Lithium Hexamethyldisilazide → (S)-3-(2'-amino-3-(3,3-difluoropyrolidin-1-yl)-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazole]-7-yl)benzonitrile
Reaction equation
[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[CH:18]=[C:17](Cl)[N:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[CH:10][CH:11]=3)[N:6]=1.Cl.[F:30][C:31]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>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].C1COCC1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[CH:18]=[C:17]([N:33]4[CH2:34][CH2:35][C:31]([F:36])([F:30])[CH2:32]4)[N:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[CH:10][CH:11]=3)[N:6]=1Participants
7
Reactant 4
Product 1
Reagents, catalysts & solvents 2
Conditions
- Temperature
- 90 °C
Procedure
To a mixture of (S)-3-(2′-amino-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazole]-7-yl)benzonitrile (0.10 g, 0.257 mmol), 3,3-difluoropyrrolidine hydrochloride (0.111 g, 0.772 mmol), pd2(dba)3 (0.012 g, 0.013 mmol), and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.015 g, 0.039 mmol) in a resealed tube was added THF (1 mL) and 1.0 M lithium bis(trimethylsilyl)amide (1.543 mL, 1.543 mmol). The resulting mixture was heated at 90° C. for 17 h. The mixture was cooled, concentrated and purified by reverse phase HPLC to afford (S)-3-(2′-amino-3-(3,3-difluoropyrolidin-1-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazole]-7-yl)benzonitrile.
Workup
- temperatureThe mixture was cooled
- concentrationconcentrated
- custompurified by reverse phase HPLC
Sources & evidence
- ORD record
- ord-2040d90e89644ea6a7feefb40291e9c0
- Source dataset
- uspto-grants-2014_11
- Patent number
- US08883782B2
Reaction notes
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