2-Aminothiazole → 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide

Temperature

0 °C

A solution of triphenylphosphine (100 mg, 0.38 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (68 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (85 mg, 0.22 mmol) in methylene chloride (3 mL). 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-aminothiazole (55 mg, 0.55 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 (30 mL) and a 1N aqueous hydrochloric acid solution (25 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 1N aqueous hydrochloric acid solution (1×50 mL), 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 (FLASH 40S, Silica, 2/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide (42 mg, 41%) as a white solid: mp 148-154° C.; EI-HRMS m/e calcd for C20H24N6O3S2 (M+) 460.1351, found 460.1356.

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 (30 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 1N aqueous hydrochloric acid solution (1×50 mL)
11. dry with materiala saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-b57d6447709a4d86830bf1227835c9db

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06369232B1