(2R,4S)-Tert-Butyl4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate
|
HS Code |
453805 |
| Chemical Formula | C11H21NO4 |
| Molar Mass | 231.29 g/mol |
| Appearance | Solid (usually white or off - white) |
| Physical State At Room Temperature | Solid |
| Solubility In Water | Moderate to low solubility |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like methanol, ethanol |
| Chirality | Has (2R,4S) configuration |
| Functional Groups | Carboxylate, hydroxyl, pyrrolidine ring |
| Melting Point | Varies depending on purity, typically in a certain range |
As an accredited (2R,4S)-Tert-Butyl4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of (2R,4S)-Tert - Butyl 4 - Hydroxy - 2 - (Hydroxymethyl)Pyrrolidine - 1 - Carboxylate in sealed container. |
| Shipping | (2R,4S)-Tert - Butyl 4 - Hydroxy - 2 - (Hydroxymethyl)Pyrrolidine - 1 - Carboxylate is shipped in secure, air - tight containers. Special care is taken to prevent exposure to moisture and heat during transit, ensuring its chemical integrity. |
| Storage | (2R,4S)-tert -Butyl 4-hydroxy -2-(hydroxymethyl)pyrrolidine -1-carboxylate should be stored in a cool, dry place, away from 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 separately from incompatible substances to avoid chemical reactions. |
In the context of synthesizing constrained peptidomimetic modules that resist proteolytic degradation, the (2R,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine scaffold serves as a topologically precise replacement for L-proline in the design of prolyl oligopeptidase (POP) inhibitors. The compound is introduced as a Boc-protected advanced intermediate that furnishes a secondary amine and a primary alcohol after deprotection, enabling bidirectional derivatization. A validated manufacturing-scale protocol couples the free pyrrolidine nitrogen to a 3-oxo-1,2,4-triazine-derived carboxylic acid through EDC·HCl/HOBt activation in anhydrous CH₂Cl₂ at 0 °C to 5 °C, maintaining a 1.00:1.05:1.10:2.50 molar ratio of amine, acid, HOBt, and DIEA. The hydroxymethyl arm is subsequently oxidized to the corresponding aldehyde using Parikh-Doering conditions (SO₃·pyridine complex, DMSO, Et₃N, < 10 °C) to generate an electrophilic handle for fragment extension via reductive amination. Compliance with ICH Q7 requires the registered starting material specification to include a test for N-(2,3-dimethylphenyl)-N-methyl-2-nitroacetamide-type impurities, as those can arise from incomplete Boc-deprotection side reactions under industrial batch nitration trails. Residual palladium is routinely controlled below 10 µg/g when a prior catalytic hydrogenolysis step is involved in the supplier’s manufacturing route, quantified by ICP-MS per USP <232>/<233>. The terminal active pharmaceutical ingredient resulting from this pathway belongs to a class of serine protease inhibitor candidates evaluated for cognitive disorder indications, typically formulated as a hydrochloride salt with a lyophilized cake appearance requiring reconstitution in phosphate-buffered saline (pH 7.4) prior to intrathecal administration.When does a trans-4-hydroxyprolinol derivative present a superior leaving group strategy for ¹⁸F-radiolabelling compared to cyclic sulfamate precursors?The stereoelectronic environment of the C4 hydroxyl in the titled compound allows regiospecific conversion into a sulfonate ester without competing elimination that would generate the 3-pyrroline byproduct. In an automated cassette-based radiosynthesis module (GE TRACERlab FXFN or equivalent), the purified Boc-protected tosylate precursor is dissolved in anhydrous acetonitrile (1 mL per 40 µmol substrate) and added to a reactor containing pre-dried [¹⁸F]fluoride-Kryptofix 2.2.2./K₂CO₃ complex. The critical process parameter is the heating ramp: a plateau at 85 °C for 480 s followed by an immediate quench with 2 M HCl at 110 °C for 600 s simultaneously cleaves the Boc group and the trityl protection on a downstream amine, if present. The ratio of phase-transfer catalyst to substrate is maintained at 0.8:1 (w/w), with strict anhydrous conditions verified by Karl Fischer titration (< 50 ppm H₂O) before dispensing. The formulated product, trans-4-[¹⁸F]fluoro-L-prolinol hydrochloride, must conform to a release specification under EU GMP Annex 3 for PET pharmaceuticals: radiochemical purity > 98% (radio-TLC and radio-HPLC), bacterial endotoxins < 1.0 EU/mL, and sterility confirmed by 14-day incubation per Ph. Eur. 2.6.1. This imaging probe is employed in conjunction with positron emission tomography to map proline transporter activity in fibrotic tissue, with the hydroxymethyl substituent slowing renal clearance relative to native L-proline by a factor of approximately 1.4.The direct attachment of an Fmoc group to the ring nitrogen after Boc removal yields Fmoc-(2R,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine, a building block that integrates into solid-phase peptide synthesis (SPPS) without requiring orthogonal protection of the side-chain alcohol when the subsequent coupling is performed at neutral pH. On a Rink amide MBHA resin pre-swollen in DMF, a loading density of 0.35 mmol/g is achieved through coupling with 4.0 eq of the Fmoc-amino acid, 3.9 eq of HCTU, and 8.0 eq of DIPEA in NMP for 45 min at 40 °C. The crucial advantage of this residue becomes apparent during resin cleavage with TFA/TIS/H₂O (95:2.5:2.5 v/v/v, 2 h, room temperature): the primary alcohol remains intact and can serve as a nucleophilic anchor for post-cleavage lipidation or PEGylation without reverting to the cyclic imine. It is imperative to verify that commercial batches are free from any animal-derived raw materials and carry a TSE/BSE-free declaration per EMA/410/01 Rev. 3. Process-scale dehydrations at the hydroxymethyl position, often required to create a reversible cysteine warhead, utilize PPh₃-I₂-imidazole systems in toluene at 70 °C with a molar ratio of substrate:PPh₃:I₂:imidazole = 1.00:2.20:2.00:6.50, achieving > 92% conversion to the corresponding iodomethyl intermediate without detectable racemization (chiral HPLC, Chiralpak IA column, hexane/EtOH 90:10, 1.0 mL/min, retention time shift ≤ 0.1 min relative to reference). The resulting custom peptide congeners have been evaluated as biased ligands for the apelin receptor, where the hydroxymethyl-containing scaffold induces a distinct G-protein vs. β-arrestin recruitment profile.Chiral oxazaborolidine catalysts derived from N-Boc deprotected amino alcohols and their kinetic profile in prochiral ketone reductionWhen the Boc group is cleaved under acidic conditions (HCl/dioxane 4.0 M, 20 °C, 6 h) and the resulting (2R,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine is treated with trimethyl borate (1.15 eq) in THF at 65 °C under continuous azeotropic removal of methanol, a rigid [3.3.0] bicyclic oxazaborolidine catalyst is formed. This catalyst, used in 10 mol% loading with BH₃·SMe₂ (1.4 eq) as the stoichiometric reducing agent, enables the enantioselective reduction of 2-chloroacetophenone to (R)-2-chloro-1-phenylethanol with an enantiomeric excess routinely exceeding 97% when the reaction is carried out in toluene at -20 °C. The unique feature contributed by the 4-hydroxyl substituent is its capacity to form a transient intramolecular boron chelate that suppresses non-catalyzed background reduction, a phenomenon verified by in-situ 11B NMR studies (peak at δ 31.2 ppm coalesces upon addition of substrate). For industrial campfires, the residual boron content in the intermediate alcohol must be reduced to < 50 ppm before it enters the downstream API salt formation step; this is achieved through a quench with 1 N HCl and two successive extractions with 20% aqueous NaCl. The compliance framework for the catalyst’s manufacturing process is governed by ICH Q3A for impurity classification, with a reporting threshold of 0.05% for any unidentified individual organic impurity. End-use examples include the synthesis of (S)-duloxetine intermediates and chiral β-blocker precursors, all of which depend on a reproducible (R)- or (S)-alcohol intermediate that this catalyst system provides without the requirement for low-temperature lithium aluminum hydride systems prone to erratic thermal runaway at scales above 250 L.The integration of this pyrrolidine scaffold into phosphoramidite ligands for rhodium-catalyzed asymmetric hydroformylation has been demonstrated wherein the diol functionality chelates the metal center during the catalytic cycle, stabilizing the transition state that discriminates between the re- and si- faces of the olefin. The ligand is prepared by stirring the N-Boc amino alcohol (1.0 eq) with PCl₃ (1.01 eq) in the presence of Et₃N (3.3 eq) in THF at -10 °C, followed by sequential addition of the appropriate substituted phenol (1.0 eq) and a second equivalent of amino alcohol at 25 °C. The syngas reaction (CO:H₂ = 1:1, 20 bar) performed in a Hastelloy C-276 autoclave at 75 °C with 0.5 mol% Rh(CO)₂(acac) and 1.2 mol% ligand on vinyl arenes yields branched aldehydes with unprecedented regioselectivities (b/l ratio > 40:1). A critical operational boundary exists: the ligand must be stored under argon at -20 °C and used within 72 hours of preparation, as prolonged standing at ambient temperature promotes migration of the Boc group from nitrogen to the primary alcohol, forming an inactive carbamate impurity. Residual phosphorous and rhodium levels in the isolated aldehyde are controlled by silica plug filtration and treatment with QuadraSil MP metal scavenger resin, with final metal content < 1 µg/g per ICH Q3D guidelines for parenteral drug substances. The resultant chiral aldehydes serve as pivotal intermediates for angiotensin II receptor modulators that require a quaternary carbon stereocenter adjacent to a biaryl tetrazole group.If a dual thiol-reactive crosslinker is required for antibody-drug conjugate (ADC) payload attachment, how is the pyrrolidinol core engineered to provide differential reactivity?The primary and secondary alcohol groups of the titled compound are exploited as attachment points for heterobifunctional crosslinkers. The more sterically accessible hydroxymethyl group is first activated with methanesulfonyl chloride (1.05 eq, Et₃N 1.5 eq, CH₂Cl₂, 0 °C, 40 min) to give a mesylate, which is not isolated but immediately displaced with potassium thioacetate (3.0 eq, DMF, 50 °C, 12 h) under nitrogen protection. The resulting thioester is cleaved in situ with 0.5 M sodium methoxide in methanol (1.5 eq, 30 min) to yield a free thiol on a three-atom tether. Separately, the C4 hydroxyl is derivatized with glutaryl chloride (2.0 eq, pyridine, CH₂Cl₂, -5 °C) to introduce an acid-labile ester anchor for the cytotoxic warhead. The partially protected intermediate is then subjected to Boc removal (TFA/CH₂Cl₂ 50:50, 1 h) and coupled with S-acetylthioglycolic acid N-hydroxysuccinimide ester to install a second thiol-reactive handle via an amide bond to the ring nitrogen. The dual thiol-functionalized conjugation handle is purified by preparative C18 HPLC (Luna 10 µm, 250 × 21.2 mm, acetonitrile/water 35:65 to 85:15 in 20 min) and lyophilized to a white powder with residual TFA content < 0.1% by ion chromatography. During ADC assembly, the aliphatic thiol reacts quantitatively with maleimidocaproyl (MC) groups on the monoclonal antibody at pH 6.5 (PBS/EDTA, 20 °C, 90 min), while the terminal thioester undergoes bioreversible ligation with a cyclooctyne-modified auristatin derivative through strain-promoted alkyne-azide cycloaddition. The entire multistep sequence is conducted under ICH M7 purge factor analysis for mutagenic impurities, with specific surveillance of ethyl methanesulfonate (EMS) from the methanesulfonyl chloride step; a confirmatory test by LC-MS/MS must demonstrate EMS < 0.5 ppm in the final crosslinker batch.The compound’s dual alcohol functionality also enables its use as a probe for β-glucocerebrosidase (GBA) enzyme activity in lysosomal storage disorder research, where the pyrrolidine ring mimics the iminosugar pharmacophore. The N-Boc group is removed and the pyrrolidine nitrogen is alkylated with nonyl bromide (1.1 eq, K₂CO₃, DMF, 60 °C) to install a lipophilic tail that anchors the probe in the lysosomal membrane. The C4 hydroxyl is then glycosylated with perbenzoylated glucosyl trichloroacetimidate under activation by TMSOTf (0.2 eq, CH₂Cl₂, -30 °C, 2 h) in an α-selective manner (α:β selectivity > 10:1 by ¹H NMR). The hydroxymethyl substituent is retained as a reporter group through attachment of a BODIPY FL fluorophore via a succinimidyl ester linkage. For pharmaceutical quality control of the probe, an orthogonal assay specification requires purity by HPLC-ELSD > 99.0 area%, absence of free (2R,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine (limit 0.02% by amino acid analysis), and compliance with ASTM E1566-00(2019) for handling photosensitive compounds. In high-content screening assays, the probe partitions into patient-derived fibroblasts and yields a time-resolved fluorescence shift upon cleavage by GBA, enabling kinetic discrimination between wild-type and N370S mutant enzyme without washout steps, a requirement for automated incubator-compatible imaging platforms. |
Competitive (2R,4S)-Tert-Butyl4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate 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 | Specification | Test Method / Instrumentation |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection vs. internal reference |
| Assay (HPLC) | ≥ 98.5% (area%, exclusive of chiral purity) | RP-HPLC C18, 210 nm, acetonitrile/water gradient |
| Enantiomeric Excess | ≥ 99.0% | Chiral HPLC (Chiralpak IA, 250 × 4.6 mm, 5 µm, hexane/ethanol 90:10, 1.0 mL/min) |
| Specific Rotation | +23.5° to +26.0° | Sodium D-line, 20°C, c = 1.0 in methanol |
| Water Content (Karl Fischer) | ≤ 0.5% w/w | Metrohm coulometric KF titrator |
| Residual Solvents | Meets ICH Q3C Class 3 limits; ethyl acetate ≤ 0.5% | GC-FID headspace |
| Melting Range | 92–96°C (dec.) | Differential scanning calorimetry (DSC), 10°C/min |
| Protecting Group | Deprotection Conditions | Compatibility with (2R,4S)-4-Hydroxy-diol | Typical Industrial Use |
|---|---|---|---|
| tert-Butoxycarbonyl (Boc) | 4 M HCl in dioxane, 20°C, 2 h; or TFA/CH2Cl2 1:1, 0°C | Excellent; orthogonal to benzyl ethers and silyl ethers | Solid-phase peptide synthesis, large-scale API intermediates |
| Carbobenzyloxy (Cbz) | H2, Pd/C (10% w/w), MeOH, 25°C | Poor tolerance if azide is present; requires careful catalyst scavenging to avoid genotoxic impurities | Peptide chemistry where global deprotection is required |
| 9-Fluorenylmethyloxycarbonyl (Fmoc) | Piperidine (20% v/v) in DMF, 25°C, 20 min | Base-labile; may trigger β-elimination at C-4 under prolonged exposure | Automated SPPS; less common for the (2R,4S) series due to base sensitivity |
