(Trifluoromethyl)trimethylsilane → HCID 117833456, compound

Temperature

0 °C

Intermediates XVII-1 and XVII-2: In a dry flask under an inert atmosphere a solution of (S)—N—((S)-1,1-difluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (XVI-1) (1.45 g, 4.51 mmol) in THF (30 ml) was treated at 0° C. with (trifluoromethyl)trimethylsilane (1.28 g, 1.33 ml, 9.02 mmol) and dropwise with TBAF (1 M in THF, dried over molecular sieves 4 Å; 0.451 ml, 0.451 mmol). The slightly exothermic addition was completed within 3 min, thereafter the reaction mixture was stirred at 0° C. for 3 h, then left to warm to r.t. and stirred overnight. For the workup, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted three times with AcOEt. The organic layers were washed with brine, dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel (eluent: heptane/AcOEt; gradient: 0-90% AcOEt) to yield the (S)-2-methyl-N-((2S,4R)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-1) (yellow oil, 377 mg as an approximately 7:3-mixture with its O-trimethylsilyl derivative) as the faster eluting epimer, the (S)-2-methyl-N-((2S,4S)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-2) (yellow solid, 209 mg, 12% yield) as the second eluting epimer [MS: m/z=392.5 (M+H)+], and the starting aldehyde (yellow oil, crystallized on standing, 627 mg, 36% yield).

1. additionThe slightly exothermic addition
2. waitleft
3. temperatureto warm to r.t.
4. stirringstirred overnight
5. customFor the workup, the reaction mixture was quenched with a saturated solution of NH4Cl
6. extractionextracted three times with AcOEt
7. washThe organic layers were washed with brine
8. dry with materialdried over MgSO4
9. customevaporated at reduced pressure
10. customThe crude product was purified by chromatography on silica gel (eluent: heptane/AcOEt; gradient: 0-90% AcOEt)

ORD record

ord-235e70540937459c86c9f2b9b07ec990

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09067926B2