Methanol → 1-{4-amino-2-(hydroxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol

HRID 598026Notes

Reaction equation

HRID 598026 reaction equation
[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 25134Boron tribromideHCID 589707101-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol

Product 1

HCID 589707111-{4-amino-2-(hydroxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-olYield 19.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A suspension of 1-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (0.800 g, 1.90 mmol) obtained from the filtrate from the trituration in Example 66, in dichloromethane (20 mL) was cooled to 0° C. Boron tribromide (9.5 mL of a 1 M solution in dichloromethane) was added dropwise, and the resulting suspension was stirred at room temperature for 15 hours. Methanol was carefully added, and the resulting solution was stirred at room temperature for one hour and concentrated under reduced pressure. The residue (1.33 g) was dissolved in DMF (15 mL), and potassium acetate was added. The mixture was heated at 50° C. for 18 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and water (10 mL), and lithium hydroxide monohydrate (1.5 g) was added. The reaction was stirred at room temperature for 64 hours and concentrated under reduced pressure. Methanol and silica gel were added, and the mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with 7% to 20% 1 M methanolic ammonia in dichloromethane) followed by recrystallization from acetonitrile after a hot filtration. The crystals were washed with acetonitrile and dried in a vacuum oven at 65° C. to provide 146 mg of 1-{4-amino-2-(hydroxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a yellow solid, mp 227-229° C.

Workup

  1. stirringthe resulting solution was stirred at room temperature for one hour
  2. concentrationconcentrated under reduced pressure
  3. dissolutionThe residue (1.33 g) was dissolved in DMF (15 mL)
  4. additionpotassium acetate was added
  5. temperatureThe mixture was heated at 50° C. for 18 hours
  6. concentrationconcentrated under reduced pressure
  7. dissolutionThe residue was dissolved in methanol (20 mL)
  8. additionwater (10 mL), and lithium hydroxide monohydrate (1.5 g) was added
  9. stirringThe reaction was stirred at room temperature for 64 hours
  10. concentrationconcentrated under reduced pressure
  11. additionMethanol and silica gel were added
  12. concentrationthe mixture was concentrated under reduced pressure
  13. customThe residue was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with 7% to 20% 1 M methanolic ammonia in dichloromethane)
  14. customfollowed by recrystallization from acetonitrile
  15. filtrationafter a hot filtration
  16. washThe crystals were washed with acetonitrile
  17. customdried in a vacuum oven at 65° C.

Sources & evidence

ORD record
ord-429ae902050a4a4d941bb146baf764e7
Source dataset
uspto-grants-2011_03
Patent number
US07897609B2

Reaction notes

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