Reaction #1121788

Reaction equation

butyl lithium

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

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

4-fluoro-N-methoxy-N-methyl-benzamide

4-Fluoro-N-methoxy-N-methyl-benzamide

→

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

Yield 95.3%

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

Yield 95.3%

Solvents

ether

ether

Conditions

Workup

1. 1
   Temperature(maintaining internal T<−70° C.)
2. 2
   workup.STIRRINGAfter stirring at −70° C. for 1.5 hours
3. 3
   Otherthe reaction is quenched by addition of 20 mL of water
4. 4
   Temperaturewarmed to room temperature
5. 5
   workup.STIRRINGwith stirring
6. 6
   workup.ADDITIONThe resulting mixture is diluted with 100 mL of EtOAc
7. 7
   Washwashed with 2×30 mL of water
8. 8
   ConcentrationThe organic layer is concentrated
9. 9
   Otherpurified by flash column chromatography (CH2Cl2 95%, EtOAc 5%)

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.

Source