Triethylamine → HCID 15524178, compound

1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoropyrrolidine (400 mg, 1.06 mmol) was dissolved in ethanol (20 ml). After adding a 5% palladium-carbon catalyst (moisture content: 55.6%, 500 mg), the mixture was stirred under a hydrogen atmosphere 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 (8 ml) and 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (289 mg, 0.88 mmol) and triethylamine (2 ml) were added thereto. Then the mixture was stirred under a nitrogen atmosphere at 100° C. for 26 hours. After allowing it to cool, dimethyl sulfoxide was removed by evaporation. The residue was dissolved in chloroform (80 ml), and washed with a 10% aqueous solution of citric acid (80 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent: chloroform:methanol=9:1) followed by concentration of the eluate under reduced pressure. Under ice cooling, concentrated hydrochloric acid (5 ml) was added dropwise into the residue followed by stirring at room temperature for 20 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 followed by washing with chloroform (100 ml×2). The pH value of this aqueous solution was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (200 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 recrystallized from ethanol and dried under reduced pressure to obtain 170 mg (42.6%) of the title compound as a yellow powder.

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 under a nitrogen atmosphere at 100° C. for 26 hours
6. temperatureto cool
7. customdimethyl sulfoxide was removed by evaporation
8. dissolutionThe residue was dissolved in chloroform (80 ml)
9. washwashed with a 10% aqueous solution of citric acid (80 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. additionUnder ice cooling, concentrated hydrochloric acid (5 ml) was added dropwise into the residue
14. stirringby stirring at room temperature for 20 minutes
15. additionAfter adding 1 N hydrochloric acid (30 ml)
16. customthe liquid reaction mixture
17. washwas washed with chloroform (50 ml×2) and its pH value
18. washby washing with chloroform (100 ml×2)
19. extractionfollowed by extraction with chloroform (200 ml×3)
20. dry with materialThe combined organic layer was dried over anhydrous sodium sulfate
21. filtrationfiltered
22. concentrationThe filtrate was concentrated under reduced pressure
23. customthe residue was recrystallized from ethanol
24. customdried under reduced pressure

ORD record

ord-5c13661e443643fdb9c8955560824df3

Source dataset

uspto-grants-2000_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06121285