Methanol → (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid

Temperature

60 °C

(S)-5-cyclopropyl-4,4-difluoro-1-methoxy-1-oxopentan-2-amine hydrochloride (250 mg, 10 mmol), trifluoroacetophenone (179 mg, 10 mmol), potassium carbonate (426 mg, 30 mmol) was charged in isopropanol (10 mL) under nitrogen. The reaction mixture stirred for 20 h at 60° C. When TLC showed an absence of starting material, is the mixture was filtered under hot and the solids were washed with isopropanol (20 mL) and the filtrates were combined and concentrated under reduced pressure. The residue (400 mg, 10 mmol) was dissolved in acetonitrile (5 mL) and methanol (1 mL) and transferred to a dropping funnel under nitrogen. The zinc borohydride suspension prepared as described above was cooled to −45° C. and treated with the imine solution which was added drop-wise and the reaction was stirred at same temperature for 1 h. Once the staring material was consumed, is the reaction mixture was quenched with 1N HCl solution (10 mL) at 0° C. and then allowed to warm to room temperature. The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic extracts washed with water (50 mL) and brine (50 mL). The organic extracts were evaporated under reduced pressure, and the residue re-dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (50 mL). The solution was dried (MgSO4) and the solvent evaporated under reduced pressure to give (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid as a pale oil (265 mg, 71.3%).

1. filtrationwas filtered under hot and the solids
2. washwere washed with isopropanol (20 mL)
3. concentrationconcentrated under reduced pressure
4. temperatureabove was cooled to −45° C.
5. additionwas added drop-wise
6. stirringthe reaction was stirred at same temperature for 1 h
7. customOnce the staring material was consumed
8. customwas quenched with 1N HCl solution (10 mL) at 0° C.
9. temperatureto warm to room temperature
10. extractionThe mixture was extracted with ethyl acetate (3×40 mL)
11. washthe combined organic extracts washed with water (50 mL) and brine (50 mL)
12. customThe organic extracts were evaporated under reduced pressure
13. dissolutionthe residue re-dissolved in ethyl acetate (20 mL)
14. washwashed with water (20 mL) and brine (50 mL)
15. dry with materialThe solution was dried (MgSO4)
16. customthe solvent evaporated under reduced pressure

ORD record

ord-a14cc067458e4bd881fde3dde17c24e8

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08367732B2