Triphenylphosphine → (E)-N-(5-bromo-pyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide

Temperature

0 °C

A solution of triphenylphosphine (525 mg, 2 mmol) in methylene chloride (12 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (356 mg, 2 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (prepared in Example 12, 376 mg, 1 mmol). The reaction mixture was stirred at 25° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (519 mg, 3 mmol), and the resulting suspension was stirred for 3 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 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 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded the (E)-N-(5-bromo-pyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (44 mg, 8.3%) as an amorphous solid: EI-HRMS m/e calcd for C22H22BrF3N2O3S (M+) 530.0487, found 530.0484.

1. stirringThe reaction mixture was stirred at 25° C. for 15 min
2. temperatureto warm to 25° C. where it
3. stirringwas stirred for 1.5 h
4. stirringthe resulting suspension was stirred for 3 d at 25° C
5. concentrationThe reaction mixture was concentrated in vacuo
6. customto remove methylene chloride
7. additionthe residue was diluted with ethyl acetate (50 mL)
8. customThe two layers were separated
9. extractionthe aqueous layer was extracted with ethyl acetate (1×30 mL)
10. washThe combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL)
11. dry with materialThe organic layer was then dried over anhydrous magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-8add7bbe1e5440dbbd2c20cd7d0afad5

Source dataset

uspto-grants-2002_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06353111B1