Hydrochloric Acid → Methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-ethylbutanoate

Temperature

45 °C

A mixture of methyl 2-amino-2-ethylbutanoate hydrochloride from Step A (2.10 g, 11.6 mmol), 3,5-difluorophenacyl bromide (2.99 g, 12.7 mmol), and NaHCO3 (2.43 g, 28.9 mmol) in DMF (20 mL) was stirred at 45° C. for 1 h, and at ambient temperature for 2 h. 1 N aqueous HCl (50 mL) was added and the mixture was extracted with EtOAc (75 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 10 by addition of saturated aqueous Na2CO3 (150 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were treated with CF3CO2H (1.5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=300 (M+1).

1. waitat ambient temperature for 2 h
2. extractionthe mixture was extracted with EtOAc (75 mL)
3. extractionthis organic extract
4. additionThe aqueous layer was adjusted to pH 10 by addition of saturated aqueous Na2CO3 (150 mL)
5. additionwas added
6. extractionthe mixture was extracted with EtOAc (3×75 mL)
7. additionThe combined organic layers were treated with CF3CO2H (1.5 mL)
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe crude product was purified by HPLC
12. washeluting with a gradient of H2O
13. extractionextracted with EtOAc
14. dry with materialThe organic extracts were dried over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated in vacuo

ORD record

ord-f46fa5e5724e47f0a66586c1d131ac99

Source dataset

uspto-grants-2009_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07625901B2