반응 #74526

반응 방정식

4-iodotetrahydro-2H-pyran

lithium chloride

3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine

ammonium chloride

dibromoethane

chlorotrimethlsilane

→

title compound

3-Cyano-4-[2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

용매

tetrahydrofuran

tetrahydrofuran

반응 조건

후처리

1. 1
   온도before cooling
2. 2
   workup.STIRRINGstirring
3. 3
   workup.WAITcontinued for 18 hours
4. 4
   workup.ADDITIONThis mixture was added to
5. 5
   workup.STIRRINGa pre-stirred
6. 6
   workup.STIRRINGThe reaction mixture was stirred at room temperature for 2 hours
7. 7
   추출The aqueous layer was extracted with ethyl acetate (3×10 mL)
8. 8
   건조The combined organic layers were dried over magnesium sulfate
9. 9
   농축concentrated in vacuo
10. 10
    기타to obtain a residue that
11. 11
    기타was purified
12. 12
    세척eluting with heptane:ethyl acetate (1:0 to 4:6, by volume)
13. 13
    workup.DISSOLUTIONThe residue was dissolved in dichloromethane (3 mL)
14. 14
    workup.ADDITIONtrifluoroacetic acid (3 mL) was added
15. 15
    workup.STIRRINGAfter stirring for 1 hour at room temperature
16. 16
    workup.ADDITIONmethanol (20 mL) was added
17. 17
    여과the resulting precipitate was filtered
18. 18
    농축the filtrate concentrated in vacuo
19. 19
    기타The crude material was purified

실험 절차

To a suspension of zinc dust (458 mg, 7.00 mmol) and lithium chloride (212 mg, 5.00 mmol) in tetrahydrofuran was added dibromoethane (0.043 mL, 0.50 mmol) under nitrogen. The mixture was heated at 70° C. for 10 minutes before cooling and adding chlorotrimethlsilane (0.013 mL, 0.10 mmol). The reaction mixture was stirred for 1 hour then 4-iodotetrahydro-2H-pyran (1060 mg, 5.00 mmol) was added and stirring continued for 18 hours. This mixture was added to a pre-stirred (10 minutes) suspension of 3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 429, 11 mg, 0.3 mmol), palladium(II) acetate (6.7 mg, 0.03 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (24.6 mg, 0.06 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours before pouring into saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to obtain a residue that was purified using an ISCO™ system eluting with heptane:ethyl acetate (1:0 to 4:6, by volume). The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was added. After stirring for 1 hour at room temperature, methanol (20 mL) was added and the resulting precipitate was filtered and the filtrate concentrated in vacuo. The crude material was purified using preparative HPLC to afford the title compound.

출처