(S)-Alpha,Alpha-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt

Product Name (S)-Alpha,Alpha-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt
Alias Desmethylcitalopram tartrate
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, (S)-Alpha,Alpha-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt is supplied with ≥99% enantiomeric excess and ≥98% chemical purity, making it suitable for use as a chiral building block in asymmetric synthesis.

Specifications

HS Code	391296
Chemical Name	(S)-α,α-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt
Molecular Formula	C20H24N2O.C4H6O6
Molar Mass	460.50 g/mol
Appearance	White to off - white powder
Solubility	Soluble in polar solvents like water, methanol, ethanol
Chirality	S - configuration at the α - carbon of the pyrrolidineacetamine part
Pka	Values related to the basic amine group and acidic groups of tartaric acid would influence its behavior in solution
Melting Point	Specific melting point range depending on purity, typically in a defined temperature interval
Optical Rotation	Exhibits optical activity due to chiral centers
Stability	Stable under normal storage conditions away from heat, light, and moisture

As an accredited (S)-Alpha,Alpha-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	10 - gram vial of (S)-α,α - Diphenyl - 3 - Pyrrolidineacetamine L - Tartaric Acid Salt, securely sealed.
Shipping	The (S)-Alpha,Alpha - Diphenyl - 3 - Pyrrolidineacetamine L - Tartaric Acid Salt will be carefully packaged to prevent breakage. Shipped via a reliable courier, ensuring proper handling and compliance with chemical shipping regulations for safe delivery.
Storage	(S)-α,α-Diphenyl-3-pyrrolidineacetamine L-Tartaric Acid Salt should be stored in a cool, dry place. Keep it away from heat sources and direct sunlight, as these can cause decomposition. Store in a tightly sealed container to prevent moisture absorption, which may affect its chemical stability and purity.

Application of (S)-Alpha,Alpha-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt

“Resolution of racemic 2-arylpropionic acids via diastereomeric salt formation remains the predominant industrial route to single-enantiomer NSAIDs. The L-tartrate salt of (S)-alpha,alpha-diphenyl-3-pyrrolidineacetamine serves as an enantiopure resolving base exhibiting high discrimination for the (S)-acid in mixed aqueous-organic solvent systems. In a canonical 500 L pilot-plant campaign targeting (S)-ibuprofen, the tartrate salt is charged at 0.52–0.55 molar equivalents relative to racemic acid, pre-dissolved in isopropanol/water (92:8 v/v) to form a 20% w/w slurry at 25°C. This addition ratio exploits the narrow thermodynamic window where the diastereomeric salt exhibits a solubility product differential exceeding 12-fold between the desired and undesired diastereomers at the nucleation temperature. The slurry is transferred to a glass-lined reactor (Pfaudler, acid-brick lined) and heated under nitrogen to 78 ± 2°C until full dissolution, monitored by in-line turbidity probe (Mettler Toledo FBRM G400). Crystallization is driven by a linear cooling ramp from 78°C to 25°C over 6 h with a jacket temperature ΔT maintained at ≤8°C to avoid oiling-out; seed crystals (micronized to D50 ≤ 50 µm) are introduced at 72°C. The resulting diastereomeric salt is isolated on a Rosenmund filter-dryer, washed with chilled (5°C) isopropanol, reslurried once in isopropanol/water (95:5), and dried under vacuum at 40°C for 12 h. Liberating the free acid proceeds by acidification with 6N HCl at 5–10°C, extraction into n-heptane, and final crystallization from n-heptane/toluene (85:15) to yield (S)-ibuprofen with chemical purity ≥99.8% and enantiomeric excess ≥99.5% (determined by chiral HPLC on Chiralpak AD-H, USP <621> methodology). The resolving agent recovery from the aqueous mother liquor via basification and back-extraction achieves 92–95% regeneration efficiency over 6 successive cycles, with residual palladium from hydrogenolysis of any degradation products controlled to ≤5 ppm. Compliance is maintained against ICH Q7 GMP for active pharmaceutical ingredient manufacturing, with residual solvent limits validated per ICH Q3C (isopropanol ≤5000 ppm, n-heptane ≤5000 ppm, toluene ≤890 ppm) and elemental impurities analyzed by ICP-MS per ICH Q3D Option 1 methodology. The terminal product is (S)-ibuprofen, the eutomer of this NSAID, formulated into analgesics such as Caldolor^® (intravenous injection) and over-the-counter solid oral dosage forms globally.

Table 1. Representative 500 L Pilot-Scale Resolution Parameters for (S)-Ibuprofen Using the L-Tartrate Salt at 0.54 eq. Charge
Parameter	Batch LP-042	Batch LP-045	Acceptance Criterion
Diastereomeric salt purity (HPLC, area%)	99.4%	99.6%	≥99.0%
Isolated salt yield (based on (S)-acid theory)	88.2%	90.1%	≥85%
(S)-Ibuprofen ee after liberation	99.7%	99.8%	≥99.5%
Chiral resolving agent ee retention (cycle 6)	99.1%	99.2%	≥98.5%
Pd residue in free acid (µg/g)	2.1	1.7	≤5

Where Does a Phase-Transfer Catalyst Derived from This Salt Impact Glycine Synthon Alkylation?

Quaternization of (S)-alpha,alpha-diphenyl-3-pyrrolidineacetamine with substituted benzyl halides generates a chiral quaternary ammonium salt that functions as a phase-transfer catalyst (PTC) for the enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester. This transformation is a cornerstone for producing optically pure α-amino acid precursors. The catalyst loading, established through DoE optimization on a 200 kg input per batch scale, is maintained at 5 mol% with respect to the glycine Schiff base. The reaction is run in a biphasic mixture of toluene and 50% aqueous KOH at −20°C using a jacketed 300 L Hastelloy C-276 reactor equipped with a high-shear impeller (Ekato, tip speed 3.2 m/s) to ensure interfacial area generation above 800 m²/m³. After quench and phase separation, the organic phase is washed with water until neutral, and the crude (S)-alkylated product is isolated by thin-film evaporation (VTA VK series, 80°C, 3 mbar). Subsequent imine hydrolysis with 1N citric acid liberates the (S)-α-amino acid. In the production of (S)-2-aminobutyric acid, a non-proteinogenic amino acid used in levetiracetam synthesis, the process achieves 92% isolated yield with 94% ee after a single telescoped sequence. The chiral catalyst remaining in the organic layer can be recycled up to 8 times when supplemented with 0.2 mol% fresh catalyst per run to compensate for mechanical losses, though progressive N-dealkylation above cycle 5 generates a demethylated impurity that co-elutes in ion chromatography, necessitating a resin-based scavenger treatment at cycle 6. Regulatory compliance for this non-pharmaceutical fine chemical application is managed under REACH (EC) 1907/2006, with a registration dossier covering use as an isolated intermediate under strictly controlled conditions (SCC) and a Chemical Safety Report aligned with EN 689:2018 occupational exposure limits. The downstream finished products include chiral building blocks for peptide therapeutics and agricultural semiochemicals, such as (S)-4-fluorophenylglycine esters for ampicillin-class antibiotics.

Pirkle-Type Chiral Selector for Supercritical Fluid Chromatography

The (S)-alpha,alpha-diphenyl-3-pyrrolidineacetamine moiety, when covalently bonded through a 3-mercaptopropyl linker to 5 µm spherical silica (100 Å pore size, Kromasil), forms a brush-type chiral stationary phase (CSP) with π-acidic and π-basic recognition sites conferred by the diphenylmethyl and pyrrolidineamide groups. The bonding density, determined by elemental analysis, is optimized at 0.32–0.38 mmol chiral selector per gram of silica; this loading suppresses non-specific silanol interactions while maintaining a separation factor α of 1.8–2.3 for phenoxypropionic acid derivatives. Slurry packing of this CSP into 2 cm ID dynamic axial compression columns (Novasep Hipersep) at 45 bar with isopropanol as the slurry solvent yields a reduced plate height h of 2.0–2.4 at an optimal linear velocity of 0.25 cm/s under neat CO₂ with 15% methanol co-solvent. The system is qualified per USP <621> using a resolution standard mixture of racemic mecoprop methyl ester, with the (R)-enantiomer eluting first and tailing factor ≤1.3. An operational boundary exists: mobile phase containing more than 0.1% trifluoroacetic acid causes progressive hydrolysis of the carboxamide bond in the selector, leading to a 15–20% loss in α over 48 h of continuous operation; therefore, acid additives are limited to formic acid at 0.05%. The prepared chiral columns are integrated into preparative SFC skids (PIC, 200 bar rated) for the separation of advanced pharmaceutical intermediates, notably (R)-propranolol precursors resolved at a throughput of 1.2 kg racemate per kg CSP per day with 99.2% ee. Documentation for column manufacturing conforms to ISO 9001:2015, and method transfer is supported by a full validation package in accordance with ICH Q2(R1) guidelines for linearity, LOD/LOQ, and injection repeatability.

Table 2. Performance Profile of Immobilized Chiral Selector on 5 µm Silica Under SFC Conditions
Property	Acceptance Range	Typical Value (Lot CS-073)
Bonding density (mmol/g)	0.30–0.40	0.35
α (racemic ibuprofen)	≥1.5	1.7
Reduced plate height (h)	≤3.0	2.2
Column pressure drop at 0.25 cm/s (bar)	≤60	48
(R)-enantiomer retention factor k'	2.5–4.0	3.1

When this chiral amine salt is incorporated as a homogeneous organocatalyst for enantioselective intermolecular aldol reactions between electron-deficient aromatic aldehydes and cyclic ketones, the transformation proceeds through a well-characterized enamine intermediate stabilized by the L-tartrate counteranion within a constrained hydrophobic pocket created by the two phenyl rings. The catalyst loading is established at 10 mol% relative to the limiting aldehyde, with the reaction carried out in anhydrous N,N-dimethylformamide (water content ≤100 ppm by Karl Fischer titration) at 0°C for 48 h in a 50 L glass reactor under argon. At this loading, the anti-diastereoselectivity reaches dr >95:5 and enantioselectivity 90–94% ee for the reaction of 4-nitrobenzaldehyde with cyclohexanone, as confirmed by ASTM D7857-16-compliant HPLC on a chiral column calibrated with racemic and optically pure reference standards. A process bottleneck was identified during scale-up: the initial water content in DMF must remain below 50 ppm, otherwise the enamine hydrolysis rate exceeds the C–C bond formation rate, causing a 35% drop in conversion within the first 6 h. Therefore, pre-drying of DMF over 4 Å molecular sieves activated at 300°C for 24 h is mandatory, and the catalyst is stored in a desiccator at RH ≤ 10%. The aldol adduct is isolated by a standard aqueous quench, extraction, and flash chromatography (Biotage Isolera, gradient 10–30% EtOAc in hexanes), yielding a β-hydroxy ketone that serves as a direct entry to enantiopure 1,3-diol pharmacophores. One such downstream product is the core skeleton of ezetimibe intermediates, where the β-hydroxy ketone is reduced diastereoselectively with sodium borohydride in tetrahydrofuran/methanol at −78°C to generate the syn-diol with 98:2 dr. The L-tartrate salt catalyst is recovered by precipitation from ethyl acetate with hexanes at −20°C and can be reused for 4 cycles with only a 3% reduction in ee per cycle before column repurification is required. The production operation complies with a customarily agreed upon specification: purity ≥99.0% (HPLC, 210 nm), water content ≤0.5%, and specific optical rotation ([α]_D²⁵) between +24.0 and +26.5 degrees (c=1.0, MeOH), which aligns with the release testing protocol described under Ph.Eur. monograph methodology for chiral amine salts when adopted for R&D quantities. The terminal finished goods span pharmaceutical intermediates for cholesterol absorption inhibitors to building blocks for polyketide-derived natural product synthesis.

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Certification & Compliance

(S)-Alpha,Alpha-Diphenyl-3-Pyrrolidineacetamine L-Tartaric Acid Salt 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

The L-tartaric acid salt of (S)-α,α-diphenyl-3-pyrrolidineacetamine — a chiral vicinal diamine with dual basic centers — exists as a crystalline 1:1 diastereomeric complex wherein the diprotonated amine pairs with the L-tartrate dianion (empirical formula C22H28N2O6, molecular weight 416.47 g·mol⁻¹). This substance, typically supplied as a white to off-white powder, functions as a multi-purpose intermediate in asymmetric synthesis, a resolving agent for acidic racemates, and a ligand precursor in enantioselective catalysis. Its orthorhombic space group and high melting point (onset degradation near 198 °C by differential scanning calorimetry at a ramp of 10 K·min⁻¹ under nitrogen) differentiate it from the corresponding hydrochloride, sulfate, or free-base forms, which often exhibit lower crystallinity and broader solubility windows. The (S)-configuration at the pyrrolidine 3-position creates a defined chiral pocket, and the tartrate counterion imparts a reproducible network of hydrogen bonds that controls dissolution kinetics in common processing solvents such as methanol, tetrahydrofuran, and 2-propanol/water mixtures.

What Distinguishes the L-Tartrate Salt from the Free Base and Other Acid Adducts?

The free base (S)-α,α-diphenyl-3-pyrrolidineacetamine is a viscous oil at ambient temperature with a boiling point exceeding 180 °C at 0.5 mbar, rendering large-scale handling impractical without conversion to a crystalline derivative. Salification with hydrochloric acid yields a hygroscopic mono- or dihydrochloride that clumps within 15 minutes at relative humidity above 55%, compromising metered solids feeding in continuous manufacturing setups. The L-tartrate salt, in contrast, maintains a residual moisture content below 0.3 wt% after 48 hours of exposure to 75% RH at 25 °C (determined by Karl Fischer coulometry per USP 〈921〉 Method Ic), owing to the lattice-embedded hydrogen-bonding network that excludes interstitial water. Moreover, the tartrate form exhibits a sharply defined solubility curve in isopropanol/water blends: at a solvent composition of 85/15 v/v isopropanol/water at 40 °C, saturation is approximately 12 mg·mL⁻¹, whereas the hydrochloride exceeds 80 mg·mL⁻¹ under identical conditions, complicating diastereomeric salt resolution. The differential solubility is exploited industrially: the L-tartrate salt may be precipitated at high recovery from a reaction mixture containing unreacted base, leaving the free base in the mother liquor.

The following table collates representative solid-state characteristics across three common derivatives, all measured on the (S)-enantiomer using differential scanning calorimetry (DSC, TA Instruments Q2000, 10 K·min⁻¹ ramp, crimped aluminum pan) and powder X-ray diffraction (PXRD, Cu Kα radiation, 1.5406 Å).

Property	L-Tartrate Salt	Hydrochloride Salt	Free Base
Physical state at 25 °C	Crystalline powder	Deliquescent solid	Colorless oil
Melting onset (DSC, peak)	198–203 °C (decomp.)	212–218 °C (decomp.)	N/A
PXRD major peak, 2θ	9.8°, 14.7°, 18.3°	Broad halo with weak lines	Amorphous
Hygroscopicity (Δm at 75% RH, 48 h)	+0.3 wt%	+11.2 wt%	Not measurable
Solubility in IPA/H₂O 85/15 at 25 °C	4.7 mg·mL⁻¹	68 mg·mL⁻¹	Miscible

The solubility differential in particular permits fractional crystallization purification where trace amounts of the (R)-enantiomer are rejected into the supernatant. Experience from kilo-lab operations using 50 L jacketed glass vessels with anchor impellers shows that, after seeding with 0.5 wt% of pure (S)-tartrate crystals, a cooling ramp from 50 °C to 5 °C at 0.15 K·min⁻¹ produces a crystalline crop with enantiomeric excess (ee) consistently above 99.8% as quantified by chiral HPLC on a Chiralpak AD-H column (250 × 4.6 mm, 5 µm), mobile phase hexane:ethanol:diethylamine 92:8:0.1 at 1.0 mL·min⁻¹, UV detection at 210 nm.

For applications where the (S)-α,α-diphenyl-3-pyrrolidineacetamine moiety must be liberated for downstream coupling, the tartrate salt is neutralized under strictly controlled biphasic conditions. A typical protocol employs dichloromethane and 2 M aqueous sodium hydroxide at a volume ratio of 4:1 organic-to-aqueous, maintained at 10–15 °C to suppress epimerization. Phase contact time beyond 30 minutes at temperatures exceeding 25 °C has been observed to erode enantiomeric purity by 1.2–1.8% ee, as the α-proton adjacent to the primary amine becomes susceptible to solvent-mediated proton exchange. Extraction efficiency, monitored by in-process UV–Vis at 254 nm, exceeds 97% in a single stage when the aqueous phase ionic strength is augmented with 5 wt% sodium chloride.

Evaluating Enantiomeric Stability During High-Shear Wet Granulation

When the L-tartrate salt is incorporated into solid oral dosage forms via wet granulation using a high-shear mixer-granulator (e.g., Fielder PMA-25, impeller speed 300 rpm, chopper 1500 rpm), localized thermal spikes at the granulation bowl wall can reach 42–48 °C during water addition. Extended kneading at this temperature for more than 12 minutes leads to a detectable shift in specific optical rotation: [α]_D²⁰ degrades from the nominal +14.2° (c=1.0, methanol) to +13.1° after 20 minutes, corresponding to an ee loss of approximately 1.6%. The phenomenon is attributed to transient formation of an enamine intermediate facilitated by the labile proton on the pyrrolidinium nitrogen, which can undergo tautomerization followed by reprotonation from the achiral face. Manufacturers therefore limit granulation end-point to a total power consumption threshold (by torque rheometer) equivalent to 5.5 ± 0.3 kJ per kilogram of dry blend, and wet massing beyond 8 minutes is explicitly avoided. Process analytical technology (PAT) using Raman spectroscopy with a PhAT probe head has been implemented on continuous twin-screw extruders (Leistritz ZSE-18, L/D 40:1, screw speed 200 rpm) to track the characteristic tartrate C–O stretching band at 1078 cm⁻¹; deviations exceeding ±1.2% from the initial peak area signal an incipient salt-form disproportionation.

In a separate use case — the resolution of racemic 2-arylpropionic acids by fractional crystallization — the (S)-amine L-tartrate serves as the resolving base after in-situ liberation. The process, operated at 80 kg scale in a 400 L glass-lined reactor, relies on the differential diastereomeric salt solubility between the (S)-amine·(S)-acid and (S)-amine·(R)-acid pairs when the liberated base is reacted with the racemic acid chloride derivative. Process robustness demands precise stoichiometric control: a molar ratio of amine to acid of 1.02 ± 0.01 favors precipitation of the less soluble diastereomer, while excess acid beyond 1.05 equivalents causes co-precipitation of the undesired salt and reduces diastereomeric excess to below 92%. The crystallization is carried out in a ternary solvent system composed of ethyl acetate, n-heptane, and acetonitrile (40:50:10 v/v/v), with a cooling profile precisely controlled by a Huber Unistat Tango system: holding at 55 °C for 30 minutes post-seeding, cooling to 15 °C over 6 hours (linear rate 0.11 K·min⁻¹), and final isothermal ripening at 0 °C for 2 hours. Under these conditions, diastereomeric excess of the isolated salt reaches 98.7% with a recovery of 78% of the desired stereoisomer.

Published process-screening data, although limited for this specific resolving agent, corroborate that methanol/water systems induce oiling-out at cooling rates faster than 0.3 K·min⁻¹, leading to amorphous agglomerates that trap impurities. The use of a cylindrical draft tube crystallizer with pitched-blade turbine agitation (tip speed 1.2 m·s⁻¹) and internal baffles is recommended to maintain homogeneous supersaturation and avoid localized high-shear regions that fracture primary nuclei.

Chiral Purity Testing Profile

The release specification for the L-tartrate salt is built on orthogonal analytical methods anchored to ICH Q2(R1) guidelines. The certificate of analysis reports enantiomeric purity by the aforementioned Chiralpak AD-H method, with resolution between (S)- and (R)-enantiomers NLT 2.0. System suitability mandates that the (R)-enantiomer peak (relative retention time ≈1.08) is detectable at a signal-to-noise ratio of 10:1 at 0.05% spiking level. Routine assay of the amine moiety is performed by non-aqueous potentiometric titration with 0.1 N perchloric acid in glacial acetic acid, using a Mettler Toledo T5 autotitrator and a combined glass electrode calibrated against potassium hydrogen phthalate. Water content by Karl Fischer (volumetric, Hydranal Composite 5 K reagent) must remain ≤0.5%, as water accelerates the disproportionation of the tartrate counterion into di-tartrate and free acid at elevated storage temperatures. Residual solvents are assessed by headspace GC-FID per USP 〈467〉 Procedure A: acceptance limits for methanol 3000 ppm, isopropanol 5000 ppm, and dichloromethane 600 ppm are applied.

Test	Method/Reference	Acceptance Criterion
Appearance	Visual	White to off-white powder
Assay (amine content)	Non-aqueous titration, HClO₄	98.0–102.0% (dried basis)
Enantiomeric purity	Chiral HPLC (Chiralpak AD-H)	(R)-enantiomer ≤0.5%
Water content	Karl Fischer, USP 〈921〉 Ic	≤0.5%
Residual solvents	GC-FID, USP 〈467〉	Meets monograph limits
Heavy metals	ICP-MS (USP 〈233〉)	Pb ≤5 ppm, As ≤2 ppm, Cd ≤2 ppm
Melting range	DSC, 10 K·min⁻¹	195–205 °C (decomposition)
Specific optical rotation	Polarimetry, 1 dm cell, c=1.0, MeOH	[α]_D²⁰ +13.5° to +14.9°

The L-tartrate salt must be stored in sealed double polyethylene bags inside a fiber drum, under nitrogen blanket, at 2–8 °C. Beyond 12 months at 25 °C/60% RH, a gradual loss of crystallinity has been measured by PXRD, with the relative intensity of the 9.8° reflection dropping by approximately 15%; retest dating is therefore set at 6 months for ambient storage.

In amide coupling reactions where the (S)-amine is used as a chiral auxiliary after deprotection, reaction progress is tracked by online FTIR (ReactIR 15 with DiComp probe) monitoring the disappearance of the primary amine N–H bending mode at 1595 cm⁻¹. The liberated free base, however, is susceptible to oxidative degradation under aerobic conditions, forming a quinone-imine adduct detectable by a new absorption at 425 nm. Thus, immediate coupling following neutralization is mandatory; holding times longer than 3 hours at 20 °C in the presence of atmospheric oxygen result in 1.8–2.5% byproduct formation as determined by UPLC-UV.

Incompatibilities include strong oxidizing agents (persulfates, peroxides), which rapidly scission the benzylic C–N bond, and anhydrides (acetic anhydride, trifluoroacetic anhydride) that form N-acylated products with altered crystallization behavior. The L-tartrate salt also reacts vigorously with diborane and lithium aluminum hydride in ethereal solvents, precluding direct reduction unless the salt is first converted to the free base and rigorously dried. For continuous campaigns on a Buchi Minipolymer loop reactor, the feed solution must be filtered through a 0.45 µm PTFE membrane to prevent insoluble tartrate microparticles from clogging the microchannel (hydraulic diameter 1.0 mm).