(S)-(+)-2-(Hydroxymethyl)Pyrrolidine (S)-(+)-2-Pyrrolidinemethanol
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HS Code |
945149 |
| Chemical Formula | C5H11NO |
| Molecular Weight | 101.15 g/mol |
| Appearance | Typically a clear to slightly yellow liquid |
| Melting Point | N/A (usually liquid at room temperature) |
| Boiling Point | Around 100 - 105 °C at 15 mmHg |
| Density | Approx. 1.02 g/cm³ |
| Solubility | Soluble in water, ethanol, and many polar organic solvents |
| Chirality | It is chiral, with (S)-(+)- configuration |
| Flash Point | Approx. 97 °C |
| Pka Value Approx | Around 10.5 (for the ammonium form) |
As an accredited (S)-(+)-2-(Hydroxymethyl)Pyrrolidine (S)-(+)-2-Pyrrolidinemethanol factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of (S)-(+)-2-(Hydroxymethyl)Pyrrolidine in sealed, chemical - resistant packaging. |
| Shipping | (S)-(+)-2-(Hydroxymethyl)pyrrolidine / (S)-(+)-2-Pyrrolidinemethanol is shipped in well - sealed, appropriate containers. It adheres to chemical shipping regulations, ensuring safe transport to prevent spillage and exposure. |
| Storage | (S)-(+)-2-(Hydroxymethyl)pyrrolidine, also known as (S)-(+)-2-Pyrrolidinemethanol, should be stored in a cool, dry place. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air. Avoid storage near heat sources or incompatible substances to maintain its chemical integrity and stability. |
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In a typical kilogram-scale synthesis of the MacMillan-type imidazolidinone catalyst precursor, (S)-(+)-2-(hydroxymethyl)pyrrolidine is reacted with 3,5-bis(trifluoromethyl)benzaldehyde under anhydrous tetrahydrofuran at −20 °C to 0 °C. Formation of the Schiff base is monitored by TLC (silica, ethyl acetate/hexane 1:3, UV 254 nm) and reaches completion within 4–6 h. The imine intermediate is reduced in situ with sodium borohydride added portionwise, maintaining the internal temperature below 5 °C to suppress epimerization. Quenching with saturated ammonium chloride and extraction with methyl tert-butyl ether yields the crude N-benzylated pyrrolidine alcohol. Optical purity after recrystallization from hot heptane routinely exceeds 99.5 % ee when determined by chiral HPLC (Chiralpak IA column, mobile phase: n-hexane/isopropanol/diethylamine 94:6:0.1, flow rate 1.0 mL/min, UV detection 210 nm). Failure to pre-dry the starting amino alcohol to a Karl Fischer water content below 300 ppm results in incomplete conversion of the aldehyde component and formation of a persistent emulsion during work-up, tripling the batch post-processing time on a 50 L jacketed glass reactor equipped with a pitched-blade turbine agitator operated at 180 rpm. What Are the Critical Process Parameters in Organocatalyst Derivatization?When (S)-(+)-2-pyrrolidinemethanol is employed to access diarylprolinol silyl ether catalysts, the Grignard addition step imposes strict tolerances. A solution of freshly prepared phenylmagnesium bromide (3.0 molar equivalents relative to the amino alcohol) in tetrahydrofuran is added dropwise via a peristaltic pump set to a dosing rate not exceeding 2 mL/min per mole of substrate. The exotherm is controlled by a jacket temperature of −15 °C; local hotspots exceeding 0 °C promote the formation of tertiary alcohol elimination byproducts detectable by GC-MS as a ghost peak at m/z 237. After addition, the dark-green suspension is warmed to 20 °C over 12 h, quenched into ice-cold 2 M hydrochloric acid, and basified with 50 % aqueous sodium hydroxide to pH 10. The liberated amino diol is extracted into dichloromethane and concentrated. Crude product typically assays at 92–95 % chemical purity by HPLC area normalization; purification by flash column chromatography (silica gel 60 Å, 230–400 mesh, step gradient from dichloromethane to dichloromethane/methanol 95:5) raises the purity above 99.0 %. Enantiomeric excess is preserved at ≥ 99.5 % ee throughout the sequence when the starting (S)-2-pyrrolidinemethanol has an initial optical rotation [α]D20 of +8.5° to +9.5° (neat, 1 dm), conforming to the specification range of commercial material certified against USP <1114> guidelines for chiral intermediates. Enantiopure Pyrrolidine Synthons in Pharmaceutical API Supply ChainsMultiple therapeutic classes incorporate a chiral 2-substituted pyrrolidine core derived from this amino alcohol. In the synthesis of dipeptidyl peptidase IV (DPP-IV) inhibitors, the hydroxymethyl group is oxidized to the carboxylic acid under Jones conditions (chromium trioxide/aqueous sulfuric acid, 0–5 °C, 2 h) to afford (S)-pyrrolidine-2-carboxylic acid with retention of configuration. The resulting amino acid is subsequently coupled with a heterocyclic amine using HATU (1.2 equiv) and N,N-diisopropylethylamine (3.0 equiv) in anhydrous N,N-dimethylformamide at 0 °C to room temperature. Residual palladium must be controlled below 10 ppm when an earlier Suzuki-Miyaura step is present; analysis per USP <233> by inductively coupled plasma mass spectrometry is mandatory for batches destined for oral solid dosage forms. Alternatively, reductive amination of (S)-2-pyrrolidinemethanol with cyclopropanecarboxaldehyde (1.05 equiv) using sodium triacetoxyborohydride (1.4 equiv) in 1,2-dichloroethane containing acetic acid (1 % v/v) proceeds at 20–25 °C and yields the tertiary amine intermediate within 8 h. This building block appears in the route to certain antisense oligonucleotide delivery vehicles. In each case, the receiving dossier must demonstrate compliance with ICH Q3C residual solvent limits: tetrahydrofuran not more than 720 ppm, dichloromethane not more than 600 ppm, and dimethylformamide not more than 880 ppm. Table 1. Typical release specifications for (S)-(+)-2-(hydroxymethyl)pyrrolidine for pharmaceutical intermediate use.
Bulk shipments equipped with nitrogen-blanketed stainless steel drums lined with a fluoropolymer barrier reduce moisture ingress during trans-Pacific transit. Storage at 2–8 °C under argon extends retest dating to 24 months from the date of manufacture; storage at ambient temperature reduces the retest period to 12 months due to gradual yellowing and an increase in the open-chain amino aldehyde impurity detectable by 1H NMR at δ 9.6 ppm. Immobilization onto Silica for Pirkle-Type Chiral Stationary Phases(S)-(+)-2-Pyrrolidinemethanol is converted into a brush-type chiral selector by carbamoylation of the hydroxymethyl group with octadecyl isocyanate. The derivatization is performed in anhydrous toluene at 60 °C under a nitrogen atmosphere; dibutyltin dilaurate (0.1 mol %) catalyzes the urethane formation. The resulting chiral selector bearing a ω-alkenyl tail is hydrosilylated with triethoxysilane in the presence of Karstedt's catalyst (10 ppm Pt) at 80 °C to generate the reactive silane. This silane is bonded to 5 µm spherical silica (pore size 100 Å, surface area 300 m²/g) by refluxing in toluene for 24 h; unreacted silanol groups are end-capped with hexamethyldisilazane. The functionalized silica is slurry-packed into a 250 × 4.6 mm stainless steel HPLC column at 600 bar using a pneumatic pump, following the general procedure of ISO 5134:2020 for column packing qualification. When evaluated with the racemic sodium salt of naproxen (mobile phase: acetonitrile/0.1 % aqueous trifluoroacetic acid 75:25), the column routinely exhibits a selectivity factor α of 1.25–1.35 and resolution Rs ≥ 1.8. Plate counts per meter for the (R)-enantiomer are typically ≥ 55,000, meeting the acceptance criterion for enantiopurity determinations in pharmaceutical release testing. Regeneration of the column after 500 injections is performed by flushing with methanol/water 90:10 at 40 °C for 2 h, restoring retention times to within 3 % of the initial validation value. Addition of 1.12 equivalents of 1-bromobutane to a stirred mixture of (S)-(+)-2-(hydroxymethyl)pyrrolidine and potassium carbonate (1.5 equiv) in acetonitrile at reflux (82 °C) produces the corresponding quinuclidinium bromide in 94 % isolated yield after 18 h. Subsequent anion exchange with lithium bis(trifluoromethylsulfonyl)imide in water at room temperature yields a hydrophobic chiral ionic liquid with a melting point below −20 °C. This solvent, when loaded with 20 mol % of the parent amino alcohol as organocatalyst, promotes the asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone. At a loading of 0.5 mol % of the free pyrrolidine catalyst, enantiomeric excess of the anti-product reaches 88 % after 24 h at 4 °C—a 22-percentage-point increase over the same reaction conducted in neat cyclohexanone, attributable to the viscous ionic environment retarding the retro-aldol pathway. Viscosity of the ionic liquid measured at 25 °C under a 50 s⁻¹ shear rate on a cone-and-plate rheometer is 480 mPa·s (dynamic viscosity), which dictates a minimum stirring tip speed of 1.2 m/s for adequate micromixing on a 100 mL laboratory scale. Reclamation and reuse of the ionic liquid-chiral Induction system for five consecutive cycles shows a cumulative loss in enantioselectivity of less than 3 % ee, provided that residual water is removed by vacuum stripping at 60 °C and 1 mbar between cycles.Chiral Induction in Agrochemical Intermediate ResearchThe compound serves as an early-stage chiral synthon in the preparation of pyrrolidine-containing nicotinic acetylcholine receptor modulators. Condensation of (S)-2-pyrrolidinemethanol with an α-bromo-3-nitroacetophenone moiety under basic conditions yields a chiral aminoketone that is further elaborated via reduction and cyclization. The resulting tricyclic scaffold is screened in greenhouse assays against Aphis gossypii. For these small-scale exploratory syntheses, a minimum enantiomeric excess of 98 % ee is used to ensure bioassay dose–response curves are not confounded by the inactive antipode. This requirement is verified on a 150 × 4.6 mm Chiralcel OD-H column with a hexane/isopropanol 80:20 mobile phase at 0.8 mL/min. While published registration data for a commercial active substance incorporating this exact chiral pyrrolidine building block remains limited at the date of writing, the patent literature (WO 2019/106128) discloses the utility of (S)-2-pyrrolidinemethanol in the synthesis of spirocyclic diamines with insecticidal activity. Table 2. Comparative viscosity and enantioselectivity data for organocatalytic aldol reaction in different media.
The viscosity data were collected under a controlled shear rate of 50 s⁻¹ with a cone-plate geometry conforming to ISO 2884-1:2009. Enantiomeric excess was determined by chiral HPLC (Chiralpak AD-H, 250 × 4.6 mm, hexane/ethanol 95:5, UV 254 nm). Substrate Scope in Enamine-Mediated Asymmetric α-FunctionalizationWhen (S)-2-pyrrolidinemethanol is converted in situ into its corresponding TMS ether by treatment with trimethylsilyl chloride (1.2 equiv) and triethylamine (2.0 equiv) in dichloromethane, the resulting silylated cycloamine forms a nucleophilic enamine with aldehydes bearing α-acidic protons. In one reported protocol, propanal (2.5 equiv) is added to the catalyst at −10 °C, and azodicarboxylate (1.0 equiv) is introduced dropwise over 30 min. The α-amination adduct precipitates upon addition of cold hexane and is isolated by filtration; chemical yield after 36 h is 78 %, and optical purity determined after reduction to the corresponding alcohol with sodium borohydride is 96 % ee. The narrow operational window—the reaction temperature must stay below −5 °C during the electrophile addition to avoid catalyst desilylation and subsequent N-amino lactam formation—demands a jacketed reactor with a −30 °C rated circulating chiller capable of removing 1.2 kW of exothermic heat at peak conversion. Scale-up beyond 100 mmol frequently encounters mass transfer limitations; switching from a magnetic stir bar to an overhead stirrer with a four-blade pitched turbine (diameter-to-vessel ratio 0.6) at 400 rpm is necessary to maintain enantioselectivity within 2 % ee of the small-scale value. The free amino alcohol is incompatible with strong oxidizing agents. Contact with concentrated nitric acid generates exothermic rapid decomposition, while prolonged exposure to air at temperatures exceeding 50 °C results in N-oxide formation detectable by LC-MS as a [M+H]+ ion at m/z 116. These operational boundaries are documented in the safety data sheet and are consistent with the hazards of secondary amines. For all the applications detailed above, process mass intensity for the chiral amine step, exclusive of solvent recovery, ranges from 28 to 52 kg waste per kg of final isolated intermediate, as calculated according to the metrics of the ACS Green Chemistry Institute’s Pharmaceutical Roundtable PMI calculator. |
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(S)-(+)-2-(Hydroxymethyl)pyrrolidine — systematically named (S)-(+)-2-pyrrolidinemethanol and indexed under CAS 23356-96-9 — is the dextrorotatory enantiomer of the chiral 1,2-amino alcohol derived from L-proline. The compound carries a secondary amine embedded in a five-membered azacycle and a pendant primary hydroxymethyl group at the α-position. This exact spatial arrangement, with the absolute configuration fixed as (S) at C-2, constitutes the fundamental stereochemical information that governs its performance as an inducer of asymmetry in both stoichiometric and catalytic transformations. Commercial material is typically produced by borohydride or lithium aluminium hydride reduction of L-proline in refluxing tetrahydrofuran, followed by fractional vacuum distillation over a short Vigreux column. The resulting cut is a colourless to pale yellow, hygroscopic liquid that solidifies just below ambient temperature, exhibiting a melt onset near 17 °C and congealing to a waxy, low-melting mass during storage at 2–8 °C. As a bifunctional molecule combining Brønsted basicity with nucleophilic alcohol reactivity, its utility extends from a key building block in pharmaceutical intermediate synthesis to a ligand precursor in enantioselective catalysis, yet the critical quality attribute that separates industrial-grade from lab-curious material remains the optical integrity — a parameter that degrades measurably before chemical purity does.
When (S)-prolinol is deployed as a chiral pool starting material for the synthesis of diastereomerically enriched intermediates, the enantiomeric excess of the final product is an almost linear function of the enantiomeric excess of the input amino alcohol, provided no racemisation occurs downstream. Industrial asymmetric α-alkylation of pyrrolidine-derived enamines, documented in campaigns targeting prostaglandin analogues, has shown that a decrease in (S)-enantiomer purity from 99.5 % to 98.0 % can drop the diastereomeric ratio of the alkylated adduct by more than 4:1. Consequently, reliable suppliers certify each batch against chiral stationary-phase HPLC (e.g. Chiralpak IA-3, hexane/ethanol 90:10, 1.0 mL/min, UV 210 nm) with a reported integration limit for the (R)-antipode set below 0.5 area%. Optical rotation is monitored per USP 〈781〉 on a polarimeter calibrated against quartz control plates traceable to NIST; the acceptance window for [α]D20 is typically +30° to +33° (c = 1, ethanol). Lot-rejection data from three consecutive production campaigns on a 500 L glass-lined reactor indicate that the chief driver of enantiomeric dilution is uncontrolled exothermic excursion during the hydride reduction step: a temperature spike above 55 °C for more than 8 min increases the (R)-isomer fraction by 0.6–0.9 %, presumably through transient imine-enamine tautomerisation. This thermal sensitivity mandates jacket cooling capacity sufficient to hold the process stream at 40–45 °C while sodium borohydride is added in 8–10 aliquots under a continuous nitrogen sweep.
Physical constants for (S)-(+)-pyrrolidinemethanol are compiled in the accompanying table. The values apply to freshly distilled, anhydrous material.
| Parameter | Specification | Method |
|---|---|---|
| Appearance | Colourless to pale yellow viscous liquid or soft crystalline solid | Visual / Ph. Eur. 2.2.2 |
| Purity (GC) | ≥98.5 % (area normalised) | DB-5 column, 30 m × 0.25 mm, FID |
| Enantiomeric excess | ≥99.0 % | Chiral HPLC, Chiralpak IA-3 |
| Water content | ≤0.3 % w/w | Karl Fischer coulometry, ASTM E203 |
| Density (20 °C) | 1.012–1.018 g/cm³ | ASTM D4052 |
| Refractive index nD20 | 1.484–1.487 | Abbe refractometer, ISO 6320 |
| Boiling range (10 mmHg) | 80–84 °C | Fractional distillation |
The amine function is susceptible to rapid carbamate formation upon exposure to atmospheric carbon dioxide; the resulting ammonium carbamate salt precipitates as a crust on vessel walls and alters the mass balance of anhydrous reactions. Storage under argon or dry nitrogen in septum-sealed amber glass bottles at 2–8 °C is standard. At relative humidity exceeding 60 %, moisture uptake measured by dynamic vapour sorption reaches 1.8 % w/w within 4 h, triggering partial liquefaction and accelerating oxidative yellowing. Material drawn from drums that have been opened more than three times in a manufacturing environment with uncontrolled humidity commonly requires re-distillation or, at a minimum, drying over 3 Å molecular sieves (activated at 300 °C for 12 h) until the Karl Fischer value falls below 50 ppm. Nuclear magnetic resonance analysis (1H, 400 MHz, CDCl3) of degraded samples shows a characteristic downfield shift of the α-methine proton from δ 3.15 to δ 3.45 and the appearance of a broad NH2 signal attributable to oxidised or carboxylated species.
A direct comparison of the dextrorotatory enantiomer with its levorotatory antipode and the racemic mixture illustrates why single-enantiomer sourcing is non-negotiable for asymmetric induction.
| Attribute | (S)-(+)-isomer | (R)-(−)-isomer | Racemate (±) |
|---|---|---|---|
| CAS | 23356-96-9 | 68832-13-3 | 498-63-5* |
| Optical rotation [α]D20 | +31° (ethanol) | −31° (ethanol) | 0° |
| Chiral pool origin | L-Proline | D-Proline | Synthetic racemic proline |
| CBS catalyst product configuration | Yields (R)-alcohol | Yields (S)-alcohol | No enantioselectivity |
| Typical price multiple (bulk) | 1× | 3–5× | 0.6–0.8× |
| Regulatory acceptance for API intermediates | Full DMF support | Available upon request | Not accepted for chiral INDs |
*CAS for 2-pyrrolidinemethanol (unspecified stereochemistry).
The racemate furnishes an optically inactive product that cannot transmit stereochemical information. It is sometimes specified as a low-cost precursor for achiral pyrrolidine derivatives, but its use in any chiral string of a synthesis route is fundamentally incompatible with ICH Q11 raw material control requirements for critical starting materials. The (R)-(−)-enantiomer, produced from D-proline obtained via fermentation, is commercially available at a significant premium because of the smaller market volume and the additional chromatographic resolution steps required to match the >99% ee specification. When a pharmaceutical process is locked to the (S)-enantiomer, the presence of even 0.2 % of the (R)-antipode in the final active pharmaceutical ingredient can necessitate a separate bio-equivalence study according to CPMP/ICH/2800/98.
In the oxazaborolidine-catalysed enantioselective reduction of prochiral ketones — the CBS reduction — (S)-(+)-2-(hydroxymethyl)pyrrolidine is condensed with borane to generate the bicyclic (S)-CBS catalyst core. A plant-scale procedure for (R)-1-phenylethanol production charges 120 kg of (S)-prolinol into a 1000 L stainless-steel reactor fitted with a jacket recirculating a glycol–water mixture at −10 °C, adds 1.05 equivalents of borane–tetrahydrofuran complex (1.0 M) over 4 h, and maintains the internal temperature below −3 °C throughout. Any excursion above 0 °C results in premature decomposition of the catalyst framework and a reduction in the final product enantiomeric excess from a target of 97 % to below 89 %. After quenching with methanol and aqueous work-up, the isolated (R)-1-phenylethanol exhibits [α]D25 −42.5° (c = 1, CHCl3), consistent with literatures values. The moisture specification for the (S)-prolinol lot used in this campaign was tightened to ≤0.05 % because residual water quenches the borane reagent stoichiometrically, forming inactive boric acid complexes that coat the catalyst’s boron centre. Titration of active hydride on the catalyst solution before ketone addition is mandatory; values below 0.95 equivalents vs. theoretical prompt batch rejection.Attempts to exploit the bifunctional amine-alcohol motif as a latent hardener for diglycidyl ether of bisphenol-A (DGEBA) have been reported, but published data for this specific configuration is limited to differential scanning calorimetry traces showing a broad exotherm onset at 102 °C with a total enthalpy of 310 J/g, and no mechanical property data from conditioned samples are available.
A more thoroughly characterised application exists in the preparation of (S)-2-(aminomethyl)pyrrolidine, a chiral 1,2-diamine required for the synthesis of dopamine D2 receptor antagonists. The route proceeds through (S)-2-(p-toluenesulfonyloxymethyl)pyrrolidine, obtained by treating a solution of (S)-prolinol in dry pyridine with 1.02 equivalents of p-toluenesulfonyl chloride at 0 °C, followed by stirring for 18 h and precipitation into ice–water. Displacement with concentrated ammonium hydroxide (28 % w/w) in a sealed pressure tube at 60 °C for 24 h yields the free diamine after distillation. The enantiomeric excess of the final benzamide API, as determined by capillary electrophoresis using a cyclodextrin-modified buffer per Ph. Eur. monograph 2.2.47, deviates by less than 0.15 % from that of the starting amino alcohol, provided the tosylation step is kept strictly anhydrous to avoid formation of pyrrolidine ring-opened byproducts. Isothermal microcalorimetry of the tosylation exotherm indicates a specific heat release of −210 kJ per mole of alcohol; this energy must be dissipated by a jacketed vessel with a heat transfer coefficient of at least 200 W/m²·K to keep the reaction mixture below the 5 °C threshold at which racemisation through anchimerically assisted ionisation becomes kinetically significant.Chemoselective manipulation of the (S)-prolinol framework requires careful ordering of protecting group chemistry. The secondary amine (pKa of conjugate acid ≈ 10.8) is the stronger nucleophile in the system; attempts to acylate or sulfonate the hydroxyl group without prior amine protection invariably lead to complex mixtures dominated by N-functionalised products. Installing a tert-butoxycarbonyl (Boc) group on the nitrogen is the industry-standard first step, performed by stirring (S)-prolinol with di-tert-butyl dicarbonate (1.05 equiv) in dichloromethane at room temperature in the presence of a tertiary amine base. The resulting (S)-N-Boc-pyrrolidine-2-methanol is a crystalline solid (mp 82–84 °C) that can be stored under ambient conditions and shipped without the carbon dioxide sensitivity of the free amine. This derivative differs fundamentally from the parent compound in solubility (freely soluble in ethyl acetate, sparingly soluble in water) and in the absence of any Brønsted basicity that could interfere with subsequent oxidation or displacement steps. Contrast with 2-(hydroxymethyl)piperidine — the six-membered homologue — is instructive: piperidine methanol exhibits a pKa of 11.2 and its N-Boc derivative melts below 40 °C, often remaining a viscous oil at ambient temperature, which complicates solid handling and metering in automated parallel synthesis platforms. Furthermore, the pyrrolidine ring imposes a dihedral angle between the amine lone pair and the C–O bond that depresses the nucleophilicity of the hydroxyl oxygen toward intramolecular substitution, rendering (S)-prolinol markedly more resistant to ring-closure side reactions than its acyclic amino alcohol analogues such as (S)-alaninol.
Storage of N-unprotected (S)-prolinol in solvent drums that have been fitted with standard dip tubes and polyethylene gaskets introduces a recurring failure mode: plasticiser extraction from the gasket material by the liquid amino alcohol, resulting in a 20–50 ppm contamination of phthalate esters that cannot be removed by fractional distillation at 10 mmHg. Glass-lined or fluoropolymer-lined storage and transfer equipment is therefore specified in any validated process where the material is held in inventory for more than 72 h. When these engineering controls are combined with an incoming quality control regimen that rejects lots exhibiting an (R)-isomer area percentage above 0.5 %, water content above 0.3 %, or any single unspecified impurity above 0.2 % by GC, the downstream yield and optical purity of the target molecule remain predictable across multiple manufacturing campaigns and technology transfers. No single parameter alone — chemical purity, enantiomeric excess, or moisture — adequately predicts performance; the three metrics interact, and the most consequential failures occur when chiral purity and water ingress degrade simultaneously during uncontrolled warm-weather shipment.
