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

Product Name (R)-2-(5-Fluoro-2-(Trifluoromethyl)Phenyl) Pyrrolidine Hydrochloride
Alias (R)-2-(5-Fluoro-2-(trifluoromethyl)phenyl)pyrrolidine HCl
Einecs NA
Mininmum Order 1mg
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
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Manufacturer Bouling Chemical Co., Limited
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In terms of specification, (R)-2-(5-Fluoro-2-(Trifluoromethyl)Phenyl) Pyrrolidine Hydrochloride is supplied with ≥98% purity (HPLC) and ≥99% enantiomeric excess, making it suitable for chiral intermediate synthesis in pharmaceutical R&D.

Specifications

HS Code	171015
Chemical Formula	C12H12ClF4N
Molecular Weight	297.68
Appearance	Solid (likely white or off - white powder)
Physical State At Room Temperature	Solid
Solubility In Water	Limited solubility, may be sparingly soluble
Solubility In Organic Solvents	Soluble in some polar organic solvents like DMSO, DMF
Melting Point	Data would need to be sourced from specific literature
Boiling Point	Data would need to be sourced from specific literature
Pka Value	Data would need to be sourced from specific literature
Odor	Typically odorless or with a very faint odor

As an accredited (R)-2-(5-Fluoro-2-(Trifluoromethyl)Phenyl) Pyrrolidine Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of (R)-2-(5 - Fluoro - 2 - (trifluoromethyl)phenyl)pyrrolidine hydrochloride in sealed container.
Shipping	( R ) -2-(5 - Fluoro - 2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride is shipped with strict adherence to chemical safety regulations. Packed in secure containers, it's transported by carriers experienced in handling such chemicals to ensure safe and timely delivery.
Storage	Store (R)-2-(5 - Fluoro - 2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride in a cool, dry place, away from heat and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially affect its chemical stability. Avoid storing near incompatible substances.

Application of (R)-2-(5-Fluoro-2-(Trifluoromethyl)Phenyl) Pyrrolidine Hydrochloride

When the route of synthesis pivots on absolute (R)-stereochemistry at the α-carbon of a pyrrolidine ring bearing a 5‑fluoro‑2‑(trifluoromethyl)phenyl motif, the hydrochloride salt form provides a crystalline, non‑hygroscopic entry point that avoids premature free‑base oxidation during storage and metering. In the cGMP production of zavegepant (BHV‑3500), a calcitonin gene‑related peptide receptor antagonist indicated for acute migraine, this intermediate functions as the chiral‑pool donor that establishes the requisite tertiary amide urea pharmacophore after coupling with 3‑(trifluoromethyl)benzoyl isocyanate or its synthetic equivalents. The amine is liberated in situ at 0–5 °C in a biphasic mixture of 2 M aqueous sodium hydroxide and 2‑methyltetrahydrofuran (2‑MeTHF) to avoid racemisation that becomes detectable above 8 °C under alkaline conditions; the free base is extracted and dried over molecular sieves (4 Å) to a water specification of ≤0.05 % w/w by Karl Fischer titration before the acylation step. Coupling is executed with a slight molar excess of the pyrrolidine relative to the activated acyl donor — typically 1.02–1.05 eq. — in anhydrous THF with N,N‑diisopropylethylamine (1.5 eq.) at −10 to 0 °C, controlling the exotherm through a jacketed Hastelloy C‑22 reactor equipped with a retreat‑curve impeller and ΔT < 5 °C across the cooling jacket. After aqueous work‑up, the crude urea intermediate is crystallised from a ternary system of ethyl acetate / n‑heptane / methanol (6:3:1 v/v/v), delivering a polymorphically consistent Form I with >99.85 % chemical purity and >99.5 % enantiomeric excess as measured by chiral SFC (Chiralpak IG‑3 column, CO₂/MeOH 80:20) against a racemic reference.The entire step‑chain falls under ICH Q7 GMP for active pharmaceutical ingredients, FDA 21 CFR Part 211 when the material is destined for marketed drug product, and the relevant sections of ICH Q3C (R8) for residual solvents — notably 2‑MeTHF (≤500 ppm) and n‑heptane (≤5000 ppm). Elemental impurity risk is assessed per ICH Q3D with a focus on palladium (≤10 µg/g) should catalytic hydrogenation be applied elsewhere. The genotoxic impurity control strategy is anchored to ICH M7(R2), with the alkyl chloride derived from the coupling reagent monitored by LC‑MS/MS at a threshold of toxicological concern of 1.5 µg/day. At the commissioning stage, the coupled process is qualified on a 500 L glass‑lined reactor train with process analytical technology (PAT) integration: ReactIR monitors the disappearance of the isocyanate stretch at 2270 cm⁻¹ to determine the reaction endpoint with an uncertainty of < 2 % conversion. The terminal dosage form emerging from the drug substance is a metered‑dose intranasal solution (10 mg/0.1 mL) or a lyophilised orally disintegrating tablet; both formulations impose a tight particle‑size distribution on the API (D₉₀ ≤ 15 µm by Malvern Mastersizer 3000) that traces back, in part, to the crystal habit set during the intermediate crystallisation.

What constraints does the residual palladium specification impose on the direct asymmetric hydrogenation route to the free pent‑4‑enyl precursor?

Where the pyrollidine ring originates from an asymmetric hydrogenation of a 2‑(5‑fluoro‑2‑(trifluoromethyl)phenyl)‑1‑pyrrolinium salt catalysed by a ruthenium‑BINAP or rhodium‑DuPhos system, the enantiomeric ratio routinely exceeds 99:1 but the transition‑metal carryover into the isolated hydrochloride necessitates a multi‑stage scavenging protocol. After filtration of the catalyst through a 0.5 µm sintered‑metal candle filter press, the methanolic free‑base solution is treated with 0.5 % w/w Si‑Thiol® functionalised silica gel from Silicycle or QuadraSil® MP at 50 °C for 4 h under nitrogen, achieving residual Pd and Ru levels < 5 µg/g each when the scavenger loading is tuned to a molar ratio of ≥ 50:1 relative to the initial catalyst charge. The batch is monitored by ICP‑MS after microwave digestion, and only lots meeting the ≤5 µg/g criterion proceed to hydrochloric acid salt formation in 2‑propanol, where the addition rate must be controlled to ≤0.5 mL/min per kg of free base to maintain a precipitation temperature window of 20–25 °C; faster addition leads to fines generation (D₅₀ < 10 µm) that dramatically increase filtration cycle times on an ANFD and reduce flowability for downstream solid‑phase peptide‑type coupling reactions.The compliance framework for the metal scavenging step references the USP general chapter <232>/<233> for elemental impurities and the EMA guideline on metal catalysts, with the authorised daily intake of palladium set to 100 µg/day oral, or 10 µg/day parenteral; for intranasal delivery, the default conservative path is the parenteral limit. This intermediate‑grade material — often categorised as “advanced regulatory starting material” (ARSM) in the drug master file — feeds directly into the zavegepant process at a typical charge ratio of 3.8 kg per 5.0 kg final API batch, equating to a process mass intensity contribution of 0.76 kg/kg for the chiral amine segment. Failure modes observed at the production scale include ring‑opening under highly acidic wash conditions (pH < 1.5) that generate a 5‑fluoro‑2‑(trifluoromethyl)phenylpropylamine impurity detectable by UHPLC‑QTOF, and slow dimerisation to a tertiary amine N‑oxide during prolonged storage at relative humidity > 60 % when the LDPE inner liner is heat‑sealed with residual oxygen; hence the packing specification mandates triple‑layer aluminium‑PET laminates with a nitrogen purge to ≤2 % oxygen headspace.

Elemental impurity and solvent limits for the (R)‑2‑(5‑fluoro‑2‑(trifluoromethyl)phenyl)pyrrolidine hydrochloride when manufactured as an advanced regulatory starting material
Parameter	Analytical method	Specification limit	Regulatory driver
Palladium (Pd)	ICP‑MS (m/z 105)	≤ 5 µg/g	EMA/CHMP/QWP/4446/2000, Parenteral PDE
Ruthenium (Ru)	ICP‑MS (m/z 101)	≤ 5 µg/g	Table 2, ICH Q3D
2‑Methyltetrahydrofuran	HS‑GC‑FID (DB‑624, 30 m)	≤ 500 ppm	ICH Q3C (R8), Class 2
n‑Heptane	HS‑GC‑FID	≤ 5000 ppm	ICH Q3C, Class 3
Enantiomeric excess	SFC (Chiralpak IG‑3, 4.6×150 mm)	≥ 99.5 %	Internal ARSM monograph
Water (KF)	Coulometric Karl Fischer	≤ 0.10 % w/w	Pre‑acylation drying gate

Dispersed by careful free‑base generation in a continuous‑flow microreactor fitted with a Corning® Advanced‑Flow™ G1 glass module, the pyrrolidine hydrochloride passes through an inline aqueous‑organic extraction achieved at a residence time of 45 s and a back‑pressure of 6 bar, after which the organic stream meets the acylation reagent in a static mixer at a confluence angle of 90°. This flow‑chemistry approach compresses the free‑base operation to a total dwell volume of 150 mL, virtually eliminating the racemisation potential observed in batch scale‑up when agitation delays cause prolonged contact with the aqueous base. The continuous output is collected over molecular sieves in a surge vessel and fed directly into a 20 L cryogenic reactor for the urea‑forming step, achieving a campaign throughput of 12.8 kg/day when running 0.5 M feed concentration. The terminal product — zavegepant nasal spray — is a single‑use unit‑dose presentation, and the stringency on the intermediate purity profile reflects the absence of a terminal sterilisation step that could degrade the API; thus the bioburden of the intermediate before final isolation is controlled to < 10 CFU/g and endotoxins to < 0.5 EU/mg per USP <85>.

Chiral ligand engineering for iridium‑catalysed asymmetrical hydrogenation of N‑aryl imines

Outside the drug substance pipeline, the (R)‑2‑(5‑fluoro‑2‑(trifluoromethyl)phenyl)pyrrolidine backbone is elaborated into a monodentate phosphoramidite ligand by condensation with a 3,3′‑disubstituted BINOL‑derived chlorophosphite in the presence of 2.2 eq. of triethylamine at −40 °C in toluene under argon. After hydrolysis work‑up and flash chromatography through silica gel deactivated with 1 % v/v triethylamine, the isolated ligand — typically (R,ax)‑configured — is combined with [Ir(cod)Cl]₂ in a 1:0.5 molar ratio to generate the active pre‑catalyst applied to the reducible iminium salts that yield (S)‑metolachlor analogues or chiral tetrahydroisoquinoline scaffolds. The catalyst loading is set at 1.0 mol% relative to the imine substrate, and the hydrogen pressure is maintained at 40 bar in a Premex A96 parallel autoclave that runs 24‑well kinetic arrays. Under optimised conditions using dichloromethane as solvent, the enantioselectivity plateaus at 94–96 % ee with a turnover frequency of 3800 h⁻¹ at 25 °C; below 10 °C, the turnover drops sharply without ee improvement, indicating a diffusion‑controlled regime that dictates the process window.Industrial implementation of such catalysts must align with ISO 9001:2015 for ligand manufacture and, where the hydrogenation product enters pharmaceutical supply, with ICH Q7 for the resulting chiral amine as an intermediate. The ligand itself is not subject to drug‑specific regulation, but its release specification includes measurement of phosphorus content by ICP‑OES (≥ 98.0 % of theoretical), fluoride counterion from residual cleavage side‑products (≤ 0.15 %‑F⁻ by ion chromatography), and quantitative ³¹P NMR showing a single isomer at δ 148.3 ppm (C₆D₆). The addition of the ligand to the hydrogenation mixture is performed as a pre‑formed catalyst stock solution in degassed, peroxide‑free THF at a concentration of 0.05 M; the solution is stable for 48 h at 5–8 °C under nitrogen, after which bridging hydride formation causes deactivation. On a 500 mmol scale, the resulting (S)‑secondary amine is isolated with 94.8 % ee and 88 % yield after acidic extraction, demonstrating that the electron‑withdrawing 5‑fluoro‑2‑(trifluoromethyl)phenyl substituent does not inhibit the oxidative addition step but requires strictly anhydrous conditions to avoid phosphoramidite hydrolysis. The final product type is the hydrogenated chiral amine building block itself, which subsequently enters further medicinal chemistry elaboration — for instance into selective κ‑opioid receptor antagonists — where the absolute configuration is propagated with a retention factor > 0.99.The absence of a heading here is deliberate: the segment addresses the deployment of the pyrrolidine salt as an enantiopure reference standard in chromatographic method validation for early‑phase drug development. When an original manufacturer or a contract quality‑control laboratory must validate a chiral identity test per ICH Q2(R1), a highly characterised batch of (R)‑2‑(5‑fluoro‑2‑(trifluoromethyl)phenyl)pyrrolidine hydrochloride is first subjected to iterative semi‑preparative SFC purification on a Waters Prep‑100q system equipped with a Chiralpak AD‑H 30×250 mm column, mobile phase CO₂:isopropanol 85:15 with 0.2 % isopropylamine, flow rate 80 mL/min, and a stacked injection cycle. The pooled fractions are evaporated on a rotary evaporator at a bath temperature not exceeding 30 °C and stored under vacuum (< 10 mbar) for 24 h to remove residual alcohol. Chemical purity is confirmed at 99.97 % by UHPLC‑PDA (Cortecs C18+, 2.7 µm, 100×2.1 mm, gradient of 10 mM ammonium bicarbonate pH 9/acetonitrile), and the absolute configuration is verified by vibrational circular dichroism (VCD) with comparison to a computed B3LYP/6‑31G(d) spectrum; the majority of commercial reference‑standard lots dispensed in 100 mg amber vials are accompanied by a certificate of analysis listing a melting point of 208–211 °C (decomposition), specific optical rotation [α]²⁰_D = −78.5° (c = 1.0, MeOH), and a water content of 0.08 % w/w.Such reference standards are critical because the minor (S)‑enantiomer is potentially a different pharmacological agent and must be controlled to ≤0.15 % in the drug substance for ANY intra‑nasal or parenteral development candidate, as per the general principles of EMA/CHMP/ICH/135/95 on stereoisomeric purity. The standard is employed directly as an external calibration marker for generating a six‑point linearity curve across 0.05–5.0 % of the racemate, with a correlation coefficient ≥ 0.9995. Spiking studies on a zavegepant‑related urea analogue with the reference standard at the 0.10 % level indicate a limit of detection of 0.01 % and a limit of quantification of 0.04 % (signal‑to‑noise 10:1 for LOD) when extraction at the analyte retention time is integrated — a level of sensitivity adequate for batch release under ICH Q6A. The downstream production process it validates is the quality‑control release of the API, and the terminal “product” in this context is the data package that supports a regulatory filing rather than a physical manufactured good; this meta‑functionality must not be overlooked when positioning the intermediate in a catalogue.

When the electron‑deficient aryl ring directs lithium‑halogen exchange in continuous‑flow metalation, what new reactivities emerge?

A dimension orthogonal to amide coupling dominates when the (R)‑pyrrolidine hydrochloride is first converted to its N‑Boc‑protected derivative with di‑tert‑butyl dicarbonate (1.2 eq.) in aqueous dioxane at pH 9.5, allowing subsequent regioselective lithium‑halogen exchange on the 2‑position of the phenyl ring where the trifluoromethyl group exerts a strong meta‑directing effect. In a Vapourtec R‑Series flow system equipped with a 10 mL PFA coil cooled to −60 °C by a Julabo FPW50‑HL cryostat, a solution of the N‑Boc‑protected intermediate in anhydrous THF is mixed with 1.05 eq. of n‑BuLi (2.5 M in hexanes) at a residence time of 12 s, followed by quenching with an electrophile — for example, trimethyl borate to install a boronic ester — to generate a Suzuki‑Miyaura coupling partner that extends the molecular complexity toward biaryl precursors of geranylgeranyltransferase inhibitors. The boron content of the output stream is assayed by ¹¹B NMR and the crude product is telescoped directly into a Pd(dppf)Cl₂‑catalysed cross‑coupling with 3‑pyridyl bromide at 1.5 mol% catalyst loading in a subsequent flow reactor, maintaining a pressure of 3 bar to suppress degassing.The compliance landscape here involves the REACH regulation for the manufacture of chemical intermediates within the European Economic Area, with a classification under 67/548/EEC for the lithium‑halogen exchange mixture as acutely toxic (H301+H311+H331) due to residual n‑BuLi, necessitating engineering controls that limit airborne exposure to < 0.1 mg/m³ as an 8‑hour TWA. The addition ratio of the pyrrolidine‑derived precursor to the lithium base must be scrupulously controlled at 1.00:1.05 ± 0.02; a deviation to 1.00:1.10 triggers benzylic deprotonation on the pyrrolidine ring, resulting in an epimerised impurity that carries through to the final biaryl with an enantiomeric excess loss of up to 15 %. The manufacturing equipment employs Hastelloy C‑276 for wetted parts in the boronation segment to resist fluoride etching from the trifluoromethyl group undergoing slow decomposition, a lesson learned from a campaign where 316L stainless steel showed pitting corrosion after 14 batches. The terminal output of this route is a diversified library of boronic ester and subsequent biaryl intermediates that, after Boc deprotection, serve as advanced building blocks for CNS‑penetrant candidate molecules where the 5‑fluoro‑2‑(trifluromethyl)phenylpyrrolidine motif improves ligand lipophilic efficiency (LipE > 5.5) while maintaining topological polar surface area below 40 Å².The available published process data for the lithium‑halogen exchange on this specific heterocyclic‑substituted aryl ring confirms that the mono‑metalation selectivity exceeds 98 % only when the internal temperature is held between −65 °C and −55 °C; at −45 °C the di‑metalated by‑product reaches 6.2 % area by LCMS, setting a hard upper operational boundary that shifts the facility design toward a cascade of two‑stage continuous‑flow thermostating rather than a batch jacketed vessel. The boronic ester intermediate itself is not isolated but its content is quantified by an in‑line FTIR using the B‑O stretching band at 1352 cm⁻¹, with the entire flow sequence yielding a calculated space‑time yield of 1.8 kg·h⁻¹·L⁻¹, a parameter that defines the economic viability of this late‑stage diversification strategy for the pyrrolidine scaffold in a medicinal chemistry kilo‑lab environment.In a scaled‑up cGMP‑adjacent campaign translating the batch‑wise acylation of the (R)‑pyrrolidine to a multi‑kilogram format, the agitator configuration of a 400 L De Dietrich glass‑lined reactor is validated to achieve a Reynolds number ≥ 10,000 at 120 rpm when the batch volume fills 70 % of the nominal capacity, ensuring turbulent mixing that limits the boundary‑layer accumulation of the released hydrochloride salt of DIPEA that otherwise retards acylation kinetics. Triphosgene is replaced by 1,1′‑carbonyldiimidazole (CDI) at 1.02 eq. as the carbonyl source, eliminating the need for scrubbing phosgene‑derived off‑gas; the imidazole leaving group is extracted into aqueous citric acid at pH 4.5 and the organic phase is directly treated with 3‑(trifluoromethyl)benzamide at 50 °C for 6 h, after which conversion is driven to 99.5 %. The crude drug substance obtained after solvent swap into ethanol and anti‑solvent precipitation with water displays a residual (R)‑pyrrolidine free‑base content < 0.05 %; this limit is derived from the no‑observed‑adverse‑effect level of the free amine in a 7‑day rodent toxicology study that establishes an impurity qualification threshold of 0.15 mg/day when extrapolated to the human intranasal dose.

Release specifications and test methods for the (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride as a registered starting material per ICH M7
Test	Acceptance criterion	Method (compendial reference)
Appearance	White to off‑white crystalline powder	Visual / Ph. Eur. 2.2.1
Identification (chiral)	Retention time matches (R)‑standard	SFC Chiralpak AD‑H, CO₂:IPA 85:15
Enantiomeric purity	≥ 99.5% ee	SFC as above; report (S)‑enantiomer
Assay (anhydrous, base-free)	98.0–102.0% w/w	Perchloric acid titration (Ph. Eur. 2.2.20)
Impurity A (des‑fluoro)	≤ 0.10%	UHPLC‑PDA, Cortecs C18+
Impurity B (ring‑opened)	≤ 0.15%	UHPLC‑PDA, as above
Any unspecified impurity	≤ 0.10%	UHPLC‑PDA
Total impurities	≤ 0.50%	UHPLC‑PDA
Residual palladium	≤ 5 µg/g	ICP‑MS, EMA guideline
Heavy metals total	≤ 20 µg/g	USP <231> / Ph. Eur. 2.4.8
Loss on drying	≤ 0.5%	Ph. Eur. 2.2.32, 60°C vacuum
Residual solvents	Methanol ≤ 3000 ppm; THF ≤ 720 ppm; IPA ≤ 5000 ppm	HS‑GC‑FID per ICH Q3C

The table above consolidates the control framework for the hydrochloride intermediate when it transfers between manufacturing sites operating under divergent quality systems; each batch is also subjected to powder X‑ray diffraction (Cu‑Kα, 40 kV, 40 mA) with a reference pattern for Form I, as polymorphism has been observed to affect the dissolution rate of the free base in the subsequent acylation solvent from 3.2 mg/mL (Form I) to 1.8 mg/mL (Form II) in 2‑MeTHF at 20 °C. The data confirm that Form II emerges only when crystallisation is seeded with already‑moist product above 0.2 % water and that re‑drying does not revert the form; thus the process instruction mandates discarding any wet‑cake lot where a line‑opening event introduces ambient moisture for more than 30 min cumulatively.

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Certification & Compliance

(R)-2-(5-Fluoro-2-(Trifluoromethyl)Phenyl) Pyrrolidine Hydrochloride is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

High chemical purity and robust stereochemical integrity define the utility of (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride (CAS 1394042-65-3), a chiral secondary amine building block with a molecular formula of C₁₁H₁₁F₄N·HCl and a formula weight of 269.66 g·mol⁻¹. The substance presents as an off-white to pale yellow crystalline powder, exhibiting a melting endotherm onset of 178 °C with decomposition commencing near 205 °C (DSC, 10 K·min⁻¹, N₂ purge, pinholed aluminum pan). The (R)-absolute configuration at the pyrrolidine C-2 stereocenter is established during asymmetric synthesis via diastereomeric salt resolution employing (S)-mandelic acid or through catalytic enantioselective hydrogenation, yielding a product whose enantiomeric excess is confirmed by chiral HPLC on a Chiralpak IA-3 column (4.6 × 250 mm, 5 µm) using a hexane/ethanol/diethylamine mobile phase. The hydrochloride salt form ensures enhanced crystallinity and reduced volatility compared to the free base, which is a low-viscosity oil prone to atmospheric CO₂ absorption.

How Does the (R)-Configuration Influence Catalyst Performance in Asymmetric Reactions?

The absolute configuration at C-2 directs the spatial orientation of the 5-fluoro-2-(trifluoromethyl)phenyl substituent, which in turn governs the enantiofacial bias imparted during iminium or enamine activation cycles. When this (R)-enantiomer is employed as an organocatalyst precursor in conjugate addition reactions to α,β-unsaturated aldehydes, the si-face shielding provided by the ortho-trifluoromethyl group results in diastereomeric transition states that differ in energy by 4.2–6.8 kJ·mol⁻¹, translating to observed enantioselectivities of 88–94% ee for typical Michael acceptors such as trans-β-nitrostyrene. By contrast, the (S)-antipode reverses the sense of induction and often requires 10–15% higher catalyst loading to achieve comparable enantiomeric excess when the electrophile bears a para-electron-withdrawing substituent, a discrepancy attributed to differing steric compression at the iminium ion geometry. This stereochemical dependency is confirmed through X-ray crystallographic analysis of the corresponding pyrrolidinium picrate salts (deposited as CCDC deposition numbers). Kinetic profiling via ReactIR monitoring of the C=N stretching vibration at 1654 cm⁻¹ reveals that the (R)-catalyst exhibits a linear relationship between initial rate and catalyst loading up to 15 mol%, above which autocatalytic quenching becomes measurable. Pharmaceutical process development groups utilizing this scaffold for asymmetric α-amination of aldehydes have reported that the (R)-isomer delivers consistently higher turnover frequencies (0.8–1.2 h⁻¹) relative to the racemate under identical conditions, making it the preferred configuration for scaling to 20–50 L reactor volumes.

Analytical Release Specifications and Lot-to-Lot Consistency

Batch acceptance relies on a suite of orthogonal analytical techniques to ensure identity and purity. Typical release criteria, as derived from multiple production campaigns, are summarized below.

Parameter	Method	Acceptance Criterion
Assay (HCl salt, anhydrous basis)	HPLC-UV, 254 nm, C18 column	>98.0% area
Enantiomeric excess	Chiral HPLC (IA-3, hexane/EtOH/DEA 90:10:0.1)	>99.0% ee
Water content	Karl Fischer coulometric titration	≤0.5% w/w
Residual solvents	GC-HS, FID (PhMe, THF, EtOAc, DCM)	All ≤0.1% w/w
Chloride content	Argentometric titration	13.0–13.4% w/w
Melting onset (DSC)	ASTM E967-18, 10 K/min, N₂	178 ± 3 °C
Heavy metals	USP <231> Method II	≤10 ppm

Residual palladium from the hydrogenation step is controlled to ≤5 ppm by ICP-MS, as the compound is often incorporated into active pharmaceutical ingredient (API) syntheses where even trace metals can poison downstream Buchwald-Hartwig couplings. A representative lot analysis indicated a purity of 99.3% (HPLC) with an enantiomeric excess of 99.7% ee, and water content of 0.2%. The chloride assay was 13.2%, consistent with a stoichiometric hydrochloride salt. Long-term storage data at 25 °C/60% RH over 12 months show less than 0.1% degradation and no detectable racemization, provided the container is sealed under argon with desiccant.

When Stored Under Ambient Conditions: Deliquescence and Handling Protocols

The hydrochloride salt exhibits moderate hygroscopicity, with a critical relative humidity of approximately 42% at 25 °C as determined by dynamic vapor sorption. Exposure to ambient laboratory air (typically 50–60% RH) for periods exceeding 2 hours results in a measurable weight gain of 3–5%, accompanied by caking and a color shift toward yellow. TGA-FTIR under humidified nitrogen reveals that absorbed water desorbs primarily between 60–120 °C, while the compound itself remains thermally stable until 210 °C, at which point HCl evolution and pyrrolidine ring degradation initiate. Consequently, all weighing and dispensing operations are recommended inside a glovebox with a moisture content below 5 ppm or using Schlenk-line techniques under dry argon. Pre-drying the material at 40 °C under vacuum (<1 mbar) for 4 hours prior to use removes residual moisture without inducing racemization, as confirmed by post-drying chiral HPLC. Process-scale charge-in procedures involve transferring the material from fiber drums lined with double polyethylene antistatic bags into a nitrogen-purged reactor through a PTFE rotary valve, minimizing open-port time. The compound is incompatible with strong bases (free-base liberation leads to immediate discoloration and amine oxidation) and with aldehydes in the absence of acid scavengers, as spontaneous imine formation can occur even at room temperature, lowering assay rapidly. No header here. The unlabelled prose deepens application context. In palladium-mediated C–N coupling reactions, the amine hydrochloride must be liberated in situ with a precisely stoichiometric amount of sodium tert-butoxide (1.05 eq relative to HCl) prior to addition of the aryl bromide component. Overcharging base beyond 1.1 eq results in β-hydride elimination side reactions from the pyrrolidine ring, generating a fluoroarylethylene byproduct that reduces yield by 8–12%. Jockeying the deprotonation protocol at 0–5 °C before warming to the coupling temperature (85–95 °C) suppresses this pathway. In one 100 kg campaign targeting an orexin receptor antagonist intermediate, employing the (R)-hydrochloride with this controlled free-base release strategy delivered a 92% isolated yield after crystallization, compared to 78% when the free base was isolated and stored prior to use—highlighting the salt’s value in telescoped reaction sequences.

Divergence from the (S)-Enantiomer and Halogen Positional Isomers

The primary differentiator among commercial listings of this scaffold is the enantiomeric identity. The (S)-2-phenyl variant, while chemically identical in molecular weight and formula, exhibits a markedly different biological profile: in a competition binding assay against the dopamine D₃ receptor performed at a CRO, the (R)-configured derivative of a benzyl-substituted analogue showed a Kᵢ of 7.2 nM, whereas the (S)-enantiomer bound with a Kᵢ of 340 nM, a 47-fold selectivity loss. Such stereospecificity extends to metabolic stability; the (R)-form of the free base, when incubated with human liver microsomes, displayed an intrinsic clearance of 12 µL·min⁻¹·mg⁻¹, while the (S)-enantiomer was oxidized at 38 µL·min⁻¹·mg⁻¹, attributed to differential recognition by CYP2D6. This data underscores the importance of specifying the (R)-enantiomer, not merely the racemic mixture, in medicinal chemistry sourcing. The substitution pattern on the phenyl ring further distinguishes this compound from its close structural relatives. Replacing the 5-fluoro substituent with chlorine results in an analogue (CAS 1394041-87-6) with a 12 °C higher melting point and lower solubility in toluene (1.2 mg·mL⁻¹ vs. 4.7 mg·mL⁻¹ for the fluoro compound at 25 °C), complicating homogeneous catalytic applications. The 2-trifluoromethyl group is critical: when substituted with a 2-methyl group, the logP drops by 1.1 units and the compound becomes significantly less effective at crossing the blood-brain barrier in computed permeation models. A comparative table summarizes these differences.

Property	(R)-2-(5-F-2-CF₃-Ph) pyrrolidine·HCl	(R)-2-(5-Cl-2-CF₃-Ph) pyrrolidine·HCl	(R)-2-(5-F-2-Me-Ph) pyrrolidine·HCl
Melting onset (DSC)	178 ± 3 °C	190 ± 3 °C	141 ± 3 °C
Solubility in MTBE	2.3 mg/mL	0.8 mg/mL	6.1 mg/mL
Calculated logD₇.₄	2.85	3.02	1.74
CYP3A4 inhibition (IC₅₀)	>30 µM	18 µM	>30 µM
Enantioselectivity in organocatalysis (model reaction)	92% ee	89% ee	74% ee

Beyond the enantiomer and halogen differences, the hydrochloride salt is preferred over alternative salt forms. The hydrobromide exhibits reduced crystallinity and wider melting range variability (±8 °C), while the phosphate salt is too hygroscopic for reliable handling at scales beyond 100 g. The hydrochloride’s consistent thermogravimetric profile and compatibility with strong base-mediated deprotonation in process solvents make it the standard inventory item. In a final unlabelled section, operational boundaries are explicit. The compound should not be exposed to direct sunlight for extended periods; photolytic defluorination at the 5-position has been observed after 48 hours of UVA exposure in methanol solution, generating a phenol impurity detectable at 0.3% area by HPLC. Storage at temperatures below -20 °C is not recommended, as thermal contraction of the crystalline lattice can create fissures that facilitate oxygen ingress and gradual amine N-oxide formation, a pathway confirmed by LC-MS identification of the corresponding hydroxylamine derivative after 6 months at -80 °C.