反应详情

A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (347 g), 3M hydrochloric acid (1.4 L) and tetrahydrofuran (2.1 L) was stirred under reflux for 16 hr. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate (2 L). The resulting aqueous layer was extracted with ethyl acetate (1 L). The combined extracts were successively washed with saturated aqueous sodium hydrogen carbonate (1 L) and brine (1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in methanol (650 mL) and tetrahydrofuran (960 mL), and the resulting solution was added to a suspension of sodium borohydride (37.3 g) in tetrahydrofuran (1.6 L) with the internal temperature maintained below 10° C. After stirring at the same temperature for 0.5 hr, saturated aqueous ammonium chloride solution (640 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2 L). The organic layer was washed with saturated brine (1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound as a diastereomeric mixture. The diastereomeric mixture obtained was dissolved in ethyl acetate (940 mL) at 50° C. Hexane (1.6 L) was added to the solution, and the resulting mixture was stirred at the same temperature for 2 hr. Additional hexane (940 mL) was added to the mixture, which was cooled to room temperature and stirred for further 0.5 hr. The precipitate was collected by filtration to give the title compound as a white solid (233 g, 73%).

1. temperatureunder reflux for 16 hr
2. extractionextracted with ethyl acetate (2 L)
3. extractionThe resulting aqueous layer was extracted with ethyl acetate (1 L)
4. washThe combined extracts were successively washed with saturated aqueous sodium hydrogen carbonate (1 L) and brine (1 L)
5. dry with materialdried over anhydrous magnesium sulfate
6. concentrationconcentrated under reduced pressure
7. customThe residue obtained
8. temperaturemaintained below 10° C
9. stirringAfter stirring at the same temperature for 0.5 hr
10. customthe solvent was evaporated under reduced pressure
11. extractionThe resulting residue was extracted with ethyl acetate (2 L)
12. washThe organic layer was washed with saturated brine (1 L)
13. dry with materialdried over anhydrous magnesium sulfate
14. concentrationconcentrated under reduced pressure
15. customThe resulting residue was purified by silica gel chromatography