2-Aminothiazole → 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide

Temperature

0 °C

A solution of triphenylphosphine (409 mg, 1.56 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (277 mg, 1.56 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (370 mg, 0.92 mmol) in methylene chloride (5 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 2 h. The reaction mixture was then treated with 2-aminothiazole (276 mg, 2.76 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 (100 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide (83 mg, 18%) as an amorphous solid: EI-HRMS m/e calcd for C20H20ClF3N6OS (M+) 484.1060, found 484.1068.

1. stirringThe clear solution was stirred for 15 min at 0° C.
2. temperatureto warm to 25° C. where it
3. stirringwas stirred for 2 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 (100 mL)
8. customThe two layers were separated
9. extractionthe aqueous layer was extracted with ethyl acetate (1×50 mL)
10. washThe combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL)
11. dry with materiala saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-6d0376b0b5e4417fa41e60080ef3ef88

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06369232B1