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

HRID 598016Notes

Reaction equation

HRID 598016 reaction equation
[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[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:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:5][C:4]=2[N:3]=1

Participants

8

Reactant 4

HCID 5234Sodium ChlorideHCID 11430Potassium CarbonateHCID 27343373,4-Difluorobenzeneboronic acidHCID 589706811-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol

Product 1

HCID 589706981-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-olYield 32%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Procedure

A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.4 g, 3.55 mmol), 3,4-difluorophenylboronic acid (1.12 g, 7.10 mmol), potassium carbonate (1.62 g, 11.7 mmol), 1,2-dimethyoxyethane (DME)(13 mL), and water (7 mL) was stirred under nitrogen. Dichlorobis(triphenylphosphine)palladium(II)(0.025 g, 0.036 mmol) was added, and the suspension was heated at reflux for five hours, allowed to cool to room temperature, diluted with water (20 mL), and extracted with dichloromethane (50 mL). An emulsion formed. Solid sodium chloride was added to saturate the aqueous layer. The organic layer was then removed under reduced pressure. The aqueous layer was extracted with dichloromethane (4×50 mL); the third extraction was allowed to stand overnight. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid (2.03 g) was dissolved in dichloromethane (45 mL), purified by automated flash chromatography (40+M silica cartridge, eluting with 3% to 10% methanol in ethyl acetate), and then triturated with acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 485 mg of 1-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 193-195° C.

Workup

  1. temperaturethe suspension was heated
  2. temperatureat reflux for five hours
  3. extractionextracted with dichloromethane (50 mL)
  4. customAn emulsion formed
  5. concentrationto saturate the aqueous layer
  6. customThe organic layer was then removed under reduced pressure
  7. extractionThe aqueous layer was extracted with dichloromethane (4×50 mL)
  8. extractionthe third extraction
  9. dry with materialThe combined organic extracts were dried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. dissolutionThe resulting brown solid (2.03 g) was dissolved in dichloromethane (45 mL)
  13. custompurified by automated flash chromatography (40+M silica cartridge, eluting with 3% to 10% methanol in ethyl acetate)
  14. customtriturated with acetonitrile
  15. customThe resulting solid was isolated by filtration
  16. washwashed with acetonitrile
  17. customdried in a vacuum oven

Sources & evidence

ORD record
ord-0fa2d44c75764813b52b1c335d212d1a
Source dataset
uspto-grants-2011_03
Patent number
US07897609B2

Reaction notes

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