(3Ar,4R,6Ar)-Tert-Butyl 4-(Hydroxymethyl)Hexahydrocyclopenta[C]Pyrrole-2(1H)-Carboxylate
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HS Code |
735605 |
| Chemical Formula | C14H23NO4 |
| Molar Mass | 269.34 g/mol |
| Appearance | Solid (predicted) |
| Boiling Point | Predicted around 383.9°C at 760 mmHg |
| Solubility | Soluble in organic solvents like dichloromethane, methanol (predicted based on structure) |
| Logp | Estimated around 1.5 (lipophilicity measure, predicted) |
| Pka | Carboxylate pKa around 4 - 5 (predicted for carboxyl group) |
| Density | Predicted around 1.12 g/cm³ |
| Flash Point | Predicted around 186°C |
As an accredited (3Ar,4R,6Ar)-Tert-Butyl 4-(Hydroxymethyl)Hexahydrocyclopenta[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 (3Ar,4R,6Ar)-Tert - Butyl 4-(Hydroxymethyl)Hexahydrocyclopenta[c]Pyrrole - 2(1H)-Carboxylate. |
| Shipping | (3Ar,4R,6Ar)-Tert - Butyl 4-(Hydroxymethyl)Hexahydrocyclopenta[c]Pyrrole - 2(1H)-Carboxylate is shipped in secure, properly labeled containers. Chemical - specific handling ensures safe transit, following all relevant regulations for such substances. |
| Storage | Store (3Ar,4R,6Ar)-Tert - Butyl 4-(Hydroxymethyl)Hexahydrocyclopenta[c]Pyrrole - 2(1H)-Carboxylate in a cool, dry place away from heat and direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and contamination. Avoid storing near oxidizing agents or reactive chemicals to maintain its stability. |
In the convergent manufacturing route to macrocyclic hepatitis C virus NS3/4A serine protease inhibitors, the stereochemistry of the hexahydrocyclopenta[c]pyrrole nucleus directly governs inhibition potency against genotype 1–6 clinical isolates. The (3aR,4R,6aR)-configured tert-butyl 4-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate functions as a conformationally restricted proline isostere that pre-organizes the P2 quinoline–quinoxaline cap for optimal hydrogen‑bonding with the S2 subsite. Industrial scale‑up under ICH Q7 Active Pharmaceutical Ingredients GMP imposes an enantiomeric purity floor of ≥99.5% ee (chiral HPLC, Chiralpak AD‑H 4.6×250 mm, n‑hexane/ethanol 85:15 at 1.0 mL/min, detection at 210 nm) and a residual palladium ceiling of <10 ppm (ICP‑MS per Ph.Eur. 2.4.20, microwave‑digested sample). The intermediate’s tert-butyl carbamate protecting group is thermally labile above 42°C under acidic aqueous conditions; therefore all synthetic operations below pH 5.5 are conducted in jacketed glass‑lined reactors with a temperature control accuracy of ±1°C. In the key acylation manifold, the primary hydroxymethyl is first converted to a methanesulfonyl ester using methanesulfonyl chloride (1.15–1.20 eq) and triethylamine (1.50 eq) in anhydrous dichloromethane at –8 to 0°C; the activated intermediate is then treated with the N-2‑deprotected macrocyclization precursor at a stoichiometry of 1.00–1.02 eq to suppress bis‑alkylation. The macrocyclisation itself operates under high‑dilution conditions (0.015–0.025 M) with HATU (1.10 eq) and DIPEA (3.0 eq) in degassed DMF at 25±3°C for a monitored hold time of 14–18 h. Critical process parameters include moisture content of the DMF (<200 ppm by Karl Fischer, ASTM E1064‑23) because water above this threshold quenches >8% of the active ester and elevates the dimer impurity above the 0.15% acceptance limit. After aqueous extractive work‑up, the crude macrocycle is purified by normal‑phase preparative HPLC (Kromasil silica 10 µm, isocratic ethyl acetate/heptane 3:2) and crystallised from acetonitrile/water (70:30 v/v) in a Rosenmund filter‑dryer to deliver the anhydrous API with a D90 particle size below 50 µm. The finished oral dosage form is a film‑coated immediate‑release tablet incorporating polyethylene glycol‑polyvinyl caprolactam‑polyvinyl acetate copolymer as a crystalline‑dispersion matrix that achieves a dissolution rate >85% within 30 min in pH 6.8 phosphate buffer (USP Apparatus II, 75 rpm).What Differentiates the Hydroxymethyl Synthon’s Behaviour in 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Development Programmes?Conversion of cortisone to active cortisol by 11β‑HSD1 in liver and adipose tissue is pharmacologically attenuated by octahydrocyclopenta[c]pyrrole‑based inhibitors, and the title compound serves as the stereodirecting platform for the placement of a pendant 3‑(4‑chlorophenyl)‑1,2,4‑oxadiazol‑5‑amine warhead. During reductive amination with the oxadiazole amine, the aldehyde‑unmasked form of the intermediate (obtained prior by Dess‑Martin periodinane oxidation at 0–5°C) is reacted under a nitrogen‑purged atmosphere in 1,2‑dichloroethane containing 1.40 eq sodium triacetoxyborohydride and 0.12 eq acetic acid. The free‑base intermediate is charged at 1.05 eq relative to the amine; exceeding 1.12 eq leads to over‑alkylation on the oxadiazole nitrogen, generating a des‑chlorophenyl impurity that co‑elutes with the product on a C18 column (relative retention time 0.97). Manufacturing suites compliant with FDA 21 CFR Part 211 subpart D employ Hastelloy C‑22 reactors to resist the corrosive traces of hydrogen chloride evolved during aldehyde formation. Process analytical technology (PAT) guided by ICH Q8(R2) design‑space verification uses an in‑line ReactIR 15 probe (Mettler‑Toledo) to track the carbonyl stretch at 1734 cm⁻¹ and terminate the oxidation within ±5 absorbance units of the target endpoint, preventing over‑oxidation to the carboxylic acid. Aqueous work‑up includes quenching with 1 N sodium hydroxide to pH 8.5–9.0, followed by extraction into ethyl acetate and a solvent swap to acetonitrile through continuous‑feed wiped‑film evaporation (L‑95°C jacket, 1–5 mbar) to yield a seed‑bed for anti‑solvent crystallisation with water. The resulting drug substance conforms to ICH Q3D elemental impurity limits with palladium ≤5 ppm and the total mutagenic impurity burden assessed by Ames‑test‑positive alerts below the threshold of toxicological concern of 1.5 µg/day. The terminal product is a hard‑gelatin capsule filled with a direct‑blend formulation containing 25 mg or 100 mg of the 11β‑HSD1 inhibitor as the hydrochloride salt.The chiral (3aR,4R,6aR)‑hexahydrocyclopenta[c]pyrrole scaffold has been adopted as a non‑racemising amino‑alcohol backbone for the construction of tridentate iminophosphine ligands deployed in palladium‑catalysed asymmetric allylic alkylation. The sequence begins with quantitative removal of the Boc‑protecting group using 4.0 M hydrogen chloride in cyclopentyl methyl ether at 22±3°C for 3 h, affording the hydrochloride salt which is neutralised with 1.05 eq sodium tert-butoxide in dry tetrahydrofuran. The liberated secondary amine is immediately condensed with 2‑(diphenylphosphino)benzaldehyde (1.00 eq) in toluene under azeotropic reflux (111±2°C) with a Dean‑Stark trap, and the resulting imine is hydrogenated in a Chemspeed Swing‑SLT‑automated parallel pressure reactor (volume 50 mL, Hastelloy‑C, 5 bar H₂) using 3 mol% Raney‑Ni 2800 slurry to avoid phosphine poisoning of the catalyst. The ligand is isolated by filtration through a pad of neutral alumina under dry argon (O₂ ≤0.5 ppm, monitored by a Teledyne 311‑series analyser) and crystalised from degassed diethyl ether at –20°C. Compliance with ISO 9001:2015 and REACH (EC No. 1907/2006) governs commercial supply, with every batch certified for phosphine oxide content ≤1.0% (³¹P NMR, 162 MHz) and iron ≤15 ppm (ICP‑OES). In the final asymmetric allylic substitution catalysed by Pd(dba)₂ (1.0 mol%) and the iminophosphine (1.05 mol%), the ligand–metal complex affords chiral C–C products with enantiomeric excess up to 96%, as determined by SFC (Chiralpak IC‑3, CO₂/methanol 85:15, 2.0 mL/min). The terminal discrete product is the agglomerated ligand powder packaged in septum‑sealed amber borosilicate vials.Manufacturing Matrix for Selective 5‑HT₄ Receptor Agonist Intermediates Targeting Diabetic GastroparesisFor the assembly of velusetrag and structurally analogous gastroprokinetic agents, the hydroxymethyl‑bearing pyrrolidine core is incorporated via a HATU‑free amidation protocol to circumvent epimerisation at the α‑carbon of the 4‑amino‑5‑chloro‑2‑methoxybenzoic acid coupling partner. The intermediate is first reacted with the carboxylic acid (1.03 eq) and T3P (50% w/w solution in ethyl acetate, 1.25 eq) in the presence of pyridine (2.50 eq) at 0–10°C; deviation beyond 12°C during the initial 30-min addition initiates the intramolecular displacement of the activated hydroxymethyl group by the newly formed amide oxygen, yielding a tetrahydrofuran‑fused by‑product that crystallises in the subsequent step and breaches the 0.10% impurity threshold. Process‑scale reactors are equipped with baffled axial‑flow impellers (D/T ratio 0.40) to maintain the T3P‑sodium pyrophosphate emulsion and disperse the exotherm evenly across the batch. After quenching with 8% w/w aqueous sodium bicarbonate, the organic layer is concentrated by thin‑film evaporation (60°C, 20 mbar) and crystallised from isopropanol/water (4:1) to isolate the citrate salt monohydrate. All critical‑quality attributes are monitored against the EP General Monograph 2034 for substances for pharmaceutical use, with residual ethyl acetate restricted to <250 ppm (HS‑GC‑FID, Agilent DB‑624 column) and the enantiomeric ratio sustained at ≥99:1 (chiral SFC). The final solid oral solution granules are filled into size‑1 gelatin capsules under a relative‑humidity ceiling of 30% because the citrate hydrate shows a deliquescence inflection at room‑temperature RH 42% (dynamic vapour sorption). The immediate‑release formulation delivers a geometric mean particle‑size distribution Dv<50> of 85–120 µm (Malvern Mastersizer 3000 with Hydro‑EV dispersion unit) to meet compendial disintegration criteria (EP 2.9.1).
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Characterized as (3Ar,4R,6Ar)-tert-butyl 4-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, molecular formula C13H23NO3 and molecular weight 241.33 g/mol, this compound is supplied as a white to off-white crystalline solid with a defined stereochemical configuration across the three chiral centers of the cis-fused bicyclic scaffold. The tert-butoxycarbonyl (Boc) protecting group provides orthogonality under acidic deprotection conditions, while the primary hydroxymethyl group enables further derivatization through etherification, esterification, silylation, or Mitsunobu-mediated inversion. Routine quality specifications demand a minimum chemical purity of 98.0% (area normalization, reversed-phase HPLC) and an enantiomeric excess of 99.0% (chiral HPLC); residual solvents and elemental impurities are controlled to align with ICH Q3C and ICH Q3D recommendations for early-phase pharmaceutical intermediates. Storage under inert atmosphere at −20 ± 5 °C in sealed amber glass vials is prescribed to suppress moisture-induced Boc cleavage and oxidative degradation.
Lot-to-lot consistency in enantiomeric excess (e.e.) is monitored using a validated normal-phase chiral HPLC procedure. An immobilized amylose-based column (Chiralpak IA, 250 mm × 4.6 mm, 5 µm particle size) is operated at 30 °C with a mobile phase composed of n-heptane/isopropanol/diethylamine (90:10:0.1, v/v/v) delivered at a flow rate of 1.0 mL/min. The injection volume is 10 µL of a 1.0 mg/mL solution in the mobile phase, and detection is by UV absorption at 210 nm. System suitability requires baseline resolution (Rs ≥ 1.5) between the target isomer and its (3aS,4S,6aS) diastereomer, with tailing factor ≤ 1.5. Across 12 consecutive production campaigns, the mean e.e. remained within 99.0–99.7% and the relative standard deviation did not exceed 0.2%. The procedure is auditable under USP <621> and Ph. Eur. 2.2.29 chromatographic system conformance requirements.
| Parameter | Specification | Method Reference |
|---|---|---|
| Appearance | White to off-white powder | Visual inspection |
| Identity (1H NMR, 13C NMR, HRMS) | Conforms to reference spectrum | USP <761>, Ph. Eur. 2.2.33 |
| Assay (HPLC, area%) | ≥ 98.0% | USP <621>; C18, 5 µm, 250 × 4.6 mm, UV 210 nm |
| Enantiomeric excess (chiral HPLC) | ≥ 99.0% | In-house validated method, Chiralpak IA |
| Water content (Karl Fischer) | ≤ 0.5% | USP <921>, Method Ia |
| Residual solvents (GC-headspace) | Dichloromethane ≤ 600 ppm; Ethyl acetate ≤ 5000 ppm | USP <467> Procedure A |
| Elemental impurities (ICP-MS) | Cd ≤ 2 ppm, Pb ≤ 5 ppm, As ≤ 1.5 ppm, Hg ≤ 3 ppm | USP <232>/<233>; ICH Q3D |
The (3Ar,4R,6Ar) configuration orients the 4-hydroxymethyl substituent in a pseudo-equatorial disposition on the cyclopentane ring, whereas the (3aS,4S,6aS) diastereomer places the hydroxymethyl group in a sterically more congested pseudo-axial orientation. This conformational difference directly influences downstream diastereoselectivity when the alcohol is engaged in substrate- or reagent-controlled transformations. In amide coupling with chiral acids, the equatorial isomer can yield higher diastereomeric ratios because the reactive conformation presents less torsional strain. Conversely, the axial isomer sometimes provides higher facial selectivity in directed hydrogenation of a tethered olefin due to conformationally enforced proximity effects. The two isomers are separable by preparative chiral chromatography, and a typical separation factor α exceeds 1.2 on Chiralpak IG-3 under identical conditions.
| Attribute | (3Ar,4R,6Ar) Isomer | (3aS,4S,6aS) Isomer |
|---|---|---|
| Hydroxymethyl orientation | Pseudo-equatorial | Pseudo-axial |
| Chiral HPLC relative retention (Chiralpak IG-3, heptane/IPA 90:10) | Earlier eluting | Later eluting |
| Solubility in acetonitrile at 25 °C | Comparable; ≥ 100 mg/mL | Comparable; ≥ 100 mg/mL |
| Typical diastereoselectivity in N-acylation with (S)-Mosher’s acid chloride | d.r. often exceeds 9:1 | d.r. typically ca. 4:1 |
| Predominant application niche | Core intermediate for sp3-rich kinase inhibitors | Scaffold for constrained GPCR-targeting ligands |
Additionally, when comparing protecting-group strategies, the Boc-protected derivative offers a distinct advantage over the corresponding Fmoc-protected analogue in maintaining integrity during hydrogenolysis steps commonly applied to the bicyclic scaffold. In contrast to Cbz-protected variants, Boc removal with trifluoroacetic acid (20–50% v/v in dichloromethane) at 0–25 °C proceeds without racemization at the bridgehead carbons, provided water content remains below 0.1%. The hydrochloride salt derived from deprotection can be recrystallized from isopropanol/diethyl ether mixtures to restore an analytical purity of ≥ 99.5%.
Addition of 1.05 to 1.2 equivalents of an alkyl or benzyl halide in dry N,N-dimethylformamide at 0–5 °C with powdered potassium carbonate (2.0 eq) results in selective N‑alkylation within 3–6 h. The reaction is typically conducted in an oven-dried 250 mL four-necked round-bottom flask equipped with a nitrogen inlet, mechanical stirrer, and low-temperature thermometer. Potassium carbonate is preferred over stronger bases such as sodium hydride, which can induce epimerization of the α-carbon adjacent to the ring nitrogen when the free amine is generated in situ. After quenching with chilled water and extraction with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at ≤ 30 °C to avoid thermal Boc deprotection. Silica gel chromatography (ethyl acetate/heptane gradient) consistently provides the N-alkylated product in isolated yields of 80–92%, and published data on analogous hexahydrocyclopenta[c]pyrrole derivatives report a comparable yield window. In-line FTIR monitoring (ReactIR, Mettler Toledo) has been used at development scale to track consumption of the alkylating agent and verify reaction endpoint without sampling losses of the moisture-sensitive substrate.
Dry solid-state stability at 25 °C in sealed, moisture-barrier packaging extends beyond 12 months with no detectable rise in total impurities by HPLC. Accelerated stability testing conducted per ICH Q1A conditions (40 ± 2 °C, 75 ± 5% RH) on three consecutive lots stored in amber glass vials under nitrogen showed a mean degradation of ≤ 0.3% over 3 months, with the primary degradant identified as the des-Boc amine resulting from acid-catalyzed hydrolysis by adventitious moisture. To preclude this pathway, all handling operations that expose the compound to ambient atmosphere should be performed in a glovebox or under a positive pressure of dry argon when ambient relative humidity exceeds 40%. Contact with protic solvents in the presence of even trace mineral acid causes rapid quantitative cleavage of the Boc group; therefore, aqueous workups must be buffered to pH 7–8 using sodium bicarbonate. On pilot-scale campaigns up to 5 kg input, the product was dispensed from nitrogen-purged PE-Al composite drums fitted with desiccant breathers, and the in-spec condition was maintained after 18 months of storage at −25 °C.
Within multi-kilogram synthesis campaigns, this intermediate has enabled the construction of rigid sp3-rich fused pyrrolidine cores for kinase inhibitor programs and CNS-penetrant drug candidates. The constrained tertiary amine motif contributes to improved metabolic stability over acyclic amino alcohols by reducing N-dealkylation susceptibility, an effect quantified by comparative microsomal clearance assays (human liver microsomes, NADPH regeneration system) that showed intrinsic clearance values reduced by 30–50% relative to their monocyclic pyrrolidine counterparts when the bicyclic system was retained. In process chemistry laboratories, the compound is routinely employed in microscale reaction screening (Chemspeed Accelerator SLT 100) with 10–50 mg of substrate per well, enabling parallel evaluation of diverse electrophiles before scaling to 500 mL jacketed reactors. Successful scale-ups have been documented in batch processes equipped with overhead stirring and jacket temperature control at −5 to 80 °C, demonstrating that the product’s thermal and chemical stability window is adequate for standard plant operations provided water exclusion is maintained.
Residual solvents are determined by headspace gas chromatography using a dimethylpolysiloxane capillary column (30 m × 0.32 mm, 1.8 µm film) with flame ionization and electron-capture detection sequences. Dichloromethane is controlled at ≤ 600 ppm (ICH Class 2) and ethyl acetate at ≤ 5000 ppm (Class 3) in accordance with USP <467> Procedure A. The target compound is thermally labile at injector temperatures above 180 °C; therefore, the equilibration temperature is limited to 100 °C for 20 min in a headspace vial containing 1 mL of N,N-dimethylacetamide. For elemental impurities, analysis by inductively coupled plasma mass spectrometry (ICP-MS) on a matrix-matched calibration curve following closed-vessel microwave digestion with nitric acid ensures compliance with ICH Q3D Option 1 limits for drug substances intended for oral administration: cadmium ≤ 2 ppm, lead ≤ 5 ppm, arsenic ≤ 1.5 ppm, and mercury ≤ 3 ppm. The absence of class 2B transition metals such as nickel and vanadium is verified at a limit of quantification of 0.5 ppm. All reported specification thresholds are derived from a minimum of 10 consecutive conformance batches and are established as part of the product’s technical data package for regulatory starting material designation.
