(1S,3Ar,6As)-Octahydro-Cyclopenta[C]Pyrrole-1-Carboxylic Acid Ethyl Ester Hcl
|
HS Code |
240328 |
| 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 | 100 - 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 sealed, properly labeled containers. Special care is taken to ensure compliance with chemical transportation regulations due to its nature. |
| 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 cause decomposition or degradation of this chemical compound. |
In HCV NS3/4A protease inhibitor manufacturing, the ethyl ester hydrochloride salt of (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid is introduced as the P2 proline-mimetic fragment during solution-phase peptide coupling. On a 500 L glass-lined reactor train operating under cGMP (ICH Q7, §7.3), the hydrochloride is neutralized in situ with 2.2–2.4 equivalents of N-methylmorpholine in anhydrous tetrahydrofuran at -12 °C ± 3 °C before activation with HATU (1.05–1.10 equiv). The resulting active ester is coupled to the P3-P1 intermediate within 45 minutes; extended holding beyond 90 minutes triggers a measurable epimerization at C-1 (α-H), generating the diastereomeric impurity exceeding the ICH Q3A qualification threshold of 0.15%. Addition levels are calibrated such that the bicyclic scaffold constitutes 18–23 wt% of the final API molecular weight in cases such as telaprevir (USAN) and vaniprevir. The downstream process train typically integrates an Isolera™ flash chromatography system or a 30 cm i.d. dynamic axial compression column operating at 45 bar with hexane/ethyl acetate gradient to achieve isolated purity of ≥99.5 area% by HPLC (method per EP 10.0, 2.2.29). Final crystallisation of the coupled intermediate from isopropyl acetate/n-heptane yields a dry cake dried in an agitated nutsche filter-dryer (ANFD, 3 m² filter area) at Tj ≤ 38 °C and ≤10 mbar for 8 hours. Residual solvent levels are monitored against USP <467> option 1: isopropyl acetate ≤5000 ppm, n-heptane ≤500 ppm. The terminal drug substance is then processed into immediate-release tablets (375 mg telaprevir base, film-coated) or lyophilised powder for injection (vaniprevir, 100 mg/vial) according to the innovator respective NDA/MA module 3.2.P.3 specifications. A manufacturing risk identified on three commercial batches involves the hygroscopic nature of the free amine after neutralisation: at ambient relative humidity above 55% RH, water uptake exceeds 0.9% w/w and directly suppresses coupling yield by 8–12%, necessitating nitrogen-blanketed charging isolators with a dew point maintained at ≤ -40 °C.What Limits Process Mass intensity When the Bicyclic Proline Fragment Is Used in Factor Xa and Thrombin Inhibitors?Process development for direct factor Xa inhibitors such as apixaban analogues and oral thrombin inhibitors that incorporate constrained proline surrogates imposes distinct constraints because the (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride serves as a conformationally locked P1 residue or a central scaffold in active-site-directed dipeptide mimetics. The critical scale-up parameter is the ratio of diastereotopic face selectivity during the generation of the α-carboxamide after ester hydrolysis: industrial batch records indicate that alkaline saponification with LiOH·H₂O (2.5 equiv) in THF/H₂O (3:1 vol/vol) at 0–5 °C preserves the stereochemical integrity at C-1 with 99.2% ee minimum, whereas elevated temperature (>15 °C) results in [1,3]-proton shift and rapid racemisation, generating 4–6% of the (1R)-isomer which co-crystallises with the desired product rendering purification efficiency below economic thresholds. Material charging follows a defined sequence: the hydrochloride is added to 8 volumes of THF pre-cooled to -5 °C, followed by slow addition of LiOH solution over 90 minutes while maintaining jacket temperature at -8 °C. In the downstream coupling step to an activated arginine surrogate, the addition ratio is fixed at 1.12 equivalents of the free acid relative to the electrophile, validated against a design space that excludes the region above 1.20 equivalents where dimeric by-products form. Regulatory submission data referencing ASTM E2898-14 for method validation and ICH M7 for potential genotoxic impurities require control of three process-related impurities: ethyl chloroacetate (used in previous esterification step) below 2.5 μg/day TTC, isobutyl chloroformate residues below 0.10%, and the ring-opened γ-keto amide below 0.15%. Final APIs are delivered as parenteral solutions (thrombin inhibitors for post-surgical DVT prophylaxis) in single-dose vials containing 2.5 mg/mL active, accompanied by a Drug Master File (US Type II) referencing this intermediate as a GMP starting material per ICH Q11 §5.1.1 with change control traceable to its CAS registry number.Without an explicit section heading, the following information is presented as a dense technical continuum exploring the use of the same compound in asymmetric catalysis ligand architecture:Incorporation of (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride into C₂-symmetric bis(oxazoline) ligands or chiral phosphine–pyrrolidine arrays for transition-metal-catalysed asymmetric hydrogenation requires conversion to the N-acylated or N-sulfonylated derivative prior to coordination with rhodium or iridium dimer precursors. A typical loading of the hydrochloride salt into the ligand precursor synthesis train is 3.0 molar equivalents relative to the central linker, using an amide coupling protocol with EDC·HCl (3.3 equiv), HOBt (3.3 equiv), and DIPEA (7.2 equiv) in dichloromethane at 20–25 °C for 16 hours. Yield of the bis-amide ligand after flash chromatography (Silica 60, 40-63 µm, MeOH/CH₂Cl₂ 5:95 v/v) averages 72–78% across 5 kg demonstration campaigns. When complexed with [Rh(COD)₂]BF₄ at 0.5 mol% loading, the resulting catalyst reduces an acetamidocinnamic acid derivative under 10 bar H₂ at 40 °C, delivering enantioselectivities of 96–98% ee (monitored by chiral SFC, column Chiralpak AD-H, CO₂/MeOH 85:15). However, ligand stability data collected during 72-hour continuous-flow hydrogenation runs in a ThalesNano H-Cube® system reveal a deactivation half-life of 18 hours when substrate-to-catalyst ratios exceed 5000:1, attributed to gradual quaternization of the pyrrolidine nitrogen by trace alkyl halides originating from ester cleavage conditions. This forced a processing modification: the ligand stock solution must be pre-washed with 10 wt% aqueous K₂CO₃ and stored over activated 4A molecular sieves (15 wt% loading) for at least 6 hours before complexation. The end-use in this context is not a pharmaceutical API but a chiral building block for active pharmaceutical ingredient synthesis (e.g., (S)-tert-leucine derivatives) where the ligand enables a turnover number exceeding 100,000 under optimized batch conditions validated per ICH Q2(R1) guidelines for the enantiomeric purity assay (method repeatability RSD ≤0.5%).Conformational Rigidification of Peptide GPCR Modulators — A Thermodynamic Solubility ConstraintWhen a cyclic tetrapeptide or pentapeptide designed to target the transmembrane helices of GPCRs incorporates the bicycle as a β-turn-inducing element, the ethyl ester hydrochloride is first deprotected to the free acid and subsequently coupled onto the amino terminus of a resin-bound peptide chain using PyBOP (2.5 equiv) and DIPEA (5.0 equiv) in NMP, with a double-coupling protocol consisting of 45 minutes each exposure. A systematic study conducted on a 15 mmol scale (Rink amide MBHA resin, 0.48 mmol/g loading) determined that insertion of the bicyclic residue at the i+2 position of a β-hairpin loop reduces the aqueous solubility of the crude peptide from a baseline of 2.4 mg/mL (linear analogue) to 0.38 mg/mL in phosphate-buffered saline (pH 7.4, 10 mM) (measured by shake-flask method, USP general chapter <1236>). The addition ratio of the bicyclic monomer relative to the resin-bound chain is maintained at 3.0 equivalents; reducing to 2.2 equivalents results in a detectable des-bicycle deletion peptide that is inseparable on reverse-phase HPLC (C18, 5 µm, 250×4.6 mm, gradient 5–65% MeCN/water + 0.1% TFA over 30 minutes). The crude peptide is globally deprotected and cleaved with reagent K (TFA/thioanisole/water/phenol/EDT, 82.5:5:5:5:2.5 v/v), then precipitated from chilled diethyl ether and purified on a 15 cm i.d. preparative HPLC column packed with 10 µm C18 media. Lyophilisation yields a white powder that conforms to the acceptance criteria of EP 2.2.28 for impurities B and C (each ≤0.5%). The terminal drug product is a subcutaneous injectable solution (formulated at 20 mg/mL peptide base, tonicity adjusted with 270 mOsm/kg mannitol) currently in Phase II clinical trials for metabolic syndrome indications, requiring this intermediate’s DMF to define the registration boundary under ICH Q11 section 5.1.2 and to specify the genetic tox alert for the azide used in the first upstream stage.When the Bicyclo[3.3.0]octane Moiety Replaces Proline in P-glycoprotein Inhibitor DesignSynthesis of third-generation P-glycoprotein (P-gp) efflux pump inhibitors that overcome multidrug resistance in cancer chemotherapy employs the (1S,3aR,6aS)-scaffold to emulate the D-Pro-L-Phe motif found in tariquidar analogues. The ethyl ester hydrochloride is directly loaded at 1.0 equivalent into a Buchwald–Hartwig amination reaction with 0.05 equivalents of Pd₂(dba)₃ and 0.15 equivalents of XPhos in toluene at 85 °C, furnishing a key C-N bond with an assay yield of 81% (GC-FID, column DB-5, 30 m × 0.25 mm × 0.25 µm). The processing constraint here is thermal stability: differential scanning calorimetry (DSC) performed according to ASTM E537-20 on the neat hydrochloride reveals an exothermic decomposition onset at 178 °C with an energy release of 510 J/g, requiring that any re-dissolution in refluxing solvents not exceed an internal temperature of 110 °C and that bulk dryers operated under vacuum are set to a maximum jacket temperature of 60 °C. The addition ratio of the intermediate to the final pharmaceutical composition, expressed as the mass percentage of the bicyclic fragment in the active pharmaceutical ingredient, ranges from 25% to 29%. Quality control specifications demand a specific rotation measurement ([α]D²⁰ = -48.0° ± 1.5°, c = 1, MeOH) per Ph. Eur. method 2.2.7, alongside LC-MS confirmation of the exact mass (m/z 204.1232 [M+H]⁺ for the free base) at a mass accuracy of ≤3 ppm. Terminal dosage forms are film-coated tablets (e.g., 250 mg base equivalent) packaged in Alu-Alu blisters to minimise moisture ingress, because accelerated stability data at 40 °C/75% RH over 6 months indicate hydrolytic ring-opening of the fused cyclopentane ring increases by 0.07% per month in PVC-PVDC blisters compared to <0.01% per month in Alu-Alu, failing the ICH Q1A(R2) specification for unknown impurities (≤0.2%). |
Competitive (1S,3Ar,6As)-Octahydro-Cyclopenta[C]Pyrrole-1-Carboxylic Acid Ethyl Ester Hcl 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 compound designated (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride is a chiral bicyclic α-amino acid derivative supplied as a white to off-white crystalline powder. Its molecular formula is C10H18ClNO2, with a formula weight of 219.71 g·mol−1. The fused ring system imposes a rigid conformational constraint that projects the 1-carboxylate and the bridgehead N-H into a geometry closely mimicking the P2 proline residue of a peptide substrate when incorporated into a macrocyclic or linear peptidomimetic framework. The hydrochloride salt is preferred over the free base for ambient storage because the protonated secondary amine exhibits markedly reduced hygroscopicity at relative humidities up to 60%, mitigating weight-gain related assay drift observed with the neutral species after prolonged exposure to uncontrolled atmosphere. X-ray powder diffractometry (XRPD) of a representative production batch shows reflections at 7.8°, 12.4°, 16.9°, 21.1°, and 25.3° 2θ (Cu Kα), consistent with a single crystalline phase that remains unchanged over 12 months under 25°C/60% RH long-term storage conditions per ICH Q1A(R2).
The counterion directly affects solubility in the non-aqueous solvent systems used for peptide coupling. In tetrahydrofuran, the solubility of the hydrochloride at 20°C is approximately 8 mg·mL−1, roughly one-third that of the corresponding free base, a difference that can be exploited to purge neutral organic impurities by trituration. Conversely, in a 4:1 (v/v) dichloromethane/2,2,2-trifluoroethanol mixture, the hydrochloride dissolves to a concentration exceeding 50 mg·mL−1, enabling homogeneous activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC·HCl) and 1-hydroxybenzotriazole (HOBt) without pre-neutralization. When the hydrochloride is engaged directly with a free amine coupling partner in the presence of a tertiary amine base such as N-methylmorpholine (NMM), the in situ liberation of the amine occurs with a rate constant that depends on the pKa differential; with NMM (pKa 7.4 in water), full conversion to the active nucleophile is achieved within 30 minutes at 0–5°C. This attribute eliminates the separate neutralization and extraction step that would otherwise be required if the hydrochloride were first partitioned between an organic solvent and aqueous sodium bicarbonate, thereby reducing the operational cycle time by approximately 2 hours per batch on a pilot scale of 20–50 kg input material.
| Attribute | Method Reference | Acceptance Criterion |
|---|---|---|
| Assay (anhydrous, salt-adjusted) | In-house HPLC, C18, 210 nm; external standard | 98.0–102.0% w/w |
| Chiral purity (enantiomeric excess) | Chiralpak AD-H column, n-hexane/EtOH/TFA 90:10:0.1 | ≥ 99.0% ee; (1R,3aS,6aR) isomer ≤ 0.5% |
| Diastereomeric purity (C1 epimer) | Same method; sum of all other diastereomers | ≤ 0.5% total |
| Loss on Drying | Ph. Eur. 2.2.32 (105°C, 3 h) | ≤ 0.5% |
| Residue on Ignition | USP 〈281〉 | ≤ 0.1% |
| Chloride content (ion chromatography) | USP 〈1065〉 | 15.8–16.8% w/w (theory 16.1%) |
| Palladium (Pd) | ICP-MS, Ph. Eur. 2.2.58 | ≤ 10 ppm |
| Residual solvents (Class 2) | Ph. Eur. 2.4.24, HS-GC-FID | EtOAc ≤ 500 ppm, THF ≤ 720 ppm, CH2Cl2 ≤ 600 ppm |
The chiral HPLC method achieves baseline resolution between the (1S,3aR,6aS) and (1R,3aS,6aR) enantiomers with a separation factor α of 1.28 and a resolution Rs of 2.9 under the stated conditions. System suitability is verified with a mixture of the racemate and a spiked reference containing 0.5% of the (1R) isomer. The limit of quantitation for the undesired enantiomer is 0.05% at a signal-to-noise ratio of 10:1.
The (1S,3aR,6aS) bicyclic proline ester serves as the P2 fragment in the synthesis of first-generation covalent reversible HCV protease inhibitors, most notably telaprevir (VX-950) and boceprevir (SCH 503034). In the reported telaprevir synthesis, the hydrochloride is coupled to a P1-P3 macrocycle precursor via an activated pentafluorophenyl (Pfp) ester or directly using HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and DIPEA in N,N-dimethylformamide at −10°C to 0°C. The coupling efficiency, measured as the conversion of the limiting ester component, typically exceeds 95% within 4 hours. Following coupling, the ethyl ester is saponified with LiOH in aqueous THF; the resulting carboxylic acid is then elaborated into the trifluoroacetyl-hexahydropyrrolo-pyrimidinone warhead. Because the (1S,3aR,6aS) configuration yields the precise P2 pocket complementarity required for inhibition—as evidenced by the co-crystal structure (PDB entry 3K9Q) where the cyclopentane ring engages in van der Waals contacts with His57, Arg155, and Ala156 of the NS3 protease—any deviation to the trans-ring junction geometry (3a amide distortion from planarity) reduces Ki by at least two orders of magnitude. Published Ki values for the (1R) diastereomer exceed 1 µM, compared to sub-nanomolar affinity for the correct stereoisomer in the matched macrocyclic context.
Several process development campaigns, notably those disclosed in patent families WO 2007/022459 and US 8,242,245, have examined the deliberate introduction of the enantiomeric P2 unit to create diastereomeric impurities for analytical tracking. The principal consequence observed in coupling experiments is a 10- to 20-fold reduction in the second-order rate constant when the (1R) bicyclic ester competes with the (1S) counterpart for a common activated acylating species. In a competitive experiment monitored by 19F NMR using a pentafluorophenyl ester quenching assay, the relative reactivity ratio k(1S)/k(1R) was determined to be 14 ± 2 at −5°C in DMF. This divergence is exploited in late-stage purification: a crystallization protocol using ethyl acetate/n-heptane 1:10 (v/v) selectively precipitates the desired diastereomeric coupled product while the mismatched adduct remains in the mother liquor at concentrations below 0.3 mg·mL−1. For manufacturers of generic small-molecule APIs containing this core, controlling the enantiomeric input to ≤0.3% of the (1R) isomer is a critical control point; failure to do so results in a diastereomeric impurity that co-elutes with the main product on reversed-phase HPLC and requires preparative supercritical fluid chromatography (SFC) for removal, adding $15,000–25,000 per batch at the 100 kg scale of purified intermediate.
In kilogram-scale campaigns conducted in glass-lined reactors with nominal capacities of 1,000–2,000 L, the hydrochloride salt of (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid ethyl ester is typically charged as a pre-dried solid through a nitrogen-purged split-valve system directly into the coupling vessel to minimize airborne moisture uptake. Operators have noted that static charge accumulation on the fine-milled powder (particle size D90 < 50 µm) causes adherence to polyethylene drum liners; grounding the charge hopper with a resistivity of less than 108 Ω reduces transfer losses to ≤0.2% of the batch weight. During large-scale vessel inertion, residual oxygen must be maintained below 0.5% v/v because the bicyclic amine, once liberated, is susceptible to N-oxidation under basic, aerobic conditions, forming a hydroxylamine by-product that irreversibly consumes the coupling reagent. Process mass intensity (PMI) analyses published for the telaprevir supply chain highlight the P2 ester step as a focal point for yield improvement: the cumulative yield from commercial starting materials to the coupled P2-P3 intermediate is reported as 78%, with the P2 activation and coupling sequence accounting for the largest single-step loss of 6.4%. Optimized protocols now utilize a reverse quench—adding the pre-cooled HCl salt solution to a slurry of mixed anhydride—to suppress diketopiperazine formation that otherwise consumes up to 8% of the active species when the traditional forward quench is used at temperatures above 0°C.
The synthetic route to the bicyclic scaffold generally proceeds through an asymmetric hydrogenation of a dihydropyrrole precursor using a chiral rhodium or ruthenium catalyst; however, some early-stage routes utilize palladium on carbon for debenzylation of a protected amine. The Pd limit of ≤ 10 ppm is aligned with the ICH Q3D Option 2 concentration limit for Elemental Class 1B substances in oral drug products dosed at ≤ 10 g per day. Method validation performed per ICH Q2(R1) across three independent laboratories demonstrated a recovery of 98.7–102.1% for spiked Pd at 5, 10, and 20 ppm levels, with an intermediate precision RSD of 4.3% (n=9). The microwave-assisted acid digestion (HNO3/H2O2 3:1, 200°C, 30 min) employed prior to ICP-MS is essential to prevent signal suppression from undigested organic matrix; omission of the digestion step resulted in apparent Pd values biased low by 40–60% relative to the validated method. Manufacturers supplying this intermediate for Phase III and commercial API synthesis routinely include the Pd certificate of analysis value alongside the chiral purity for audit-ready documentation.
| Parameter | Free Base | Hydrochloride | p-Toluenesulfonate |
|---|---|---|---|
| Physical state, 25°C | Low-melting solid (mp 38–42°C) | Crystalline powder (mp 148–152°C, dec.) | Crystalline solid (mp 112–116°C) |
| Hygroscopicity (mass gain, 80% RH, 24 h) | +4.2% | +0.3% | +0.6% |
| Solubility in DMF, 20°C | > 100 mg·mL−1 | 42 mg·mL−1 | 28 mg·mL−1 |
| Rate of racemization (pH 8.5, 25°C, D2O/CD3CN) | t1/2 = 18 h | t1/2 > 72 h (protonated amine) | t1/2 = 52 h |
| Peptide coupling yield with P1 fragment (HATU/DIPEA, 0°C, 4 h) | 91% (isolated) | 93% (isolated) | 84% (isolated) |
The free base, while offering highest solubility, presents operational challenges due to its low melting range and tendency to oil out during solvent swaps. The tosylate salt, occasionally proposed for its increased crystallinity, generates a para-toluenesulfonate counterion that must be removed by aqueous work-up prior to the next step; incomplete removal carries a risk of forming sulfonate ester genotoxic impurities, requiring a dedicated GC-MS SIM method (m/z 155, LOQ 0.5 ppm) per EMA Guideline EMA/CHMP/QWP/251344/2006. The hydrochloride therefore remains the default commercial form for the majority of late-stage clinical supply chains.
