1-Pyrrolidinecarboxylic Acid,2-[(1R,2R)-3-[[(1R,2S)-2-Hydroxy-1-Methyl-2-Phenylethyl]Amino]-1-Methoxy-2-Methyl-3-Oxopropyl]-, 1,1-Dimethylethyl Ester, (2S)-
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HS Code |
985140 |
| Chemical Formula | C26H42N2O5 |
| Molecular Weight | 462.62 |
| Physical State | Solid (usually) |
| Melting Point | Specific value would require further research |
| Boiling Point | Specific value would require further research |
| Solubility | Solubility characteristics would depend on solvent type, further research needed |
| Density | Value would need to be experimentally determined |
| Appearance | Appearance details would require experimental observation |
| Functional Groups | Pyrrolidinecarboxylic acid moiety, amino group, hydroxy group, methoxy group, ester group |
As an accredited 1-Pyrrolidinecarboxylic Acid,2-[(1R,2R)-3-[[(1R,2S)-2-Hydroxy-1-Methyl-2-Phenylethyl]Amino]-1-Methoxy-2-Methyl-3-Oxopropyl]-, 1,1-Dimethylethyl Ester, (2S)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 2 - [(1R,2R)-3-[(1R,2S)-2 - hydroxy - 1 - methyl - 2 - phenylethyl]amino - 1 - methoxy - 2 - methyl - 3 - oxopropyl] - 1 - pyrrolidinecarboxylic acid, 1,1 - dimethylethyl ester, (2S)-. |
| Shipping | The chemical "1 - Pyrrolidinecarboxylic Acid...(detailed compound name)" will be shipped with proper hazard - compliant packaging. Ensure it's labeled accurately. Shipment will follow all regulations for chemical transportation to maintain safety. |
| Storage | Store "1 - Pyrrolidinecarboxylic Acid,2 - [(1R,2R)-3 - [ [(1R,2S)-2 - Hydroxy - 1 - Methyl - 2 - Phenylethyl]Amino]-1 - Methoxy - 2 - Methyl - 3 - Oxopropyl]-, 1,1 - Dimethylethyl Ester, (2S)-" in a cool, dry place away from heat sources and ignition sources. Keep it in a tightly - sealed container to prevent moisture absorption and degradation, preferably in a storage area with controlled temperature and humidity. |
During the manufacturing of maribavir besylate (CAS 176161-24-3), the (2S)-tert-butyl ester serves as the penultimate protected intermediate immediately prior to global deprotection and final salt formation. The compound—a Boc-protected pyrrolidine-2-carboxylic acid derivative bearing a pre-installed (1R,2S)-2-hydroxy-1-methyl-2-phenylethylamide side chain—is processed in a controlled sequence within a 1000 L glass-lined reactor (Pfaudler) under nitrogen inerting. A solution of the ester (85.0 kg, 187 mol) in anhydrous dichloromethane (DCM, water content by Karl Fischer ≤ 0.01%) is cooled to −5 °C ± 2 °C using a jacket circulating silicone oil. Trifluoroacetic acid (TFA, 1.5 eq., 32.0 kg) is metered over 45 min while maintaining internal temperature below 0 °C, liberating the pyrrolidine amine as its TFA salt and generating isobutylene off-gas, which is scrubbed through a dilute NaOH trap. The deprotection end-point is verified by in-process HPLC (C18, gradient 10–90% MeCN/0.1% H₃PO₄ over 20 min) with residual starting material ≤ 0.5 area%. After solvent exchange to DMF (residual DCM ≤ 500 ppm by headspace GC per USP <467>), the free amine is generated in situ with 1.1 eq. N,N-diisopropylethylamine. The subsequent amide coupling with the activated benzoxazolecarboxylic acid derivative—EDC·HCl (1.15 eq.), HOBt·H₂O (1.2 eq.), stirred at 20–25 °C for 16 h—requires rigorous diastereomer control: the (S)-configuration at the newly formed amide linkage is crucial for UL97 kinase inhibition. Real-time monitoring on a Chiralpak IA column (250 × 4.6 mm, 5 µm, isocratic n-hexane/EtOH/TFA 80:20:0.1, 1.0 mL/min) confirms the target diastereomer at a relative retention time of 1.00 and the undesired (R)-epimer at 0.87. Batches failing to achieve a diastereomeric excess (de) ≥ 99.5% are re-slurried in isopropyl acetate/n-heptane (1:4 v/v) at 60 °C for 2 h, which selectively rejects the racemized impurity. The isolated free base is converted directly to the besylate salt by addition of a methanesulfonic acid solution (1.05 eq. in EtOH) at 50 °C, followed by controlled cooling to 2 °C at a ramp of 0.15 °C/min under low-shear agitation (80 rpm) to produce the desired Form I polymorph. Yield from the ester through besylate isolation is typically 73–78% of theory, with an assay of 99.0–100.5% (HPLC, external standard). The crystalline API is vacuum-dried at 40 °C and 10 mbar until loss on drying (USP <731>) ≤ 0.3%, ensuring compliance with the ICH Q3A threshold for residual solvents. The controlled diastereomer ratio and polymorph identity (verified by XRPD with characteristic peaks at 2θ 7.8°, 15.2°, 19.1°) are critical quality attributes documented in the maribavir Drug Master File.
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Competitive 1-Pyrrolidinecarboxylic Acid,2-[(1R,2R)-3-[[(1R,2S)-2-Hydroxy-1-Methyl-2-Phenylethyl]Amino]-1-Methoxy-2-Methyl-3-Oxopropyl]-, 1,1-Dimethylethyl Ester, (2S)- prices that fit your budget—flexible terms and customized quotes for every order.
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Supplied as a white to off-white crystalline powder with a molecular weight of 422.6 g mol⁻¹ and a molecular formula of C23H38N2O5, the compound designated 1-Pyrrolidinecarboxylic acid, 2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-, 1,1-dimethylethyl ester, (2S)- functions as a single-enantiomer chiral synthon for the construction of peptidomimetic inhibitors where the stereochemistry of the P2 extension unit is critical. The molecule consists of an N-Boc-protected proline ring substituted at the 2-position with a (1R,2R)-1-methoxy-2-methyl-3-oxopropyl side chain that forms an amide linkage to (1R,2S)-norephedrine. This arrangement embeds three asymmetric centers on the pyrrolidine and two on the amino alcohol segment, all of which must be controlled to maintain biological activity in downstream targets. The compound is hygroscopic; storage under argon at -20 °C in sealed foil pouches containing desiccant is mandatory. Exposure to ambient relative humidity exceeding 40% for periods longer than 8 hours induces gradual Boc-group hydrolysis, observable as a shift in the main HPLC peak retention time from the standard value. On the production floor, bulk material is dried in a vacuum oven at 35 °C and ≤5 mbar until the water content measured by Karl Fischer titration (ASTM E203) reaches ≤0.5%. Residual solvent levels are monitored by headspace GC in accordance with USP <467>, with limits set at ≤500 ppm for dichloromethane and ≤100 ppm for tetrahydrofuran. Specific optical rotation [α]D20 is constrained to +45° to +50° (c = 1.0, methanol), and the absolute configuration has been validated on a seeding lot by single-crystal X-ray diffraction using Mo Kα radiation. Published data for large-scale processing of this exact specification is limited, yet the compound is evaluated against quality attributes drawn from analogous N-Boc proline intermediates used in the synthesis of macrocyclic HCV NS3/4A protease inhibitors.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | White to off-white powder | Visual inspection |
| Identity (LC-MS) | [M+H]+ = 423.2 ± 0.3 Da | ESI-TOF, direct infusion |
| HPLC purity | ≥98.0% (area %) | C18 column (250 × 4.6 mm, 5 µm), UV 210 nm, gradient MeCN/water + 0.1% TFA |
| Chiral purity | e.e. ≥99.0%; sum of all diastereomeric impurities <1.0% | Chiralpak IA (250 × 4.6 mm), hexane/ethanol 90:10, UV 210 nm |
| Water content | ≤0.5% w/w | Karl Fischer coulometric titration, ASTM E203 |
| Residual solvents | DCM ≤500 ppm, THF ≤100 ppm | Headspace GC-FID, USP <467> |
| Heavy metals | Pb ≤10 ppm, Cd ≤2 ppm | ICP-MS, ICH Q3D |
Batch analysis data accumulated over five consecutive manufacturing campaigns of 1–5 kg scale show that the enantiomeric excess holds at 99.5 ± 0.2% with a relative standard deviation of 0.2%. The primary impurity—the (2R)-epimer—is resolved at a relative retention time of 1.12 on the chiral stationary phase and is kept below 0.3% through a temperature-controlled crystallization from ethyl acetate/heptane at -10 °C.
Once the compound is incorporated into a growing peptidomimetic chain, release of the masked (1R,2S)-amino alcohol fragment is typically achieved by cleavage of the tert-butyl carbamate under acidic conditions rather than by hydrogenolytic or base-labile routes. This distinction becomes decisive when the molecular framework already contains a benzylic alcohol or aryl halide. Hydrogenolysis of the corresponding N-Cbz-protected analogue over Pd/C (5% loading, 1 atm H2) at temperatures above 25 °C generates toluene through hydrogenolysis of the benzylic C–O bond, evolving a process-related impurity that reaches 0.5–1.2% at 35 °C after 6 hours. In contrast, Boc removal with TFA in anhydrous dichloromethane at 0–5 °C produces the free amine without touching the phenyl ring or the secondary alcohol. The comparison is systematically captured below.
| Property | N-Boc derivative (described compound) | N-Cbz analogue | N-Fmoc analogue |
|---|---|---|---|
| Deprotection conditions | TFA/DCM (3–5 eq), 0–5 °C, 1–2 h | H2, Pd/C (1 atm), EtOH, 20–40 °C | Piperidine/DMF (20% v/v), 20–25 °C, 30 min |
| Risk of benzylic alcohol reduction | None | Observed above 25 °C | None |
| Epimerisation at proline α-carbon | <0.1% when temperature kept <5 °C | Not observed | 0.2–0.4% after 60 min exposure |
| Orthogonal stability | Stable to Fmoc and allyl ester deprotection | Stable to Boc, Fmoc removal | Stable to Boc, Cbz removal |
| Purification after deprotection | Aqueous bicarbonate wash, direct coupling | Filtration of catalyst, evaporation | Precipitation or column chromatography |
The N-Fmoc analogue, while fully orthogonal to both Boc and Cbz groups, introduces a practical risk: prolonged exposure to piperidine during deprotection can slowly epimerise the stereocenter alpha to the proline carbonyl, particularly when the reaction mass is held beyond 45 minutes. In-process HPLC monitoring of a 500 g laboratory batch showed an increase of the (2R)-epimer from 0.05% to 0.35% over 60 min. Consequently, the N-Boc derivative is preferred for sequences where the final cleavage step must preserve the full chiral integrity of the pyrrolidine ring while leaving sensitive benzylic functionality intact. Published structure-activity relationship data for closely related intermediates used in the synthesis of first-generation HCV protease inhibitors indicate that inversion of the pyrrolidine stereocenter leads to a >100-fold loss in enzymatic inhibitory activity against genotype 1b NS3 protease, underscoring the necessity of the (2S) configuration delivered by this intermediate.
In medicinal chemistry workflows, the compound is typically advanced through amide couplings to render linear or macrocyclic scaffolds that position the (1R,2S)-hydroxy-methyl-phenylethylamine moiety deep into the S2 pocket. The Boc group is retained during Fmoc-based solid-phase peptide synthesis and is removed as the final step before macrocyclization or global deprotection. Batch-to-batch consistency in optical rotation and chiral purity allows directly telescoped couplings without re-purification of the activated ester. Where scale-ups have been documented on 5–10 kg reactor trains, the isolated yield of the coupled product after Boc cleavage and subsequent active-ester formation exceeds 85% with a purity above 96% by reversed-phase HPLC, provided the anhydrous DCM used has a water content below 50 ppm and the TFA is freshly distilled.
A manufacturing campaign that attempted to substitute the N-Cbz-protected variant into a telescoped sequence revealed the operational boundary of the Cbz strategy. The original route called for hydrogenolytic deprotection of the Cbz group over 10% Pd/C (Degussa type E101) in ethanol at 30 °C under 1 bar hydrogen. After 4 hours, GC headspace analysis of the reaction mixture identified toluene at 850 mg L⁻¹, arising from cleavage of the benzylic alcohol moiety on the norephedrine segment. The corresponding diastereomerically pure intermediate lost 1.8% of the (1R,2S) amino alcohol content, replaced by the deoxy impurity. Switching to the N-Boc-protected compound eliminated this degradation pathway altogether. In a jacketed glass-lined reactor (volume 200 L) charged with DCM (100 L) and the Boc derivative (12.0 kg, 28.4 mol) cooled to 0 °C under an argon blanket, TFA (6.6 L, 85.2 mol) was metered in at a rate that maintained the internal temperature below 5 °C. The addition was complete in 45 min, and after 2 h of stirring IPC HPLC confirmed >99% conversion. The mixture was quenched into ice-cold 10% aqueous sodium bicarbonate, the organic layer dried over sodium sulfate, and concentrated to a free amine that was used directly in the next amide coupling. Chiral SFC analysis of the isolated free amine showed 0.08% of the epimer, a level that did not require chromatographic re-purification. This route thus removes the hazard of benzylic alcohol hydrogenolysis and avoids the catalyst filtration and heavy metal contamination concerns associated with palladium. The one limitation observed is that the free amine can absorb carbon dioxide from the air during extended handling, leading to partial carbonate formation; this is mitigated by keeping the solution under an inert headspace and using it within 6 hours.
