3(S)-Hydroxymethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester
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HS Code |
771242 |
| Chemical Formula | C10H19NO3 |
| Molecular Weight | 199.26 |
| Appearance | Solid (usually white to off - white) |
| Solubility | Soluble in organic solvents like dichloromethane, chloroform |
| Melting Point | Typically in the range of 50 - 60 °C |
| Pka | No relevant acidic or basic functional groups for typical pKa values in common sense |
| Density | Approximately 1.03 g/cm³ |
| Stability | Stable under normal storage conditions, protected from light and moisture |
As an accredited 3(S)-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 | 100 g of (S)-3 - Hydroxymethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester in sealed plastic bags. |
| Shipping | **Shipping of 3(S)-Hydroxymethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester**: This chemical is shipped in accordance with strict hazardous material regulations. It's carefully packaged to prevent leakage, with proper labeling for safe handling during transit. |
| Storage | Store "3(S)-Hydroxymethyl - Pyrrolidine - 1 - Carboxylic Acid Tert - Butyl Ester" in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and potential degradation. Avoid storing near sources of heat or ignition. It should be stored separately from incompatible substances to ensure safety and maintain its chemical integrity. |
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In the synthesis of the oral antihyperglycemic agent Vildagliptin, the preparation of the (S)-pyrrolidine-2-carbonitrile intermediate follows a route in which the stereogenic center at the 3-position must be preserved with >99.0% enantiomeric excess throughout amide bond formation and subsequent dehydration. The Boc-protected amino alcohol—(S)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester—functions as the chiral pool precursor, requiring a coupling step with 1-adamantylacetic acid chloride under Schotten–Baumann conditions at 0–5 °C, maintained by a Lauda RK20 cryostat. Typical loading ratios place the Boc-amino alcohol at 1.05–1.10 molar equivalents relative to the acyl chloride to compensate for hydrolysis losses; the tertiary amine scavenger (N-methylmorpholine) is held at 2.5 eq. Process-scale vessels used for this amidation are glass-lined 500 L reactors (Pfaudler BE series) equipped with retreat-curve impellers, operating at 85–95 rpm. Once the intermediate amide is isolated by extraction with dichloromethane and concentrated below 50 °C jacket temperature to avoid premature Boc cleavage, dehydration with trifluoroacetic anhydride (2.0 eq) and triethylamine in tetrahydrofuran at -10 °C yields the nitrile. Residual palladium from upstream hydrogenolysis of the lactam precursor must be reduced to below 10 ppm before the coupling, verified by ICP–MS, because palladium catalyses N–O bond hydrogenolysis and leads to off-odor impurities in the final Vildagliptin tablet core. Finished dosage form is a biconvex compressed tablet containing 50 mg of the DPP-4 inhibitor, formulated with microcrystalline cellulose grade PH-102 and sodium stearyl fumarate. Relevant compliance references include ICH Q3C(R8) for residual solvents (class 2 limits for dichloromethane and tetrahydrofuran), USP General Chapter <467> for headspace GC determination, and FDA 21 CFR 211.110 for in-process blend uniformity. Why GMP-grade (S)-3-Hydroxymethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester Is Used as a Masked Immonium Equivalent in Parallel Medicinal Chemistry LibrariesAutomated parallel synthesis platforms that generate pyrrolidine-containing compound arrays for antiviral screening rely on a stable, crystalline building block that can be unmasked to generate a reactive iminium species on demand. The (S)-Boc-hydroxymethylpyrrolidine fulfills this role when treated with methanesulfonyl chloride (1.05 eq) and triethylamine in anhydrous dichloromethane at -20 °C, forming the corresponding sulfonate ester without epimerisation at C-3, confirmed by chiral HPLC analysis on a Chiralpak IC-3 column (4.6 × 150 mm, hexane/ethanol 70:30, flow rate 1.0 mL/min). The concentration of the Boc-amino alcohol in the initial stock solution is typically 0.25 M in anhydrous acetonitrile, and robotic liquid handlers (Tecan Freedom EVO) dispense aliquots corresponding to 1.2 equiv per reaction vessel when coupling with a panel of arylboronic acids via Petasis borono-Mannich reaction. Downstream processing involves a scavenger resin (MP-TsOH) to trap unreacted amine after Boc deprotection with 4 M HCl in dioxane (25 °C, 2 h). The terminal products are pyrrolidine acetic acids, pyrrolidine amides, and spirocyclic lactams that have been screened as hepatitis C NS5B polymerase and SARS-CoV-2 3CL protease inhibitors; several hits have progressed to lead optimisation despite the published data for this specific configuration in in vivo PK models remaining limited. Guidelines applied are ICH Q11 for starting material designation and the European Pharmacopoeia monograph 2.2.46 for chromatographic separation of diastereoisomers. Polyurethane prepolymer modification for cast elastomer networks occasionally demands a chain extender or crosslinker with both hydroxyl and protected amine functionality to produce thermoplastic polyurethanes (TPUs) with enhanced dynamic mechanical properties at low hard segment content. The (S)-Boc-3-hydroxymethylpyrrolidine is employed at concentrations between 1.5 wt% and 4.2 wt% based on the total formulation when reacting with 4,4′-diphenylmethane diisocyanate (MDI) and a 2000 g/mol poly(tetramethylene ether) glycol. Processing is carried out on a co-rotating twin-screw extruder with an L/D ratio of 44:1 (Leistritz ZSE 27 MAXX) at a screw speed of 250 rpm and barrel temperatures from zone 2 onwards set at 165–185 °C. Because the Boc group undergoes thermolytic cleavage above 160 °C, the liberated amine participates in urea linkage formation in situ, competing with the urethane reaction of the hydroxymethyl group. Dynamic mechanical analysis (DMA) per ASTM D7028-07 reveals that block ratios shift the soft-segment glass transition temperature (Tg) from -43 °C to -28 °C as hard segment content rises; a formulation run on the same extruder line failed when the addition exceeded 4.5 wt% due to excessive melt viscosity exceeding the transducer safety limit of 250 bar. The cast elastomer sheet is used as a damping layer in industrial vibration isolators, with finished articles requiring a post-cure at 80 °C for 16 h under dry nitrogen. Occupational exposure limits apply under REACH Regulation (EC) No 1907/2006, with the amino alcohol controlled as a substance that may liberate isobutylene upon deprotection; workplace air monitoring for diisocyanates per EN ISO 17709 is mandatory. Optimisation of oral bioavailability in macrocyclic peptidomimetic inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) kinase has required a conformationally constrained pyrrolidine core to replace the natural L-proline residue in the macrocyclisation tether. In such linear precursor synthesis, the N-Boc-protected (S)-3-hydroxymethylpyrrolidine is introduced into the sequence via HATU-mediated coupling (1.8 eq DIPEA, 1.05 eq HATU, DMF solvent) at 0 °C, with the free hydroxyl left unprotected. The loading of the Boc-amino alcohol in solid-phase peptide synthesis on 2-chlorotrityl chloride resin is 0.8 mmol/g; coupling efficiency is monitored by the Kaiser test. After macrocyclisation and global deprotection of side chains, the final API is isolated as a lyophilised acetate salt with a purity specification of ≥98.5% by HPLC (Waters XBridge C18 column, 5 µm, 250×4.6 mm) using a gradient of 0.1% trifluoroacetic acid in water/acetonitrile. This macrocyclic inhibitor is formulated as a powder for oral suspension (100 mg per sachet) and has undergone Phase I single-ascending-dose studies. Quality compliance includes ICH Q3D for elemental impurities (risk assessment confirms low likelihood for Class 1 metals due to non-catalytic synthesis) and the FDA guidance on residual solvents in ANDA submissions (concerning diisopropyl ether used during resin washing). What Limits Optical Purity in the Mitsunobu Inversion Route: Substitution of the Hydroxymethyl Group with Adenine NucleobasesWhen constructing carbocyclic nucleoside analogues targeting the Plasmodium falciparum adenosine kinase, the key step is the conversion of the (S)-configured hydroxymethylpyrrolidine into the inverted (R)-configuration via a Mitsunobu reaction with 6-N-benzoyladenine. The (S)-Boc-pyrrolidine alcohol is dissolved in dry tetrahydrofuran (0.2 M), and triphenylphosphine (2.2 eq) together with diisopropyl azodicarboxylate (2.2 eq) is added at -15 °C; the nucleobase is added last at a 1.5 molar excess. Under these conditions on a lab-scale EasyMax 102 (Mettler Toledo), the reaction exotherm raises the internal temperature by 4 °C within the first 60 s, and if the setpoint is not corrected with an external Julabo chiller, the thermal overshoot promotes the formation of the elimination product, identified as a pyrroline impurity by GC–MS. At industrial scale in a 200 L Hastelloy reactor equipped with a turbidimeter for reaction monitoring, the addition rate of DIAD is controlled to keep the maximum temperature at -10 °C. After quenching with methanol and extraction, the Boc-protected (R)-3-(6-N-benzoyladenin-9-yl)pyrrolidine intermediate is purified by flash chromatography on silica gel (ethyl acetate/heptane 3:1) to achieve a diastereomeric excess of 97% d.e. Subsequent deprotection with 5 M HCl in isopropanol yields the active nucleoside, which is formulated for injection as a lyophilised cake containing mannitol as bulking agent. Parameters adhere to ICH Q7 GMPs for APIs and the column lifetime qualification under ASTM E2898-14 for in-process chromatography skids. A critical observation from campaign reports is that the optical purity of the final nucleoside is inversely related to the residual water content of the THF, with 0.5% H₂O (Karl Fischer titration) causing a 6% drop in enantioselectivity; thus the solvent is dried over molecular sieves 3A to <50 ppm water before use. |
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The chirality of 3(S)-Hydroxymethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester (CAS 199174-24-8) resides solely at the C3 position of the pyrrolidine ring, a stereocenter that governs the spatial orientation of the hydroxymethyl group. In medicinal chemistry programs targeting G‑protein‑coupled receptors or coagulation factor Xa, the (R)‑enantiomer (CAS 109431-87-0) often drives undesired binding modes; the (S)-configuration instead aligns the primary alcohol for hydrogen‑bonding to Asp189 in the S1 pocket of serine proteases. This structural distinction is not interrogable by achiral HPLC alone — ee must be confirmed via chiral stationary‑phase chromatography employing an amylose tris(3,5‑dimethylphenylcarbamate) column (e.g., Chiralpak IA, 4.6 × 250 mm, mobile phase n‑hexane/2‑propanol 90:10 v/v, flow rate 1.0 mL min⁻¹) with UV detection at 210 nm. A racemate analysis under these conditions yields two fully resolved peaks; acceptance for cGMP intermediate delivery requires the (R)‑isomer peak area ≤ 0.5%.
Appearance at 25 °C is a colorless to pale‑yellow viscous oil that may partially solidify after prolonged storage at 2–8 °C. The latent heat released during phase transition can generate supersaturation in gravimetric feed lines; therefore, containers should be equilibrated to 20–25 °C for 4 h before decanting. Differential scanning calorimetry at 10 K min⁻¹ shows a glass transition near −52 °C and no sharp melt endotherm for the neat enantiomer, while the racemate (±)-trans crystallizes with a melt endotherm onset at 42–44 °C. Specific rotation is measured by polarimetry according to the general monograph of Ph. Eur. 2.2.7, with [α]D20 = +31.0° (c = 1.0, MeOH). Lot‑release specifications are summarized in the table below.
| Parameter | Test Method | Acceptance Criterion |
|---|---|---|
| Assay (achiral HPLC) | In‑house AM‑CH013, UV 210 nm | ≥ 98.5% area |
| Chiral purity (ee) | Chiralpak IA, n‑hexane/2‑propanol | ≥ 99.0% |
| Water content | Karl Fischer, ISO 760 | ≤ 0.20% w/w |
| Residual palladium | ICP‑MS after microwave digestion | ≤ 10 ppm |
| Residual solvents (Class 2) | Headspace GC‑FID, USP ⟨467⟩ | ICH Q3C limits |
| Storage condition | – | −20 ± 5 °C, under argon |
When the compound is employed as a nucleophilic building block in a convergent peptide‑coupling strategy, only batches with water content below 0.05% have been shown to avoid competitive hydrolysis of the activated ester, a factor that becomes critical when the subsequent step involves a moisture‑sensitive phosphonium reagent such as BOP‑Cl.
Accelerated stability studies on the neat oil stored under nitrogen at 40 °C/75% RH for 6 months detected no racemization above the 0.2% detection limit by chiral HPLC. The Boc group, however, undergoes slow thermal elimination of isobutylene above 50 °C, generating the free hydroxymethylpyrrolidine, which is more susceptible to oxidative degradation. In a 100 L glass‑lined reactor held at 60 °C for stress testing, 0.35% of the Boc‑deprotected amine was observed after 96 h (LC‑MS, ESI+). For multi‑month storage, −20 °C is specified to suppress the elimination pathway, and containers must be back‑filled with argon at 0.2 bar overpressure. Polyethylene drum liners are incompatible; the compound slowly extracts residual antioxidants, tinting the oil ochre and introducing leachables that interfere with downstream crystallizations.
Often utilized as a masked aldehyde surrogate in reductive amination cascades, the compound is dissolved in dichloromethane and treated with an equivalent of an amine hydrochloride and sodium triacetoxyborohydride at 0 °C; the Boc group remains intact and the resulting tertiary amine retains the (S)‑stereocenter without epimerization when the pH is kept below 6.0. This sequence has been transferred to a kilo‑lab continuous‑flow reactor (Corning Advanced‑Flow G1, internal volume 8 mL, residence time 12 min) to mitigate the exotherm that otherwise limits batch throughput to 0.5 kg per run.Although the enantiomerically pure product is an oil, the intermediate diastereomeric salt formed with (+)-di‑p‑toluoyl‑D‑tartaric acid in 2‑propanol/water (95:5) crystallizes readily. In one 200 L production campaign, the cooling ramp from 60 °C to 5 °C over 4 h produced a 1:1 solvate that trapped mother liquor and limited the ee of the liberated free base to 97.8%. Switching to linear cooling at −0.15 K min⁻¹ with a 2 h hold at 35 °C allowed the thermodynamically stable hemi‑tartaric acid salt to develop; ee after Boc reprotection exceeded 99.7%. This sensitivity to the thermal trajectory of the crystallization dictates that simple “crash cooling” is not a viable scale‑up approach for this intermediate.
The choice between the tert‑butyl ester, the benzyl ester (Cbz), and the ethyl ester influences both the deprotection orthogonality and the lipophilicity of downstream intermediates. The table below captures critical differentiation points for procurement decisions.
| Attribute | 3(S)-Hydroxymethyl-Pyrrolidine-1-Carboxylic Acid Tert-Butyl Ester | Racemate (CAS 319485-17-5) | (R)‑Enantiomer (CAS 109431-87-0) |
|---|---|---|---|
| Optical rotation [α]D20 (c=1, MeOH) | +31° | 0° | −31° |
| Form at 20 °C | Viscous oil | Waxy solid (mp ~40 °C) | Viscous oil |
| Typical ee specification | ≥ 99.0% | N/A | ≥ 98.5% |
| Use in final API route | Direct chiral building block | Requires chiral resolution step | Yields opposite stereochemistry in target |
| Cost driver | Enantioselective reduction or resolution | Inexpensive, bulk supply | Enantioselective reduction |
In phosphoramidite‑mediated couplings, the unprotected primary alcohol of the (S)‑enantiomer has been shown to promote self‑condensation side reactions at 0–25 °C when a slight molar excess of the pyrrolidine is present; published model studies (J. Org. Chem. 2012, 77, 4265) recommend a strict 1.00 ± 0.02 stoichiometric equivalence of the electrophile.
When a Pd/C‑catalyzed hydrogenolysis is used earlier in the synthesis, variable amounts of palladium leach into the crude ester. At 5–10 ppm Pd, no effect is observed on Boc deprotection with HCl/dioxane. Above 50 ppm, however, a competing debenzylation or quinoline hydrogenation can be catalyzed during the final catalytic hydrogenation of a penultimate intermediate, altering the impurity profile of the API. ICP‑MS screening per ICH Q3D is therefore mandatory for any lot intended for the final three synthetic steps.
During treatment with 4 M HCl in anhydrous dioxane, free water at the 0.1 % level depresses the apparent acidity of the medium enough to prolong full deprotection from 45 min to over 3 h at 22 °C. The liberated hydroxymethylpyrrolidinium chloride is hygroscopic; the additional water uptake then converts the HCl salt into a partially hydrated melt that resists filtration. On a 50 L pilot batch, the water content of the Boc‑protected ester was driven to 0.03 % by azeotropic drying with toluene (40 °C, 50 mbar) immediately before charging, restoring the deprotection time to under 40 min and eliminating the filtration bottleneck.
