Water → (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one

Temperature

-78 °C

Diisopropylamine (122 mL) was dissolved in tetrahydrofuran (400 mL), and n-butyllithiun (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and then cooled to −78° C. A solution (150 mL) of N,N-diethyl-2,3-dimethylbenzamide (85.4 g) in tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at −78° C. for 0.5 hr. The reaction mixture was cooled to −78° C. and a solution (150 mL) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran was added dropwise to the mixture. The reaction mixture was allowed to warm to room temperature. After the completion of the reaction, water was added to the reaction mixture and the organic layer was separated and concentrated. The residue was dissolved in chloroform and the solution was washed with saturated brine and dried over magnesium sulfate. The organic layer was extracted with 1N hydrochloric acid, and the layer was basified. The aqueous layer was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (23.6 g).

1. additionn-butyllithiun (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-
2. temperaturecooling
3. temperaturecooling for 30 min
4. stirringthe mixture was stirred at −78° C. for 0.5 hr
5. temperatureThe reaction mixture was cooled to −78° C.
6. temperatureto warm to room temperature
7. additionwas added to the reaction mixture
8. customthe organic layer was separated
9. concentrationconcentrated
10. dissolutionThe residue was dissolved in chloroform
11. washthe solution was washed with saturated brine
12. dry with materialdried over magnesium sulfate
13. extractionThe organic layer was extracted with 1N hydrochloric acid
14. extractionThe aqueous layer was extracted with chloroform
15. dry with materialthe extract was dried over magnesium sulfate
16. concentrationThe solvent was concentrated
17. customthe obtained residue was purified by silica gel column chromatography

ORD record

ord-bfae3f29a8804a43b82bbc0a74fbda9d

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07459465B2