1,2-Dimethoxyethane → 1-[4-amino-2-(ethoxymethyl)-7-(6-fluoropyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol

HRID 598018Notes

Reaction equation

HRID 598018 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[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[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:30]=[N:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:5][C:4]=2[N:3]=1

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 2783397(6-Fluoropyridin-3-yl)boronic 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 589707161-[4-amino-2-(ethoxymethyl)-7-(6-fluoropyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-olYield 36.4%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
110 °C

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), 6-fluoropyridine-3-boronic acid (0.597 g, 4.26 mmol), potassium carbonate (1.62 g, 11.7 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.025 g, 0.036 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere and then heated at 110° C. for 17.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the residue was partitioned between water (25 mL) and dichloromethane (25 mL). A solid was present in the organic layer, and methanol was added to dissolve the solid. The aqueous layer was extracted with dichloromethane (3×20 mL). Silica gel was added to the combined organic fractions, and the mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 15% methanol in ethyl acetate) followed by recrystallization from acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 530 mg of 1-[4-amino-2-(ethoxymethyl)-7-(6-fluoropyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as white crystals, mp 218-220° C.

Workup

  1. temperatureto cool to room temperature
  2. customThe volatiles were removed under reduced pressure
  3. customthe residue was partitioned between water (25 mL) and dichloromethane (25 mL)
  4. additionwas added
  5. dissolutionto dissolve the solid
  6. extractionThe aqueous layer was extracted with dichloromethane (3×20 mL)
  7. additionSilica gel was added to the combined organic fractions
  8. concentrationthe mixture was concentrated under reduced pressure
  9. customThe residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 15% methanol in ethyl acetate)
  10. customfollowed by recrystallization from acetonitrile
  11. customThe crystals were isolated by filtration
  12. washwashed with acetonitrile
  13. customdried in a vacuum oven

Sources & evidence

ORD record
ord-1de03654983c4ee18c90c6b231155573
Source dataset
uspto-grants-2011_03
Patent number
US07897609B2

Reaction notes

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