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

HRID 598025Notes

Reaction equation

HRID 598025 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][C:27]([F:30])=[C:26]([F: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][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 25134Boron tribromide2×HCID 589706981-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol

Product 1

HCID 589707011-[4-amino-7-(3,4-difluorophenyl)-2-(hydroxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-olYield 36.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A suspension of 1-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (0.790 g, 1.85 mmol), obtained from the filtrate from the trituration in Example 59, in dichloromethane (20 mL) was cooled to 0° C. Boron tribromide (5.54 mL of a 1 M solution in dichloromethane) was added dropwise, and the reaction was stirred at room temperature for 22.5 hours. An analysis by LC/MS indicated the reaction was incomplete, and additional boron tribromide (2.7 mL) was added. The reaction was stirred for three hours at room temperature, and then methanol (25 mL) was carefully added. The resulting solution was stirred at room temperature for one hour and concentrated under reduced pressure. A solution of ammonia in methanol (30 mL of 2 M) was added, and the mixture was stirred for 30 minutes and then diluted with methanol (50 mL) and dichloromethane (50 mL). Silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by chromatography according to the method described in Example 62. The resulting solid was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 269 mg of 1-[4-amino-7-(3,4-difluorophenyl)-2-(hydroxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a light yellow solid, mp 256-258° C.

Workup

  1. stirringThe reaction was stirred for three hours at room temperature
  2. stirringThe resulting solution was stirred at room temperature for one hour
  3. concentrationconcentrated under reduced pressure
  4. additionA solution of ammonia in methanol (30 mL of 2 M) was added
  5. stirringthe mixture was stirred for 30 minutes
  6. additiondiluted with methanol (50 mL) and dichloromethane (50 mL)
  7. additionSilica gel was added
  8. concentrationthe mixture was concentrated under reduced pressure
  9. customThe residue was purified by chromatography
  10. customThe resulting solid was triturated with acetonitrile
  11. customisolated by filtration
  12. washwashed with acetonitrile
  13. customdried in a vacuum oven

Sources & evidence

ORD record
ord-e0db5c5de9b346fdaf53dd70312abafd
Source dataset
uspto-grants-2011_03
Patent number
US07897609B2

Reaction notes

Loading…