Cesium carbonate → N-(3-(3-amino-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)cyclopropanecarboxamide

HRID 715101Notes

Reaction equation

HRID 715101 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH:21]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.CCOC(C)=O>[NH2:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:26][C:24]([CH:21]2[CH2:23][CH2:22]2)=[O:25])[CH:11]=3)[CH:14]=[CH:15][C:16]=1[F:20]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 80376CyclopropanecarboxamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 898155055-(7-Chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline

Product 1

HCID 89815976N-(3-(3-amino-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)cyclopropanecarboxamideYield 34.2%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Sparge a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline (0.5 g, 1.738 mmol) in dioxane (15 mL) with argon, add cyclopropanecarboxamide (0.739 g, 8.69 mmol), XantPhos (0.101 g, 0.174 mmol), Cs2CO3 (1.699 g, 5.21 mmol) and Pd2(dba)3 (0.080 g, 0.087 mmol) and heat at 80° C. overnight. Cool to RT, add EtOAc and MeOH, remove the solids via filtration through diatomaceous earth, rinse well with EtOAc and H2O and separate the layers of the filtrate. Wash the organic layer with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (200 mg, 34%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 9.13 (d, J=0.9 Hz, 1H), 8.44 (m, 1H), 8.17 (s, 1H), 7.08 (m, 1H), 6.82 (dd, J=8.7, 2.2 Hz, 1H), 6.59 (m, 1H), 5.28 (s, 2H), 2.56 (s, 3H), 2.02 (m, 1H), 0.88-0.81 (m, 4H); MS(ESI) m/z: 337.1 (M+H+).

Workup

  1. temperatureCool to RT
  2. customremove the solids
  3. filtrationvia filtration through diatomaceous earth
  4. washrinse well with EtOAc and H2O
  5. customseparate the layers of the filtrate
  6. washWash the organic layer with brine
  7. dry with materialdry over Na2SO4
  8. concentrationconcentrate to dryness
  9. custompurify via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-3e4ec0ce9179417490e5d41152791abe
Source dataset
uspto-grants-2015_11
Patent number
US09187474B2

Reaction notes

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