Cesium carbonate → HCID 67490824, compound

Temperature

95 °C

To a solution of tris(dibenzylideneacetone)dipalladium (0) (414 mg, 0.452 mmol) and 4,5-bis(diphenyl)phosphino-9,9-dimethylxanthene (522 mg, 0.902 mmol) in 1,4-dioxane (20.0 ml) were added ethyl 7-bromo-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.28 g, 3.31 mmol), (1R,5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo[3.2.0]heptane (693 mg, 3.01 mmol) and cesium carbonate (1.96 g, 6.02 mmol) and the mixture was stirred at 95° C. for 14 hours under nitrogen atmosphere. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate; 100:0→95:5→90:10→75:25→5:95→0:100) to afford a pale yellow solid. To a solution of this solid in ethanol (15.9 ml) was added 1 mol/l aqueous solution of sodium hydroxide (5.98 ml) in an ice bath and the mixture was stirred at room temperature for 13 hours. To this reaction solution was added 1 mol/l aqueous solution of hydrochloric acid (5.98 ml) in an ice bath and the organic layer was concentrated under reduced pressure. The aqueous solution was diluted with water (80 ml) and extracted with ethyl acetate (100 ml×1, 80 ml×1). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2→97:3→96:4→95:5→94:6→93:7) to afford a pale yellow solid. The solid was dissolved in concentrated hydrochloric acid (3.0 ml) in an ice bath and the aqueous solution was washed with chloroform (40 ml×4). To the aqueous layer was added saturated solution of sodium hydroxide to adjust pH to 12.0 and the basic aqueous solution was adjusted with hydrochloric acid to pH 7.4. The solution was extracted with chloroform (250 ml×4). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to afford the title compound 690 mg (56%) as pale yellow solid.

1. extractionextracted with ethyl acetate (100 ml×2)
2. dry with materialThe organic layer was dried with anhydrous sodium sulfate
3. concentrationconcentrated under reduced pressure
4. customThe residue was purified by silica gel column chromatography (n-hexane-ethyl acetate; 100:0→95:5→90:10→75:25→5:95→0:100)
5. customto afford a pale yellow solid
6. stirringthe mixture was stirred at room temperature for 13 hours
7. concentrationthe organic layer was concentrated under reduced pressure
8. additionThe aqueous solution was diluted with water (80 ml)
9. extractionextracted with ethyl acetate (100 ml×1, 80 ml×1)
10. dry with materialThe organic layer was dried with anhydrous sodium sulfate
11. concentrationconcentrated under reduced pressure
12. customThe residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2→97:3→96:4→95:5→94:6→93:7)
13. customto afford a pale yellow solid
14. washthe aqueous solution was washed with chloroform (40 ml×4)
15. additionTo the aqueous layer was added saturated solution of sodium hydroxide
16. extractionThe solution was extracted with chloroform (250 ml×4)
17. dry with materialThe organic layer was dried with anhydrous sodium sulfate
18. concentrationconcentrated under reduced pressure
19. customThe residue was purified by recrystallization from ethanol

ORD record

ord-ea6ce067d7744297b7444d209fe966fb

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618094B2