Cesium carbonate → 7-(Cyclopropanecarboxamido)-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide

HRID 1502477Notes

Reaction equation

HRID 1502477 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:46]1[CH:55]=[C:54]2[C:49]([CH:50]=[C:51]([C:57]3[CH:58]=[N:59][CH:60]=[C:61]([F:64])[C:62]=3[CH3:63])[N+:52]([O-:56])=[CH:53]2)=[CH:48][N:47]=1.[CH:65]1([C:68]([NH2:70])=[O:69])[CH2:67][CH2:66]1>O1CCOCC1.ClCCl.CO>[CH:65]1([C:68]([NH:70][C:46]2[CH:55]=[C:54]3[C:49]([CH:50]=[C:51]([C:57]4[CH:58]=[N:59][CH:60]=[C:61]([F:64])[C:62]=4[CH3:63])[N+:52]([O-:56])=[CH:53]3)=[CH:48][N:47]=2)=[O:69])[CH2:67][CH2:66]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 80376CyclopropanecarboxamideHCID 25112535BrettphosHCID 866749847-Chloro-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide

Product 1

HCID 679747407-(Cyclopropanecarboxamido)-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (28 mg, 0.035 mmol), cesium carbonate (227 mg, 0.69 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (19 mg, 0.035 mmol), 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (100 mg, 0.35 mmol), and cyclopropanecarboxamide (59 mg, 0.69 mmol) in dioxane (2 mL) was heated at 100° C. for 8 hours in a vial sealed with a Teflon cap. The reaction mixture was diluted with dichloromethane (50 mL) and methanol (5 mL), filtered over Celite, and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% ACN in water w/0.1% NH4OH, 14 min) Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.14 (s, 2H), 8.63 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 2.12 (d, J=1.5 Hz, 3H), 2.08 (m, 1H), 0.86 (m, 4H). LCMS (Method E): RT=3.626 min, M+H+=339.2.

Workup

  1. customcap
  2. filtrationfiltered over Celite
  3. concentrationconcentrated in vacuo
  4. customto provide a residue that
  5. customwas purified by reverse phase HPLC purification (5-85% ACN in water w/0.1% NH4OH, 14 min) Desired fractions
  6. customevaporated in vacuo

Sources & evidence

ORD record
ord-b28a3a5791b04bc18793d0e8846d8470
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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