Dichloromethane → 4-Benzylamino-6-methoxy-[1,5]naphthyridin-3-ol

HRID 1422923Notes

Reaction equation

HRID 1422923 reaction equation
[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=C(C(C)C)C(C2C(C)=C(C)C(C)=C(C)C=2P(C)C)=C(C)C=1)(C)C.[OH-:48].[K+].ClCCl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[OH:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 14797Potassium HydroxideHCID 67255893Benzyl-(3-bromo-6-methoxy-[1,5]naphthyridin-4-yl)-amineHCID 86671532(4',6'-Diisopropyl-3,4,5,6,2'-pentamethyl-biphenyl-2-yl)-dimethyl-phosphane

Product 1

HCID 1363447114-Benzylamino-6-methoxy-[1,5]naphthyridin-3-olYield 36.8%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

Tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol, 0.04 eq) is added at room temperature to a stirred solution of benzyl-(3-bromo-6-methoxy-[1,5]naphthyridin-4-yl)-amine (100 mg, 0.29 mmol, 1.0 eq) in dioxane (6 mL) and water (3 mL), followed by (4′,6′-diisopropyl-3,4,5,6,2′-pentamethyl-biphenyl-2-yl)-dimethyl-phosphane (8 mg, 0.016 mmol, 0.06 eq). After 10 minutes stirring at room temperature, a solution of potassium hydroxide (82 mg, 1.46 mmol, 5.0 eq) in water (3 mL) is added and the resulting mixture is stirred at 105° C. for 16 hours. The reaction mixture is cooled down to room temperature, extracted with ethyl acetate (3×10 mL) and water (10 mL) and the pH is adjusted to 6 by the addition of a 1N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 5:1, v/v) to afford 4-benzylamino-6-methoxy-[1,5]naphthyridin-3-ol as a light yellow solid (30 mg, 36% yield).

Workup

  1. stirringthe resulting mixture is stirred at 105° C. for 16 hours
  2. temperatureThe reaction mixture is cooled down to room temperature
  3. extractionextracted with ethyl acetate (3×10 mL) and water (10 mL)
  4. additionthe pH is adjusted to 6 by the addition of a 1N hydrochloric acid aqueous solution
  5. dry with materialThe combined organic layers are dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give the crude product that
  9. customis purified by column chromatography (silica gel, eluent

Sources & evidence

ORD record
ord-745fbc17ed0a49a8917ca69a0bc361d7
Source dataset
uspto-grants-2015_01
Patent number
US08927541B2

Reaction notes

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