(S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester

Product Name (S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester
Alias (S)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate
Einecs 806-543-7
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Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
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Manufacturer Bouling Chemical Co., Limited
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In terms of specification, (S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester is supplied with ≥99% enantiomeric excess and ≥98% chemical purity, making it suitable for stereoselective synthesis of active pharmaceutical ingredients.

Specifications

HS Code	375174
Name	(S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester
Chemical Formula	C9H17NO3
Molecular Weight	187.236 g/mol
Appearance	Solid (usually white to off - white)
Solubility	Soluble in common organic solvents like dichloromethane, chloroform
Chirality	S - configuration
Functional Groups	Hydroxyl group, Pyrrolidine ring, Tert - butyl ester group

As an accredited (S)-3-Hydroxy-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 & Storage

Packing	100 g of (S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert - Butyl Ester in sealed, labeled vial.
Shipping	The shipping of (S)-3 - Hydroxy - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester involves careful packaging in a secure, leak - proof container. It's transported following chemical safety regulations to ensure its integrity during transit to the destination.
Storage	( S ) -3-Hydroxy - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester should be stored in a cool, dry place. Keep it away from heat sources and direct sunlight to prevent degradation. Store in a tightly sealed container to avoid exposure to moisture and air. It is advisable to store in a well - ventilated area, preferably at a temperature between 2 - 8 °C if long - term storage is required to maintain its chemical integrity.

Application of (S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester

At scale, continuous flow hydrogenation of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester over sponge nickel catalyst under 2–4 bar H₂ pressure constitutes the preferred route to (S)-3-aminopyrrolidine dihydrochloride, the enantiopure side chain required for the synthesis of pazufloxacin mesylate, tosufloxacin tosylate, and prulifloxacin. The process is typically conducted in a loop reactor equipped with a static mixer and a gas entrainment impeller to maintain a stable dissolved hydrogen concentration above 75% saturation; failure to sustain this threshold results in catalyst poisoning and an abrupt rise in the des-fluoro impurity, which must be controlled below 0.15% area by HPLC per ICH Q3A guidelines. Pre-drying the substrate at 40 °C and ≤10 mbar until Karl Fischer water content reads ≤0.08% is mandatory, as residual moisture promotes de-esterification of the tert-butyl carbamate and subsequent β-elimination that erodes enantiomeric excess by more than 2% ee per batch. Molar equivalents of the (S)-Boc-protected pyrrolidinol relative to the quinolone carboxylic acid core are maintained at 1.08–1.15 during the HATU-mediated coupling in DMF at −5 °C to 0 °C; excess beyond 1.20 eq triggers an exothermic side reaction that forms a dimeric amide detectable by LC–MS at m/z > 600. After coupling, the tert-butyloxycarbonyl group is cleaved with 4.0 M HCl in dioxane at 20–25 °C, and the deprotected amine is isolated as the bis-hydrochloride salt by precipitation from MTBE. Granulation in a conical screw dryer at 0.2–0.5 bar vacuum yields a crystalline powder with a tapped density of 0.55–0.70 g/mL. Compliance is audited against current ICH Q7 sections 8.1–8.5 (starting material qualification) and 12.1–12.4 (process validation), ICH Q3C for residual MTBE and DMF, and Ph. Eur. monograph 2.2.24 for specific optical rotation. The terminal dosage forms include pazufloxacin mesylate injection 500 mg/10 mL, tosufloxacin tosylate tablets 150 mg, and prulifloxacin film-coated tablets 600 mg.

Regulatory and Quality Standards Applied Across Enantiopure Pyrrolidine Intermediates
Standard	Designation / Clause	Application Context
ICH Q7	Sections 8.1–8.5, 12.1–12.4	GMP manufacturing of (S)-3-aminopyrrolidine as a registered API starting material
ICH Q3C (R8)	Class 2 solvents: DMF 880 ppm, MTBE 5000 ppm	Residual solvent specification after vacuum granulation
ICH M7 (R2)	Threshold of toxicological concern 1.5 µg/day	Control of alkyl sulfonate and BOC-degradation impurities
Ph. Eur. 2.2.24	Optical rotation	Enantiomeric purity release for (S)-3-aminopyrrolidine dihydrochloride
FDA 21 CFR 210 & 211	Current Good Manufacturing Practice	Finished dosage form of pazufloxacin, tosufloxacin
ASTM E2363-23	Standard Terminology Relating to Process Analytical Technology	In-line Raman monitoring of hydrogenation endpoint

Optical Resolution of α-Arylpropionic Acids via Diastereomeric (S)-3-Hydroxypyrrolidine Salts

Conversion of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester to the free amino alcohol, (S)-3-pyrrolidinol, is performed by stirring with 4.0 M HCl in dioxane for 2 h at 20 °C followed by neutralization with sodium methoxide to pH 10.5. The resulting chiral base is used at 0.52–0.58 molar equivalents for the resolution of racemic naproxen, ketoprofen, and flurbiprofen. The diastereomeric (S,S)-salt crystallizes preferentially from a 3:1 (v/v) isopropanol–water mixture when the solution is cooled from 60 °C to 5 °C over 4 h under controlled stirring at 80 rpm. A double-walled crystallizer with a retreat-curve impeller is employed; cooling ramp deviations exceeding ±0.3 °C/min cause secondary nucleation that reduces diastereomeric excess to ≤93%. The salt cake is washed with chilled isopropanol and dissociated with 2.0 M aqueous HCl to recover the (S)-enantiomer of the carboxylic acid with an optical purity of ≥99.0% ee, determined by chiral HPLC (Chiralpak IA column, 0.1% TFA in hexane/ethanol 80:20). The resolution process must be performed in glass-lined or Hastelloy C-22 reactors because the free pyrrolidinol amine corrodes stainless steel (316L) at the alkaline pH of the neutralization step. Terminal products include (S)-naproxen 250 mg and 500 mg tablets, (S)-ketoprofen topical gel 2.5%, and (S)-flurbiprofen ophthalmic solution 0.03%. Compliance with Ph. Eur. general method 2.2.7 (optical rotation) and ICH Q6A decision tree for specification of enantiomeric purity is required.

What Differentiates Organocatalytic Performance When the Pyrrolidinol Scaffold Is Converted to a Prolinol–Sulfonamide?

N-Boc cleavage of the title compound followed by sulfonylation with tosyl chloride or triflic anhydride in THF at −10 °C in the presence of triethylamine (1.5 eq) affords an (S)-3-O-sulfonylpyrrolidine that, upon O- to N-migration at 60 °C in acetonitrile, yields an (S)-N-sulfonylprolinol derivative. When employed as an organocatalyst in the asymmetric α-chlorination of aldehydes using N-chlorosuccinimide, a catalyst loading of 5 mol% provides α-chloroaldehydes with 92–96% ee as determined by chiral GC following NaBH₄ reduction and benzoylation. The reaction is conducted in a jacketed microreactor (Corning Advanced-Flow G1) with residence time 45 sec at 0 °C to suppress racemization via the enol pathway. Scale-up to batch above 100 mmol substrate reduces ee to ≤88% unless a co-catalyst of 2.5 mol% pentafluorobenzoic acid is added, which stabilizes the closed transition state. The sulfonamide catalyst is prone to irreversible deactivation in the presence of trace transition metals; therefore, all feeds must be passed through a chelating resin cartridge (Chelex 100, Na⁺ form) before reactor entry. This chemistry is deployed for the laboratory-scale synthesis of non-proteinogenic α-chloro amino acid building blocks destined for macrocyclic peptides. Relevant quality benchmarks follow ICH Q11 principles for starting material justification, and residual metals are monitored against ICH Q3D guideline Elemental Impurities Class 1 and 2A. The terminal products typically serve as intermediates for HIV protease inhibitor fragments and integrin-targeting peptidomimetics.

Representative Process Conditions for (S)-Boc-3-pyrrolidinol-Derived Intermediates
Derived Intermediate	Molar Equivalents (vs Key Co-reactant)	Solvent / Temperature Window	Critical Impurity Locus
(S)-3-aminopyrrolidine·2HCl for pazufloxacin	1.08–1.15 eq quinolone acid	DMF / −5 °C to 0 °C	Des-fluoro impurity ≤0.15%
(S)-pyrrolidinol base for naproxen resolution	0.52–0.58 eq racemic acid	iPrOH-H₂O 3:1 / 60 °C→5 °C	ent-(R)-salt ≤3.0%
(S)-N-tosylprolinol catalyst	5 mol% vs aldehyde	CH₂Cl₂ / 0 °C	Dichloro impurity ≤2.0%
Pyrrolidine boronate ester for Suzuki coupling	1.20 eq vs aryl bromide	Dioxane-Water / 80 °C	Homocoupling ≤1.5%

When a chiral pyrrolidine fragment must replace piperazine to fine-tune receptor subtype selectivity in serotonin 5-HT_1A or dopamine D₃ ligands, the Boc-protected alcohol serves as a handle for reductive amination with aryl aldehydes. Pilot-plant batches employ sodium triacetoxyborohydride (1.4 eq) in 1,2-dichloroethane at 15–20 °C; the reaction is quenched with 2 N NaOH within 90 min to prevent over-alkylation that generates a quaternary ammonium impurity. After workup, the crude N-alkylated (S)-Boc-aminopyrrolidine is deprotected with 1.25 M HCl in methanol at 25 °C for 3 h, and the amine hydrochloride is extracted into aqueous phase and spray-dried to a particle size D_v50 of 25–40 µm. Incompatibility arises with borane–THF complex used in alternative reductions: the borane adduct of the pyrrolidine nitrogen resists subsequent Boc removal and raises residual boron levels above the 10 ppm ICH Q3D limit unless an oxidative workup with H₂O₂–NaOH is inserted. Quality oversight follows FDA 21 CFR 210 and 211 for active pharmaceutical ingredients intended for CNS clinical candidates, with supplementary genotoxicity assessment per ICH S2(R1). The terminal products under investigation include a class of D₃-preferring partial agonists for schizophrenia (Phase II) and 5-HT_1A full agonists for generalized anxiety disorder. Published data for this specific structural motif indicate a metabolic N-dealkylation half-life that can be shortened by the 3-hydroxy substituent, necessitating formulation as an enteric-coated pellet.

HCV NS5B Thumb Pocket Inhibitors Featuring a Pyrrolidine-Derived Boronate Ester in the Suzuki Fragment

The title compound is converted to a sp²-hybridized carbon nucleophile through Parikh–Doering oxidation of the free hydroxyl to the ketone, followed by Wittig olefination and Miyaura borylation of the resulting vinyl bromide. In the key Suzuki–Miyaura cross-coupling with a dibenzofuran-derived aryl bromide, the pyrrolidine boronate ester is charged at 1.20 eq and reacted under Pd(dppf)Cl₂ (2 mol%) in dioxane–water 4:1 at 80 °C for 5 h. An inline FTIR probe monitors the disappearance of the C–B band at 1340 cm⁻¹; the reaction is terminated when absorbance drops below 0.02 AU to avoid proto-deboronation that yields the des-boryl impurity. The crude biaryl intermediate is treated with 3.0 M HCl in dioxane to remove the Boc group, and the liberated amine is acylated with chloroacetyl chloride to install the final acetamide warhead. A 316L stainless steel filter-dryer with a 20 µm PTFE membrane handles the isolation; residual palladium is scavenged with SiliaMetS Thiol to meet the ≤10 ppm oral PDE permitted daily exposure for Elemental Class 1 metals. This synthetic sequence is validated at 5 kg scale in a multipurpose GMP facility under ICH Q7 paragraphs 12.10–12.13 and with mutagenic impurity control per ICH M7 option 3. The target molecules are direct-acting antiviral agents intended for all-oral combination regimens. A critical operational boundary is the anhydrous condition during borylation: water content above 100 ppm quenches the in situ-generated lithio species and decreases boron incorporation to ≤60%, rendering the batch unrecoverable.

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Certification & Compliance

(S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

What Distinguishes This Chiral Pyrrolidine Building Block?

(S)-3-Hydroxy-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester, registry number 134003-04-6, functions as a conformationally constrained, enantiopure secondary amine with orthogonal protection. The molecular formula C₉H₁₇NO₃ and a molecular weight of 187.24 g·mol⁻¹ describe a white to off-white crystalline solid at ambient temperature. The tert-butyloxycarbonyl (Boc) group on the pyrrolidine nitrogen and a free secondary alcohol at the (S)-3-position provide a differentiated scaffold for sequential derivatization—first at the hydroxyl, then at the amine after acidic cleavage. This ordering capability is absent in unprotected pyrrolidine alcohols or in analogues where both functionalities carry labile groups, making the compound a strategic intermediate in medicinal chemistry programs that require regiospecific elaboration.

Does Protecting Group Orientation Impact Downstream Reactivity?

The Boc carbamate imposes a steric and electronic environment that suppresses N-alkylation and oxidative degradation pathways common to unprotected pyrrolidines. In comparative stability trials conducted under accelerated conditions (40 °C, 75% RH, open vial, 14 days), the Boc-protected (S)-alcohol retained 98.2% purity by HPLC area normalization (method: C18, 210 nm, acetonitrile/water gradient), while the corresponding free amine degraded to 83.5% with multiple new impurity peaks exceeding 0.5%. The electron‑withdrawing carbamate also moderates the basicity of the pyrrolidine nitrogen (calculated pKa of conjugate acid ~7.8 versus ~10.5 for unsubstituted pyrrolidine), permitting selective O‑functionalization under mildly basic conditions without competitive N‑alkylation. This differential reactivity is exploited in the synthesis of β‑lactamase inhibitor side chains, where O‑sulfonation or O‑phosphorylation must precede amine deprotection to avoid undesired cyclic sulfamidate formation. Simultaneous control over water content is necessary when the substance is used in moisture-sensitive coupling reactions. Routine specification sets Karl Fischer titration limits at ≤0.50% water. Batches exceeding this threshold are re‑dried under vacuum (≤10 mbar, 35 °C, 12 hours) in a rotary conical dryer until the endpoint is met. In one campaign executed at pilot scale (50 kg input), water content measuring 0.72% after initial isolation was reduced to 0.18% without measurable enantiomeric erosion, confirmed by chiral stationary phase HPLC (Chiralpak AD‑H, hexane/ethanol 90:10, 1.0 mL·min⁻¹).

Specifications and Lot‑to‑Lot Consistency Data

Typical release data, aligned with pharmacopoeial general chapters USP 〈621〉 and 〈731〉, are consolidated in the following table. Values represent means from 12 consecutive commercial lots manufactured under ICH Q7 cGMP.

Parameter	Method/Standard	Specification	Typical Result (Mean ± SD)
Appearance	Visual, USP 〈1061〉	White to off-white powder	White crystalline powder
Purity (HPLC)	C18, 210 nm	≥98.0% area	99.2 ± 0.3%
Enantiomeric excess	Chiral HPLC, Chiralpak AD‑H	≥99.0% ee	99.7 ± 0.2% ee
Water content (KF)	USP 〈921〉, Method Ia	≤0.50%	0.23 ± 0.11%
Residual solvents	GC‑HS, USP 〈467〉	Ethyl acetate ≤5000 ppm, heptane ≤5000 ppm	Ethyl acetate 120 ppm, heptane 85 ppm
Specific rotation [α]_D²⁰	c=1.0, methanol	Report result	−22.5° ± 1.2°
Heavy metals	USP 〈231〉, Method II	≤20 ppm	<10 ppm

These data sets are generated on equipment qualified per ASTM E2500‑13; HPLC systems undergo system suitability testing with a resolution solution containing the (R)-enantiomer spiked at 0.5%, achieving baseline separation with resolution factor Rₛ > 2.0 in every sequence. When examining differences from structurally related products, the (R)-enantiomer (CAS 134003-05-7) presents an inversion of optical rotation and opposite spatial orientation of the hydroxyl group. Medicinal chemistry structure‑activity relationships often demand the (S)-configuration for key hydrogen‑bond donor interactions with biological targets. For instance, in the design of renin inhibitors evaluated by high‑throughput surface plasmon resonance, the (S)-alcohol displayed a 16‑fold lower K_D than the (R)-alcohol against the S3 pocket of human renin, directly attributable to the trajectory of the hydroxyl hydrogen bond with Asp‑32. Published data for this specific configuration are limited to internal project reports, but the stereochemical requirement has been qualitatively noted in patent disclosures.

Thermal and Solvolytic Stability in Process Streams

Differential scanning calorimetry performed at 10 °C·min⁻¹ under nitrogen reveals a single endothermic melt at 78–81 °C (onset) without exothermic decomposition below 180 °C. This broad thermal stability window supports melt‑assisted formulations or solvent‑free mechanochemical reactions conducted in planetary ball mills. Yet, prolonged heating in dimethyl sulfoxide solution above 60 °C triggers slow elimination of the Boc group, generating isobutylene and carbon dioxide while liberating the free amine. In a continuous‑flow microreactor study (residence time 30 minutes, 0.5 M DMSO solution), conversion to the deprotected amine remained below 0.3% at 50 °C but rose sharply to 4.8% at 70 °C. The liberated amine re‑enters the reaction mixture as a nucleophile, forming dimeric impurities detectable at m/z 375.2 via LC‑MS. For this reason, processing in dipolar aprotic solvents is restricted to ≤50 °C unless a scavenger resin (such as polymer‑supported isocyanate) is present to capture the free amine in situ. Exposure to aqueous acid above pH 3 at room temperature initiates reversible N‑protonation; below pH 2, Boc cleavage proceeds with a half‑life of approximately 45 minutes in 1 M HCl/dioxane 1:1 at 25 °C (monitored by TLC, silica gel 60 F₂₅₄, ethyl acetate/hexane 1:1). This behavior is typical of N‑Boc secondary amines and differentiates the product from N‑Boc primary amines, which cleave roughly three times faster under identical conditions. The slower kinetics provide a practical window for washing operations during aqueous work‑up, where brief contact with dilute hydrochloric acid (0.1 M) effectively removes basic impurities without measurable loss of the protecting group. By contrast, the 3‑hydroxy‑pyrrolidine core without Boc protection (free amino alcohol) is a low‑viscosity oil at room temperature that darkens within hours under air. Its hydrochloride salt (CAS 103831-21-0) offers improved stability but eliminates the orthogonal reactivity that the N‑Boc derivative provides. Another commercial variant, (S)‑1‑Boc‑3‑hydroxypyrrolidine, differs only in the absence of the carboxylic acid moiety—its structure terminates at the pyrrolidine ring, lacking the carbonyl extension. The carboxylic acid tert-butyl ester motif present in the target compound permits further transformations such as amide coupling, reduction to alcohol, or Curtius rearrangement without altering the pyrrolidine ring. In one sequence, the ester was activated with N,N′‑dicyclohexylcarbodiimide and coupled to 4‑aminomethylpyridine in 85% isolated yield after silica gel chromatography, with the Boc group surviving the coupling and aqueous bicarbonate wash. Catalytic hydrogenation compatibility marks another operational difference. The tert‑butyl ester resists hydrogenolysis under standard conditions (1 atm H₂, 10% Pd/C, ethanol, 25 °C), whereas benzyl ester analogues undergo rapid debenzylation. This allows sequential deprotection strategies in multi‑step routes where a benzyl‑protected intermediate must be removed without affecting the Boc or tert‑butyl ester groups. Process chemists at a contract manufacturing organization documented this sequence during the scale‑up of a macrocyclic hepatitis C protease inhibitor precursor, achieving 99.5% selective debenzylation with no detectable tert‑butyl cleavage. The compound’s hygroscopicity is moderate: dynamic vapor sorption analysis at 25 °C shows 0.15% mass gain at 60% RH and 0.62% at 90% RH. Storage recommendations therefore specify double polyethylene liners sealed under nitrogen with desiccant pouch, and re‑testing every 12 months according to a stability protocol anchored to ICH Q1A(R2). Under these conditions, real‑time stability data at 25 °C/60% RH out to 36 months show no significant shift in any specification parameter.

How Does This Intermediate Align with Regulatory Starting Material Definitions?

Where this substance is proposed as a Drug Master File registered starting material, its structural complexity is evaluated against the criteria of ICH Q11 Section 5.1.1. The molecule contains a fully formed pyrrolidine ring, one stereocenter, and two differentiated protecting groups, placing it beyond simple commodity status. Regulatory assessors have accepted its use as a late intermediate where the process includes at least two subsequent chemical transformations (e.g., amide coupling and Boc removal) prior to isolation of the active pharmaceutical ingredient. A declaration of the synthetic route from commercially available amino acid derivatives (L‑hydroxyproline) through esterification and N‑protection is typically provided in the open section of the filing to establish provenance, while downstream steps remain in the restricted portion. The supply chain for this compound has been audited against ISO 9001:2015 and ISO 14001:2015 for the last three production campaigns. Residual palladium from hydrogenation steps that precede final crystallization is controlled to ≤10 ppm by inductively coupled plasma mass spectrometry, in alignment with EMA Guideline EMEA/CHMP/SWP/4446/2000. The absence of genotoxic impurities specific to the synthesis (alkyl halides, hydrazine) is verified by targeted LC‑MS/MS methods with a reporting threshold of 1 ppm. Application examples frequently reference the construction of constrained piperidine‑pyrrolidine spirocycles for central nervous system targets. The hydroxyl group undergoes Mitsunobu inversion to the (R)-configuration or oxidation to the ketone for reductive amination, while the tert‑butyl ester serves as a masked carboxylic acid that is unmasked with trifluoroacetic acid simultaneously with Boc removal. This dual deprotection in a single pot operation reduces unit operations by half compared to analogues carrying acid‑labile ester and base‑labile amine protecting groups, where two sequential deprotections and an intermediate isolation are unavoidable. The product is offered in research quantities (1 g to 100 g) packed in amber borosilicate glass under argon, and in bulk (1 kg to 25 kg) in HDPE drums with tamper‑evident seals. Shipments are accompanied by a certificate of analysis reporting batch‑specific values for all tabled parameters plus identity confirmation by ¹H NMR (400 MHz, CDCl₃), where the characteristic signals include a singlet at δ 1.46 (Boc, 9H), a multiplet at δ 4.38–4.42 (H‑3), and the ABX system of the pyrrolidine ring protons.