Reaction equation
[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[C:16]([F:27])=[CH:17][N:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[N:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]Participants
Procedure
Diethyl malonate (12.4 mL, 81.7 mmol) was added to a suspension of NaH (3.0 g, 47.9 mmol, 60% in mineral oil) in dioxane (35 mL). The mixture was stirred at rt for 5 min and then heated at 80° C. for 1 h. After cooling to rt, CuBr (1.4 g, 9.6 mmol) and 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (7.0 g, 27.2 mmol, prepared according to WO 2007/122258) were added. The mixture was stirred at 100° C. for 6 h. After cooling to rt, 10% NaHSO4 (100 mL) was added. The mixture was stirred for 30 min at rt. The two layers were decanted and the aq. layer was extracted three times with EA (3×150 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 3:1 then 1:1) to afford the title intermediate as a yellow oil (8.22 g, 90% yield).
Workup
- temperatureheated at 80° C. for 1 h
- temperatureAfter cooling to rt
- stirringThe mixture was stirred at 100° C. for 6 h
- temperatureAfter cooling to rt
- stirringThe mixture was stirred for 30 min at rt
- customThe two layers were decanted
- extractionthe aq. layer was extracted three times with EA (3×150 mL)
- washlayers were washed with brine
- dry with materialdried over Na2SO4
- filtrationfiltered
- concentrationconcentrated to dryness
- customThe residue was purified by CC (Hept-EA 3:1
Sources & evidence
- ORD record
- ord-3b512a5083db4f8b8253aafef9ab4677
- Source dataset
- uspto-grants-2016_05
- Patent number
- US09346804B2
Linked notes
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