Sodium hydride → 4-[4-(1-Cyclopentylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile

HRID 272918Notes

Reaction equation

HRID 272918 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]1([N:23]2[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:18]1([N:23]2[CH2:28][CH2:27][CH:26]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:19][CH2:20][CH2:21][CH2:22]1

Participants

8

Reactant 3

HCID 24758Sodium hydrideHCID 230916094-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrileHCID 86601898Methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester

Product 1

HCID 598374144-[4-(1-Cyclopentylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrileYield 13%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolvent3×HCID 14798Sodium HydroxideSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
75 °C

Procedure

4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (447 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by successive column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a pale yellow solid (81 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.36 (m, 1H), 4.11-4.04 (m, 2H), 3.89 (td, 2H), 2.91-2.77 (m, 2H), 2.67-2.25 (m, 2H), 2.15-1.99 (m, 7H), 1.95-1.81 (m, 4H), 1.78-1.64 (m, 2H), 1.62-1.39 (m, 4H).

Workup

  1. stirringstirred for 6 hrs
  2. temperatureto cool to room temperature
  3. washThe organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude reaction
  8. customwas purified by successive column chromatography
  9. washeluting with DCM:MeOH:NH3 (98:1:1)

Sources & evidence

ORD record
ord-204b467618604aaaa0e043413b978fee
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

Loading…