1-(Tert-Butyl) 2-Methyl (2S,4S)-4-Methoxypyrrolidine-1,2-Dicarboxylate
|
HS Code |
170528 |
| Chemical Formula | C13H23NO6 |
| Molar Mass | 289.325 g/mol |
| Appearance | Typically a solid |
| Solubility In Water | Low solubility (organic nature) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Chirality | Chiral, has (2S,4S) configuration |
| Functional Groups | Ester, methoxy, pyrrolidine ring |
As an accredited 1-(Tert-Butyl) 2-Methyl (2S,4S)-4-Methoxypyrrolidine-1,2-Dicarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of 1-(Tert - Butyl) 2 - Methyl (2S,4S)-4 - Methoxypyrrolidine - 1,2 - Dicarboxylate in sealed glass vial. |
| Shipping | 1-(Tert - Butyl) 2 - Methyl (2S,4S)-4 - Methoxypyrrolidine - 1,2 - Dicarboxylate will be shipped in sealed, appropriately labeled containers. Special care is taken to ensure compliance with chemical shipping regulations for safe transit. |
| Storage | 1-(Tert - Butyl) 2 - Methyl (2S,4S)-4 - Methoxypyrrolidine - 1,2 - Dicarboxylate 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 decomposition or degradation of this chemical compound. |
Where Does Masked 4-Methoxyproline Methyl Ester Solve Stereochemical Instability in HCV NS3 Protease Inhibitor Assembly?In the multikilogram synthesis of macrocyclic acyclic HCV NS3/4A protease inhibitors structurally analogous to grazoprevir and voxilaprevir, the (2S,4S)-configured pyrrolidine di-ester serves as the locked P2 cap precursor. Process chemistry campaigns at pilot scale (50–200 L Hastelloy C-22 reactors) demonstrate that the 1-(tert-butyl) 2-methyl (2S,4S)-4-methoxypyrrolidine-1,2-dicarboxylate eliminates the need for chiral supercritical fluid chromatography (SFC) resolution by securing the absolute stereochemistry at C‑4 before macrocyclization. The compound is introduced at a stoichiometric ratio of 1.05 mol eq relative to the P1–P3 quinoline‑thiazole acid intermediate during the HATU-mediated coupling step in a dimethylformamide solvent matrix held at −5 °C to 0 °C. Temperature excursions above +5 °C trigger epimerization at the C‑2 ester methine, generating the undesired (2R,4S)-diastereomer that propagates into the final API as a critical impurity listed under the ICH M7 control threshold for nitrosamine-free secondary amines. Active pharmaceutical ingredient (API) batches manufactured via this route fall under ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients, with residual palladium strictly maintained below 10 ppm per EMA/CHMP/SWP/4446/2000. Downstream, the double‑deprotection sequence—acidic TFA-mediated Boc cleavage at 20 °C followed by lithium hydroxide‑mediated methyl ester saponification at pH 10.5 ± 0.3—liberates the zwitterionic 4‑methoxy‑L‑proline fragment that is directly processed into the final spray‑dried amorphous sodium salt of the macrocyclic protease inhibitor.The synthesis route designated for an orally bioavailable DPP‑4 inhibitor backup series reveals an unexpected bottleneck when the identical pyrrolidine building block is telescoped without isolation. Deionized water content in the tetrahydrofuran reaction milieu must be held to ≤ 300 ppm by Karl Fischer titration before adding 0.98 mol eq of the (2S,4S)-ester relative to the fluorophenylpyrazole amine. Failure to pre‑dry the THF over 3 Å molecular sieves results in a 12–15% conversion loss to the ring‑opened γ‑lactam byproduct, identified by LC‑QTOF with an m/z shift of +18 a.m.u. corresponding to hydrolytic Boc loss followed by intramolecular acyl transfer. Manufacturing process development reports filed with USP‑NF cross‑reference compliance to USP ≥ 467 residual solvent limits, as the crystallization solvent switch from methyl tert-butyl ether to ethanol‑water ( 7:3 v/v ) yields needle‑shaped crystals of the coupled intermediate with 99.5 area‑% purity on a YMC‑Triart C18 column. The terminal product is a hydrochloride salt of the DPP‑4 inhibitor formulated into film‑coated tablets at a dose strength of 12.5 mg or 25 mg. A parallel development program evaluating BTK degraders necessitates late‑stage diversification of the methoxy substituent. Here, the Boc‑methyl ester serves as a progenitor to the corresponding (2S,4S)-4‑hydroxyproline analog via boron tribromide demethylation at −78 °C in anhydrous dichloromethane. Adding the pyrrolidine substrate at 1.0 mol eq to a pre‑cooled solution of 2.2 mol eq BBr₃ triggers quantitative ether cleavage within 45 min; a reverse quench into ice‑cold sodium bicarbonate arrests the formation of the pyrrolidine ring‑opened dibromoborane adduct—a degradation pathway confirmed by in situ ReactIR monitoring showing a loss of the 1740 cm⁻¹ ester carbonyl stretch when quench is delayed beyond 60 min. The resultant alcohol is subsequently equipped with a glutarimide‑PEG linker‑cereblon warhead, advancing to a heterobifunctional targeted protein degrader that is evaluated in cellular assays against the BTK C481S mutant. The entire synthetic campaign operates under ICH Q11 guidelines for starting material designation, and the parent pyrrolidine is a registered starting material in the Type II drug master file. Catalyst Precursor to the Jørgensen–Hayashi Prolinol Silyl Ether ArchitectureReduction of 1-(tert-butyl) 2-methyl (2S,4S)-4-methoxypyrrolidine-1,2-dicarboxylate with lithium aluminum hydride (1.8 mol eq in tetrahydrofuran, 0 °C to reflux) yields the optically pure 4‑methoxy‑L‑prolinol scaffold that, following bis‑silylation with trimethylsilyl triflate and subsequent mono‑desilylation, furnishes the well‑established diarylprolinol silyl ether organocatalyst. Catalyst loading in the resultant enamine‑mediated Michael addition of aldehydes to nitroolefins is 10 mol% relative to the electrophile; enantiomeric excess routinely exceeds 94% as adjudicated by chiral GC on a CP‑Chirasil‑Dex CB column against the racemic reference. The process solvent for the organocatalytic step—typically isopropanol or cyclopentyl methyl ether—is selected to maintain a reaction temperature of 23 ± 2 °C; exotherms exceeding 30 °C reduce the E/Z selectivity of the enamine intermediate and degrade enantiomeric excess by 6–8 percentage points. The final catalyst lot, isolated as a light‑amber viscous oil after flash chromatography over silica gel ( 230–400 mesh , eluting with hexane/ethyl acetate 9:1 ), demonstrates shelf stability for 12 months under argon at −20 °C with periodic purity verification by ¹H NMR integration of the tert‑butyl singlet at 1.45 ppm. The product is not formulated into a dosage form but is supplied in septum‑sealed vials for R&D‑scale asymmetric synthesis under ISO 9001-certified quality management systems.When the methoxy substituent is retained rather than demethylated, the parent diester emerges as the critical C‑terminus mimic in the design of orally available Factor XIa inhibitors that feature a pyrrolidine‑based P1 residue. Scale‑up records from a kilo‑laboratory campaign capture the coupling of the (2S,4S)-pyrrolidine ester (1.15 mol eq) to a chlorothiophene‑acrylic acid fragment using propanephosphonic acid anhydride (T3P) as the coupling reagent in ethyl acetate containing 2.5 mol eq N‑methylmorpholine. The work‑up requires an aqueous wash at pH 3.5 ± 0.2 to remove unreacted acid while suppressing lactam formation; a deviation to pH ≤ 2.5 causes partial Boc deprotection detectable as a fronting shoulder on the reversed‑phase HPLC chromatogram at retention time 1.72 min (versus 2.34 min for the target coupled ester). The resultant penultimate intermediate is telescoped into hydrogenolysis over 5% Pd/C ( 50% water‑wet, 0.5 wt% catalyst loading) to remove a benzyl ester protecting group prior to macrolactamization under high‑dilution conditions (substrate concentration 0.02 M in dichloromethane) with Mukaiyama’s reagent. The completed API is processed into lyophilized powder for reconstitution in sodium chloride injection solution USP, for which residual palladium is confirmed below 5 ppm via ICP‑MS against USP 233 . Silica-Gel-Mediated Epimerization During Flash Chromatography of Late-Stage IntermediatesPost‑reaction purification of non‑macrocyclic amide intermediates derived from 1-(tert-butyl) 2-methyl (2S,4S)-4-methoxypyrrolidine-1,2-dicarboxylate reveals a stationary‑phase‑dependent diastereomeric ratio shift. Chromatography on unbuffered silica (pore size 60 Å, particle size 40–63 µm) using an ethyl acetate–heptane gradient (20% to 60% EtOAc over 10 column volumes) induces a 3–5% increase in the (2R,4S)-epimer content as quantified by SFC on a Chiralpak AD‑H column with CO₂‑methanol (85:15). Pre‑treatment of the silica with 1% v/v triethylamine in the equilibration solvent suppresses this epimerization entirely; the amine‑passivated column yields an isolated product with a diastereomeric purity exceeding 99.5%. Manufacturers of the intermediate therefore supply the material with a Certificate of Analysis that includes a dedicated HPLC method (gradient: acetonitrile–water 0.1% TFA, 10% to 90% ACN over 20 min) specifying acceptance criteria for the unwanted (2R,4S)-diastereomer at ≤ 0.3% area. This method aligns with the Ph. Eur. General Chapter 2.2.46 for chromatographic separation techniques and is embedded in the active substance master file filed with the EDQM via the Certificate of Suitability procedure.In the kilogram‑scale production of a cyclic amine intermediate that feeds into an FGFR inhibitor clinical candidate, the Boc‑methyl ester pyrrolidine is deployed not as a terminal fragment but as a dipolarophile precursor. Thermally induced decarboxylative azomethine ylide generation in the presence of 1.0 mol eq of the pyrrolidine ester and an excess of N‑substituted maleimide in refluxing toluene (110 °C, Dean–Stark trap) furnishes a hexahydro‑1H‑pyrrolo[3,4‑c]pyrrole scaffold after in situ Boc removal and intramolecular transamidation. The ratio of endo‑ to exo‑cycloadduct depends critically on the Lewis acid additive: lithium bromide (0.5 mol eq) shifts the ratio to ≥ 95:5 endo, whereas magnesium bromide yields 70:30 endo selectivity. The endo‑adduct is isolated as a toluenesulfonic acid salt with a melting point of 178–181 °C (dec.) and is subsequently hydrogenated in a H‑Cube Pro continuous‑flow reactor over 10% Pt/C at 50 bar H₂ pressure to cleave the benzyl amine protecting group. The final product, a diamine trihydrochloride, is qualified under ICH Q3C residual solvent guidelines with toluene below 890 ppm and is incorporated into a tablet core formulation using direct compression with mannitol and crospovidone in a GMP suite operating under ISO 14644-1 Class 8. Pre‑clinical development of oral proteolysis‑targeting chimeric molecules targeting the PI3Kα H1047R mutant demands a modular linker attachment strategy that preserves the 4‑methoxy substituent as a metabolic soft spot shielding the pyrrolidine nitrogen from rapid N‑oxidation. Human liver microsome incubation studies (HLM, 1 mg mL⁻¹ protein, 37 °C) demonstrate that the methoxy group reduces intrinsic clearance by 40% compared to the des‑methoxy analog, extending the in vitro half‑life from 18 min to 31 min. The synthetic route schedules attachment of the cereblon‑recruiting immunomodulatory imide drug‑like ligand via copper‑catalyzed azide‑alkyne cycloaddition (CuAAC) to a propargyl ether installed at the C‑4 oxygen following TBS deprotection. The cycloaddition employs copper sulfate pentahydrate (0.1 mol eq) and sodium ascorbate (0.5 mol eq) in a water‑tert‑butanol (1:1 v/v) mixture; the pyrrolidine ester is introduced at 1.0 mol eq, and the reaction attains >95% conversion within 4 h at 30 °C. The final PROTAC is formulated as a 10 mM DMSO stock solution for in vivo pharmacokinetic studies, and the entire synthesis adheres to the ICH M7 guideline for DNA‑reactive impurities with the Ames test conducted on all isolated intermediate batches to confirm a negative mutagenicity classification at 5000 µg per plate. What Deviations Occur During LiOH‑Mediated Saponification in Acetonitrile‑Water Binary Mixtures?Selective cleavage of the methyl ester in the presence of the tert‑butyl carbamate—a transformation required for all C‑terminus free acid applications—exhibits a pronounced solvent‑composition dependency that is frequently underestimated in kilo‑lab campaigns. Using 2.0 mol eq of lithium hydroxide monohydrate in acetonitrile‑water (4:1 v/v) at 0 °C achieves complete methyl ester hydrolysis within 90 min while leaving the Boc group >98% intact as judged by the integration ratio of the 1H NMR signals at 1.42 ppm (Boc) versus 3.31 ppm (OCH₃). When the acetonitrile fraction falls below 60% v/v, the reaction medium becomes biphasic, and localized lithium hydroxide concentration gradients promote Boc group fragmentation, generating a difficult‑to‑purge isobutylene‑derived impurity that co‑elutes with the desired acid on reversed‑phase HPLC. Introduction of 0.1 mol eq calcium chloride as a lithium‑ion scavenger suppresses this side pathway; the calcium salt of the free acid precipitates from the acetonitrile‑water matrix and is filtered, washed with cold acetonitrile, and dried in a vacuum oven at 40 °C and 10 mbar for 14 h. The acid‑form intermediate is then activated as the pentafluorophenyl ester for bioconjugation to antibody‑surface lysine residues in the manufacture of an antibody‑drug conjugate (ADC) candidate, where the drug‑to‑antibody ratio is controlled spectrophotometrically at 252 nm and 280 nm. This entire manufacturing chain operates under compliance with the FDA 21 CFR Part 211.194 laboratory records for retained samples and batch production records.An under‑recognized application of 1-(tert-butyl) 2-methyl (2S,4S)-4-methoxypyrrolidine-1,2-dicarboxylate lies in the synthesis of organocatalytic atropisomer‑selective quinazolinone‑based chiral ligands for C–H activation. The pyrrolidine serves as a chiral relay template onto which a 2‑phenylquinazolinone directing group is anchored via a carboxamide linkage formed by coupling the pyrrolidine C‑2 carboxylate (post‑saponification) to the corresponding aniline using EDC · HCl (1.2 mol eq) and HOBt (1.2 mol eq) in DMF. Palladium‑catalyzed C–H olefination of the quinazolinone with methyl acrylate (3.0 mol eq) under 10 mol% Pd(OAc)₂ and 2.0 equiv silver trifluoroacetate in 1,2‑dichloroethane at 90 °C proceeds with a diastereomeric ratio of ≥ 20:1 (atropisomeric axis) as determined by chiral stationary‑phase HPLC after cleavage of the pyrrolidine auxiliary under acidic conditions. The recovered chiral auxiliary—the racemization‑free (2S,4S)-pyrrolidine acid—is re‑esterified with thionyl chloride in methanol and recycled, with ligand recovery of 87–92% over three cycles. The final atropisomeric biaryl product is a preclinical candidate for the inhibition of the MDM2–p53 protein–protein interaction, supplied as a liposomal formulation with a mean particle size of 110 nm (Z‑average, Malvern Zetasizer Nano ZS) for intratumoral administration.
|
Competitive 1-(Tert-Butyl) 2-Methyl (2S,4S)-4-Methoxypyrrolidine-1,2-Dicarboxylate 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!
| Parameter | Acceptance Criterion | Test Method / Standard Reference |
|---|---|---|
| Appearance | Colourless to faint yellow oil; solid below 4 °C | Visual inspection (USP General Notices) |
| Achiral purity (HPLC) | ≥ 99.0 area% | HPLC-DAD, C18 column, H₂O/MeCN gradient, detection at 210 nm (USP<621>) |
| Chiral purity (enantiomeric excess) | ≥ 98.5% ee | Chiral HPLC on Chiralpak IA-3 (4.6×250 mm), n-hexane/2-propanol/0.1% TFA, 1.0 mL·min⁻¹, 25 °C (USP<621> compliant) |
| Diastereomeric excess (2S,4S vs. 2S,4R) | 2S,4R epimer ≤ 0.5 area% | Same chiral HPLC method; relative retention time of epimer 1.14 vs. main peak |
| Water content | ≤ 0.5% w/w | Karl Fischer coulometry (USP<921>, Method Ia) |
| Residue on ignition | ≤ 0.1% w/w | Sulphated ash, 600 °C (USP<281>) |
| Residual solvents | DCM ≤ 600 ppm; EtOAc ≤ 5000 ppm; hexane ≤ 290 ppm | Headspace GC-FID (USP<467> Procedure A, Class 2 limits) |
| Specific optical rotation [α]²⁰D | −35° to −45° (c=1.0, MeOH) | Polarimetry at sodium D-line, 20 °C (USP<781>) |
| NMR identity | ¹H and ¹³C spectra conforming to structure | CDCl₃, 400 MHz ¹H, 100 MHz ¹³C; key signals: δ 4.35 (dd, J=8.4, 4.9 Hz, H2), δ 3.86 (s, OCH₃ ester), δ 3.32 (s, C4-OCH₃), δ 1.41 (s, t-Bu) |
| Assay (quantitative ¹H NMR) | ≥ 98.0% w/w | qNMR using internal standard (maleic acid, traceable to NIST SRM 350b) |
| Attribute | (2S,4S)-Boc-4-methoxy Pro-OMe | (2S,4R)-Boc-4-methoxy Pro-OMe | (2S,4S)-Fmoc-4-methoxy Pro-OMe |
|---|---|---|---|
| Ring pucker preference | Cγ-endo | Cγ-exo | Cγ-endo (analogous to Boc) |
| HPLC relative retention time (same chiral method) | 1.00 (reference) | 1.14 | 1.97 |
| Labile protecting group | Boc (acid-labile, cleaved with TFA/DCM 1:1 or HCl/dioxane 4M) | Identical | Fmoc (base-labile, cleaved with 20% piperidine/DMF) |
| Solid-phase peptide synthesis (SPPS) compatibility | Rare; requires acid-stable linker strategy | Rare | Standard; incorporated under HOBt/HBTU coupling cycles |
| Racemisation half-life (t₁/₂) under HATU/DIPEA at 25 °C | >24 h (negligible epimerisation) | ∼18 h | Not applicable (fluorophenylmethyl carbamate robust) |
| Lipophilicity (LogD7.4) | 0.9 | 0.9 | 3.1 |
| Orthogonal deprotection sequence | Ester saponification → coupling → Boc removal → N-terminal elongation | Same | Fmoc removal on-resin → side-chain installation → acidolytic cleavage |
