Tetrahydrofuran → N-[(R)-1-(2-cyano-1-methyl-ethyl)piperidin-4-yl]-N-(4-methoxy-phenyl)-nicotinamide

HRID 1782562Notes

Reaction equation

HRID 1782562 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:20])[CH2:17][C:18]#[N:19])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C[CH2:22][N:23](C(C)C)[CH:24](C)C.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[C:18]([CH2:17][C@H:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:34](=[O:33])[C:30]2[CH:31]=[CH:32][CH:24]=[N:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:20])#[N:19]

Participants

4

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 81531DiisopropylethylamineHCID 68969354(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyronitrile

Product 1

HCID 68971071N-[(R)-1-(2-cyano-1-methyl-ethyl)piperidin-4-yl]-N-(4-methoxy-phenyl)-nicotinamideYield 81%

Conditions

Temperature
0 °C

Procedure

The residue was suspended in THF (30 mL) and cooled to 0° C. A solution of (R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyronitrile (1.09 g, 1 eq.) and DIPEA (1.5 mL, 2 eq.) in THF (10 mL) was added drop-wise and the mixture was stirred at 0° C. for 30 min. The reaction was quenched with saturated NaHCO3 (50 mL) and extracted with DCM (150 mL in 3 extracts). The organic layer was washed once with saturated NaHCO3 (20 mL), dried with Na2SO4 and filtered through a silica plug (35 mL glass frit, 1 cm). The plug was washed with 50 mL 5:1 Et2O-MeOH, and the filtrate was concentrated. The residue was purified by flash chromatography on 150 mL silica using 10:1 Et2O-MeOH as the eluent to give N-[(R)-1-(2-cyano-1-methyl-ethyl)piperidin-4-yl]-N-(4-methoxy-phenyl)-nicotinamide (1.23 g, 81%) as light brown thick oil. 1H NMR (δ, CDCl3): 8.44 (1H, s), 8.39 (1H, d, J=4.8 Hz), 7.53 (1 H, d, J=7.5 Hz), 7.08 (1 H, dd, J=7.5, 4.8 Hz), 6.90 (2 H, d, J=8.7 Hz), 6.72 (2 H, d, J=8.7 Hz), 4.69 (1 H, t, br, J=12.9 Hz), 3.73 (3 H, s, and an overlapping 1 H, m), 3.05-2.95 (1 H, m), 2.95-2.75 (2 H, dd, J=20, 11), 2.53-2.25 (4 H, m), 1.96-1.80 (3 H, m), 1.50 (2 H, qd, J=11.4, 2.4 Hz), 1.77(3 H, d, J=6.9 Hz), 1.01 (2 H, d, J=6.3 Hz).

Workup

  1. customThe reaction was quenched with saturated NaHCO3 (50 mL)
  2. extractionextracted with DCM (150 mL in 3 extracts)
  3. washThe organic layer was washed once with saturated NaHCO3 (20 mL)
  4. dry with materialdried with Na2SO4
  5. filtrationfiltered through a silica plug (35 mL glass frit, 1 cm)
  6. washThe plug was washed with 50 mL 5:1 Et2O-MeOH
  7. concentrationthe filtrate was concentrated
  8. customThe residue was purified by flash chromatography on 150 mL silica using 10:1 Et2O-MeOH as the eluent

Sources & evidence

ORD record
ord-1ddec1011fa542afb37a6fbc35319775
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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