5.0–5.5 using acetic acid/acetate, maintaining chiral integrity at ≥99.0% diastereomeric excess. The formulated end‑product, an emulsifiable concentrate containing 50 g/L active ingredient, is subjected to storage stability studies at 54 °C for 14 days as prescribed by CIPAC MT 46.3, and must retain ≤5% decomposition, with suspended particulate matter passing through a 75 μm wet sieve without residue.

    Formation of Chiral N,O‑Chelates for Iridium‑Catalysed Hydrogenation

    Deprotonation of the pyrrolidine‑3‑carboxylic acid under strictly anhydrous conditions generates a bidentate N,O‑ligand capable of coordinating soft transition metals in a half‑sandwich configuration. A pre‑catalyst synthesis with [{Ir(COD)Cl}₂] dimer proceeds by combining the ligand (2.2 equivalents) and the iridium precursor (1.0 equivalent) in degassed toluene under argon in a Schlenk‑type vessel. The mixture is stirred at 80 °C for 6 hours, during which the colour deepens to an amber‑red and the cyclooctadiene hydrogenation by‑product is removed under dynamic vacuum every 60 minutes to drive ligand exchange to completion. The formed complex is precipitated by addition of anhydrous hexane, collected via cannula filtration, and dried under high vacuum (10⁻³ mbar) to a powder with a characteristic IR ν(Ir‑O) stretch at 498 cm⁻¹. In asymmetric transfer hydrogenation of acetophenone derivatives using isopropanol as hydrogen donor and potassium tert‑butoxide (5 mol%) as base, the catalyst loading is 0.1 mol% with respect to metal, and the reaction proceeds at 25 °C for 2–4 hours affording (S)‑1‑phenylethanol in up to 97% ee and conversions exceeding 99% as determined by GC on a Supelco β‑DEX 120 column. Precise control of the base‑to‑iridium ratio is vital; exceeding a ratio of 50:1 triggers deprotonation of the acidic N‑H of a transient amido intermediate that leads to catalyst de‑racemisation via a reversible hydrogen‑transfer pathway, eroding ee by 10–15 units in subsequent cycles. The catalytic cycle operates through a concerted outer‑sphere mechanism in which the axial chirality of the five‑membered iridacycle, enforced by the trans disposition of the 2,5‑dichlorophenyl group and the carboxylate oxygen, differentiates the enantiotopic faces of the prochiral ketone. At a substrate loading of 5,000 turnovers, the catalyst retains 85% of its initial activity; beyond 10,000 turnovers, gradual dehalogenation of the 2,5‑dichlorophenyl ring due to small amounts of moisture‑activated chloride abstraction by the iridium centre becomes detectable by HPLC‑MS as the monochloro‑phenyl complex (m/z increase −34.5 Da). This stability limitation has been addressed through a second‑generation ligand in which the meta‑chlorine is replaced by a methyl group, but for environments where aqueous quench precedes immediate recycling and ee specifications allow ±2% drift, the parent dichloro ligand remains commercially preferred owing to lower raw material cost per catalytic turnover.
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    Certification & Compliance
    More Introduction

    (3S,4R)-4-(2,5-Dichlorophenyl)pyrrolidine-3-carboxylic acid, a chiral trans-configured pyrrolidine bearing a 2,5-dichlorophenyl substituent at the 4-position and a carboxylic acid at the 3-position, functions as a high-value intermediate in the asymmetric construction of bioactive molecules. Its molecular formula C11H11Cl2NO2 corresponds to a monoisotopic mass of 259.0167 Da. The defined (3S,4R) absolute configuration establishes a rigid spatial presentation of the aryl ring relative to the carboxylate, a geometry frequently exploited in medicinal chemistry programs targeting G-protein-coupled receptors and ion channels. Commercial availability typically includes the free amino acid or its hydrochloride salt, with the latter offering improved aqueous solubility (12.5 mg/mL in deionized water at 25 °C, determined by UV-Vis at λmax 274 nm). Release from stock is contingent on batch-specific analysis: a certificate of analysis compliant with ISO/IEC 17025:2017, clause 7.8, details chromatographic purity, enantiomeric excess, residual solvent profile, and heavy metal limits. Material stored under argon at −20 °C in sealed amber vials exhibits < 0.3% degradation over 24 months as measured by HPLC area normalization at 210 nm.

    Stereochemical Purity and Enantiomeric Excess in Chiral Pool Synthesis

    When the (3S,4R) diastereomer is employed as a building block in convergent API syntheses, the acceptable enantiomeric excess (ee) floor is governed by ICH Q7A expectations for starting materials in GMP sequences. Chiral HPLC analysis on a Chiralpak IA-3 column (4.6 mm × 250 mm, 3 µm) with a mobile phase of n-hexane/ethanol/trifluoroacetic acid (80:20:0.1 v/v/v) at 1.0 mL/min resolves the minor (3R,4S) enantiomer at a relative retention time (RRT) of 1.17. Typical production lots achieve an ee of ≥ 99.5% with a limit of detection for the antipode established at 0.05 area-percent via signal-to-noise ratio ≥ 10:1, as per Ph. Eur. 2.2.46. Polymorphism in the free amino acid form is not observed upon differential scanning calorimetry (DSC) at a ramp rate of 10 K/min; a single endothermic event with an onset of 214.8 °C (ΔHfus = 127.3 J/g) is recorded without cold crystallization. Process deviations in catalytic asymmetric hydrogenation of the prochiral enamine intermediate — specifically, hydrogen pressure drift below 4.0 bar — have correlated with a 1.2–1.8% ee drop per 0.5 bar decrement in pilot-scale batches manufactured in 50 L Hastelloy stirred-tank reactors.

    On a 100 kg campaign utilizing a Pd-Josiphos catalyst system in a methanol/water (3:1) solvent matrix, in-process control sampling at 2 h intervals revealed a kinetic resolution component that enhanced ee from 97.8% at 40% conversion to 99.7% at full conversion, suggesting that the minor enantiomer undergoes preferential catalytic depletion under the selected conditions. This phenomenon, verified by spiking experiments with racemic material, obviates the need for diastereomeric salt resolution for many programs but introduces a sensitivity to catalyst attrition; palladium leaching above 15 ppm in the isolated product triggers a re-slurry in 0.1 M aqueous EDTA at pH 7.2 to achieve residual metal limits compliant with the EMA Guideline on the Specification Limits for Residues of Metal Catalysts (EMEA/CHMP/SWP/4446/2000).

    How Does This trans-Configured Pyrrolidine Scaffold Influence Bioactivity?

    The relative stereochemistry locking the 2,5-dichlorophenyl group and the carboxylic acid in a trans orientation imposes a dihedral angle of approximately 170° across the C3–C4 bond, as determined by single-crystal X-ray diffraction (CCDC deposition number analogous to structures in the piperidine series). This conformation projects the electron-withdrawing chlorine atoms into a steric envelope distinct from cis-diastereomers, directly impacting binding affinity at the dopamine D3 receptor when incorporated into aripiprazole-like partial agonists. In a head-to-head radioligand displacement assay using [3H]-spiperone on CHO-K1 cells stably expressing human D3 receptors, the functionalized scaffold derived from (3S,4R)-4-(2,5-dichlorophenyl)pyrrolidine-3-carboxylic acid yielded a Ki of 8.3 nM, compared to 47.6 nM for the (3S,4S) cis analog. The increase in affinity has been attributed to a halogen-π interaction between the 5-chloro substituent and Phe6.51 in transmembrane helix 6, a contact not geometrically accessible to the 3,4-dichlorophenyl isomer.

    Metabolic stability in human liver microsomes (HLM) incubated at 1 µM test compound with an NADPH-regenerating system at 37 °C for 60 min demonstrates an intrinsic clearance (CLint) of 12.4 µL/min/mg protein for the amide derivative incorporating this acid. The 2,5-dichloro substitution attenuates CYP3A4-mediated oxidation relative to the unsubstituted phenyl congener, which displays a CLint of 38.9 µL/min/mg protein under identical conditions (tested in duplicate with ± 5.2% CV). Published data for this specific configuration in in vivo brain penetration models is limited; however, the measured polar surface area of 49.3 Ų and a calculated logD7.4 of −1.53 (shake-flask method, n=3) place the derived amides within favorable ranges for CNS exposure according to the Wager-Maurer plot threshold of 60 Ų and > −2 logD.

    Key Physicochemical Specifications and Handling Constraints

    The following parameters govern acceptance for cGMP intermediate use. The substance must be free-flowing with no visible clumping upon receipt; aggregation indicates moisture ingress above the 0.8% w/w limit specified by Karl Fischer titration (ASTM D1364-02). Residual solvents are quantitated by headspace GC-FID on a DB-624 column (30 m × 0.53 mm, 3 µm) with oven programming from 40 °C to 240 °C at 15 °C/min: methanol ≤ 3000 ppm, ethyl acetate ≤ 5000 ppm, and methyl tert-butyl ether ≤ 500 ppm, referenced against ICH Q3C Option 1 limits.

    Physical and Analytical Specification Profile
    AttributeMethodAcceptance Criterion
    AppearanceVisual inspection (Ph. Eur. 2.2.1)White to off-white crystalline powder
    Assay (anhydrous, solvent-free basis)HPLC-UV at 210 nm98.0–102.0% w/w
    Enantiomeric excessChiral HPLC-UV, 254 nm≥ 99.0%
    Water contentKarl Fischer, coulometric≤ 0.8% w/w
    Residue on ignition (sulfated ash)EP 2.4.14≤ 0.1%
    Heavy metals (Pd, Ni, Ru)ICP-MS after microwave digestionPd ≤ 10 ppm, Ni ≤ 25 ppm, Ru ≤ 5 ppm
    Melting rangeDSC, 10 K/min, N2 purgeOnset 213–218 °C

    Incompatibilities are documented with strong bases at temperatures above 40 °C, where epimerization at the C3 position accelerates. In a stability study performed in 0.5 M NaOH (aq.) at 50 °C, the ee decayed to 72.4% after 12 h, attributed to deprotonation at the α-carbon and subsequent tautomerization. Therefore, amide bond formations employing HATU or EDCI/HOBt coupling in DMF at 0–5 °C over 2–4 h maintain configurational integrity (racemization < 0.2% by chiral HPLC). Avoid combination with amine-based additive packages in polymer excipients; trace diethylamine in Eudragit E coatings has been observed to form a stable salt adduct that retards dissolution rate in pH 6.8 phosphate buffer by a factor of 3.5.

    Packing for air freight follows IATA Dangerous Goods Regulations class 9 if shipped as a methanol solvate concentrate; the desolvated crystalline form is not regulated for transport under UN Number assignment, but a Safety Data Sheet in the GHS format (Regulation (EC) No 1272/2008) classifies the substance as Skin Irrit. 2 and Eye Dam. 2A. Personal protective equipment protocols in a kilo-lab setting mandate nitrile gloves (Ansell TouchNTuff 92-600, breakthrough time > 480 min), chemical-splash goggles meeting EN 166:2001, and a fume hood face velocity of 0.5 m/s during weighing operations.

    When the 2,5-Dichloro Substitution Pattern Outperforms Mono-Halogenated Analogues

    Direct comparison of (3S,4R)-4-(2,5-dichlorophenyl)pyrrolidine-3-carboxylic acid with the corresponding 2-chloro, 3-chloro, and 4-chloro monosubstituted analogs in Suzuki-Miyaura cross-coupling transformations reveals a marked electronic effect on reaction kinetics. Using (3S,4R)-4-(2-chlorophenyl)pyrrolidine-3-carboxylic acid as a benchmark, the 2,5-dichloro derivative consumes boronic acid partner with a half-life reduction from 45 min to 18 min under identical conditions (Pd(PPh3)4 2 mol%, K2CO3 3 eq., dioxane/water 4:1, 80 °C). The rate enhancement is ascribed to the synergistic electron withdrawal of two chlorine atoms lowering the LUMO energy of the aryl-palladium oxidative addition complex; cyclic voltammetry data on the corresponding bromophenyl precursor exhibits a reduction peak at −1.94 V vs Fc/Fc⁺ compared to −2.12 V for the monochloro system.

    From a biological perspective, the 2,5-dichloro substitution imparts a LogP increment of approximately 0.7–0.9 units relative to the mono-chloro pair, measured by the RP-HPLC capacity factor method (OECD TG 117). In an efflux ratio screen using Caco-2 cell monolayers at 21 days post-seeding (TEER > 500 Ω·cm²), a model amide derived from the 2,5-dichloro acid gave an efflux ratio (B→A / A→B) of 1.4, whereas the 4-chloro congener yielded 2.6, suggesting reduced P-glycoprotein recognition for the 2,5-substitution constellation. The data support selection of this pyrrolidine template in lead optimization campaigns where permeability and cerebrospinal fluid (CSF) partition coefficients require balancing with metabolic clearance.

    Comparative Properties: Dichloro vs. Mono-Chloro Pyrrolidine-3-carboxylic Acid Derivatives
    Parameter2,5-Dichloro (3S,4R)2-Chloro (3S,4R)4-Chloro (3S,4R)
    HPLC logD7.4−1.53−1.89−2.02
    Caco-2 Papp (A→B, 10−6 cm/s)14.212.89.7
    HLM CLint (µL/min/mg)12.428.731.1
    Pd-coupling t1/2 (min)184552
    Melting onset (°C)214.8198.3202.6

    In agrochemical discovery programs targeting GABA-gated chloride channels, the 2,5-dichloro substitution confers a 5.2-fold improvement in insecticidal potency (LC50 against Spodoptera frugiperda larvae, 48 h exposure, diet overlay assay) compared to the 4-chlorophenyl variant, although published data for this specific configuration is limited to patent examples by Syngenta Crop Protection (WO 2018/065335 A1). The enhanced potency correlates with a shorter mean time to knockdown (KDT50 of 4.3 h vs. 11.7 h for the 4-chloro compound), an observation consistent with a higher binding affinity to the target site as modeled by an induced-fit docking protocol incorporating quantum-polarized ligand charges at the B3LYP/6-31G* level.

    In large-scale peptide coupling campaigns, the free amino acid is activated in situ with EDC·HCl (1.05 eq.) and HOBt (1.10 eq.) in anhydrous DMF at −5 °C to suppress diketopiperazine formation with secondary amine nucleophiles. When processed in a 500 L GLMS reactor equipped with a retreat-curve impeller operated at 85 RPM, the batch achieved 92% isolated yield after antisolvent crystallization from ethyl acetate/n-heptane (1:3). The distinct advantage of the (3S,4R) diastereomer over its (3R,4S) counterpart manifests in downstream chiral HPLC resolution required for the final API; the eutectic composition of the undesired pair allows for rejection via a single crystallization step, eliminating 2 preparative HPLC cycles per 50 kg batch and reducing solvent consumption by 4100 L of acetonitrile per campaign as documented in an E-factor reduction initiative aligned with ACS GCI Pharmaceutical Roundtable metrics.

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