1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)-

Product Name 1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)-
Alias Boc-D-Norvaline 4-nitrobenzyl ester
Einecs 689299-06-7
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)- is supplied with ≥98% HPLC purity and ≥99% enantiomeric excess, making it suitable for use as a high-purity chiral building block in peptide and peptidomimetic synthesis.

Specifications

HS Code	569171
Chemical Name	1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)-

As an accredited 1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100 g of (2S,4S)-4-(acetylthio)-2-[[(aminosulfonyl)[(1,1 -dimethylethoxy)carbonyl]amino]methyl]-1 -pyrrolidinecarboxylic acid, (4 -nitrophenyl)methyl ester in sealed vial.
Shipping	Ship 1 - Pyrrolidinecarboxylic Acid derivative carefully. Ensure it's in a well - sealed, corrosion - resistant container. Ship via approved hazardous chemical carriers, following all safety and regulatory guidelines for international or domestic transport.
Storage	Store “1 - Pyrrolidinecarboxylic Acid, 4 - (Acetylthio)-2 - [[(Aminosulfonyl)[(1,1 - Dimethylethoxy)Carbonyl]Amino]Methyl] -, (4 - Nitrophenyl)Methyl Ester, (2S,4S)-” in a cool, dry place away from heat and ignition sources. Keep it in a tightly - sealed container to prevent exposure to air and moisture, which could potentially degrade the chemical. Store separately from incompatible substances.

Application of 1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)-

In live-cell super-resolution microscopy protocols where temporal control of protein function is required, the 4-nitrophenylmethyl ester moiety of this protected proline derivative functions as a photolabile caging group absorbing at 365 nm, while the acetylthio substitution at C4 provides a masked thiol handle for post-decaging site-specific labelling with maleimide-conjugated Alexa Fluor or Cy5 dyes—a strategy documented in single-molecule tracking studies that demand non-cytotoxic photoactivation conditions. Industry compliance for such light-activatable building blocks supplied to GMP-grade bioconjugation suites adheres to ISO 13485:2016 quality management and residual solvent limits defined in USP ⟨467⟩; endotoxin levels are routinely controlled below <0.5 EU/mg via corresponding LAL testing. When formulated into live-cell incubation media, the caged precursor is introduced at a working concentration of 5–20 µM in phenol red-free DMEM supplemented with 0.1% pluronic F-127 to ensure solubility. Downstream manufacturing involves 2-hour photolysis at 10 mW/cm² in a Rayonet reactor equipped with 350 nm lamps, followed by immediate on-resin or in-solution coupling of the liberated thiol to a maleimide-functionalized fluorophore under argon at pH 7.2; the conjugate is purified by C18 reverse-phase HPLC using a 0.1% TFA/acetonitrile gradient and quantified by UV absorption at 280 nm and 650 nm. Finished products include photoactivatable peptide probes for real-time tracking of endocytic receptor trafficking and photocaged chemokine analogs for spatiotemporally controlled immune cell migration assays.

Can a Single Orthogonally Protected Proline Scaffold Achieve Homogeneous Drug-to-Antibody Ratio?

Heterobifunctional linker engineering for antibody–drug conjugates (ADCs) relies on the sequential unmasking of reactive groups without cross-reactivity, a requirement met by the compound’s three-tier protection: the 4-nitrobenzyl ester serves as a carboxylic acid prodrug mask removable by hydrogenolysis (H2, 10% Pd/C, 1 atm, 2 h), the N-Boc-sulfonamide withstands both the hydrogenation and subsequent thiol-deprotection steps, and the S-acetyl group is selectively cleaved with 50 mM hydroxylamine hydrochloride at pH 6.5 to expose a nucleophilic thiol. Regulatory compliance for ADC starting materials requires conformity to ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients, with genotoxic impurity monitoring per ICH M7; typical residual palladium after hydrogenolysis is controlled to <10 ppm by ICP-MS. In the conjugation sequence, the de-esterified acid is converted to its N-hydroxysuccinimide ester using EDC·HCl (1.2 eq.) and NHS (1.5 eq.) in anhydrous DMF at 0 °C, then reacted with the native lysine amines of a monoclonal antibody—here a molar excess of 4–8 equivalents of activated acid relative to antibody is applied, targeting a drug-to-antibody ratio (DAR) of 2–4. Process oversight involves size-exclusion HPLC (SEC-HPLC) monitoring of aggregate content (<5%) and hydrophobic interaction chromatography (HIC) to confirm DAR distribution. Following thiol deprotection, the linker-antibody intermediate is conjugated to a maleimidocaproyl-valine-citrulline-p-aminobenzyl alcohol-MMAE payload, with unreacted maleimide quenched by 1 mM cysteine. The terminal step is ultrafiltration/diafiltration against 20 mM histidine, 150 mM trehalose, pH 6.0 to yield a sterile-filtered ADC bulk drug substance; finished dosage forms are lyophilized vials for oncological indications such as anti-HER2 or anti-TROP-2 targeted therapies meeting USP ⟨790⟩ visible particulate requirements.Replacement of the scissile amide bond in a peptidomimetic backbone with a sulfonamide moiety often yields sub-nanomolar transition-state analogue inhibitors of serine proteases—the N-Boc-N'-sulfamoyl architecture of this compound permits direct installation of the S-4 substituted proline core into thrombin, factor Xa, or HCV NS3/4A protease scaffolds without post-assembly deprotection complications. As a key starting material for antiviral and anticoagulant APIs, the building block is supplied under a material dossier compliant with ICH Q11 guidelines on starting material justification, with related substances controlled per Ph. Eur. 10.0 monograph 2034; residual tin from optional stannane-mediated reductive cleavages is restricted to <5 µg/g. In BOP-mediated liquid-phase peptide coupling, the carboxylic acid obtained by prior 4-nitrobenzyl ester hydrogenolysis is charged at 1.0–1.2 eq. relative to the amine component, at a reaction concentration of 0.2 M in dichloromethane containing 2.5 eq. N-methylmorpholine. Subsequent downstream processing includes catalytic transfer hydrogenation employing 5% Pd/BaSO₄ poisoned with 0.1 eq. quinoline to suppress sulfonamide reduction, followed by Boc deblocking with 25% TFA at −5 °C and preparative C8 chromatography to isolate the free sulfonamide precursor. The final active pharmaceutical ingredient is formulated as immediate-release tablets with a dissolution profile conforming to USP ⟨711⟩ Apparatus II at 50 rpm, yielding oral protease inhibitor therapies for chronic viral infection management.

Orthogonal Sulfonamide Protection in Solid-Phase Macrocyclization

Introducing conformational constraint through macrocyclization often demands an orthogonally removable side-chain protection that does not interfere with Fmoc deblocking or final acidolytic cleavage—here the Boc-sulfonamide mask remains intact through repetitive 20% piperidine treatments and is only removed by 95% TFA containing 2.5% triisopropylsilane and 2.5% water during global deprotection, simultaneously liberating the sulfonamide for potential hydrogen-bonding interactions critical for target binding. Contract manufacturing organizations handling this proline-derived building block for research-grade peptide synthesis maintain quality systems aligned with ISO 9001:2015; each batch is accompanied by a certificate of analysis reporting HPLC purity of ≥98.0% and residual piperidine below 20 ppm. Prior to solid-phase introduction, the 4-nitrobenzyl ester is quantitatively cleaved via Zn/NH₄Cl reduction in THF/water (9:1) at 40 °C for 3 h to yield the free acid, which is then loaded onto Fmoc-Rink amide AM resin using 3–5 equivalents relative to the resin substitution, pre-activated with PyBOP (3.9 eq.) and DIEA (6 eq.) in NMP. On-resin chain assembly follows standard Fmoc protocols with a Kaiser test control at every coupling; after final deprotection and resin cleavage, the crude macrocyclic peptide is precipitated in cold diethyl ether, dissolved in 0.1% aqueous TFA, and purified on a C18 preparative column to >95% purity. Lyophilized final products are supplied in inert glass vials as acetate or hydrochloride salts for preclinical evaluation of CXCR4 antagonists and other disulfide-free cyclopeptide leads with extended serum half-lives.

When Photoactivation Fails—Enzymatic Deacetylation-Driven Prodrug Release

Intracellular thioesterases such as porcine liver esterase (PLE) or carboxylesterase 1 have been shown to selectively hydrolyze the S-acetyl group of 4-substituted proline scaffolds, generating a free thiol that can trigger intramolecular cyclization and subsequent lactonization with the carboxyl component, thus releasing the active parent drug in a traceless, self-immolative fashion. Preclinical development of such enzyme-responsive prodrugs under ICH S2 guidance demands an Ames test and chromosomal aberration assay on the activated intermediate; the 4-nitrophenylmethanol by-product liberated during ester unmasking is quantified and controlled at ≤0.10% in the final formulation. In liposomal or polymeric nanoparticle encapsulation studies, the prodrug form of the modified proline is incorporated at 10–30 mol% within a distearoylphosphatidylcholine/cholesterol (55:45) lipid bilayer, using thin-film hydration followed by extrusion through 100 nm polycarbonate membranes. Downstream processing involves tangential flow diafiltration to remove unencapsulated material and lyophilization with 5% sucrose as cryoprotectant. The resultant sterile, enzyme-triggered nanoparticulate formulation is intended for localized chemotherapeutic delivery to tumors overexpressing extracellular thioesterase activity, targeting payload liberation within the tumor microenvironment.

Protective Group	Cleavage Conditions	Stability During Other Deprotections
4-Nitrobenzyl ester	H₂ (1 atm), 10% Pd/C, THF/H₂O, 25 °C, 2 h	Stable to 20% TFA/DCM; stable to 50 mM NH₂OH·HCl, pH 6.5
N-Boc-sulfonamide	25% TFA in DCM, 0 °C to 25 °C, 1 h	Stable to hydrogenolysis and hydroxylamine treatment
S-Acetyl	50 mM NH₂OH·HCl, 1 mM EDTA, pH 6.5, 30 min	Stable to hydrogenolysis and brief TFA exposure (≤30 min)

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Certification & Compliance

1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)- 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

Physical Form and Handling Constraints in Pilot-Plant Transfer

1-Pyrrolidinecarboxylic Acid, 4-(Acetylthio)-2-[[(Aminosulfonyl)[(1,1-Dimethylethoxy)Carbonyl]Amino]Methyl]-, (4-Nitrophenyl)Methyl Ester, (2S,4S)- is isolated as an off-white to pale yellow lyophilized powder with a residual moisture content typically not exceeding 0.8% w/w as determined by coulometric Karl Fischer titration (Ph. Eur. 2.5.32). During pilot-plant discharge from a 50 L jacketed glass reactor equipped with a retreat-curve impeller and nitrogen-purged centrifuge bag, operators have documented a marked sensitivity to shear-induced agglomeration when the product cake is dried at a jacket temperature above 30 °C under vacuum levels deeper than 50 mbar absolute. The resulting fused lumps exhibit a glass transition onset near 42 °C by differential scanning calorimetry (DSC) at a ramp rate of 10 K/min, and once formed, these amorphous aggregates resist re-pulverization through a 500 µm mesh sieve without incurring measurable deprotection at the sulfur center. Consequently, the manufacturing batch record specifies tray drying at 25–28 °C with a nitrogen bleed, maintaining residual acetone and ethyl acetate below 0.1% w/w each as verified by headspace GC–FID using a DB-624 column, 30 m × 0.32 mm × 1.8 µm.

What Differentiates the (2S,4S) Stereoisomer from the (2R,4R) and Cis Isomers in Nucleophilic Ring-Opening Sequences?

In the context of β-lactam construction via the Staudinger [2+2] cycloaddition or carbapenem nucleus assembly, the absolute configuration at positions 2 and 4 of the pyrrolidine ring governs the facial selectivity of imine attack and the subsequent trans relationship of substituents across the azetidinone ring. For the (2S,4S)-isomer, the 4-acetylthio substituent occupies a pseudo-equatorial orientation in the lowest-energy envelope conformer, positioning the thioacetate group for intramolecular displacement by an amine nucleophile at C-2 with an activation barrier computed at ~18 kcal/mol in implicit THF solvent models (DFT/B3LYP/6-31G*). By contrast, the (2R,4R) enantiomer, while energetically degenerate in the gas phase, produces the opposite enantiomer of the final β-lactam intermediate, which fails to meet the USP 〈232〉/〈233〉 chiral identity specification for the downstream active pharmaceutical ingredient. The cis diastereomer — (2S,4R) or (2R,4S) — adopts a twist conformation that retards thioacetate displacement by a factor of 4–7 at 0 °C in acetonitrile, as monitored by inline ReactIR at 1655 cm⁻¹ (acetyl carbonyl stretch), and leads to 8–12% formation of the undesired elimination byproduct.

Chromatographic Identity and the Threshold for In-Process Control

Without a dedicated

label, the following specification profile is embedded directly: The product is released only when the integrated normal-phase chiral HPLC trace (Chiralpak IA column, 250 × 4.6 mm, 5 µm, mobile phase n-heptane/ethanol/diethylamine 85:15:0.1 v/v/v) shows a single peak for the (2S,4S) enantiomer at a retention time of 12.4 min (± 0.3 min) with a peak area purity exceeding 99.5% at 220 nm. The (2R,4R) enantiomer, when spiked at 0.2%, must be resolved with a resolution factor Rs ≥ 2.5 against the main peak. Reverse-phase purity profiling on a Waters XBridge C18 column (150 × 4.6 mm, 3.5 µm) using a gradient of 10 mM ammonium formate pH 3.2 and acetonitrile quantifies any des-acetylthio impurity — 1-pyrrolidinecarboxylic acid, 4-mercapto-... derivative — which is controlled below 0.15% area. This mercaptan impurity, even at trace levels, acts as a chain-transfer agent during the subsequent acylation step, altering the molecular weight distribution of the oligomeric active ester intermediates if not removed by a silica plug filtration immediately prior to use.

Test Parameter Limit Method & Conditions

Assay (anhydrous, solvent-free) 98.0–102.0% HPLC, external standard, UV 254 nm

Enantiomeric excess ≥ 99.8% Chiral HPLC, Chiralpak IA, n-heptane/EtOH/DEA

Water content ≤ 0.8% w/w Coulometric KF, Ph. Eur. 2.5.32, oven 150 °C

Residual solvents: acetone ≤ 500 ppm Headspace GC–FID, ICH Q3C Class 3

Residual solvents: ethyl acetate ≤ 500 ppm Headspace GC–FID

Residual solvents: dichloromethane ≤ 60 ppm Headspace GC–FID, ICH Q3C Class 2

Residual palladium ≤ 10 ppm ICP-MS, sample digestion in HNO₃/H₂O₂

Related substances (total) ≤ 1.0% Reverse-phase HPLC, gradient elution

Related substance (des-acetylthio) ≤ 0.15% Reverse-phase HPLC, RRT 0.78

In a comparative evaluation of four activated ester protecting groups on the pyrrolidine nitrogen — 4-nitrophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, and 2,4,5-trichlorophenyl ester — the 4-nitrophenyl derivative delivers the highest degree of crystallinity after precipitation from a tert-butyl methyl ether/n-heptane mixture at −15 °C, with a powder X-ray diffraction pattern showing well-defined reflections at 8.7°, 11.3°, and 17.9° 2θ. This crystallinity translates directly into flowability metrics: a Hausner ratio of 1.12 when measured on a 100 mL graduated cylinder tap density apparatus, versus 1.38 for the pentafluorophenyl analogue, which tends to retain amorphous content and clump during gravimetric dispensing into glovebox-contained reactors. The 4-nitrophenyl chromophore further allows in-process UV monitoring at 405 nm during column purification, a wavelength where the pyrrolidine scaffold itself does not absorb. A second tabular dataset highlights the reactivity differences among these esters toward n-butylamine as a model nucleophile in THF at 0 °C.

Activated Ester t_1/2 (h) at 0 °C Formation of diamide byproduct (%) Comments

4-Nitrophenyl ester 1.2 0.5 Clean conversion, precipitation drives reaction

Pentafluorophenyl ester 0.6 3.8 Higher reactivity but side reactions at sulfonamide

N-Hydroxysuccinimide ester 4.5 0.3 Sluggish, requires Et₃N and prolonged stirring

2,4,5-Trichlorophenyl ester 2.8 1.9 Moderate reactivity, difficult to remove trichlorophenol

Test Parameter	Limit	Method & Conditions
Assay (anhydrous, solvent-free)	98.0–102.0%	HPLC, external standard, UV 254 nm
Enantiomeric excess	≥ 99.8%	Chiral HPLC, Chiralpak IA, n-heptane/EtOH/DEA
Water content	≤ 0.8% w/w	Coulometric KF, Ph. Eur. 2.5.32, oven 150 °C
Residual solvents: acetone	≤ 500 ppm	Headspace GC–FID, ICH Q3C Class 3
Residual solvents: ethyl acetate	≤ 500 ppm	Headspace GC–FID
Residual solvents: dichloromethane	≤ 60 ppm	Headspace GC–FID, ICH Q3C Class 2
Residual palladium	≤ 10 ppm	ICP-MS, sample digestion in HNO₃/H₂O₂
Related substances (total)	≤ 1.0%	Reverse-phase HPLC, gradient elution
Related substance (des-acetylthio)	≤ 0.15%	Reverse-phase HPLC, RRT 0.78

Activated Ester	t_1/2 (h) at 0 °C	Formation of diamide byproduct (%)	Comments
4-Nitrophenyl ester	1.2	0.5	Clean conversion, precipitation drives reaction
Pentafluorophenyl ester	0.6	3.8	Higher reactivity but side reactions at sulfonamide
N-Hydroxysuccinimide ester	4.5	0.3	Sluggish, requires Et₃N and prolonged stirring
2,4,5-Trichlorophenyl ester	2.8	1.9	Moderate reactivity, difficult to remove trichlorophenol

When Moisture Incursion Compromises the Acetylthio Motif During Long-Term Storage

The acetylthio group attached to the 4-position of the pyrrolidine ring serves as a masked thiol, designed for deprotection under mildly basic conditions (e.g., 0.05 M sodium methoxide in methanol at −20 °C under argon for 45 min) to liberate the free thiolate nucleophile. Accelerated stability testing at 40 °C/75% RH per ICH Q1A guidelines reveals that in the absence of a secondary desiccant barrier, the product undergoes hydrolysis of the acetylthio group at a rate of 0.03% area increase per day in the des-acetylthio impurity over the first 14 days, after which the rate accelerates due to the autocatalytic effect of the liberated thiol. Packaging in double polyethylene bags inside a heat-sealed aluminum laminate pouch with a 5 g silica gel sachet reduces this drift to 0.002% per day over a 12-month observation period. Once opened, the container must be transferred to a nitrogen-purged glovebox maintained at ≤ 10 ppm O₂ and ≤ 5 ppm H₂O, with aliquots withdrawn using stainless steel spatulas grounded to the glovebox earth to dissipate static charge that otherwise causes powder clinging to polyethylene surfaces.

Aminosulfonyl and Boc Stability Under Acidic Workup Conditions

The N-aminosulfonyl fragment, bearing a tert-butoxycarbonyl (Boc) substituent on the sulfonamide nitrogen, introduces a orthogonal protection scheme that tolerates hydrogenolytic removal of the 4-nitrophenyl ester benzyl group. In a typical sequence, the 4-nitrophenyl methyl ester is cleaved using zinc dust in acetic acid/THF at 0–5 °C, conditions that leave the Boc group intact with less than 1% loss as tracked by ¹H NMR integration of the tert-butyl singlet at 1.42 ppm. This contrasts with the corresponding benzyl carbamate (Cbz) protection, which undergoes concurrent reductive cleavage under the same conditions, reducing the yield of the isolated carboxylic acid intermediate to 62% versus 89% for the Boc analogue. The sulfonamide N–H remains sufficiently acidic (pKa ~ 9.2 in 1:1 MeOH/water) to direct regioselective acylation at the pyrrolidine nitrogen when using 1.05 eq of acyl chloride in the presence of 1.2 eq of N-methylmorpholine in dichloromethane at −40 °C.

Process Safety: Thermal Hazards of the Solid and Solution Phases

Differential scanning calorimetry analysis of the neat solid reveals an exothermic onset at 167 °C with an energy of decomposition of −780 J/g, consistent with the nitro group decomposing autocatalytically. Adiabatic calorimetry (accelerating rate calorimeter, ARC) with a phi-factor of 1.3 indicates a time-to-maximum-rate (TMR_ad) of 24 hours at 135 °C and 8 hours at 150 °C. On a production scale, the bulk solid must not be exposed to temperatures exceeding 80 °C for any period during drying or packaging, and the 4-nitrophenyl ester solution in THF is routinely dosed into the next reaction step at temperatures below 5 °C to avoid runaway cleavage. A dedicated safety interlock on the 200 L glass-lined reactor maintains cooling brine circulation when the internal temperature exceeds 10 °C during the ester activation sequence.

Is the Supplied ‘Model’ Grade Suitable for cGMP Peptide Coupling Campaigns?

The term “model” in this product’s designation does not imply a reduced purity threshold. Rather, it refers to a standardized batch size of 250 g or 1.0 kg, pre-weighed in an ISO 7 cleanroom environment and documented with a certificate of analysis meeting the requirements of ICH Q7 for pharmaceutical intermediates. This material has been qualified by a contract manufacturing organization using the same batch as input for a 3-step sequence to yield the corresponding carbapenem intermediate, with end-of-campaign performance parameters: 67% molar yield over three stages, 99.7% chiral purity of the final N-protected carbapenem acid, and residual palladium below 2 ppm. The deep-frozen stock solution of the free thiol generated in situ from this intermediate exhibits an oxidation half-life of 6 h at −20 °C under nitrogen, compared to 45 min for the thiol derived from the methyl ester analogue, a difference attributed to the differential solubility of disulfide byproducts. Storage and distribution of the packaged product follows a validated cold chain under constant temperature monitoring with calibrated PT-100 probes, maintaining 2–8 °C during transit from the fill/finish facility in Frankfurt, DE to the end user’s manufacturing suites. Any excursion above 15 °C for a cumulative duration exceeding 2 hours triggers a mandatory retest of the des-acetylthio impurity and enantiomeric excess before release to production. This protocol was instituted following a 2022 investigation where a single consignment experienced a 22 h hold at 22 °C in a temporary warehouse, resulting in a 3.2-fold increase in the mercaptan impurity and failure to meet the 0.15% specification.