Reaction #499705

Reaction equation

lithium diisopropylamide tetrahydrofuran

1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester

7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester

ammonium chloride

→

title compound

7-[4-Ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic Acid tert-Butyl Ester

Solvents

tetrahydrofuran

tetrahydrofuran

water

Conditions

Workup

1. 1
   workup.STIRRINGin stirring
2. 2
   workup.ADDITIONwere added
3. 3
   Extractionthe mixture was extracted with ethyl acetate
4. 4
   DryingThe organic layer was dried over anhydrous sodium sulfate
5. 5
   Otherthe solvent was evaporated
6. 6
   workup.DISSOLUTIONthe obtained residue was dissolved in methanol (150 ml)
7. 7
   Temperaturecooling
8. 8
   workup.STIRRINGthe mixture was stirred at room temperature for 1 hour
9. 9
   OtherThe solvent was evaporated
10. 10
    Extractionthe obtained residue was extracted with ethyl acetate
11. 11
    Dryingdried over anhydrous sodium sulfate
12. 12
    OtherThe solvent was evaporated
13. 13
    Otherthe obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1-10:1)
14. 14
    Otherdried under reduced pressure

Procedure

To a solution of 1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (Tetrahedron, vol. 44, No. 23, p. 7095 (1988)) (13.4 g) in tetrahydrofuran (300 ml) was dropwise added a 2M-lithium diisopropylamide-tetrahydrofuran solution (31 ml) at −70° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 45 min. To this solution was dropwise added a solution of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (7.4 g) in tetrahydrofuran (80 ml) at the same temperature, and the mixture was allowed to warm to room temperature in 5.5 hours in stirring. After completion of the reaction, aqueous ammonium chloride solution (50 ml) and water (50 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was dissolved in methanol (150 ml). Thereto was dropwise added 1N aqueous sodium hydroxide solution (50 ml) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the obtained residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1-10:1) and dried under reduced pressure to give the title compound (10.87 g).

Source