Cesium carbonate → 6-(benzylthio)-1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,8-naphthyridin-2(1H)-one

HRID 1504534Notes

Reaction equation

HRID 1504534 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[CH2:18]([S:25][C:26]1[CH:27]=[C:28](/[CH:33]=[CH:34]/[C:35](OCC)=[O:36])[C:29](Cl)=[N:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=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+]>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].O1CCOCC1>[CH2:18]([S:25][C:26]1[CH:27]=[C:28]2[C:29](=[N:30][CH:31]=1)[N:8]([C:6]1[C:5]([O:9][CH3:10])=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[C:2]([Cl:1])[CH:7]=1)[C:35](=[O:36])[CH:34]=[CH:33]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 1177372802-Chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-amineHCID 117749120(E)-ethyl 3-(5-(benzylthio)-2-chloropyridin-3-yl)acrylate

Product 1

HCID 1177371276-(benzylthio)-1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,8-naphthyridin-2(1H)-oneYield 68%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A vial was charged with 2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-amine (302 mg, 1.198 mmol), (E)-ethyl 3-(5-(benzylthio)-2-chloropyridin-3-yl)acrylate (400 mg, 1.198 mmol), Xantphos (69.3 mg, 0.120 mmol), Pd2 dba3 (54.9 mg, 0.060 mmol), cesium carbonate (781 mg, 2.396 mmol) and 1,4-dioxane (4793 pp. The mixture was purged with argon, the vial was sealed, and the reaction was heated at 100° C. for 5 h. Upon cooling to RT, 10 mL methanol was added, and the mixture was heated at 80° C. for 2 h. Upon cooling to RT the mixture was loaded onto silica gel and purified using 0-50% EtOAc/heptane to provide 6-(benzylthio)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,8-naphthyridin-2(1H)-one (410 mg, 0.815 mmol, 68.0% yield) as a light orange foamy solid. m/z (ESI) 503.0 (M+H)+.

Workup

  1. customThe mixture was purged with argon
  2. customthe vial was sealed
  3. temperatureUpon cooling to RT
  4. addition10 mL methanol was added
  5. temperaturethe mixture was heated at 80° C. for 2 h
  6. temperatureUpon cooling to RT the mixture
  7. custompurified

Sources & evidence

ORD record
ord-b632c1375a9e4116bbc2d2eb1a7e4e14
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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