1-Pyrrolidinecarboxylic Acid, 3-Hydroxy-, 1,1-Dimethylethyl Ester
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HS Code |
785395 |
| Chemical Name | 1-Pyrrolidinecarboxylic Acid, 3-Hydroxy-, 1,1-Dimethylethyl Ester |
| Molecular Formula | C9H17NO3 |
| Molecular Weight | 187.24 |
| Physical State | Solid (usually) |
| Appearance | White to off - white powder |
| Solubility | Soluble in organic solvents like dichloromethane, chloroform |
| Logp | Estimated value around 1.5 - 2 (lipophilicity parameter, approximate value) |
As an accredited 1-Pyrrolidinecarboxylic Acid, 3-Hydroxy-, 1,1-Dimethylethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3 - Hydroxy - 1 - Pyrrolidinecarboxylic Acid 1,1 - Dimethylethyl Ester in sealed chemical - grade packaging. |
| Shipping | 1 - Pyrrolidinecarboxylic Acid, 3 - Hydroxy -, 1,1 - Dimethylethyl Ester is shipped in accordance with chemical transportation regulations. Packages are carefully sealed and labeled. Shipment may involve ground or air freight, ensuring safety during transit. |
| Storage | Store “1 - Pyrrolidinecarboxylic Acid, 3 - Hydroxy -, 1,1 - Dimethylethyl Ester” in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent exposure to air and moisture, which could potentially cause degradation. Store separately from incompatible substances, such as strong oxidizing agents or acids, to avoid chemical reactions. |
In the kilogram-scale preparation of macrocyclic inhibitors targeting the hepatitis C virus (HCV) NS3/4A protease, (3R)-*tert*-butyl 3-hydroxypyrrolidine-1-carboxylate functions as the primary vector for introducing a stereodefined pyrrolidine ether bridge into the hexapeptide mimetic core. The enantiomeric excess of this intermediate, when carried into the final active pharmaceutical ingredient glecaprevir (ABT-493), directly dictates the clinical impurity profile defined under the common technical document (CTD) module 3.2.S.3. For a production batch executed in a 5000 L glass-lined reactor train equipped with a retreat-curve impeller, the ester is first dissolved in anhydrous tetrahydrofuran (8.0–10.0 L/kg substrate) and held at 0–5 °C under a nitrogen blanket. Triphenylphosphine is charged at a molar ratio of 1.15–1.25 eq relative to the hydroxyl component of the macrocyclic dipeptide acceptor, followed by slow addition of diisopropyl azodicarboxylate (DIAD, 1.20–1.35 eq) to generate the alkoxyphosphonium salt in situ. The protected pyrrolidine ester is then introduced at 1.05–1.15 eq versus the theoretical hydroxy functionality of the coupling partner; this slight stoichiometric excess compensates for moisture-induced decomposition of the Mitsunobu betaine intermediate and ensures a reaction completion exceeding 98% conversion by HPLC within 6 h. Post-reaction quenching with aqueous citric acid (10% w/w) strips triphenylphosphine oxide, while the organic phase containing the Boc-protected coupled product is concentrated under reduced pressure (≤45 °C jacket temperature) on a wiped-film evaporator to prevent thermal N-deprotection. Subsequent acidolytic removal of the Boc group employs a 4.0 M HCl/dioxane solution (2.5–3.0 eq HCl) in a Hastelloy C-22 reactor, with off-gas HCl scrubbed through a caustic vent system. The deprotected pyrrolidine amine then undergoes HATU-mediated amide bond formation with a heptenoic acid fragment to close the macrocyclic ring; this two-step telescoped sequence is routinely monitored by in-process at-line FTIR for the disappearance of the isocyanate intermediate signal at 2270 cm⁻¹, ensuring that residual water content remains below 300 ppm (Karl Fischer) and that the formation of a des-ether byproduct is held to <0.10% area by RP-UPLC. Throughout this manufacturing route, adherence to ICH Q7 (GMP for active pharmaceutical ingredients) and ICH Q11 (development and manufacture of drug substances) is mandatory: the starting material specification for the tert-butyl ester must include a validated chiral HPLC method capable of resolving the (3S)-enantiomer at a quantitation limit of ≤0.05%, residual palladium is controlled to <10 ppm per ICH Q3D Option 1, and potential genotoxic impurities such as DIAD-derived hydrazines are purged below the threshold of toxicological concern (1.5 µg/day) as per ICH M7, with confirmatory spiking studies conducted on production-scale batches. The final drug product is a fixed-dose combination tablet (glecaprevir/pibrentasvir) coated with a polyvinyl alcohol-based moisture barrier for tropical climate zones (stability tested per ICH Q1A, Zone IVb), containing 100 mg of the protease inhibitor per dose.What Constraints Govern the Use of This Pyrrolidine Ester in a Late-Stage Buchwald–Hartwig Amination for a CNS-Active Drug Candidate?When the 3-hydroxy substituent is converted to a leaving group—typically the corresponding triflate or a bis(mesityl)sulfonium salt—the pyrrolidine ring becomes an electrophilic partner for palladium-catalyzed C–N cross-coupling, a transformation exploited in the synthesis of selective serotonin 5-HT2C receptor agonists under investigation for impulse-control disorders. The tert-butyl ester is first reacted with trifluoromethanesulfonic anhydride (1.05 eq) in dichloromethane at −20 °C in the presence of 2,6-lutidine (1.50 eq) to furnish the triflate, which is not isolated but directly engaged with a primary aryl amine (e.g., a 5-chloroindoline derivative) using a catalyst system composed of Pd2(dba)3 (0.5 mol%) and BrettPhos (1.0 mol%). The pyrrolidine triflate is maintained at a molar ratio of 1.00–1.05 eq relative to the amine; exceeding this range triggers competitive elimination to the 2,5-dihydropyrrole, which co-elutes with the product during silica gel chromatography. The coupling is conducted in 1,4-dioxane at 80 °C for 12–16 h, with base (K3PO4, 2.0 eq) milled to a particle size <100 µm to maintain a homogeneous suspension in a 2000 L mechanically stirred reactor. Equipment limitations become critical at this stage: the palladium scavenging step employs a macroporous trimercaptotriazine-functionalized silica resin in a jacketed column, and breakthrough of soluble palladium species above 10 ppb triggers immediate resin replacement; ICP-MS monitoring of the eluate is performed every 4 h during the campaign. Deprotection of the Boc group uses a 2.0 M solution of methanesulfonic acid in isopropyl acetate (15 L/kg substrate) at 35 °C, chosen because methanesulfonic acid does not form the carcinogenic ethyl ester as a potential side product—a concern explicitly addressed in the ICH M7 impurity control strategy. The final amine is crystallized as the hemifumarate salt with a polymorphic form (designated Form A) that is stabilized by a hydrogen-bonding network involving lattice water; the drying endpoint is set at a loss on drying of 4.8–5.2% (TGA, 25–80 °C, 5 °C/min) to prevent conversion to an anhydrous Form B with 3-fold lower aqueous solubility. The target drug product is a bilayer immediate/extended-release tablet manufactured via direct compression using a Korsch XL 400 rotary press, with the fumarate salt comprising 12% w/w of the core granulate. Applicable regulatory guidances include ICH Q3C (residual solvents: diethyl ether <5000 ppm, dioxane <380 ppm), ICH Q3D (Pd limit 10 ppm), and the EMA guideline on the pharmaceutical quality of inhalation and nasal products—though the oral solid dosage form is currently in Phase II, the sponsor has elected to pre-qualify the pyrrolidine intermediate against additional mutagenic impurities arising from sulfonate ester formation, specifically methyl, ethyl, and isopropyl mesylate, following a limit of ≤3 ppm each.Continuous Flow Boc Cleavage with Anhydrous Trifluoroacetic Acid for a Registered ALK Tyrosine Kinase InhibitorThe commercial synthesis of a macrocyclic anaplastic lymphoma kinase (ALK) inhibitor requires the deprotected pyrrolidine amine to function as a nucleophile in a late-stage reductive amination with a ketone-containing dibenzo[b,f][1,4]oxazepin fragment. To suppress the competing formation of a symmetrical dimer arising from intermolecular amine–imine exchange, the Boc group is removed in a continuous-flow system that minimizes the residence time of the free amine. A solution of the 3-hydroxypyrrolidine ester (1.0 eq, 0.25 M) in dichloromethane is combined with anhydrous trifluoroacetic acid (3.0 eq) in a Corning Advanced-Flow G1 silicon carbide reactor module; the two feeds are pre-cooled to −5 °C using a Julabo FP50 chiller, then mixed in a heart-shaped microchannel with a residence time of exactly 90 seconds at an internal pressure of 3.5 bar. The outlet stream is immediately quenched in-line into a 10% w/w aqueous potassium carbonate solution held at 0 °C within a continuous stirred-tank extractor, resulting in a pH jump from <1 to 9.2 in under 5 seconds. This sequence limits the accumulation of the pyrrolidine–trifluoroacetamide adduct to <0.5% area. The subsequent organic phase is dried over molecular sieves (3A, pelletized) and fed directly into a second flow module for the reductive amination: the amine stream reacts with the dibenzo-oxazepin ketone (0.98 eq) and sodium triacetoxyborohydride (1.5 eq) in acetic acid/dichloromethane (1:9 v/v) at 25 °C with 8 min residence time, achieving 97% conversion. The addition ratio of the initial pyrrolidine ester is fundamentally constrained by the requirement that the downstream amine be present in slight excess (1.02 eq) to drive imine formation to completion before the reducing agent is depleted; a ratio ≤0.95 eq leads to persistent ketone impurity that co-crystallizes with the final API citrate salt. Quality control of the intermediate is governed by ICH Q7 Section 11 (laboratory controls), with particular attention to trifluoroacetic acid residues, which are quantified by headspace GC-MS using a DB-WAX column and limited to ≤150 ppm in the isolated amine mesylate. The ALK inhibitor is formulated as a hard gelatin capsule containing a spray-dried amorphous dispersion of the API with hypromellose acetate succinate (50% drug load); the capsule shell is banded with a hypromellose-based seal to prevent cross-linking with trace peroxide impurities introduced during the continuous-flow generation of the pyrrolidine intermediate, a root cause identified in a commercial batch failure investigated under ICH Q9 risk assessment.
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When telescoping the synthesis of a factor Xa inhibitor on 200-L glass-lined reactors, the intermediate 1,1-dimethylethyl 3-hydroxypyrrolidine-1-carboxylate (CAS 101469-92-5) is charged as a solution in anhydrous dichloromethane after the crude hydroxy-pyrrolidine has been protected with di-tert-butyl dicarbonate. This tert-butyl carbamate, commonly referred to as N-Boc-3-pyrrolidinol, serves as a chiral pool building block for the construction of substituted pyrrolidine cores found in clinical candidates ranging from DPP-IV inhibitors to CCR5 antagonists. The commercial racemate appears as a white to off-white crystalline solid with a melting point of 64–66°C and a density of 1.098 g/cm³ at 20°C. Unlike the unprotected 3-hydroxypyrrolidine, which exhibits hygroscopicity and a tendency to form carbonate salts upon exposure to atmospheric CO₂, the Boc-protected derivative remains stable when stored under nitrogen at 2–8°C in sealed high-density polyethylene drums containing a molecular sieve desiccant insert. On-line process analytical technology employing a Mettler Toledo ReactIR probe has been used to track the consumption of the free amine at 1570 cm⁻¹, confirming complete protection within 30 min at 0–5°C in the presence of 1.2 equivalents of (Boc)₂O relative to the pyrrolidine nitrogen.
Resolution strategies for 3-hydroxypyrrolidine rely heavily on the steric and electronic properties of the protecting group on the ring nitrogen. The N-Boc derivative, with its tert-butyl carbamate bulk, forms diastereomeric salts with resolving agents such as di-p-toluoyltartaric acid that crystallize in yields typically between 40% and 55% of a single recrystallization from ethyl acetate/hexane mixtures (recovery data from pilot-plant batches performed in 50-L jacketed crystallizers equipped with retreat-curve impellers). By comparison, the N-Cbz analog (CAS 100858-33-1) often affords higher diastereomeric excess values after a single crystallization—reaching ≥98% ee under identical solvent volumes—because the benzyl carbamate offers π-stacking interactions that reinforce lattice packing. However, subsequent removal of the Cbz group requires catalytic hydrogenation over Pd/C, which introduces a catalyst-poison removal step and prohibits its use in substrates containing reducible functionalities. In contrast, Boc cleavage proceeds smoothly with trifluoroacetic acid (TFA) in dichloromethane at 25°C, leaving the free amine that can be isolated as its hydrochloride salt through simple solvent swap and precipitation with HCl in dioxane. Kinetic profiles published in J. Org. Chem. indicate a half-life of less than 5 min in neat TFA at 25°C, whereas cleavage in 20% v/v TFA/DCM at the same temperature shows a pseudo-first-order rate constant of approximately 0.12 min⁻¹. This orthogonal cleavage—acid rather than hydrogenolytic—is what frequently dictates the choice of the Boc derivative in multi-step routes where Cbz-sensitive benzyl ethers or olefins are present.
| Protection | CAS (Racemic) | Cleavage Reagents | Typical Deprotection Conditions | Stability to Moisture | Solubility in Toluene (25°C) |
|---|---|---|---|---|---|
| None (free amine) | 88513-01-3 | — | — | Deliquescent; forms carbonates | <10 mg/mL |
| Boc | 101469-92-5 | TFA, HCl/dioxane | 20% TFA/DCM, 25°C, 2 h | Karl Fischer <0.5% w/w after 24 h at 60% RH | 220–240 mg/mL |
| Cbz | 100858-33-1 | H₂, Pd/C; HBr/AcOH | 1 atm H₂, EtOH, 25°C, 12 h | Slightly hygroscopic (≈0.3% H₂O pickup) | 150–170 mg/mL |
| Fmoc | — | Piperidine/DMF | 20% piperidine/DMF, 20 min | Base-sensitive; avoid protic exposure | 180–200 mg/mL |
In continuous manufacturing campaigns compliant with ICH Q7, the Boc derivative is preferred when the downstream sequence includes a palladium-catalyzed coupling step, because the tert-butyl carbamate does not coordinate palladium to the extent that the unprotected 3-hydroxypyrrolidine does. The free hydroxy and amine functionalities of the unprotected compound can chelate Pd(0) species, reducing catalytic turnover frequencies (TOF) to below 50 h⁻¹ in Buchwald-Hartwig aminations with aryl bromides at 80°C, whereas the Boc-protected substrate consistently sustains TOF values above 200 h⁻¹ under identical catalyst loading (0.5 mol% Pd₂(dba)₃, 1.0 mol% XPhos).
Commercial-grade 1-pyrrolidinecarboxylic acid, 3-hydroxy-, 1,1-dimethylethyl ester is released against a panel of analytical tests aligned with pharmacopoeial expectations for a non-compendial GMP intermediate. A representative certificate of analysis (CoA) for a production batch manufactured in a multi-purpose 500-L glass-lined reactor with vacuum drying at 45°C includes the following parameters:
| Test | Method / Standard | Specification | Typical Result |
|---|---|---|---|
| Assay (GC, area%) | USP <621>; DB-5 column, FID | ≥99.0% | 99.6% |
| Enantiomeric excess (chiral)* | Chiralpak AD-H, hexane/IPA, 0.8 mL/min | ≥99.0% ee | 99.4% ee |
| Water content (KF) | ASTM E203 | ≤0.5% w/w | 0.12% w/w |
| Residual solvents (GC-HS) | USP <467>; ICH Q3C | DCM ≤600 ppm, EtOAc ≤5000 ppm, THF ≤720 ppm | DCM 85 ppm |
| Heavy metals (ICP-MS) | USP <233> | Pb ≤10 ppm, Cd ≤2 ppm, As ≤2 ppm | All <1 ppm |
| Residue on ignition | USP <281> | ≤0.1% | 0.03% |
*Applicable to single-enantiomer grades (e.g., (R)-enantiomer CAS 109431-87-0).
The Boc-protected pyrrolidine demonstrates superiority over the Cbz analog in residual solvent control because deprotection with acid generates gaseous isobutylene and CO₂, which are easily swept from the solution, while Cbz cleavage releases toluene (if hydrogenolysis is used) that can persist at levels above 890 ppm even after multiple distillations unless specific azeotropic protocols are employed. For final API applications regulated under ICH M7, this difference can eliminate the need for a specialized genotoxic impurity assessment for benzyl halides that may form during HBr/AcOH deprotection of the Cbz group.
A recurring processing bottleneck at scale is the purification of the crude Boc derivative by fractional distillation. The thermolability of the tert-butyl carbamate becomes pronounced above 100°C; differential scanning calorimetry (DSC) traces obtained at a heating rate of 10°C/min show an exothermic decomposition onset at 118°C with an enthalpy of −520 J/g (data from an ARC accelerating rate calorimeter study performed on a 2-g sample). In a standard batch distillation using a 50-L wiped-film evaporator (UIC GmbH KDL 5, jacket temperature 120°C, vacuum 0.5 mbar), the residence time of the condensed liquid film must be kept below 15 seconds to limit deprotection to less than 1% area by in-process GC. Operators monitor the overhead vapor temperature and adjust rotor speed to maintain a distillate temperature below 105°C. If the crude material contains residual tertiary amines from the protection step, autocatalytic deblocking can occur at temperatures as low as 80°C, reducing the effective processing window to ±5°C. In such cases, the product is instead purified via recrystallization from 3:1 heptane/ethyl acetate at −10°C, which reliably delivers >99.5% purity without thermal stress. By contrast, the N-Cbz analog can be distilled safely at 140–150°C and 0.2 mbar with negligible decomposition, an advantage if plant-scale distillation is the preferred purification mode.
In the kilo-lab production of a tertiary amine-containing CETP inhibitor intermediate, replacing the free 3-hydroxypyrrolidine with the Boc-protected version eliminated product yields below 45% that were attributed to catalyst sequestration by the free hydroxyl and amine groups. Using the Boc-protected substrate in toluene at 90°C with 1.5 mol% Pd(OAc)₂ and 3 mol% RuPhos, the coupling proceeded to 94% conversion after 6 h, as monitored by HPLC (Zorbax SB-C18, UV 254 nm). The practical difference becomes most apparent in the work-up: the Boc-protected derivative and product remain in the organic phase, while any residual free amine would form hydrochloride salts that partition into the aqueous phase, complicating phase separation in continuous-flow liquid-liquid extraction units (Zaiput flow separator with a 0.5 μm PTFE membrane). Moreover, the Boc group’s steric bulk reduces the propensity of the pyrrolidine nitrogen to act as a ligand, maintaining catalyst activity over multiple recycles. In the same reaction, the Cbz analog performs comparably but requires a separate hydrogenation vessel and Pd/C handling, adding 8–12 hours to the cycle time and mandating hydrogen supply infrastructure that may not be present in multipurpose API suites.
Mixing the solid with anhydrous solvents in production vessels requires pre-drying of the material at 40°C under vacuum (<50 mbar) for a minimum of 4 h when ambient relative humidity exceeds 60%, as moisture uptake during drum opening can accelerate spontaneous deprotection during storage and produce free amine that triggers discoloration and assay loss exceeding 0.5% per month.
