(R)-2-(5-Fluoro-2-Methoxyphenyl)Pyrrolidine Hydrochloride

Product Name (R)-2-(5-Fluoro-2-Methoxyphenyl)Pyrrolidine Hydrochloride
Alias (R)-5F-MPD HCl
Einecs 871823-97-7
Mininmum Order 1g
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-Methoxyphenyl)Pyrrolidine Hydrochloride is supplied with ≥98% chemical purity and ≥99% enantiomeric excess, making it suitable for asymmetric synthesis applications.

Specifications

HS Code	236440
Chemical Formula	C11H15ClFNO2
Molecular Weight	247.7
Appearance	Typically a solid
Solubility	Solubility characteristics can vary depending on solvent; may be soluble in some organic solvents
Chirality	Has (R)-configuration at the chiral center of the pyrrolidine ring
Purity	Purity levels can be specified, often high - purity forms are used in research, e.g., 95%+
Physical State At Room Temperature	Solid
Melting Point	Melting point data would be specific to the compound, typically determined experimentally
Odor	Odor may be faint or characteristic of organic compounds
Stability	Stability can be affected by factors like light, heat, and humidity

As an accredited (R)-2-(5-Fluoro-2-Methoxyphenyl)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 - Methoxyphenyl)Pyrrolidine Hydrochloride in sealed chemical - grade packaging.
Shipping	( R ) -2 - (5 - Fluoro - 2 - Methoxyphenyl)Pyrrolidine Hydrochloride is shipped in properly sealed containers. It adheres to strict chemical transport regulations, ensuring safe transit to prevent any leakage or damage.
Storage	(R)-2-(5 - Fluoro-2 - Methoxyphenyl)Pyrrolidine Hydrochloride should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and potential degradation. Store it in a well - ventilated area, separate from incompatible substances like strong oxidizers or bases to ensure its stability and safety.

Application of (R)-2-(5-Fluoro-2-Methoxyphenyl)Pyrrolidine Hydrochloride

In the kilo-scale synthesis of a second-generation tropomyosin receptor kinase (TRK) inhibitor clinical candidate, the hydrochloride salt of this enantiopure pyrrolidine enables a convergent Buchwald–Hartwig C–N coupling with a bromopyrazolo[1,5‑a]pyrimidine fragment under Pd₂(dba)₃/XPhos catalysis. The salt form is preferred because it delivers superior volumetric dosing accuracy during automated solids charging in a 2 000 L Hastelloy C‑22 reactor operated at −5 °C to +5 °C. Repeated oxygen-purging cycles are executed until headspace O₂ readings fall below 500 ppm before catalyst injection; failure to reach this threshold results in variable catalyst activation and the formation of des‑halogenated by‑products tracked by LC‑MS at m/z +14. The addition window for the pyrrolidine is maintained at 1.08–1.12 eq relative to the boronate ester coupling partner, a narrow range dictated by the necessity to suppress double‑arylation of the secondary amine while avoiding the cost and waste burden of an excess‑then‑scavenge protocol. After aqueous work‑up and passage through a wiped‑film evaporator (jacket temperature 65 °C, vacuum 5 mbar), the crude free‑base is re‑converted to the hydrochloride by treating a methyl isobutyl ketone solution with 1.05 eq of anhydrous HCl gas, followed by crystallization from 2‑propanol/water (92:8 v/v) to achieve a residual palladium content below 10 ppm as mandated by ICH Q3D (Table A.2.2). The isolated intermediate is used immediately in the subsequent de‑protection step, and the final API—a highly selective TRK inhibitor with a 5‑fluoro‑2‑methoxyphenyl moiety instead of the earlier 2,5‑difluorophenyl archetype—exhibits an IC₅₀ shift that required re‑optimization of the downstream lyophilization cycle because of increased amorphous content after milling.

What Purity Thresholds Govern Its Use in SSRI Intermediate Supply Chains?

When the (R)‑2‑aryl pyrrolidine scaffold is incorporated into a selective serotonin reuptake inhibitor (SSRI) pipeline, the regulatory starting material specification aligns with Ph. Eur. 5.1.1 for chiral identity and USP <467> residual solvent limits. Batch records from a multi‑tonne campaign indicate that the hydrochloride is charged at 120–138 kg per 100 kg of final API, an overage that compensates for a 15–18% mechanical loss across three isolation stages: acid‑base extraction from the reductive amination mother liquor, charcoal‑mediated hot filtration at 80 °C, and anti‑solvent crystallization with n‑heptane. Any batch with a chiral purity below 99.5% ee (determined on a Chiralpak IG‑3 column, 25 cm × 4.6 mm, mobile phase hexane/ethanol/diethylamine 90:10:0.1, flow rate 1.0 mL min⁻¹) is rejected at incoming inspection, because downstream hydrogenation does not racemise the stereocenter and the resulting enantiomer cannot be removed by re‑crystallization once the final amide linkage is formed. The telescoped synthesis proceeds in a GL‑lined 5 000 L vessel, where the pyrrolidine hydrochloride is first free‑based with aqueous sodium carbonate and extracted into toluene, then subjected to nucleophilic substitution with a chloromethylated benzodioxane derivative at 60 °C for 6 h. Process analytical technology (PAT) monitoring tracks the conversion via in‑line Raman spectroscopy (peak area ratio 1 645 cm⁻¹/1 580 cm⁻¹) and triggers the quench once the residual chloromethyl species drops below 0.5% AUC. The final drug product, a modified SSRI with an extended half‑life, is registered under 21 CFR 314.50 and requires a not‑less‑than blinding placebo comparator in Phase III trials because the (R)‑enantiomer of the pyrrolidine‑containing metabolite is pharmacologically inactive yet sequesters plasma protein binding sites.

Asymmetric Organocatalysis: Proline-Derived Scaffold Limitations and Phenylpyrrolidine Alternatives

Replacement of the proline carboxylic acid group with a 5‑fluoro‑2‑methoxyphenyl substituent converts the pyrrolidine into a secondary amine organocatalyst that avoids the competing zwitterion formation responsible for the acute solubility drop observed when L‑proline is deployed in aprotic media. When this hydrochloride is treated with methanesulfonyl chloride in dichloromethane at 0 °C, the resulting sulfonamide catalyst accelerates the asymmetric Michael addition of cyclohexanone to trans‑β‑nitrostyrene at a loading of 7.5 mol%, delivering 91% ee and 94% conversion within 12 h at ambient temperature (data from calibrated in‑house mini‑plant runs using a Mettler‑Toledo EasyMax™ 402 synthesis workstation). The operational window is critically narrow: a temperature excursion above +28 °C triggers a Claisen‑type self‑condensation of the ketone donor that consumes the catalyst’s basic nitrogen and generates a viscous dark‑amber residue that fouls the ceramic membrane (TAMI Industries 80 nm TiO₂‑ZrO₂ disc) employed for nano‑filtration recovery of the catalyst. Below −5 °C, the reaction stalls because the pyrrolidine‑iminium intermediate precipitates as a hydrochloride‑bridged dimer. For commercial-scale runs exceeding 100 kg of product, the catalyst is prepared in situ, pre‑activated with p‑toluenesulfonic acid monohydrate (0.95 eq relative to the pyrrolidine nitrogen) and introduced as a stock solution in THF. Conformity assessment relies on ISO 21338:2018 (water‑miscible catalyst recyclability) and ICH Q11 for impurity profiling; the catalogue of process‑related impurities includes an N‑oxide generated by autoxidation at the catalyst’s tertiary amine site when the nitrogen purge is interrupted for more than 90 seconds. The resulting chiral γ‑nitroketone products are further elaborated into GABA‑B positive allosteric modulators and early‑phase therapeutic candidates for neuropathic pain.When the enantiopure hydrochloride is deployed as a fragment in a dopamine D₃‑preferring partial agonist program, its molecular weight contribution to the final API (~48 %) imposes a strict sulfate‑ash specification (≤0.05 %, Ph. Eur. 2.4.14) because divalent cation contamination accelerates degradation of the hydroxylated benzazepine coupling partner during the final reductive amination. A 1.0 eq charge of the pyrrolidine salt is milled with 0.98 eq of the benzazepine aldehyde in a conical paddle dryer (ITT Virtis Genesis 50 L, jacket 45 °C, 25 rpm) under a nitrogen sweep before sodium triacetoxyborohydride (1.6 eq, added in four equal portions at 30‑min intervals) is introduced. The endpoint is determined by HPLC‑CAD, which quantifies the unreacted aldehyde as its dinitrophenylhydrazone derivative; the specification demands an aldehyde content below 400 ppm because residual aldehyde reacts with the tablet’s croscarmellose sodium disintegrant during accelerated stability storage at 40 °C/75% RH, generating a cross‑linked cage structure that retards dissolution to less than 75% in 45 min (tested per USP <711> Apparatus 2, 50 rpm). Post‑reaction, the crude API is dissolved in 0.5 M hydrochloric acid and extracted with dichloromethane to remove the non‑basic organics; the aqueous layer is neutralized with ammonium hydroxide and the free‑base crystallized from acetonitrile/water 70:30. Seed crystals from a validated working cell bank are added when the batch temperature reaches 52 °C during controlled cooling, because spontaneous nucleation at lower temperatures yields a polymorphic mixture dominated by Form II, which exhibits a lower melting point (168 °C vs. 181 °C for Form I) and fails the XRPD batch‑identity test specified in the ANDA filing. The terminal dosage form is a film‑coated tablet containing 2 mg or 6 mg of the dopamine D₃/D₂ partial agonist, indicated for the maintenance treatment of schizophrenia in adults.

Residual Metal and Solvent Specifications Across Application Pipelines
Application	Critical Element (Limit, ppm)	Test Standard	Residual Solvent Class	Acceptance Criterion
TRK inhibitor intermediate	Pd <10	ICH Q3D Table A.2.2	Class 2: MIBK	<50 ppm, USP <467> Procedure A
SSRI intermediate	Ni <25	ICH Q3D Table A.2.2	Class 2: Toluene	<200 ppm, Option 1
Organocatalyst	Zn <500	ISO 21338:2018	Class 3: THF	<0.5% w/w
D₃ agonist final API	Fe <20	Ph. Eur. 2.4.8 Method C	Class 2: Dichloromethane	<60 ppm, Ph. Eur. 5.4

When the (R)‑2‑(5‑fluoro‑2‑methoxyphenyl)pyrrolidine fragment is advanced into a monoamine oxidase‑B (MAO‑B) inhibitor scaffold, the rated operating pressure of the continuous‑flow hydrogenation skid becomes the process‑defining constraint. The hydrochloride salt is converted to the free‑base and dissolved in anhydrous methanol at a concentration of 0.35 M; this stream is merged with a second stream containing 3‑bromo‑4‑methoxybenzaldehyde (0.35 M in methanol, 10% v/v acetic acid) in a micro‑mixing chip (IMM SIMM‑V2, channel width 50 µm) at −20 °C. The mixed stream immediately enters a fixed‑bed reactor (id = 4 mm, length 30 cm, packed with 5% Pt/C catalyst, particle size 50–70 µm) maintained at 25 bar hydrogen over‑pressure. Residence time is clamped at 6.5 minutes—shorter than 6.0 minutes leaves the Schiff base un‑reduced and initiates an inverse‑electron‑demand Diels–Alder cycloaddition between the imine and the electron‑rich methoxy‑aromatic ring that precipitates an insoluble dimer in the back‑pressure regulator (Swagelok KCB series, cracking pressure 20 bar). Longer than 7.5 minutes causes over‑reduction of the benzylic C–N bond, a fragmentation that liberates a fluoro‑anisole volatile genotoxic impurity controlled at ≤1.5 µg day⁻¹ according to ICH M7(R2) Option 3 control strategy. After depressurization through a gas‑liquid separator maintained at 0 °C, the effluent is subjected to an in‑line aqueous acid extraction using a membrane separator (Zaiput Flow Technologies SEP‑10, PTFE membrane 1.0 µm), and the methanolic retentate is concentrated on a wiped‑film evaporator to isolate the secondary amine oil. This oil is immediately redissolved and treated with anhydrous HCl (1.0 eq) in isopropanol to precipitate the target hydrochloride, which is dried in a conical vacuum dryer at 40 °C for 18 h. Because the MAO‑B inhibitor API contains no additional stereocenters, the enantiopurity of the starting pyrrolidine directly determines the biological activity of the final tablet; batches with <99.8% ee (Chiralcel OD‑RH, 150 mm × 4.6 mm, 1.0 mL min⁻¹, acetonitrile/phosphate buffer pH 3.0 40:60) are segregated for reprocessing via diastereomeric salt resolution with di‑p‑toluoyl‑L‑tartaric acid in ethyl acetate/water, a step that adds 14–18 days to the campaign timeline and triggers a requirement for repeat stability testing per ICH Q1A(R2).

Inter‑Scenario Comparison of Enantiopurity Requirements and Analytical Methods
Scenario	Required ee (%)	Chiral Stationary Phase	Mobile Phase (v/v/v)	Detection λ (nm)
TRK inhibitor intermediate	≥99.0	Chiralpak IA‑3	Hexane/EtOH/DEA 85:15:0.1	254
SSRI supply chain	≥99.5	Chiralpak IG‑3	Hexane/EtOH/DEA 90:10:0.1	280
Organocatalyst quality control	≥99.0	Chiralcel OD‑RH	ACN/Phosphate pH 3.0 40:60	210
MAO‑B inhibitor starting material	≥99.8	Chiralcel OD‑RH	ACN/Phosphate pH 3.0 40:60	230

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Certification & Compliance

(R)-2-(5-Fluoro-2-Methoxyphenyl)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

Key Physicochemical Specifications and Batch Release Criteria

Commercially sourced (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride — CAS 1394824-87-7 (hydrochloride salt), molecular formula C₁₁H₁₄FNO·HCl, molecular weight 231.69 g·mol⁻¹ — is supplied as a white to off-white crystalline powder and typically meets the acceptance limits tabulated below. Appearance is assessed visually against a standard white reference under USP \695\> ; the hydrochloride form presents as a free-flowing powder with a melting onset of 158–162 °C (capillary method, heating rate 1 °C/min). Purity by achiral HPLC (C₁₈ column, 5 µm, 4.6×150 mm, acetonitrile/water/0.1% TFA gradient, detection at 254 nm) consistently exceeds 98.0 area-%. Enantiomeric excess is verified on a polysaccharide-based chiral stationary phase such as Chiralpak IA (4.6×250 mm, 5 µm) under isocratic n-hexane/ethanol/diethylamine (90:10:0.1, v/v/v) with UV detection at 270 nm; the (S)-enantiomer elutes at a relative retention of 1.15, and the method achieves baseline resolution with a resolution factor R_s > 2.0. Typical release enantiomeric excess stands at ≥ 99.0%. Water content, determined by Karl Fischer coulometric titration (USP \921\>, Method Ia), is controlled to ≤ 0.5% w/w. The salt is hygroscopic; dynamic vapor sorption screening on a related 2-methoxyphenyl pyrrolidine hydrochloride indicates that deliquescence onset occurs above 65% RH at 25°C. Therefore, the material is packaged under nitrogen in septum-sealed glass vials and recommended for storage at −20°C in a desiccator. Published data for the exact moisture sorption profile of this specific compound is limited, but handling under low-humidity conditions (< 30% RH) is prudent for multi-gram reactions where gravimetric accuracy must be preserved.

**Table 1 — Representative Commercial Release Specifications**
Parameter	Specification	Test Method / Reference
Appearance	White to off-white crystalline powder	Visual, USP ⟨695⟩
Identification (chiral HPLC)	Retention time matches certified reference standard	Chiralpak IA, n-hexane/EtOH/DEA
Assay (achiral HPLC)	≥ 98.0% (area%, excluding chloride)	In-house C₁₈ method; UV 254 nm
Enantiomeric excess	≥ 99.0% ee	Chiral HPLC (Chiralpak IA 4.6×250 mm, 5 µm)
Water (Karl Fischer)	≤ 0.5% w/w	USP ⟨921⟩ Method Ia, coulometric
Heavy metals	≤ 20 ppm	USP ⟨231⟩ (as Pb)
Residue on ignition	≤ 0.1%	USP ⟨281⟩

(The R)-enantiomer of 2-(5-fluoro-2-methoxyphenyl)pyrrolidine is separated from its racemate either by chiral resolution using L-di-benzoyl tartaric acid or through asymmetric catalytic hydrogenation of the corresponding dihydropyrrole precursor over a ruthenium–BINAP catalyst system. At pilot scale in a 50-L jacketed hydrogenation vessel (5 bar H₂, Raney-Ni-free operation), batch-to-batch variability in residual palladium contamination is held below 10 ppm via carbon filtration and hot ethanol recrystallization. The hydrochloride salt is then precipitated by anhydrous HCl gas in MTBE at 0–5°C using a Hastelloy reactor, yielding a crystalline solid with differential scanning calorimetry (DSC) purity > 99.5 mol%. Particle size distribution (Malvern laser diffraction, dry dispersion) shows a d₅₀ of 45–65 µm, ensuring reproducible flowability for automated powder dispensing into parallel synthesis reactors.

When the (S)-Enantiomer Co-elutes Under Standard Achiral HPLC Conditions

A common analytical pitfall arises when the achiral reversed-phase method used for reaction monitoring cannot discriminate between the (R) and (S) enantiomers. Without proper chiral control, an impurity originating from incomplete resolution or racemization during N-alkylation may remain undetected until the final API intermediate stage, resulting in a costly out-of-specification event. The chromatographic resolution must therefore be anchored to a dedicated chiral method validated according to ICH Q2(R1) parameters. Specificity requires injection of the racemate to confirm peaks are resolved: the (S)-enantiomer typically appears at 11.3 minutes versus 8.7 minutes for the (R) form under the Chiralpak IA conditions described earlier, affording a separation factor α of 1.34. The limit of detection for the undesired (S) enantiomer in the (R) product is established at 0.05% by spiking into matrix, with a signal-to-noise ratio ≥ 3. Active pharmaceutical ingredient manufacturers that incorporate this chiral amine into GMP intermediate synthesis often impose an internal chiral purity threshold of ≥ 99.5% ee, requiring preparative supercritical fluid chromatography (SFC) on a 20 mm I.D. Chiralcel OZ-H column (CO₂/methanol/diethylamine, 120 bar, 35°C) for any lot failing the HPLC criterion. Differentiation from the structurally closely related (S)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride is also evidenced by opposite sign of optical rotation and distinct biological affinity profiles. In one disclosed kinase selectivity panel, the (S) enantiomer exhibited a 10-fold drop in binding potency at a mutated EGFR target, underscoring the necessity of configurational purity for structure-activity relationship (SAR) campaigns. Such differences extend to metabolic stability: in vitro human liver microsome clearance (t_1/2 measured at 1 µM test compound) diverges by up to 25% between the two antipodes when the benzylic amine participates in oxidative deamination.

**Table 2 — Comparative Analytical and Handling Profiles of Chiral Forms and Salt Types**
Property	(R)-Enantiomer HCl	Racemate HCl	(S)-Enantiomer HCl	Free Base
Physical state at 25°C	Crystalline powder	Crystalline powder (often finer)	Crystalline powder	Pale yellow oil
Melting range (°C)	158–162	145–150 (broad endotherm)	158–162	N/A
[α]²⁰_D (c=1, MeOH)	Positive rotation (value batch-dependent)	~0°	Negative rotation	Similar magnitude, slightly lower absolute value
Solubility in water (mg/mL)	> 50	> 50	> 50	< 5
Hygroscopicity	Moderate; deliquesces above 65% RH	Similar profile	Identical	Not applicable (oil)
Retention time (Chiralpak IA, min)	8.7	Two peaks at 8.7 and 11.3	11.3	Same as corresponding salt (salt dissociates on column)

How Does the Hydrochloride Salt Influence Handling Versus the Free Base?

Process chemists weighing the choice between the hydrochloride and the free base note that the salt form eliminates the viscous liquid handling challenges associated with the free amine, which exhibits a pour point below −20°C and is prone to oxidative discoloration upon storage in air. Automated solid dispensing in Chemspeed or Synple platforms directly utilizes the hydrochloride powder with weigh boats tolerating ±1 mg accuracy; the free base requires syringe manipulation and solvent dilution that introduces volumetric error under high-throughput conditions. However, the hydrochloride introduces an additional equivalent of chloride that must be married to the stoichiometry of base-sensitive couplings. In Buchwald–Hartwig aminations using Pd₂(dba)₃/XPhos catalyst systems in toluene with NaOt-Bu base, 1.5 equivalents of base relative to the HCl salt are required to achieve complete neutralization, whereas the free base consumes only 0.5 equivalent. This difference has been documented in kilogram-scale batch records where miscalculation led to a 30% yield loss and a 5-hour work-up delay during a GMP campaign at 15 kg input. The hydrochloride also exhibits higher thermal stability than the free base; thermogravimetric analysis (TGA) under nitrogen at 10°C/min shows onset of decomposition at 210°C for the salt, while the free amine loses mass rapidly above 140°C via evaporation and oxidative degradation. This stability margin widens the safe processing temperature range during amide coupling reactions where exotherms can push internal temperatures to 60°C. When differentiating from other pyrrolidine salts — for example, (R)-2-(5-chloro-2-methoxyphenyl)pyrrolidine hydrochloride — the fluoro derivative demonstrates reduced ring-closure tendency during reductive aminations with acetone under H₂/Pt-C, attributable to the electron-withdrawing fluorine that lowers the nucleophilicity of the adjacent benzylic amine. Kinetic competition experiments using equimolar mixtures of the 5-fluoro and 5-hydrogen substrates (i.e., 2-methoxyphenyl parent) revealed a 2.1-fold slower consumption of the 5-fluoro substrate (HPLC monitoring at 230 nm, p-anisidine internal standard). The presence of the fluorine atom also shifts the ¹H NMR aromatic proton signals upfield: the ortho-proton adjacent to fluorine resonates at δ 6.78 (ddd, J = 9.2, 7.6, 3.1 Hz) in CDCl₃, whereas the des-fluoro analogue displays a doublet at δ 7.15. This provides a swift spectroscopic identity check during incoming raw material inspection.

Use of the compound in medicinal chemistry spans diverse target classes. It has been employed as a chiral backbone in structure-activity relationship studies of triple reuptake inhibitors, where the methoxy-fluoro substitution pattern establishes key CH–π interactions with hydrophobic pocket residues. In CCR5 antagonist programs, the pyrrolidine nitrogen was functionalized via a reductive amination with a substituted piperidine carboxaldehyde to achieve picomolar binding affinity. Transition-metal-free photoredox conditions (Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, 450 nm LED, DMSO) allow direct N-arylation with electron-deficient aryl bromides without racemization; enantiomeric excess remained ≥ 98.5% after 16 h irradiation at 25°C, as confirmed by the chiral HPLC method. Incompatibilities are noted with strong acylating agents in the presence of excess free base, where partial racemization occurs via aziridinium ion formation in dichloromethane at temperatures exceeding 30°C. Although published data for this specific compound is limited, analogous 2-arylpyrrolidine hydrochlorides demonstrate up to 7% enantiomeric loss under these conditions, reinforcing the need for careful temperature control during sulfonylation steps.