Hydrochloric Acid → 2-(6-Hydroxy-1-benzofuran-3-yl)acetic acid

Temperature

60 °C

Sodium hydroxide (135 g) was dissolved in water (830 mL) to prepare a 14% aqueous sodium hydroxide solution. To a solution (623 mL) of 4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (254 g) in water was added the above-mentioned 14% aqueous sodium hydroxide solution at 5° C., and the mixture was stirred at 25° C. for 1 hr and at 60° C. for 4 hr. The concentrated hydrochloric acid (270 mL) was added at 35° C., a seed crystal was added, and the reaction mixture was stirred at 35° C. for 1 hr and at 5° C. for 1 hr. The precipitated crystals were collected by filtration, washed with water (123 mL), and dried at 60° C. under reduced pressure. To the crystals was added ethyl acetate (1.9 L), and the mixture was stirred at room temperature for 1 hr. After filtration, the insoluble material was washed with ethyl acetate (144 mL). To the filtrate was added activated carbon (16.5 g), and the mixture was stirred at 25° C. for 1 hr and filtered again. The filtrate was concentrated and dried under reduced pressure to give (6-hydroxy-1-benzofuran-3-yl)acetic acid (146 g). (6-Hydroxy-1-benzofuran-3-yl)acetic acid (130 g) was dissolved in methanol (270 mL), a solution of (1R)-1-phenylethylamine (82 g) in methanol (90 mL) was added at 60° C., and diisopropyl ether (3.6 L) was added at 55° C. After stirring at 25° C. for 2 hr, the precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent (445 mL) of methanol-diisopropyl ether (1:9), and dried at 50° C. under reduced pressure to give the title compound (198 g) as white crystals.

1. additiona seed crystal was added
2. stirringthe reaction mixture was stirred at 35° C. for 1 hr and at 5° C. for 1 hr
3. filtrationThe precipitated crystals were collected by filtration
4. washwashed with water (123 mL)
5. customdried at 60° C. under reduced pressure
6. additionTo the crystals was added ethyl acetate (1.9 L)
7. stirringthe mixture was stirred at room temperature for 1 hr
8. filtrationAfter filtration
9. washthe insoluble material was washed with ethyl acetate (144 mL)
10. additionTo the filtrate was added activated carbon (16.5 g)
11. stirringthe mixture was stirred at 25° C. for 1 hr
12. filtrationfiltered again
13. concentrationThe filtrate was concentrated
14. customdried under reduced pressure

ORD record

ord-8e87088cc0f9462e8546583a5c475bec

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08952185B2