3-Hydroxymethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester
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HS Code |
468161 |
| Chemical Formula | C10H19NO3 |
| Molar Mass | 201.26 g/mol |
| Appearance | Typically a solid (physical state may vary based on purity and conditions) |
| Solubility | Soluble in some organic solvents like dichloromethane, less soluble in water |
| Melting Point | Data may vary, generally in a specific range for pure compound |
| Boiling Point | Would have a boiling point under appropriate pressure conditions |
| Pka | Relevant acidic or basic functional groups have characteristic pKa values |
| Flash Point | Flammability related property with a specific value |
| Density | Has a defined density value |
| Stability | Stable under normal storage conditions but may react under certain chemical environments |
As an accredited 3-Hydroxymethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3 - Hydroxymethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester in sealed chemical - grade packaging. |
| Shipping | 3 - Hydroxymethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester is shipped in well - sealed containers, following strict chemical transport regulations. Special care is taken to prevent leakage and ensure safe transit, with proper labeling for hazard information. |
| Storage | Store 3 - Hydroxymethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester 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. As it's a chemical, store it in an area compliant with safety regulations, separate from incompatible substances to avoid potential reactions. |
In the convergent synthesis of pyrrolidine-containing antiviral agents targeting the NS3/4A serine protease of hepatitis C virus, the (S)-enantiomer of 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester functions as the chiral core that maps directly onto the P2 proline or proline-like subsite of the catalytic triad. A production-scale coupling sequence typically initiates with activation of the unprotected hydroxyl under anhydrous conditions in tetrahydrofuran at −10 °C to 0 °C, using methanesulfonyl chloride (1.05 eq) and triethylamine (1.2 eq) over molecular sieves 4A to sequester HCl. After aqueous workup with 10% w/w potassium carbonate, the resulting mesylate is telescoped into a nucleophilic displacement with a P2 amine fragment, for instance a (1R,2S)-aminoindanol derivative, in acetonitrile at 50 °C for 18 h under a nitrogen blanket. Process analytical technology, namely in-line FTIR monitoring of the sulfonate S=O asymmetric stretch at 1360 cm⁻¹, controls the end point to within ±0.5% conversion, preventing accumulation of a genotoxic mesylate impurity. Residual mesylate is further reduced to below 1 ppm via a proprietary polymer-bound nucleophilic scavenger (QuadraPure™ TU) in a plug-flow cartridge prior to batch concentration. The crude product is dissolved in isopropyl acetate and passed through a 0.2 µm PTFE membrane to reach a clarity specification per Ph. Eur. 2.2.1 before solvent switching to n-heptane for cooling crystallization. The (S)-mesylate intermediate is isolated at ≥99.0% ee, as determined by chiral HPLC (Chiralpak AD-H, 250 × 4.6 mm, n-hexane:ethanol 85:15 v/v, flow rate 0.8 mL/min, detection at 210 nm), with a typical yield of 78–82% over the two telescoped steps at a 50 kg input scale in a glass-lined reactor equipped with a retreat-curve impeller. Subsequent Boc deprotection employs a controlled dose of anhydrous HCl in isopropanol (4.0 eq) at 22 ± 2 °C, quenched by drowning into pre-cooled methyl tert-butyl ether to precipitate the pyrrolidine hydrochloride salt. Any residual tert-butyl alcohol and isobutylene off-gassing are scrubbed with a 0.1 M sodium hypochlorite solution to meet emission limits under the Industrial Emissions Directive (IED) for volatile organic compounds. The final coupling to a macrocyclic core, via HATU (1.1 eq) and DIPEA (2.5 eq) in DMF at 0–5 °C, yields the drug substance intermediate after a gravity silica gel plug (Merck Grade 60, 15–40 µm) with an overall purity of 99.5% by area at λ = 254 nm and residual Pd content below 10 µg/g measured by ICP-OES (Method USP <730>). The terminal drug products derived from this intermediate target genotype 1a and 1b HCV infections and demonstrate nanomolar EC₅₀ values in replicon assays; however, the exact structure–activity relationship around the 3-hydroxymethyl conformation is considered proprietary by the innovator.What Limits the Reductive Amination Yield When Coupling to Bulky Aldehyde Partners?A recurrent bottleneck encountered during the construction of pyrrolidine-based JAK inhibitors and tropomyosin receptor kinase (Trk) antagonists is the direct reductive amination of the deprotected 3-aminomethyl moiety — obtained after Boc removal and oxidation — with sterically encumbered biaryl aldehydes. The aldehydes frequently present a di-ortho-substituted phenyl ring that slows imine formation to an extent where the competing reduction of the free aldehyde by sodium triacetoxyborohydride (STAB) dominates the reaction manifold. To mitigate this, a two-stage protocol has been scaled: imine equilibration is driven in refluxing toluene at 111 °C with azeotropic removal of water using a Dean–Stark trap, applying the free pyrrolidine and the aldehyde in a 1.0:1.05 molar ratio and 0.5 mol% of p-toluenesulfonic acid monohydrate. After cooling to −5 °C, the imine solution is transferred by cannula into a suspension of STAB (1.4 eq) in anhydrous dichloromethane held at −10 °C in a jacketed 100 L reactor. Quenching is performed with 2 M aqueous sodium hydroxide to pH 8.5, followed by liquid–liquid extraction with dichloromethane and continuous back-extraction of the aqueous phase. Despite these measures, a dimethylacetamide-based N-oxide adduct — identified via UPLC-QTOF as a retro-aza-Michael product — reaches levels of 2.7–3.4 area% when the water content of the reduction phase exceeds 250 ppm by Karl Fischer titration. Therefore, a pre-drying step on the imine solution over freshly activated 3A molecular sieve beads (20% w/v) for at least 12 h is mandated; the use of sieves with a binder and clay matrix is prohibited because leached alkali metals catalyse a Cannizzaro-like disproportionation of the aldehyde that consumes up to 15% of the limiting electrophile. Under carefully controlled moisture conditions, isolated yields of the secondary amine reach 67–73% on a 20 mol scale, with ≤0.3% dialkylated impurity and residual aldehyde below 0.1% by GC-FID (DB-5 column, 30 m × 0.32 mm, 0.25 µm film). The secondary amine is subsequently reprotected as the corresponding tert-butyl carbamate by treatment with Boc anhydride (1.2 eq) in THF/water (4:1 v/v) in the presence of sodium carbonate, regenerating a structurally elongated analog of the original intermediate.Oxidation Pathways and Process Safety Boundaries for the Hydroxymethyl MoietyConversion of the 3-hydroxymethyl substituent to the corresponding aldehyde (or, in the context of succinate dehydrogenase inhibitor fungicide intermediates, to the carboxylic acid) is a chemically straightforward but operationally hazardous transformation whose runaway potential must be assessed via adiabatic calorimetry. A comparison of four oxidising systems conducted under identical mass-transfer conditions (Rushton turbine, gas-entrainment at 1 vvm, 30 °C) is given below.
Scale-Up Distillation Challenges Are Exacerbated by the tert-Butyl Carbamate’s Thermal LabilityA substantial fraction of the cost incurred in purifying 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester by fractional distillation arises from the decomposition threshold inherent in the Boc group. When the bulk material is subjected to simple batch distillation in a wiped-film evaporator configuration (UIC KDL 5, jacket surface area 0.05 m²), the measurable onset of thermal decomposition in the bottoms occurs at a film temperature of 128 °C at an operating pressure of 2 mbar, as indicated by a sharp increase in the condenser volatile trap (cold finger at −78 °C) trapping isobutylene and tert-butyl alcohol quantified by micro-GC. To avoid thermal stress, a short-path distillation with internal condenser at 115 °C and 1.5 mbar provides a distillate stream of 99.2% purity (GC-FID area) with less than 0.1% w/w of olefinic decomposition artifacts. The optimal feed rate for a 6-inch wiped-film unit processing 80 kg of crude ester is maintained at 12–14 L/h; any interruption in the mechanical wiper seal leads to a stagnant film hot-spot and generates a volatile impurity that subsequently poisons the downstream Pd/C hydrogenolysis catalyst used in the synthesis of the active pharmaceutical ingredient. A purification campaign on a 200 kg crude lot sourced from a generic manufacturer exhibited a batch-to-batch variability in the distillation residue level from 2.3% to 6.7%, which correlated linearly (R² = 0.94) with the sodium content of the input ester as determined by ICP-OES. It was found that sodium ions above 20 µg/g catalyse a retro-ene fragmentation of the carbamate; consequently, the incoming material specification now enforces a sodium limit of <15 µg/g, and a pre-distillation scrub with 0.5 N citric acid is implemented when the result exceeds the limit. The purified distillate is transferred to a receiving vessel blanketed with dry nitrogen containing <5 ppm oxygen and is stored at 2–8 °C under an inert atmosphere; under these conditions, re-test dating supports a shelf-life of 24 months with total related substances maintained below 1.0% measured according to ISO 17025-accredited HPLC methodology.
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The product 3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS 131257-93-6, C10H19NO3, MW 201.26 g/mol) is supplied as a colourless to pale-yellow viscous oil or low-melting solid, typically at ≥97.0% purity by HPLC. The tert-butyl carbamate (Boc) group serves as an acid-labile amine protection strategy, while the free primary hydroxyl at the 3-position of the pyrrolidine ring permits subsequent derivatisation—etherification, esterification, or oxidation to carboxylic acid—without interfering with the Boc-directed orthogonal deprotection sequence. Distinct from N-Cbz- or N-Fmoc-protected analogues, the Boc group resists hydrogenolysis and base-mediated cleavage, enabling synthetic routes that involve catalytic reduction or saponification steps prior to amine liberation. The compound is available in both racemic and enantiomerically pure forms; the (R)- and (S)-enantiomers are routinely resolved by chiral stationary-phase chromatography or prepared from chiral pool pyrrolidine precursors, with enantiomeric excesses exceeding 99.0%. Batch-specific certificates of analysis report assay (HPLC area-%), water content (Karl-Fischer titration), and residual solvents (GC-HS).
The Boc-protected pyrrolidine core is inherently susceptible to trace acid-catalysed cleavage, and ambient moisture amplifies degradation by generating free amine and evolving isobutylene/CO2 via hydrolysis. Pre-drying is mandatory if the material has been exposed to relative humidity above 60%. Long-term storage at -20°C under argon in sealed amber glass vials extends the re-test period to 24 months. When stored in original LDPE containers at 25°C/60% RH, HPLC monitoring of N-Boc-proline derivatives has shown a purity decline of 0.3–0.7% per month over 6 months; extrapolation to a 12-month open-bottle scenario suggests 4–8% deprotection, predominantly yielding 3-hydroxymethylpyrrolidine. ICH Q1A(R2) guidelines recommend confirmatory testing at 12 months for long-term condition packages. Pre-drying under dynamic vacuum (<10 mbar, 40 °C, 4 h) restores water content to <0.1% as measured by coulometric Karl Fischer titration (ISO 760:1978), effectively suppressing acid-catalysed scission during weighing and reaction set-up. Introducing molecular sieves (3A) into the headspace during repetitive sampling is advised to maintain a local atmosphere below 10% RH.
| Parameter | Specification | Test Method |
|---|---|---|
| Assay (anhydrous, solvent-free basis) | ≥97.0% | HPLC, UV detection at 205 nm; C18 column, gradient of MeCN/water (0.1% TFA) |
| Enantiomeric excess (single enantiomer grade) | ≥99.0% | Chiral HPLC, Chiralpak AD-H, n-hexane/ethanol 90:10, flow rate 0.8 mL/min |
| Water content | ≤0.5% | Coulometric Karl Fischer titration (ISO 760:1978) |
| Residual tert-butanol | ≤0.5% | Headspace GC-FID, DB-624 column, Ph. Eur. 2.4.24 general procedure |
| Residual dichloromethane | ≤600 ppm | Headspace GC-FID, DB-624 column, Ph. Eur. 2.4.24 |
| Specific rotation (enantiomers) | Reported per batch; typical [α]D20 ±20–25° (c=1, MeOH) | Polarimetry, Ph. Eur. 2.2.7 |
The above reflect typical release values; certificates of analysis should be consulted for lot-specific data. Stability-indicating HPLC methods confirm that no secondary degradants exceed 0.5 area-% when the material is handled as recommended.
In solid-phase peptide synthesis employing the Fmoc/tBu strategy, incorporation of 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a proline surrogate or γ-turn inducer proceeds through standard carbodiimide-mediated coupling. The free hydroxyl group is pre-activated as the 4-nitrophenyl carbonate or coupled directly via Mitsunobu etherification prior to resin loading. The Boc-protected amine allows on-resin global deprotection with TFA cleavage cocktails (e.g., TFA/TIS/H2O 95:2.5:2.5) after chain assembly, whereas the hydroxyl enables post-synthetic modification with fluorescent probes or biotin late in the sequence. In contrast to Fmoc-3-hydroxymethylpyrrolidine—which requires repeated piperidine treatments incompatible with base-sensitive sequences—the Boc derivative preserves Fmoc orthogonality until the final cleavage. Coupling efficiency has been evaluated on a Liberty Blue microwave synthesizer using HATU/DIEA (DMF, 2.0 equiv of the acid, 2×30 min at 50°C). On a Rink amide AM resin (initial loading 0.6 mmol/g), resin substitution after coupling routinely reaches 0.82–0.88 mmol/g as determined by Fmoc UV quantification at 301 nm. The 3-hydroxymethyl substituent creates a distinct spatial orientation compared to the 2-hydroxymethyl isomer; molecular modelling suggests a dihedral angle (C2–C3–CH2–O) of approximately 60° in low-energy conformers, a feature exploited in the design of peptidomimetic scaffolds that require a well-defined projection of the hydroxyl away from the pyrrolidine backbone.
| Compound | Boc Deprotection t50 (min) in 30% TFA/CH2Cl2 at 25°C | Calculated logP (ACD/Labs) | Relative HPLC Retention |
|---|---|---|---|
| 3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester | 5–8 | 0.92 | 1.00 (reference) |
| N-Boc-3-hydroxymethylpiperidine | 12–18 | 1.28 | 1.4 |
| N-Boc-2-hydroxymethylpyrrolidine | 4–6 | 0.95 | 0.9 |
| N-Cbz-3-hydroxymethylpyrrolidine | Not applicable (Cbz removed via H2/Pd) | 1.18 | 1.2 |
Half-life data were estimated from in-house HPLC monitoring and may vary with batch purity and residual solvent levels. The faster deprotection of the five-membered pyrrolidine compared to the homologous piperidine is consistent with increased ring strain and lower amine pKa of the carbamate, facilitating acid-mediated cleavage. The Boc strategy also avoids the metal contamination risks associated with catalytic transfer hydrogenation required for Cbz removal, a crucial advantage when the final peptide is intended for pharmacological testing with endotoxin and heavy-metal specifications below 0.5 EU/mg and 10 ppm, respectively.
Differential scanning calorimetry (DSC) of the neat compound in a sealed gold-plated pan under nitrogen (ramp rate 5 K/min) shows a minor endotherm at 32°C associated with melting, followed by an exothermic decomposition with an onset temperature of 88°C and a total energy release of 540 J/g. Upon addition of 2 equivalents of TFA, the exotherm shifts significantly lower—onset approximately 55°C—accompanied by vigorous gas evolution from isobutylene and CO2, indicating rapid Boc scission. Accelerating rate calorimetry (ARC) on an analogous Boc-pyrrolidine ester gives a time to maximum rate (TMRad) of 24 h at 45°C. Process safety assessments therefore dictate that batch deprotection must be carried out with jacket cooling maintaining the reaction mass below 25°C and with adequate vent sizing to accommodate the gas flow from isobutene release (1 mol/mol of Boc group). Incompatibilities include prolonged contact with concentrated mineral acids during pre-drying or storage, which can lower the onset temperature into the ambient range and trigger autocatalytic runaway. Published adiabatic data for this specific ester are limited; a formal hazard evaluation (RC1e reaction calorimetry and Phi-Tec II adiabatic calorimetry) is recommended before scaling operations above 10 kg.
Residual solvent profiles are controlled in accordance with ICH Q3C Option 2: dichloromethane ≤600 ppm, tert-butanol ≤5000 ppm, and ethyl acetate ≤5000 ppm. The substance has been pre-registered under EU REACH for use as an intermediate with an annual volume band of 1–10 tonnes; a PPORD exemption may apply depending on the end-use classification. Batches destined for in vivo studies undergo endotoxin testing by the LAL assay (acceptance criterion <0.5 EU/mg) and are verified for heavy metals (Pb, Cd, Hg, As) by ICP-MS, each element below 10 ppm.
