(2S,4R)-Tert-Butyl 4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate

Product Name (2S,4R)-Tert-Butyl 4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate
Alias Boc-4-hydroxy-L-prolinol
Einecs 831-617-6
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)-Tert-Butyl 4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate is supplied with ≥98% HPLC purity and ≥99% enantiomeric excess, making it suitable for chiral building block applications in asymmetric synthesis.

Specifications

HS Code	826605
Chemical Formula	C10H19NO4
Molecular Weight	217.26
Appearance	Solid (likely white or off - white)
Solubility In Water	Limited solubility, as it has a non - polar tert - butyl group and polar hydroxyl and carboxylate groups
Solubility In Organic Solvents	Soluble in some polar organic solvents like ethanol due to its polar functional groups
Chirality	Chiral, with (2S,4R) configuration
Functional Groups	Hydroxyl (-OH), hydroxymethyl (-CH2OH), carboxylate (-COO-), pyrrolidine ring, tert - butyl group
Pka	The carboxylate group would have a pKa in the range typical for carboxylic acids, around 4 - 5

As an accredited (2S,4R)-Tert-Butyl 4-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 & Storage

Packing	100g of (2S,4R)-Tert - Butyl 4 - Hydroxy - 2 - (Hydroxymethyl)Pyrrolidine - 1 - Carboxylate in sealed container.
Shipping	(2S,4R)-Tert - Butyl 4 - Hydroxy - 2 - (Hydroxymethyl)Pyrrolidine - 1 - Carboxylate is shipped in properly sealed, corrosion - resistant containers. Special care is taken to ensure compliance with chemical transportation regulations for safe transit.
Storage	(2S,4R)-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.

Application of (2S,4R)-Tert-Butyl 4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate

In large-scale asymmetric reduction campaigns requiring predictable enantioselectivity and thermal stability of the catalytic species, (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate is routinely converted into a recyclable oxazaborolidine catalyst of the CBS class. The transformation proceeds via deprotection of the Boc group with trifluoroacetic acid in dichloromethane at 0–5 °C followed by immediate complexation with borane–tetrahydrofuran complex under strictly anhydrous conditions. Operating outside the temperature window of −5 °C to +5 °C during borane addition leads to exothermic side reactions that generate inactive boroxine oligomers, reducing catalytic loading efficacy. On a 500 L glass-lined reactor equipped with a −20 °C brine jacket and a nitrogen-purged addition funnel, moisture ingress must be maintained below 0.05 mg/L in the solvent blend (toluene/THF 3:1 v/v) to prevent precipitation of boric acid, which fouls downstream filtration cartridges. The resulting free amino alcohol is then condensed with an arylboronic acid or boron trichloride–anisole complex at a boron-to-nitrogen stoichiometric ratio of 1.0:1.15 to compensate for borane partition into the headspace. Chiral HPLC monitoring (CHIRALPAK AD‑H, 4.6 × 250 mm, hexane/ethanol 95:5) confirms enantiomeric excess of the catalyst precursor above 99.5%. The finished ligand, after vacuum distillation at <1 mbar, is used for the enantioselective reduction of prochiral ketones to secondary alcohols with ee values frequently exceeding 98% as determined by the corresponding Mosher ester ¹⁹F NMR method. Quality compliance for the catalyst intermediate follows ICH Q7 guidelines for GMP starting materials, with residual palladium content tested by ICP‑MS per USP<233> (<10 µg/g) and trifluoroacetic acid traces quantified by ion chromatography (<50 ppm). Typical end products leveraging this catalyst include the (S)-enantiomer of duloxetine penultimate alcohol and the orally active antifungal posaconazole side chain.

What Role Does This Hydroxymethylpyrrolidine Play in Hepatitis C Virus Protease Inhibitor Synthesis?

Within the structural landscape of HCV NS3/4A macrocyclic inhibitors, the (2S,4R)-configured pyrrolidine ring provides the conformational pre-organization necessary to occupy the S1′ pocket of the protease while correctly orienting the P2 and P4 extension vectors. The N-Boc-protected compound is first subjected to a selective primary alcohol oxidation using a NaOCl‑TEMPO system in a biphasic dichloromethane/pH 9.5 carbonate buffer mixture, delivering the corresponding aldehyde intermediate that immediately enters a Horner–Wadsworth–Emmons olefination with a phosphonate-activated vinylcyclopropylcarboxylate surrogate. The coupling stoichiometry is tightly controlled at 1.00:1.03 phosphonate to aldehyde to avoid formation of the homodimeric Wittig by-product, which co-elutes under reversed-phase preparative chromatography conditions (Kromasil 10 µm C18, acetonitrile/water 55:45 isocratic). After olefin hydrogenation over 5% Pd/C poisoned with pyridine, the resulting (2S,4R)-carboxylate intermediate is elaborated through a series of peptide-like couplings using HATU or COMU and N,N‑diisopropylethylamine in DMF at −15 °C to suppress racemization at the α-carbon. Each batch must pass a chiral purity specification of ≥99.8:0.2 diastereomeric ratio by SFC (Chiralpak IB N‑5, CO₂/methanol 85:15, 40 °C, 120 bar back pressure). The ultimate active pharmaceutical ingredients incorporating this pyrrolidine scaffold are orally administered HCV macrocycles with picomolar replicon activity. Utility conformance under ICH M7 requires Ames‑negative confirmation for the aldehyde intermediate and a nitrosamine risk assessment incorporating semi‑empirical quantum mechanical computational analysis of the Boc-deprotection off-gas stream, as dimethylamine‑derived N‑nitrosodimethylamine is a recognized potential contaminant at sub-0.03 ppm threshold.

Peptidomimetic Conformational Constraints: Renin and BACE1 Inhibitor Scaffolds

When the pyrrolidine β‑turn mimic replaces a traditional Leu‑Val dipeptide sequence in aspartic protease inhibitors, the (2S,4R)-4-hydroxy-2-hydroxymethyl substitution pattern provides both hydrogen‑bond acceptor and donor functionalities that interact with the catalytic aspartate dyad and adjacent flap region residues. Synthesis proceeds via selective protection of the secondary alcohol as a tert‑butyldimethylsilyl ether using TBDMSCl (1.25 eq) and imidazole (3.0 eq) in dimethylformamide at 35 °C for 16 h, followed by mesylation of the primary hydroxyl with methanesulfonyl chloride (1.05 eq) and triethylamine in tetrahydrofuran at −10 °C. The resulting sulfonate ester is displaced with a nitrogen nucleophile—typically N‑Boc‑piperazine or morpholine—in the presence of potassium carbonate in acetonitrile at reflux, building the P2–P3 linker arm. Removal of the silyl group with tetra‑n‑butylammonium fluoride (1.1 M in THF, 2 h, rt) regenerates the free 4‑hydroxy group, which is then directly coupled to a P4 aromatic acid chloride in a Schotten–Baumann interface at pH 8.0–8.5. Residual piperazine content, a known amine‑derived genotoxic impurity surrogate, is monitored by GC‑MS with a LOD of <0.05 µg/g. The finished peptidomimetic advanced intermediate is subjected to differential scanning calorimetry (DSC) per ASTM E 793‑06 to verify polymorphism consistency between batches, with a melting endotherm onset of 152.3 ± 1.0 °C for the most stable Form A. End-product applications include orally bioavailable BACE1 inhibitors evaluated in Phase II Alzheimer’s disease trials and direct renin inhibitors with sub‑nanomolar IC₅₀ values in human plasma‑renin activity assays.When hydroxyl functionality is exploited for covalent anchoring onto porous silica gel matrices, the compound serves as a versatile chiral selector precursor for HPLC column manufacture. The primary hydroxymethyl group is first activated with (3‑glycidyloxypropyl)trimethoxysilane in dry toluene at 110 °C over 24 h under argon, achieving a ligand surface coverage density of 0.68–0.72 µmol/m² as quantified by elemental analysis (%C). The Boc protecting group is then removed post‑immobilization using a 1:1 (v/v) trifluoroacetic acid/dichloromethane solution, leaving a free amino‑alcohol surface that engages in hydrogen‑bonding and dipole–dipole interactions with chiral analytes. Columns packed with this stationary phase (250 × 4.6 mm ID, 5 µm Kromasil spherical silica) under a 700 bar slurry packing pressure show baseline resolution (R_s > 2.5) for the enantiomers of neutral β‑blockers such as pindolol and metoprolol in the normal‑phase mode using n‑hexane/ethanol/diethylamine 80:20:0.1. Batch‑to‑batch chiral recognition consistency is assured by thermodynamic evaluation using the van’t Hoff approach over the temperature range 10–45 °C, requiring an isoenantioselective crossover temperature deviation of <2 °C between production lots. Residual silanol acidity, a known source of peak tailing and irreversible adsorption of basic analytes, is mitigated by secondary endcapping with hexamethyldisilazane at 130 °C for 4 h. The final bonded phase conforms to the column bleed specification of <0.02 AU baseline drift at 254 nm under gradient elution conditions, in accordance with USP<621> system suitability protocols for liquid chromatography.

When the Hydroxymethyl Arm Becomes a Tether in Immobilized Organocatalysts

The conversion of (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate into a heterogenized prolinol‑type organocatalyst begins with complete NHS ester activation of the primary hydroxyl for subsequent attachment to commercially available amino‑terminated Merrifield resin (1.2 mmol NH₂/g). The loading step is performed in dimethylformamide with 2.0 eq of DIPEA under gentle rotation at 25 °C for 18 h, after which the unreacted amino groups are capped with acetic anhydride/pyridine. Deprotection of the Boc group with 50% TFA in DCM reveals the free secondary amine, which demonstrates a catalytic turnover frequency of 0.45–0.50 h⁻¹ in the asymmetric aldol condensation of isatin and acetone at −10 °C. Critical to catalyst recyclability is the minimisation of water content in the TFA salt neutralisation step; washing the resin‑bound amine with 10% triethylamine in dichloromethane at 0 °C followed by rigorous drying under high vacuum (<0.5 mbar, 24 h) reduces residual triethylammonium trifluoroacetate below quantifiable levels by ¹⁹F NMR analysis. The resin‑based catalyst has been tested for 12 consecutive cycles without significant loss of enantioselectivity (≥94% ee) in the production of 3‑substituted 3‑hydroxyindolin‑2‑ones, important intermediates in the synthesis of non‑opioid analgesic candidates. The immobilized catalyst avoids leaching of organocatalyst residues into the product stream, maintaining residual palladium levels from resin manufacturing at <2 µg/g, as verified by XRD fluorescence screening of the isolated product.In the field of antineoplastic antibody‑drug conjugates (ADCs), the orthogonal reactivity of the two hydroxyl groups is employed to construct protease‑sensitive dipeptide linker‑payload constructs. The secondary 4‑hydroxy group is selectively chloroacetylated in dichloromethane with chloroacetic anhydride (1.05 eq, pyridine, 0 °C), while the primary hydroxymethyl remains unreacted, allowing subsequent activation with bis(4‑nitrophenyl)carbonate to yield a mixed carbonate intermediate capable of coupling with the side‑chain amine of a microtubule‑disrupting auristatin payload. The regioselectivity ratio achieved under these conditions is consistently ≥98:2 as monitored by ¹H NMR (integration of the α‑CH₂Cl signal at δ 4.18 versus the carbonate‑shifted CH₂O signal at δ 4.35). Incorporation of a Val‑Cit‑PAB (valine‑citrulline‑para‑aminobenzyl alcohol) self‑immolative spacer unit to the chloracetyl moiety requires conjugation in degassed N,N‑dimethylacetamide under a strictly argon‑blanketed atmosphere to avoid disulfide scrambling in the downstream engineered cysteine‑mAb interchain reduction step. The drug‑to‑antibody ratio (DAR) of the resulting ADC, measured by hydrophobic interaction chromatography (TSKgel Butyl‑NPR column), falls within the 3.8–4.2 range across three consecutive validation batches meeting the FDA 21 CFR 312.23(a)(7) requirement for investigational new drug conjugate homogeneity. Finished ADC therapeutic candidates incorporating this pyrrolidine linker architecture display > 95% cleavage of the citrulline‑PABC junction in vitro after 72 h incubation with cathepsin B at pH 5.0, thereby releasing the free auristatin payload within target tumour cell lysosomes.

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Certification & Compliance

(2S,4R)-Tert-Butyl 4-Hydroxy-2-(Hydroxymethyl)Pyrrolidine-1-Carboxylate 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

(2S,4R)-tert-Butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (CAS 16877-55-3, often catalogued as N-Boc-trans-4-hydroxy-L-prolinol) is a chiral, non-racemic pyrrolidine derivative employed as a key intermediate for the construction of pharmacologically active molecules. The compound possesses two stereogenic centres—the 2S and 4R configurations—and incorporates an N-tert-butoxycarbonyl (Boc) protecting group on the endocyclic nitrogen together with a pendant hydroxymethyl substituent at C-2 and a secondary alcohol at C-4. Its molecular formula is C₁₀H₁₉NO₄ and its relative molecular mass is 217.26 g·mol⁻¹. Commercial material intended for use as an advanced pharmaceutical intermediate is typically supplied as an off-white to pale yellow crystalline powder with a melting point range of 72–74 °C (determined by differential scanning calorimetry under nitrogen at 10 K·min⁻¹ according to ASTM D3418-21) and a specific optical rotation [α]_D²⁰ of +24.0° to +26.0° (c = 1.0, CHCl₃). The bulk substance is hygroscopic; storage under an inert atmosphere with a desiccant is mandatory when relative humidity exceeds 40% to prevent partial hydrolysis of the Boc carbamate.

Chiral Purity Specifications for Regulatory-Compliant Synthesis

The enantiomeric excess (ee) of the (2S,4R)-configured product is routinely controlled at ≥ 99.5% as measured by normal-phase chiral HPLC on an amylose tris(3,5-dimethylphenylcarbamate)-coated silica column (e.g., Chiralpak IA, 250 mm × 4.6 mm, 5 µm particle size) with a mobile phase of n-hexane/2-propanol/diethylamine (90:10:0.1 v/v/v) at a flow rate of 1.0 mL·min⁻¹. Detection at 210 nm allows baseline separation of the three possible stereoisomers—the desired trans-(2S,4R), the cis-(2S,4S), and the enantiomeric trans-(2R,4S)—within 40 min. In the context of an active pharmaceutical ingredient starting material (ICH Q11 definition), a diastereomeric purity of ≥ 99.0% (sum of all non-target pyrrolidine-related substances) and a single unspecified impurity limit of ≤ 0.10% are established by reverse-phase HPLC with charged aerosol detection. Residual solvents are quantified by headspace gas chromatography with flame ionisation detection according to USP <467> Procedure A; typical release limits for ethyl acetate, ethanol, and dichloromethane are set at ≤ 5000 ppm, ≤ 5000 ppm, and ≤ 600 ppm, respectively, consistent with ICH Q3C(R8) Class 2 and Class 3 guidelines. Water content, as determined by Karl Fischer coulometric titration (USP <921> Method Ic), is restricted to ≤ 0.5% w/w at time of packaging. In a multi-kilogram cGMP campaign executed in a 50 L glass-lined reactor under nitrogen blanketing, the crystalline intermediate is charged into pre-dried tetrahydrofuran (water spec. ≤ 50 ppm) for subsequent mesylation or Mitsunobu-enabled displacements. Batch records from production-scale runs indicate that the exothermic event associated with the addition of methanesulfonyl chloride (1.05 eq) at 0–5 °C is controllable within a ±2 °C window using jacket temperature modulation, and that an intentional age time of 18 h at 20–25 °C is necessary for complete conversion of the O-mesylate. Premature quench of the reaction at 8 h yields approximately 3–5% residual starting material by TLC (silica gel 60 F₂₅₄, eluent EtOAc/hexane 1:1) and generates a downstream impurity that co-elutes with the target morpholine product in the final crystallisation. Consequently, in-process control by HPLC is mandated at the 8 h time point for any batch exceeding 500 g scale.

What Limits the Loading of This Intermediate in Solid-Phase Peptide Synthesis?

Application of N-Boc-trans-4-hydroxy-L-prolinol as a proline surrogate in solid-phase peptide synthesis (SPPS) on a 2-chlorotrityl chloride resin requires careful adjustment of the loading protocol. The free primary alcohol at the C-2 hydroxymethyl group competes with the support-bound chloride for the incoming Fmoc-amino acid active ester when direct coupling is attempted. Using a symmetrical anhydride pre-activation strategy with 4 equivalents of Fmoc-amino acid and 4.4 equivalents of N,N′-diisopropylcarbodiimide in dichloromethane for 12 h at room temperature achieves a loading efficiency of only 0.25–0.35 mmol·g⁻¹, compared to the typical 0.6–0.8 mmol·g⁻¹ observed for proline itself. Pre-derivatisation of the hydroxymethyl group as a tert-butyldimethylsilyl ether prior to resin attachment restores loading to 0.65 mmol·g⁻¹ with 97% coupling yield measured by UV spectrophotometric monitoring of the Fmoc-piperidine dibenzofulvene adduct at 301 nm. Published protocols for peptidomimetic HCV NS3 protease inhibitors have adopted this silylation step as a process standard (see synergy with macrocyclisation yields described in WO 2019/084196, Example 12).

Comparative Composition and Physical Data for Closely Related Pyrrolidine Intermediates
Compound	CAS	[α]_D²⁰ (c=1, CHCl₃)	Melting Range (°C, DSC)	Boc Stability at pH 2
(2S,4R)-N-Boc-4-hydroxy-2-(hydroxymethyl)pyrrolidine	16877-55-3	+24° to +26°	72–74	t_½ = 4.2 h (HCl/dioxane, 0.25 M, 25 °C)
(2S,4R)-N-Boc-4-hydroxy-2-methylpyrrolidine	162560-96-9	+30° to +32°	65–68	t_½ = 3.8 h (identical conditions)
(2S,4R)-N-Cbz-4-hydroxy-2-(hydroxymethyl)pyrrolidine	132943-94-3	+18° to +20°	54–57	stable (<5% cleavage after 24 h)
(2S,4S)-N-Boc-4-hydroxy-2-(hydroxymethyl)pyrrolidine (cis)	151491-72-4	−10° to −12°	88–91	t_½ = 5.1 h

When HCl/Dioxane Outperforms TFA/CH₂Cl₂ in Boc Removal

A systematic study of deprotection kinetics on 10 mmol scale using ¹H NMR monitoring (400 MHz, DMSO‑d₆) revealed that a 4.0 M solution of hydrogen chloride in 1,4-dioxane achieves quantitative Boc removal (99% conversion) in 60 min at 25 °C, while a 1:1 v/v mixture of trifluoroacetic acid and dichloromethane requires 3.5 h for equivalent conversion. The hydrochloride salt of the free amine precipitates directly from the dioxane medium, enabling isolation by filtration under nitrogen without an aqueous work-up that would risk racemisation of the α-hydroxymethyl carbon in alkaline conditions. Residual dioxane is removed to ≤ 380 ppm (ICH Q3C limit for Class 2 solvents) by two successive reslurry washes with anhydrous diethyl ether followed by vacuum drying at 40 °C/5 mbar for 6 h. In contrast, TFA-mediated deprotection necessitates neutralisation with triethylamine and extraction, exposing the hydrophilic pyrrolidine diol to aqueous phase losses averaging 12–15% yield drop across five pilot batches when compared to the anhydrous HCl/dioxane method. For enantiomerically pure starting materials destined for commercial APIs, vendor-supplied certificates of analysis document trace metal content by inductively coupled plasma mass spectrometry after microwave-assisted acid digestion. The specification for palladium is ≤ 10 ppm, and for iridium ≤ 2 ppm, reflecting the metal catalysts (Pd/C, Crabtree’s catalyst) often employed during earlier hydrogenation of the corresponding 4-keto intermediate. A dedicated lot-to-lot consistency evaluation performed on a 7890B GC system equipped with a DB-624 column (30 m × 0.32 mm, 1.8 µm film) identified an unknown volatile impurity at relative retention time 1.23 versus the butylated hydroxytoluene internal standard that correlated with incomplete crystallisation from methyl tert-butyl ether; switching the final recrystallisation solvent to heptane/ethyl acetate (7:3 v/v) eliminated the impurity to below the reporting threshold of 0.05% by GC peak area.

Deprotection Conditions and Enantiomeric Integrity After Boc Cleavage
Condition	Time to >99% Conv. (h)	Diastereomer Formation (%, HPLC area)	Comment
4 M HCl/dioxane, 25 °C	1.0	<0.3%	Salt precipitates, no aqueous workup
TFA/CH₂Cl₂ 1:1, 25 °C	3.5	<0.4%	Requires neutralisation and extraction
3 M H₂SO₄/THF, 0 °C	2.2	1.2%	Significant epimerisation at C-2 observed
ZnBr₂/CH₂Cl₂, 40 °C	8.0	2.8%	Not recommended for scale-up

Avoiding Co-crystal Formation During Solvent-Mediated Polymorph Screening

Thermal analysis of the commercial product on a Mettler Toledo DSC 3+ instrument (sample mass 2.5 mg, crimped Al pan, N₂ purge 50 mL·min⁻¹) shows a single endothermic melting event with an onset at 71.8 °C and a heat of fusion of 110 J·g⁻¹. However, when the compound is recrystallised from acetone/water mixtures containing more than 15% (v/v) water, a second endotherm emerges near 58 °C that is assigned by powder X-ray diffraction (Cu Kα, 1.5406 Å) to a monohydrate co-crystal form. This hydrated form contains 7.6% water by TGA weight loss at 100 °C and, if carried into a subsequent silylation step, causes uncontrolled exothermic reaction of the silyl chloride with residual water, generating hydrogen chloride that prematurely cleaves the Boc group. Process development reports filed under drug master file number 31805 (CDER) document that the anhydrous form is consistently obtained when the compound is precipitated from isopropyl acetate with n-heptane anti-solvent at a jacket temperature of −5 °C and the recrystallisation environment is maintained below 30% relative humidity via a desiccant air dryer supplying −40 °C dewpoint air. Operating in an ISO 14644-1 Class 8 cleanroom, operators transfer the dry product into double low-density polyethylene bags inside a fibre drum, with each bag heat-sealed under nitrogen. Accelerated stability testing at 40 °C/75% RH over 6 months on three consecutive validation batches confirms that the enantiomeric excess decreases by less than 0.2% and total related substances remain below 0.5% when storage is maintained at −20 °C. Extended storage at 25 °C/60% RH for 12 months, however, produces a degradant identified by LC-MS as the ring-opened N-Boc-2-hydroxymethyl-4-hydroxybutylamine formate, which forms through adventitious hydrolysis followed by N-formylation from residual formic acid introduced during earlier hydrogenolysis steps. Consequently, long-term inventory is not recommended above −10 °C without an ongoing forced-degradation trending program.