Hydrochloric Acid → 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-(4-methyl-2-oxopentyloxy)-1isoindolinone

HRID 1199040Notes

Reaction equation

HRID 1199040 reaction equation
[H-].[Na+].[OH:3][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.Cl[CH2:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([O:3][CH2:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 137209281-Chloro-4-methylpentan-2-oneHCID 141821812-(7-Methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone

Product 1

HCID 198676522-(7-Methoxy-1,8-naphthyridin-2-yl)-3-(4-methyl-2-oxopentyloxy)-1isoindolinoneYield 24.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

An oily suspension (50% by weight; 1.8 g) of sodium hydride 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 (9.3 g) in anhydrous dimethylformamide (120 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. 1-Chloro-4-methyl-2-pentanone (8.1 g) is then added dropwise while the temperature is maintained at 0° C., and stirring is continued for a further 1 hour at 0° C. and then for 4 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of ice (150 g) and water (350 cc), neutralized with 1N hydrochloric acid solution and extracted with dichloromethane (3×250 cc). The organic phases are combined, washed with water (4×75 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is taken up with ethyl acetate (25 cc) and the insoluble product is separated by filtration, washed successively with ethyl acetate (10 cc) and diisopropyl ether (10 cc) and then discarded. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is purified by chromatography on silica (120 g) contained in a column 3 cm in diameter [eluant: dichloromethane/methanol (98.5:1.5 by volume)]. Elution is first performed with 170 cc of solvent: the corresponding eluate is discarded; elution is then performed with 800 cc of solvent and the corresponding eluate concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization of the residue in ethyl acetate, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(4-methyl-2-oxopentyloxy)-1isoindolinone (3 g), m.p. 120° C., is obtained. 1-Chloro-4-methyl-2-pentanone may be prepared by the method described by ASINGER F., et al., Ann. Chem., 1964, 672, 156.

Workup

  1. customthe suspension obtained
  2. temperatureis maintained at 0° C.
  3. stirringstirring
  4. waitis continued for a further 1 hour at 0° C.
  5. waitfor 4 hours at a temperature in the region of 20° C
  6. extractionextracted with dichloromethane (3×250 cc)
  7. washwashed with water (4×75 cc)
  8. dry with materialdried over magnesium sulphate
  9. filtrationfiltered
  10. concentrationconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C
  11. customThe residue obtained
  12. customthe insoluble product is separated by filtration
  13. washwashed successively with ethyl acetate (10 cc) and diisopropyl ether (10 cc)
  14. concentrationThe filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C
  15. customThe residue obtained
  16. customis purified by chromatography on silica (120 g)
  17. washElution
  18. washelution
  19. concentrationthe corresponding eluate concentrated to dryness under reduced pressure (2.7 kPa)
  20. customAfter recrystallization of the residue in ethyl acetate

Sources & evidence

ORD record
ord-8902fc1001454cd6b6210839488ec182
Source dataset
uspto-grants-1990_02
Patent number
US04898871

Reaction notes

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