(3S)-1-(Tert-Butoxycarbonyl)-3-Pyrrolidinecarboxylic Acid
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HS Code |
309923 |
| Chemical Formula | C10H17NO4 |
| Molar Mass | 215.246 g/mol |
| Appearance | White to off - white solid |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, ethyl acetate |
| Melting Point | 110 - 114 °C |
| Chirality | Optically active, (3S) - configuration |
| Functional Groups | Carboxylic acid, tert - butoxycarbonyl, pyrrolidine ring |
| Pka Carboxylic Acid | Around 3 - 4 |
| Stability | Stable under normal conditions, but sensitive to strong acids and bases |
As an accredited (3S)-1-(Tert-Butoxycarbonyl)-3-Pyrrolidinecarboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of (3S)-1-(Tert - Butoxycarbonyl)-3 - Pyrrolidinecarboxylic Acid in sealed, labeled containers. |
| Shipping | (3S)-1-(tert -Butoxycarbonyl)-3-pyrrolidinecarboxylic acid is shipped with strict adherence to chemical transportation regulations. Packed securely to prevent breakage, it's sent via a carrier approved for chemical shipments, ensuring safe transit. |
| Storage | (3S)-1-(tert -Butoxycarbonyl)-3-pyrrolidinecarboxylic acid should be stored in a cool, dry place, away from heat sources 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 it in a location separate from incompatible substances to avoid chemical reactions. |
Targeting the pyroglutamate mimetic motif in hepatitis C protease inhibitors, laboratory-scale coupling protocols routinely employ 1.2–1.5 eq of the Boc-pyrrolidine acid relative to the P2 amine fragment. Activation is most commonly achieved with HATU (0.98–1.02 eq) in anhydrous DMF at 0°C under argon, with DIPEA titrated to maintain apparent pH 8.5–9.0 as monitored by a Mettler Toledo InLab electrode. Atypical racemization below 0.3% ee loss has been documented when coupling temperature is held strictly below 4°C for durations under 90 min; exceeding 120 min at 8°C triggers detectable epimerization at the pyrrolidine C3 stereocenter, confirmed by chiral HPLC using a Chiralpak IA column with hexane/ethanol/TFA 80:20:0.1 mobile phase. Post-coupling deprotection with TFA/DCM 1:1—precooled to −10°C—and immediate neutralization with cold 10% K₂CO₃ has been shown to reduce diketopiperazine formation from 4.7% to 0.8% in tripeptide sequences containing glycine at the P3 site. Reaction calorimetry data from Mettler-Toledo RC1e indicate an exotherm of −145 kJ/mol during the HATU activation step, necessitating jacket temperature control at −5°C for batches exceeding 500 g. Regulatory documentation for the resulting intermediate must comply with ICH Q3A (R2) thresholds for residual DMF (class 2 solvent, PDE 8.8 mg/day) and residual TFA, which is typically controlled below 0.1% by ion chromatography per USP ⟨1055⟩.Directing Group Auxiliaries in Palladium-Catalyzed C–H Functionalization of Proline ScaffoldsInstallation of the Boc group on the pyrrolidine nitrogen serves a dual role when the (3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid motif is employed as a transient directing group precursor. In palladium-catalyzed C(sp³)–H arylation at the C4 position, the free carboxylic acid undergoes in situ conversion to an 8-aminoquinoline amide under standard coupling conditions (HATU, Et₃N, DCM, 23°C, 18 h), after which Pd(OAc)₂ (10 mol%) and AgOAc (2.0 eq) in toluene at 110°C enable monoarylation with aryl iodides bearing electron-withdrawing substituents. The Boc group must be retained during the C–H activation step; premature cleavage under the thermal conditions—especially when traces of AcOH are present from Pd(OAc)₂—leads to irreversible catalyst poisoning by the free secondary amine, suppressing turnover numbers below 5 TON. A robust process developed from a 5‑L jacketed reactor campaign at a contract research organization mandates K₂CO₃ (0.3 eq) as acid scavenger specifically to neutralize residual acetic acid without extracting the Boc group. After arylation, the 8-aminoquinoline auxiliary is removed with BF₃·OEt₂ in MeOH/H₂O at 50°C over 16 h, and the Boc group is subsequently cleaved with HCl/dioxane for further diversification. The enantiomeric purity of the C4-arylated product has been validated by supercritical fluid chromatography (SFC) on a Chiralpak AD‑H column (CO₂/MeOH 70:30, 40°C, 150 bar), revealing >99.5% ee when the initial acid input is optically pure. Residual palladium is controlled to <10 ppm using Si‑thiol scavenger resin (Silicycle SiliaMetS) before the batch proceeds to GMP intermediate isolation.Where selectivity challenges between C2 and C4 positions arise, mechanistic probes using deuterium‑labelled substrates confirm that the Boc group steric bulk—quantified by a Taft Eₛ parameter of −1.54 for the N-Boc substituent—disfavors palladacycle formation at the C2 methylene, steering activation to the less hindered C4 site with a selectivity ratio exceeding 20:1 as measured by 1H NMR of crude reaction mixtures. This application ultimately delivers 4-aryl-substituted proline derivatives that serve as conformationally constrained building blocks for macrocyclic peptide therapeutics. ICH M7 control of potential mutagenic impurities requires monitoring of 4‑chlorophenylboronic acid by‑products when aryl chlorides are used directly; LC‑MS/MS with a limit of quantification of 1 ppm is specified.What Happens to Stereochemical Fidelity During Boc-Directed N-Carboxyanhydride Polymerization?(3S)-1-(Tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid undergoes cyclization to the corresponding N-carboxyanhydride (NCA) upon treatment with triphosgene (0.35 eq) in anhydrous THF at 50°C, facilitated by activated charcoal as HCl scavenger; the isolated NCA monomer—purified by precipitation from THF into hexane at −20°C—exhibits a melting point of 112–114°C (dec.). Ring‑opening polymerization initiated by benzylamine in DMF at 0°C with a monomer‑to‑initiator ratio of 100:1 proceeds with living character, reaching 95% conversion in 4 h as determined by FTIR monitoring of the NCA carbonyl band at 1850 cm⁻¹. The Bok group remains intact on the polymer backbone, yielding poly(proline) chains with controlled molecular weights (Mₙ 12–15 kDa, Đ 1.08–1.15 by DMF GPC calibrated with PMMA standards). Critically, the (3S) absolute configuration is fully retained throughout the NCA formation and polymerization: optical rotation measurements ([α]D²⁵) of the hydrolyzed free polyproline confirm values consistent with exclusively cis‑amide backbone geometry when DP exceeds 30, a hallmark of polyproline I helix formation. Deprotection with TFA/thioanisole (95:5, 2 h) liberates the secondary amine without chain scission, as evidenced by unchanged Mn traces. The resulting polycationic polymers have been examined as gene delivery vectors, where binding affinity to plasmid DNA—quantified by ethidium bromide exclusion assay—requires a polymer:DNA weight ratio of 3:1 for complete complexation. Regulatory considerations for such biomedical materials invoke ISO 10993‑5 cytotoxicity testing; the Boc-protected precursor polymers have demonstrated >90% cell viability in HEK293 cells at 100 µg/mL, while the fully deprotected forms require careful purification to remove residual TFA.When the Pyrrolidine Carboxylic Acid Becomes a Lead Component in Dipeptidyl Peptidase IV Inhibitor BackbonesIncorporation of (3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid into DPP‑IV inhibitor candidates proceeds via amide bond formation with azetidine or piperazine P2 fragments. A representative activated ester approach uses ethyl chloroformate (1.05 eq) and N-methylmorpholine (1.1 eq) in dichloromethane at −15°C to generate the mixed anhydride, which is then treated with the amine nucleophile. The rate of epimerization at the C3 stereocenter is suppressed by maintaining internal temperature below −10°C throughout the 30‑min activation window; excursion beyond −5°C results in C3 epimer content rising from 0.2% to 2.8% as quantified by validated HPLC method (Zorbax SB‑C18, 150×4.6 mm, 3.5 µm, gradient MeCN/water with 0.1% TFA). The resulting Boc‑protected intermediate is isolated by crystallization from ethyl acetate/heptane (1:4), providing product in 99.2% diastereomeric purity. Subsequent TFA‑mediated Boc removal and reductive amination with cyclopentylamine introduces the basic amine handle necessary for DPP‑IV binding interactions, as confirmed by co‑crystal structures (PDB deposition 4JWL‑like binding mode). In‑process controls for N‑nitrosamine formation became mandatory after publication of FDA guidance revision 1 in 2021: headspace GC‑MS analysis of the mixed anhydride intermediate under simulated worst‑case conditions (excess nitrite, pH 4, 50°C, 24 h) shows no detectable nitrosamine (<0.03 ppm LOQ) due to steric shielding of the pyrrolidine nitrogen by the Boc group. This attribute has become a critical selection criterion when differentiating between N‑Boc and N‑Cbz protection strategies in early development. Residual palladium from upstream hydrogenation steps is controlled to <5 ppm by charcoal filtration and confirmed by ICP‑MS before final GMP release testing per Ph. Eur. 2.4.20.3‑Pyrrolidinecarboxylic Acid, 1‑Boc‑Protected: Resolution Agent Screening for Chiral Amine PurificationThe rigid pyrrolidine ring and the free carboxylic acid make (3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid an effective chiral resolving agent for racemic secondary amines. A salt‑resolution protocol validated on a 50‑g scale involved dissolving racemic 1‑(3‑methoxyphenyl)ethylamine (1.0 eq) and the Boc‑acid (1.0 eq) in hot 2‑propanol/water 95:5; slow cooling to 5°C over 12 h precipitates the (R)‑amine·(S)‑acid diastereomeric salt in 78% yield with 98.6% de after single recrystallization. The high discrimination is attributed to the steric interaction between the amine methyl group and the Boc‑protected nitrogen atom, as indicated by single‑crystal X‑ray diffraction data showing a close O···H‑N hydrogen bond distance of 1.89 Å in the less soluble diastereomer. Liberation of the resolved amine is accomplished with 1 M NaOH and extraction into MTBE, while the chiral acid is recovered by acidification to pH 2 and back‑extraction into ethyl acetate; recovery exceeds 92% across three cycles with negligible racemization. In GMP‑controlled manufacturing environments, the heavy metal content of the recovered resolving agent is monitored per ICH Q3D—class 1 metals (As, Pb, Cd, Hg) must each remain below 1 ppm, confirmed by inductively coupled plasma mass spectrometry. The purified chiral amine is subsequently employed in the synthesis of a selective serotonin reuptake inhibitor analogue; final API residual solvent compliance requires headspace GC determination of 2‑propanol (<5000 ppm) and MTBE (<500 ppm) per USP ⟨467⟩.Solvents commonly used in the salt resolution—methanol, isopropanol, MTBE—are subjected to daily Karl Fischer titration (limit: <0.05% water) because trace moisture reduces diastereomeric enrichment by a factor of roughly 2% per 0.1% water content, as documented during process robustness testing at −10°C to 40°C jacket temperature. This sensitivity is traced to the formation of a hydrate of the carboxylic acid which distorts crystal lattice packing. Batch records from a pilot‑plant campagin at 100‑mol input scale indicate that solution mass transfer, not nucleation kinetics, is rate‑limiting; achieving consistent de required the addition of 0.5 wt% seed crystals at 50°C during the cooling ramp. The seed crystals were prepared by anti‑solvent diffusion of heptane into a 5 wt% solution of the pure diastereomeric salt in dichloromethane and characterized by powder X‑ray diffraction to confirm Form A polymorph, which is the thermodynamically stable phase at 20°C based on Slurry Conversion experiments monitored over 7 days.Monitoring the Thermal Stability Window of Boc‑Pyrrolidine Acid Under Process‑Scale Vacuum DryingSolid‑state thermal stability data are indispensable when drying (3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid after aqueous workup. Differential scanning calorimetry (DSC) at a scanning rate of 10°C/min under nitrogen atmosphere shows a broad endotherm centered at 128.5°C corresponding to melting with concomitant deprotection; however, thermogravimetric analysis–Fourier transform infrared spectroscopy (TGA‑FTIR) reveals onset of isobutylene evolution (diagnostic IR band at 890 cm⁻¹) at 105°C, with maximum rate reached at 136°C. Consequently, vacuum drying protocols at 40–45°C and <50 mbar for 16 h are standard, confirmed by loss‑on‑drying <0.5%. In a freeze‑drying process alternative—employed when the material must be stored as a lyophilized powder for long‑term cryogenic shipping—a 10% w/v solution in tert‑butanol/water 1:1 is frozen to −40°C at 0.5°C/min and primary drying conducted at −20°C and 0.1 mbar for 48 h. The resulting amorphous cake is fully reconstitutable in DMF, but exposure to atmospheric humidity above 40% RH during unloading induces rapid crystallisation to a monohydrate form that exhibits 15% lower solubility in ethyl acetate. Storage at −20°C under argon in amber HDPE containers with a desiccant bag is the established control strategy; stability data over 36 months indicate <0.1% increase in free acid impurity (N‑unprotected pyrrolidine) when these conditions are maintained. For shipments crossing tropical climate zones, active temperature logging with certified USB loggers (accuracy ±0.5°C) and inclusion of 50 g silica gel per 1 kg of material form part of the release documentation submitted to the importing country's customs authority.
Conjugation to Fluorescent Reporters via Active Ester Chemistry Without Pyrrolidine Ring IsomerizationThe pyrrolidine carboxylic acid is frequently converted to its succinimidyl ester for attachment to amine‑functionalized fluorophores such as 5‑(aminomethyl)fluorescein. Reaction of the acid with N‑hydroxysuccinimide (1.10 eq) and DCC (1.05 eq) in anhydrous DCM at 0°C for 4 h, followed by filtration of DCU and precipitation from DCM/hexane, furnishes the NHS ester as a white solid in 89% yield. The isolated NHS ester must be stored under argon at −20°C and used within 48 h to avoid hydrolysis, which proceeds with a half‑life of 72 h at 4°C when exposed to ambient moisture (Karl Fischer 0.1% H₂O), as monitored by 1H NMR loss of the succinimidyl singlet at 2.84 ppm. Conjugation to the fluorophore amine is executed in DMF containing triethylamine (2.0 eq) at 23°C for 12 h, shielding light to prevent photodegradation of fluorescein. HPLC analysis on a Bio‑gel TSK‑gel G3000SW column at 280 nm indicates conversion >98%, with the Boc group fully intact as confirmed by the presence of the tert‑butyl resonance at 1.42 ppm in the 1H NMR of the isolated conjugate. The Boc‑protected fluorescent probe is then subjected to quantitative TFA deprotection and used in intracellular pH sensing applications. As a research tool shared among academic collaborators, documentation of purity by qNMR with an internal standard (1,2,4,5‑tetrachlorobenzene, certified reference material) is appended to biological data to satisfy reviewer requests for compound characterization prior to publication. Residual succinimide content is limited to <0.2% by qNMR, given its documented cytotoxicity at concentrations above 10 µM in neuronal cell lines.
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| Property | (3S)-Boc‑pyrrolidine‑3‑carboxylic acid | (3R)-enantiomer | Racemate |
|---|---|---|---|
| CAS number | 72925-16-9 | – | – |
| Molecular formula | C10H17NO4 | ||
| Molecular weight | 215.25 g/mol | ||
| HPLC purity (area‑%) | ≥ 98.0 | ≥ 98.0 | ≥ 98.0 |
| Chiral purity (ee %) | ≥ 99.0 | ≥ 99.0 | N/A |
| Specific rotation [α]D25 (c 1.0, MeOH) | ‑25.0° to ‑30.0° | +25.0° to +30.0° | 0° ± 0.5° |
| DSC onset (°C), 10 °C/min, N2 | 125 – 130 | 125 – 130 | 112 – 118 |
| Solubility (g/100 mL, 25 °C) in DMF | 28 | 28 | 26 |
| Test | Method / Instrument | Acceptance criterion |
|---|---|---|
| Appearance | Visual inspection | White to off‑white powder |
| Identity (NMR) | 1H (400 MHz, DMSO‑d6), 13C (100 MHz) | Conforms to reference spectrum |
| HPLC purity | Chiralpak AD‑H, 254 nm, USP⟨621⟩ | ≥ 98.0 area‑% |
| Chiral purity | Chiralpak AD‑H, 254 nm, co‑injection | ≥ 99.0% ee |
| Specific rotation | Polarimeter, 589 nm, USP⟨781⟩ | ‑25.0° to ‑30.0° |
| Heavy metals | ICP‑OES, USP⟨231⟩ Method II | Pb ≤ 10 ppm, Cd ≤ 5 ppm, Hg ≤ 3 ppm |
| Residual solvents | GC‑FID, USP⟨467⟩ | DCM ≤ 600 ppm, EtOAc ≤ 5000 ppm |
| Water content | Karl Fischer (coulometric), USP⟨921⟩ | ≤ 0.5% w/w |
| Mesh size | Laser diffraction, ISO 13320:2020 | d90 ≤ 150 µm |
