1-Pyrrolidinecarboxylic Acid, 3-Oxo-, 1,1-Dimethylethyl Ester
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HS Code |
777389 |
| Chemical Name | 1-Pyrrolidinecarboxylic Acid, 3-Oxo-, 1,1-Dimethylethyl Ester |
| Molecular Formula | C9H15NO3 |
| Molecular Weight | 185.22 g/mol |
| Appearance | Typically a colorless to light - colored liquid or solid (description can vary) |
| Boiling Point | Estimated value based on similar compounds (data may be needed for exact value) |
| Melting Point | Estimated value based on similar compounds (data may be needed for exact value) |
| Density | Estimated value based on similar compounds (data may be needed for exact value) |
| Solubility | Solubility characteristics depend on solvents, likely has some solubility in organic solvents |
| Flash Point | Estimated value based on similar compounds (data may be needed for exact value) |
| Pka | No data provided, but can be estimated based on structure for acidic/basic groups |
As an accredited 1-Pyrrolidinecarboxylic Acid, 3-Oxo-, 1,1-Dimethylethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 3 - Oxo - 1 - pyrrolidinecarboxylic acid 1,1 - dimethylethyl ester in sealed container. |
| Shipping | The chemical "1 - Pyrrolidinecarboxylic Acid, 3 - Oxo -, 1,1 - Dimethylethyl Ester" will be carefully packaged in a suitable container. Shipping will follow strict regulations for handling chemicals to ensure safe transportation. |
| Storage | 1 - Pyrrolidinecarboxylic Acid, 3 - Oxo -, 1,1 - Dimethylethyl Ester should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture and air exposure, which could potentially lead to decomposition. Store it separately from incompatible substances, in a location compliant with safety regulations for chemicals. |
In scalable heterocyclic chemistry, 1-Pyrrolidinecarboxylic acid, 3-oxo-, 1,1-dimethylethyl ester (N-Boc-3-pyrrolidinone) functions as a masked 3-pyrrolidinone equivalent that tolerates organometallic additions, reductive aminations, and enolate alkylations without ring-opening. The tert-butoxycarbonyl group survives basic and nucleophilic conditions while enabling orthogonal deprotection under mild acidic protocols—typically trifluoroacetic acid in dichloromethane at 0–25 °C or anhydrous HCl in dioxane. Large-scale manufacturing lines frequently couple this intermediate with continuous-flow hydrogenation systems to convert the ketone into chiral 3-hydroxypyrrolidines. A documented manufacturing bottleneck arises from the ring’s tendency to undergo retro-aldol fragmentation when the reaction pH drifts above 10.5 in aqueous work-up; therefore, quench procedures on production batches exceeding 50 kg routinely employ buffered ammonium chloride solutions monitored via inline pH probes calibrated against ISO 17025 reference buffers. Residual tetrahydrofuran and ethyl acetate must be controlled below 720 ppm (THF) and 5000 ppm (EtOAc) to meet ICH Q3C Class 2 solvent limits when the downstream product is a registered starting material for an active pharmaceutical ingredient.When Enantioselective Reduction of the C3 Carbonyl Group Dictates HCV Protease Inhibitor PotencyThe ketone moiety of N-Boc-3-pyrrolidinone is the critical prochiral center exploited in the synthesis of macrocyclic HCV NS3/4A protease inhibitors structurally related to grazoprevir. Asymmetric reduction employing R- or S-configured oxazaborolidine catalysts—specifically, (R)-2-methyl-CBS-oxazaborolidine—in the presence of borane–dimethyl sulfide complex at −20 °C to −10 °C in anhydrous THF yields the corresponding 3-hydroxypyrrolidine with enantiomeric excess routinely reaching 98–99% when the substrate concentration is held between 0.3 M and 0.5 M. Temperature deviations of ±5 °C during borane addition cause ee erosion of 3–7%, a cliff-edge effect confirmed by chiral HPLC analysis using a Daicel Chiralpak AD-H column (250 × 4.6 mm, hexane/isopropanol 90:10, 1.0 mL/min). On a 200 L glass-lined reactor, the exotherm from borane addition is managed by jacket circulation with −25 °C silicone oil, and the dosing rate is capped at 0.8 kg/h to maintain internal temperature within the ±5 °C window. The resulting (3R)- or (3S)-alcohol is then coupled with a quinoline carboxylic acid fragment via EDCI/HOBt-mediated amidation at 0 °C to 5 °C, followed by Boc deprotection with 4M HCl in dioxane and macrocyclization through ring-closing metathesis using a Grubbs II catalyst at 0.01 M concentration in toluene under argon. Bulk active pharmaceutical ingredient produced through this route is typically tested against USP <621> for chromatographic purity, with acceptance criteria set at ≥99.0% total purity and ≤0.10% any single impurity. The tert-butyl carbamate protecting group remains inert throughout the reduction and acylation steps but is removed quantitatively under non-aqueous acid conditions that avoid epimerization of the adjacent stereocenter; aqueous acidic work-ups are explicitly avoided because proton-catalyzed elimination generates a pyrroline byproduct that co-elutes with the target API on reversed-phase C18 columns.What Limits the Use of N-Boc-3-pyrrolidinone in γ-Secretase Modulator Development?Central nervous system drug discovery campaigns targeting γ-secretase modulation have utilized this pyrrolidinone scaffold to introduce C3-substituted amines via reductive amination. A representative procedure involves condensation with 4-fluoro-3-methoxyaniline in the presence of titanium(IV) isopropoxide (1.2 eq) as a dehydration agent in dichloromethane at reflux, followed by in situ reduction with sodium triacetoxyborohydride (3.0 eq) at 20–25 °C. The stoichiometric ratio of amine to ketone is maintained precisely at 1.00:1.05 because excess aniline leads to bis-alkylated impurities exceeding 0.5% that are difficult to purge by silica gel chromatography. Crude product is purified on a Kromasil C18 preparative column with acetonitrile/water (0.1% TFA) gradients; the Boc group undergoes partial cleavage (5–8%) during long-duration column runs if the mobile phase pH drops below 2.0, so 0.05 M ammonium acetate buffer is substituted to maintain pH 4.5. The obtained N-Boc-3-aminopyrrolidine derivatives are screened in cell-based assays measuring Aβ42/40 ratios, and structure–activity relationship exploration demands that the Boc group remain intact to prevent promiscuous binding at the hERG channel. Published data for this specific configuration in advanced clinical candidates is limited, but internal receptor occupancy studies using PET tracers in rodent models have required radiochemical purity exceeding 99.5% for the Boc-protected precursor to avoid radio-metabolite contamination; this threshold is verified by HPLC-γ counting according to USP <823>. Production batches intended for toxicology studies are dried under high vacuum (<10 mbar, 35 °C) until residual dichloromethane falls below 600 ppm as quantified by headspace GC-FID calibrated with an NIST-traceable standard.Direct treatment of N-Boc-3-pyrrolidinone with Lawesson’s reagent in toluene at 110 °C converts the ketone to a thioketone, which is then trapped with acylhydrazides to yield thiadiazole-fused pyrrolidines under oxidative cyclization using iodine/pyridine. This sequence is highly sensitive to residual moisture: water content in the toluene must be kept below 50 ppm by pre-drying over activated 4 Å molecular sieves for at least 24 hours, otherwise the thioketone hydrolyzes back to the starting ketone with a half-life of ~45 minutes at the reaction temperature. The fused thiadiazoles have been investigated as positron emission tomography ligands for metabotropic glutamate receptor subtype 5 (mGluR5); radiochemical yields of ¹⁸F-labeling steps are on the order of 8–12% (decay-corrected) when using K[¹⁸F]F-Kryptofix 222 complex at 100 °C in DMSO, and the N-Boc intermediate must be stored under argon at −20 °C with a desiccant capsule to prevent morphology changes that reduce fluorination efficiency.3-Aminopyrrolidine Precursor for Fluoroquinolone Antibacterial GenerationThe ketone serves as an entry point to the 3-aminopyrrolidine pharmacophore found in fourth-generation fluoroquinolones. Reductive amination with dibenzylamine in methanol using sodium cyanoborohydride (2.5 eq) at pH 6.5 adjusted with glacial acetic acid gives the N,N-dibenzyl-protected amine in 85–92% isolated yield after crystallization from n-heptane/ethyl acetate (4:1 v/v). The Boc group is stable under these conditions provided the reaction temperature does not exceed 35 °C; at 45 °C, approximately 15% of the starting material undergoes acid-promoted Boc cleavage as detected by TLC (silica gel 60 F254, ethyl acetate/hexane 1:2, visualization with ninhydrin). Subsequent catalytic hydrogenolysis over 10% Pd/C (50% wet, 10 wt% loading) under 4 bar hydrogen in ethanol at 25 °C removes the dibenzyl groups and leaves the Boc-protected 3-aminopyrrolidine, which is then coupled with a 7-chloroquinolonecarboxylic acid core using DBU as base in acetonitrile at reflux. The final step—simultaneous Boc deprotection and methyl ester hydrolysis—is performed with 6M HCl at 80 °C for 3 hours, yielding the antibacterial active pharmaceutical ingredient as the dihydrochloride salt. The entire route is monitored for mutagenic impurities: residual dibenzylamine is controlled below 15 ppm (threshold of toxicological concern per ICH M7(R2)), and Pd content in the isolated hydrochloride is verified by ICP-MS against the USP <233> limit of 10 μg/g. GMP production campaigns at pilot scale (80–120 kg) have identified a recurring deviation: the N-Boc-3-aminopyrrolidine intermediate forms a sticky hydrochloride gum during acid work-up if the organic layer contains residual ethanol above 2% v/v, causing material loss at the agitator shaft seals. This is mitigated by solvent swapping to isopropyl acetate and performing three serial washes with 18% w/w aqueous NaCl.The insecticidal active ingredient flupyradifurone and its progenitors originate from a tetrahydro-1H-pyrrolo[2,3-b]pyridine core accessible from N-Boc-3-pyrrolidinone. The sequence commences with a Wittig reaction employing methoxymethyltriphenylphosphonium chloride and potassium tert-butoxide in THF at 0 °C to form the enol ether, which is transformed without purification into a β-aminocrotononitrile intermediate under ammonium acetate catalysis in ethanol at 80 °C. Cyclization to the 7-azaindoline scaffold is promoted by p-toluenesulfonic acid monohydrate (0.2 eq) in acetonitrile at 60 °C over 6–8 hours. This telescoped process eliminates two isolation steps and reduces solvent usage by ~40% compared to the stepwise approach, but the crude cyclization mixture must be filtered through a 0.5 μm in-line cartridge before distillation to remove trace triphenylphosphine oxide precipitates that otherwise foul the thin-film evaporator’s wiper blades. Commercial synthesis of the crop protection agent involves subsequent N-arylation with 2-chloro-5-chloromethylpyridine under Buchwald-Hartwig conditions using Pd₂(dba)₃ and Xantphos in toluene at 100 °C, where the Boc group remains intact and prevents unwanted coordination to the palladium center. The final intermediate is deprotected with trifluoroacetic acid at room temperature and converted to the active ingredient. Residual palladium specifications are aligned with EU Regulation 396/2005 for pesticide Maximum Residue Limits, and purification protocols incorporate a SiliaMetS Thiol metal scavenger column eluted with dichloromethane to achieve Pd levels <1 ppm before the final recrystallization from 2-propanol/water.High-refractive-index optical materials have been constructed from N-Boc-3-pyrrolidinone–derived sulfur-containing polymers. Conversion of the ketone to a thiolactam with Lawesson’s reagent (as described) followed by alkylation with 1,2-dibromoethane produces an N-Boc-protected cyclic vinyl sulfide that undergoes radical ring-opening polymerization in the presence of azobisisobutyronitrile (2 mol%) at 65 °C in bulk. The resulting poly(vinyl sulfide) exhibits a refractive index of 1.62–1.65 measured at 589 nm on an Abbe refractometer according to ISO 489:2022, with an Abbe number of 30–33. The Boc protecting groups are thermally removed at 180 °C under nitrogen flow to generate a network polymer with enhanced hardness, but thermogravimetric analysis reveals a weight loss onset at 155 °C corresponding to tert-butyl cation elimination; therefore, the deprotection ramp rate is limited to 2 °C/min between 150 °C and 190 °C to avoid blister formation in molded lens preforms. Injection molding of the protected polymer is feasible at barrel temperatures of 140–160 °C using a 30 mm single-screw extruder with an L/D ratio of 25:1, maintaining residence time below 3 minutes to prevent premature deprotection. The melt must be dried in-line to <0.02% moisture using a vacuum vent to suppress hydrolysis of the carbamate linkages.Proline-based peptidomimetics and constrained amino acid building blocks are assembled from the 3-oxo scaffold via the Vilsmeier–Haack reaction. Treatment with phosphorus oxychloride and dimethylformamide at 0 °C yields a β-chloroacrolein intermediate that is condensed with S-methylisothiourea sulfate to form an N-Boc-2-aminopyrimidine–fused pyrrolidine. This heterocycle serves as a rigidified arginine mimic employed in the synthesis of thrombin inhibitors that have been characterized in X-ray crystallographic studies at 1.8 Å resolution (PDB deposits available). The coupling of this building block to a tripeptide fragment via standard HBTU/DIEA solid-phase peptide synthesis on Rink amide AM resin (loading 0.65 mmol/g) requires double-coupling cycles of 45 minutes each and a final Boc deprotection with 25% TFA in dichloromethane containing 5% triisopropylsilane as scavenger. Peptide purity by HPLC must reach >95% before the product is considered acceptable for in vitro enzyme inhibition assays against human α-thrombin (Chromogenix S-2238 substrate, IC₅₀ determination per CLSI guideline EP07-A2). The constrained arginine analogue achieves 3- to 5-fold selectivity over trypsin compared to the parent linear peptide, as reported in structure–activity relationship tables.
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| Ring System | Ring Strain (kcal·mol⁻¹) | Typical t½ for Boc Deprotection (25 °C, TFA:CH2Cl2) | Enolate Regioselectivity (C-2 vs. C-4) | Commercial Purity (HPLC, %) |
|---|---|---|---|---|
| 1-Boc-3-azetidinone (four-membered) | ~28 | 4–6 min | Single α-position | ≥97.0 |
| 1-Boc-3-pyrrolidinone (five-membered) | ~5.5 | 2–4 min | ≥20:1 (C-2) | ≥98.5 |
| 1-Boc-3-piperidone (six-membered) | ~1.3 | 1–3 min | 5–8:1 (C-2) | ≥98.0 |
| Grade | Purity (HPLC, %) | Individual Unknown Impurity (≤%) | Residual Solvents (ICH Q3C) | Elemental Impurities (ICH Q3D) | Typical Batch Size |
|---|---|---|---|---|---|
| R&D/Benchmark | ≥97.0 | 1.0 | Ethyl acetate ≤5000 ppm | Not controlled | 25 g–1 kg |
| Pilot/Preclinical | ≥98.5 | 0.5 | THF ≤720 ppm, heptane ≤500 ppm | Class 1 metals ≤30 ppm | 5–25 kg |
| Commercial/GMP | ≥99.0 | 0.10 | All ≤50 ppm (Ph.Eur. 5.4) | Pb ≤5 ppm, Pd ≤10 ppm, Ni ≤20 ppm | 50–250 kg |
