4-Fluorophenol → 3-(4-Fluoro-phenoxy)-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine

HRID 1038652Notes

Reaction equation

Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O.[Cu]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:7]=2)=[CH:26][CH:25]=1

Participants

Conditions

Temperature: 190 °C

Procedure

The mixture of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (3) (2.0 g, 5.54 mmole), 4-fluorophenol (3.1 g, 27.7 mmole), copper oxide (0.5 g, catalyst) and cesium carbonate (5.4 g, 16.6 mmole) in 10 mL of 1-N-methyl-2-pyrrolidinone is heated to 190° C. in a microwave reactor for 30 minutes. The reaction solution is diluted with 150 mL of EtOAc and filtered through celite. The filtrate is washed with 4×30 mL of water. The organic layer is concentrated and purified by flash column chromatography (hexane 100% to hexane 60% and EtOAc 40% by gradient in 20 minutes)) to give 3-(4-fluoro-phenoxy)-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4) (1.98 g, yield 91%) as a light yellow viscose liquid.

Workup

filtrationfiltered through celite
washThe filtrate is washed with 4×30 mL of water
concentrationThe organic layer is concentrated
custompurified by flash column chromatography (hexane 100% to hexane 60% and EtOAc 40% by gradient in 20 minutes))

Sources & evidence

ORD record: ord-a9accb8c57e84c6fa0e24e30cf1022b6
Source dataset: uspto-grants-2013_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08552003B2

Reaction notes

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