反应详情

温度

-78 °C

A solution of tert-butyl 2-phenylacetate (8.5 g, 44.2 mmol) in THF (400 mL) in a 1 L round-bottomed flask was cooled in −78° C. bath and treated with a solution of KHMDS, 0.5M in toluene (97 mL, 48.6 mmol) via cannula over 10 minutes. After 10 minutes the mixture was removed from the bath and placed in a room temperature water bath and stirred for 15 minutes and then again cooled in −78° C. bath. After 15 minutes a solution of Preparation 4D (R)-benzyl 5,5,5-trifluoro-2-(((trifluoromethyl)sulfonyl)oxy)pentanoate (19.18 g, 48.6 mmol) in THF (50 mL) in a 100 ml, round bottom flask was added over 10 min via cannula with a 20 mL THF rinse. The reaction mixture turned cloudy. The reaction mixture was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The mixture was removed from −78° C. bath, diluted with 10% LiCl aq and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated. The resulting light brown residue was dissolved in 100 mL CH2Cl2 and treated with charcoal and MgSO4. The mixture was filtered to give an almost colorless solution. The CH2Cl2 solution was concentrated and diluted with hexane and cooled in −20° C. freezer. The resulting solids were filtered and rinsed with cold hexane (containing 5% MTBE) and dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g. The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour and then cooling at −20° C. for 3 hours before filtering the white solid and washing with cold solvent (10:1 hexane:MTBE) to give (2R,3R)-1-benzyl 4-tert-butyl 3-phenyl-2-(3,3,3-trifluoropropyl)succinate (7.16 g, 37% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.32-7.23 (m, 8H), 7.05-6.97 (m, 2H), 4.89-4.76 (m, 2H), 3.69 (d, J=11.4 Hz, 1H), 3.23 (ddd, J=11.2, 9.9, 3.9 Hz, 1H), 2.19-2.04 (m, 2H), 2.03-1.88 (m, 2H), 1.40 (s, 9H).

1. customAfter 10 minutes the mixture was removed from the bath
2. customplaced in a room temperature
3. washrinse
4. stirringThe reaction mixture was stirred at −78° C. for 1 hour
5. customquenched with saturated aqueous NH4Cl
6. customThe mixture was removed from −78° C. bath
7. additiondiluted with 10% LiCl aq
8. extractionextracted with Et2O
9. dry with materialThe organic layer was dried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated
12. dissolutionThe resulting light brown residue was dissolved in 100 mL CH2Cl2
13. additiontreated with charcoal and MgSO4
14. filtrationThe mixture was filtered
15. customto give an almost colorless solution
16. concentrationThe CH2Cl2 solution was concentrated
17. additiondiluted with hexane
18. temperaturecooled in −20° C. freezer
19. filtrationThe resulting solids were filtered
20. washrinsed with cold hexane (containing 5% MTBE)
21. customdried on a fitted
22. filtrationfilter funnel under a stream of nitrogen
23. customto give 8.16 g
24. customThe solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour
25. temperaturecooling at −20° C. for 3 hours
26. filtrationbefore filtering the white solid
27. washwashing with cold solvent (10:1 hexane:MTBE)