Potassium Phosphate, Tribasic → N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

HRID 40358Notes

Reaction equation

HRID 40358 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][NH2:19])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:21]1[CH:22]=[CH:23][N:24]=[C:25]2[C:30]=1[N:29]=[CH:28][C:27]([O:31][CH3:32])=[CH:26]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][NH:19][C:21]4[C:30]5[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][N:29]=5)[N:24]=[CH:23][CH:22]=4)=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 634876Binap, (A+-)-HCID 57691311(5-(3,5-Difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamineHCID 594273408-Chloro-3-methoxy-1,5-naphthyridine

Product 1

HCID 57691354N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amineYield 36.1%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

A sealable microwave vial was charged with (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (177.6 mg, 682 μmol), 8-chloro-3-methoxy-1,5-naphthyridine (146 mg, 751 μmol), and potassium phosphate (435 mg, 2047 μmol). A septum was attached and the vial was flushed with N2, then toluene (5 mL) and H2O (1 mL) were added and the was solution sparged with N2 for 5 min. The septum was then quickly removed and tris(dibenzylideneacetone)dipalladium (0) (15.6 mg, 17.1 μmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (42.5 mg, 68.2 μmol) were added together as solids. The vial was then sealed and the resulting purple solution was sparged again for 5 min. The mixture was then heated at 100° C. for 20 h. The mixture was concentrated in vacuo for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH gradient to afford a tan amorphous solid. This solid was additionally triturated with CH2Cl2 (2×0.5 mL) to give N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (103 mg, 36.1% yield). LRMS (ESI) m/z calcd for C23H17F2N4O2 (M+H) 419.1. found 419.2.

Workup

  1. customthe vial was flushed with N2
  2. additiontoluene (5 mL) and H2O (1 mL) were added
  3. customthe was solution sparged with N2 for 5 min
  4. customThe septum was then quickly removed
  5. customThe vial was then sealed
  6. customthe resulting purple solution was sparged again for 5 min
  7. concentrationThe mixture was concentrated in vacuo for purification by MPLC (Teledine Isco combiFlash Companion)
  8. customabsorbed onto a 25 g loading cartridge
  9. customMeOH to 90:10 CH2Cl2: MeOH gradient to afford a tan amorphous solid
  10. customThis solid was additionally triturated with CH2Cl2 (2×0.5 mL)

Sources & evidence

ORD record
ord-d3bb3afee5c4405cb0a72d74be5f996b
Source dataset
uspto-grants-2013_09
Patent number
US08524900B2

Reaction notes

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