Sodium Hydroxide → (R)-3-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)-5-methylisoquinolin-1(2H)-one

(R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methylisocoumarin hydrochloride (62 g) and acetic acid (186 mL) were added and ammonium carbonate (74.4 g) was gradually added to the mixture with stirring. After bubbling, the reaction mixture was heated and stirred at 130° C. for 2 hr with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature and aqueous sodium hydroxide (140 g) solution (200 mL) was added. The mixture was stirred at 80° C., and after the completion of the reaction, the reaction mixture was concentrated. The methanol fraction was evaporated and the mixture was extracted twice with chloroform. The organic layer was extracted twice with 3N hydrochloric acid (300 mL and 100 mL), and potassium carbonate was added to the aqueous layer to basify the layer. The aqueous layer was extracted twice with chloroform, and the extract was dried over magnesium sulfate. The solvent was concentrated and ethyl acetate was added to the obtained residue. The mixture was further concentrated and the residue was dissolved in a small amount of ethyl acetate with heating. Diethyl ether was added to the solution and the precipitated crystals were collected by filtration to give (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (41.5 g).

1. customAfter bubbling
2. temperaturethe reaction mixture was heated
3. stirringstirred at 130° C. for 2 hr
4. temperaturewith heating
5. customAfter the completion of the reaction
6. stirringThe mixture was stirred at 80° C.
7. customafter the completion of the reaction
8. concentrationthe reaction mixture was concentrated
9. customThe methanol fraction was evaporated
10. extractionthe mixture was extracted twice with chloroform
11. extractionThe organic layer was extracted twice with 3N hydrochloric acid (300 mL and 100 mL), and potassium carbonate
12. additionwas added to the aqueous layer
13. extractionThe aqueous layer was extracted twice with chloroform
14. dry with materialthe extract was dried over magnesium sulfate
15. concentrationThe solvent was concentrated
16. additionethyl acetate was added to the obtained residue
17. concentrationThe mixture was further concentrated
18. dissolutionthe residue was dissolved in a small amount of ethyl acetate
19. temperaturewith heating
20. additionDiethyl ether was added to the solution
21. filtrationthe precipitated crystals were collected by filtration

ORD record

ord-636cf8c24d5f47c0abc48e9995a902e6

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07459465B2