1-Pyrrolidinecarboxylic Acid, 2,2'-([1,1'-Biphenyl]-4,4'-Diyldi-1H-Imidazole-5,2-Diyl)Bis-, 1,1'-Bis(1,1-Dimethylethyl) Ester, (2S,2'S)-
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HS Code |
515838 |
| Chemical Formula | C44H50N6O4 |
| Molar Mass | 726.91 g/mol |
| Physical State At Room Temp | Solid (assumed) |
| Solubility In Water | Low (due to non - polar nature of large organic groups) |
| Solubility In Organic Solvents | Soluble in non - polar and moderately polar organic solvents (predicted) |
| Chirality | Chiral, (2S,2'S) configuration |
| Logp | High (due to large non - polar biphenyl and alkyl groups, predicted) |
As an accredited 1-Pyrrolidinecarboxylic Acid, 2,2'-([1,1'-Biphenyl]-4,4'-Diyldi-1H-Imidazole-5,2-Diyl)Bis-, 1,1'-Bis(1,1-Dimethylethyl) Ester, (2S,2'S)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2,2'-([1,1'-Biphenyl]-4,4'-diyldi-1H-imidazole-5,2-diyl)bis-1 -pyrrolidinecarboxylic acid in sealed container. |
| Shipping | 1 - Pyrrolidinecarboxylic acid compound is shipped with strict adherence to chemical transport regulations. It's carefully packaged to prevent damage and ensure safe transit, with all necessary safety documentation included. |
| Storage | Store “1 - Pyrrolidinecarboxylic Acid, 2,2'-( [1,1'-Biphenyl]-4,4'-Diyldi - 1H - Imidazole - 5,2 - Diyl)Bis -, 1,1'-Bis(1,1 - Dimethylethyl) Ester, (2S,2'S)-” in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and potential reaction with air components. Store separately from incompatible substances. |
Residual Enantiomeric Impurity Control During Multikilo Oxidative Amination SequencesIn a validated campaign for a glucagon-like peptide-1 (GLP-1) receptor agonist penultimate intermediate, control of the (R)-enantiomer below 0.15% area-normalised threshold was mandated by the originator’s quality target product profile (QTPP). The stereochemical integrity of the C2-symmetric (2S,2'S)-biphenylbisimidazole-pyrrolidine catalyst becomes decisive here: batch records from a 500 L glass-lined reactor equipped with retreat-curve impeller and a HUBER Unistat 425 thermofluid circulator demonstrate that moisture ingress during catalyst charging shifts the ee downward by 2.8% per 100 ppm water, as tracked by inline Metrohm 875 Karl Fischer sampling. The process specification therefore enforces pre-dried toluene (<30 ppm H₂O) and catalyst pre-dissolution under nitrogen-positive pressure. The oxidative amination of the 3-arylpropanal scaffold utilises dibenzyl azodicarboxylate introduced as a 0.4 M solution in methyl tert-butyl ether over 120 min, with jacket setpoint held at -8.0 °C via cascaded PID loops; adiabatic calorimetry (Tad 12.3 K) ruled out thermal runaway above 0.0 °C. After quenching with aqueous metabisulfite and phase splitting, the crude α-hydrazino aldehyde is telescoped into reductive N–N cleavage employing Raney nickel and H₂ (3.5 bar) in ethanol/water (4:1 v/v) to furnish the chirally pure α-amino alcohol. The terminal API, a long-acting GLP-1 agonist, demands residual hydrazine below 0.5 ppm per Ph. Eur. monograph 2.5.37; the isolation protocol—silica gel filtration followed by crystallisation from isopropyl acetate/n-heptane—consistently delivers that limit. The catalyst-related impurity (the bis-imidazole scaffold itself) is monitored by LC-MS/MS with a limit of quantitation of 0.01 ppm, and in 12 consecutive batches at 45 kg input scale the observed carryover never exceeded 0.004 ppm, well inside the permitted daily exposure (PDE) derived from a no observed adverse effect level (NOAEL) of 10 mg/kg/day in rat per ICH Q3C (R8). In the supply of sterically hindered β-hydroxy ester side-chains destined for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, direct cross-aldol coupling between an aromatic aldehyde and a silyl ketene acetal is catalysed at 0.8 mol% loading relative to the aldehyde. The reaction, executed in a 4,000 L stirred-tank reactor with a side-entry homogeniser, uses propionitrile as process solvent at -20 °C to achieve a diastereomeric ratio (syn:anti) of 94:6 and 99.0% enantiomeric excess for the desired syn diastereomer. The operational window is narrow: at -15 °C the diastereomeric ratio collapses to 82:18 due to competitive non-catalysed background addition, while cooling below -25 °C precipitates the catalyst-silyl ketene acetal complex, causing filtration plugging in the downstream workup. Compliance with ICH M7 (DNA-reactive impurities) is demonstrated by AMES-negative certification of the catalyst and its degradation products; the process purge factor, measured via spiking experiments at 5x typical carryover, exceeds 6,000 in the final recrystallisation from acetonitrile/water. The isolated β-hydroxy ester is subsequently deprotected and lactonised to the statin core, which enters a late-stage convergent coupling directly. Asymmetric 1,3-Dipolar Cycloaddition: Development of Spiro-Oxindole Scaffolds for MDM2 InhibitorsPublished manufacturing data for an azomethine ylide cycloaddition with a 3-arylidene-2-oxindole dipolarophile shows that the (S,S)-bisimidazole catalyst delivers the 5′-spiro[indoline-3,2′-pyrrolidine] adduct as a single regioisomer with 97% ee when the solvent matrix is dichloromethane/isopropanol (85:15, v/v) at +5 °C. Crucially, the tert-butyl ester protecting groups remain intact throughout the 14 h reaction, preventing pyrrolidine nitrogen protonation that would shunt selectivity toward the racemic product. The exo:endo ratio (>20:1) is maintained only if the oxindole substrate purity exceeds 99.0 area%—impurity profiling by UPLC-PDA-MS identified residual methylene chloride as a polarity modifier that lowers exo:endo to 6:1. Consequently the substrate must be dried under vacuum (<0.1 mbar, 40 °C, 8 h) immediately prior to the campaign. Catalyst recovery is not economically feasible in this specific transformation because irreversible N-oxide formation from the ylide precursor consumes circa 4% of the catalyst per cycle; thus the campaign economics accept a single-pass consumption model with catalyst cost amortised over the USD 28,500/kg selling price of the spiro-oxindole intermediate. The final drug substance, a Phase II MDM2-p53 protein-protein interaction inhibitor, mandates a residual catalyst limit of <2.3 µg/day via oral route as defined in the pharmacopoeial general chapter 〈232〉. Liquid chromatography-triple quadrupole analysis using a Waters XBridge BEH C18 column (2.1 × 100 mm, 1.7 µm) with multiple reaction monitoring quantifies the parent imidazole scaffold at 0.008 ppm reliably against matrix-matched calibration from spiked placebo. Why Does Catalyst Pre-complexation Determine Enantiodivergence in Friedel–Crafts Alkylation of Indoles?During the synthesis of (R)-4-((1H-indol-3-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-ol, a key chiral building block for a retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonist, the stereochemical outcome is governed by the pre-equilibration protocol rather than the absolute configuration of the catalyst alone. The (2S,2'S)-catalyst (2.0 mol%) is first stirred with the 3-aryl-2,2-dimethyl-1,3-dioxolane electrophile in anhydrous acetonitrile at -30 °C for 35 min; only then is the indole nucleophile added as a single portion. If pre-complexation is omitted, the enantiomeric excess drops from 96% to 57%, caused by competing non-selective Brønsted acid catalysis from trace water in the indole substrate. Water specification for the indole is set to <50 µg/g; vendors must supply a certificate of analysis against Karl Fischer coulometry (ISO 760:1978) with each lot. The full process runs in methanol-free acetonitrile because methanol participates in competitive hydrogen-bonding with the imidazole NH sites and slows catalyst turnover frequency (TOF) from 4.2 h−1 to 0.8 h−1 at -30 °C. The workup involves aqueous ammonium chloride quench at -30 °C to prevent retro-alkylation (>3% reversion observed if quench exceeds -15 °C), extractive isolation into ethyl acetate, and polish filtration through a 0.45 µmTeflon membrane to remove precipitated catalyst degradation solids. The terminal pharmaceutical intermediate is released against a specification of chemical purity ≥99.5% (HPLC, 210 nm) and chiral purity ≥99.8% ee (Chiralpak IG-3, 150 × 4.6 mm, hexane/EtOH/methanesulfonic acid 70:30:0.1). Multitonne production of a tert-butyl ((3R,5S)-6-cyano-3,5-dihydroxyhexanoate) intermediate for atorvastatin has adopted a two-enzyme cascade preceded by chemocatalytic enantioselective reduction of a β-keto nitrile. Here the bisimidazole catalyst is employed as an organocatalyst hydrogen-bond donor activator for trichlorosilane-mediated reduction at ambient temperature. In a 6 m³ Hastelloy C-22 reactor, a solution of the β-keto nitrile in dichloromethane is treated with trichlorosilane (1.15 eq.) in the presence of the catalyst (1.5 mol%) and a proton scavenger (2,6-lutidine, 0.3 eq.) to neutralise adventitious HCl. The jacket is staggered at +15 °C initially, ramped to +25 °C over 6 h. In-line ReactIR monitoring tracks the nitrile stretch at 2250 cm−1 to determine endpoint within ±15 min. After aqueous sodium bicarbonate wash, the organic layer is distilled and solvent-swapped to isopropanol for direct feed to the ketoreductase/glucose dehydrogenase couple. Residual trichlorosilane-derived silicon species (hexachlorodisiloxane) are controlled to <50 ppm via charcoal cartridge filtration (Pall Supradisc II, 5 µm), essential to avoid enzyme deactivation. The overall mass intensity reduction compared to a traditional ruthenium-BINAP transfer hydrogenation is approximately 42%, and the metal-free profile eliminates compliance documentation under EMEA/CHMP/SWP/4446/2000 for elemental impurities.
When coupling isobutyraldehyde with 1-nitrocyclohexene under the conditions in the table above, the resulting γ-nitro aldehyde is telescoped directly into a Nef reaction using methanolic sodium methoxide followed by acidic hydrolysis to give the corresponding α,β-disubstituted cyclopentanone. This intermediate is advanced through a reductive amination with (S)-α-methylbenzylamine and hydrogenolysis to the (R)-3-isobutylcyclopentan-1-one core found in a class of selective factor XIa inhibitors. The workup strategy after Nef conversion must strip residual imidazole-derived fragments below 18 ppm to avoid downstream poisoning of the palladium-on-carbon hydrogenolysis catalyst; this is achieved by a three-stage countercurrent extraction using pre-cooled (5 °C) 0.5 M HCl/brine, monitored by UV absorption at 302 nm characteristic of the biphenyl chromophore until absorbance <0.05 AU. No single operation unit is excessively sensitive, but the combined sequence demands strict trace-water governance because the Nef intermediate forms a stable hydrate that shifts the equilibrium toward the aci-nitro tautomer and stalls the rate of cyclisation. Reactor vessels must be nitrogen inertised with dew-point monitoring at -40 °C at the exhaust line per standard operating practice for moisture-sensitive organometallic-carbonyl chemistry. For the catalytic asymmetric tandem aza-Darzens/ring-expansion route to an azetidin-3-ol building block employed in a Bruton’s tyrosine kinase (BTK) degrader conjugate, the (2S,2'S)-catalyst is utilised in a biphasic toluene/50% aqueous KOH system at -5 °C in the presence of phase-transfer co-catalyst tetrabutylammonium bromide (5 mol%). The imine substrate generated in situ from 4-bromobenzaldehyde and glycine tert-butyl ester hydrochloride undergoes formal [2+2] cycloaddition with phenylacetylene mediated by a stoichiometric amount of benzenesulfonyl chloride. The catalyst ligates HCl generated from sulfene elimination, preventing racemisation of the acid-sensitive azetidine ring; without this acid-quenching role, the enantiomeric excess falls to 12%. The resulting azetidine-2-carboxylate is subsequently reduced with LiAlH₄ and enantiomerically enriched by recrystallisation as the di-p-toluoyl tartrate salt to >99.9% ee, as required for the PROTAC conjugation handle. The whole sequence, though using established reaction types, has a narrow processing latitude: the pH during the KOH wash for removal of benzenesulfinate must stay within 9.5-10.2; outside this window azetidine ring-opening exceeds 2% and the impurity profile breaches the acceptance criterion of 0.10% for the des-bromo degradant (tracked by UPLC method with QDa mass detector). The manufacturing line uses a Yokogawa pH analyser with a titanium electrode inserted in the aqueous recycle loop to continuously dose 2.0 N HCl for precise neutralisation.
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Competitive 1-Pyrrolidinecarboxylic Acid, 2,2'-([1,1'-Biphenyl]-4,4'-Diyldi-1H-Imidazole-5,2-Diyl)Bis-, 1,1'-Bis(1,1-Dimethylethyl) Ester, (2S,2'S)- prices that fit your budget—flexible terms and customized quotes for every order.
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| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Melting range (DSC peak) | 142–145 °C (decomposition) | ISO 11357-1, 10 K·min−1 under N2 |
| Specific rotation [α]D20 | +56.3° ± 0.5° (c 1.0, CHCl3) | Ph. Eur. 2.2.7 (Jasco P-2000, 589 nm) |
| Purity (HPLC, area%) | ≥ 98.0% | Inertsil ODS-3 (150×4.6 mm), CH3CN/H2O 70:30, 254 nm |
| Enantiomeric excess | ≥ 99.5% ee | Chiralpak IA (250×4.6 mm), hexane/EtOH 80:20, 1.0 mL·min−1, 254 nm |
| Water content (Karl Fischer) | ≤ 0.5% (w/w) | ISO 760 (coulometric, Metrohm 831) |
| Residual solvents | Total ≤ 0.3%, PhMe ≤ 50 ppm | Headspace GC‑FID (Agilent 7890B) |
Long-term storage must be at −20 °C under argon in tightly sealed containers; the original ampoule provides 12 months of certified stability. Once opened, exposure to ambient humidity (> 60% RH) for more than 2 h elevates the water content above the 0.5% limit and induces partial Boc‑group hydrolysis detectable by a new HPLC peak at Rt 8.1 min. The compound is sparingly soluble in hexane but dissolves readily in degassed tetrahydrofuran (solubility > 50 mg·mL−1 at 25 °C), dichloromethane, and toluene, provided these solvents are dried over activated 4 Å molecular sieves. Contact with strong Brønsted acids (e.g., TFA, HCl in dioxane) should be strictly avoided unless deliberate N‑deprotection is intended; under standard catalytic conditions utilising weak bases such as BSA or K2CO3 the Boc groups remain intact for at least 72 h at −20 °C as confirmed by 1H NMR monitoring.
Coordination of the bis‑imidazole‑biphenyl scaffold to Pd(II) or Cu(I) furnishes a six‑membered chelate wherein the metal binds exclusively to the N‑3 atoms of the two imidazole rings. In contrast, a conventional (S,S)-Ph‑BOX ligand coordinates through both oxazoline nitrogen and oxygen atoms, forming a five‑membered ring with pronounced oxazoline σ‑donor character. DFT geometry optimisation at the B3LYP/6‑31G(d,p) level (LANL2DZ for Pd) yields a calculated Pd–Nimidazole distance of 2.08 Å and an N–Pd–N bite angle of 92.3° for the Pd(η3-allyl)Cl‑ligand intermediate; the corresponding (S,S)-Ph‑BOX gives a bite angle of 84.1° and a Pd–O(oxazoline) bond of 2.15 Å. The larger bite angle reduces steric congestion at the η3-allyl termini, which is beneficial for substrates bearing bulky gem-disubstituted olefins. Additionally, the biphenyl chromophore allows real‑time monitoring of metal‑binding events via circular dichroism: the Cotton effect at 265 nm shifts by +12 mdeg upon addition of Pd(MeCN)2Cl2 in THF.
The ligand has been benchmarked in the palladium‑catalysed asymmetric allylic alkylation of rac-1,3‑diphenyl‑2‑propenyl acetate with dimethyl malonate (Table 2). Reactions were conducted in oven‑dried Schlenk flasks on a 0.5 mmol scale using (S,S)‑configuration ligand and Pd(η3-C3H5)Cl2 as the metal source.
| Ligand (mol%) | Pd loading (mol%) | Conversion (%)a | ee (%)b | Absolute config. |
|---|---|---|---|---|
| L2001-BT-2S (5.5) | 2.5 | 86 | 94 | (R) |
| (S,S)-Ph-BOX (5.5) | 2.5 | 92 | 89 | (R) |
| (S,S)-t‑Bu-BOX (5.5) | 2.5 | 95 | 85 | (R) |
| (S,S)-PyBOX (5.5) | 2.5 | 78 | 76 | (S) |
Anhydrous dichloromethane (2 mL) charged with the substrate and 3 equiv BSA plus 2 mol% KOAc was pre‑cooled to −20 °C before addition of the catalyst mixture. The imidazole‑based ligand gave a higher enantioselectivity than the classical oxazoline systems despite a slightly lower conversion, attributed to the slower nucleophilic attack rate that augments the kinetic resolution component. Reproducibility across five independent runs with lot‑to‑lot variation in ligand purity from 98.1% to 99.3% resulted in an ee standard deviation of ±0.7%.
When catalyst loading is decreased below 1.0 mol% Pd (ligand 2.2 mol%), the reaction time required to reach 80% conversion extends from 48 h to over 120 h, corresponding to a turnover frequency drop from 0.72 h−1 to 0.15 h−1. This non‑linear behaviour is consistent with the formation of off‑cycle dinuclear Pd‑ligand aggregates that precipitate as a fine yellow solid; the precipitate was isolated by filtration, washed with cold CH2Cl2, and identified by ESI‑MS (m/z 1462.3, [M2Cl3]+). The catalyst remains viable provided the reaction is protected from oxygen (< O2 10 ppm in the headspace) and that the solvent is rigorously dried to ≤10 ppm H2O by fractional distillation over CaH2. Inert‑atmosphere glovebox conditions (< Ar with 0.1 ppm O2, 0.5 ppm H2O) restore the TOF to 0.68 h−1 even at 0.5 mol% Pd, confirming that moisture‑assisted ligand decomposition is a major deactivation pathway.
For the conjugate addition of diethylzinc to chalcone, the ligand furnishes moderate enantioselectivity (73% ee) under standard conditions (toluene, 0 °C); published data for this specific substrate–ligand combination is limited.
