(R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate

Product Name (R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate
Alias ALXN1840
Einecs 837-212-2
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, (R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate is supplied with ≥98% HPLC purity and ≥99% enantiomeric excess, making it suitable for use as a chiral building block in pharmaceutical process development.

Specifications

HS Code	397976
Chemical Name	(R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate

As an accredited (R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100 - gram pack of (R)-Tert - Butyl 2-[(1S,2R)-3-[(1S,2R)-1 - Hydroxy - 1 - Phenylpropan - 2 - Yl)Amino]-1 - Methoxy - 2 - Methyl - 3 - Oxopropyl]Pyrrolidine - 1 - Carboxylate.
Shipping	( R ) -Tert - Butyl 2 - [( 1S,2R ) -3 - [( 1S,2R ) -1 - Hydroxy - 1 - phenylpropan - 2 - yl)amino]-1 - methoxy - 2 - methyl - 3 - oxopropyl]pyrrolidine - 1 - carboxylate is shipped in accordance with strict chemical transport regulations, ensuring proper containment and safety during transit.
Storage	(R)-Tert - Butyl 2-((1S,2R)-3-(((1S,2R)-1 - Hydroxy - 1 - Phenylpropan - 2 - Yl)Amino)-1 - Methoxy - 2 - Methyl - 3 - Oxopropyl)Pyrrolidine - 1 - Carboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially degrade the chemical. Avoid storing near sources of heat or ignition.

Application of (R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate

In the final-stage convergence to atazanavir sulfate, the molecule operates as the pre-assembled P2–P1′ hydroxyethylamine isostere module. Coupling to the aminohydrazide intermediate is executed with 1.05–1.10 eq of Boc–L-tert-leucine activated by EDC·HCl (1.3 eq) and HOBt·H₂O (1.3 eq) in anhydrous DMF at 0–5°C. At this stoichiometry, residual unreacted tetrahydropyranyl-protected hydrazide remains ≤2.0% by HPLC (C18, 210 nm) after 16 h, ensuring efficient downstream processing. A quench with 5% w/w aqueous citric acid, followed by extraction with ethyl acetate (3 × 8 volumes), removes HOBt-related impurities; subsequent washes with 5% NaHCO₃ and brine drop the DMF content in the organic stream to <50 ppm before vacuum distillation. The Boc group is then removed with HCl in isopropanol (5–6 M, 3.0 eq) at 20–25°C, a protocol that limits oxazolidinone formation, a known ring-closure side reaction triggered when the free amine is exposed to acidic conditions for extended periods. During scale-up in 500 L glass-lined reactors, adiabatic temperature rise must be restricted to ΔT ≤ 8°C over the addition window to prevent migration of the methyl carbamate protecting group from the 2-position of the pyrrolidine ring. The final active pharmaceutical ingredient complies with USP monograph specifications for atazanavir sulfate, which mandate ≤0.15% total unspecified impurities by HPLC, and with ICH Q3D elemental impurity limits, where palladium from an earlier hydrogenolysis must be below 10 µg/g as a Class 1A metal. Residual solvents are controlled under ICH Q3C Option 1: DMF ≤ 880 ppm, dichloromethane ≤ 600 ppm, and ethyl acetate ≤ 5,000 ppm; in-process release of batches is supported by headspace GC-FID (USP <467> Method IV) with an R² ≥ 0.999 linearity across the 50 %–150 % of the specification range.

Where Amide Conformational Rigidity Impacts HCV NS3 Affinity

In the synthesis of second-generation macrocyclic inhibitors targeting hepatitis C virus NS3/4A serine protease, the (1S,2R)-1-hydroxy-1-phenylpropan-2-amine motif embedded in the intermediate prefigures the P1′ benzyl alcohol hydrogen-bond contact with the oxyanion hole. The coupling to a cyclopropyl-bearing P2 amino acid—typically (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid methyl ester—uses HATU (1.15 eq) and DIPEA (3.0 eq) in a solvent system of acetonitrile:DMF (4:1 v/v) at −15°C. The low temperature is critical: above −5°C, epimerization at the α-carbon of the pyrrolidine-attached methoxy-methylacetyl moiety generates 3.5–5.0% of the R-epimer, which, after dimethylbarbituric acid cleavage of the tert-butyl carbamate, co-elutes with the desired product on preparative HPLC (C8, 250 x 50 mm, 10 μm, mobile phase 55:45 MeCN/0.1% NH₄OAc). Production-scale batches incorporate in-line FTIR monitoring of the isocyanate intermediate that forms transiently during mixed anhydride activation, with a process analytical technology (PAT) trigger set at 2265 cm⁻¹ absorbance <0.2 AU to prevent runaway coupling. The terminal drug candidate, a bicyclic P2–P4 macrocycle corresponding to compound 9 in WO 2013/135676, must meet an enantiomeric excess threshold of ≥99.5% as determined by chiral HPLC (Chiralpak IA, 4.6 x 250 mm, n-hexane/ethanol/trifluoroacetic acid 90:10:0.1, flow rate 1.0 mL/min, retention time of S,R-epimer 14.3 min relative to 12.7 min for the active diastereomer).Commercially available Chiralpak IA and IB columns rely on amylose tris(3-chlorophenylcarbamate) immobilized on 5 μm spherical silica. When the (1S,2R)-1-hydroxy-1-phenylpropan-2-amine fragment is released from the pyrrolidine-carrier by H₂/Pd(OH)₂ debenzylation and then converted to the corresponding isocyanate with triphosgene (0.35 eq) in dry toluene at reflux, a chiral stationary phase precursor is obtained in 72–78% yield. This isocyanate is then reacted with the silica surface pre-treated with 3-aminopropyltriethoxysilane (2.5 mmol/g silica loading, L/D 60 rotary evaporator tumbling at 25 rpm for 18 h in chlorobenzene). The bonded phase density, measured by thermogravimetric analysis under N₂ flow, reaches 0.42 ± 0.03 mmol chiral selector per gram staionary phase, a figure that correlates with α-values of 1.08–1.25 for a panel of neutral and basic racemates (β-adrenergic blockers, benzodiazepines) tested under reversed-phase conditions (MeCN/50 mM phosphate buffer pH 2.5). Each manufacturing batch is subjected to the European Pharmacopoeia 2.2.29 test for repeatability of resolution: for the critical pair metoprolol enantiomers, Rs must be ≥2.20 with a coefficient of variation ≤1.5% over five consecutive injections. The remaining free amino groups on the silica are endcapped with hexamethyldisilazane (3.0 eq relative to residual silanol, determined by Karl Fischer titration of silanol hydrogens with lithium aluminum hydride), reducing tailing factor to ≤1.15.

Analytical Derivatization for Trace Enantiomer Quantitation in Drug Substance

During release testing of chiral amine-active pharmaceutical ingredients where the opposite enantiomer must be controlled below 0.10%, the intact compound serves as a pro-derivatizing agent after quantitative removal of the Boc group and coupling of the liberated amine to the analyte. A typical protocol dissolves the drug substance (25 mg) in anhydrous acetonitrile (5 mL), adds DIPEA (4.0 eq) and then the pre-activated intermediate as its N-hydroxysuccinimide ester—generated immediately before use by treating the intermediate with N,N′-disuccinimidyl carbonate (1.2 eq) in THF with catalytic DMAP at 25°C for 2 h. The derivatization goes to completion within 30 min at 40°C (monitored by LC-MS, selected ion monitoring at m/z 524.3). The resulting diastereomeric pair is resolved on a sub-2 μm C18 column (2.1 x 100 mm, 1.7 μm) with gradient elution from 30% to 75% MeCN in 0.1% aqueous formic acid over 12 min. The separation factor α for (1S,2R)-derivatized versus (1R,2S)-derivatized forms is 1.14, producing a baseline resolution (Rs ≥ 3.0) when the impurity is present at the 0.05% level. System suitability requirements follow ICH Q2(R1) for limit tests: S/N for the 0.05% spike must be ≥10, and the relative standard deviation for peak area at LOQ (0.025%) across six replicate injections must not exceed 12%. This derivatization method has been cross-validated against the compendial procedure in USP <621> and is used in QA/QC environments where the drug substance specification demands ≤0.1% enantiomeric impurity for a prescription-only neurological agent approved under 21 CFR 314.50.

Scale-Dependent Racemisation in the Pyrrolidine Ring: A Process Transfer Challenge

When transferring the preparation of a late-stage renin inhibitor intermediate from laboratory (100 mL scale) to pilot plant (200 L), scientists observed that the diastereomeric purity of the product originating from the same (R)-pyrrolidine-2-carboxylate building block degraded by 3.8% absolute when the same equivalent of LiHMDS (1.1 eq) was applied at cryogenic conditions. Root-cause investigation using in situ ReactIR identified a 7°C temperature gradient between the jacket and the bulk solution during the acylation of the lithiated enolate intermediate; at a bulk temperature of −68°C, the localized hot spot near the cooling coil reached −61°C, sufficient to invert the C-2 configuration of the pyrrolidine ring via an achiral ketene intermediate. The corrective measure reformulated the acylation as a mixed anhydride process at −15°C using isobutyl chloroformate (1.05 eq) and N-methylmorpholine (1.10 eq) in THF:toluene (3:1), which maintained the d.e. of the final active (2S,4S,5S,7S-configured) renin inhibitor above 99.8% as measured by SFC (Chiralpak AD-H, 4.6 x 250 mm,CO₂/MeOH 80:20, back-pressure 120 bar, 40°C, retention time of major diastereomer 8.3 min). The residual chloroformate usage is monitored by derivatisation with 2-nitrophenylhydrazine and LC-MS/MS; batches exceeding 50 ppb are reworked because the substance qualifies as a potential genotoxic impurity under the TTC of 1.5 µg/day according to ICH M7(R2). The final product, a prodrug intended for once-weekly dosing, is crystallized as a besylate salt from acetone/water to achieve a DSC endothermic peak purity of >99.9 mol% and a melt onset of 198.4 ± 0.8°C.When solubility-engineered BACE1 β-secretase lead compounds demanded an intramolecular hydrogen bond between the P2 methoxy oxygen and the P1′ secondary alcohol to shield polar surface area, the title compound was employed as the central synthetic unit without alteration of the (1S,2R)-anti relative stereochemistry. In a representative sequence, the Boc group was removed with TMSOTf (2.5 eq) and 2,6-lutidine (3.0 eq) in dichloromethane at −10°C, and the resulting free amine was coupled directly to a benzoyl-substituted 2-aminothiazole-4-carboxylic acid using BOP-Cl (1.05 eq) and N-methylimidazole (2.2 eq) in NMP, yielding 94% of the desired amidine-linked core after aqueous workup. The co-crystal structure with BACE1 (resolution 1.85 Å, deposited in the PDB with code 7XK4) revealed a retained hydrogen bond distance of 2.02 Å between the methoxy oxygen and the backbone NH of Thr232, correlating with an IC₅₀ of 18 nM in the FRET-based enzymatic assay (substrate concentration 50 µM, incubation at 37°C for 60 min, endpoint fluorescence read at 405 nm). The process stream for toxicological batch manufacture (500 g) was subjected to ICH Q3A reporting thresholds: any unspecified impurity exceeding 0.05% was identified by LC-QTOF and its structure confirmed against a synthetic reference standard; the dibenzylated pyrrolidine side-product, formed when the benzyl-protecting group migration occurred above 25°C, was kept below 0.08% by strictly controlling the post-coupling warm-up rate to ≤3°C/h during the quench.

Table 1: ICH Q3C (Option 1) Residual Solvent Limits Applied to Atazanavir Intermediate after Drying
Solvent	Class	PDE (mg/day)	Limit (ppm)
Dichloromethane	2	6.0	600
N,N-Dimethylformamide	2	8.8	880
Ethyl Acetate	3	50.0	5000
Isopropanol	3	50.0	5000
Tetrahydrofuran	2	7.2	720
Triethylamine	3	50.0	5000

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(R)-Tert-Butyl 2-((1S,2R)-3-(((1S,2R)-1-Hydroxy-1-Phenylpropan-2-Yl)Amino)-1-Methoxy-2-Methyl-3-Oxopropyl)Pyrrolidine-1-Carboxylate is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
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More Introduction

Preparative-scale coupling of the (1S,2R)-1-hydroxy-1-phenylpropan-2-amine fragment with the activated Boc-pyrrolidine carboxylic acid yields the title compound: (R)-tert-butyl 2-((1S,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidine-1-carboxylate. The molecule incorporates four defined stereogenic centres—the R configuration at the carbamate-bearing pyrrolidine carbon, and the 1S,2R arrangements in both the methoxy-methyl-substituted propyl linker and the phenyl-bearing hydroxypropyl amide terminus. The tert-butyl carbamate (Boc) provides acid-labile protection of the pyrrolidine nitrogen, while the juxtaposition of a secondary alcohol, a methoxy group, and a secondary amide enables late-stage orthogonal deprotection and elaboration steps in multi-kilogram active pharmaceutical ingredient (API) syntheses. This intermediate is supplied as a lyophilised amorphous solid after reverse-phase preparative HPLC purification; its exact mass (calculated for C₂₄H₃₈N₂O₅, [M+H]⁺ = 435.2856) is confirmed by high-resolution mass spectrometry and its structural integrity by ¹H, ¹³C, HSQC, and HMBC NMR at 600 MHz.

What Differentiates This Boc-Protected Chiral Pyrrolidine from Its Diastereomeric and Unprotected Counterparts?

When compared with the (S)-tert-butyl carbamate diastereomer, where the pyrrolidine C2 stereocentre is inverted, the present R-configured Boc compound displays a distinct retention behaviour on chiral stationary phases. Analytical-scale supercritical fluid chromatography (SFC) on a Chiralpak IA-3 column (4.6 × 150 mm, 3 µm) with a CO₂/isopropanol gradient resolves the two diastereomers with a resolution factor Rs > 2.5, allowing quantification of diastereomeric purity at the 0.1 % (w/w) level. In downstream peptide coupling, the R-isomer affords a bond orientation that places the Boc group on the sterically less congested convex face of the pyrrolidine, reducing the propensity for diketopiperazine formation during subsequent N-deprotection-amidation sequences by a factor of 3–5 compared to the S-isomer, as measured by HPLC peak area of the side product in a model coupling with glycine methyl ester. The corresponding N-unprotected pyrrolidine congener (free amine) shows poor storage stability due to intramolecular aza-Michael addition across the conjugated amide; the Boc group blocks this degradation path and raises the onset of thermal decomposition from 88 °C to 135 °C (DSC, 10 K/min, N₂ atmosphere). Published thermal data for the unprotected form are limited, but accelerated stability studies (40 °C/75 % RH open vial, 7 days) demonstrate <2 % net degradation for the Boc-protected solid versus >35 % for the free amine, as judged by the sum of related substances by UPLC-UV at 210 nm. Under mildly acidic aqueous work-up conditions (pH 3.5–5.0), the adjacent benzylic hydroxy group and the electron-withdrawing amide carbonyl create a conjugation pathway that can promote retro-aldol-type cleavage if the solution temperature exceeds 15 °C for more than 30 min. Process development runs conducted in a 20 L jacketed glass reactor equipped with pitched-blade turbine stirring (tip speed < 2.5 m/s) showed that maintaining the biphasic mixture below 5 °C and using a buffered aqueous phase containing 0.5 M potassium phosphate at pH 4.2 suppresses the formation of the benzaldehyde fragment (detected by headspace GC-MS) below the 0.15 % threshold. The methoxy group on the propyl chain introduces a conformational bias; 2D-NOESY spectra recorded at 298 K in DMSO‑d₆ indicate a gauche conformation between the methoxy oxygen and the amide carbonyl that shields the C2‑C3 bond from base-catalysed epimerisation. When coupling reactions are activated with HATU (1.1 equiv) and diisopropylethylamine (2.5 equiv) in anhydrous N,N‑dimethylformamide at −10 ± 2 °C, the epimerisation at the α-position of the phenyl-propanol moiety remains below 0.5 % (chiral HPLC area percent, monitored at 254 nm), whereas temperatures above +10 °C generate the 1R,2S diastereomer in 3.8–4.2 % yield within 2 h. Pre-drying of the starting aminopropanol hydrochloride with two azeotropic toluene evaporations and storage of the title compound over phosphorus pentoxide in a desiccator at −20 ± 5 °C under argon is essential when ambient relative humidity exceeds 40 %; water uptake promotes partial Boc deprotection and subsequent inter‑molecular carbamate formation, visible as a high-molecular-weight shoulder in size‑exclusion chromatography (SEC) with THF eluent.

Analytical Release Specifications and Batch-to-Batch Consistency Verification

Each production batch is qualified against a panel of validated test procedures that conform to applicable general chapters of the United States Pharmacopeia (USP) and the International Council for Harmonisation (ICH) guidelines. Table 1 summarises the routine release criteria and the referenced analytical instrumentation.

Parameter	Method / Equipment	Acceptance Criterion
Appearance	Visual inspection under D65 illumination	White to off‑white lyophilised powder
Assay (anhydrous, solvent‑free basis)	Reverse‑phase UPLC‑UV (C18, 1.7 µm, 210 nm), external standard calibration	≥ 95.0 % (w/w)
Chiral purity (diastereomeric excess)	SFC‑UV on Chiralpak IA-3 (4.6 × 150 mm, 3 µm), CO₂:MeOH 85:15, 220 nm	≥ 99.0 % de (corresponding to ≤ 0.5 % of the S‑Boc diastereomer)
Related substances (total)	Gradient UPLC‑UV as above, reporting threshold 0.05 %	≤ 2.5 %
Water content	Coulometric Karl Fischer titration (Hydranal‑Coulomat AG)	≤ 0.5 %
Residual solvents (ICH Q3C Class 2 and 3)	Headspace GC‑FID (DB‑624 column, 30 m × 0.32 mm, 1.8 µm film), equilibrated 30 min at 80 °C	Ethyl acetate ≤ 5000 ppm, n‑heptane ≤ 5000 ppm, DMF ≤ 880 ppm, dichloromethane ≤ 600 ppm
Heavy metals (ICP‑MS)	Digestion in closed‑vessel microwave, analysis per USP <232>	Pb ≤ 10 ppm, Cd ≤ 5 ppm, As ≤ 2 ppm, Hg ≤ 1 ppm

Identity confirmation is performed by ¹H‑NMR (600 MHz, CDCl₃) with characteristic resonances for the tert‑butyl singlet at δ 1.42 ppm, the methoxy singlet at δ 3.28 ppm, and the hydroxy doublet at δ 4.72 ppm (J = 4.1 Hz). The ¹³C DEPT‑Q spectrum shows the Boc carbonyl at δ 154.2 ppm. Batch‑to‑batch consistency across 15‑kg campaigns produced in a 50 L Hastelloy reactor yielded assay RSDs below 1.8 % and de RSDs below 0.3 %, reflecting a robust crystallisation‑free isolation process that relies on rapid lyophilisation after a single‑pass silica plug filtration (Davisil® grade 633, 200–425 mesh, 10:1 w/w loading).

Deprotection Chemistry and Cross-Product Comparison Matrix

The Boc group is cleaved under mildly acidic conditions that leave the benzylic hydroxy and the methoxy‑methyl array intact. Treatment with 20 % (v/v) trifluoroacetic acid in dichloromethane at 0–5 °C for 45–60 min achieves quantitative deprotection without detectable O‑desmethylation or benzylic oxidation, provided the reaction mixture is quenched into cold (5 °C) 2 M aqueous sodium bicarbonate. In contrast, the equivalent Cbz‑protected pyrrolidine requires hydrogenolysis over 10 % Pd/C (dry basis, 5 % w/w loading) under 3 bar H₂ pressure, conditions that can partially reduce the phenyl ring if the catalyst is not sufficiently poisoned; this risk constrains the use of the Cbz congener in substrates that lack a reducible aromatic group. The Fmoc‑protected analogue is deprotected with 20 % piperidine in DMF, but subsequent removal of the dibenzofulvene adduct requires repetitive trituration and leads to 1–2 % loss of the hydroxy‑propyl stereocenter due to retro‑Mannich fragmentation, as confirmed by chiral HPLC monitoring over a 4‑h window. Table 2 contrasts these three common protecting‑group strategies as applied to the pyrrolidine intermediate platform.

Feature	Boc (This Product)	Cbz Analog	Fmoc Analog
Grams per litre solubility in THF at 25 °C	~120	~95	~60
Optimal deprotection reagent	TFA/CH₂Cl₂	H₂ (g), Pd/C	20 % piperidine/DMF
Epimerisation observed during deprotection (α‑phenyl position)	<0.2 % under chilled conditions	<0.1 % (non‑acidic pathway)	1.2–2.5 % (via retro‑Mannich pathway)
Compatibility with subsequent solid‑phase peptide synthesis	Excellent; global Boc removal with TFA	Moderate; requires separate hydrogenator	Compatible (standard SPPS cycles)
Residual metal risk	None	Pd ≤ 50 ppm (requires scavenger resin)	Dibenzofulvene‑derived adducts require LC‑MS tracking
Long‑term solid‑state stability (−20 °C, argon, 12 months)	Assay drop <1 %	Partial debenzylation reported at RH >60 %	Dimers form via fulvene‑amine addition; 3–5 % loss