N-methyl-2-pyrrolidone → (S)-tert-butyl 3-((6-bromo-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate
Reaction equation
[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Br:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24]C=2)[CH:20]=[C:19](Br)[N:18]=1.C[N:29]1CCCC1=O>O>[Br:16][C:17]1[CH:26]=[C:21]2[C:20](=[C:19]([O:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[N:18]=1)[N:29]=[CH:24][CH:23]=[CH:22]2Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- 160 °C
Procedure
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (890 mg, 4.75 mmol) in N-methyl-2-pyrrolidinone (16 mL) at 0° C. was added NaH (60%) (158.4 mg, 3.96 mmol). The mixture was stirred for 5 minutes. Next, 1,3-dibromoisoquinoline (1139 mg, 3.96 mmol) was added and the reaction mixture was stirred at RT for 5 minutes and then heated in a microwave reactor at 135° C. for 30 minutes and at 160° C. at for another 30 minutes. The mixture was subsequently diluted with water and extracted with EtOAc (2×). The organic phase was separated, dried over Na2SO4, and concentrated. The crude product was purified by silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane over a 45 minute period to give the title compound (1.3 g, 70% from two batches).
Workup
- stirringthe reaction mixture was stirred at RT for 5 minutes
- extractionextracted with EtOAc (2×)
- customThe organic phase was separated
- dry with materialdried over Na2SO4
- concentrationconcentrated
- customThe crude product was purified by silica column chromatography
- washeluting with a gradient of 0-75% EtOAc in hexane over a 45 minute period
Sources & evidence
- ORD record
- ord-e5e88b268cd34b499075f4411f33647b
- Source dataset
- uspto-grants-2016_08
- Patent number
- US09402841B2
Reaction notes
Loading…