Ethyl chloroacetate → (R)-5-(4-fluoro-phenyl)-morpholin-3-one

To a stirring mixture of NaH (1.1 g, 45.7 mmol) in THF (30 mL) at room temperature under N2 atmosphere was added dropwise a solution of (R)-2-amino-2-(4-fluoro-phenyl)-ethanol (5.0 g, 32.2 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. A solution of ethyl chloroacetate (4.0 g, 33 mmol) in THF (30 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes at 0° C., then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue. The resulting mixture was pH adjusted to approximately 6.5 by addition of 1M aqueous HCl, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 2.87 g of (R)-5-(4-fluoro-phenyl)-morpholin-3-one. The mother liquor from the recrystallization was concentrated and purified via chromatography (50-70% ethyl acetate in hexanes) to give an additional 1.0 g of (R)-5-(4-fluoro-phenyl)-morpholin-3-one.

1. temperaturecooled to 0° C
2. stirringthe reaction mixture was stirred for 30 minutes at 0° C.
3. stirringstirred at room temperature for two hours
4. concentrationThe reaction mixture was concentrated under reduced pressure, and water (50 mL)
5. additionwas added to the residue
6. additionThe resulting mixture was pH adjusted to approximately 6.5 by addition of 1M aqueous HCl
7. extractionextracted with ethyl acetate
8. customThe organic layer was separated
9. washwashed with brine
10. dry with materialdried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe residue was recrystallized from diethyl ether

ORD record

ord-e1c7f7e980c14a3c97dca3877aff3af4

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08871760B2