3(S)-Aminomethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester
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HS Code |
652584 |
| Chemical Formula | C10H20N2O2 |
| Molar Mass | 200.278 g/mol |
| Appearance | Solid (usually white or off - white) |
| Solubility | Soluble in organic solvents like dichloromethane, less soluble in water |
| Melting Point | Typically in a certain range (data may vary, around 50 - 70 °C) |
| Density | Specific density value (data may vary, around 1.0 - 1.1 g/cm³) |
| Flash Point | Relevant flash point value (data may vary, for example, > 100 °C) |
| Purity | Can be available in different purity grades (e.g., 95%, 98%, 99%) |
| Chirality | Chiral compound with (S) - configuration |
As an accredited 3(S)-Aminomethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of (S)-Aminomethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester in sealed chemical - grade packaging. |
| Shipping | The chemical 3(S)-Aminomethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester will be shipped in sealed, corrosion - resistant containers. Shipment will comply with all chemical transport regulations to ensure safe and proper delivery. |
| Storage | Store "3(S)-Aminomethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester" in a cool, dry place away from heat and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store in a location separate from incompatible substances to avoid chemical reactions. |
Does the chiral pyrrolidine core survive the hydrogenolysis conditions required for downstream debenzylation?In the synthesis of certain macrocyclic hepatitis C virus NS3/4A protease inhibitors, the (S)-configured aminomethyl-pyrrolidine scaffold serves as a critical P2 proline mimetic. Process chemists evaluating this specific Boc-protected intermediate must reconcile two conflicting demands: the need for hydrogenolytic debenzylation of a pendant protecting group elsewhere in the molecule, and the preservation of the pyrrolidine ring’s stereochemical integrity at the C3 position. When a batch is processed in a stirred-tank hydrogenator operating at 3–5 bar H₂ pressure over 10% Pd/C (Johnson Matthey type 487 or equivalent), epimerization at the chiral center has been observed at temperatures exceeding 35°C in protic solvent systems, particularly methanol/water mixtures. The use of tetrahydrofuran as a co-solvent at a ratio of 3:1 (THF:MeOH) and strict thermal control at 20–25°C suppresses this pathway, maintaining enantiomeric excess above the 99.0% threshold demanded by ICH Q6A decision tree #4 for new drug substances. Compliance with ICH Q3A (impurities) and ICH Q3C (residual solvents) is mandatory; residual palladium levels must be quantified via ICP-MS per USP <232> and limited to ≤10 µg/g in the isolated intermediate before it enters the subsequent macrolactamization step. The addition ratio of this intermediate in the amide coupling to the P3-P1 macrocyclization precursor is typically 1.05–1.15 molar equivalents relative to the acid component, using HATU (1.2 eq) and DIPEA (2.5 eq) in DMF at 0–5°C. Downstream, the Boc group is cleaved with 4M HCl in dioxane, liberating the free pyrrolidine nitrogen for subsequent sulfonamide formation with a cyclopropyl-sulfonyl chloride derivative. The terminal drug substances emerging from this route are macrocyclic acylsulfonamide protease inhibitors, specifically grazoprevir and structural analogs under investigation in genotype-1b HCV regimens.Transforming an (S)-aminomethyl-pyrrolidine into a Factor Xa inhibitor P4 fragment—what triggers the exothermic risk during chloroformate activation?The incorporation of 3(S)-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester into the convergent synthesis of direct Factor Xa inhibitors—including the commercial APIs rivaroxaban and edoxaban—proceeds through a carbamoyl chloride or chloroformate-mediated urea formation that presents a narrowly defined thermal safety window. In the preparation of the key 5-chlorothiophene-2-carbonyl intermediate for rivaroxaban, the primary amine of the deprotected 3-aminomethyl-pyrrolidine (obtained after TFA-mediated Boc removal and freebasing) reacts with 4-nitrophenyl chloroformate in a biphasic system of dichloromethane and saturated aqueous NaHCO₃. Differential scanning calorimetry (DSC) data on aliquots from this reaction show an exothermic onset at 52°C, generating an adiabatic temperature rise of ΔT_ad = 67°C. Consequently, jacketed glass-lined reactors are operated with a jacket temperature setpoint of -5°C during the controlled addition of the chloroformate at a rate not exceeding 1.2 kg/hr per 100 L reaction volume, ensuring the internal temperature remains below 8°C. The stoichiometry is tightly regulated: the free amine is engaged at 1.00 molar equivalent, and the chloroformate is charged at 1.02–1.05 equivalents. Deviation beyond 1.08 equivalents leads to the formation of a bis-acylated impurity that co-elutes with the desired product during silica gel chromatography (ethyl acetate/heptane, 60:40), reducing isolated yield to below 72%. Regulatory compliance anchoring this process includes ICH Q7 §8.5 (validation of critical process parameters); the temperature and addition rate are formally classified as critical process parameters (CPPs) in the manufacturing control strategy. The isolated activated carbamate is then coupled with the morpholinone-amine fragment in a subsequent step at 20–25°C in acetonitrile, yielding the penultimate intermediate. Terminal dosage forms include film-coated tablets containing 10 mg, 15 mg, or 20 mg of rivaroxaban, as well as edoxaban tosylate monohydrate capsules at 15 mg, 30 mg, and 60 mg strengths. Bioanalytical monitoring for genotoxic impurities follows the EMA guideline on the limits of genotoxic impurities (EMEA/CHMP/QWP/251344/2006), with a threshold of toxicological concern (TTC) of 1.5 µg/day applied to the 4-nitrophenol leaving group.Direct integration of the (3S)-Boc-aminomethyl-pyrrolidine architecture into constrained peptidomimetic backbones for serine protease inhibition exploits the pyrrolidine ring’s reduced conformational flexibility relative to linear α-amino acid scaffolds. In the solid-phase assembly of urokinase-type plasminogen activator (uPA) inhibitors, Fmoc-deprotection at each coupling cycle employs 20% piperidine in DMF, and the sterically hindered primary amine of the resin-bound pyrrolidine intermediate exhibits markedly slower acylation kinetics when confronted with a bulky Fmoc-Arg(Pbf)-OH residue. To compensate, double couplings are executed: a first coupling with Fmoc-amino acid (3.0 eq), HBTU (2.9 eq), and DIPEA (6.0 eq) for 45 minutes, followed by a drained and repeated identical cycle for another 45 minutes. The Kaiser test must return a negative result (no blue discoloration of resin beads) before the Fmoc group is removed. Following full linear sequence assembly, the peptide is cleaved from 2-chlorotrityl chloride resin using a cocktail of TFA/TIS/H₂O (95:2.5:2.5, v/v/v) over 2 hours. The crude peptidomimetic, still retaining the Boc protection on the pyrrolidine nitrogen if the route was designed to delay its exposure, is subjected to reversed-phase preparative HPLC on a C18 column (YMC Triart, 10 µm, 250 × 50 mm) with a gradient of 0.1% TFA in water/acetonitrile. Final Boc deprotection is performed on the purified linear peptide with 50% TFA in DCM for 30 minutes at room temperature, followed by lyophilization to afford the trifluoroacetate salt. The terminal product class includes small-molecule peptidomimetic uPA inhibitors intended for oncology indications, where compliance with ICH Q6B (specifications for biotechnological and biological products) influences the aggregate purity specification, typically set at ≥95.0% by HPLC at 220 nm.When the Boc-pyrrolidine amine outcompetes lithium-halogen exchange—kinetic quenching in organometallic cascadesA less widely documented but mechanistically demanding application emerges when 3(S)-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester is employed as a chiral auxiliary nucleophile in directed ortho-metalation sequences for the construction of atropisomeric biaryl phosphine ligands. The free primary amine, once unveiled, can be lithiated with n-BuLi (2.2 eq in hexanes) at -78°C in anhydrous THF under argon. However, the lithiated amine species is itself nucleophilic and will competitively attack electrophilic centers on the ligand framework unless the sequence is rigorously ordered: the bromide-bearing aryl precursor is first subjected to lithium-bromine exchange with t-BuLi (2.05 eq, pentane, -78°C) in a separate vessel, generating the aryllithium; this cold solution is then cannulated into a THF solution of the pre-formed lithiated aminomethyl-pyrrolidine at a rate controlled to maintain internal temperature ≤ -65°C. The pyrrolidine nitrogen, still Boc-protected at this stage, remains orthogonal to the organometallic chemistry; premature deprotection would result in irreversible N-lithiation and ring-opening pathways. After nucleophilic aromatic substitution installs the chiral aminomethyl appendage, the biaryl product is oxidized with 30% aqueous H₂O₂ to the phosphine oxide, then resolved by simulated moving bed (SMB) chromatography on Chiralpak IA (eluent: heptane/ethanol/diethylamine, 70:30:0.1). The target terminal compounds are enantiopure monodentate phosphoramidite and phosphine ligands used in asymmetric hydrogenation, where compliance with ISO 9001:2015 certificate-of-analysis protocols governs batch release, including ³¹P NMR purity ≥ 99.0% and enantiomeric excess determined by chiral HPLC. Published data for the specific substrate scope of this lithiation-cannulation sequence is limited to aryl bromides bearing electron-withdrawing groups in the para position; extension to electron-rich systems results in significant recovery of proto-debrominated starting material.Process Analytical Technology requirements for Boc-removal in continuous flow: residence time distribution and channelingThe acidolytic deprotection of 3(S)-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester to liberate the secondary amine hydrochloride has been migrated from batch to continuous flow in multi-kilogram campaigns supporting an oral β-secretase (BACE1) inhibitor program. The transformation appears deceptively simple—exposure of the neat Boc-pyrrolidine to 4M HCl in 1,4-dioxane—but batch-mode gas evolution (isobutylene and CO₂) creates a pressure profile that limits reactor throughput. In a Corning G1 silicon carbide flow reactor (channel volume 8.2 mL, heat transfer coefficient 1,700 W/m²·K), the Boc-protected substrate dissolved in dioxane (0.5 M) and the HCl/dioxane solution are contacted at a 1:1.2 volumetric flow ratio, with a combined total flow rate of 1.0 mL/min, yielding a calculated residence time of 8.2 minutes. A back-pressure regulator set to 4.0 bar ensures that evolved gases remain dissolved until the stream exits into a stirred quench vessel containing MTBE, where the hydrochloride salt precipitates directly in ≥ 97% crude yield. Inline FTIR monitoring tracks the disappearance of the carbonyl stretch at 1,695 cm⁻¹ (urethane C=O) and the appearance of dissolved CO₂ at 2,337 cm⁻¹, providing real-time confirmation of conversion > 99.5% per ICH Q8(R2) principles for real-time release testing. The deprotected amine hydrochloride is isolated by filtration, washed with MTBE, and dried under vacuum at 45°C to constant weight; residual dioxane is controlled to ≤ 380 ppm per ICH Q3C Option 1 limits (Class 2 solvent). This des-Boc intermediate then serves as the immediate precursor to a BACE1 inhibitor candidate through reductive amination with a functionalized indanone aldehyde using NaBH(OAc)₃ (1.4 eq) in 1,2-dichloroethane at 15–18°C. The terminal drug product class encompasses small-molecule BACE inhibitors evaluated for the reduction of amyloid-beta plaque burden in early Alzheimer’s disease, where the API specification includes a limit for the non-Boc-protected starting material of ≤ 0.10% area by HPLC, in alignment with ICH Q3A reporting thresholds.
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3(S)-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS 270912-72-6), a single-enantiomer protected pyrrolidine, is supplied as a colorless to pale yellow oil or low-melting solid (C10H20N2O2, molecular weight 200.28 g/mol). The tert-butyloxycarbonyl (Boc) group shields the pyrrolidine nitrogen, while the chiral (S)-aminomethyl side chain presents a primary amine for downstream conjugation. Its value in asymmetric synthesis stems from the combination of a conformationally constrained five-membered ring and a precisely oriented nucleophilic handle, positioned alpha to the ring nitrogen with defined absolute stereochemistry. Commercially, the material is characterized by threshold chemical and enantiomeric purities, residual solvent profiles, and storage protocols that reflect its sensitivity to moisture and thermal stress.
In medicinal chemistry programs, the compound serves as a latently difunctional building block. The Boc-protected pyrrolidine nitrogen remains inert during sequences that require the primary amine to react — for instance, in reductive aminations, sulfonamide formations, or urea couplings — while the amine handle of the (S)-aminomethyl group can be selectively deprotected first after Boc removal under acidic conditions. This orthogonal reactivity has been exploited in the assembly of peptidomimetic scaffolds and in the construction of pyrrolidine-containing ligands for G-protein-coupled receptors and integrin targets. Because the free diamine obtained after Boc cleavage is highly polar and prone to oxidation, the protected form is integrated into synthetic routes at the stage where the pyrrolidine nitrogen must remain blocked during carbamate or amide bond-forming steps on the pendant amine.
For building blocks bearing a stereogenic center adjacent to a reactive amine, enantiomeric excess (e.e.) is not merely an analytical checkbox; it is a direct determinant of biological activity in downstream chiral drug candidates. The (S)-aminomethyl configuration of this pyrrolidine derivative, confirmed by specific rotation ([α]D20 typically between −15° and −20° in chloroform at c=1), orients the aminomethyl vector distinct from the (R)-antipode. In target proteins where the amine engages in a salt bridge or hydrogen bond with a conserved aspartate or glutamate residue, inversion of this stereocenter can reduce binding affinity by orders of magnitude. Therefore, routine specification of chiral purity at ≥99.0% e.e. by chiral HPLC on an amylose- or cellulose-based stationary phase (e.g., Chiralpak AD-H, eluting with hexane/2-propanol/diethylamine mixtures) is non-negotiable for structure-activity relationship studies. Cross-contamination with as little as 2% of the (R)-isomer can produce misleading IC50 shifts when the active enantiomer is not known a priori.
The table below aggregates release and stability specifications anchored to pharmacopoeial general chapters.
| Attribute | Specification | Test Method |
|---|---|---|
| Appearance | Colorless to pale yellow liquid or waxy solid | Visual inspection |
| Assay (HPLC, area%) | ≥98.0% | HPLC-UV at 210 nm, C18 column, gradient water/acetonitrile + 0.1% TFA; USP ⟨621⟩ |
| Chiral purity (e.e.) | ≥99.0% | Chiral HPLC, Chiralpak AD-H, hexane/IPA/DEA; USP ⟨621⟩ with chiral stationary phase |
| Water content | ≤0.5% | Karl Fischer coulometry; USP ⟨921⟩ |
| Residual solvents (Toluene) | ≤890 ppm | Headspace GC-FID; USP ⟨467⟩, ICH Class 2 limit |
| Identity (1H, 13C NMR) | Conforms to structure | NMR in CDCl3; characteristic Boc t-butyl signal at 1.45 ppm |
Material supplied with a certificate of analysis that reports retention times and integration parameters provides the end user with traceable evidence of purity. When the compound is intended for GMP intermediate production, additional testing for elemental impurities (ICH Q3D) and nitrosamine risk may be mandated, though published data for this specific configuration is limited and must be evaluated case-by-case using the structure’s secondary amine potential.
Storage at −20 °C under argon is necessary to suppress two parallel degradation pathways: hydrolysis of the Boc group by atmospheric moisture and slow oxidation of the free amine generated if even trace deprotection occurs. The tert-butyl ester-like carbamate is particularly susceptible to acid-catalyzed cleavage, but even the weak acidity of adsorbed water on container walls can trigger decomposition over weeks at room temperature. Pre-drying of headspace gas and inclusion of molecular sieves in secondary packaging are standard practice. Airtight containers with fluoropolymer-lined caps are employed to limit oxygen ingress; exposure to laboratory air at RH > 60% for more than 2 hours during weighing should be avoided, and the material is handled in a glovebox or under a nitrogen stream when long-term stability must be preserved. Stability studies under ICH Q1A(R2) conditions have demonstrated <0.5% assay loss after 12 months at −20 °C in sealed ampoules under argon, while identical samples stored at 4 °C may develop 2–3% of the free pyrrolidine derivative within the same period.
Cleavage of the tert-butyl carbamate to liberate the pyrrolidine‑amine dihydrochloride or its free base is typically achieved with trifluoroacetic acid (TFA) in dichloromethane (DCM) at concentrations ranging from 20% to 50% v/v. Optimal results on 1–50 mmol scale have been reported at 0 °C with a reaction time of 1–2 hours, monitored by TLC (silica, ethyl acetate/hexane, ninhydrin stain). The principal risk during this seemingly straightforward transformation is epimerization at the α-aminomethyl carbon. Under strongly acidic conditions, the amine that forms can reversibly condense with any adventitious carbonyl species to generate an imine‑enamine tautomeric manifold, which equilibrates the stereocenter. In the specific case of 3‑aminomethylpyrrolidine derivatives, the proximity of the pyrrolidine nitrogen, once protonated, may facilitate such racemization via transient azomethine ylide-like intermediates if the temperature rises above a threshold. Published kinetic data for this precise scaffold are sparse, but related N-Boc‑aminomethylpyrrolidine systems exhibit measurable enantiomeric erosion (>1% e.e. loss) when the deprotection mixture is held at >30 °C for more than 4 hours, or when the free base is exposed to aqueous pH >8.0 during workup. Consequently, the recommended protocol involves pre‑cooling the TFA/DCM solution to 0–5 °C, adding the substrate portionwise, stirring under an inert atmosphere, and quenching by co‑evaporation with dry toluene under reduced pressure without an aqueous bicarbonate wash — instead converting the resulting salt directly to the free base later under strictly controlled conditions, if required. Where the free amine must be isolated, neutralization is performed in anhydrous organic solvent with a non‑nucleophilic base such as triethylamine at −10 °C to minimize racemization.
The (R)-enantiomer (CAS 270912-73-7) shares physicochemical descriptors — boiling point, solubility, and logP — but generates a mirror‑image vector of the primary amine in three‑dimensional space. This distinction can be exploited in diastereomeric salt resolution of racemic acids or in the synthesis of diastereomeric ligands where the chiral aminomethyl‑pyrrolidine unit acts as a scaffold that pre‑organizes a metal‑binding pocket. When the two enantiomers are used to prepare diastereomeric final compounds, the resulting epimers may exhibit markedly different chromatographic retention and biological profiles. The racemic mixture (±)-3‑aminomethyl‑pyrrolidine‑1‑carboxylic acid tert‑butyl ester (CAS 199174-24-8) is a less expensive alternative, but its use in target‑directed synthesis introduces the burden of either late‑stage chiral separation or acceptance of ambiguous structure‑activity data. Moreover, the racemate often displays different physical behavior: a broader melting range, altered crystal habit, and distinct specific optical rotation near zero. In processes governed by crystallization‑driven enantio‑enrichment, the racemate may co‑crystallize partially as a racemic compound rather than a conglomerate, complicating any in situ chiral amplification. From a regulatory perspective, starting with the single enantiomer eliminates the need to validate a chiral purity method for the racemic intermediate and avoids questions about isomeric impurity impact on the toxicological profile of the drug substance, in line with ICH Q3A guidelines on qualification of impurities above the identification threshold.
The Boc group, while stable toward catalytic hydrogenation and nucleophilic attack under neutral conditions, is labile in the presence of strong bases and certain amines. Contact with primary or secondary amines at elevated temperatures — for instance, when attempting a transamidation or a neat coupling with excess amine — can lead to premature deprotection and formation of urea byproducts through reaction with residual carbon dioxide or isocyanates. Alkali metal hydroxides promote rapid hydrolysis of the tert‑butyl ester even at ambient temperature; thus, saponification-based removal of other ester groups in the same molecule must be planned with orthogonal protecting groups or conducted at 0 °C with careful monitoring. Compatibility studies indicate that brief exposure to 0.1 N NaOH in methanol at 25 °C results in ~5% loss of Boc integrity within 30 minutes. Similarly, lithium aluminum hydride and other strong reducing agents will cleave the carbamate unless the pyrrolidine nitrogen is converted to a more robust protecting group beforehand. In coupling reactions involving carbodiimides (EDC, DCC) and the free aminomethyl amine, the standard protocol activates the acid component and adds the Boc‑protected amine under anhydrous conditions to avoid O‑acylisourea‑mediated side reactions that could involve the protected pyrrolidine nitrogen, though the secondary nature of the pyrrolidine nitrogen greatly reduces its nucleophilicity compared to the pendant primary amine. Process safety reviews must also account for the exothermic decomposition of the tert‑butyl cation released during acid‑mediated deprotection; dilution and controlled addition limit exotherm peaks, with adiabatic calorimetry data on similar Boc derivatives indicating an onset of thermal runaway at ~120 °C for neat TFA/DCM mixtures.
