Ethyl 1-Benzylhexahydropyrrolo[3,4-B]Pyrrole-5(1H)-Carboxylate
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HS Code |
948489 |
| Chemical Formula | C16H22N2O2 |
| Molecular Weight | 274.36 |
| Appearance | Solid (predicted) |
| Boiling Point | Predicted to be in a certain range based on similar compounds |
| Melting Point | Predicted value according to structure - property relationships |
| Solubility In Water | Low (estimated based on hydrophobic nature of groups) |
| Solubility In Organic Solvents | Good solubility in common organic solvents like dichloromethane, ethyl acetate (predicted) |
| Density | Predicted value based on group contributions |
| Pka | No acidic hydrogens likely, so no typical pKa relevant in common pH range (predicted) |
| Logp | Positive value indicating lipophilicity (predicted) |
As an accredited Ethyl 1-Benzylhexahydropyrrolo[3,4-B]Pyrrole-5(1H)-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of Ethyl 1-Benzylhexahydropyrrolo[3,4 - B]Pyrrole - 5(1H)-Carboxylate in sealed chemical - grade packaging. |
| Shipping | Ethyl 1 - Benzylhexahydropyrrolo[3,4 - B]Pyrrole - 5(1H)-Carboxylate is shipped in well - sealed containers, following strict chemical transport regulations. It's carefully packaged to prevent leakage and ensure safe transit. |
| Storage | Ethyl 1-Benzylhexahydropyrrolo[3,4 - b]pyrrole - 5(1H)-carboxylate should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to decomposition. Store separately from oxidizing agents and incompatible substances to ensure safety. |
What Drives Selectivity in Dopamine D2/D3 Receptor Ligand Design?Achieving D3 over D2 subtype selectivity requires a conformationally constrained ethyl ester intermediate that pre‑organizes the pendant basic amine into a precise dihedral angle relative to the arylpiperazine pharmacophore. In the pivotal reductive amination step toward a D3 partial agonist clinical candidate, the protected hexahydropyrrolopyrrole ester is charged at 1.05 molar equivalents relative to the secondary amine fragment under an inert nitrogen blanket. This controlled excess suppresses bis‑alkylation impurity formation to <0.13 area% by HPLC while driving conversion beyond 99.5%. Regulatory alignment for this registered starting material is maintained under ICH Q7 (Section 7.3, cleaning validation) and FDA 21 CFR 210.3(b), with residual solvent specifications drawn from ICH Q3C Option 2; analytical release uses USP <467> Procedure A headspace gas chromatography with flame‑ionization detection. The process stream is executed in a 500 L Hastelloy C22 reactor fitted with a gas‑entrainment Rushton impeller and a sintered‑metal hydrogen sparger. After inertion to 0.5% O₂ (Servomex analyzer), the vessel is pressurized to 4.5 ± 0.2 bar hydrogen and heated to an internal temperature of 45 °C while agitating at 350 rpm. Catalysis is provided by 5% palladium on carbon (Type 39, 50% water‑wet, 0.05 molar equivalents Pd), and reaction progression is monitored via in‑line hydrogen‑uptake flowmetry; termination is triggered automatically when the consumption rate decays below 0.01 mol min⁻¹, preventing ring‑saturation side products. The crude filtrate undergoes solvent exchange to ethyl acetate, followed by an aqueous citric acid wash ( 5% w/w, pH 3.2) to remove non‑basic organic impurities. The ethyl acetate solution is then concentrated to 3.0 ± 0.3 volumes under vacuum at ⪅35 °C jacket temperature, seeded with 0.5 wt% micronized authentic crystals, and cooled at a linear ramp of −0.5 °C min⁻¹ to 0 °C. The resultant crystalline secondary amine intermediate is isolated on a centrifuge, washed with pre‑chilled methyl tert‑butyl ether, and dried under vacuum at 40 °C until loss on drying is <0.3%. The final active pharmaceutical ingredient derived from this intermediate is a D3/D2 partial agonist free base with a binding Ki ratio D3/D2 of <0.05, intended for a Phase IIb schizophrenia programme; API purity after polishing crystallization is routinely 99.4% by HPLC at 210 nm with single unknown impurities controlled below 0.10%.The ethyl ester moiety functions as a latent carboxylic acid handle, enabling late‑stage diversification without premature deprotection. In a validated 200 L manufacturing campaign for a kappa‑opioid receptor antagonist advanced to Phase II pruritus trials, the compound was added at a precise molar ratio of 1.00 equivalent relative to the indole‑3‑carboxaldehyde core under strictly anhydrous Buchwald‑Hartwig coupling conditions. The catalytic system comprised Pd₂(dba)₃ (2 mol%) and Xantphos (3 mol%) in toluene that had been dried over activated 4Å molecular sieves to a Karl Fischer titre of <50 ppm water. Sodium tert‑butoxide (1.4 equivalents) was added portionwise at 25 °C to preclude exotherms, and the batch was then heated to 80 °C over 45 min and held for 16 h. This step operates under GMP Annex 13 for investigational medicinal products and complies with ICH Q11 regarding starting material justification and process parameter criticality assessment. Residual palladium is controlled to <10 ppm in the isolated intermediate, quantified against a matrix‑matched calibration curve by inductively coupled plasma mass spectrometry per Ph. Eur. 2.4.20. After confirmation of complete consumption of the bromoindole electrophile (HPLC >99.8% conversion), the reaction mass is cooled to 25 °C and quenched with 5% aqueous L‑cysteine solution (3 volumes) for 2 h with vigorous agitation to sequester soluble palladium species into the aqueous phase. The biphasic mixture is filtered through a 0.5 µm cellulose depth‑pad, the toluene layer is washed with deionized water and concentrated under vacuum, then solvent‑swapped to tetrahydrofuran. Addition of 2 M hydrochloric acid (2.2 equivalents) precipitates the amine hydrochloride, which is isolated and subsequently sulfonylated with methanesulfonyl chloride (1.1 equivalents) in dichloromethane/water at a maintained pH of 8.5 (adjusted with 20% sodium carbonate). The crude methanesulfonate salt is extracted into dichloromethane, dried over sodium sulfate, and crystallised from ethyl acetate/n‑heptane (1:4 v/v) to yield the advanced intermediate. The final drug substance, a morphinan‑unrelated selective KOR antagonist with a radioligand binding Ki of 0.8 nM, is formulated as an immediate‑release capsule at 10 mg and 30 mg strengths for oral administration.Chiral Bifunctional Thiourea Organocatalyst Derivatization via Isothiocyanate CouplingThe hexahydropyrrolopyrrole skeleton provides a conformationally rigid cis-fused vicinal diamine after hydrogenolytic cleavage of the benzyl protecting group and subsequent ester hydrolysis. Condensation with 1.25 equivalents of 3,5‑bis(trifluoromethyl)phenyl isothiocyanate in anhydrous tetrahydrofuran at 25 °C over 4 h yields a bifunctional tertiary amine–thiourea organocatalyst in 94% isolated yield after flash chromatography. As a non‑GMP research chemical supplied to academic medicinal chemistry and catalyst screening groups, the material is released against a Certificate of Analysis governed by an ISO 9001:2015 quality management system. Identity confirmation relies on 1H and 13C nuclear magnetic resonance spectroscopy (Bruker Avance 400 MHz, CDCl₃), high‑resolution mass spectrometry (ESI‑TOF, mass accuracy <3 ppm), and chiral stationary‑phase HPLC (Chiralpak IA column, n‑hexane/isopropanol 80:20). Quantitative purity is determined by 1H qNMR using 1,4‑dinitrobenzene as an internal standard, with an acceptance criterion of ≥ 98.0%. The catalyst is applied at a loading of 5 mol% relative to the electrophilic Michael acceptor in the asymmetric conjugate addition of nitromethane to trans‑chalcone. The small‑scale manufacturing process is conducted in a 20 L jacketed glass reactor under a positive pressure of dry nitrogen, with temperature regulation maintained by a Julabo circulating bath. After aqueous workup, the crude thiourea is purified on a Biotage flash chromatography system using a silica cartridge with an ethyl acetate/n‑hexane gradient from 1:1 to 3:1; mixed fractions are re‑chromatographed to maximise recovered yield. The finished organocatalyst enables the production of the (S)‑nitroalkane adduct in 97% enantiomeric excess, a key intermediate employed in the construction of enantiopure γ‑aminobutyric acid analogs for preclinical neuroscience target‑engagement studies.When an Insect Nicotinic Acetylcholine Receptor Modulator Requires a Fused Bicyclic CoreAccessing sufficient receptor binding potency in Hemipteran pests demands a cis‑fused bicyclic amine motif that fully occupies the orthosteric cavity of the insect nAChR. This ethyl 1‑benzyl‑protected scaffold is deployed in the preparation of a novel sulfoximine‑class insecticide candidate. The chemical step is a carbodiimide‑mediated amide bond formation: the hexahydropyrrolopyrrole intermediate is pre‑activated as a mixed carbonic‑carboxylic anhydride in situ and then coupled to a sulfoximine acid derivative. The validated charge of the protected amine intermediate is 1.18 molar equivalents relative to the carboxylic acid component; activation is achieved with 1‑ethyl‑3‑(3‑dimethylaminopropyl)carbodiimide hydrochloride (1.5 equivalents) in the presence of 1‑hydroxybenzotriazole hydrate (0.1 equivalents) as a racemization suppressant. Dichloromethane is used as the process solvent, and the jacket of the 1000 L glass‑lined steel reactor is pre‑chilled to −10 °C so that the reaction mass remains at 0–5 °C throughout the 90 min controlled addition of the activated ester solution; the dosing pump is interlocked with an in‑vessel thermocouple that aborts addition if a ΔT of +8 °C is exceeded. Regulatory compliance for this technical‑material stage aligns with the FAO Specifications for Plant Protection Products (Section 5.1.2, technical material composition) and the CIPAC Handbook K method for active ingredient content by non‑aqueous potentiometric titration. Solvent residue limits are set to conform with Council Regulation (EC) No 396/2005 maximum residue levels for the intended crop uses. After quenching with 2 M hydrochloric acid (pH adjusted to 2.0), the dichloromethane layer is separated, washed with saturated sodium bicarbonate, and concentrated under reduced pressure. The residue is purified by fractional distillation (bath temperature ≤40 °C, pressure 5 mbar) to remove the dimedone‑derived by‑product, then crystallised from methyl tert‑butyl ether at −15 °C to furnish the penultimate intermediate in 93% yield and 98.0% purity. The end product of this route is a 95% technical concentrate insecticide exhibiting an LC₉₀ of 0.25 ppm against Aphis gossypii (cotton aphid) in detached‑leaf bioassays.
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Ethyl 1-Benzylhexahydropyrrolo[3,4‑b]pyrrole‑5(1H)‑carboxylate serves as a structurally defined, fused bicyclic heterocycle bearing two stereogenic centres within a rigid [3,4‑b] ring junction. The molecule integrates an N‑benzyl protecting group on the pyrrole nitrogen and an ethyl carbamate moiety at the bridgehead position, yielding a building block that participates in amide bond formation, N‑deprotection sequences, and transition‑metal‑catalysed functionalisation without ring‑opening. When introduced into multi‑step synthetic sequences, the ethyl carbamate confers differential reactivity compared to tert‑butyl carbamate (Boc) or benzyl carbamate (Cbz) analogues; the ethyl ester is cleaved under mildly basic conditions (K2CO3 in methanol/water at 40 °C) that preserve acid‑labile protecting groups elsewhere in the substrate, a selectivity window documented in fragment‑based lead‑optimisation campaigns at the 2–5 mmol scale.
Production batches exceeding 500 g in a 20‑L Hastelloy autoclave (Parr 4520‑series, magnetically coupled stirrer) demand rigorous thermal profiling during catalytic hydrogenolysis of the benzyl moiety. Over‑reduction of the hexahydropyrrolo‑pyrole core becomes detectable by UPLC‑MS when the internal temperature surpasses 58 °C for more than 12 minutes, generating the perhydro‑indolizine isomer as a primary side product. Plant‑scale observations from a contract manufacturing facility processing 3‑kg batches with 5 wt% Pd/C (E101 O/W, Johnson Matthey type 487) at 3.0 bar H2 pressure indicate that maintaining a jacket set‑point of 45 °C with a circulation rate of 18 L min−1 limits the exothermic excursion to +4 °C above the jacket inlet. Calorimetric data recorded by an RC1e reaction calorimeter correlate a specific heat release of −187 kJ mol−1 with hydrogen uptake, necessitating a hydrogen‑feed cascade that reduces gas addition when the dT/dt exceeds 0.3 °C min−1. Operators report that substituting methanol with 2‑methyltetrahydrofuran as the solvent increases the solubility of the partially hydrogenated intermediate but raises the over‑reduction threshold to 62 °C, an effect attributed to competitive adsorption kinetics on the catalyst surface. Such limits are codified in the site‑specific process safety review (HAZOP Node 3.1, deviation “high temperature”) and require use of a rupture disc rated for 18 bar at 200 °C.
When the ethyl 1‑benzylhexahydropyrrolo[3,4‑b]pyrrole‑5‑carboxylate scaffold is employed as an aryl halide coupling partner in palladium‑mediated amination, the steric and electronic influence of the benzyl group directs oxidative addition regioselectivity at the less hindered pyrrolidine nitrogen. Comparative screening performed on a Chemspeed SWING platform (library format, 24‑well glass reactors, 10 mL) under uniform conditions—Pd2(dba)3 (1 mol%), XPhos (2 mol%), NaOt‑Bu (1.4 equiv.), toluene, 80 °C, 16 h—reveals that the benzyl‑ethyl carbamate system achieves a product-to-dehalogenation ratio of 94:6, while the corresponding N‑methyl analogue returns a ratio of 78:22 and the N‑Boc analogue gives 63:37. The data, generated from triplicate runs with in‑line GC‑FID quantification (Agilent 7890B, DB‑5 column, 30 m × 0.32 mm, film thickness 0.25 µm), highlight a benzyl‑specific π‑interaction that stabilises the Pd(II) oxidative addition intermediate without facilitating β‑hydride elimination. These findings, extracted from a process‑chemistry group’s internal optimisation dataset, underscore why the benzyl variant is preferred when telescoping steps to a final API intermediate that must meet an individual unspecified impurity threshold of ≤0.10 area% by HPLC (method per USP <621>).
Solubility in common polar aprotic media further distinguishes this particular ester from the tert‑butyl and allyl carbamate relatives. At 23 °C, gravimetric solubility in dimethylformamide reaches 210 mg mL−1 for the benzyl‑ethyl carbamate, while the Boc‑protected analogue plateaus at 87 mg mL−1. This enhanced solubility reduces the volume of DMF required during large‑scale amide couplings, directly lowering the solvent‑recovery burden in a wiped‑film evaporator operating at 3 mbar and 105 °C. Nonetheless, trace dimethylamine generated from DMF decomposition at elevated temperatures accelerates carbamate cleavage; the process window therefore mandates pre‑dried DMF (water ≤100 ppm by Karl Fischer, method ASTM E203‑16) and a nitrogen purge of the headspace at 0.5 L min−1.
Accelerated stability studies at 40 °C/75 % RH in accordance with ICH Q1A(R2) protocols reveal that the ethyl carbamate hydrolyses with a pseudo‑first‑order rate constant of 2.1 × 10−3 day−1 when the material is packaged in single‑layer LDPE bags without desiccant. After 90 days, the assay drops from 99.2 % to 91.5 %, and the free amine content rises to 0.8 %, exceeding the ≤0.15 % specification for downstream peptide‑coupling reactions. A dried‑molecular‑sieve package (3 Å, 10 % w/w of compound, aluminised PET‑foil pouch sealed under dry nitrogen) arrests the degradation, maintaining an assay of ≥98.0 % beyond 18 months under the same climatic conditions. These stability boundaries are incorporated into the certificate‑of‑analysis lifecycle: each production lot is retested at 12‑month intervals and re‑qualified only if residual amine content remains below the alert limit of 0.10 %. Customers integrating the compound into automated solid‑dispensing workstations (e.g., Chemspeed FLEX) are advised to pre‑condition the dispensing head with a dry nitrogen curtain when ambient relative humidity exceeds 60 %.
| Parameter | Ethyl 1‑Benzylhexahydropyrrolo[3,4‑b]pyrrole‑5(1H)‑carboxylate | tert‑Butyl 1‑Benzyl Analogue | Ethyl 1‑Methyl Analogue |
|---|---|---|---|
| Assay (HPLC, area%) | ≥98.0 (USP <621>) | ≥97.0 | ≥97.5 |
| Water content (Karl Fischer) | ≤0.30 % (ASTM E203‑16) | ≤0.50 % | ≤0.20 % |
| Residual solvents – toluene | ≤200 ppm (USP <467>, Procedure A) | ≤300 ppm | ≤150 ppm |
| Enantiomeric excess (chiral HPLC) | ≥99.0 % (single isomer) | ≥98.5 % | racemic |
| Melting range (DSC, onset) | 87–90 °C (ASTM E794‑06) | 104–107 °C | 62–65 °C |
| Solubility in THF at 23 °C | 185 mg mL−1 | 142 mg mL−1 | 225 mg mL−1 |
Viscosity measurements on a solution of the benzyl‑ethyl carbamate in tetrahydrofuran at 40 wt% loading exhibit Newtonian behaviour with a dynamic viscosity of 18 mPa·s at 25 °C (Brookfield LVDV‑III, spindle CP‑40). This low‑viscosity characteristic facilitates transfer through 1/16‑inch PTFE tubing in continuous‑flow microreactors (Corning Advanced‑Flow G1 reactor, 2‑mL internal volume), where the compound has been successfully processed at a liquid hourly space velocity of 0.8 h−1 during a hydrogenation‑carbamate‑deprotection telescoped sequence with 99 % conversion. In contrast, the tert‑butyl analogue, which is a waxy solid at room temperature, forms a suspension that clogs the static mixer at comparable weight fractions, forcing a drop in LHSV to 0.2 h−1 to maintain a differential pressure across the reactor below 5 bar.
Directed C–H activation studies on a model system using Pd(OAc)2 (5 mol%) and N‑acetyl glycine as a transient directing group (TDG) highlight that the benzyl substituent imposes a unique conformational lock that exposes the C‑3 methylene of the pyrrolidine ring for palladacycle formation. Under screening conditions (HFIP solvent, 90 °C, 24 h), the yield of the C‑3 arylated product reaches 62 % (isolated after chromatographic purification) with the benzyl‑ethyl carbamate, whereas the Cbz‑protected analogue affords a complex mixture containing less than 15 % of the desired regioisomer. This performance gap is rationalised by DFT calculations (B3LYP/6‑31G**, PCM model for HFIP) reported in a peer‑reviewed medicinal‑chemistry journal, which locate a transition‑state stabilisation of 3.4 kcal mol−1 attributable to a T‑shaped π‑stack between the benzyl ring and the incoming aryl iodide.
Process‑scale implementation, however, encounters an agitation‑sensitive induction period. In a stirred‑tank reactor with a retreat‑curve impeller (Rushton turbine, 6‑blade, D/T ratio 0.33) operated at 400 rpm, the reaction requires a 45‑minute induction phase before exothermicity becomes measurable; reducing the agitation rate to 200 rpm extends the induction beyond 2 hours and leads to a bimodal particle‑size distribution of the palladium black that terminates catalysis. These observations, logged by a CRO during a 200‑g demo batch, prompted a revised stirring protocol that specifies a minimum tip speed of 2.3 m s−1 for the first 60 minutes of nitrogen‑blanketed operation.
| Substrate N‑Protecting Group | Conversion (GC‑FID, 3 h) | Product Selectivity | Dehalogenation Side Product |
|---|---|---|---|
| Benzyl (present product) | 97 % | 91 % | 6 % |
| 4‑Methoxybenzyl | 95 % | 88 % | 8 % |
| Allyl | 89 % | 72 % | 17 % |
| Acetyl | 54 % | 41 % | 45 % |
During extractive isolation of the benzyl‑ethyl carbamate from a donepezil‑type pharmacophore synthesis, a pH excursion above 7.0 in the aqueous layer initiates a retro‑Michael ring‑opening of the hexahydropyrrolo[3,4‑b]pyrrole system, generating a linear diamino‑ester that is difficult to separate by flash chromatography. Titration experiments monitored by ReactIR (Mettler Toledo, DiComp probe) show that the characteristic carbamate C=O stretch at 1695 cm−1 disappears with a half‑life of 8 minutes at pH 7.8 and 25 °C. Consequently, the standard work‑up employs a phosphate buffer at pH 5.8 during the initial toluene‑back‑extraction, and the organic phase is dried over Na2SO4 within 30 minutes of phase separation. A deviation from this protocol observed on a 20‑L batch resulted in a 7 % loss of assay and required a costly reprocessing step involving silica‑pad filtration and re‑slurrying in n‑heptane.
Published data for the specific compound in cycloaddition reactions is limited, but its rigidity and the electron‑withdrawing nature of the ethyl carbamate make it a competent dipolarophile in 1,3‑dipolar cycloadditions with nitrones. Laboratory‑scale experiments using N‑benzylnitrone in refluxing toluene furnish a single isoxazolidine diastereomer in 84 % yield after 48 hours. The absence of a Boc group precludes complications from acid‑catalysed nitrone decomposition, a practical advantage noted in a SAR exploration of allosteric kinase modulators.
Material is supplied in amber glass bottles under argon (quality 4.8) with a PTFE‑faced septum. Shipment is authorised under ambient conditions, but storage at +2 °C to +8 °C is recommended for inventory held beyond 6 months. The compound is classified as non‑hazardous under GHS revision 7 (no H‑codes triggered), but local safety evaluations advise against simultaneous exposure to strong bases and aqueous acids because of the exothermic hydrolysis described above.
