Water → [2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cycloheptyl-acetic acid ethyl ester

Temperature

100 °C

To a solution of 2.2 g (8.31 mmol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 1, intermediate a) in 22 ml N,N-dimethyl formamide was added 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester. The reaction mixture was stirred at 100° C. for 1 hour. Then, 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester were added. Stirring was continued at 100° C. for another 6 hours. Another 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester were added and the reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured on 200 ml water and 200 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 200 ml ethyl acetate. The organic layers were washed with 200 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow solid (63%). MS (Turbo Spray): m/z=447.2 [M+H].

1. stirringStirring
2. waitwas continued at 100° C. for another 6 hours
3. stirringthe reaction mixture was stirred at 100° C. for 18 hours
4. customthe layers were separated
5. extractionThe aqueous layer was extracted a second time with 200 ml ethyl acetate
6. washThe organic layers were washed with 200 ml brine
7. dry with materialdried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated under vacuum
10. customThe residue was purified by silica gel chromatography
11. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40)

ORD record

ord-a0158b43fc4746f4a4da043538889681

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08088930B2