Potassium bis(trimethylsilyl)amide → (2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate

Temperature

-78 °C

In a 250 mL round-bottomed flask, a solution of tert-butyl 2-(3-methylisoxazol-4-yl)acetate (1.75 g, 8.87 mmol) in THF (56 mL) and toluene (27 mL) was cooled in a −78° C. bath and treated with a solution of 1M KHMDS (11.09 mL, 11.09 mmol) in THF dropwise over 2 minutes via syringe. After stirring for 15 minutes at −78° C., the reaction mixture was placed in a room temperature water bath for 15 minutes and then placed in a −78° C. bath for another 15 minutes before a solution of Intermediate S5D, (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (4.55 g, 11.53 mmol) in 6 mL THF and 3 mL toluene was added over 2 minutes. The reaction mixture was stirred in −78° C. bath for 2 hours before being quenched with saturated aqueous NH4Cl and then warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 filtered and concentrated. The residue was purified on silica gel column (330 g ISCO) eluting with a gradient of 0-30% EtOAc/CH2Cl2. Tubes were collected containing the product, which was concentrated to afford Intermediate S6A (2.394 g, 61% yield) containing about 30% of the (2R,3S) isomer.

1. customwas placed in a room temperature
2. customfor 15 minutes
3. customplaced in a −78° C.
4. customfor another 15 minutes
5. additionwas added over 2 minutes
6. stirringThe reaction mixture was stirred in −78° C. bath for 2 hours
7. custombefore being quenched with saturated aqueous NH4Cl
8. temperaturewarmed to room temperature
9. additionThe mixture was diluted with brine
10. extractionextracted with EtOAc
11. dry with materialThe organic layer was dried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated
14. customThe residue was purified on silica gel column (330 g ISCO)
15. washeluting with a gradient of 0-30% EtOAc/CH2Cl2
16. customTubes were collected
17. additioncontaining the product, which
18. concentrationwas concentrated
19. customto afford Intermediate S6A (2.394 g, 61% yield)
20. additioncontaining about 30% of the (2R,3S) isomer

ORD record

ord-a1b7f81d44be4b178f58cc88aa8741a2

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09249157B2