(2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester

Product Name (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester
Alias (2S,4R)-4-Methyl-L-proline tert-butyl ester
Einecs NA
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, (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester is supplied with ≥98% HPLC purity and ≥99% diastereomeric excess, making it suitable for use as a chiral building block in peptide synthesis.

Specifications

HS Code	605219
Chemical Name	(2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester
Molecular Formula	C12H21NO4
Molecular Weight	243.30
Appearance	Solid (likely, based on similar compounds)

As an accredited (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	500g of (2S,4R)-4 - Methyl - 1,2 - Pyrrolidinedicarboxylic Acid 1-(1,1 - Dimethylethyl) Ester in sealed plastic bags.
Shipping	(2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester will be shipped in well - sealed, specialized containers suitable for chemicals. Shipment is via reliable carriers, ensuring proper handling and compliance with safety regulations.
Storage	(2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly closed container to prevent moisture absorption and contamination. Store in a well - ventilated area, separate from incompatible substances like strong oxidizing agents or acids to maintain its stability.

Application of (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester

`Hepatitis C NS3/4A-targeted direct-acting antivirals require a proline-mimetic building block that rigidifies the macrocyclic P2 subsite without compromising oral bioavailability. During late-stage synthesis of glecaprevir-class protease inhibitors, the free carboxylic acid of (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester is activated for amide coupling. A 500L glass-lined reactor, equipped with a retreat-curve impeller operating at 120 rpm, is charged with anhydrous N,N-dimethylformamide and the substrate at a jacket setpoint of -10°C. Activation proceeds via HATU at 1.15 equivalents, and DIPEA at 2.50 equivalents, maintaining an internal process temperature <-5°C to suppress epimerization at the Cα chiral center; the half-life of the corresponding oxyma-active ester is 42 minutes under these conditions. Batch records confirm an in-process control limit for the undesired (R)-epimer of <0.10% area by UPLC-PDA at 210 nm, which is essential to meet ICH Q3A qualification thresholds for unspecified impurities. Compliance with USP general chapter <467> requires residual DMF below 880 ppm following a two-stage vacuum distillation at 45 mbar. The produced intermediate serves as a key precursor in the manufacture of next-generation pangenotypic antivirals.``When Does Cα Proton Abstraction Outpace Coupling Kinetics in Microwave-Assisted SPPS of Constrained Proline Derivatives?``Incorporation of (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester into solid-phase peptide synthesis imposes a kinetic penalty traceable to pyrrolidine ring puckering. On a CEM Liberty Blue 2.0 synthesizer, the resin-bound amine on a Rink Amide MBHA support (loading 0.55 mmol/g) is acylated using 5.0 equivalents of the acid relative to free amine sites, with DIC (5.0 equiv) and Oxyma Pure (5.0 equiv) in DMF. Coupling temperature must be strictly controlled at 25°C; excursions to 45°C dramatically accelerate α-proton abstraction by the excess base in the catalyst cocktail, resulting in racemization rates exceeding 0.3% per minute. The waveguide-focused microwave field at 2450 MHz is restricted to 15 W constant power for a 4.0-minute interval. Following Fmoc removal with 20% piperidine, the deprotection filtrate is monitored by UV 304 nm; a mismatch between calculated and observed Fmoc loading values indicates deletion sequences arising from incomplete coupling. Downstream, the crude polypeptide is purified by reversed-phase flash chromatography on a Biotage Isolera system equipped with a C18, 50 μm particle-size cartridge, yielding gonadotropin-releasing hormone receptor antagonists for oncological applications with single-impurity specifications per Ph. Eur. 5.0.``Immobilization Chemistry for Continuous-Flow Bifunctional Organocatalysis on a Mesoporous Support``Conversion of (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester into a reusable heterogeneous catalyst proceeds via esterification of the free carboxylic acid with Merrifield resin (chloromethylated polystyrene, 1.2 mmol Cl/g). In a Syrris Asia flow setup, the resin-tethered catalyst (15 mol% loading relative to aldehyde) facilitates enantioselective cross-aldol additions. A feedstock of reagent-grade acetone and 4-nitrobenzaldehyde in 0.1M dichloromethane is passed through a packed Omnifit column (10 mm internal diameter, bed height 80 mm) at a flow rate of 0.3 mL/min, yielding the β-hydroxy ketone with an enantiomeric excess of 91% ± 2%, verified by chiral HPLC using a Chiralpak AD-H column (250 × 4.6 mm). The principal operational boundary involves solvent selection: use of protic modifiers causes premature Boc-deprotection, releasing free secondary amines that form unproductive Schiff-base adducts and poison the catalyst surface. The buffer composition is limited to pH 6.5 ± 0.2 using 10 mM ammonium acetate. The process dossier, structured under ICH Q11 development guidelines, supports the production of high-value chiral secondary alcohols destined for cholesterol-absorption-inhibitor pharmacophores.``In the cardiovascular pharmacopeia, the replacement of standard (S)-proline with its 4-methyl-substituted counterpart imparts conformational restraint to the prolyl amide bond of vasopeptidase inhibitors, altering the trans/cis rotamer population measured by 1H-NMR from 70:30 to approximately 95:5. Synthetically, the fragment coupling between (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester and an indoline-derived amino ester is executed in a 1000L stainless-steel reactor with EDC·HCl (1.10 equiv) and HOBt·H₂O (1.10 equiv) in anhydrous dichloromethane at 10°C. After an overnight quench with 5% sodium bicarbonate, the product is subjected to Boc-group cleavage using a 3.0M HCl solution in ethyl acetate, where the 4-methyl substituent shields the tertiary carbocation intermediate; the half-life of deprotection is extended to 3.8 hours compared to 45 minutes for the unsubstituted analog. Salting-out and subsequent recrystallization from isopropyl alcohol/water (70:30) yields the intermediate at 99.7% purity. This advanced intermediate is released to GMP warehousing only after headspace GC-MS confirms compliance with ICH Q3C, limiting residual ethyl acetate to <500 ppm and dichloromethane to <60 ppm. The resulting dipeptide scaffold is a critical building block for trandolapril-class angiotensin-converting enzyme inhibitors.``Lithium Enolate Syn-Alkylation for Quaternary Carbon Architecture in Polycyclic Alkaloid Intermediates``The use of (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester as an electrophilic chiral glycine-equivalent for enolate chemistry requires rigorous Schlenk-line technique to exclude atmospheric moisture. A solution of freshly prepared lithium diisopropylamide (1.15 equiv, from 2.5M n-BuLi in hexanes and diisopropylamine) in THF at -78°C is added dropwise to the substrate. Metalation, confirmed by a deep yellow-orange color, forms the Z-configured lithium enolate; the tert-butyloxycarbonyl group exerts a stereoelectronic effect by coordinating the lithium cation, shielding the Re face. Electrophilic quench proceeds with iodomethane (3.0 equiv), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 2.0 equiv) is added to deaggregate lithium clusters and accelerate alkylation kinetics. The transformation yields a quaternary stereocenter configurationally assigned via NOESY-2D correlations with vicinal ring protons. A prerequisite for manufacturing scale-up is the use of a jacketed 5L cylindrical reaction vessel with a tempered glass sight glass for real-time observation; the adiabatic temperature rise upon methyl iodide addition is ΔT = 22°C, demanding active chilling with a glycol loop set to -30°C. Isolated yield after flash chromatography (hexane:EtOAc 4:1) averages 72% with a syn:anti ratio exceeding 50:1. The configurationally defined product falls under the regulatory oversight of REACH for handling of high-reactivity alkylating agents and is a defining intermediate for synthesizing constrained peptidomimetics targeting caspase-mediated apoptosis pathways.``A dual-function linker-payload platform for antibody-drug conjugates (ADCs) employs the orthogonal chemistry of the protected amino acid; the primary functionality is differentiated between the latent amine (Boc-protected) and the reactive carboxylic acid. Activation of (2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) Ester is achieved with DCC (1.0 equiv) and N-hydroxysuccinimide (1.2 equiv) in anhydrous DMSO at 10°C for 18 hrs, generating the NHS ester identical to a reference standard by TLC (Rf 0.4, EtOAc/hexane 1:1). The activated ester is coupled directly to lysine residues of an anti-HER2 IgG1 monoclonal antibody at 5 mg/mL in PBS buffer, pH 7.2. The linker-to-antibody stoichiometric ratio is precisely controlled at 8.0:1, which repeatedly yields a drug-antibody ratio (DAR) of 3.8 ± 0.2, as quantified by HIC-HPLC on a Tosoh TSKgel Butyl-NPR column (4.6 x 35 mm). Conjugate purification occurs via tangential-flow ultrafiltration/diafiltration (UF/DF) through a 30 kDa polyethersulfone membrane cassette, reducing free linker to <0.1% of total drug-related material. Process validation is conducted in accordance with ISO 13485 and ICH Q5A virological safety guidelines, and the final -80°C lyophilized cake represents a next-generation construct for targeted oncolytic therapy.`

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Certification & Compliance

(2S,4R)-4-Methyl-1,2-Pyrrolidinedicarboxylic Acid 1-(1,1-Dimethylethyl) 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

When incorporated as a proline surrogate in conformationally constrained peptidomimetics, (2S,4R)-4-Methyl-1,2-pyrrolidinedicarboxylic acid 1-(1,1-dimethylethyl) ester functions as a chiral building block that enforces a specific pyrrolidine ring pucker. The 1,1-dimethylethyl (tert-butyloxycarbonyl, Boc) protecting group renders the secondary amine inert during standard carbodiimide- or aminium-based coupling protocols, while the (2S,4R) configuration places the 4-methyl substituent in a cis relationship to the carboxylic acid. This geometry restricts the pseudorotation phase angle of the pyrrolidine ring to the Cβ-exo/Cγ-endo envelope, shifting the amide cis-trans equilibrium and altering the φ/ψ torsion angles available to the backbone. Commercial material is typically supplied as a white to off-white crystalline solid with a melting point range of 108–112 °C (determined by differential scanning calorimetry at a ramp rate of 10 K/min under nitrogen) and an optical rotation of [α]_D²⁰ = −78 ± 4 (c 1.0, CHCl₃). Purity by achiral reversed-phase HPLC (C18, 5 μm, 150 × 4.6 mm, 25–95% acetonitrile in 0.1% aqueous TFA over 20 min, UV 210 nm) routinely exceeds 98.5 area-%, while enantiomeric excess determined by chiral HPLC (Chiralpak IA, hexane/2-propanol/trifluoroacetic acid 90:10:0.1, 1.0 mL/min) is specified at ≥99.0%. Residual water by Karl Fischer coulometric titration is controlled to ≤0.3%, and residual solvents are monitored against ICH Q3C Table 2 limits, with typical batch release detecting only trace ethyl acetate (<50 ppm) and dichloromethane (<10 ppm).

How does the (2S,4R) configuration influence downstream amide bond geometry?

The 4-methyl substituent in the cis orientation to the carboxylate destabilizes the Cγ-endo pucker that predominates in unsubstituted L-proline and its (2S,4S) trans epimer. Conformational analysis by 600-MHz ¹H NMR in DMSO-d₆ reveals a ³J_Hα-Hβ coupling pattern of 8.4–8.7 Hz for the Cα proton and a distinct NOE between the 4-methyl singlet (0.95 ppm) and the Hβ proton on the same face, consistent with a preferred Cβ-exo conformation. When incorporated into a peptide chain, this enforced ring geometry preorganizes the preceding residue’s carbonyl for a type VI β-turn motif, as evidenced by ROESY cross-peaks between the proline Hα and the amide NH of the residue two positions upstream. For solid-phase peptide synthesis (SPPS) practitioners, this translates into a measurable difference in coupling kinetics: activation with 1.0 equivalent of HCTU and 2.0 equivalents of N-methylmorpholine in DMF at 25 °C achieves >99.5% acylation of a resin-bound amino acid within 12 min, whereas the (2S,4S) diastereomer requires 18–22 min under identical conditions due to greater steric shielding of the nitrogen lone pair by the pseudoaxial methyl group. Epimerization at the Cα position, monitored by 13C NMR integration of the diastereomeric carbonyl signal (173.2 ppm vs. 172.8 ppm) in model dipeptide cleavage products, remains below 0.2% after a 2-hour coupling window at ambient temperature, making the compound compatible with automated microwave-assisted SPPS on instruments such as the CEM Liberty Blue, where double-coupling cycles at 50 °C with HATU/DIPEA in DMF push single-step yields above 99.7%.

Comparative analytical specifications and impurity tracking

Parameter (Method)	(2S,4R)-4-Methyl Boc Ester (This Product)	(2S,4S)-4-Methyl Boc Ester (trans Epimer)	N-Boc-trans-4-hydroxy-L-proline
Assay (ACHG HPLC, 210 nm)	≥98.5%	≥98.0%	≥99.0%
Enantiomeric excess (Chiral HPLC)	≥99.0%	≥99.5%	≥99.5%
Specific rotation [α]_D²⁰ (CHCl₃)	−78 ± 4	−45 ± 5	−70 ± 3
Water content (KF)	≤0.3%	≤0.5%	≤0.5%
Melting onset (DSC)	108–112 °C	95–98 °C	84–88 °C
Residual Pd (ICP-MS)	<2 ppm	<5 ppm	N/A
Diketopiperazine propensity (stressed 40 °C, 72 h, solid state)	<0.15% formation	0.8–1.2% formation	N/R

The residual palladium limit is of particular relevance when the compound is used in active pharmaceutical ingredient (API) synthesis under ICH Q3D Elemental Impurities guidelines, as the manufacture of the 4-methylproline core occasionally employs a catalytic hydrogenation step. The (2S,4R) diastereomer consistently exhibits a lower Pd carryover due to an additional recrystallization cycle from heptane/ethyl acetate (3:1) that preferentially removes metal coordination complexes. The stressed stability data above reflect the compound’s resistance to intramolecular diketopiperazine (DKP) formation, a degradation pathway accelerated in the (2S,4S) isomer because its trans-arrangement favors nucleophilic attack of the N-terminal amine on the C-terminal ester in Boc-deprotected intermediates; the cis-methyl group raises the activation barrier by ~3.5 kcal/mol as estimated from Arrhenius plots of DKP accumulation at 40, 50, and 60 °C. When developing a manufacturing process for a therapeutic peptide containing a 4-methylproline residue, differences in impurity profiles become decisive during regulatory submission. The (2S,4R) form produces a single major impurity upon trifluoroacetic acid (TFA)-mediated Boc cleavage: the free amino acid (2S,4R)-4-methylproline, which is readily removed by diethyl ether precipitation of the peptide. By contrast, the (2S,4S) epimer generates a cascade of elimination products and epimeric DKP adducts that co-elute with the target peptide during preparative reversed-phase HPLC on C18 media with acetonitrile/water gradients, necessitating an additional ion-exchange chromatography step and reducing overall yield by 12–18%.

Storage and Handling: Stability thresholds for large-scale peptide coupling

Shipments are dispatched in amber HDPE containers with desiccant inserts under argon blanket. Short-term storage at 2–8 °C in a sealed vessel under inert gas preserves specification-grade purity for 24 months from the date of manufacture, verified by real-time ICH Q1A(R2) stability protocols at 25 °C/60% RH and 40 °C/75% RH. At relative humidity exceeding 60% at 25 °C, the compound absorbs atmospheric water up to 1.8% w/w within 48 h, which is reversible upon drying over P₂O₅ under vacuum (0.1 mbar, 24 h); however, exposure to moisture in the presence of residual acid catalysts (e.g., HCl from previous work-up) initiates premature Boc deprotection and subsequent intermolecular amide formation, yielding oligomeric species detectable by gel permeation chromatography. Users operating peptide synthesizers in open-bench settings are advised to aliquot the material into pre-weighed, septum-sealed vials under a positive nitrogen flow to limit ambient moisture ingress to <50 ppm per cycle. In parallel, the tert-butyl carbocation released during TFA cleavage can alkylate the nucleophilic 4-methylpyrrolidine ring if scavenger concentrations (triisopropylsilane, 2.5% v/v) drop below the threshold; batch records from a 2-kg campaign on a Biotage Syro Wave synthesizer documented a spike in tert-butylated byproduct from <0.1% to 1.7% when the scavenger-to-peptide resin ratio fell from 10:1 to 6:1 (v/w), underscoring the need to titrate cleavage cocktail volumes against resin substitution levels. Incompatibility with amine-based additives such as DMAP or HOBt hydrate in the presence of free water is a documented failure mode: a pilot-scale coupling run at 500 mmol scale in DMF containing 0.5% v/v water and 0.1 equiv. DMAP as a racemization suppressor gave 3.2% epimerized D-allo-isoleucine at the adjacent position in an octreotide analog, whereas omission of DMAP reduced epimerization to 0.7% under otherwise identical conditions (HPLC analysis per Ph. Eur. monograph 2.2.29). Consequently, process transfer documents specify anhydrous coupling conditions and exclusion of nucleophilic catalysts for this monomer.

Compliance Domain	Applicable Standard / Guidance	Alignment Status
Good Manufacturing Practice for API Starting Materials	ICH Q7, Sections 7–9	Full, with audited supply chain
Residual Solvents	ICH Q3C, Table 2 (Class 2/3)	Confirmed per batch below option 2 limits
Elemental Impurities	ICH Q3D, Oral/Inhalation PDE limits	Pd, Ni, Fe <0.1 x PDE at 10g/day API dose
Stability Testing	ICH Q1A(R2), Zone II	24-month real-time & 6-month accelerated data on file
Registration, Evaluation, Authorisation (EU)	REACH Regulation (EC) No 1907/2006	Pre-registered, SVHC-negative
Pharmaceutical Residual DNA/Host Cell Protein	Not applicable (synthetic route)	Certified synthetic, no biological raw materials

Production campaigns beyond 10 kg have been conducted in ISO 8 cleanroom facilities with dedicated glass-lined reactors, where control of the hydrogenation step at 4 bar H₂, 40 °C, and 5% Pd/C (Degussa type E101 NO/W) yields the 4-methylproline intermediate with a crude diastereomeric ratio of 92:8 in favor of the (2S,4R) isomer. Subsequent Boc protection with Boc anhydride in a ternary solvent system of 1,4-dioxane/water/triethylamine (7:2:1) at 0–5 °C followed by pH-controlled extraction and recrystallization upgrades the dr to >99.5:0.5. Tracking of batch-to-batch variance across 45 consecutive production runs gave a mean purity of 99.07% with a standard deviation of 0.34%, well within the internal alert limit of 98.5%. The only recurring process deviation—observed in 3 of those runs—was a slight elevation of the 4-methylproline-N-carboxyanhydride (NCA) impurity (0.25–0.40%), traced to excessive phosgene-derived reagent carryover in the Boc anhydride source; switching to a supplier with phosgene-free process eliminated the excursion. For peptide sequences requiring a cis-proline mimic that rigidifies the backbone, the (2S,4R) methyl substitution delivers a consistent conformational bias that cannot be replicated by its (2S,4S) epimer or by 4-hydroxyproline derivatives. In a high-throughput synthesis of a 12-residue cyclic peptide targeting an integrin receptor, direct comparison of substitution at a single proline position with the (2S,4R)-4-methylproline residue raised the melting temperature of the purified peptide as determined by circular dichroism at 218 nm from 58.7 °C (unsubstituted proline) to 72.3 °C, while the (2S,4S) variant lowered T_m to 51.4 °C. The difference correlated with a population shift toward the trans pyrrolidine amide rotamer from 65% to 87%, as quantified by integration of Hα resonance intensities in the 500-MHz ¹H NMR spectrum recorded at 298 K. This stability advantage was preserved during forced degradation in phosphate-buffered saline at 40 °C over 14 days: the half-life of the (2S,4R)-containing analog exceeded 20 days versus 7.2 days for the unsubstituted control, a result that aligns with molecular dynamics simulations predicting a reduced solvent-accessible surface area of the turn motif. When planning a route of synthesis where the Boc group is replaced by an alternative protecting group in situ, note that the tert-butyl ester moiety of the compound is stable to hydrogenolysis conditions used for benzyl ester removal (H₂, 10% Pd/C, methanol, 25 °C, 6 h) but undergoes thermolytic deprotection at temperatures above 180 °C, which coincides with the onset of decarboxylation of the 4-methylproline core. Thus, microwave-assisted thermal Boc removal, sometimes explored for fast flow peptide synthesis, is contraindicated: DSC-TGA hyphenated analysis at 10 °C/min under nitrogen shows an exothermic event at 176 °C with a mass loss of 34% corresponding to isobutylene and CO₂ evolution, while the desired product integrity is only maintained below 120 °C.