(R)-2-(5-Fluoro-2-(2-Methoxyethoxy)Phenyl)Pyrrolidine Hydrochloride

A pale, fine crystalline powder, hygroscopic at ambient humidity above 40% RH, marks the physical starting point for chiral amine coupling strategies reliant on arylpyrrolidine geometry. The product, catalogued under model CRF-1972-HCl in several compound management libraries, is the hydrochloride salt of (R)-2-[5-fluoro-2-(2-methoxyethoxy)phenyl]pyrrolidine. Its free base empirical formula is C₁₃H₁₈FNO₂ (molar mass 239.28 g·mol⁻¹) and the hydrochloride salt, C₁₃H₁₉ClFNO₂, carries a molar mass of 275.75 g·mol⁻¹. When handled in a glovebox purged with dry nitrogen (dew point ≤ −40 °C), the material exhibits a melting onset in the range 178–183 °C by differential scanning calorimetry at a ramp rate of 10 K·min⁻¹, consistent with salt dissociation and decomposition. The (R) absolute configuration at the pyrrolidine C-2 stereocenter is confirmed via vibrational circular dichroism cross-referenced against single-crystal X-ray diffraction data for the corresponding (S)-enantiomer, and the batch-specific optical rotation, measured at the sodium D-line in methanol (c = 1.0), generally falls between +12° and +16°. This physical profile differs sharply from the free amine, which remains a low-viscosity oil susceptible to aerobic N-oxidation within 48 h of exposure to laboratory atmosphere.

What Distinguishes the (R)-Enantiomer from the Racemic Mixture in Receptor Binding Assays?

The chiral pyrrolidine nitrogen, when locked in the (R)-configuration, places the 5-fluoro-2-(2-methoxyethoxy)phenyl substituent in a pseudo-equatorial orientation that has been shown to alter dissociation kinetics at monoaminergic transporters in competition binding studies using [³H]WIN 35,428 at human dopamine transporter (hDAT) expressed in HEK-293 cell membranes. Published structure–activity data for closely related 2-aryl pyrrolidines indicate that the (R)-enantiomer’s K_i at hDAT can differ by more than one order of magnitude from the (S)-antipode under identical assay buffer conditions (50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4, 25 °C). The racemate does not represent an arithmetic average of the two enantiomers’ affinities; competitive displacement curves often display Hill coefficients measurably below unity, indicative of multiple binding modes that obscure pharmacological interpretation. For laboratories generating structure–activity relationship (SAR) libraries, batch release documentation tracks enantiomeric excess (e.e.) by chiral HPLC on a polysaccharide-based chiral stationary phase (CSP), typically a CHIRALPAK IA-3 column, 4.6 × 250 mm, particle size 3 µm, using a n-hexane/2-propanol/diethylamine (90/10/0.1) mobile phase at a flow rate of 0.8 mL·min⁻¹ and UV detection at 254 nm. The specification threshold of e.e. ≥ 99.0% is enforced through careful integration of the (S)-enantiomer peak, which must not exceed 0.5% area.

Comparative enantiomeric purity and physical form of accessible configurations

Configuration	Typical e.e. (%)	Physical State (20 °C)	Stability Under Air (7 days)	Catalog Designation
(R)-enantiomer · HCl	≥ 99.0	Crystalline solid	No detectable oxidation	CRF-1972-HCl
(S)-enantiomer · HCl	≥ 98.5	Crystalline solid	No detectable oxidation	CRF-1973-HCl
Racemate · HCl	—	Crystalline solid	Negligible discoloration	CRF-1974-HCl
Free base (racemic, glass)	—	Amber oil	Brown discoloration, N-oxide formation	CRF-1974-FB

The hydrochloride salt’s aqueous solubility exceeds 25 mg·mL⁻¹ in deionized water at 23 °C, which facilitates direct formulation for in vivo pharmacological profiling in rodent models of CNS disorders. By contrast, the free base requires co-solvent systems (typically 5% DMSO, 10% PEG-400 in saline) and can precipitate upon intraperitoneal injection unless the vehicle pH is titrated below 4.5.

Analytical Specification and Impurity Thresholds

Release of each batch is gated by a panel of orthogonal methods aligned with ICH Q2(R1) validation parameters. Purity by achiral reverse-phase HPLC is performed on a C18 column (150 × 4.6 mm, 5 µm) with a mobile phase gradient of 0.1% trifluoroacetic acid in water and acetonitrile over 25 min. The main peak typically elutes at 14.8 min with a tailing factor ≤ 1.3 (USP method, tangent method). Total related substances are controlled to ≤ 1.0%, with any single unspecified impurity ≤ 0.10%. The primary process-related impurity, the des-fluoro analog arising from incomplete halogenation of the starting phenyl precursor, is quantitated at a relative retention time of 0.89 against the main peak and is limited to 0.15%. Residual solvent analysis by headspace GC-FID, performed according to USP <467>, confirms that 2-propanol and n-hexane used in crystallization remain below the ICH Q3C Option 1 limits of 5000 ppm and 290 ppm respectively. Elemental analysis acceptance criteria for carbon, hydrogen, and nitrogen are set within ±0.4% of theoretical values (C 56.66%, H 6.95%, N 5.08%). The chloride content, determined by potentiometric titration with 0.1 N silver nitrate after sample dissolution in aqueous methanol, must fall between 12.5% and 13.3% (theoretical 12.86%) to confirm stoichiometric salt formation. Water content by Karl Fischer coulometry is routinely 0.3% w/w for freshly opened containers and is monitored over the shelf life; acceptance is ≤ 1.0%. When the (S)-enantiomer hydrochloride is required as a matched-pair negative control for assay validation, the same specification framework applies except that the allowable (R)-enantiomer cross-contamination is set to ≤ 1.5% due to the asymmetric synthetic route’s lower inherent diastereoselectivity in the final resolution step. This is a critical difference between the two products and one that should guide selection for single-dose tox studies where enantiomeric crosstalk could confound no-observed-adverse-effect level (NOAEL) determination.

Storage Conditions That Preserve Optical Integrity

The crystalline hydrochloride, sealed under argon in amber glass vials with PTFE-faced silicone septa, maintains enantiomeric purity within specification for 36 months when stored at −20 °C in the absence of light, as demonstrated by real-time stability monitoring on three consecutive production lots following ICH Q1A(R2) conditions. At 5 °C (refrigerated storage), moderate moisture ingress through repeated septa punctures elevates water content and correlates with a slow racemization rate of approximately 0.02% e.e. loss per month, attributable to proton-mediated ring-opening–reclosure at the pyrrolidine benzylic position. Storage at 25 °C/60% RH (ICH long-term Zone II) over 12 months results in visible caking and a shift in melting point endotherm to 170–176 °C, though HPLC purity loss remains ≤ 0.2%. Once a container is opened, the material should be handled in a dry atmosphere (glove box or desiccated balance enclosure) and returned to −20 °C within 30 minutes to avoid deliquescence. The free base, even when stored at −20 °C, discolors within weeks due to trace peroxide accumulation; therefore the hydrochloride is the recommended storage form for inventory held longer than 90 days. Laboratories undertaking long synthetic sequences that require liberation of the free amine in situ often prepare it immediately before use by partitioning the salt between dichloromethane and saturated aqueous sodium bicarbonate, drying over anhydrous sodium sulfate, and concentrating at reduced pressure at ≤ 30 °C. The resulting oil is used within 4 h without further purification. When used in direct amidation with acyl chlorides or active esters, the hydrochloride is suspended in dichloromethane and N-methylmorpholine (1.5 eq) is added to generate the free amine in situ. Attempts to isolate the intermediate free base and store it for later coupling have been shown to reduce amide yield by 12–18% relative to a single-pot salt-breaking procedure, consistent with pyrrolidine N-oxide formation detected by LC-MS (m/z +16 Da adduct).

When the Free Base Is Preferable to the Hydrochloride Salt

A narrow set of reductive amination protocols employing sterically hindered ketones (e.g., 2,6-dimethylcyclohexanone) benefit from the direct use of the pre-formed free amine oil, as the presence of even 1.0 eq of hydrogen chloride can shunt the imine equilibrium toward enamine tautomers and produce complex byproduct mixtures. In such cases, one production-scale workaround involves charging the hydrochloride to a biphasic mixture of methyl tert-butyl ether and 2 M aqueous sodium hydroxide at 5 °C, separating the organic layer, and drying it via a molecular sieve column (3 Å) packaged in a jacketed glass column, 20 cm bed height, under a continuous nitrogen sweep. The dry free base solution, assayed by ¹H NMR integration of the α-pyrrolidine proton at δ 3.8 ppm against an internal standard of 1,3,5-trimethoxybenzene, is immediately transferred to the reaction vessel. Published data for this specific configuration are limited, but process development reports from kilo-lab campaigns describe yields of 82–85% for the secondary amine alkylation product when this free-base approach is used, versus 55–62% from the hydrochloride suspension method with triethylamine basification. The methoxyethoxy side chain introduces a degree of water miscibility that distinguishes this building block from simpler 2-phenylpyrrolidine hydrochlorides. Partition coefficient determination (shake-flask method, octanol/water, 25 °C) gives log P of approximately 0.8 for the free amine, meaning the compound does not cleanly extract into organic solvents from neutral aqueous solution. This property forces an ether-class extraction solvent (methyl tert-butyl ether or diethyl ether) rather than toluene or heptane, and batch records detail emulsion problems during large-scale aqueous workup when ethyl acetate is substituted. The 5-fluoro substituent further polarizes the aromatic ring and directs electrophilic substitution primarily to the C-4 position (ring numbering relative to phenyl–pyrrolidine bond), which can be exploited in late-stage diversification to install iodine or nitro groups without compromising the chiral center, provided radical conditions are avoided. The absence of a basic amine guard in the free base form also means that any condensation with isocyanates or isothiocyanates to form urea/thiourea derivatives must be executed at strictly controlled stoichiometry (NCO:NH 1.00:1.00), because the free pyrrolidine will catalyze trimerization of aromatic isocyanates to isocyanurates faster than primary alkyl amines. Process analytical technology (PAT) utilizing ReactIR with a diamond ATR probe has been deployed in a few pilot batches to track the disappearance of the NCO band at 2275 cm⁻¹ and to arrest reagent addition upon reaching the endpoint, preventing the exothermic isocyanurate-forming side reaction which can raise internal temperature by 18°C in a 50 L reactor within 90 s.

Physical compatibility of the hydrochloride salt with common reaction solvents

Solvent	Solubility (mg·mL⁻¹, 25 °C)	Observation After 24 h	Suitability for Salt-Breaking Protocol
Dichloromethane	2.5	Undissolved salt, free base enters solution upon basification	Recommended
Tetrahydrofuran	1.8	Fine suspension, minimal swelling	Acceptable with extended stirring
Acetonitrile	12.0	Clear solution	Preferred for amide couplings with HATU/DIPEA
Methanol	45.0	Clear, slight yellow tint after 48 h	Use only for analytical prep, not for isolation
Water	25.0	Clear, no degradation	Suitable for in vivo formulation vehicles

Early medicinal chemistry campaigns frequently substituted the racemic 2-(4-fluorophenyl)pyrrolidine scaffold, which lacks the methoxyethoxy group entirely and displays a starkly different metabolic soft spot: the 4-fluoro analog undergoes rapid N-dealkylation in human liver microsomes (intrinsic clearance > 200 µL·min⁻¹·mg⁻¹), whereas the 5-fluoro-2-(2-methoxyethoxy)phenyl variant reduces intrinsic clearance to approximately 45 µL·min⁻¹·mg⁻¹ under the same incubation conditions (0.5 mg·mL⁻¹ microsomal protein, 1 µM substrate, NADPH regenerating system). The difference is attributed to the steric shielding of the pyrrolidine ring by the ortho methoxyethoxy chain, and to the electron-withdrawing effect of the 5-fluoro substituent modulating the basicity of the amine (calculated pK_a of the conjugate acid on the free base is 8.2 compared with 9.7 for the unsubstituted phenylpyrrolidine). This lower basicity reduces lysosomal trapping in hepatocyte assays, an advantage that in vitro-to-in vivo extrapolation (IVIVE) models attempt to capture through hepatocyte binding correction factors. Raw material sourcing for the chiral intermediate rests on an enantioselective hydrogenation of the corresponding cyclic imine, catalyzed by a Ru-(S)-BINAP complex, which sets the stereocenter with an initial e.e. of 94–96%. An upgrade to > 99% e.e. is achieved via diastereomeric salt resolution with di-p-toluoyl-D-tartaric acid in methanol/water. The resolved (R)-amine is then converted to the hydrochloride using anhydrous hydrogen chloride in isopropanol at 0–5 °C, precipitated with methyl tert-butyl ether, and dried under vacuum with a nitrogen bleed at 40 °C for 18 h. Trace tartrate contamination, assayed by ion chromatography with conductivity detection, remains below 0.05% in all launched batches—a specification not universally applied for generic aryl pyrrolidine vendors. This purity gap can become consequential when the compound is used as a fragment for phosphoramidite ligand synthesis, where residual carboxylic acids poison the palladium catalyst in subsequent cross-coupling steps. Operational incompatibilities mirror those of secondary amine hydrochlorides more broadly. Combination with strong bases (sodium hydride, potassium tert-butoxide) in aprotic media liberates the free amine cleanly, but the presence of alpha-hydrogens to the pyrrolidine nitrogen makes the free base prone to deprotonation at the C-2 position under highly basic conditions, forming a nucleophilic carbanion that can undergo intermolecular alkylation with the methoxyethoxy chain if the temperature exceeds 40 °C. To avoid intramolecular N→O alkyl migration, reactive alkyl halide substrates are added at ≤ −20 °C and the reaction is quenched into cold 0.5 M HCl within 5 min of completion. Use of this compound in copper-catalyzed Ullmann-type aminations without prior protection of the secondary amine is not advised, as the free pyrrolidine coordinates Cu(I) and forms an inert tetrakis-amine copper complex, shutting down catalytic turnover. These boundary conditions have been communicated through published process safety memoranda and are part of the vendor’s technical data sheet, which also notes that waste streams containing the compound should not be combined with sodium hypochlorite solutions, as the resulting N-chloramine derivative is potentially explosive as a solid residue upon concentration.