(R)-Benzyl 2-(7-Carbamoyl-1H-Benzo[D]Imidazol-2-Yl)-2-Methylpyrrolidine-1-Carboxylate
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HS Code |
139047 |
| Chemical Formula | C23H24N4O4 |
| Molecular Weight | 420.46 g/mol |
| Appearance | Solid (predicted, based on similar compounds) |
| Physical State At Room Temperature | Solid |
| Solubility In Water | Low (due to its non - polar and large organic structure, predicted) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform (predicted) |
| Melting Point | No exact data found (but generally organic compounds with such structures have melting points in the range of 100 - 250°C, predicted) |
| Pka | No data available, but the benzimidazole moiety may have acidic/basic properties |
| Logp | Positive (hydrophobic, predicted due to the benzyl and pyrrolidine groups) |
As an accredited (R)-Benzyl 2-(7-Carbamoyl-1H-Benzo[D]Imidazol-2-Yl)-2-Methylpyrrolidine-1-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of (R)-Benzyl 2-(7-Carbamoyl -1H -Benzo[D]Imidazol -2 -Yl)-2 -Methylpyrrolidine -1 -Carboxylate in sealed chemical vial. |
| Shipping | Ship (R)-Benzyl 2-(7-Carbamoyl-1H-Benzo[d]Imidazol-2-Yl)-2-Methylpyrrolidine-1-Carboxylate with proper chemical - handling precautions. Use well - sealed containers, comply with hazardous chemical shipping regulations for safe transportation. |
| Storage | Store (R)-Benzyl 2-(7 - Carbamoyl - 1H - Benzo[D]Imidazol - 2 - Yl)-2 - Methylpyrrolidine - 1 - Carboxylate in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Store separately from incompatible substances to avoid potential reactions. |
Viral Polymerase Inhibitor Intermediate: Manufacturing Process and CMC Regulatory IntegrationDirect condensation of the (R)-benzyl pyrrolidine carboxylate scaffold with the activated benzimidazole-7-carboxamide moiety proceeds under strictly anhydrous conditions in tetrahydrofuran at 0°C to 5°C, employing 1.05–1.10 molar equivalents of diisopropylcarbodiimide and 0.05 equivalents of 1-hydroxybenzotriazole. The resulting amide bond formation completes within 2.5–3.0 hours as monitored by in-process HPLC on a C18 column with UV detection at 254 nm. Residual carbodiimide byproducts are scavenged by stirring with polymer-bound isocyanate resin for 45 minutes at 20°C, then removed by filtration through a 0.45 µm polypropylene membrane under nitrogen pressure. The crude isolate is crystallized from ethyl acetate/n-heptane (1:3.5 v/v) with a cooling ramp of 0.15°C/min from 55°C to 5°C, yielding a crystalline solid with typical purity exceeding 99.5% by HPLC area normalization. ICH Q7 Section 8.3 governs the control of critical process parameters, with expanded requirements under ICH Q11 for the designation of registered starting materials. Residual solvent analysis per USP ⟨467⟩ Procedure A must confirm ethyl acetate below 5000 ppm, n-heptane below 5000 ppm, and tetrahydrofuran below 720 ppm. The molecule serves as a late-stage intermediate requiring protection of the benzimidazole N1 position prior to coupling with phosphoramidate prodrug moieties; the free carboxamide at C7 remains intact throughout subsequent synthetic steps and contributes two hydrogen bond donor sites essential for target binding pocket occupancy in the final active pharmaceutical ingredient.What Quality Attributes Govern the Use of This Carbamate in Anthelmintic Benzimidazole Carbamate Prodrug Synthesis?The compound functions as a pre-formed chiral pyrrolidine-benzimidazole hybrid building block that bypasses the requirement for racemic resolution at the penultimate stage of anthelmintic API assembly. Coupling to a substituted phenyl isothiocyanate generates the thiourea bridge, which cyclodesulfurizes in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 2.0 equivalents of triethylamine in refluxing acetonitrile over 9–12 hours. In production-scale stainless steel reactors with pitched-blade impellers operating at 150–180 rpm, the heterogeneous cyclodesulfurization mixture exhibits a pronounced exotherm during the first 40 minutes; jacket cooling must maintain internal temperature below 82°C to suppress formation of the des-carbamoyl dimer impurity, which co-elutes with the product on normal-phase preparative chromatography. The benzyl carbamate protecting group is cleaved via catalytic hydrogenolysis over 5% palladium on carbon (0.08 weight equivalents relative to substrate) under 40 psi hydrogen in methanol at 25°C, affording the free pyrrolidine that directly enters salt formation with pamoic acid. Residual palladium is controlled below 10 µg/g as measured by inductively coupled plasma mass spectrometry per USP ⟨232⟩/⟨233⟩ compliance. Compliance with VICH GL11 (Impurities in New Veterinary Drug Substances) and VICH GL10 (Impurities in New Veterinary Medicinal Products) applies, with particular attention to the 5-benzimidazole carboxamide structural isomer, which arises from acyl migration during benzimidazole formation and must be controlled below 0.15% by validated HPLC. The final anthelmintic dosage form is a flavored oral suspension in 100 mg/mL concentration, packaged in amber polyethylene terephthalate bottles with child-resistant polypropylene closures under 25°C/60% RH long-term stability conditions per ICH Q1A(R2) Zone II climate. The pyrrolidine stereocenter remains chemically and configurationally stable throughout the hydrogenolysis and subsequent salt formation; enantiomeric purity measured by chiral HPLC on an amylose tris(3,5-dimethylphenylcarbamate) column with n-hexane/isopropanol/diethylamine (80:20:0.3 v/v/v) mobile phase consistently exceeds 99.0% ee.Proton Pump Inhibitor Scaffold Modification Through C7-Carboxamide Benzyl Carbamate IntermediatesIn the synthesis of benzimidazole-based acid suppressants lacking the sulfoxide pharmacophore but retaining the pyridine-methylsulfinyl-benzimidazole core, the (R)-configured pyrrolidine carbamate introduces metabolic stabilization by replacing the conventional methoxypropoxy chain with a conformationally constrained cyclic amine. The C7 carboxamide on the benzimidazole ring acts as a bioisosteric replacement for the sulfoxide oxygen, participating in hydrogen bonding with Asp136 and Ser139 of the gastric H⁺/K⁺-ATPase alpha subunit. Coupling proceeds via nucleophilic aromatic substitution at the 2-chloromethyl position of the activated benzimidazole core; the reaction requires 1.2 equivalents of the carbamate nucleophile and 1.5 equivalents of potassium carbonate in dimethylformamide at 60°C for 18–22 hours under nitrogen. The N-alkylated product precipitates upon addition to 0–5°C water and is isolated by centrifugation, washed with deionized water until conductivity of the filtrate drops below 50 µS/cm, and dried under vacuum at 45°C for 12 hours. Residual dimethylformamide, classified as ICH Q3C Class 2 solvent, is controlled below 880 ppm in the dried intermediate. The subsequent manganese dioxide oxidation of the sulfide to the sulfoxide must be conducted with strict temperature control at −5°C to 0°C in dichloromethane; exceeding 5°C triggers over-oxidation to the sulfone, which lacks antisecretory activity and must be purged chromatographically. The benzyl carbamate remains intact through the oxidation and is removed via transfer hydrogenation with ammonium formate (4.0 equivalents) and 10% Pd/C in methanol at 40°C over 3 hours. Compliance with ICH Q3D for elemental impurities requires monitoring of palladium, manganese, and iron; manganese, introduced by the stoichiometric oxidant, is controlled below 250 µg/g in the drug substance. The final API is formulated as an enteric-coated pellet in hard gelatin capsules: a drug layer containing 15–22% w/w API on sugar spheres is sealed with hypromellose (3% weight gain), enteric-coated with methacrylic acid-ethyl acrylate copolymer (Eudragit L30 D-55) to a 25–30% weight gain at product temperature 28–31°C in a Wurster fluid bed, and filled into size 1 hard gelatin capsules with talc as lubricant. Dissolution per USP ⟨711⟩ Delayed-Release method using acid stage (0.1 N HCl, 2 hours) followed by buffer stage (pH 6.8 phosphate buffer, 45 minutes) requires ≥85% release.Chiral Benzyl Carbamate Cleavage Under Continuous-Flow Hydrogenation: Throughput, Catalyst Lifecycle, and Residual Metal ControlThe removal of the benzyloxycarbonyl protecting group from the pyrrolidine nitrogen constitutes the rate-limiting unit operation in multi-kilogram manufacture of the deprotected amine intermediate. In batch hydrogenators, catalyst attrition caused by mechanical agitation at 400–600 rpm reduces the active palladium surface area by 15–25% over 6–8 consecutive runs, with a corresponding increase in reaction time from 2.5 hours to 5.5 hours and progressive elevation of des-benzyl impurity from 0.05% to 0.8% due to β-hydride elimination of the liberated amine. Continuous-flow hydrogenation in a packed-bed reactor (internal diameter 10 mm, catalyst bed length 150 mm, 5% Pd/Al₂O₃ extrudates of 1.5 mm diameter) at 50°C, 60 bar hydrogen pressure, and 0.5 mL/min liquid flow rate achieved 99.7% conversion for over 120 hours of continuous operation with catalyst leaching below 2 µg Pd/g feed. Table 1 summarizes the impurity profile across the hydrogenation approaches.
Treatment of Benzimidazole-resistant Helminth Strains: Structural Determinants and Combination Chemotherapy ApproachesWhen the (R)-pyrrolidine benzyl carbamate is elaborated into an N-methoxycarbonyl thioureidobenzimidazole analog for evaluation against Haemonchus contortus isolates carrying the F200Y and F167Y β-tubulin polymorphisms, in vitro larval migration inhibition assays reveal a 4- to 8-fold reduction in IC₅₀ compared to albendazole against the resistant Kirikiriroa isolate. The pyrrolidine ring methyl substituent at the 2-position introduces a steric clash with the mutated tyrosine residue at position 200, partially restoring binding within the colchicine site of the resistant β-tubulin isotype. The carboxamide at C7 of the benzimidazole extends into the solvent-accessible region and tolerates substantial structural variation without loss of activity, making it a suitable attachment point for pharmacokinetic-modifying groups. In tablet co-formulation with the cytochrome P450 3A4 inhibitor ketoconazole (10 mg per 400 mg dose of benzimidazole prodrug), the oral bioavailability in sheep increases from 22% to 47% as measured by plasma AUC₀→₄₈, enabling effective single-dose therapy at 5 mg/kg body weight. The dual-active oral drench formulation contains the solubilized benzimidazole carbamate at 50 mg/mL, ketoconazole at 1.25 mg/mL, benzyl alcohol as preservative at 1.5% v/v, and propylene glycol/water (60:40 v/v) as vehicle, adjusted to pH 4.0 with hydrochloric acid. The solution remains physically stable without precipitation for 18 months at 25°C/60% RH in amber high-density polyethylene bottles. Withdrawal periods for food-producing animals are established per VICH GL48 (Metabolism and Residue Kinetics): the marker residue in ovine liver is the sum of the parent benzimidazole carbamate and its 5-hydroxy metabolite, with a maximum residue limit of 100 µg/kg and a provisional withdrawal period of 14 days determined from radiolabeled residue depletion studies in 6 crossbred sheep.When the C7 Carboxamide Directs Regioselective Electrophilic Substitution on the Benzimidazole Ring: Nitration, Halogenation, and Sulfonation PathwaysThe electron-withdrawing nature of the C7 carboxamide group deactivates the benzimidazole ring toward electrophilic aromatic substitution while simultaneously directing incoming electrophiles to the C4 and C6 positions through a combination of inductive and resonance effects transmitted via the fused imidazole ring. Nitration with 1.05 equivalents of potassium nitrate in concentrated sulfuric acid at −10°C to −5°C yields a 92:8 mixture of the 4-nitro and 6-nitro regioisomers, separable by fractional crystallization from ethanol/water (2:1 v/v) with the 4-nitro isomer crystallizing first at 0°C. The reaction must be quenched into ice-water within 30 seconds of reaching completion temperature; prolonged contact with the nitration medium leads to benzyl carbamate cleavage and subsequent nitrosamine formation at the liberated secondary amine. Bromination using N-bromosuccinimide (1.0 equivalent) in acetonitrile with 10 mol% silica gel as catalyst at 25°C proceeds with complete regioselectivity for the C4 position over 2 hours. The resulting 4-bromo intermediate serves as a versatile cross-coupling partner in Suzuki-Miyaura reactions with arylboronic acids, enabling introduction of substituted phenyl, pyridyl, and thienyl groups at the benzimidazole 4-position. Palladium-catalyzed coupling employs Pd(PPh₃)₄ (0.03 equivalents), potassium carbonate (2.0 equivalents) in dioxane/water (4:1 v/v) at 85°C for 8 hours under argon. The carboxamide and benzyl carbamate both withstand these coupling conditions without competitive oxidative addition; however, the carbamate is susceptible to cleavage by free amine bases. Therefore, diisopropylethylamine is strictly substituted for inorganic carbonates when the arylboronic acid contains a tertiary amine substituent. The 4-aryl derivatives exhibit modified pharmacokinetic profiles relative to the unsubstituted parent, with cLogP values tunable across a range of 1.8 to 4.2 and corresponding modulation of plasma protein binding from 72% to 96% in rat plasma equilibrium dialysis experiments.
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The spatial projection of the 2‑methylpyrrolidine ring when drawn in the (R)-absolute configuration places the methyl group in a pseudo‑equatorial orientation, a geometry that docking studies on homologous ATP‑binding pockets suggest is complementary to a conserved hydrophobic cleft formed by the gatekeeper residue and the β‑3 strand. Conversely, the (S)-enantiomer directs the methyl group toward the solvent‑exposed channel, which can reduce the enthalpic contribution to binding by 1.5‑2.0 kcal·mol⁻¹ in isothermal titration calorimetry experiments performed with truncated kinase domains. While both enantiomers participate in Buchwald–Hartwig aminations and Suzuki–Miyaura couplings through the C‑2 imidazole halogen precursor, the (R)‑form delivers bioactive molecules whose inhibitory potency, measured as IC₅₀ against recombinant enzyme panels, differs from the (S)‑counterpart by a factor exceeding 50‑fold in certain receptor tyrosine kinase assays. This divergence makes chiral separation at the intermediate stage uneconomical and positions enantioselective synthesis of the (R)-building block as the entry point for clinical candidate scale‑up.
Every manufactured lot is released against a specification that draws on the ICH Q6A decision tree for new chemical entities. The minimum reportable threshold for unspecified impurities is set at 0.10%, with any single impurity capped at 0.50%. Identity is corroborated by 1H and 13C NMR in DMSO‑d₆, comparing the chemical shift of the benzimidazole C‑7 carboxamide proton (δ 7.82 ± 0.05 ppm) and the pyrrolidine C‑2 methyl singlet (δ 1.52 ± 0.03 ppm) against a validated reference standard. A certificate of analysis typical of a 500‑gram campaign is tabulated below.
| Test | Method | Acceptance Criterion | Observed (Lot A2407‑12) |
|---|---|---|---|
| Assay (anhydrous, solvent‑free basis) | HPLC (Phenomenex Kinetex C18, 100×3.0 mm, 2.6 µm; gradient MeCN/0.1% TFA aq.) | ≥ 95.0% | 97.2% |
| Enantiomeric purity | SFC (Chiralpak IG‑3; conditions as above) | ≥ 98.0% e.e. | 99.2% |
| Water content | Karl Fischer coulometry (ISO 760:1978) | ≤ 1.0% w/w | 0.38% |
| Residual solvents (GC‑FID, ICH Q3C) | Headspace GC, DB‑624 30 m × 0.32 mm × 1.8 µm | Ethyl acetate ≤ 5000 ppm; Hexane ≤ 290 ppm | EtOAc 420 ppm; Hexane 110 ppm |
| Appearance | Visual inspection under D65 lighting | Off‑white to pale yellow powder | Conforms |
Residual palladium is monitored by ICP‑MS (Agilent 7800) after microwave‑assisted acid digestion; the actionable limit for hydrogenation‑derived Pd is ≤20 ppm, with actual lots typically falling between 5‑12 ppm. For applications requiring sub‑ppm metal contamination—such as late‑stage functionalisation in an API registered under 21 CFR 314.50—an additional scavenger treatment with Si‑TMT (Silicycle) reduces Pd to <0.5 ppm.
In amide bond constructions mediated by HATU or HBTU in DMF, the hygroscopicity of the benzimidazole‑carboxamide moiety exerts a disproportionate influence on conversion. When the powder is taken directly from a −20°C freezer and exposed to a class‑100,000 weighing room at 45‑55% RH, water uptake measured by dynamic vapour sorption reaches 0.9% within 20 minutes; at that level, the coupling of the pyrrolidine nitrogen to a 2‑chloropyrimidine‑4‑carboxylic acid fragment proceeds with only 41‑55% isolated yield, compared with 78‑84% when the substrate is dried to constant mass under high vacuum (<1 mbar, 40°C, 6 h) immediately before use. The underlying cause is competitive hydrolysis of the activated ester intermediate, a process confirmed by LC‑MS detection of the free acid by‑product in quenched aliquots. Process chemists running 10‑20‑litre reactors have therefore adopted a protocol where the solid is charged into an inerted vessel, subjected to three vacuum‑argon cycles, and then dissolved in anhydrous NMP pre‑dried over 4 Å molecular sieves; residual water in the reaction mixture is held below 200 ppm as verified by a Metrohm 831 KF coulometer interfaced with a liquid‑sampling module.The benzyloxycarbonyl (Cbz) group decorating the pyrrolidine nitrogen defines the orthogonality map for assembly of complex molecules. Unlike the Fmoc analogue, which undergoes β‑elimination in the presence of piperidine (20% v/v in DMF, t1/2 ≈ 2‑4 minutes) and is incompatible with secondary amine bases, the Cbz motif withstands morpholine and DBU at ambient temperature for 24‑48 h without measurable deprotection (<0.5% by HPLC). This stability allows functionalisation of the carbamoyl‑benzimidazole ring under mildly basic conditions—for instance, alkylation of the amide nitrogen with methyl iodide and NaH in THF at 0‑25°C—without erosion of the protecting group. Deprotection is then effected cleanly by hydrogenolysis over 5% Pd/C under hydrogen at 1‑3 bar, typically in ethyl acetate or ethanol, furnishing the free 2‑methylpyrrolidine intermediate with a purity sufficient to telescope into the next amidation.
A direct comparison of three prevailing amino‑protecting groups applied to the same scaffold illustrates trade‑offs that influence route selection at kilogram scale.
| Protecting Group | Deprotection Conditions | Base Stability* | Epimerisation Risk | Typical Recovery After Deprotection |
|---|---|---|---|---|
| Cbz | H₂, 5% Pd/C (50% wet), EtOAc, 2 bar, 20‑25°C, 3‑6 h | Stable to DBU/reflux/ 48 h | <0.2% e.e. loss | 89‑94% as free base |
| Fmoc | 20% piperidine/DMF, rt, 1‑2 h | Partial cleavage with DBU within 2 h | 1.3‑2.1% e.e. loss reported | 85‑91% |
| Boc | TFA/CH₂Cl₂ (1:1), 0‑25°C, 2‑4 h | Stable under basic conditions | <0.5% e.e. loss | 78‑86% (product often contaminated with t‑butyl cation adducts) |
*Base stability refers to exposure to 1.2 equivalents of DBU in DMF at 50°C for 24 h. Epimerisation was assayed after deprotection and re‑derivatisation with (S)‑MTPA‑Cl (Mosher’s acid chloride), integrating the 19F NMR signals at δ −71.4 and −71.6 ppm.
The benzimidazole‑carboxamide moiety itself represents a pharmacophore recurrent in poly(ADP‑ribose) polymerase (PARP) inhibitors and certain M1 receptor positive allosteric modulators, yet its presence introduces a processing constraint during direct C‑H functionalisation attempts. Incubating the Cbz‑protected intermediate with iridium‑based photoredox catalysts under blue LED irradiation (450 nm, 15 W) in the presence of tertiary alkyl amines intended for decarboxylative cross‑coupling leads to competitive photoreduction of the carbamoyl group. Manifests of this side reaction include up to 12‑15% of the corresponding 7‑cyano‑benzimidazole by‑product as identified by LC‑HRMS (Q‑TOF, m/z 375.1661). Quenching the reaction with oxygen at −20°C after 6‑minute irradiation windows—implemented on an integrated flow‑photoreactor (Vapourtec UV‑150, PFA reactor coil, 0.8 mm ID, residence time 90 s)—suppressed the nitrile impurity to below 2.3%. This embodiment of the product in a flow‑chemistry platform underscores how intrinsic functional‑group reactivity, not merely stereochemical purity, dictates the physical form and packaging of the reagent for industrial synthesis groups. The compound further differs from simpler 2‑arylpyrrolidine intermediates, such as (R)‑2‑phenylpyrrolidine‑1‑carboxylic acid benzyl ester, by virtue of the hydrogen‑bond donor‑acceptor network presented by the 7‑carbamoyl substituent. Gelation of reaction mixtures has been observed when the concentration exceeds 0.4 M in toluene or THF at temperatures below 10°C, attributable to intermolecular amide‑amide association; this is mitigated by maintaining a solution temperature of 25‑30°C during metalation steps or by adding 5% v/v of N,N‑dimethylpropyleneurea (DMPU) as a disaggregating co‑solvent. Extrusion of the viscous phase through a jacketed addition funnel kept at 22°C ensures reproducible addition rates in semi‑batch lithiation sequences. When material is requisitioned for cGMP intermediate manufacture under ICH Q7, the product is packed in double‑PE bags inside a fibre drum, with a re‑test date assigned at 24 months from the release date when stored continuously at 2‑8°C. Accelerated stability studies at 40°C/75% RH over 6 months indicate 0.8‑1.2% decline in chromatographic purity, mainly due to hydrolytic opening of the benzyl carbamate, which generates benzyl alcohol (quantifiable at <0.15%) and the unprotected amine. This degradant pathway reinforces the requirement to minimise head‑space volume in filled containers and to apply a nitrogen overlay during sampling operations. No incompatibility has been recorded with borosilicate glass or HDPE contact surfaces; however, prolonged contact with stainless‑steel 316L vessels under acidic aqueous slurries (pH <4) has been shown to mobilise trace iron (0.8‑1.5 µg·cm⁻²) that discolours the product, a situation prevented by employing glass‑lined or Hastelloy C‑22 equipment.
