1-Methyl-3-pyrrolidinol → (Racemic) 6-amino-4-((1-methylpyrrolidin-3-yl)oxy)nicotinonitrile
Reaction equation
[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:18][C:19]1[CH:26]=[C:25](F)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CC(N(C)C)=O.CCOC(C)=O.O>[NH2:18][C:19]1[CH:26]=[C:25]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)[C:22]([C:23]#[N:24])=[CH:21][N:20]=1Participants
Reactant 3
Product 1
Reagents, catalysts & solvents 3
Conditions
- Temperature
- 100 °C
Procedure
1-methylpyrrolidin-3-ol (89 mg, 0.875 mmol) was treated at room temperature with KHMDS (1 M in THF, 0.788 ml, 0.788 mmol). The reaction mixture was stirred for 10 min, then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 60 mg, 0.438 mmol) in DMA (1 ml). The mixture was then heated at 100° C. for 40 min, cooled to room temperature, diluted with EtOAc and water. The layers were separated and aq. layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a light brown wax. (UPLC-MS 3) tR 0.27 min; ESI-MS 219.1 [M+H]+.
Workup
- temperaturecooled to room temperature
- customThe layers were separated
- extractionaq. layer was extracted with EtOAc (3×)
- dry with materialThe combined organic layers were dried over Na2SO4
- filtrationfiltered
- concentrationconcentrated
- customThe crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100)
Sources & evidence
- ORD record
- ord-b52446a0592e47529a352909a6da1b4b
- Source dataset
- uspto-grants-2016_02
- Patent number
- US09266883B2
Reaction notes
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