4-Fluoro-N-methoxy-N-methylbenzamide → (4-Fluoro-phenyl)-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-methanone

HRID 1038649Notes

Reaction equation

HRID 1038649 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.C([Li])CCC.[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33](N(OC)C)=[O:34])=[CH:31][CH:30]=1>CCOCC>[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33]([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)=[O:34])=[CH:31][CH:30]=1

Participants

5

Reactant 3

HCID 140693474-Fluoro-N-methoxy-N-methylbenzamideHCID 581118453-Bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridineHCID 178418339Butyllithium

Product 1

HCID 69810699(4-Fluoro-phenyl)-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-methanoneYield 95.3%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-73 °C

Procedure

To a solution of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (3) (6.0 g, 16.6 mmole) in 100 mL of ether at −73° C., is added a solution of butyl lithium (7.3 mL, 18.3 mmole, 2.5 M in hexane) slowly (maintaining internal T<−70° C.). After stirring at −73° C. for 30 minutes, a solution of 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (4.56 g, 24.9 mmole) in 15 mL of ether is added slowly (maintaining internal T<−70° C.). After stirring at −70° C. for 1.5 hours, the reaction is quenched by addition of 20 mL of water and warmed to room temperature with stirring. The resulting mixture is diluted with 100 mL of EtOAc and washed with 2×30 mL of water. The organic layer is concentrated and purified by flash column chromatography (CH2Cl2 95%, EtOAc 5%) to give (4-fluoro-phenyl)-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-methanone (4) (6.4 g, yield 86%) as a light brown viscose liquid.

Workup

  1. temperature(maintaining internal T<−70° C.)
  2. stirringAfter stirring at −70° C. for 1.5 hours
  3. customthe reaction is quenched by addition of 20 mL of water
  4. temperaturewarmed to room temperature
  5. stirringwith stirring
  6. additionThe resulting mixture is diluted with 100 mL of EtOAc
  7. washwashed with 2×30 mL of water
  8. concentrationThe organic layer is concentrated
  9. custompurified by flash column chromatography (CH2Cl2 95%, EtOAc 5%)

Sources & evidence

ORD record
ord-102f38c6aa6b46b48346a3a0956b3d07
Source dataset
uspto-grants-2013_10
Patent number
US08552003B2

Reaction notes

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