Methyl Acetate → (S)-methyl 3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorobutanoate

Temperature

0 °C

A flame dried RBF equipped with an addition funnel was charged with DIPA (9.32 ml, 66.5 mmol, Aldrich) and THF (70 ml). The solution was cooled to 0° C. before adding a solution of n-butyllithium (2.5M in hexanes; 26.8 ml, 67 mmol, Aldrich) drop wise. The reaction was stirred at 0° C. for 15 minutes then cooled to −78° C. A solution of methyl acetate (4.9 g, 66.5 mmol, Aldrich) in THF (25 ml) was added dropwise via cannula to the LDA solution at −78° C. After 30 minutes, a solution of chlorotitanium triisopropoxide, (18.5 g, 71.0 mmol, Aldrich) in THF (70 ml) was added drop wise via cannula and the reaction was stirred at −78° C. After 1 h, a solution of (R)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (15.0 g, 27.1 mmol, step 3) in THF (100 ml), was added drop wise via cannula at −78° C. and the reaction was stirred at −78° C. for 45 minutes. The reaction was quenched with aqueous, saturated ammonium chloride solution, diluted with water and EtOAc and stirred vigorously for 20 minutes. The reaction was filtered through celite and the filter cake was washed with additional EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography using a solvent gradient of 10-60% acetone in hexanes to afford the title compound as a light yellow oil (12.0 g, 29.1 mmol, 65.6% yield, dr: 97:3 by LC/MS). MS m/z=411.9 M+. Calculated for C15H20BrF2NO3S: 412.290

1. customA flame dried RBF
2. customequipped with an addition funnel
3. additionwas charged with DIPA (9.32 ml, 66.5 mmol, Aldrich) and THF (70 ml)
4. temperaturethen cooled to −78° C
5. waitAfter 30 minutes
6. stirringthe reaction was stirred at −78° C
7. waitAfter 1 h
8. stirringthe reaction was stirred at −78° C. for 45 minutes
9. customThe reaction was quenched with aqueous, saturated ammonium chloride solution
10. additiondiluted with water and EtOAc
11. stirringstirred vigorously for 20 minutes
12. filtrationThe reaction was filtered through celite
13. washthe filter cake was washed with additional EtOAc
14. customThe organic layer was separated
15. washwashed with brine
16. dry with materialdried over MgSO4
17. concentrationconcentrated under reduced pressure
18. customThe crude material was purified via silica gel flash chromatography

ORD record

ord-f75050b9f0624dd59ebb10a88815b0e4

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296734B2