1,4-Dioxane → HCID 59371497, compound

HRID 2095377Notes

Reaction equation

HRID 2095377 reaction equation
C(O[Na])(C)(C)C.Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1.Cl.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][NH:31][CH2:30]2.O1CCOCC1>[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[CH2:15][O:14][C:12]1[CH:13]=[C:8]([N:31]2[CH2:32][CH:33]3[CH2:36][CH:29]([CH2:35][CH2:34]3)[CH2:30]2)[CH:9]=[N:10][CH:11]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 229236613-azabicyclo[3.2.1]octane hydrochlorideHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 59371497HCID 59371497, compoundYield 65%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

Palladium catalyst A (6.2 mg, 7.5 μmol, 83 mequiv.), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (Xphos, 3.7 mg, 7.5 μmol, 83 mequiv.), tert-BuONa (206 mg, 2.1 mmol, 2.8 equiv.), 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (268 mg, 0.75 mmol) and 3-azabicyclo[3.2.1]octane hydrochloride (Arkè Organics srl, Zona Industriale della Botte No. 4, 56012 Fornacette (PI), Italy; 133 mg, 0.90 mmol, 1.2 equiv.) were filled into a 25 mL round bottom-flask with a side neck. The flask was equipped with a stir bar, a condenser, and rubber septa. The atmosphere was exchanged with Ar (3 times), and anhydrous dioxane (3 mL) was added via syringe. The mixture was stirred at 100° C. for 5 h and cooled to room temperature. Water (10 mL) was added to quench the reaction. The product was extracted into EtOAc (40 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by CC (SiO2, 25×2.5 cm, EtOAc) to give the crude product, which was further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 32.6-36.9 min) to give the title compound as a yellowish oil (198 mg, 65%). MS (EI) m/z 387 (M+, 16%).

Workup

  1. addition133 mg, 0.90 mmol, 1.2 equiv.) were filled into a 25 mL round bottom-flask with a side neck
  2. customThe flask was equipped with a stir bar, a condenser
  3. additionwas added via syringe
  4. temperaturecooled to room temperature
  5. customto quench
  6. customthe reaction
  7. extractionThe product was extracted into EtOAc (40 mL)
  8. washThe organic phase was washed with brine (10 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customThe residue was purified by CC (SiO2, 25×2.5 cm, EtOAc)
  12. customto give the crude product, which
  13. customwas further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min
  14. wait100% CH3CN for 20 min

Sources & evidence

ORD record
ord-4090d2e00411477bb1724d531904c418
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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