Réaction #155558

Équation de réaction

N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Triethylamine

nonafluorobutanesulfonyl fluoride

→

title compound

Rendement 65.6%

N-((4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Rendement 65.6%

Solvants

THF

Conditions de réaction

Traitement

1. 1
   Autreremoved from the ice bath
2. 2
   workup.WAITAfter 120 minutes at RT
3. 3
   Autrethe reaction was quenched with saturated aqueous NaHCO3 (25 mL)
4. 4
   AutreThe THF was removed in vacuo
5. 5
   Autrethe mixture was partitioned between EtOAc and water
6. 6
   AutreThe layers were separated
7. 7
   Extractionthe aqueous layer was further extracted with EtOAc (×2)
8. 8
   LavageThe combined extracts were washed with brine (×1)
9. 9
   Séchagedried (Na2SO4)
10. 10
    Filtrationfiltered
11. 11
    Autreevaporated
12. 12
    workup.ADDITIONThe residue was treated with DCM (˜20 mL)
13. 13
    Autreto give a gelatinous precipitate
14. 14
    FiltrationThis mixture was filtered
15. 15
    Lavage(washing with DCM)
16. 16
    ConcentrationThe filtrate was concentrated to ˜3 mL
17. 17
    Autrepurified by chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per mm, gradient 5% to 35% n-hexane in EtOAc)

Mode opératoire

A solution of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (2.2 g, 5.44 mmol) in dry THF (40 mL) under nitrogen was cooled to 0° C. Triethylamine (4.55 mL, 32.6 mmol), triethylamine tri-hydrogen fluoride (1.77 mL, 10.9 mmol) and nonafluorobutanesulfonyl fluoride (1.95 mL, 10.9 mmol) were then added. The colourless solution was stirred at 0° C. for 10 minutes and then removed from the ice bath. After 120 minutes at RT, the reaction was quenched with saturated aqueous NaHCO3 (25 mL). The THF was removed in vacuo and then the mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was treated with DCM (˜20 mL) to give a gelatinous precipitate. This mixture was filtered (washing with DCM). The filtrate was concentrated to ˜3 mL and loaded directly on to the column and purified by chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per mm, gradient 5% to 35% n-hexane in EtOAc) to give the title compound (1.45 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.97 (br. d, J=13.00 Hz, 1 H) 3.10-3.28 (m, 2 H) 4.02 (br. s., 1 H) 4.45-4.61 (m, 3 H) 4.62-4.71 (m, 1 H) 6.98-7.12 (m, 2 H) 7.40-7.51 (m, 2 H) 7.51-7.62 (m, 2 H) 8.03 (br. s., 2 H).

Source