反应详情

温度

50 °C

Cis 1-[(1-(S)-phenylethyl]-4-(1-tert-butoxycarbonylaminocyclobutyl)-3-fluoropyrrolidine (optical isomer B; 1.13 g, 3.12 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 10% palladium-carbon catalyst (water content, 55.6%; 1.0 g) and stirred at 50° C. for 18 hours under a hydrogen atmosphere. The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (10 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (1.18 g, 3.78 mmol) and triethylamine (5 ml) and stirred at 140° C. for 4 days under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (50 ml) and washed with a 10% citric acid aqueous solution (50 ml) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with an eluant of chloroform:methanol 9:1. The eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 30 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative TLC (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1) to obtain a crude title compound, and this was recrystallized from a mixture of ethanol and ether to obtain 157 mg (17%) of the title compound.

1. customThe catalyst was removed by celite filtration (methanol washing)
2. concentrationthe filtrate was concentrated under reduced pressure
3. dissolutionThe thus obtained residue was dissolved in dimethyl sulfoxide (10 ml)
4. stirringstirred at 140° C. for 4 days under a nitrogen atmosphere
5. temperatureAfter cooling
6. customdimethyl sulfoxide was evaporated under reduced pressure
7. dissolutionthe thus obtained residue was dissolved in chloroform (50 ml)
8. washwashed with a 10% citric acid aqueous solution (50 ml) and saturated brine (100 ml) in that order
9. dry with materialthe organic layer was dried over anhydrous sodium sulfate
10. filtrationAfter filtration
11. concentrationthe filtrate was concentrated under reduced pressure
12. washeluted with an eluant of chloroform:methanol 9:1
13. concentrationThe eluate was concentrated under reduced pressure
14. temperatureTo the thus obtained residue, which was cooled in an ice bath
15. additionwas added dropwise concentrated hydrochloric acid (5 ml)
16. waitfollowed by 30 minutes
17. stirringof stirring at room temperature
18. additionAfter adding 1 N hydrochloric acid (30 ml) to the reaction solution
19. washthe aqueous solution was washed with chloroform (50 ml×2)
20. washThe aqueous solution was washed with chloroform (100 ml)
21. extractionextracted with chloroform (150 ml×3)
22. dry with materialdried over anhydrous sodium sulfate
23. filtrationfiltered
24. concentrationthe filtrate was concentrated under reduced pressure
25. additionwith the bottom layer of a mixture of chloroform
26. custommethanol:water=7:3:1) to obtain a crude title compound
27. customthis was recrystallized from a mixture of ethanol and ether