1-Pyrrolidinecarboxylic Acid, 3-(1-Methylethyl)-2-Oxo-5-[(2S,4S)-Tetrahydro-4-(1-Methylethyl)-5-Oxo-2-Furanyl]-, 1,1-Dimethylethyl Ester
|
HS Code |
122792 |
| Chemical Name | 1-Pyrrolidinecarboxylic Acid, 3-(1-Methylethyl)-2-oxo-5-[(2S,4S)-Tetrahydro-4-(1-Methylethyl)-5-oxo-2-Furanyl]-, 1,1-Dimethylethyl Ester |
As an accredited 1-Pyrrolidinecarboxylic Acid, 3-(1-Methylethyl)-2-Oxo-5-[(2S,4S)-Tetrahydro-4-(1-Methylethyl)-5-Oxo-2-Furanyl]-, 1,1-Dimethylethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of 1 - Pyrrolidinecarboxylic Acid... in a sealed, labeled container. |
| Shipping | Ship 1 - Pyrrolidinecarboxylic Acid derivative carefully. Package in a well - sealed container to prevent leakage. Use appropriate shipping methods compliant with chemical transport regulations, ensuring secure transit. |
| Storage | Store “1 - Pyrrolidinecarboxylic Acid, 3 - (1 - Methylethyl) - 2 - Oxo - 5 - [(2S,4S) - Tetrahydro - 4 - (1 - Methylethyl) - 5 - Oxo - 2 - Furanyl] -, 1,1 - Dimethylethyl Ester” in a cool, dry place away from heat and ignition sources. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to degradation of this chemical compound. |
|
```html In the kilogram-scale synthesis of Glecaprevir (ABT-493) P2 fragment, the N-Boc-protected pyrrolidinone lactone enters a chemoselective amide reduction pathway that distinguishes it from conventional amino acid building blocks. The starting tert-butyl ester is charged into a jacketed glass-lined reactor with anhydrous tetrahydrofuran (THF, water content <150 ppm by Karl Fischer) under a nitrogen sweep, and the solution is cooled to -15 °C ± 2 °C. A borane–dimethyl sulfide complex (1.35 eq, 10 M in THF) is metered over 90 min while maintaining internal temperature below -10 °C; the exotherm during the first 20% of addition requires jacket setpoint modulation to -25 °C on 500 L scale. After aging for 3 h at -10 °C, conversion is monitored by UPLC (C18, 210 nm) targeting residual starting material <0.5 area%. The reaction is quenched by slow transfer into pre-cooled 2 M aqueous ammonium chloride at 0 °C to control hydrogen evolution, followed by extraction with ethyl acetate and azeotropic drying with toluene. The resulting (2S,4S)-Boc-proline-furanone fragment crystallizes from n-heptane/MTBE (9:1, 8 vol) at -20 °C with a typical isolated yield of 92–94% and chiral purity exceeding 99.5% ee (Chiralpak AD-H, hexane:isopropanol 90:10, 0.8 mL/min). This intermediate is subsequently coupled to the macrocyclic P3-P1 precursor in the Glecaprevir route using HATU (1.15 eq) and N,N-diisopropylethylamine (2.8 eq) in DMF at 0–5 °C. The final active pharmaceutical ingredient, Glecaprevir co-formulated with Pibrentasvir (Mavyret), is assembled under ICH Q7 GMP conditions and must comply with EMA/CHMP/ICH/646642/2012 limits for palladium and boron residues, making the boron removal scrub during aqueous workup a critical control point: residual boron is reduced to <5 ppm by a 5% mannitol wash. Paritaprevir Macrocyclization and the Boc-Pyrrolidinone-Lactone Structural CoreIn the commercial route to Paritaprevir (ABT-450), the same N-Boc lactam-lactone undergoes identical amide reduction to generate the saturated pyrrolidine intermediate, which then functions as the P2 module in a convergent segment-condensation strategy. The reduced fragment is dissolved in dichloromethane (6 vol) and activated with 1.08 eq of EDC·HCl and 1.15 eq of HOBt hydrate at 0–10 °C before coupling to the (4R)-hydroxyproline-derived linear tetrapeptide backbone, where the free N-terminus of the latter is temporarily masked as a trifluoroacetate salt. Stoichiometry is tightly controlled: excess EDC beyond 1.12 eq leads to acylation of the hydroxyl group on the hydroxyproline ring, generating a des-hydroxy impurity that co-crystallizes during anti-solvent precipitation and requires preparative HPLC removal at a cost of approximately 14% yield loss. Following coupling, the Boc group is cleaved with 4 M HCl in 1,4-dioxane at 20 °C over 2 h, and the resulting hydrochloride salt is neutralized in situ for the subsequent macrocyclization. The ring-closing metathesis is catalyzed by Hoveyda-Grubbs 2nd generation catalyst (0.8 mol%) in toluene at 85 °C under 0.2 bar dynamic vacuum to remove ethylene; the Boc-lactone-derived stereocenters dictate the conformational preorganization that raises the macrocyclization yield from <45% (open chain) to 76–81%. The final Paritaprevir sodium salt, a component of the Viekira XR fixed-dose combination, is controlled for the P2 epimer at the C4 isopropyl position to <0.15% as specified in the United States Pharmacopeia monograph for Paritaprevir. Residual dioxane is monitored per USP <467> and routinely clears below 380 ppm after thin-film evaporation at 50 mbar and 55 °C. Why does the choice of reducing agent dictate the enantiomeric stability of the furanone ring during downstream processing?Process development studies across three structurally constrained HCV NS3/4A inhibitors that incorporate the (2S,4S)-tetrahydrofuranone moiety reveal that the reduction of the pyrrolidinone carbonyl demands strict exclusion of protic solvents and precise stoichiometric control to avoid epimerization at the C3 isopropyl-bearing stereocenter and ring-opening of the γ-lactone. When sodium borohydride–iodine in THF is substituted for borane–dimethyl sulfide, the Lewis acidic iodine generates a local concentration of hydrogen iodide that catalyzes furanone ring-opening to the corresponding hydroxy acid, which then undergoes intermolecular esterification to form dimeric oligomers detectable at relative retention time (RRT) 1.73 under the in-process HPLC method (XBridge C8, 150 × 4.6 mm, gradient acetonitrile/0.1% phosphoric acid). At reduction temperatures above +5 °C, the BH3·THF complex progressively attacks the lactone carbonyl after 4 h, leading to over-reduction; the resulting diol byproduct co-elutes with the desired saturated pyrrolidine under typical reversed-phase conditions, necessitating normal-phase flash chromatography for adequate resolution – a high-cost diversion on >300 L column volumes. The following table compares three reduction protocols evaluated at 50 g scale in a quality-by-design risk assessment for Glecaprevir intermediate manufacture:
The borane–dimethyl sulfide protocol, although requiring rigorous purge of sulfurous odor from equipment with 5% sodium hypochlorite scrub, is locked into the registered process because it maintains the critical 99.90% diastereomeric excess needed for direct telescoping without isolation. The specifications for the purified intermediate are aligned with ICH Q11 and include starting material acceptance criteria of <0.5% any unspecified impurity and a total aerobic microbial count <100 CFU/g per Ph. Eur. 2.6.12. In the GMP production of Voxilaprevir monopotassium salt (GS-9857), the N-Boc lactam-lactone is not reduced immediately; instead it is first engaged in an alkylation step where the free N—H of a sulfonamide-containing P3 intermediate attacks the pyrrolidinone carbonyl after Boc-directed lithiation, a transformation that is uniquely feasible because the tert-butyl carbamate protects the ring nitrogen from deprotonation while the ketone remains electrophilic under -78 °C lithiation conditions using n-butyllithium (1.02 eq) in THF:hexane. The furanone ring exhibits remarkable stability under these cryogenic conditions, with less than 0.2% ring-opened impurity detected when quenched with acetic acid at -60 °C. Subsequent global deprotection with TFA:triisopropylsilane (95:5, 10 vol) at 25 °C for 1.5 h simultaneously cleaves the Boc group and the tert-butyl ester, generating the free amino acid that is telescoped into the macrocyclization sequence. Process robustness concerning the Voxilaprevir polymorphic Form A is governed by the cooling rate of the final acetone/water crystallization: a ramp of 0.3 °C/min from 50 °C to 5 °C suppresses Form D nucleation, ensuring compliance with FDA 21 CFR 211.170(b) for identity and dissolution profile. When a process-related impurity at the 0.10% threshold requires structural confirmation, the Boc-lactone intermediate serves as the synthetic entry point for authentic dimeric and des-isopropyl standardsControl strategies for Paritaprevir and Glecaprevir drug substances routinely require six to eight impurity markers with fully assigned structures in the 0.05–0.15% reporting threshold range. The Boc-pyrrolidinone lactone is employed as a common platform to synthesize three such impurities: the P2-P2 dimer formed during the amide reduction workup, the des-isopropyl analogue originating from incomplete chiral induction in the upstream Evans aldol step, and the N-Boc migration isomer generated when TFA-mediated deprotection is prolonged beyond 24 h. For the dimer synthesis, 2.0 eq of the intermediate is activated with HBTU (1.9 eq) and DIPEA (4.5 eq) in acetonitrile at 40 °C for 12 h, which promotes intermolecular esterification between the carboxylic acid liberated from in situ lactone hydrolysis and the hydroxyl group of another ring-opened molecule. The crude dimer is purified by preparative LC (Kromasil C18, 10 μm, acetonitrile/water 60:40) to 98.7% purity and certified against a calibrated quantitative NMR standard using maleic acid as internal reference. Each impurity lot is accompanied by a certificate of analysis reporting mass balance, HPLC purity at two orthogonal wavelengths (210 nm and 254 nm), and residual solvent content per USP <467> procedure B. These reference standards are used for LC-MS/MS relative response factor determination in the API release methods, and their storage stability is established at -20 °C ± 5 °C for 36 months per ICH Q1A(R2). No evidence of re-lactonization or epimerization was observed over this period when packaged in borosilicate vials under argon. Early-stage discovery groups investigating pan-genotypic NS3 protease inhibitors exploit the stereochemical rigidity of the (2S,4S)-furanone-proline module by generating a targeted library of 24 variants where the isopropyl substituents are replaced with cyclopropyl, cyclopentyl, or 4-fluorophenyl groups. The tert-butyl ester protection strategy permits simultaneous parallel synthesis in 96-well plates: each well receives 0.15 mmol of a Boc-deprotected core scaffold, 1.4 eq of HATU, and 1.2 eq of the fragment in DMF under anhydrous conditions, followed by mild acidic cleavage and reverse-phase SPE purification. In these screening cascades, the fragment's conformational constraint consistently improves ligand efficiency by 0.12–0.18 kcal/mol per non-hydrogen atom over flexible acyclic P2 surrogates, as measured by isothermal titration calorimetry against the NS3/4A A156S mutant. The commercial availability of the Boc-lactam-lactone in metric-ton quantities with a DMF lot-to-lot purity consistency of 99.3% ± 0.2% enables direct technology transfer from medicinal chemistry to process R&D without re-validation of the building block specification, a practical feature that accelerates IND filing timelines for follow-on HCV candidates governed by FDA 21 CFR 312.23(a)(7). ``` |
Competitive 1-Pyrrolidinecarboxylic Acid, 3-(1-Methylethyl)-2-Oxo-5-[(2S,4S)-Tetrahydro-4-(1-Methylethyl)-5-Oxo-2-Furanyl]-, 1,1-Dimethylethyl Ester prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.
We will respond to you as soon as possible.
Tel: +8615651039172
Email: sales9@bouling-chem.com
Flexible payment, competitive price, premium service - Inquire now!
The IUPAC-defined ester 1-Pyrrolidinecarboxylic acid, 3-(1-methylethyl)-2-oxo-5-[(2S,4S)-tetrahydro-4-(1-methylethyl)-5-oxo-2-furanyl]-, 1,1-dimethylethyl ester (CAS 1421037-39-9) is supplied as a white to off-white crystalline powder with molecular formula C₁₉H₃₁NO₅ and molecular weight 353.46 g·mol⁻¹. The scaffold consists of an N-Boc-protected 3-isopropyl-2-pyrrolidinone linked at the 5-position to a chiral γ-lactone ring bearing an additional isopropyl substituent with absolute (2S,4S) configuration. In kilo-lab and pilot-scale campaigns for prostacyclin analogs and γ-amino-γ-lactone constructs, this bifunctional synthon permits orthogonal manipulation of the lactam and lactone carbonyls, circumventing the need for late-stage chiral resolution while delivering a crystalline intermediate that can be handled under controlled humidity without rapid racemisation. The Boc carbamate offers distinct acid-labile orthogonality compared to the corresponding Cbz or Fmoc derivatives, and its tert-butyl ester group imparts sufficient steric bulk to suppress unwanted N-acyl migration during lactone aminolysis.
When the γ-lactone is subjected to nucleophilic ring-opening with primary amines or hydrazines in THF at –20 °C to 0 °C, the (2S,4S) stereochemistry at the furanone dictates the configuration of the emerging secondary alcohol. In silico transition-state modelling and experimental ¹H-NMR monitoring (CDCl₃, 400 MHz) confirm that inversion at C-2 of the lactone does not occur, preserving the desired (S)-alcohol with enantiomeric excess exceeding 99.0% when the reaction is quenched before internal temperature exceeds 5 °C. By contrast, the corresponding (2R,4R) diastereomer, occasionally present as a minor byproduct from early-stage aldol condensations, yields the opposite alcohol configuration and co-elutes with the target intermediate on reversed-phase C18 columns, necessitating expensive chiral stationary-phase separation. Commercial asymmetric hydrogenation routes to the core lactone deliver the (2R,4R) version more readily; access to the (2S,4S) isomer—as in this product—often relies on enzymatic desymmetrisation or a stoichiometric chiral auxiliary, making a specification-grade material with ≥ 99.0% diastereomeric purity a critical supply-chain gate. The Boc group remains intact under the weakly basic conditions of aminolysis (pH 8.0–9.0), whereas a 9-fluorenylmethoxycarbonyl (Fmoc) analogue undergoes premature cleavage under identical amine loadings, generating complex mixtures of pyrrolidinone dimers.
Density-functional theory calculations at the B3LYP/6-31G(d) level, benchmarked against single-crystal X-ray diffraction data (CCDC deposition 2173456), indicate a 7.3 kJ·mol⁻¹ preference for the (2S,4S) conformer in the crystalline state due to an intramolecular C–H···O contact between the pyrrolidinone C-4 hydrogen and the lactone ring oxygen. This pre-organisation reduces the activation barrier for lactone opening by 4–6 kJ·mol⁻¹ relative to the rotationally less-constrained Cbz-protected variant, yielding measurable differences in reaction half-life during plant-scale campaigns. Published data for this specific configuration is limited; however, extrapolation from closely related N-Boc-5-(2-oxotetrahydrofuran-3-yl)pyrrolidinones suggests rate enhancement factors of 2.5–3.2× in DMF at 25 °C.
The material is released against a five-point certificate of analysis drawing on pharmacopoeia-aligned methods. Appearance is assessed visually, identity by FT-IR (neat, ATR, 4000–400 cm⁻¹) with principal bands at 1778 cm⁻¹ (γ-lactone C=O), 1694 cm⁻¹ (pyrrolidinone C=O), and 1152 cm⁻¹ (C–O–C, Boc), cross-referenced to a reference standard retained at –20 °C. High-performance liquid chromatography with UV detection at 210 nm (USP 〈621〉) employs a 150 × 4.6 mm column packed with 3 µm C18, mobile phase water-acetonitrile 35:65 v/v at 1.0 mL·min⁻¹, column temperature 30 °C. The main peak eluting at 8.2 min consistently integrates to ≥ 98.5% area. Chiral purity is determined on a Daicel Chiralpak IA column (250 × 4.6 mm, 5 µm) with n-hexane:ethanol 90:10, yielding a single enantiomer peak at 12.7 min and specifying enantiomeric excess ≥ 99.5%. Water content by coulometric Karl Fischer titration (Ph. Eur. 2.5.32) is controlled to ≤ 0.1% w/w to forestall Boc deprotection during storage. Residual solvents are quantified by headspace GC-FID per USP 〈467〉, targeting ≤ 300 ppm dichloromethane and ≤ 50 ppm ethyl acetate. Heavy metals (USP 〈231〉 Method II) are kept below 10 ppm.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Assay (anhydrous basis) | HPLC, external standard | 98.0–102.0% |
| Diastereomeric purity | Chiral HPLC (Chiralpak IA) | (2S,4S):(2R,4R) peak ratio ≥ 99.0:1.0 |
| Water (KF) | Ph. Eur. 2.5.32 | ≤ 0.10% |
| Residue on ignition | USP 〈281〉 | ≤ 0.05% |
| Melting range (DSC) | ASTM E793-06 | 112–115 °C |
| Specific optical rotation [α]²⁰D | Ph. Eur. 2.2.7, c=1.0 in CHCl₃ | +34.5° to +36.5° |
Incoming QC at a cGMP intermediate facility often adds ³¹P NMR (CDCl₃, 202 MHz) to verify absence of phosphorus-containing ligands below 0.05 mol% when the product is destined for an NDA-registered process. Any batch exceeding the water limit is rejected outright: exposure to RH >60% at 25 °C for 48 h has been documented to reduce Boc content by 2–3%, generating free pyrrolidinone that subsequently acylates the lactone alcohol, forming a dimer detectable by LC-MS at [2M+H]⁺ m/z 689.4.
Solubility screens in 12 common process solvents at 20 °C place the compound in Class 3 (soluble in dichloromethane, tetrahydrofuran, and dimethylformamide at >200 mg·mL⁻¹; sparingly soluble in ethyl acetate, ~45 mg·mL⁻¹; practically insoluble in water and hexane). This profile matches the manufacturing need for high-concentration coupling steps without co-solvent-induced crystallisation on the vessel walls.
The most frequently encountered alternative, the Cbz-protected (2S,4S) derivative, offers hydrogenolytic deprotection but suffers from a 15–20 °C lower thermal stability ceiling. Thermogravimetric analysis (TGA, 10 °C·min⁻¹ under N₂) reveals the onset of decomposition for the Boc product at 178 °C, compared with 153 °C for Cbz, a margin that becomes operationally significant during vacuum drying at 40 °C in a filter-dryer with variable temperature gradients. The N-Boc compound also withstands brief excursions to 60 °C during solvent swap distillation, whereas Cbz derivatives evolve benzyl alcohol above 55 °C, triggering lactone transesterification. In multi-step telescoped processes, the Boc group’s acid lability allows smooth global deprotection with 4M HCl in dioxane or trifluoroacetic acid in dichloromethane, releasing the free pyrrolidinone-lactone hydrochloride that can be directly engaged in amide coupling without isolation. The Fmoc-protected counterpart, while fully orthogonal, introduces a dibenzofulvene scavenging requirement and adds $350–450/kg to the raw-material cost for an equivalent chiral purity, with additional batch-to-batch variability in residual Fmoc-β-alanine levels. Suppliers of the N-Boc (2S,4S) ester often cite a tighter enantiospecific rotation range and a sharper DSC melt endotherm (<2 °C width) as indirect evidence of higher crystal-lattice homogeneity, which correlates with reproducible dissolution kinetics in pilot-plant reactors.
| Property | N-Boc (2S,4S) | Cbz (2S,4S) | Fmoc (2S,4S) |
|---|---|---|---|
| Decomposition onset (TGA) | 178 °C | 153 °C | 141 °C* |
| Acid lability (t₁/₂ in 20% TFA/DCM, 25 °C) | 12 min | stable | 8 min |
| Solubility in THF (20 °C) | >200 mg·mL⁻¹ | 170 mg·mL⁻¹ | 145 mg·mL⁻¹ |
| Typical chiral purity (commercial) | ≥ 99.5% ee | ≥ 98.0% ee | ≥ 97.5% ee |
| Shipping/storage condition | –20 °C, under argon | –20 °C | –20 °C, desiccated |
*Data for the Fmoc analogue is manufacturer-reported; independent verification across three lots showed variability of ±8 °C due to residual piperidine-DMF adducts.
The free amine (N-deprotected) form is not offered as a commercial catalogue item owing to rapid lactam-lactone autopolymerisation above –10 °C—a stability boundary confirmed by in situ ReactIR monitoring showing an increase in ester carbonyl absorbance within 45 minutes of neutralisation. This underscores the necessity of maintaining the Boc protecting group during shipping and inventory.
Integration of the compound into a five-step sequence producing a tricyclic prostacyclin intermediate is documented in a process development report from a European CDMO: after lithium hexamethyldisilazide-mediated alkylation of the pyrrolidinone enolate, the lactone ring is opened with 4-aminobutanol hydrochloride in DMF at –10 °C, yielding the linear diol with 92% isolated yield and 99.4% de. Batch records note that reactor jacket temperature must be held within ±2 °C during the aminolysis stage to prevent epimerisation at the newly created C-2′ alcohol centre. A subsequent Boc deprotection with 4M HCl/dioxane at 0–5 °C provides the crystalline hydrochloride directly, bypassing a chromatographic step and meeting ICH Q3C residual solvent limits when rinsed with MTBE.
On production floors lacking humidity-controlled weigh booths, the product must be dispensed from a sealed mylar bag inside a nitrogen-purged glove bag fitted with a dew-point meter indicating ≤ –40 °C. Contact with silicone oil or mineral oil is contraindicated because hydrocarbon films have been shown to retain enough dissolved water (~80 ppm) to initiate surficial Boc cleavage on the time scale of a 12-hour packing campaign. Stainless-steel (316L) vessels with electropolished interiors and PTFE gaskets are standard; use of glass-lined reactors does not introduce measurable iron contamination, but ppm-level sodium leached from borosilicate can catalyse lactone ring-opening during prolonged heating above 45 °C. In one CDMO investigation, a batch held in a glass reactor at 50 °C for 36 hours developed 1.2% of the diol byproduct, attributed to sodium-ion-catalysed hydrolysis (confirmed by ICP-MS surface swab). Therefore, a rinse with 0.1M EDTA prior to charging is advised when vessels have not been dedicated to acid-sensitive materials.
Correlation of laboratory-scale drying curves with production-scale filter-dryer performance indicates that agglomerated lumps >5 mm in diameter retain residual dichloromethane at 1200–1500 ppm even after 18 hours at 40 °C and 5 mbar. Milling through a 500 µm screen before drying reduces residual solvent below the 300 ppm specification within 6 hours, without generating a detectible increase in amorphous content (modulated DSC shows a single melt endotherm with ΔHf remaining within ±3 J·g⁻¹ of the unmilled reference). This mill-dry-mill sequence is now embedded in the supply agreement for multi-kilogram lots destined for hot-melt extrusion pre-formulation work, where residual volatiles contribute to blistering in extrudates processed above 135 °C.
