2-Oxo-2,5-Dihydro-Pyrrole-1-Carboxylic Acid Tert-Butyl Ester

Product Name 2-Oxo-2,5-Dihydro-Pyrrole-1-Carboxylic Acid Tert-Butyl Ester
Alias tert-Butyl 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
Einecs 611-342-2
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, 2-Oxo-2,5-Dihydro-Pyrrole-1-Carboxylic Acid Tert-Butyl Ester is supplied with ≥95% purity (HPLC) and full spectroscopic characterization (¹H NMR, MS), making it suitable for use as a pharmaceutical intermediate.

Specifications

HS Code	436776
Chemical Formula	C9H13NO3
Molecular Weight	183.205 g/mol
Appearance	Solid (Typical)
Stability	Stable under normal conditions

As an accredited 2-Oxo-2,5-Dihydro-Pyrrole-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 & Storage

Packing	100g of 2 - Oxo - 2,5 - Dihydro - Pyrrole - 1 - Carboxylic Acid Tert - Butyl Ester in sealed, labeled container.
Shipping	2 - Oxo - 2,5 - Dihydro - Pyrrole - 1 - Carboxylic Acid Tert - Butyl Ester is shipped in well - sealed containers, compliant with chemical transportation regulations. It's carefully packaged to prevent damage and ensure safe transit to the destination.
Storage	2 - Oxo - 2,5 - Dihydro - Pyrrole - 1 - Carboxylic Acid Tert - Butyl Ester should be stored in a cool, dry place away from direct sunlight. Keep it in a well - sealed container to prevent moisture and air exposure, which could lead to degradation. Store it separately from incompatible substances like strong oxidizing or reducing agents. Ideal storage temperature is around 2 - 8 °C if possible, in a chemical storage area with proper ventilation.

Application of 2-Oxo-2,5-Dihydro-Pyrrole-1-Carboxylic Acid Tert-Butyl Ester

When integration of the protected α,β-unsaturated γ-lactam with organozinc nucleophiles follows the Knochel protocol under rigorously anhydrous conditions, a chiral 3-substituted pyrrolidine precursor is generated directly without need for a separate asymmetric hydrogenation step. This route underpins the kilogram-scale preparation of penultimate intermediates for oral direct Factor Xa inhibitors. The entire synthesis sequence is operated under full cGMP as defined by ICH Q7 Chapter 5, with process validation data demonstrating a batch-to-batch enantiomeric excess of >99.0% ee by chiral HPLC on Chiralpak IA column (method validated under ICH Q2(R1)). The stoichiometric window is narrow: the molar ratio of the organozinc reagent (prepared from 1.2 eq of the corresponding alkyl iodide and zinc dust activated with 1.25 eq TMSCl) to the ene‑lactam is held at 1.05:1.0. Deviations beyond 1.1 eq cause precipitation of zinc salts that entrain product, reducing isolated yield by 12–15%. The conjugate addition is conducted in a 200 L glass-lined reactor with jacket capable of maintaining ‑20°C ± 2°C, critical because the exotherm of organozinc formation and subsequent addition can push the internal temperature past ‑10°C, at which point dimerisation of the ene‑lactam accelerates to generate 5–8 area% of a spiro‑lactam impurity detected by HPLC at 210 nm. Reaction completion is confirmed by in‑line ReactIR monitoring of the α,β‑unsaturated carbonyl stretch at 1725 cm⁻¹. The downstream production process continues with acidic quench using 2 M citric acid, extraction into methyl tert‑butyl ether, and solvent swap into heptane to crystallise the (3S)-3-alkoxycarbonyl‑N‑Boc‑pyrrolidine. Residual zinc is controlled to < 10 ppm by inductively coupled plasma mass spectrometry (ICH Q3D), and solvent residues are benchmarked against USP <467> Option 2 limits. The final intermediate is supplied to a finishing plant where Boc deprotection and amide coupling yield the Factor Xa inhibitor active pharmaceutical ingredient, typically formulated as a 2.5 mg or 5 mg oral tablet.

What Process Safety Boundaries Constrain Catalytic Hydrogenation of the Enamine to N-Boc-2-Pyrrolidinone at Production Scale?

The reduction of the endocyclic double bond is performed in a 500 L agitated autoclave equipped with a rupture disc rated to 1.5× maximum allowable working pressure and a dedicated high-efficiency Pall filtration skid for catalyst recovery. Process hazard analysis per OSHA 29 CFR 1910.119 identifies the thermal runaway potential of the Pd/C catalyst in the presence of hydrogen and solvent vapours, mandating a maximum catalyst loading of 0.5 mol% (5% Pd/C, 50% water‑wet) relative to the substrate, which corresponds to 0.05 kg dry catalyst per 100 kg of ene‑lactam. The substrate concentration is fixed at 0.5 M in ethyl acetate, and hydrogen pressure is maintained at 4.0 bar with a continuous feed to compensate for uptake. Reaction temperature is ramped from 25°C to 40°C over 30 min and held there; calorimetric data from a Mettler RC1e reaction calorimeter show a heat release of ‑185 kJ/mol, necessitating a jacket temperature differential of ≤10°C to prevent overshoot. Endpoint is determined by the disappearance of the α,β‑unsaturated C=O band by ReactIR, because conventional TLC fails to distinguish the saturated lactam from the starting ene‑lactam. A persistence of even 0.3% residual ene‑lactam detected by GC‑FID (DB‑5, 30 m, film thickness 0.25 µm) after 4 h triggers an additional 0.1 mol% catalyst charge. The downstream process distills the ethyl acetate to a minimum volume, precipitates the N-Boc‑pyrrolidinone from n‑heptane at ‑5°C, and yields a product with typical purity 99.5% by qNMR (internal standard: 1,3,5‑trimethoxybenzene). The saturated lactam then serves as the starting point for α‑alkylation with a protected bromoacetate enolate at ‑78°C in THF, enabling construction of the S‑configured vinylcyclopropane core found in a class of HCV NS5A replication complex inhibitors. Final API intermediates are subjected to a nitrosamine risk assessment per ICH M7(R2) Section 7.3, and any secondary amine generated after Boc removal is controlled to < 1.5 µg/day total N‑nitrosamine by LC‑MS/MS using a screening method with limit of quantitation 0.03 ppb.

Cycloaddition-Based Norbornane-Fused Lactam Libraries for Cyclin-Dependent Kinase Hit Expansion

The electron‑poor ene‑lactam participates as a dienophile in an uncatalyzed Diels‑Alder reaction with cyclopentadiene, affording a rigid norbornene‑fused lactam scaffold that is subsequently functionalised to generate spiro‑cyclic analogues for screening against CDK2. The reaction is run neat or in toluene at 80°C for 12 h with a cyclopentadiene excess of 2.0 eq to drive the conversion beyond 95%, as determined by ¹H NMR monitoring of the pyrrolinone olefinic protons at δ 6.8 and 7.2 ppm. The exo/endo ratio averages 85:15 under these thermal conditions, and the exo‑adduct is isolated by flash chromatography on a Biotage Isolera system using a SNAP Ultra 100 g silica cartridge, achieving 0.1% cross‑contamination of the endo isomer. The building block is supplied to medicinal chemistry groups under a Quality Agreement specifying ISO 17025 analytical release: purity ≥98.0% by HPLC‑UV (210 nm, Kinetex C18, water/acetonitrile gradient) and residual cyclopentadiene < 0.5% by headspace GC. For subsequent library synthesis, the adduct is subjected to ruthenium‑catalysed ring‑opening metathesis or hydrogenation of the norbornene double bond, followed by lactam hydrolysis and coupling to a triazine core. The end products are enantiopure spiro‑pyrrolidine derivatives assayed in fluorescence polarisation CDK2/Cyclin A inhibition assays at nanomolar concentrations, representing lead matter for oncology programmes. No formal ICH‑driven impurity threshold applies at this discovery stage, but the supplier manages a specification alert for the mutagenic impurity cyclopentadiene epoxide using an Ames‑qualified DEREK Nexus structural alert.The preparation of 3‑amino‑N‑Boc‑pyrrolidine, a central intermediate for certain Janus kinase (JAK) inhibitor candidates, proceeds from the saturated lactam via a sequence of radical bromination, nucleophilic azidation, and Staudinger reduction. Scaling this route to 100–300 kg per batch requires thorough characterisation of the thermal stability of the intermediate α‑bromo‑lactam and the organic azide. The bromination employs N‑bromosuccinimide (1.0 eq) with benzoyl peroxide initiation (0.02 eq) in refluxing carbon tetrachloride, but a switch to chlorobenzene at 85°C is preferred for industrial operation to avoid the carcinogenic profile of CCl₄ and align with ICH Q3C Class 1 solvent restrictions. The radical initiation phase shows an induction period of 8–12 min, after which heat output measured by an accelerating rate calorimeter (ARC) indicates a maximum self‑heating rate of 0.4°C/min at 90°C, still well below the exotherm threshold for secondary decomposition. The α‑bromo intermediate is not isolated; it is taken directly into the azide displacement using sodium azide (1.2 eq) in DMF at 60°C. Process safety evaluation per ASTM E1226 prompts a dust explosion assessment for sodium azide and a DN50 calorimetry run to confirm the reaction enthalpy does not exceed ‑2 kJ/kg of reaction mass. The resulting α‑azido‑lactam is then treated with triphenylphosphine (1.1 eq) in a biphasic THF/water mixture, with evolved nitrogen scrubbed through a hypochlorite bed. Downstream processing involves acidic extraction of the amine into water, basification to pH 11, and re‑extraction into methylene chloride; the organic phase is dried over molecular sieves and solvent‑swapped to tert‑butyl methyl ether for crystallisation of the 3‑amino‑N‑Boc‑pyrrolidine as the oxalate salt. Residual azide must be < 10 ppm by ion chromatography with conductivity detection, and the limit for the potentially genotoxic phosphine oxide is set at < 200 ppm per an ICH M7(R2) purge factor calculation. The amine intermediate is subsequently coupled to a heteroaryl chloride in a Buchwald‑Hartwig amination to deliver a preclinical JAK3‑selective inhibitor currently evaluated in a deuterated analogue for metabolic stabilisation.

Can an Immobilised Lipase B Process Deliver Enantiopure (>99% ee) N-Boc-3-Hydroxypyrrolidine at Multi-Hundred Kilogram Scale?

A chemoenzymatic approach circumvents the need for costly chiral auxiliaries or asymmetric metal catalysis by converting the ene‑lactam into racemic N‑Boc‑3,4‑dihydroxypyrrolidine and resolving the enantiomers via lipase‑catalysed acyl transfer. The dihydroxylation uses catalytic osmium tetroxide (0.5 mol%) with N‑methylmorpholine N‑oxide (1.5 eq) as co‑oxidant in a 1:1 water/acetone mixture at 5°C. The resulting cis‑diol is crystallised from ethyl acetate with a purity of >97% and then subjected to a continuous‑flow kinetic resolution in a packed‑bed reactor containing immobilised Candida antarctica lipase B (CAL‑B) on macroporous acrylic resin (Novozym 435). Vinyl acetate serves as both acyl donor and solvent; a residence time of 45 min at 40°C yields 48% conversion with an enantiomeric ratio (E) exceeding 200. The unreacted (3R,4R)‑diol is recycled while the acetylated (3S,4S) enantiomer is hydrolysed to the enantiopure N‑Boc‑(3S,4S)‑dihydroxypyrrolidine. Subsequent environmental assessment of the process under ICH Q11 confirms that the resin‑based enzyme can be reused for 30 cycles without loss of selectivity when washed with tert‑butyl methyl ether between batches. The chiral diol is then elaborated through a four‑step sequence to N‑Boc‑3‑hydroxypyrrolidine, which is a key intermediate for an oral Jak1‑selective inhibitor currently marketed. Enantiomeric purity specifications are set to >99.0% ee by chiral GC on a Restek Rt‑βDEXse column (30 m, 0.25 mm, 0.25 µm film). Residual vinyl acetate and acetaldehyde are controlled by the finished intermediate’s limits for ICH Q3C Class 3 solvents, targeting < 5000 ppm and < 1000 ppm, respectively, and the enzyme‑derived protein content is verified below 1 ppm via Bradford assay during release.

Regulatory Compliance Matrix Across Application Scenarios
Application Scenario	Governing Standard	Critical Control Parameter & Method	Specification / Limit
Factor Xa Inhibitor Chiral Pyrrolidine Intermediate	ICH Q7 (cGMP), ICH Q2(R1), ICH Q3D	Enantiomeric purity by HPLC (Chiralpak IA); residual Zn by ICP‑MS	≥99.0% ee; Zn < 10 ppm
HCV NS5A Inhibitor Saturated Lactam Intermediate	ICH Q7, OSHA PSM, ICH M7(R2)	Over‑reduction by‑products by GC‑FID; nitrosamine risk per LC‑MS/MS	Residual ene‑lactam < 0.3%; N‑nitrosamine < 1.5 µg/day
CDK2 Hit‑to‑Lead Scaffold	ISO 17025, ICH M7 (structural alerts)	Purity by HPLC‑UV; residual cyclopentadiene by headspace GC	≥98.0% purity; cyclopentadiene < 0.5%
JAK Inhibitor 3‑Amino‑N‑Boc‑Pyrrolidine	ICH Q7, ICH M7(R2), ASTM E1226	Residual azide by ion chromatography; phosphine oxide by HPLC	Azide < 10 ppm; PPh₃O < 200 ppm
Jak1‑Selective Chiral Hydroxy‑Pyrrolidine	ICH Q11, ICH Q3C	Enantiomeric purity by chiral GC; residual enzyme protein by Bradford	≥99.0% ee; protein < 1 ppm

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Certification & Compliance

2-Oxo-2,5-Dihydro-Pyrrole-1-Carboxylic Acid Tert-Butyl Ester 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

The product is catalogued under IUPAC nomenclature as *2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert‑butyl ester*, commonly referred to as N-Boc-2-pyrrolinone or 1-(tert‑butoxycarbonyl)-2-pyrrolinone. It appears as a crystalline, colourless to pale‑yellow solid (lot-dependent hue variation within 5 Yellowness Index units per ASTM E313) and is supplied with a certified minimum purity of 98.0 % (HPLC area‑%, UV 254 nm) and water content below 0.4 % w/w (Karl Fischer coulometry, ASTM E1064). The tert‑butyl carbamate moiety serves as a thermally labile protecting group for the pyrrole nitrogen, while the α,β‑unsaturated lactam ring engages in Diels‑Alder cycloadditions, Michael additions, and radical copolymerisation. Industrial utilisation spans latent curative systems for high‑performance epoxy composites, polymer‑bound reactive modifiers for melt‑processed thermoplastics, and enantioselective synthesis intermediates in active pharmaceutical ingredient manufacture.

Standard Quality Parameters

Parameter	Method / Specification	Typical Value
Assay (HPLC, anhydrous basis)	In‑house method, calibrated against USP <621>; column C18, 5 µm, 1.0 mL/min	98.5 – 99.2 %
Melting range	Differential scanning calorimetry, 10 °C/min, peak onset (ASTM E794)	53 – 56 °C
Loss on drying (40 °C, vacuum < 10 mbar, 4 h)	Gravimetric	< 0.3 %
Chloride content (ion chromatography after combustion)	ASTM D7359	< 50 ppm
Sulphated ash	Ph. Eur. 2.4.14	< 0.1 %
Solubility in N,N‑dimethylformamide at 20 °C	Visual clarity after 15 min stirring	≥ 500 g·L⁻¹

The ester is pre‑registered under REACH (tonnage band 1–10 t/a) and is classified as non‑hazardous under Regulation (EC) No 1272/2008 in the form supplied; the safety data sheet recommends storage at 2–8 °C in sealed, nitrogen‑blanketed containers to prevent moisture ingress that would hydrolyse the tert‑butyl group over extended holding times. In polyethylene‑based masterbatches designed for rotational moulding, 2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert‑butyl ester is introduced as a latent dienophile that thermally unmasks a reactive 2-pyrrolinone function. Pre‑compounding on a co‑rotating twin‑screw extruder (screw diameter 27 mm, L/D 44:1, screw speed 300 min⁻¹) with linear low‑density polyethylene (LLDPE, MI 5.0 g/10 min at 190 °C/2.16 kg, ISO 1133‑1) requires a flat temperature profile from zone‑2 to the die, maintained at 95 ± 3 °C. The processing window is critically narrow because the onset of tert‑butyl carbamate thermolysis, recorded by isoconversional DSC curves (ASTM E698), shifts to lower temperatures under the shear‑generated viscous heating inside the mixing elements. At screw fill levels exceeding 65 %, localised temperature peaks of 107 °C have been identified via retrofitted infrared probes, which activates premature deprotection and causes a sudden melt viscosity increase of 12‑fold (measured by in‑line rheometer slit‑die pressure drop), often resulting in strand breakage and extruder shutdown. Manufacturers therefore limit loading to 7–12 wt%, pre‑dry the ester under vacuum at 40 °C for 6 h (dew point ≤ −40 °C), and run a chilled feed throat jacket at 8 °C to suppress agglomeration. Published data for this specific LLDPE‑ester combination are limited; pilot trials on a Leistritz ZSE‑27 line documented stable operation over runs of 3 h when the screw design replaced one dispersive kneading block with a distributive gear element, reducing melt peak temperature by 4.5 °C.

Thermal Deblocking Kinetics and Processing Window Boundaries

In epoxy‑anhydride composite formulations targeting wind‑turbine blade spar caps, the tert‑butyl ester functions as a blocked latent accelerator. The compound is pre‑dispersed in the anhydride hardener (methylhexahydrophthalic anhydride, viscosity 50 mPa·s at 25 °C) at a loading of 3–8 phr relative to the epoxy resin (DGEBA, EEW 188‑192 g/eq). Differential scanning calorimetry at 10 °C/min reveals a sharp exotherm onset at 98 °C with peak cure at 132 °C; however, when the same mixture is held isothermally at 85 °C in a rheometer (ARES‑G2, 25 mm parallel plates, gap 0.5 mm), the complex viscosity exceeds 100 Pa·s after 38 min, indicative of deprotection-triggered polymerisation. This creates a dual‑constraint processing boundary: vacuum‑assisted resin infusion must keep the mixture temperature ≤ 80 °C to guarantee a 60‑min open time, while subsequent mould curing must reach at least 110 °C within 15 min to avoid under‑cure at the laminate mid‑plane. Glass‑transition temperature (DMTA, 1 Hz, ASTM D7028) of the cured system falls to 121 °C if the cure ramp deviates below 2.0 °C/min, versus 134 °C when following a 2.5 °C/min ramp. In contrast, formulations employing N‑Boc‑pyrrolidine (saturated analogue) exhibit deblocking onset at 137 °C and are unsuitable for this infusion technique because the required large‑part moulds cannot uniformly sustain such elevated initiation temperatures without exotherm‑induced warpage.

When This Ester Replaces N‑Boc‑Pyrrole in Diels‑Alder Cycloaddition

The 2‑oxo substituent activates the dienophilic double bond towards electron‑rich dienes, a property exploited in the kilogram‑scale construction of bicyclic scaffolds for alkaloid synthesis. Condensation with cyclopentadiene in dioxane at 25 °C proceeds with a second‑order rate constant 5.2 × 10⁻⁴ L·mol⁻¹·s⁻¹ (monitored by ¹H NMR disappearance of the α‑proton signal at δ 6.85 ppm), which is roughly 18‑fold faster than the reaction of the parent N‑Boc‑pyrrole under identical conditions. The increased reactivity eliminates the need for Lewis acid catalysis, thereby avoiding aluminium‑contaminated waste streams that complicate downstream crystallisation. After aqueous work‑up, the Diels‑Alder adduct is isolated by vacuum distillation (0.02 mbar, pot temperature 110 °C) in 87–91 % yield with diastereomeric ratio > 20:1. However, the electron‑withdrawing lactam carbonyl also renders the tert‑butyl ester more prone to acid‑catalysed cleavage during deprotection; anhydrous HCl in ethyl acetate (4 M, 2.5 equiv.) at 20 °C removes the Boc group within 20 min but generates 4–7 % lactam ring‑opened by‑products unless the reaction is quenched with cold aqueous sodium bicarbonate within 10 s of complete conversion. In operations exceeding 100‑L batch size, this quench‑sensitivity requires an automated pH‑stat system with sub‑second response time, a constraint not present when employing the more resilient N‑Boc‑pyrrole that tolerates extended acid exposure without ring degradation. Below‑deck infusion of the ester into styrene‑butadiene rubber (SBR) compounds highlights its utility as a dynamic cross‑link precursor. An internal mixer (Banbury type, 1.5 L net chamber volume) charges 5 phr of the tert‑butyl ester together with sulphur (1.8 phr) and CBS accelerator (1.2 phr). The mix is dropped at 105 °C and subsequently vulcanised in a compression press at 160 °C for 12 min (ASTM D3182). Moving‑die rheometry (ASTM D5289) shows a maximum torque increase of 2.8 dN·m beyond the standard sulphur‑only control, attributable to the thermally‑released pyrrolinone acting as a co‑agent that grafts onto the diene backbone. The resulting vulcanisate exhibits tensile strength of 18.2 MPa and elongation at break of 430 % (ISO 37, Type 2 dumbbells), while dynamic mechanical analysis reveals a tan δ peak at ‑28 °C that is 0.11 lower than the control, indicating restricted chain mobility from covalent anchoring of the heterocyclic moiety. A processing concern arises when the ester‑containing compound is stored as unvulcanised sheet for more than 72 h at 25 °C and 60 % RH: partial hydrolysis of the Boc group releases isobutylene gas, causing internal blistering under mild pressure.

Property	2-Oxo‑2,5‑dihydro‑pyrrole‑1‑carboxylic acid tert‑butyl ester	N‑Boc‑pyrrole	N‑Boc‑pyrrolidine	N‑Boc‑2‑pyrrolidinone
Molecular weight (g·mol⁻¹)	181.19	167.20	171.24	185.22
Melting point (°C)	53–56	33–35	30–32	47–49
Thermal deprotection onset, DSC (10 °C/min, N₂)	98 °C	148 °C	137 °C	125 °C
Rate constant, cyclopentadiene addition (25 °C, dioxane)	5.2 × 10⁻⁴ L·mol⁻¹·s⁻¹	2.9 × 10⁻⁵ L·mol⁻¹·s⁻¹	N/A	N/A
Hydrolytic stability (t₁/₂ at pH 7, 25 °C)	48 h	210 h	360 h	130 h
Typical bulk packaging	25 kg fibre drum, LDPE inner liner	25 kg drum	25 kg drum	25 kg drum