Acetic Acid → (+)-Ethyl [6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]acetate

A mixture of methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-methylpropanoate from Step A (8.60 g, 31.7 mmol), glycine ethyl ester hydrochloride (44.3 g, 317 mmol), and AcOH (5.71 mL, 95 mmol) in MeOH (300 mL) was stirred at ambient temperature for 10 min. NaCNBH3 (2.39 g, 38.0 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary. The reaction mixture was heated to 50° C. for 18 h. Additional AcOH (4 mL) was added and the reaction mixture was heated to 60° C. for 6 h then allowed to cool and concentrated in vacuo to a volume of ca. 150 mL. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (300 mL) and then extracted with CH2Cl2 (1 L). The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=327 (M+1).

1. temperatureThe reaction mixture was heated to 50° C. for 18 h
2. temperaturethe reaction mixture was heated to 60° C. for 6 h
3. temperatureto cool
4. concentrationconcentrated in vacuo to a volume of ca. 150 mL
5. customThe resulting mixture was carefully quenched with saturated aqueous NaHCO3 (300 mL)
6. extractionextracted with CH2Cl2 (1 L)
7. extractionThe organic extract
8. washwas washed with brine
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe crude product was purified by silica gel chromatography
13. washeluting with hexane

ORD record

ord-2eca8ff6a6e64cd487df3214728fdc4c

Source dataset

uspto-grants-2009_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07629338B2