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

Temperature

70 °C

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.

1. temperaturebefore cooling
2. stirringstirring
3. waitcontinued for 18 hours
4. additionThis mixture was added to
5. stirringa pre-stirred
6. stirringThe reaction mixture was stirred at room temperature for 2 hours
7. extractionThe aqueous layer was extracted with ethyl acetate (3×10 mL)
8. dry with materialThe combined organic layers were dried over magnesium sulfate
9. concentrationconcentrated in vacuo
10. customto obtain a residue that
11. customwas purified
12. washeluting with heptane:ethyl acetate (1:0 to 4:6, by volume)
13. dissolutionThe residue was dissolved in dichloromethane (3 mL)
14. additiontrifluoroacetic acid (3 mL) was added
15. stirringAfter stirring for 1 hour at room temperature
16. additionmethanol (20 mL) was added
17. filtrationthe resulting precipitate was filtered
18. concentrationthe filtrate concentrated in vacuo
19. customThe crude material was purified

ORD record

ord-3dddf41ee66e46e0b40e156d76ce4b97

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541588B2