Sodium hydride → 3-(4-Dimethylamino-2-oxobutyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone

HRID 1087776

Reaction equation

HRID 1087776 reaction equation
[H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH2:31][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 5469134-(Dimethylamino)butan-2-oneHCID 141821812-(7-Methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone

Product 1

HCID 221638203-(4-Dimethylamino-2-oxobutyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinoneYield 24.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-5 °C

Procedure

Sodium hydride (0.7 g) is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (8.0 g) in anhydrous dimethylformamide (125 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. and then treated with a solution of 4-dimethylamino-2-butanone (3.5 g) in anhydrous dimethylformamide (5 cc). The mixture is stirred for 3 hours at a temperature in the region of 20° C., and is then poured into distilled water (500 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is dissolved in ethyl acetate (400 cc) and the solution obtained is extracted with 1 N aqueous hydrochloric acid solution (2×100 cc). The aqueous phases are combined, washed with ethyl acetate (50 cc), alkalinized with 10 N aqueous sodium hydroxide solution to a pH in the region of 11 and extracted with ethyl acetate (2×250 cc). The organic phases are combined, washed with distilled water (3×30 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in acetonitrile, 3-(4-dimethylamino-2-oxobutyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (2.6 g), m.p. 140° C., is obtained.

Workup

  1. customThe suspension obtained
  2. stirringThe mixture is stirred for 3 hours at a temperature in the region of 20° C.
  3. additionis then poured
  4. distillationinto distilled water (500 cc)
  5. extractionextracted with dichloromethane (3×200 cc)
  6. washwashed with distilled water (4×25 cc)
  7. dry with materialdried over magnesium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C
  10. customThe oily residue obtained
  11. customthe solution obtained
  12. extractionis extracted with 1 N aqueous hydrochloric acid solution (2×100 cc)
  13. washwashed with ethyl acetate (50 cc)
  14. extractionextracted with ethyl acetate (2×250 cc)
  15. washwashed with distilled water (3×30 cc)
  16. dry with materialdried over magnesium sulphate
  17. filtrationfiltered
  18. concentrationconcentrated to dryness under reduced pressure (2.7 kPa) at 60° C
  19. customAfter recrystallization in acetonitrile

Sources & evidence

ORD record
ord-cb084915d157454ebacbd5a21ff9a48c
Source dataset
uspto-grants-1990_10
Patent number
US04960779

Linked notes

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