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). After adding a 10% palladium-carbon catalyst (moisture content: 55.6%, 1.0 g), the mixture was stirred under a hydrogen atmosphere at 50° C., for 18 hours. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (10 ml), and 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) were added thereto. Then, the mixture was stirred in a nitrogen atmosphere at 140° C. for 4 days. After allowing it to cool, dimethyl sulfoxide was evaporated under reduced pressure and the residue was dissolved in chloroform (50 ml) and washed successively with a 10% aqueous solution of citric acid (50 ml) and a saturated aqueous solution of sodium chloride (100 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was then subjected to flash silica gel column chromatography (eluent:chloroform:methanol=9:1) and the eluate was concentrated under reduced pressure. Under ice cooling, concentrated hydrochloric acid (5 ml) was dropped into the residue followed by stirring at room temperature for 30 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×2) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide. The liquid reaction mixture was washed with chloroform (100 ml) and then its pH value was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (150 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (developed at the bottom layer of chloroform:methanol:water=7:3:1) to obtain the title compound as a crude product. After recrystallizing from ethanol/ether, 157 mg (17%) of the title compound was obtained.

1. filtrationAfter filtering off the catalyst
2. washthrough celite (washed with methanol)
3. concentrationthe filtrate was concentrated under reduced pressure
4. customThe residue thus obtained
5. stirringThen, the mixture was stirred in a nitrogen atmosphere at 140° C. for 4 days
6. temperatureto cool
7. customdimethyl sulfoxide was evaporated under reduced pressure
8. dissolutionthe residue was dissolved in chloroform (50 ml)
9. washwashed successively with a 10% aqueous solution of citric acid (50 ml)
10. dry with materialThe organic layer was dried over anhydrous sodium sulfate
11. filtrationAfter filtering
12. concentrationthe filtrate was concentrated under reduced pressure
13. concentrationthe eluate was concentrated under reduced pressure
14. additionUnder ice cooling, concentrated hydrochloric acid (5 ml) was dropped into the residue
15. stirringby stirring at room temperature for 30 minutes
16. additionAfter adding 1 N hydrochloric acid (30 ml)
17. customthe liquid reaction mixture
18. washwas washed with chloroform (50 ml×2) and its pH value
19. customThe liquid reaction mixture
20. washwas washed with chloroform (100 ml)
21. extractionfollowed by extraction with chloroform (150 ml×3)
22. dry with materialThe combined organic layer was dried over anhydrous sodium sulfate
23. filtrationfiltered
24. concentrationThe filtrate was concentrated under reduced pressure
25. customthe residue was purified by preparative TLC (