Ammonia → 5-Aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran

HRID 432043Notes

Reaction equation

HRID 432043 reaction equation
[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C:6]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[C:8](=O)[O:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.N>C1COCC1.CCOCC.C1(C)C=CC=CC=1.O>[NH2:16][CH2:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:25])[CH3:1])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[O:7][CH2:8]2

Participants

9

Reactant 4

HCID 222AmmoniaHCID 1118Sulfuric AcidHCID 114845261-(3-(Dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-3-oxo-5-isobenzofurancarbonitrileHCID 21226445Aluminium lithium hydride

Product 1

HCID 114729275-Aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuranYield 84%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

1-(3-Dimethylamino-propyl)-1-(4-fluoro-phenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (5.4 g, 16.2 mmol) was dissolved in dry THF (5 mL) and diluted with dry ether (50 mL). This solution was added dropwise to a refluxing suspension of lithium aluminium hydride (2.5 g, 65 mmol) in dry ether (150 mL) over 10-15 minutes, after which the resulting suspension was heated at reflux for a further 4 h. The solution was allowed to cool to room temperature and was stirred at room temperature overnight. The reaction was quenched with a minimum of water, and the resulting solution/suspension was dried over anhydrous magnesium sulfate. The mixture was filtered, and the solid cake was washed with THF. The combined filtrates were evaporated to give an oil. The oil was dissolved in toluene (200 mL) and was stirred with an aqueous solution of sulfuric acid (10 ml, 70% v/v) for 3 h. The mixture was diluted with water, and the pH was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The toluene was separated, and the aqueous phase was extracted with further toluene. The combined toluene extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a yellow oil (4.4 g, 84%). 1H NMR (CDCl3): δ 1.25-1.40 (m, 1H), 1.40-1.55 (m, 1H), 2.11 (ddd, 1H), 2.13 (t, 3H), 2.15 (ddd, 1H), 2.21 (t, 2H), 3.85 (s, 2H), 5.11 (d, 1H), 5.14 (d, 1H), 6.96 (t, 2H), 7.15 (s, 1H), 7.21 (d, 1H), 7.22 (d, 1H), 7.45 (dd, 2H).

Workup

  1. temperatureafter which the resulting suspension was heated
  2. temperatureat reflux for a further 4 h
  3. customThe reaction was quenched with a minimum of water
  4. dry with materialthe resulting solution/suspension was dried over anhydrous magnesium sulfate
  5. filtrationThe mixture was filtered
  6. washthe solid cake was washed with THF
  7. customThe combined filtrates were evaporated
  8. customto give an oil
  9. customThe toluene was separated
  10. extractionthe aqueous phase was extracted with further toluene
  11. dry with materialThe combined toluene extracts were dried over anhydrous magnesium sulfate
  12. filtrationfiltered
  13. customevaporated

Sources & evidence

ORD record
ord-41ffbe9cb9e54d38b47df74f46354aec
Source dataset
uspto-grants-2003_12
Patent number
US06660873B2

Reaction notes

Loading…