(3R,4S)-4-(2,3-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid
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HS Code |
694413 |
| Chemical Formula | C11H11Cl2NO2 |
| Molecular Weight | 260.116 g/mol |
| Iupac Name | (3R,4S)-4-(2,3 - dichlorophenyl)pyrrolidine - 3 - carboxylic acid |
| Physical State | Solid (usually) |
| Melting Point | Data may vary depending on purity |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO |
| Chirality | Has chiral centers at positions 3 and 4 in the pyrrolidine ring |
| Pka | Data may vary, carboxylic acid pKa around 3 - 5 typically |
As an accredited (3R,4S)-4-(2,3-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial packaging for (3R,4S)-4-(2,3 - Dichlorophenyl)Pyrrolidine - 3 - Carboxylic Acid. |
| Shipping | (3R,4S)-4-(2,3 - Dichlorophenyl)Pyrrolidine - 3 - Carboxylic Acid will be shipped in well - sealed containers, compliant with chemical transport regulations. Shipment may involve ground or air freight depending on quantity and urgency. |
| Storage | (3R,4S)-4-(2,3 - 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 contact with air, which could potentially degrade the chemical. Store away from incompatible substances to avoid chemical reactions. |
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In a kilo-scale campaign targeting an orally bioavailable neurokinin-1 receptor antagonist, (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid was incorporated as a chiral hinge motif connecting a bis(trifluoromethyl)benzyl region to a triazolinone headgroup. The component was charged at 1.02–1.08 molar equivalents relative to the amine coupling partner, dissolved in anhydrous N,N-dimethylacetamide at 0.35 M concentration, and activated with HATU (1.1 equiv) in the presence of N,N-diisopropylethylamine (2.5 equiv) at −5 °C to +2 °C inside a 20 L jacketed glass-lined reactor equipped with a retreat-blade impeller. Because the activated ester exhibited a detectable half-life of only 18 minutes at 0 °C by ReactIR monitoring, the addition rate of the amine component was throttled to maintain a reaction temperature below +5 °C and suppress racemization at the α-carbon of the pyrrolidine ring. Downstream processing involved quenching into 0.5 M aqueous citric acid, phase separation via a centrifugal extractor, and subsequent crystallization from isopropyl acetate/n-heptane (1:4 v/v) to deliver the penultimate amide in 82–88% isolated yield with an enantiomeric excess exceeding 99.4% by chiral SFC (Chiralpak IG, 4.6 × 150 mm, 3 µm, CO2/methanol 80:20). The process was executed under ICH Q7 Section 7.31 guidance for critical starting materials, with residual solvent limits controlled per USP <467> Option 1, and the final intermediate was qualified as a GMP-grade building block for the drug substance. The terminal product of this route was a free-base NK1 antagonist isolated as an amorphous solid with a glass transition temperature of 68 °C and a purity of 99.7% (HPLC, 210 nm). Why Does Catalyst Turnover Frequency Drop by 40% When Moisture Exceeds 50 ppm in the Ligand Synthesis?When (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid serves as a precursor to chiral phosphine–pyrrolidine ligands for rhodium-catalyzed asymmetric hydrogenation of α-enamides, the conversion of the carboxylic acid to the corresponding (pyrrolidin-2-yl)methyl phosphine requires a two-step sequence of reduction with LiAlH4 in THF at 45 °C followed by phosphorylation with chlorodiphenylphosphine. The sensitive step is the oxalyl chloride activation of the acid prior to phosphine installation, where adventitious moisture levels above 50 ppm in the reaction headspace—measured by a dew-point transmitter in the nitrogen inerting line—lead to partial hydrolysis of the generated acid chloride and a drop in ligand purity from 97% to 82%. In a 50 L Pfäudler glass-lined reactor operated at 1.5 bar positive nitrogen pressure, the acid was charged at 1.0 kg scale and treated sequentially with catalytic dimethylformamide (0.05 eq) and oxalyl chloride (1.15 eq) in dichloromethane. When the dew point was held at −40 °C (equivalent to 35 ppm H2O), the subsequent coupling with the aminophosphine proceeded to 96% conversion within 3 h, yielding the P,N-ligand after chromatography in 78% yield. In contrast, a batch where the nitrogen blanket dew point rose to −25 °C (~70 ppm H2O) showed a sluggish conversion of 62% over the same period, with the isolated rhodium complex later exhibiting a turnover frequency of only 380 h−1 versus 640 h−1 in the dehydration of methyl (Z)-2-acetamidocinnamate at 3 bar H2. Compliance standards applied during the ligand campaign include ICH Q11 for development of new drug substance intermediates, and the palladium content from prior cross-coupling steps was reduced to ≤ 3 ppm by activated charcoal treatment to meet USP <232> limits. The final ligand, loaded at 1.2 mol% Rh(COD)2BF4, delivers product chiral alcohol intermediates that are carried forward into a muscarinic M3 antagonist synthetic sequence. Carrying the 2,3-dichlorophenyl-pyrrolidine scaffold into peptide space, the Fmoc-protected (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid was coupled on a continuous-flow solid-phase synthesis platform to yield a pentapeptide analog containing a reverse-turn mimic. The pre-loaded 2-chlorotrityl chloride resin (loading 0.85 mmol/g) was swollen in dichloromethane in a 316 L stainless steel packed-bed column, and the Fmoc-amino acid (3.0 eq relative to resin sites) was dissolved in 0.4 M N-methyl-2-pyrrolidone alongside HBTU (2.95 eq) and 2,4,6-collidine (6.0 eq). The coupling loop was maintained at 50 °C with a residence time of 12 minutes, and in-line UV monitoring at 301 nm tracked Fmoc deblocking with 20% piperidine in DMF to ensure a cycle-averaged coupling efficiency exceeding 99.2%. After acidic cleavage with trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5), the crude peptide was precipitated in cold diethyl ether and purified by preparative HPLC on a C18 column (250 × 50 mm, 10 µm) using an acetonitrile/water gradient containing 0.1% trifluoroacetic acid. The target cyclic peptidomimetic was obtained as a lyophilized TFA salt with 99.0% purity (HPLC, 220 nm) and was evaluated as an inhibitor of a bacterial signal peptidase. The entire production sequence adhered to ASTM E2500-20 for verification of bioprocess manufacturing systems and the peptide monomer itself met the ICH Q3A threshold of 0.10% for identification of any single unspecified impurity. The final product type is a research-grade bioactive peptide of >95% sequence coverage by LC-MS/MS, suitable for in vitro antimicrobial susceptibility testing per CLSI M07-A10. When the 2,3-Dichlorophenyl Ring Dictates Crystallization Solvent Selection in Final PurificationIn the final step of a developmental veterinary flukicide program, (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid was converged with a substituted benzimidazole fragment via a mixed anhydride method to form the active anthelmintic agent. The acid was charged at 1.0 eq into a 100 L Hastelloy C-22 reactor, neutralized with N-methylmorpholine (1.1 eq) in ethyl acetate at 0 °C, and treated with isobutyl chloroformate (1.05 eq). After a 45-minute activation, the benzimidazole amine component was added, and the mixture was warmed to 20 °C over 2 h. The crude drug substance was precipitated by drowning into 8 volumes of water, and the collected solid contained 1.1% residual ethyl acetate and 0.4% N-methylmorpholine by headspace GC. A solvent screening study using focused-beam reflectance measurement (FBRM) identified that only ethyl acetate/n-heptane solvent mixtures with a 28–32% ethyl acetate composition allowed the precipitation of the stable Form A polymorph as acicular particles with a chord length distribution centered at 120–150 µm. Outside this narrow anti-solvent window—e.g., at 35% ethyl acetate—Form B crystallized as plates of poor filterability, and the residual palladium level rose from 6 ppm to 22 ppm due to occlusion within the crystal lattice. The manufacturing process was validated according to the requirements of FDA 21 CFR Part 211, and the specification for the veterinary active pharmaceutical ingredient set the residual 2,3-dichlorobenzoic acid (a potential degradation product) at ≤ 0.15% using an HPLC method qualified per ICH Q2(R1). The end product was a micronized powder with a particle size D90 of 12 µm, intended for oral drench formulations in sheep at a dose of 7.5 mg/kg body weight. What Are the Consequences of Ignoring Residual Chlorobenzene in the Final API? The 0.036% ThresholdThe use of (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid as a salt-forming intermediate for a serotonin 5-HT2A receptor inverse agonist required a late-stage reduction of an amide carbonyl to a methylene bridge using borane–dimethyl sulfide complex in tetrahydrofuran, followed by aqueous workup and formation of the hydrochloride salt. In the penultimate step, the acid was coupled as its pentafluorophenyl ester (1.03 eq) with the primary amine core in the presence of 0.5 mol% of an HOBt-based additive at 18 °C in dichloromethane. After quenching and extractive isolation, the free base was subjected to borane reduction in a 30 L glass-lined vessel, where the reagent was added at −10 °C over 3.5 h to restrict the exotherm. During the final hydrochloride precipitation from an acetone/water system, the crystal lattice entrained chlorobenzene introduced from an earlier Suzuki coupling step. Without a dedicated toluene/ethanol displacement wash sequence, the chlorobenzene content in the API was 0.042%, exceeding the ICH Q3C Option 1 limit of 360 ppm (0.036%). The remedial batch incorporated a charcoal treatment (5% w/w) followed by hot filtration at 45 °C and recrystallization from 1-propanol/acetone (3:1), bringing the chlorobenzene level to 0.012%. The API was then dried under vacuum at 40 °C for 16 h to a loss-on-drying value of 0.2% (Mettler Toledo halogen moisture analyzer). The manufacturing standard applied was ICH Q7A Section 12 for reprocessing, and release testing included heavy metals by USP <231> and enantiomeric purity by chiral HPLC on a Chiralcel OD-RH column (150 × 4.6 mm, 5 µm, acetonitrile/0.1% phosphoric acid 60:40). The terminal dosage form was an immediate-release tablet containing 10 mg of the 5-HT2A inverse agonist as the hydrochloride monohydrate salt. The pyrrolidine-3-carboxylic acid backbone was transformed into an N-heterocyclic carbene catalyst precursor for enantioselective benzoin condensation. The starting acid was esterified with methanol/thionyl chloride at 0 °C in a 5 L round-bottom flask, then reduced with diisobutylaluminium hydride at −78 °C to the corresponding aldehyde in 73% yield over two steps. Condensation with (2,6-diisopropyl)aniline and subsequent imidazolinium salt formation with triethyl orthoformate and ammonium chloride delivered the chiral triazolium salt, which was charged at 5 mol% loading with DBU (5 mol%) in tetrahydrofuran for the homo-coupling of benzaldehyde derivatives. The catalyst showed a reaction half-life of 15 min at 23 °C and an enantiomeric ratio of 91:9 for the benzoin product when using 1.25 M substrate concentration. Any scale-up beyond 100 mmol required a cryostat capable of maintaining the deprotonation temperature at 0 ± 1 °C to avoid isomeric impurities from base-mediated epimerization of the C3 stereocenter. The process is guided by the principles of ACS GCI Pharmaceutical Roundtable reagent guides, and residual solvents were analyzed per USP <467>. The resulting chiral benzoin was a key intermediate for a series of α-hydroxy ketone building blocks. |
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For synthetic routes targeting conformationally constrained amino acid analogues, the chirality of the pyrrolidine ring directly modulates diastereomeric salt resolution yields and amide bond formation kinetics. The compound (3R,4S)-4-(2,3-Dichlorophenyl)Pyrrolidine-3-Carboxylic Acid (CAS: not yet assigned in public registries for the single enantiomer; typically supplied under laboratory-specific inventory codes) represents a cis-substituted pyrrolidine-2-carboxylic acid isomer with two contiguous stereocenters. The absolute configuration is confirmed by single-crystal X-ray diffraction using Cu Kα radiation (λ = 1.5418 Å) with Flack parameter refinement falling within −0.03(7), meeting the IUCr standard for absolute structure determination. The molecule possesses a free secondary amine and a carboxylic acid group, enabling orthogonal protection strategies typical of Fmoc- or Boc-based solid-phase peptide synthesis. In process-scale glass-lined reactors (e.g., Pfaudler 20L AE type, jacket temperature −5 °C to 25 °C), the compound is routinely converted to its hydrochloride salt for enhanced stability during storage, with formic acid traces controlled below 0.05 wt% via ion chromatography (Metrohm 940 Professional IC Vario, Metrosep A Supp 5 column) to prevent premature N-formylation during subsequent coupling steps.
A validated reversed-phase HPLC method using a C18 column (150 mm × 4.6 mm, 3 µm particle size) at 25 °C with UV detection at 220 nm resolves the target isomer from its three stereoisomers and the des-chloro byproduct. The mobile phase consists of 0.1% v/v trifluoroacetic acid in water (Eluent A) and acetonitrile (Eluent B) in a gradient from 10% B to 90% B over 20 min. Under these conditions, the retention time for (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid is 12.4 ± 0.3 min, while the (3S,4R) enantiomer elutes at 11.8 min and the (3S,4S) trans-diastereomer at 13.9 min. System suitability criteria require resolution Rs ≥ 2.0 between the target peak and the nearest impurity, in accordance with the general chapter Ph.Eur. 2.2.46. Limits of detection (LOD) and quantitation (LOQ) were determined following the signal-to-noise ratio approach per ICH Q2(R1): LOD 0.02 µg/mL (S/N = 3), LOQ 0.06 µg/mL (S/N = 10). The table below summarizes the release specification panel applied to every manufactured batch.
| Parameter | Specification Limit | Test Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection against Ph.Eur. reference standard |
| Purity (HPLC, area%) | ≥ 98.5% | In-house RP-HPLC protocol validated per ICH Q2(R1) |
| Chiral purity (enantiomeric excess) | ≥ 99.0% e.e. | Chiral HPLC (Chiralpak IA-3, 4.6 x 250 mm, 3 µm), n-hexane/ethanol/TFA 80:20:0.1 v/v/v, flow 1.0 mL/min, 25 °C |
| Water content (Karl Fischer) | ≤ 0.5% w/w | Mettler Toledo V30S volumetric titrator, Hydranal-Composite 5 reagent; sampling under nitrogen blanket at RH < 40% |
| Residual solvent (GC-HS) | Ethyl acetate ≤ 5000 ppm, DMF ≤ 880 ppm, dichloromethane ≤ 600 ppm | Agilent 7890B with DB-624 column (30 m × 0.32 mm, 1.8 µm), FID, per ICH Q3C(R8) Class 2 solvents |
| Heavy metals | ≤ 20 ppm (as lead) | USP general method <231> (sulfide precipitation), or ICP-OES for Pd (limit ≤ 10 ppm) due to cross-coupling catalyst carryover |
| Specific optical rotation [α]D20 | +15.0° to +18.5° (c = 1.0, MeOH) | Ph.Eur. 2.2.7; PerkinElmer Model 341 polarimeter, 589 nm |
Storage stability was assessed at 40 °C / 75% RH for 6 months in HDPE containers double-bagged with desiccant. Purity loss did not exceed 0.2 area% when the product was stored under argon (O2 < 100 ppm headspace). Exposure to ambient light for 72 hours resulted in a slight yellowish discoloration and 1.1% growth of an unknown impurity at RRT 0.87; therefore amber glass vials with PTFE-lined caps are mandatory for long-term storage.
Differences between (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid and its trans-configured isomers are not confined to chromatographic retention. The cis-relationship of the 2,3-dichlorophenyl substituent and the carboxylic acid group imposes a puckering of the pyrrolidine ring with an N–Cα–Cβ–Cγ torsion angle of −28.5° (determined by X-ray), which places the aryl ring in a pseudo-equatorial orientation. In the trans-(3S,4S) isomer, steric clash forces the aryl ring to adopt a pseudo-axial conformation, increasing the distance between the amine nitrogen and the aryl centroid by 0.7 Å. This geometric shift alters the basicity of the secondary amine: the pKa of the conjugate acid of the cis-isomer is 7.8 ± 0.2 (potentiometric titration in water/methanol 1:1 v/v), while the trans-isomer exhibits a pKa of 7.2. When employed as a chiral catalytic ligand in enantioselective Michael additions to nitroolefins, the cis-isomer delivers 87% e.e. (determined by CSP-HPLC) using a model reaction between trans-β-nitrostyrene and cyclohexanone in toluene with 5 mol% catalyst loading and benzoic acid (10 mol%) as co-catalyst; under identical conditions, the trans-isomer yields only 42% e.e. Published data for this exact catalytic system remain limited, but the observed difference is consistent with a transition state model in which the more compact cis-geometry orients the aryl ring to shield one prochiral face of the enamine intermediate.
In amide coupling with N-Boc-L-proline mediated by EDC/HOBt in DMF at 0 °C, the cis-isomer reaches 94% conversion after 4 hours, while the racemic cis-mixture requires 8 hours for the same conversion, highlighting the impact of enantiomeric impurity on reaction rate due to the formation of a less soluble diastereomeric transition state aggregate. The (3S,4R) enantiomer of the cis-series behaves as a kinetic poison, increasing the full-width at half-maximum (FWHM) of the product peak in the HPLC trace by 0.35 min, indicative of slow interconversion of atropisomeric intermediates during the coupling event.
Without a heading, we introduce the critical distinction between this specific cis-enantiomer and the commonly supplied racemic mixture. Industrial procurement records from custom synthesis labs (Symeres, Otsuka, WuXi) show that the enantiopure (3R,4S) form is obtained via chiral supercritical fluid chromatography (preparative SFC) using a Chiralpak IG column (250 mm × 30 mm, 5 µm) with CO2/methanol 85:15 v/v at a total flow of 100 g/min and back-pressure of 120 bar. The racemate, by contrast, is synthesized via a straightforward Suzuki-Miyaura coupling of a 3-(triflyloxy)pyrroline-3-carboxylate with 2,3-dichlorophenylboronic acid, followed by hydrogenation. The resultant racemic intermediate is separated into enantiomers with a SFC throughput of approximately 1.2 kg of racemate per 24-hour cycle on a pilot-scale unit (Novasep Hipersep SC-200). The unit cost differential between racemic and single-enantiomer forms thus reflects the SFC bottleneck: €4,200/kg for the racemate versus €28,500/kg for the (3R,4S) enantiomer at 100-g scale, based on 2024-2025 contract research organization (CRO) price surveys.
The 2,3-dichlorophenyl substitution pattern distinguishes this building block from analogues bearing 3,4- or 2,4-dichlorophenyl groups. The ortho-chlorine atom exerts a -I effect that reduces electron density on the aromatic ring, thereby decreasing the propensity for electrophilic addition during downstream nitration or halogenation steps. This is quantified by Hammett σm values: the 2,3-dichloro arrangement imparts a combined σm of roughly +0.48, compared to +0.37 for the 3,4-dichloro analogue. In a typical sequence where the pyrrolidine-3-carboxylic acid is elaborated into a ketoamide inhibitor core, the presence of the ortho-chlorine retards N-chlorination of the secondary amine by 30% (time to 1% N-chloro impurity extended from 45 min to 62 min in the presence of 1.1 eq. trichloroisocyanuric acid in CH2Cl2 at −10 °C), as monitored by in-line ReactIR (Mettler Toledo ReactIR 15, diamond ATR probe, peak area at 1635 cm−1 for the tert-carbamate).
Compatibility with automated peptide synthesizers (CEM Liberty Blue, 0.1 mmol scale) has been tested using a pre-loaded 2-chlorotrityl chloride resin. The free amine of (3R,4S)-4-(2,3-dichlorophenyl)pyrrolidine-3-carboxylic acid withstands extended coupling cycles with HATU/NMM activation (2 × 10-min double couplings) without epimerization detectable at the adjacent stereocenter (chiral purity post-cleavage 99.6% e.e.). By contrast, the corresponding 4-(2,4-dichlorophenyl) analogue shows 0.8% epimerization under identical conditions, attributed to the different steric environment around the C-4 position. Operational boundaries include strict anhydrous environment for esterification: when forming the methyl ester via thionyl chloride in methanol at 0 °C, any residual water above 300 ppm leads to formation of the carboxylic acid dimer, which precipitates and clogs the 2-μm inline filter of the continuous flow reactor (Vapourtec R2+/R4 combination) within 15 min of operation.
Differential scanning calorimetry (DSC) of the compound as a dry solid reveals an exotherm onset at 185 °C with an energy release of 620 J/g (Mettler DSC 3+, sealed gold-plated crucible under nitrogen, heating rate 5 °C/min). While this is well above ambient, the N-Boc protection using Boc2O in THF at 20–25 °C generates an immediate exotherm of −ΔTad = 28 °C as measured by reaction calorimetry (Mettler RC1e, 1.2 L jacketed glass reactor). The calculated adiabatic temperature rise for the desired reaction alone, assuming complete conversion of a 1 M solution, is 34.5 °C. However, when scaled to 10 kg batch size in a 160 L Hastelloy reactor with jacket cooling capacity of 0.5 W/cm2, the heat removal rate becomes limiting: a dosing rate exceeding 0.15 kg/min of Boc2O causes the internal temperature to surpass the decomposition onset of the Boc-protected derivative (onset 112 °C), triggering a rapid gas evolution from decarboxylation and formation of isobutylene. Process safety data requires a maximum allowable dose time of 45 min and a reactor pressure relief system sized for a two-phase venting scenario per DIERS methodology (vent size 80 mm, rupture disc set pressure 2 barg). This hazard is not mitigated by the 3,4-dichloro analogue, which exhibits a decomposition onset 17 °C lower due to reduced steric shielding of the carbamate group.
| Comparative Property | (3R,4S)-4-(2,3-Dichlorophenyl) compound | (3R,4S)-4-(3,4-Dichlorophenyl) analogue | Impact on Processing |
|---|---|---|---|
| Aqueous solubility at pH 7.4 (µg/mL) | 45 | 128 | Requires co-solvent (10% DMSO) in biological assays; lower solubility can simplify phase separation during extractive workup by reducing emulsions. |
| pKa of pyrrolidine NH2+ | 7.8 | 8.2 | Less protonated at physiological pH; may alter passive membrane permeability in prodrug forms. |
| Retention factor k’ (RP-HPLC, conditions as above) | 3.4 | 2.9 | Slightly higher hydrophobicity aids separation from polar synthesis intermediates. |
| Boc-protected melting point (°C) | 138–141 | 152–154 | Lower melting point reduces risk of solidification in transfer lines during continuous processing at 50 °C. |
Pre-drying of the compound is mandatory when relative humidity exceeds 60% during weighing and charging operations. In a Lödige FM-50 plow mixer used for blending with HOBt hydrate prior to coupling, exposure to 65% RH for 20 min resulted in an increase in Karl Fischer water from 0.15% to 0.92%, accompanied by the formation of the hydrate needles that screened subsequent HPLC analysis to give a 3.2 area% overestimation of the des-carboxy impurity. This artifact is eliminated by vacuum drying at 40 °C / 5 mbar for 4 hours immediately before use.
In contrast to para-substituted variants, the 2,3-dichloro isomer shows markedly lower affinity for cytochrome P450 3A4 during preliminary microsomal stability tests (t1/2 > 60 min in human liver microsomes at 1 µM). This property, although assessed outside the scope of typical building-block release criteria, is relevant when the pyrrolidine is embedded as a terminal pharmacophore in drug candidates requiring reduced metabolic clearance. Nevertheless, direct biological application data are proprietary to pharmaceutical sponsors and not part of the standard certificate of analysis.
