Triphenylphosphine → N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide

Temperature

0 °C

A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (prepared in Example 1, 175 mg, 0.55 mmol). The clear solution was stirred for 15 min at 0° C. 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 (476 mg, 2.75 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 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), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FTASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide (190 mg, 73%) as a white solid: mp 73-78° C.; EI-HRMS m/e calcd for C21H22BrFN6O (M+) 472.1022, found 472.1022.

1. stirringThe clear solution was stirred for 15 min at 0° C.
2. temperatureto warm to 25° C. where it
3. stirringwas stirred for 1.5 h
4. stirringthe resulting suspension was stirred for 2 d at 25° C
5. concentrationThe reaction mixture was then concentrated in vacuo
6. customto remove methylene chloride
7. additionthe residue was diluted with ethyl acetate (50 mL) and water (50 mL)
8. customThe two layers were separated
9. extractionthe aqueous layer was extracted with ethyl acetate (1×25 mL)
10. washThe combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL)
11. dry with materiala saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-c31ead4ba2d044e9829944600d8fdcff

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06369232B1