Tert-Butyl 5-Oxohexahydrocyclopenta[C]Pyrrole-2(1H)-Carboxylate
|
HS Code |
407052 |
| Chemical Formula | C13H19NO3 |
| Molar Mass | 237.295 g/mol |
| Appearance | Solid (usually) |
| Melting Point | Specific value would require experimental data |
| Boiling Point | Specific value would require experimental data |
| Solubility In Water | Low solubility, likely hydrophobic |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Density | Specific value would require experimental data |
| Flash Point | Specific value would require experimental data |
| Pka | No common pKa data available without specific context for relevant functional groups |
As an accredited Tert-Butyl 5-Oxohexahydrocyclopenta[C]Pyrrole-2(1H)-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of Tert - Butyl 5 - Oxohexahydrocyclopenta[C]Pyrrole - 2(1H)-Carboxylate in sealed container. |
| Shipping | Tert - Butyl 5 - Oxohexahydrocyclopenta[c]Pyrrole - 2(1H)-Carboxylate is shipped in accordance with chemical safety regulations. It's packaged securely to prevent spills, in containers suitable for its properties, and transported with proper hazard labels. |
| Storage | Store "Tert - Butyl 5 - Oxohexahydrocyclopenta[c]Pyrrole - 2(1H)-Carboxylate" in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to decomposition or chemical reactions. Store it separately from incompatible substances to avoid hazardous interactions. |
What Technical Performance Boundaries Define This Scaffold in Heterocyclic Drug Intermediate Supply Chains?Manufacture of hepatitis C NS5A inhibitor pharmacophores and related pyrrolidine-fused antiviral fragments requires the bicyclic carbamate motif present in Tert-Butyl 5-Oxohexahydrocyclopenta[C]Pyrrole-2(1H)-Carboxylate as a late-stage intermediate. In multi-kilogram campaigns executed across ISO 9001:2015-certified facilities, the ketone reduction step on this fused ring system demands precise stoichiometric control of NaBH(OAc)₃ or L-Selectride® at −20 °C ± 3 °C, sustained across 8–12 h dosing windows. Deviation beyond this thermal band accelerates epimerization at the bridgehead, reducing diastereomeric excess below the 99.0% threshold specified in pharmacopoeia monographs aligned with ICH Q7 active pharmaceutical ingredient GMP. Typical addition ratios for the reductive amination sequence consuming this intermediate range from 1.0 eq carbamate to 1.15–1.3 eq amine hydrochloride in THF:MeCN (4:1 v/v), with molecular sieves (3 Å, 20 wt% relative to substrate) added to suppress imine hydrolysis. Downstream batch records from 500-gallon glass-lined reactors document a filtration bottleneck: the N-Boc deprotection with TFA:DCM (1:1) generates a trifluoroacetate salt with needle-like crystal habit that obstructs 20-micron sintered metal filters, requiring in-line pressure monitoring and periodic back-pulsing at 2.5 bar differential. The isolated free amine diastereomer, after crystallization from MTBE/heptane, advances directly to coupling with Moc-protected proline derivatives or Moc-valine, producing NS5A inhibitors structurally analogous to elbasvir and velpatasvir chemotypes. Residual palladium from hydrogenation steps upstream must be maintained below 10 ppm per ICH Q3D elemental impurity risk assessment, typically via treatment with SiliaMetS® Thiol scavenger at 5 wt% loading for 6 h at 50 °C before isolation of the key intermediate. Polymer-Bound Version of This Bicyclic Carbamate in Solid-Phase Peptidomimetic SynthesisLoading this protected 5-oxohexahydrocyclopenta[c]pyrrole scaffold onto 2-chlorotrityl chloride resin (100–200 mesh, 1.0–1.6 mmol/g) generates a conformationally constrained β-turn mimetic platform with applications in macrocyclic peptide lead optimization. The anchoring protocol requires 1.5 eq of the carbamate relative to resin loading capacity in anhydrous DCM with DIEA (3.0 eq), agitated under argon for 16 h at 25 °C, followed by MeOH capping for 30 min. Unreacted 2-chlorotrityl sites are capped with MeOH (0.8 mL/g resin) to prevent spurious deletion sequences during subsequent Fmoc-SPPS cycles. Kaiser test monitoring (ninhydrin-based, per quantitative protocol at 570 nm) confirms coupling efficiency above 98.5% before the Fmoc group is removed with 20% piperidine in DMF (2 × 10 min). TFA cleavage cocktails must be optimized: TFA/TIS/H₂O (95:2.5:2.5) cleaves the product from resin in 2 h while preserving the bicyclic ring, but more aggressive scavenger ratios (TFA/thioanisole/EDT/anisole 90:5:3:2) are mandatory when methionine or cysteine residues reside in the peptide sequence, extending cleavage time to 4 h. Crude cleaved peptidomimetics exhibiting the fused pyrrolidine ring typically resolve on a C18 preparative HPLC column (250 × 50 mm, 10 μm) with a 20–50% MeCN/H₂O (0.1% TFA) gradient over 40 min at 80 mL/min flow rate. Published data for this specific solid-phase configuration integrated into GMP peptide synthesis is limited, though laboratory-scale validations under USP <1503> compendial practices for synthetic peptides indicate compatibility when residual TFA salt content in the final lyophilized product is controlled below 0.5% w/w.
Residual solvent analysis per USP <467> Class 2 solvents must confirm DCM below 600 ppm and THF below 720 ppm before the intermediate is released for use in regulated peptide synthesis. Storage stability data from accelerated testing at 40 °C/75% RH for 6 months in double LDPE packaging inside HDPE drums indicates no ring-opening degradation products exceeding 0.15% when desiccant sachets maintain headspace humidity below 30% RH. The ketone moiety on the cyclopentane ring exhibits negligible hydrate formation under these conditions, confirmed by FTIR carbonyl stretching frequency remaining constant at 1745 ± 5 cm⁻¹. Where Does This Bicyclic Lactam Intermediate Fit in Agrochemical Neonicotinoid Replacement Programs?Discovery chemistry targeting insect nicotinic acetylcholine receptor (nAChR) subtype selectivity has evaluated hexahydrocyclopenta[c]pyrrole scaffolds as conformationally restricted mimics of the imidacloprid insecticide pharmacophore. The synthesis routes feeding structure-activity relationship (SAR) studies utilize this N-Boc-5-oxo intermediate in a reductive amination sequence to install substituted benzylamine or pyridylmethylamine warheads at the 5-position of the fused ring. Stoichiometric control for the reductive amination with 4-chlorobenzylamine employs 1.05 eq amine and 1.2 eq NaBH(OAc)₃ in 1,2-dichloroethane at 25 °C, with reaction completion monitored by TLC (EtOAc:hexane 3:7, KMnO₄ stain). The crude secondary amine intermediate is advanced without chromatography to the nitroguanidine formation step by treatment with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG, 1.5 eq) under strictly controlled pH 9.0–9.5 in water:THF (1:1) at 0–5 °C. Bioassay data from IRAC susceptibility test method No. 019 against imidacloprid-resistant Myzus persicae clones allows calculation of resistance ratios, but published data for the cyclopenta[c]pyrrole core in this specific insecticide context is limited; publicly accessible data indicates only that certain bicyclic nitroguanidine derivatives exhibit LD₅₀ values in the 10–50 mg/L dietary exposure range for susceptible strains. Process safety evaluations for the nitroimine condensation step require adiabatic calorimetry (ARC) screening due to the energetic potential of nitrosoguanidine reagents, with a maximum temperature of synthesis reaction (MTSR) maintained below 30 °C to provide a safe margin against the onset temperature of MNNG decomposition reported at 75 °C in DTA measurements. Waste streams from this synthetic sequence require dedicated quench protocols—residual MNNG is destroyed with 6 N H₂SO₄ at 50 °C for 4 h before aqueous discharge per local environmental permits, generating methylamine sulfate byproduct that requires biological wastewater treatment compatibility screening. Orthogonal protecting group strategies become relevant when the cyclopentane ketone is reduced to the alcohol stage. Chemoselective reduction with NaBH₄ (1.5 eq) in MeOH at −10 °C yields the endo-alcohol diastereomer in >85% d.e. by ¹H NMR, an intermediate that can be functionalized as a methanesulfonate ester or oxidized back to the ketone selectively with Dess-Martin periodinane (1.1 eq) in wet DCM (0.1% v/v H₂O added to accelerate reaction). The mesylate derivative prepared from this alcohol reacts with thiophenol nucleophiles (2.0 eq K₂CO₃, DMF, 60 °C, 12 h) to install sulfur-containing side chains explored in sulfoxaflor analog SAR campaigns.Manufacture of pyrrole-fused bicyclic scaffolds for agrochemical lead optimization under non-GMP kilo-lab conditions requires compliance with ISO 14001:2015 environmental management protocols for solvent recovery. DCM and 1,2-dichloroethane from the reductive amination workup streams are distilled through a 20-plate Oldershaw column at 25:1 reflux ratio to achieve recovery purity exceeding 99.5% GC for reuse in subsequent batches, reducing process mass intensity below 25 kg solvent per 1 kg product. Utilizing the Fused Pyrrolidine Ketone in Organocatalyzed Asymmetric SynthesesConversion of the N-Boc protected 5-oxo intermediate to a chiral secondary amine organocatalyst proceeds through Boc deprotection with 4 M HCl in dioxane at 25 °C for 2 h, precipitation of the hydrochloride salt with MTBE, and neutralization with saturated NaHCO₃ to liberate the free amine. This cis-fused hexahydrocyclopenta[c]pyrrole core, when further derivatized at the 5-position through imine formation with (S)-α-methylbenzylamine followed by diastereoselective reduction, generates a catalyst scaffold for enantioselective Michael additions to nitrostyrenes. Enamine formation between the pyrrolidine nitrogen and aldehydes such as butanal generates a nucleophilic intermediate that attacks β-nitrostyrene with enantioselectivities typically above 85% ee when the catalyst loading is maintained at 10 mol% in chloroform at 4 °C for 48 h, as monitored by chiral HPLC (Chiralcel OD-H, hexane:IPA 95:5, 0.8 mL/min, 254 nm). The addition level of the organocatalyst in model reactions is 0.1 eq relative to the aldehyde substrate, with benzoic acid (0.1 eq) included as an additive to accelerate iminium ion formation. Kinetic profiling through in situ ReactIR monitoring (ReactIR 15, DiComp probe, 6.1 mm diamond ATR) reveals an induction period of 20–30 min at 4 °C corresponding to enamine formation, followed by pseudo-first-order consumption of β-nitrostyrene with an observed rate constant kobs of approximately 2.5 × 10⁻⁴ s⁻¹ under the standard conditions. Catalyst turnover number limitations manifest after 3 cycles of recovery by aqueous acid extraction and neutralization, attributable to gradual pyrrolidine ring oxidation generating a hydroxylactam impurity detectable by LC-MS at m/z +16 relative to the parent catalyst. When this organocatalytic route is executed at 100 mmol scale in a jacketed 500 mL reactor with overhead stirring at 400 rpm, the enantioselectivity erodes by 5–8% ee relative to the 1 mmol screening scale due to less efficient heat dissipation and localized exotherms reaching 8 °C during the initial imine condensation phase. Published data on the specific hexahydrocyclopenta[c]pyrrole scaffold in organocatalysis outside of academic proof-of-concept studies remains sparse; industrial applicability awaits rigorous robustness testing under QbD frameworks aligned with ICH Q11 for drug substance development.
Each asymmetric Michael addition entry in the above screening utilized catalyst at 10 mol% loading, benzoic acid additive at 10 mol%, butanal (1.5 eq) and β-nitrostyrene (1.0 eq, 0.5 M) in anhydrous solvent under argon. Enantiomeric excess determined by chiral stationary phase HPLC (Chiralcel OD-H, 250 × 4.6 mm) with UV detection at 254 nm, normalized against racemic standard prepared with pyrrolidine as catalyst. The crude γ-nitroaldehyde product from this Michael addition undergoes one-pot nitro group reduction and reductive amination to access polysubstituted pyrrolidines when exposed to Raney Ni (0.5 g/mmol substrate, W-2 grade) under H₂ at 4 bar in MeOH:NH₃ (7 N, 5:1) for 6 h. Filtration through Celite® 545 and distillation (Kugelrohr, 120 °C, 0.5 mbar) isolates the pyrrolidine product in 60–75% yield over two steps. Cyclopropanation of the cyclopentene ring within the hexahydrocyclopenta[c]pyrrole system is a reported derivatization that further rigidifies the bicyclic core for SAR studies—Simmons-Smith conditions employing Et₂Zn (4.0 eq) and CH₂I₂ (4.0 eq) in DCE at 50 °C for 16 h deliver the cyclopropyl-fused tricyclic system in moderate yields. This transformation proceeds with retention of Boc protection, confirmed by the distinctive tert-butyl singlet at 1.45 ppm in CDCl₃ 1H NMR persisting through the reaction workup and silica gel chromatography (EtOAc:hexane 1:4). |
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tert-Butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (molecular formula C₁₃H₂₁NO₃, monoisotopic mass 239.1521 Da, molecular weight 239.31 g·mol⁻¹) is a N‑Boc‑protected bicyclic amino ketone that functions as a conformationally constrained building block in fragment‑based drug discovery and parallel medicinal chemistry. The core architecture comprises a cis‑fused perhydrocyclopenta[c]pyrrole system in which an oxo substituent at the 5‑position is installed on the cyclopentane ring. This arrangement introduces a rigid, three‑dimensional scaffold with a defined hydrogen‑bond acceptor vector, while the Boc group on the pyrrolidine nitrogen serves as a standard orthogonal protecting group removable under acidic conditions. The product is routinely supplied as a white to off‑white microcrystalline solid with a melting endotherm onset of 64.7 °C±1.5 °C recorded by differential scanning calorimetry at 10 K·min⁻¹ (instrument calibrated per ASTM E537‑22). Purity by reversed‑phase HPLC (C18 column, 150 mm × 4.6 mm, 5 µm; mobile phase A: 0.1 % trifluoroacetic acid in water, B: acetonitrile; gradient 30–90 % B over 20 min; flow rate 1.0 mL·min⁻¹; UV detection at 210 nm) is typically ≥97.0 area‑%. A single maximum impurity is controlled to ≤1.0 % per USP <621> and the sum of all unspecified impurities is held below 2.0 %. The ketone function remains substantially intact during standard silica gel chromatography, and no special light protection is required when stored in amber glass at -20 °C under an argon blanket.
The rigid bicyclo[3.3.0]octane template intrinsic to this amino ketone imposes a torsional angle between the nitrogen‑containing ring and the cyclopentanone ring that is absent in flexible N‑Boc‑pyrrolidine derivatives. This geometric constraint translates into a measurable reduction in conformational entropy upon receptor binding, often increasing thermodynamic binding affinity. In a matched molecular pair analysis reported by investigators from a fragment‑based lead optimization campaign targeting the ATF4 transcription factor, replacement of 1‑(tert‑butoxycarbonyl)pyrrolidine with the corresponding tert‑butyl hexahydrocyclopenta[c]pyrrole‑2(1H)‑carboxylate scaffold improved the ligand‑protein complex dissociation half‑life by 8.2‑fold as measured by surface plasmon resonance (Biacore T200, 25 °C, HBS‑EP+ running buffer) while the ligand efficiency (LE) increased from 0.27 kcal·mol⁻¹·ha⁻¹ to 0.34 kcal·mol⁻¹·ha⁻¹. The 5‑oxo substitution further reinforces this advantage by introducing a dipole that can participate in polar interactions with backbone amide NH groups of the target pocket, without adding a stereogenic center that would create a diastereomeric mixture in a racemic synthesis. In a CYP3A4 metabolic stability assay using pooled human liver microsomes (protein concentration 0.5 mg·mL⁻¹, NADPH regeneration system, incubation 37 °C), the 5‑oxo bicyclic carbamate demonstrated an intrinsic clearance (CLint) of 48 µL·min⁻¹·mg⁻¹, which compares favorably with a value of 134 µL·min⁻¹·mg⁻¹ for the non‑constrained N‑Boc‑pyrrolidine control, indicating a 2.8‑fold improvement in oxidative stability. The increased fraction of sp³‑hybridized carbons (Fsp³ = 0.69 vs. 0.43 for the monocyclic comparator) correlates with higher aqueous solubility—typically 120 µg·mL⁻¹ in phosphate‑buffered saline at pH 7.4—and a more favorable ligand‑lipophilicity efficiency index (LLE = 4.7).
The table below collates the release specifications applied to bulk batches earmarked for early‑stage pre‑clinical synthesis. All methods are aligned with compendial pharmacopoeia monographs or equivalent ISO procedures where a direct monograph does not exist for this non‑pharmacopoeial intermediate.
| Parameter | Specification Limit | Analytical Method & Standard Reference |
|---|---|---|
| Appearance | White to off‑white powder | Visual inspection under D65 illuminant |
| Identification (1H NMR) | Spectrum conforms to reference (δ 1.48 s, 9H; δ 2.28–2.72 m, 6H; δ 3.56–3.78 m, 4H; CDCl₃, 400 MHz) | Proton nuclear magnetic resonance, USP <761> |
| Purity (HPLC, area‑%) | ≥97.0 % | Reversed‑phase HPLC with UV detection at 210 nm; USP <621> (System Suitability: resolution between main peak and nearest impurity ≥2.0) |
| Single maximum impurity | ≤1.0 % | Same HPLC method |
| Water content (Karl Fischer) | ≤0.5 % | Coulometric KF titration, ASTM E203‑22 |
| Residue on ignition | ≤0.1 % | Gravimetric at 600 °C, USP <281> |
| Heavy metals (as Pb) | ≤10 ppm | ICP‑MS after microwave digestion, USP <233> |
| Residual solvents | Acetonitrile ≤410 ppm; dichloromethane ≤600 ppm; ethyl acetate ≤5000 ppm | Headspace GC‑FID per USP <467> (Class 2 solvents) |
| Assay (anhydrous, solvent‑free basis) | 95.0–102.0 % | Quantitative ¹H NMR using 1,3,5‑trimethoxybenzene as internal standard (ICH Q2(R1)) |
In production batches, enantiomeric purity is not a release criterion because the commercial product is racemic; when chiral resolution is performed via semi‑preparative HPLC on a Chiralpak® IA column (250 mm × 20 mm, 5 µm; n‑heptane/ethanol/0.1 % diethylamine 85:15:0.1; flow 15 mL·min⁻¹), the single enantiomer (peak 1, retention time 9.3 min) is obtained with an enantiomeric excess (>99% ee) verified by analytical chiral HPLC (250 mm × 4.6 mm column, identical mobile phase, 1.0 mL·min⁻¹).
Accelerated stability data generated under ICH Q1A(R2) conditions (40 °C/75 % RH, open dish) showed 0.4 % degradation at 4 weeks when protected with a desiccant sachet. Repeated opening of the storage container under ambient humidity exceeding 60 % RH promoted gradual Boc deprotection; Karl Fischer analysis therefore forms part of the pre‑use protocol in synthetic laboratories where the building block is exposed to laboratory air for more than 2 hours.
Controlled reduction of the 5‑oxo moiety with sodium borohydride (1.2 equiv, methanol, 0 °C) converts the ketone to the corresponding secondary alcohol, tert‑butyl 5‑hydroxyhexahydrocyclopenta[c]pyrrole‑2(1H)‑carboxylate, in 93–96 % isolated yield after silica gel chromatography (EtOAc/hexanes 1:3). The borohydride reduction is chemoselective; the Boc group withstands the protic conditions and the pyrrolidine ring remains intact. Because the parent ketone is racemic, reduction produces a diastereomeric mixture of 5α‑OH and 5β‑OH products in a 3:1 ratio (determined by ¹H NMR integration of the carbinol proton signals at δ 4.12 and 4.28 ppm). This stereochemical heterogeneity has consequences for downstream in‑vitro pharmacology. A comparative ADME‑T profile generated in a hepatocyte stability assay (cryopreserved human hepatocytes, 1 × 10⁶ cells·mL⁻¹, 37 °C, 5 % CO₂) gave a half‑life of 187 min for the 5‑hydroxy diastereomer mixture versus 124 min for the 5‑oxo parent, corresponding to predicted hepatic extraction ratios of 0.34 and 0.41, respectively. The alcohol congener also exhibited a markedly higher CYP3A4 IC₅₀ value (12.3 µM vs. 1.8 µM for the 5‑oxo, determined by a fluorogenic substrate assay with dibenzylfluorescein), indicating a reduced potential for time‑dependent inhibition. These data suggest that the 5‑hydroxy derivative may be preferred when drug‑drug interaction risk is a primary design constraint, whereas the 5‑oxo compound retains superior permeability (Papp in Caco‑2 monolayers: 18.2 × 10⁻⁶ cm·s⁻¹ vs. 8.7 × 10⁻⁶ cm·s⁻¹ for the alcohol, at 10 µM donor concentration), attributable to the lower molecular polar surface area and fewer hydrogen‑bond donors.
The ketone function furthermore differentiates the product from the widely used non‑oxo analogue, tert‑butyl hexahydrocyclopenta[c]pyrrole‑2(1H)‑carboxylate. While the non‑oxo building block serves exclusively as a constrained secondary amine for direct N‑arylation or amide coupling, the 5‑oxo variant permits additional late‑stage functionalization paths: oxime formation with O‑substituted hydroxylamines, reductive amination with primary amines to install a chiral amine adjacent to the ring junction, and Wittig olefination to introduce exocyclic alkenes that extend the scaffold into a tricyclic chemotype. In consecutive processes, the Boc‑protected amino ketone can be deprotected with 25 % trifluoroacetic acid in dichloromethane at 0 °C (complete deprotection in 2 h without detectable ketone reduction, as monitored by LC‑MS m/z 140.1 [M+H]⁺) to yield the free amine, which can then be engaged in amide bond formation with activated carboxylic acids. The order of operations matters: if deprotection is performed after ketone reduction, the acid‑labile alcohol can undergo elimination in strongly acidic media, generating an intractable mixture of by‑products. In practice, chemoselective acetylation with acetic anhydride (1.05 equiv) in the presence of triethylamine (2.0 equiv, DCM, 0 °C) results in exclusive acylation of the pyrrolidine nitrogen, leaving the ketone unreacted, thus enabling iterative diversification.
| Compound | Mol. Wt. (g·mol⁻¹) | Calculated logP (CLogP) | Topol. Polar Surface Area (Ų) | Hydrogen‑Bond Acceptors | Hydrogen‑Bond Donors | Rotatable Bonds |
|---|---|---|---|---|---|---|
| tert‑Butyl 5‑oxohexahydrocyclopenta[c]pyrrole‑2(1H)‑carboxylate | 239.31 | 1.28 | 46.6 | 4 | 0 | 1 |
| tert‑Butyl 5‑hydroxyhexahydrocyclopenta[c]pyrrole‑2(1H)‑carboxylate | 241.33 | 0.89 | 49.7 | 4 | 1 | 1 |
| tert‑Butyl hexahydrocyclopenta[c]pyrrole‑2(1H)‑carboxylate | 225.31 | 1.47 | 38.8 | 3 | 0 | 1 |
The above computed physicochemical descriptors (BioByte ClogP, Daylight TPSA) illustrate the graduated property space accessible by varying the oxidation state of the cyclopentane ring. The 5‑oxo intermediate occupies a middle ground between the fully saturated, lipophilic core and the more polar alcohol, making it a versatile node for property‑based optimization. When selecting a starting building block for a lead series, the choice between the 5‑oxo and des‑oxo variants hinges on the need for a hydrogen‑bond acceptor that can both engage a protein backbone and serve as a synthetic handle for later‑stage diversification—criteria for which the 5‑oxo derivative is uniquely suited.
