2-Aminothiazole → (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-N-thiazol-2-yl-acrylamide

Temperature

0 °C

A solution of triphenylphosphine (847 mg, 3.2 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (575 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. For 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-acrylic acid (507 mg, 1.9 mmol) in methylene chloride (4 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (476 mg, 4.75 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (75 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (2×30 mL), a saturated aqueous sodium bicarbonate solution (2×30 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 to 4/1 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-N-thiazol-2-yl-acrylamide (520 mg, 78%) as an amorphous solid: EI-HRMS m/e calcd for C18H18F2N2OS (M+) 348.1108, found 348.1104.

1. stirringThe clear solution was stirred for 10 min at 0° C.
2. temperatureto warm to 25° C. where it
3. stirringwas stirred for 1 h
4. stirringthe resulting suspension was stirred for 15 h at 25° C
5. concentrationThe reaction mixture was concentrated in vacuo
6. customto remove methylene chloride
7. additionthe residue was diluted with ethyl acetate (75 mL)
8. washThe organic layer was washed successively with a 1N aqueous hydrochloric acid solution (2×30 mL)
9. dry with materialThe organic layer was then dried over anhydrous magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo

ORD record

ord-27877b8d2b4b4bb5801bba6276f1ed30

Source dataset

uspto-grants-2002_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06353111B1