Lithium Hexamethyldisilazide → 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

Temperature

-50 °C

N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 14, 5.72 g, 22.8 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL) and the suspension cooled to −50° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (34.1 mL, 34.1 mmol) was added slowly over 15 minutes. This suspension was stirred at −50° C. for 5 minutes, warmed to 10° C. then cooled again to −78° C. A solution of 3-cyano-4-fluorobenzene-1-sulfonyl chloride (10 g, 45.5 mmol) in tetrahydrofuran (20 mL) was then added drop wise. The pale orange solution was allowed to warmed to 20° C. for 18 hours. The reaction was quenched with an aqueous solution of saturated ammonium chloride (50 mL) and stirred vigorously for 5 minutes. Ethyl acetate (100 mL) was added and the layers separated. The organic layer was washed with water (100 mL) and concentrated in vacuo to give an orange gum. The gum was dissolved in ethyl acetate and eluted through a silica plug before being purified by silica gel column chromatography (ISCO™, 50% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (2.96 g).

1. temperaturewarmed to 10° C.
2. temperaturethen cooled again to −78° C
3. temperatureto warmed to 20° C. for 18 hours
4. customThe reaction was quenched with an aqueous solution of saturated ammonium chloride (50 mL)
5. stirringstirred vigorously for 5 minutes
6. additionEthyl acetate (100 mL) was added
7. customthe layers separated
8. washThe organic layer was washed with water (100 mL)
9. concentrationconcentrated in vacuo
10. customto give an orange gum
11. washeluted through a silica plug
12. custombefore being purified by silica gel column chromatography (ISCO™, 50% ethyl acetate in heptane)

ORD record

ord-54162c2e962247e9a0a2783901caa675

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08772293B2