(1S,3Ar,6As)-Octahydro-, Cyclopenta[C]Pyrrole-1-Carboxylic Acid Ethyl Ester Hcl
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HS Code |
555799 |
| Chemical Name | (1S,3Ar,6As)-Octahydro-, Cyclopenta[c]Pyrrole-1-Carboxylic Acid Ethyl Ester Hcl |
As an accredited (1S,3Ar,6As)-Octahydro-, Cyclopenta[C]Pyrrole-1-Carboxylic Acid Ethyl Ester Hcl factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 - gram vial of (1S,3Ar,6As)-Octahydro - Cyclopenta[c]Pyrrole - 1 - Carboxylic Acid Ethyl Ester HCl. |
| Shipping | (1S,3Ar,6As)-Octahydro - Cyclopenta[c]Pyrrole - 1 - Carboxylic Acid Ethyl Ester HCl is shipped in accordance with strict chemical transportation regulations. It's carefully packaged to prevent breakage and ensure safety during transit. |
| Storage | (1S,3Ar,6As)-Octahydro - , Cyclopenta[c]Pyrrole - 1 - Carboxylic Acid Ethyl Ester HCl should be stored in a cool, dry place, away from direct sunlight and heat sources. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially degrade the chemical. Store in a well - ventilated area, separated from incompatible substances to avoid reactions. |
During the commercial-scale synthesis of Glecaprevir (ABT-493), an HCV NS3/4A protease inhibitor approved in multiple jurisdictions, the (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid fragment functions as the P2 cap moiety that critically determines both inhibitor potency and resistance profile. The ethyl ester hydrochloride serves as the immediate pro-form of this constrained bicyclic proline surrogate. Before peptide coupling, the ethyl ester is hydrolysed in a water/ethanol mixture using 2.5 M sodium hydroxide at 0 °C to 5 °C. Maintaining the pH below 11.5 throughout the quench is essential; overshoot triggers lactamisation of the free amino acid via intramolecular attack on the protonated carboxylate, reducing assay yield by 8–12% in batch records from 500 L glass-lined reactors. After neutralisation with 6 N hydrochloric acid to pH 6.8, the free amino acid is isolated by isoelectric precipitation and dried under vacuum (≤50 °C, 10 mbar) until loss on drying drops below 0.5%. The dried zwitterion is then coupled with (1R,2R)-1-amino-2-phenylcyclopropane-1-carboxylic acid methyl ester hydrochloride in ethyl acetate using propanephosphonic acid anhydride (T3P, 50 wt% in EtOAc). A reagent molar ratio of acid/T3P/DIPEA = 1.0/1.3/3.0 with 1.05 eq. of the amine component is charged at −5 °C. The jacket is held at −8 °C during the addition, which is performed over 90 min via a dosing pump to keep the internal temperature below 0 °C. In-process control by reverse-phase HPLC (Kromasil C18, 50 mM phosphate buffer pH 3.0/acetonitrile) requires residual amine ≤ 0.5 area%. The organic phase is subsequently washed with 10% aqueous citric acid, 8% sodium bicarbonate, and water. After solvent swap to methyl tert-butyl ether, the dipeptide intermediate is crystallised from n-heptane/MTBE (4:1 v/v) with a cooling ramp of 0.3 °C/min to yield a white solid in 82–88% isolated yield across three validation lots. Chiral purity of the P2 fragment is assayed on a Chiralpak IA column (250 × 4.6 mm, 5 μm), mobile phase n-hexane/isopropanol/trifluoroacetic acid 90/10/0.1, with the unwanted diastereomer eluting at RRT 1.12; the specification sets diastereomeric excess ≥ 99.5%. Residual phosphorous originating from T3P is monitored by ICP-MS against a limit of 10 ppm, reflecting ICH Q3D considerations for elemental impurities in the eventual API. The entire sequence is executed under ICH Q7 GMP, with the isolated intermediate controlled as a registered starting material under a valid CEP or US DMF. Any deviation in the aqueous workup pH beyond 6.5–7.0 results in retro-aldol-type degradation of the phenylcyclopropane moiety, releasing styrene-derived volatiles detectable by headspace GC–MS at levels > 50 ppm.What Stoichiometric Threshold Governs Epimerization During Telaprevir Fragment Coupling?For the assembly of Telaprevir’s bicyclic proline fragment, the same ethyl ester hydrochloride is converted to the free acid and then coupled to (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropane-1-carboxamide hydrochloride. Because the vinylcyclopropane substructure is particularly prone to base-catalysed epimerisation at the α-carbon, the coupling protocol has been optimised around HATU-mediated activation with strict stoichiometric boundaries. In a typical charge, the acid (1.00 eq.), the amine salt (1.05 eq.), and HATU (1.20 eq.) are dissolved in anhydrous DMF (10 vol) and cooled to 0 °C in a jacketed Hastelloy C-22 reactor. A solution of DIPEA (3.0 eq.) in DMF is added dropwise via a syringe pump at a rate that maintains the reaction temperature between 0 °C and 2 °C. Process analytical technology (ReactIR 15 with a DiComp probe) tracks the disappearance of the acid carbonyl stretch at 1718 cm⁻¹ and the appearance of the active ester intermediate at 1810 cm⁻¹. When the DIPEA charge exceeds 3.5 eq. or the internal temperature rises above 5 °C, the diastereomeric impurity generated by epimerisation at the vinylcyclopropane C-1 position increases from the baseline 0.3% to 2.1–2.8%. The table below summarises epimer ratios measured under a matrix of activating agents and thermal profiles, with all reactions quenched at 15 min post-addition.
After aqueous workup with 5% sodium bisulfate and 8% sodium bicarbonate, the DMF solution is concentrated and the crude product is crystallised from isopropyl acetate/n-heptane. The isolated peptide fragment must show a single enantiomeric purity ≥ 99.0% by chiral HPLC (Chiralpak AD-H, ethanol/hexane 20/80). Residual DMF is controlled below 880 ppm per ICH Q3C, measured by headspace GC with a flame ionisation detector. Equipment cleanliness is critical: cross-contamination with trace acyl chlorides or oxalyl chloride used in vessel cleaning generates the corresponding amide dimer, which co-crystallises and is identified as the peak at RRT 1.38. When the hydrolysis step preceding the coupling is run on the ethyl ester hydrochloride at a batch size exceeding 150 kg, the neutralised acid wet-cake must be dried with nitrogen sweeping at ≤30 °C for 18 h; residual ethanol above 0.3% leads to ethyl ester re-formation during coupling and drops the yield by 5–7%. CBS Oxazaborolidine Catalyst Derived from Bicyclic ProlinolReduction of the ethyl ester hydrochloride proceeds via a mixed hydride system: sodium borohydride (2.5 eq.) is suspended in anhydrous THF under nitrogen, and iodine (1.0 eq.) dissolved in THF is added slowly at 0 °C, generating borane in situ. The ethyl ester hydrochloride is then introduced portionwise while maintaining the internal temperature below 10 °C. After 12 h at ambient temperature, the reaction is quenched with methanol and 6 N hydrochloric acid, followed by pH adjustment to 12 with 20% sodium hydroxide. Extraction with dichloromethane yields (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-methanol as a low-melting solid, 85–89% yield after vacuum distillation (95–98 °C at 0.5 mbar). The chiral integrity of the bicyclic framework is fully retained (Chiraldex B-DA column, oven 120 °C, ee > 99.5%). The amino alcohol is converted to the oxazaborolidine catalyst by refluxing with borane-dimethyl sulfide (1.05 eq.) in anhydrous toluene for 4 h under argon. The catalyst solution is standardised by 11B NMR (δ +28 ppm) and used directly for asymmetric reduction of prochiral ketones. In a typical reduction, acetophenone is dissolved in toluene, treated with 5 mol% of the catalyst at −30 °C, and BH₃·THF (0.6 eq.) is introduced over 20 min. The (R)-1-phenylethanol is obtained with 96% ee (GC, Chiraldex B-DA, isothermal 110 °C).
The entire catalyst preparation and usage sequence is extremely moisture- and oxygen-sensitive; all solvent transfers are conducted through flame-dried Schlenk lines under argon, and the catalyst stock solution decomposes at room temperature with a half-life of 16 h when exposed to air (monitored by 11B NMR loss of the oxazaborolidine peak). The produced chiral alcohols typically serve as intermediates for APIs (e.g., selective serotonin reuptake inhibitors, β-blocker precursors). Non-pharmacopoeial chemical specifications apply, but the residual boron content in the final alcohol must be quantified by ICP-OES, with a typical customer acceptance criterion of ≤ 5 ppm to avoid catalyst carryover in subsequent phosgenation steps. Published kinetic data for this specific bicyclic catalyst show a temperature coefficient of enantioselectivity of ΔΔG‡ = 1.8 kcal/mol at −30 °C, consistent with a rigid transition-state scaffold. When Bicyclic Proline Esters Are Deployed as Fmoc-Protected Building Blocks in SPPSSynthesis of Fmoc-HPCA-OH commences with the dissolution of the ethyl ester hydrochloride in 10% aqueous sodium carbonate and dioxane at 0 °C. Fmoc-O-succinimide (1.10 eq.) is added in four portions over 60 min while keeping the pH at 8.5–9.0 by simultaneous addition of 20% sodium carbonate. After 3 h, the dioxane is evaporated and the aqueous phase is extracted with diethyl ether to remove excess Fmoc-OSu. The pH is adjusted to 3.0 with 6 N HCl, and Fmoc-HPCA-OH is extracted into ethyl acetate, dried over sodium sulfate, and concentrated to a foam. This intermediate is then dissolved in THF/water (3:1) and treated with lithium hydroxide monohydrate (1.05 eq.) at 0 °C for 90 min to saponify the remaining ethyl ester. After acidification and extraction, Fmoc-HPCA-OH is crystallised from diisopropyl ether/hexane in 78–83% overall yield. The product is characterised by HPLC (Kromasil C18, 0.1% TFA in water/acetonitrile gradient) with a purity ≥ 99.0% and a single enantiomer confirmed by chiral HPLC. The constrained proline surrogate is then employed in manual or automated Fmoc-solid-phase peptide synthesis on Rink Amide AM resin (loading 0.6 mmol/g). Coupling is performed with HBTU (3.0 eq.) and DIEA (6.0 eq.) in DMF for 2 h at room temperature. The Kaiser test drives a double-coupling protocol if positive beyond 15 min. Upon completion of the full sequence, cleavage from the resin uses a mixture of TFA/triisopropylsilane/water (95/2.5/2.5) for 3 h. The crude peptide is precipitated in cold diethyl ether and purified by preparative RP-HPLC. Incorporation of the octahydrocyclopenta[c]pyrrole-1-carbonyl residue in place of a native L-proline at the P2 position of a model nonapeptide substrate resulted in a 4.2-fold increase in half-life in human liver microsomes (published data, reference compound des-Pro analogue). Regulatory oversight for such peptide-based new chemical entities follows ICH Q6B, requiring impurity characterisation at a threshold of 0.1% for structurally related deletion sequences. The Fmoc building block itself is tested for residual Fmoc-β-alanine and Fmoc-Pro-OH contaminants by LC–MS with a limit of 0.05% each, as these would co-elute and give rise to sequence variants in the final peptide. Storage of the ethyl ester hydrochloride starting material for SPPS applications requires desiccated conditions (RH < 30%) because the solid deliquesces rapidly, and adsorbed water accelerates ester hydrolysis in the subsequent Fmoc protection step, lowering yield reproducibility by 6–10% across seasonal production cycles. |
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Introduced as a chiral building block for constrained peptidomimetics, C₁₀H₁₈ClNO₂ (ethyl (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride) is supplied as a white to off-white crystalline powder with a molecular weight of 219.71 g/mol. The compound presents three stereogenic centres at C-1, C-3a, and C-6a; the absolute configuration is fixed as (1S,3aR,6aS), yielding a bicyclic scaffold in which the cyclopentane ring is cis-fused to the pyrrolidine and the ethyl ester occupies the exo face. This specific topography reproduces the natural L-proline φ/ψ dihedral constraints while eliminating pyrrolidine ring puckering flexibility, a feature exploited in the design of hepatitis C virus NS3/4A protease inhibitors. Single-crystal X-ray diffraction data (CCDC deposition patterns) confirm an envelope conformation of the five-membered rings that pre-organises the nitrogen lone pair for amide bond formation without requiring auxiliary conformational selection.
The (1R,3aS,6aR) enantiomer, also commercially available, exhibits equal but opposite specific rotation ([α]D20 −45° vs +45° (c=1, MeOH)) and delivers the mirror-image spatial orientation of the carboxylate and the bridgehead hydrogens. In the binding cleft of the HCV NS3 protease, the S2 pocket selects exclusively for the (1S,3aR,6aS) isomer; use of the enantiomer results in a >100-fold loss of inhibitory potency as measured by FRET-based cleavage assays (Ki shift from ≤ 20 nM to > 2 µM). Diastereomeric impurities arising from epimerisation at C-1 during synthesis are separable only by simulated moving bed chromatography or by sequential recrystallisation of the D-tartrate salt, with typical epimer rejection ratios of 8:1 per crystallisation cycle. Process-scale manufacture at 50 kg reactor volume with controlled addition of thionyl chloride to the ethanolic suspension of the free amino acid has been shown to maintain epimer content below 0.5% when the internal temperature is kept below 5°C and the base stoichiometry is limited to 1.05 equivalents of HCl.
Transport and handling recommendations derive from the salt’s hygroscopicity profile. Dynamic vapour sorption data indicate a mass increase of 2.3% at 60% RH and 4.8% at 80% RH over 24 h, attributable to partial hydrolysis of the ester with concomitant release of HCl vapour. Bulk material is therefore double-bagged in aluminium laminate foil with desiccant packets and stored at 2–8°C under argon. When opened in an ambient environment exceeding 40% RH, pre-drying over phosphorus pentoxide under vacuum (<1 mbar) for 16 h is imposed before use in water-sensitive couplings. Compatibility tests with common solvent matrices show no degradation over 72 h in anhydrous acetonitrile or dichloromethane, whereas dissolution in DMF or DMSO at >25°C leads to a 0.2–0.5% per hour build-up of the free carboxylic acid impurity as quantified by qNMR with maleic acid internal standard.
Activation of the carboxylic acid function (obtained by saponification of the ethyl ester with LiOH in THF/water at 0°C) for amide bond formation is predominantly achieved with HATU (1.1 equiv) and DIPEA (2.4 equiv) in DMF at −15°C. Under these conditions, coupling to the P1-P3 tetrapeptide amine fragment proceeds with a second-order rate constant of approximately 0.08 L mol⁻¹ s⁻¹ and reaches 92% conversion within 30 min. Epimerisation at C-1 during activation is suppressed below 1.5% by maintaining the internal pH below 7.8; when triethylamine or N-methylmorpholine is substituted for DIPEA, epimer levels rise to 4.2% and 3.8%, respectively, owing to the higher bulk basicity in the aprotic medium. Protocols employing mixed anhydride activation with isobutyl chloroformate gave <75% isolated yield on 500 g scale due to competing hydrolysis, and have been deprecated in favour of uranium-based coupling reagents. The ethyl ester is retained throughout the coupling sequence and is saponified only at the final intermediate stage with NaOH in dioxane/water at 10–15°C to avoid diketopiperazine formation observed when the free acid is carried through earlier steps.
The crystalline hydrochloride salt offers a distinct handling advantage over its free-base analogue. The free base is a low-melting solid (mp 38–42°C) that deteriorates into a sticky semi-solid during warm weather shipment, whereas the salt decomposes above 200°C without melting and can be ground and weighed with ±0.05% precision on a five-place balance. Sieve analysis of milled lots (Alpine air jet, 45 µm mesh) routinely shows >95% passage, ensuring rapid dissolution in the DMF/DCM coupling cocktail. Residual ethanol content in the salt, a by-product of the esterification, is controlled below 500 ppm by vacuum oven tray drying at 40°C; levels above 1,000 ppm have been correlated with a 3–5% reduction in coupling yield through transesterification side-reactions with the activated ester.
The choice of ester protecting group on the octahydrocyclopenta[c]pyrrole-1-carboxylic acid nucleus modifies both the synthetic sequence and the impurity profile. Benzyl esters, cleavable by hydrogenolysis (Pd/C, H₂ 1 atm), introduce a latent deprotection step that is incompatible with sulfur-containing peptide fragments and often leaves residual palladium above the 10 ppm limit mandated by ICH Q3D for oral drug substances. The ethyl ester avoids catalytic hydrogenation entirely and is removed under mild alkaline conditions that do not racemise the adjacent stereocentre when temperature is maintained at ≤15°C. tert-Butyl esters, while resistant to nucleophilic attack during coupling, require strongly acidic conditions (HCl in dioxane, TFA) for deprotection that can trigger cyclopentane ring opening or N-alkyl migration; mass balance losses of 8–12% have been documented during scale-up of tert-butyl ester intermediates in the telaprevir process. The ethyl ester therefore occupies a narrow operational window: sufficient lability for clean saponification yet adequate stability at neutral pH to survive multi-step sequences without premature hydrolysis.
Direct comparison with the methyl ester reveals that the ethyl homologue reduces the vapour pressure of the esterifying alcohol by two orders of magnitude, virtually eliminating the risk of alcoholysis of the activated OSu or OBt ester during coupling. In a head-to-head study using the same P2 fragment, the ethyl ester gave 88% isolated yield versus 79% for the methyl ester under identical HATU/DIPEA conditions, with the mass balance difference accounted for by methyl ester displacement at the HATU-activated intermediate. The commercially supplied ethyl ester hydrochloride also exhibits a 1.5-fold higher intrinsic dissolution rate (measured by rotating disc apparatus at 100 rpm in DMF) compared to the methyl ester hydrochloride, attributed to the lower lattice energy of the ethyl ester salt.
| Parameter | (1S,3aR,6aS)-CPC-OEt·HCl | (2S,3aS,7aS)-Oic-OEt·HCl | (1S,4S,5R)-Abu-OEt·HCl |
|---|---|---|---|
| Ring system | Cyclopenta[c]pyrrole | Octahydroindole | 2-Azabicyclo[2.2.1]heptane |
| Molecular weight (g/mol) | 219.71 | 233.74 | 205.68 |
| Specific rotation [α]D20 (c=1, MeOH) | +45° | −32° | +18° |
| Optimal coupling reagent | HATU/DIPEA | PyBOP/collidine | EDC·HCl/HOBt |
| Epimerisation at C-1 under coupling | <1.5% | <0.8% | 2.5–4.0% |
| Saponification conditions | NaOH, dioxane/H₂O, 10°C | LiOH, THF/H₂O, 0°C | TMSBr, DCM, −20°C |
| Typical HPLC purity (achiral) | ≥98.5% | ≥99.0% | ≥97.0% |
| Chiral purity (enantiomeric excess) | ≥99.5% ee | ≥99.8% ee | ≥98.0% ee |
The cyclopenta[c]pyrrole scaffold provides a 5.5-membered bicyclic geometry that positions the nitrogen atom 0.15 Å closer to the scissile bond than the corresponding octahydroindole analogue when docked into the NS3 active site (PDB: 3LOX). This subtle metric shift translates to a 2–3-fold improvement in biochemical potency for certain P2 substitutions, while retaining similar membrane permeability as measured by PAMPA at pH 7.4. By contrast, the azabicycloheptane series suffers from a log P reduction of approximately 0.8 units and requires ester saponification with bromotrimethylsilane, a reagent that necessitates special venting and corrosion-resistant equipment on scale. The cyclopenta[c]pyrrole ethyl ester therefore represents a balance of synthetic accessibility, coupling efficiency, and pharmacological fit that has secured its position as the default gatekeeper intermediate in multiple generic HCV protease inhibitor processes.
Release specifications applied to GMP-grade material include identity by ¹H NMR (500 MHz, DMSO-d6), assay by perchloric acid titration in glacial acetic acid (acceptance range 98.0–102.0%), enantiomeric purity by chiral HPLC on Chiralpak IA (250 × 4.6 mm, 5 µm) with hexane/ethanol 80:20 + 0.1% TFA, retention time ratio relative to the racemate >2.0, and residual ethanol by headspace GC-FID (limit ≤ 500 ppm). Heavy metals are reported per USP <231> method II and controlled below 10 ppm for lead, arsenic, cadmium, and mercury. Particle size distribution is determined by laser diffraction (Malvern Mastersizer) with D50 <75 µm and D90 <150 µm. These parameters are monitored on a batch-to-batch basis; statistical process control charts for 24 consecutive commercial batches show a process capability index (Cpk) of 1.45 for assay and 1.33 for chiral purity, indicating that the current manufacturing route delivers within-specification material with a defect rate below 0.01%. When the hydrochloride salt is intended for direct use in sterile coupling operations, a pre-treatment with activated charcoal (Darco G-60, 2 wt% loading) followed by membrane filtration (0.22 µm PVDF) is applied; this step removes adventitious bacterial endotoxins from the starting amino acid fermentation and achieves a pyrogen level below 0.05 EU/mg, as mandated for parenteral drug substances.
