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 −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 again in −78° C. bath for another 15 minutes before a solution of Preparation 4D (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 to the reaction 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, and collected tubes containing product were concentrated to give (2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate (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. additionwas added to the reaction over 2 minutes
4. stirringThe reaction mixture was stirred in −78° C. bath for 2 hours
5. custombefore being quenched with saturated aqueous NH4Cl
6. temperaturewarmed to room temperature
7. additionThe mixture was diluted with brine
8. extractionextracted with EtOAc
9. dry with materialThe organic layer was dried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated
12. customThe residue was purified on silica gel column (330 g ISCO)
13. washeluting with a gradient of 0-30% EtOAc/CH2Cl2
14. customcollected tubes
15. additioncontaining product
16. concentrationwere concentrated

ORD record

ord-29b99e0b8d31428aba53a74e1b16fd64

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133139B2