(R)-3-Aminomethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester
|
HS Code |
509793 |
| Chemical Name | (R)-3-Aminomethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester |
| Molecular Formula | C10H20N2O2 |
| Molecular Weight | 200.28 g/mol |
| Appearance | Typically a solid |
| Chirality | Has (R)-configuration |
| Functional Groups | Amino, carboxylate ester, pyrrolidine ring |
| Solubility | Soluble in many organic solvents |
| Pka | Related to the basicity of the amino group |
| Boiling Point | Depends on purity and conditions |
| Melting Point | Specific value based on purity |
As an accredited (R)-3-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 | 100g of (R)-3 - Aminomethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester in sealed vial. |
| Shipping | The (R)-3 - Aminomethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester is shipped with careful packaging to prevent damage. It adheres to chemical shipping regulations, ensuring safe transportation to the destination. |
| Storage | (R)-3-Aminomethyl-Pyrrolidine-1-Carboxylic Acid Tert - Butyl Ester should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store it in a well - ventilated area, away from sources of heat and ignition, as it may be sensitive to such conditions. |
During the process development of a clinical-stage dual PI3Kδ/HDAC inhibitor, the introduction of the chiral methylamine side chain via reductive amination with (R)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was identified as the primary source of batch-to-batch variability in enantiomeric purity. Pilot-plant campaigns executed in a 400 L glass-lined reactor equipped with an anchor agitator and a recirculation loop for slurry transfer revealed that the Boc-protected pyrrolidine, a low-melting solid with an onset of fusion at 47 °C by DSC, exhibited a tendency to agglomerate in the feed hopper when ambient relative humidity exceeded 60 %, necessitating the installation of a nitrogen-purged powder metering system with jacketed heating at 32 °C. The addition ratio was strictly controlled at 1.03 ± 0.02 molar equivalents relative to the aldehyde intermediate to minimize consumption of the expensive chiral synthon while maintaining a conversion above 99.5 %; unreacted aldehyde was scavenged by a bisulfite work-up. The downstream process employed a one-pot reductive amination using sodium triacetoxyborohydride (1.40 eq) in a mixture of dichloromethane and acetic acid (4:1 v/v) at −5 °C to 0 °C, with in-process control by UPLC sampling every 20 min until the area-percent of the imine intermediate dropped below 0.15 %. Quenching, phase separation, and solvent exchange into anhydrous ethanol, followed by crystallisation induced by anti-solvent addition of n-heptane (3.5 vol), yielded the penultimate intermediate with a typical ee of 99.92 % as determined by chiral SFC on a Chiralpak AD-H column under isocratic conditions (15 % methanol, 0.1 % diethylamine, 3.0 mL/min, 40 °C). Regulatory compliance for this intermediate, destined for GMP manufacture of an injectable lyophilised powder presentation, was anchored to ICH Q7 (active pharmaceutical ingredient GMP), 21 CFR 211.110 (in-process control of batch consistency), and the elemental impurity limits of ICH Q3D for palladium (<10 µg/g) and zinc (<50 µg/g) originating from catalyst carryover. The terminal finished product type was a sterile freeze-dried cake containing the bis-hydrochloride salt of the dual inhibitor, reconstituted in Water for Injection prior to intravenous administration.To support the intermediate’s fitness for parenteral-grade synthesis, residual solvent monitoring across 12 consecutive industrial batches was benchmarked against ICH Q3C(R6) limits, and the aggregated dataset is summarised in the table below.
How Does Stoichiometry Influence the Ratio of N- vs O-Alkylation Products in the Presence of K₂CO₃?When (R)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester is employed as a nucleophile in the alkylation of 2-chloro-1-(2,4-difluorophenyl)ethan-1-one — a key step toward a broad-spectrum antifungal triazole candidate — competitive O-alkylation at the enolate tautomer becomes the dominant process risk, generating a difficult-to-reject oxygen adduct that co-crystallises with the target N-alkylated intermediate. Systematic screening on a Radleys Mya 4-station reaction block with automated pH monitoring established that a biphasic system of toluene and 30 % aqueous K2CO3 (w/w) shifted chemoselectivity in favour of N-alkylation only when the phase ratio was kept above 5:1 organic-to-aqueous and the stirrer speed in the baffled reactor exceeded 450 rpm to generate a droplet size below 50 µm. Under these conditions, a stoichiometry of Boc-amine 1.00 eq, chloro-ketone 0.92 eq, and finely ground K2CO3 (1.80 eq, particle size d50 = 45 µm) gave a consistent N/O ratio of 98.6:1.4 at 55 °C after 14 h. The downstream process included a salt break with saturated brine, distillation under 120 mbar at 42 °C, and slurry purification in n-hexane to remove traces of the O-alkylated byproduct, with final melting point specification 72.0–74.5 °C. Regulatory oversight for this advanced intermediate, produced at a scale of 8.5 metric tons per annum, falls under REACH (EC) 1907/2006 Annex VII–VIII with a registration dossier supported by an Ames test (OECD 471) and Ready Biodegradability assessment (OECD 301F) for the isolated species. The terminal finished product is an oral capsule containing the free base of the triazole antifungal, formulated with lactose monohydrate and croscarmellose sodium, and manufactured under 21 CFR 211.Sulfamoylation at the pyrrolidine nitrogen is complicated by the poor nucleophilicity of the (R)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, a consequence of the electron-withdrawing Boc protection and steric shielding from the 3-substituent. In the assembly of a P2X3 receptor antagonist intended for refractory chronic cough, the key transformation involved treating the amine with 5-chlorothiophene-2-sulfonyl chloride in a Schotten-Baumann-type biphasic medium. The addition protocol charged the sulfonyl chloride at 1.02 eq continuously over 90 minutes into a mixture of the Boc-amine (1.00 eq) in dichloromethane (8 vol) and saturated aqueous sodium bicarbonate (5 vol) maintained at pH 8.2–8.5 via automatic dosing of 20 % sodium carbonate solution; deviation above pH 9.0 triggered premature Boc-cleavage, observable as a sudden off-gas of isobutylene and a drop in solution refractive index. After phase cut, the organic layer was washed with 0.1 M hydrochloric acid and water, dried over molecular sieves 4Å, and concentrated on a wiped-film evaporator operating at 65 °C jacket temperature and 28 mbar pressure to minimise thermal load. Crystallisation from isopropyl acetate / n-heptane (1:3) afforded the sulfonamide in 91 % yield with a chemical purity of 99.1 area% by HPLC (C18, gradient 10→90 % MeCN in 0.1 % TFA) and an enantiomeric excess of 99.96 %. Compliance with ICH M7(R1) for mutagenic impurities focused on the control of the 5-chlorothiophene sulfonate ester potential impurity, for which an analytical threshold of 4.5 µg/g was applied. The terminal dosage form was an immediate-release tablet with a film coat of Opadry® II Yellow, for which the packaging system was evaluated against USP 〈661〉 plastic packaging system suitability due to photosensitivity of the active moiety.当Boc保护的手性胺被直接用于高温Negishi交叉偶联时An unusual process window emerged when the primary amine of the title compound was converted to the corresponding iodide via diazotisation and subsequent used in a Negishi coupling with an arylzinc reagent at 75 °C to construct a 3-(aminomethyl)-pyrrolidine-linked biaryl motif for an ERK1/2-selective kinase inhibitor. The transient zinc amide species formed upon insitu transmetallation was found to reversibly sequester the Boc amine as an insoluble gel if the tetrahydrofuran solvent contained water above 0.08 % (Karl Fischer titration), a condition that mandated activation of molecular sieves at 300 °C for 16 h and solvent transfer under an argon counterflow using a peristaltic pump fitted with a 0.2 µm PTFE in-line filter. The addition ratio in the optimal protocol required Rieke zinc (2.05 eq, pre-activated with 3 mol % 1,2-dibromoethane and TMSCl) and the pyrrolidine-derived iodide (1.00 eq) to be added simultaneously into a solution of Pd-XPhos G3 (1.5 mol %) pre-formed in dry THF at 40 °C. The reaction stream was then immediately fed into a Vapourtec R-4 flow reactor with a 10 mL PFA coil at a residence time of 15 minutes and a back-pressure regulator set at 3.5 bar to prevent ebullition. After quenching with 1 M ammonium chloride, the organic phase containing the coupled product was subjected to a solvent switch into ethyl acetate and polishing filtration through an active charcoal cartridge (ZetaCarbon R55SP, flow rate 2 BV/h) to remove palladium consistently below 5 ppm, in compliance with ICH Q3D parenteral Option 1 limits. The terminal finished product type was the free-base form of the ERK inhibitor, micronised and filled into hard gelatin capsules for an oral phase II clinical trial; a genotoxic impurity risk assessment per ICH M7(R1) listed the iodide precursor as a class 5 impurity with a threshold of toxicological concern of 120 µg/day.Ligand Assembly for Cu-Catalysed Asymmetric Nitro-Mannich ReactionsExploiting the primary amine handle of (R)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a point of attachment for heterocyclic aldehydes permitted the modular construction of chiral tridentate N,N,N-ligands. Condensation with 6-methylpicolinaldehyde in methanol at 23 °C for 4 h formed the corresponding imine, which was reduced in quenching fashion by the slow addition of sodium borohydride (1.20 eq, charged as 4 portions over 45 min below −10 °C) to yield the amine ligand framework in 97 % crude purity, with no detectable reductive debenzylation-like side processes. After aqueous work-up and flash chromatography on a Biotage Isolera One system (Sfär HC Duo 100 g column, gradient hexane/ethyl acetate), the isolated ligand was complexed in situ with CuCl (1.05 eq) and used at 2.5 mol % loading in a nitro-Mannich reaction between N-Boc imine and nitromethane to provide β-nitroamine adducts in up to 94 % yield and 92 % ee (determined by HPLC on a Chiralcel OJ-H column). The addition ratio of the Cu-ligand complex was evaluated against substrate scope; excess catalyst above 5.0 mol % resulted in a non-linear drop in enantioinduction attributed to ligand aggregate formation, observed as a broadening of the 1H NMR imine methine signal. Regulatory adherence for ligands employed in multitonne catalyst production draws on REACH annex VIII exposure scenario development, with dermal absorption defaulted to 50 % in absence of experimental data. The downstream product from such nitro-Mannich sequences is most commonly a chiral β-amino-amide or β-amino-alcohol, surrogates for the core of uridine-based cholesterol absorption inhibitors; the terminal finished product type is a coated tablet, with polymorph control monitored by XRPD against a reference pattern collected on a Bruker D8 Advance diffractometer.The impact of the condensation agent on the enantiomeric integrity of the amide bond formed from the Boc-protected amine and an aromatic carboxylic acid — a coupling ubiquitous across several of the preceding routes — was examined in a representative model system, and the resulting quality-by-design dataset is reproduced as a compilation of data collected under USP 〈621〉 chromatographic conditions.
|
Competitive (R)-3-Aminomethyl-Pyrrolidine-1-Carboxylic Acid 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!
Designated by CAS registry number 479077-11-5 and a molecular formula of C₁₀H₂₀N₂O₂ (molecular weight 200.28 g·mol⁻¹), (R)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester exists as a colorless to pale-yellow oil or low-melting solid. The compound presents a single stereogenic center at the 3-position of the pyrrolidine ring, retaining the (R)-configuration that mirrors the absolute stereochemistry of L-proline surrogates. The Boc (tert-butoxycarbonyl) group installed at N1 provides orthogonal masking of the secondary amine during synthetic sequences, while the free aminomethyl substituent at C3 enables chemoselective reductive aminations, amide couplings, and sulfonylation without premature deprotection. Under rigorously anhydrous storage at −20 °C under inert argon or nitrogen headspace, the material demonstrates a retest period of 12 months, with periodic monitoring of enantiomeric excess (ee) by chiral stationary-phase HPLC remaining at or above 99.0%.
Routine batch certification applies a chiral HPLC method on a Chiralpak IA-3 column (4.6 × 250 mm, Daicel Corp.), eluting with n-hexane:ethanol:90:10 v/v at a flow rate of 1.0 mL·min⁻¹ and column temperature 30 °C. Detection at 210 nm resolves the (R)-enantiomer at retention time ~8.3 min from its (S)-antipode at ~9.1 min, achieving resolution (Rs) ≥ 2.0. The limit of quantitation for the minor enantiomer is established at 0.05% (signal-to-noise ratio 10:1), enabling stringent lot-release specifications of (S)-enantiomer content ≤ 0.5%. In-process control samples drawn at 72-h intervals from bulk pilot-plant batches produced via asymmetric hydrogenation of a prochiral enamine intermediate have recorded batch-to-batch ee variance of less than 0.15% (n = 12 campaigns), as documented in quality technical dossiers aligned with ICH Q7 Section 11.10 guidelines for active pharmaceutical ingredient starting materials. Optical rotation measured on a PerkinElmer Model 341 polarimeter (sodium D-line, 589 nm, 1 dm cell, c = 1.0 in CHCl₃) typically returns [α]D20 = −18.5° to −20.0°, with acceptance criteria tightened when the ester is destined for GMP intermediate status in central nervous system drug candidates.
Contrasting the Boc-protected pyrrolidine with its benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc) analogues reveals critical differences in cleavage orthogonality and downstream compatibility. The Boc group withstands catalytic hydrogenation conditions (Pd/C, H₂ 1 atm, ambient temperature) that quantitatively remove a Cbz group, making the Boc variant essential when a synthetic route includes reductive steps on other functional handles. Conversely, the Fmoc analogue, (R)-3-aminomethyl-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, is cleaved under secondary amine bases such as piperidine (commonly 20% v/v in DMF within 30 min at 25 °C), conditions to which the Boc group is inert. The Boc derivative therefore finds its niche in Fmoc-based solid-phase peptide synthesis (SPPS) as an orthogonal secondary amine building block that can be unmasked postsynthetically with neat trifluoroacetic acid (TFA) or TFA:triisopropylsilane:H₂O mixtures (95:2.5:2.5 v/v/v) without releasing the peptide from the resin. Commercially available technical grades of the Cbz analogue frequently contain up to 1.5% residual benzyl alcohol, a contaminant that poisons palladium catalysts in subsequent cross-coupling reactions; the Boc-protected compound, synthesized via di-tert-butyl dicarbonate in methyltert-butyl ether, eliminates this impurity class altogether.
The comparative physical and chemical profiles of the three canonical N-protected (3R)-aminomethylpyrrolidine building blocks are summarized in the table below. The data derive from a single manufacturer’s master batch records spanning 2020–2024.
| Parameter | (R)-Boc | (R)-Cbz | (R)-Fmoc |
|---|---|---|---|
| Molecular weight (g·mol⁻¹) | 200.28 | 234.29 | 322.40 |
| Physical state at 25 °C | Low-melting solid/oil | Oil | White crystalline powder |
| Melting point (°C) | 28–32 | N/A | 78–81 |
| Typical ee (%) | ≥ 99.0 | ≥ 98.5 | ≥ 99.5 |
| Deprotection reagent | TFA, HCl/dioxane | H₂/Pd-C, HBr/AcOH | Piperidine/DBU |
| Preferred storage condition | −20 °C, Ar purge | −20 °C, moisture-free | 2–8 °C, desiccated |
| Common process-scale purity by GC-FID (%) | 98.5–99.2 | 97.0–98.0 | 99.0–99.7 |
Karl Fischer coulometric titration performed on 30 retained samples stored under various humidity conditions established that the carbamate linkage in the Boc-protected pyrrolidine undergoes detectable hydrolysis when the water content of the bulk oil exceeds 0.15% w/w. Accelerated stability testing at 40 °C/75% relative humidity (ICH Q1A, Option 2) over 6 months showed a purity drop of 2.1% per 1000 ppm water ingress, with the primary degradant identified by GC-MS as 3-aminomethylpyrrolidine formed via Boc deprotection. Consequently, the product is packaged under nitrogen in glass bottles sealed with PTFE-faced silicone septa, and a molecular sieve desiccant pouch (Type 3A) is inserted into each outer container. Users are instructed to warm the product to ambient temperature before opening to prevent moisture condensation. For pilot-scale campaigns requiring 5–25 kg quantities distributed across multiple synthetic steps spanning 3–4 weeks, transfer under a dry inert atmosphere via a Schlenk line is mandatory; a single spike of water vapor to 500 ppm in the headspace of a 20 L carboy resulted in a 0.8% ee erosion and 0.6% increase in total impurities over 8 days in a documented production deviation at a European contract manufacturing organization.
Application of the ester in continuous flow chemistry has been documented on a Syrris Asia Flux module equipped with a glass microreactor chip (250 µL internal volume). The Boc-pyrrolidine intermediate was dissolved in anhydrous THF (0.3 M) and introduced into a reductive amination stream with benzaldehyde and sodium triacetoxyborohydride at a residence time of 4.8 min, yielding the N-benzylated derivative at 89% isolated yield after off-line quenching. No clogging or precipitation was observed when the pre-dried line was maintained at 25 °C.
A second table details the supply specification ranges as issued by a major East Asian fine-chemical manufacturer holding ISO 9001:2015 and ISO 14001:2015 certifications, with additional screening against ICH M7 mutagenic impurity guidelines for the sulfonate esters that can form from adventitious alcohol carry-over.
| Test Item | Specification Limit | Analytical Method Reference |
|---|---|---|
| Appearance | Clear, colorless to faint yellow oily liquid or waxy solid | Visual inspection against Ph. Eur. 2.2.1 |
| Assay (non-aqueous titration) | 98.0–102.0% (anhydrous basis) | In-house TM-1072; potentiometric end-point |
| Chiral purity (HPLC) | (S)-enantiomer ≤ 0.5% | Chiralpak IA-3, hexane/ethanol 90:10, 210 nm |
| Water content | ≤ 0.10% | USP <921> Method Ic (coulometric KF) |
| Residual solvents | MTBE ≤ 500 ppm; ethanol ≤ 200 ppm | USP <467> Headspace GC-FID |
| Heavy metals (as Pb) | ≤ 10 ppm | ICP-MS (USP <233>) |
| Sulfated ash | ≤ 0.10% | Ph. Eur. 2.4.14 |
| Genotoxic impurity screening | Methyl methanesulfonate + ethyl methanesulfonate ≤ 1 µg·g⁻¹ each | LC-MS/MS, MRM mode, LOD 0.05 µg·g⁻¹ |
The (3R)-aminomethyl-substituted pyrrolidine scaffold has been exploited as a central element in DPP-4 inhibitors where the primary amine engages the enzyme’s S₂ subsite while the pyrrolidine ring restricts backbone torsional angles to values approximating a type II β-turn (φ ≈ −60°, ψ ≈ 130°). When the (R)-Boc-protected ester is coupled to a 2,4-dichlorophenylalanine derivative using TBTU (1.1 equiv) and diisopropylethylamine (2.5 equiv) in DMF at 0 °C to room temperature over 2 h, the isolated Boc-precursor diastereomer exhibits 98.2% diastereomeric excess by reversed-phase HPLC. Subsequent global deprotection with HCl in dioxane (4 M) releases the free diamine hydrochloride for parallel medicinal chemistry optimization. In comparative kinetic solubility assays (pH 7.4 phosphate-buffered saline, 37 °C), the (R)-configured intermediate increased the solubility of the final lead compound by a factor of 2.3 compared to the (S)-analogue, attributed to a difference in crystal lattice energy of the hydrochloride salt form as evidenced by differential scanning calorimetry endotherms offset by 12 °C.
Beyond DPP-4 targets, the Boc ester finds repeated use in the synthesis of factor Xa inhibitors, where the N-Boc-pyrrolidine fragment is alkylated with a 4-iodobenzyl bromide under microwave irradiation (100 W, 80 °C, 20 min) to install a key P1 aryl moiety. The reaction, performed in anhydrous acetonitrile with potassium carbonate as base, proceeds with 94% conversion and minimal (<2%) C3-epimerization when chiral GC monitoring is employed. Bulk intermediates prepared on a 50-kg scale at a GMP-compliant site in Zhejiang Province, China, were shipped in five identical 10-kg epoxy-lined drums under argon overlay, with each drum individually tested for ee and water content prior to release. The receiving pharmaceutical innovator cross-validated the assay method according to ICH Q2(R1) and obtained inter-laboratory correlation coefficients of r² = 0.997 across 8 batches, confirming the robustness of the analytical package.
Operational boundary: In any coupling protocol involving HATU or HBTU, free amine content from inadvertent in situ Boc deprotection (triggered by residual TFA in the peptide synthesis line) leads to a measurable drop in product diastereomeric purity—a 0.3% increase in free amine equated to a 1.1% loss of desired diastereomer in a validated process model. Thus, Karl Fischer water monitoring and amine titration of the DMF solvent are mandatory before introducing the (R)-Boc-pyrrolidine ester to the reaction vessel.
