Sodium hydride → N-[6-Cyano-9-(3-fluoro-pyridin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide

HRID 545559Notes

Reaction equation

HRID 545559 reaction equation
[H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)#[N:4].Cl[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1)[C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:9][C:8]2=1)#[N:4]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 151336022-(Chloromethyl)-3-fluoropyridineHCID 57431662N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Product 1

HCID 59161258N-[6-Cyano-9-(3-fluoro-pyridin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramideYield 38%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Suspend sodium hydride (60% suspension in mineral oil, 114 mg, 1.64 mmol) in dimethylformamide (7 mL) and cool to 0° C. Add a solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (385 mg, 1.37 mmol) in dimethylformamide (3.5 mL). After several minutes, warm the reaction to room temperature, and stir for 30 min, after which time add 2-chloromethyl-3-fluoro-pyridine (Preparation 60). Stir the reaction overnight and then dilute with ethyl acetate (100 mL). Wash the reaction mixture sequentially with brine (3×75 mL), water (75 mL), and brine (75 mL). Separate the organic layer, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography [silica gel, gradient from 0:100 to 20:80 (90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide):dichloromethane] to provide 184 mg (38%) of the title compound as an off-white solid. m.p.=213-216° C.; MS: m/z 391 [C23H23FN4O+1]+; 1H NMR (300 MHz, DMSO-d6): δ 8.29-8.31 (m, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.71-7.78 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.38-7.44 (m, 2H), 5.56 (s, 2H), 3.99-4.04 (m, 1H), 2.73-3.00 (m, 3H), 2.49-2.55 (m, 1H), 2.37 (septet, J=6.8 Hz, 1H), 1.96-2.00 (m, 1H), 1.76-1.83 (m, 1H), 1.01 (d, J=6.8 Hz, 6H).

Workup

  1. waitAfter several minutes
  2. temperaturewarm
  3. customthe reaction to room temperature
  4. stirringStir
  5. customthe reaction overnight
  6. washWash the reaction mixture sequentially with brine (3×75 mL), water (75 mL), and brine (75 mL)
  7. customSeparate the organic layer
  8. dry with materialdry over magnesium sulfate
  9. filtrationfilter
  10. concentrationconcentrate under reduced pressure
  11. customPurify

Sources & evidence

ORD record
ord-e402575b4f07434b9464da56fb08544a
Source dataset
uspto-grants-2011_05
Patent number
US07935722B2

Reaction notes

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