3-Carboxypyrrolidine Tert-Butyl Ester, Beta-Proline Tert-Butyl Ester
|
HS Code |
917676 |
| Chemical Formula | C9H17NO2 |
| Molecular Weight | 171.24 g/mol |
| Appearance | Typically a colorless to light - yellow liquid or solid |
| Melting Point | Data may vary depending on purity, usually within a certain range |
| Solubility | Soluble in many organic solvents like dichloromethane, ethyl acetate |
| Purity | Can be obtained in various purity levels, e.g., 95%, 98% etc. |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 3-Carboxypyrrolidine Tert-Butyl Ester, Beta-Proline Tert-Butyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3 - Carboxypyrrolidine Tert - Butyl Ester in a sealed, labeled chemical container. |
| Shipping | 3 - Carboxypyrrolidine Tert - Butyl Ester (Beta - Proline Tert - Butyl Ester) is shipped with strict adherence to chemical safety regulations. Packed in suitable containers, it's transported via approved carriers to ensure secure and compliant delivery. |
| Storage | Store "3 - Carboxypyrrolidine Tert - Butyl Ester, Beta - Proline Tert - Butyl Ester" in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and oxidation. Store separately from incompatible substances to avoid potential reactions. Ensure the storage area is well - ventilated. |
|
In GMP-compliant solid-phase β-peptide manufacturing, the orthogonal stability of side-chain carboxyl protections directly dictates overall crude purity prior to HPLC purification. (S)-3-Carboxypyrrolidine tert-butyl ester, functioning as a cyclic β-amino acid building block with a base-labile tert-butyl shield, is routinely converted to its Fmoc derivative for integration into Merrifield-based protocols. The primary industry compliance anchor is ICH Q7 Section 7.3 (cleaning validation and cross-contamination prevention), coupled with the enantiomeric purity specification of ≥99.5% ee determined by chiral stationary-phase HPLC in accordance with USP 〈621〉. In the Fmoc protection step executed within a 500 L glass-lined reactor equipped with a retreat-blade impeller, the molar ratio of the ester to Fmoc-OSu is maintained at 1.00:1.05 in a biphasic dichloromethane–10% aqueous Na2CO3 system at 0–5 °C; exceeding 10 °C initiates premature tert-butyl ester cleavage detectable as free acid by TLC (Rf 0.15 shift). Downstream processing proceeds through an in-line centrifugal extractor for phase separation, an organic-phase wash train of 1 M HCl and brine, drying over molecular sieves to a Karl Fischer endpoint of ≤0.05% H2O, and crystallization from ethyl acetate/n-heptane at a controlled cooling ramp of −0.3 °C/min to isolate crystalline Fmoc-(S)-β-Pro(tBu)-OH of ≥98% chromatographic purity. The terminal manufactured good is a Fmoc- and tert-butyl-protected β-proline cassette deployed in automated microwave-assisted Fmoc-SPPS synthesizers (CEM Liberty BlueTM or equivalent) for constructing protease-resistant β-peptide foldamers targeting intracellular protein–protein interaction interfaces. Under strictly anhydrous conditions, the free secondary amine of (S)-3-carboxypyrrolidine tert-butyl ester participates directly as an organocatalyst in the enantioselective α-chlorination of unbranched aldehydes, a transformation that delivers stereodefined α-chlorocarbonyl intermediates en route to HIV protease inhibitor pharmacophores. Operating envelope limitations are set by the moisture sensitivity of the iminium–enamine catalytic cycle: reactor headspace dew point must not exceed −60 °C as verified by a chilled-mirror hygrometer, otherwise hydrolysis of the activated iminium species reduces turnover frequency below practical thresholds. Catalyst loading is fixed at 5 mol% relative to the aldehyde substrate, introduced as a predissolved stock in anhydrous dichloromethane (≤30 ppm H2O by Karl Fischer) into a jacketed 100 L Hastelloy C-22 reactor. The α-chlorination protocol adds N-chlorosuccinimide (1.2 eq) portionwise over 90 min at −15 to −10 °C internal temperature, followed by a 4 ‑h age period during which chiral HPLC sampling confirms enantiomeric excess typically converging to a 92–96% range for hexanal-derived substrates. Post-reaction quenching with saturated aqueous NH4Cl, continuous counter-current extraction, and vacuum distillation through a wiped-film evaporator (≤1 mbar, jacket 80 °C) isolates the α-chloroaldehyde. Residual catalyst is quantified by LC–MS/MS and must not exceed the ICH Q3A reporting threshold of 0.05% in the final intermediate. The downstream formulated product is a kilogram-scale chiral α-chlorocarbonyl synthetic intermediate supplied under a drug master file for integrase strand-transfer inhibitor backbones. When a Beta-Proline Scaffold Access Route Eliminates Hazardous Azide IntermediatesIn the manufacture of CCR5 receptor antagonist candidates bearing a 3-aminomethylpyrrolidine warhead, (S)-3-carboxypyrrolidine tert-butyl ester serves as a non-hydrazine-based entry point that obviates the use of azide displacement chemistry altogether. The applicable regulatory framework spans ICH M7 (control of mutagenic impurities) for the elimination of residual azide concerns and REACH Annex XVII restrictions on hydrazine handling. The molecule is reductively aminated with a substituted benzylamine (1.05 eq) in the presence of sodium triacetoxyborohydride (1.4 eq) in 1,2-dichloroethane at 20–25 °C, with the reagent-to-substrate stoichiometry scrupulously controlled to avoid over-alkylation of the pyrrolidine nitrogen. The process is executed in a 200 L glass-lined tandem reactor train with continuous nitrogen inertisation, monitored by inline ReactIR for imine intermediate disappearance at 1645 cm⁻¹. Following reductive amination, an acidolytic deprotection with 4 M HCl in 1,4-dioxane at 0–5 °C cleaves the tert-butyl ester within 2 h; the free carboxylic acid is then coupled to a morpholine fragment using HATU and N,N-diisopropylethylamine (1.8 eq) in DMF. The terminal active pharmaceutical ingredient intermediate is a zwitterionic 3-((substituted amino)methyl)pyrrolidine-3-carboxylic acid scaffold that enters salt formation and final formulation stages under ICH Q11 development guidelines. Melt Polycondensation of a Regiochemically Defined Poly(ester amide) Incorporating a Cyclic β-Amino AcidFor fully resorbable implantable devices such as tendon anchors and osteosynthesis plates, the introduction of (S)-3-carboxypyrrolidine tert-butyl ester as a comonomer into a poly(ε-caprolactone-co-serine ester amide) backbone modulates hydrophilicity and enzymatic degradation rate without sacrificing backbone crystallinity. The bioresorbable device compliance matrix requires ISO 10993-5 (cytotoxicity, extract dilution method), ISO 10993-1:2020 (biological evaluation), and ASTM F1635-16 (in vitro degradation testing). Monomer feed composition targets a molar incorporation of the β-proline derivative at 12–18 mol%, a range identified by differential scanning calorimetry: exceeding 20 mol% depresses the as-synthesized glass transition temperature below 37 °C and results in dimensional instability under simulated in vivo loading. Prior to polymerization, the ester monomer is dried in a rotary-cone vacuum dryer at 40 °C and ≤0.5 mbar until residual moisture drops below 80 ppm (DIN 51777 Part 1); failure to meet this specification causes chain-stopping hydrolysis of the lactone and a molecular weight collapse from Mn ~85 kDa to oligomeric chains below 10 kDa. Polycondensation is performed in a co-rotating twin-screw extruder with L/D ratio 40:1, segmented screw profile, and ten barrel zones ramped from 140 °C to 195 °C, with stannous octoate catalyst (0.05 wt%) pre-dispersed in anhydrous toluene and metered via a triple-shot precision pump. The extrudate is pelletized under dry nitrogen, devolatilized, and subjected to solid-state post-polycondensation under vacuum at 155 °C for 24 h to achieve the target inherent viscosity of 1.8–2.1 dL/g (chloroform, 0.1 g/dL, 25 °C). The resulting implant-grade poly(ester amide) is subsequently injection-molded into osteofixation devices using a 120‑ton electric IMM with a clamping force profile validated against ISO 294-1:2017. Resolution of racemic 2-arylpropionic acids by diastereomeric salt formation remains a scalable alternative to asymmetric hydrogenation when the precursor cost of a chiral auxiliary is justified by downstream crystallinity advantages. In this application, the tert-butyl ester is first deprotected using trifluoroacetic acid–triisopropylsilane–H2O (95:2.5:2.5, v/v/v) at 20–25 °C for 1.5 h to liberate (S)-β-proline hydrochloride; subsequent neutralization with propylene oxide yields the free amino acid. The resolving agent is then combined with racemic naproxen free acid in a 1.00:1.00 molar ratio in 95% ethanol–water at 60 °C, and the solution is cooled along a programmed cubic cooling curve to 5 °C to foster selective nucleation of the (S,S)-diastereomeric salt. Process robustness is validated in a 50 L DIN stainless-steel crystallizer with retreat-curve impeller and focused-beam reflectance measurement (FBRM®) tracking chord length distribution; the targeted crystal size of 150–250 µm is maintained by a seed addition at 45 °C (seed loading 0.5 wt%). Purity compliance follows USP 〈941〉 for particle size distribution and Ph. Eur. 2.2.29 for chiral identity. After diastereomeric salt cleavage with 2 M HCl and ethyl acetate extraction, the resolved (S)-naproxen is released with optical purity of ≥99.0% ee and isolated yield historically averaging 42–48% of the theoretical maximum for a single crystallization. The downstream finished product is micronized (D90 ≤ 100 µm) (S)-naproxen of compendial-grade quality meeting USP–NF specifications for non-steroidal anti-inflammatory drug formulations. |
Competitive 3-Carboxypyrrolidine Tert-Butyl Ester, Beta-Proline Tert-Butyl Ester 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!
3-Carboxypyrrolidine tert-butyl ester, systematically named tert-butyl pyrrolidine-3-carboxylate, is a conformationally constrained β-amino acid building block employed in peptidomimetic synthesis, structure‑activity relationship exploration, and medicinal chemistry campaigns requiring backbone rigidification. The compound is typically supplied as the (S)-enantiomer hydrochloride salt (CAS 1841080-29-8), which corresponds to the β‑proline scaffold, or as the free base obtained via neutralization. The empirical formula of the free base is C₉H₁₇NO₂, yielding a molecular weight of 171.24 g·mol⁻¹; the hydrochloride adds 36.46 g·mol⁻¹. Because the carboxyl group is positioned at the pyrrolidine 3‑position rather than the more common 2‑position (α‑proline), the amino group retains a secondary amine character with a measured conjugate‑acid pKa near 10.2 in aqueous solution, distinctly higher than that of proline (10.6). This electronic shift—together with the increased spacing between the amine and carboxyl—modulates coupling kinetics and reduces premature N‑terminus protonation during activation steps. The tert‑butyl ester remains stable under the mildly basic conditions required for 9‑fluorenylmethoxycarbonyl (Fmoc) deprotection by piperidine–DMF solutions, yet undergoes quantitative acidolysis with trifluoroacetic acid (TFA)‑based cleavage cocktails, enabling fully orthogonal protection when combined with acid‑labile side‑chain protecting groups.
Material intended for solid‑phase peptide synthesis (SPPS) or solution‑phase coupling is released against a panel of pharmacopoeial and industry‑standard methods. Typical batch‑release data for the (S)-β‑proline tert‑butyl ester hydrochloride are summarised below.
| Parameter | Specification | Method |
|---|---|---|
| Appearance | White to off‑white crystalline powder | Visual inspection |
| Assay (anhydrous, solvent‑free) | 98.0–102.0 % | Ph. Eur. 2.2.46 (HPLC‑UV at 210 nm) |
| Enantiomeric purity | ≥99.0 % ee | Daicel Chiralpak IA‑3, hexane/ethanol/0.1 % TFA; USP 〈621〉 general validation |
| Water content | ≤0.5 % | Karl Fischer coulometry (USP 〈921〉) |
| Residual solvents | Methanol ≤3000 ppm, dichloromethane ≤600 ppm, others report according to ICH Q3C | Headspace GC‑FID (Ph. Eur. 2.4.24) |
| Heavy metals (as Pb) | ≤20 ppm | Ph. Eur. 2.4.8 |
| Storage | −20 °C ± 5 °C, desiccated | — |
| Retest period (sealed, N₂ atmosphere) | 24 months from date of manufacture | Stability program per ICH Q1A(R2) |
The tert‑butyl ester exhibits no detectable hydrolysis after 72 h of exposure to 0.1 M phosphate buffer at pH 7.4 and 25 °C, confirming its resistance to neutral aqueous conditions. However, contact with bulk water at ambient relative humidity >60 % over extended periods initiates slow ester cleavage; therefore pre‑drying over phosphorus pentoxide or via azeotropic distillation with toluene is mandated before coupling reactions that use anhydrous conditions.
In Fmoc‑based SPPS, the β‑proline tert‑butyl ester is incorporated as the free amino acid—Fmoc‑(S)‑β‑Pro‑OtBu—prepared by standard procedures. Activation with 1‑[bis(dimethylamino)methylene]‑1H‑1,2,3‑triazolo[4,5‑b]pyridinium 3‑oxid hexafluorophosphate (HATU, 1.2 equiv.) and N,N‑diisopropylethylamine (DIPEA, 2.5 equiv.) in anhydrous DMF at 20 °C achieves coupling yields typically within 95–98 % as monitored by Kaiser test or on‑resin colourimetric assay after a 90‑min single coupling. The slightly reduced pKa of the β‑amino group relative to standard α‑amino acids lowers the rate of acyl‑pyridinium intermediate consumption, necessitating extended coupling times for sequences that place β‑Pro immediately C‑terminal to sterically hindered residues. On an automated microwave‑assisted synthesizer (CEM Liberty Blue, 20 mL reactor volume), the double‑coupling protocol with 5‑min cycles at 50 °C raises the incorporation to ≥99.5 % per position, as confirmed by ultra‑performance liquid chromatography–mass spectrometry (UPLC‑MS) following micro‑cleavage from a Tentagel S RAM resin.
A critical processing nuance arises from the sensitivity of the tert‑butyl protector to extended amine exposure at elevated temperature. During manufacturing‑scale Fmoc deprotection using 20 % piperidine in DMF (v/v) at 35 °C, premature ester cleavage has been observed at levels of 3.5–5 % after cumulative deprotection steps exceeding 4 h. This side reaction generates free carboxyl groups that can undergo in‑situ cyclisation with the deprotected N‑terminus, producing an unreactive diketopiperazine and permanently capping the growing peptide chain. On a 5 L jacketed reactor employed for gram‑scale peptide production, the failure mode was circumvented by reducing the jacket temperature to 18 °C and limiting each deprotection cycle to 2 × 5 min. Residual free acid was then quantified by a 2‑(1H‑benzotriazole‑1‑yl)‑1,1,3,3‑tetramethyluronium hexafluorophosphate (HBTU)‑mediated capping assay; batches exceeding 0.5 % free acid were rejected because the impurity co‑elutes with the target peptide during reversed‑phase purification.
Final global deprotection and cleavage from the resin employ a TFA‑triisopropylsilane‑water mixture (95:2.5:2.5 v/v/v) at 25 °C for 2.5–3 h. Under these conditions, the tert‑butyl ester is cleaved quantitatively while peptide‑resin bond scission proceeds, releasing the fully deprotected β‑Pro‑containing peptide without requiring a separate solution‑phase saponification step. This contrasts sharply with methyl ester analogues that demand post‑cleavage treatment with LiOH in THF/H₂O at 0 °C—a step that can promote epimerisation at the adjacent chiral centre if the pH exceeds 11.5.
| Protecting Group | Cleavage Conditions | Cleavage Efficiency after 3 h | Fmoc‑SPPS Compatibility | Key Limitation |
|---|---|---|---|---|
| tert‑Butyl (tBu) | TFA‑TIS‑H₂O (95:2.5:2.5), 25 °C | >99 % | Full | Premature cleavage above 30 °C and extended base exposure |
| Methyl (Me) | 0.2 M LiOH, THF/H₂O, 0 °C, then neutralise | 85–92 % (peptide recovery) | Full | Epimerisation risk; requires separate deprotection step after cleavage |
| Benzyl (Bn) | H₂ (1 atm), 10 % Pd/C, MeOH | >98 % | Partial—hydrogenolysis incompatible with thioether‑containing sequences | Equipment constraints; catalyst poisoning by peptides |
| Allyl (All) | Pd(PPh₃)₄, PhSiH₃, DCM, 25 °C | >95 % | With caution: allyl group removed on‑resin; Pd traces must be scavenged | Palladium contamination can exceed 10 ppm after cleavage |
The β‑carbon of the pyrrolidine ring in β‑proline is not directly attached to the carboxyl carbonyl, rendering the α‑proton less acidic than that of α‑amino acid esters. Nevertheless, long‑term exposure to strong bases such as DBU or prolonged heating with ≥3.0 equiv. of DIPEA can induce partial racemisation via a transient enolate. Racemisation is monitored by chiral HPLC using the Chiralpak IA‑3 column referenced in the release specifications; a systematic stability study revealed that treatment with HATU/DIPEA (2.0 equiv. DIPEA, 0.5 M in DMF, 25 °C) for 4 h resulted in 0.3 % of the (R)-enantiomer, whereas substitution of DIPEA with N‑methylmorpholine (3.0 equiv.) reduced the enantiomer content to below the limit of detection (0.05 %). Coupling protocols that employ carbodiimides with 1‑hydroxybenzotriazole (HOBt) additives maintain optical purity within the same limits, provided the reaction temperature is kept below 0 °C during activation, a recommendation adopted from peptide segment condensation procedures on industrial kilo‑lab scales.
The hydrochloride salt form of the tert‑butyl ester is the preferred starting material for Fmoc protection, as the free base can absorb atmospheric CO₂ and form carbamates that complicate subsequent acylation. In a multi‑batch campaign for a β‑turn mimetic that required 500 g of Fmoc‑(S)‑β‑Pro‑OtBu, the free‑base route yielded 8–12 % batch‑to‑batch variation in Fmoc installation efficiency, attributed to variable carbamate content. Switching to the hydrochloride salt with a pre‑liberation step using 1.05 equiv. of sodium bicarbonate in chilled acetone eliminated the variability entirely, and the protected amino acid was isolated in 91 % yield after crystallisation, with chiral HPLC confirming 99.8 % ee.
Discrepancy alert: Published data for the exact racemisation half‑life of β‑proline tert‑butyl ester under microwave irradiation at 60 °C remains limited; early reports from peptide microsphere arrays indicate that the scaffold tolerates brief 5‑min cycles without measurable optical degradation, but direct extrapolation to 10 g solution‑phase reactions is not validated.
When the β‑proline tert‑butyl ester is compared to its α‑proline counterpart—proline tert‑butyl ester—the relocation of the carboxyl group from the 2‑ to the 3‑position removes the conformational rigidity imposed by the 2‑substituent near the amide bond. In practice, this yields a ring that is still locked in a pyrrolidine envelope but allows greater rotational freedom of the exocyclic N–C bond, which translates into slower coupling kinetics: Acylation of H‑Gly‑OMe with Fmoc‑β‑Pro‑OtBu using HATU/DIPEA in DMF reaches ≥99 % conversion after 60 min, whereas Fmoc‑Pro‑OtBu completes within 30 min under identical conditions. However, the β‑Pro building block shows markedly less interference with N‑methylation and N‑acylation‑induced ring opening, making it the scaffold of choice when the peptide backbone requires a tertiary amide within the cyclic constraint. Moreover, the enhanced acid stability of the tBu ester relative to trityl‑ or 2‑phenylisopropyl‑based groups allows the β‑Pro‑containing peptide to withstand acidic scavenger washes that are frequently necessary for methionine or tryptophan side‑chain deprotection—a process that would remove more labile ester protections prematurely. Any co‑formulation with free‑amine additives must be avoided, because amine‑catalysed β‑elimination of the tert‑butyl cation can lead to irreversible ester decomposition even at neutral pH if the reaction mixture contains adventitious moisture.
