Potassium Phosphate, Tribasic → Ethyl 2-{4-[(9R)-9-hydroxy-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionate

Temperature

100 °C

Under an argon atmosphere, (9R)-4-chloro-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-9-ol (49.5 g) was dissolved in toluene (445 ml), ethyl 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate (59.2 g), water (149 ml), tripotassium phosphate (54.3 g), palladium acetate (2.9 g) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) (10.5 g) were added, and the mixture was stirred at an oil bath temperature of 100° C. for 3.5 hr. The reaction mixture was cooled to room temperature, and water (300 ml) was added. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (150 ml) and water (50 ml). The obtained filtrates were combined to allow for layer separation. The obtained organic layer was washed successively with water (500 ml) and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture of (hexane:ethyl acetate) at a mixing ratio 2:1, and then with the mixture at a mixing ratio 1:1, and further with the mixture at a mixing ratio 1:2), and further purified by silica gel column chromatography (a mixture of hexane and acetone was used as an elution solvent, first eluted with a mixture of (hexane:acetone) at a mixing ratio 2:1, and then with the mixture at mixing ratios 4:1, 3:1, 2:1, 1:1, 2:3, and further with the mixture at a mixing ratio 1:2) to give the title compound (68.4 g).

1. temperatureThe reaction mixture was cooled to room temperature
2. filtrationThe insoluble material was filtered off through celite
3. washthe insoluble material was washed with toluene (150 ml) and water (50 ml)
4. customto allow for layer separation
5. washThe obtained organic layer was washed successively with water (500 ml) and saturated brine (500 ml)
6. dry with materialThe obtained organic layer was dried over anhydrous sodium sulfate
7. filtrationthe insoluble material was filtered off
8. customthe solvent in the filtrate was evaporated
9. customThe obtained residue was purified by silica gel column chromatography (
10. additiona mixture of hexane and ethyl acetate
11. washfirst eluted with a mixture of (hexane:ethyl acetate) at a mixing ratio 2:1
12. customwith the mixture at a mixing ratio 1:1, and further with the mixture at a mixing ratio 1:2), and further purified by silica gel column chromatography (
13. additiona mixture of hexane and acetone
14. washfirst eluted with a mixture of (hexane:acetone) at a mixing ratio 2:1
15. additionwith the mixture at mixing ratios 4:1, 3:1, 2:1, 1:1, 2:3

ORD record

ord-8d348db1cd6f40149cc647375318ec0a

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040717B2