Potassium Iodide → 1-{[4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2H-pyran-4-yl]methyl}pyrrolidin-2-one

HRID 272957Notes

Reaction equation

HRID 272957 reaction equation
[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][CH2:30][CH2:31]Br)C.C(N(CC)C(C)C)(C)C.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][N:24]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:27])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 76300Ethyl 4-bromobutyrateHCID 81531DiisopropylethylamineHCID 68576458(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine

Product 2

HCID 222AmmoniaHCID 598374551-{[4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2H-pyran-4-yl]methyl}pyrrolidin-2-oneYield 11.6%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (100 mg, 0.301 mmol) in toluene (2 ml) was added ethyl-4-bromobutyrate (43 μl, 0.301 mmol), N,N-diisopropylethylamine (157 μl, 0.904 mmol) and potassium iodide (5 mg, 0.030 mmol). Reaction mixture heated at 80° C. for 48 hours, then increased to reflux. Potassium carbonate (83 mg, 0.602 mmol) was added and reaction left at reflux for a further 24 hours until reaction complete. Reaction mixture was partitioned between ethyl acetate (20 ml) and saturated NaHCO3 (10 ml). Organic washings were dried over Na2SO4 and concentrated in vacuo to give a brown oil (101 mg crude, 84%). The compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:ammonia, 100:0:0 to 98:2:0.2, to give the title compound as an oil (7 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 7.90 (d, 2H), 4.22-4.36 (m, 1H), 4.80-4.90 (m, 2H), 3.52-3.67 (m, 2H), 3.40 (s, 2H), 2.72-3.88 (several multiplets, 3H), 2.50 (t, 2H), 2.34-2.44 (m, 2H), 2.21-2.30 (t, 2H), 1.60-2.10 (several multiplets, 10H), 1.08 (d, 6H).

Workup

  1. customReaction mixture
  2. temperatureincreased
  3. temperatureto reflux
  4. customreaction
  5. waitleft
  6. temperatureat reflux for a further 24 hours until reaction complete
  7. customReaction mixture
  8. customwas partitioned between ethyl acetate (20 ml) and saturated NaHCO3 (10 ml)
  9. dry with materialOrganic washings were dried over Na2SO4
  10. concentrationconcentrated in vacuo
  11. customto give a brown oil (101 mg crude, 84%)
  12. customThe compound was purified by column chromatography on silica gel
  13. washeluting with dichloromethane

Sources & evidence

ORD record
ord-658f6bc1584d4ac4bda6ea1133371700
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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