5-amino-6,7,8-trifluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid → 5-Amino-7-{3-(R)-[1-amino-1-(2-pyridyl)methyl]-1-pyrrolidinyl}-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidine [F1] (339 mg, 1.22 mmol) was added to an acetonitrile suspension (10 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316 mg, 1.00 mmol), and the mixture was heated under reflux for 14 hours in the presence of triethylmine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (150 ml), this was washed with 10% citric acid (80 ml) and saturated brine (80 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (10 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at roan temperature and then washed with chloroform (50 ml×4), and the insoluble matter was removed by filtration. This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property adding 10 mol/l sodium hydroxide aqueous solution. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×4). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 316 mg (67%) of the title compound.

1. temperaturethe mixture was heated
2. temperatureunder reflux for 14 hours in the presence of triethylmine (0.5 ml)
3. temperatureAfter cooling
4. customthe solvent of the reaction solution was evaporated under a reduced pressure
5. dissolutionThe resulting residue was dissolved in chloroform (150 ml)
6. washthis was washed with 10% citric acid (80 ml) and saturated brine (80 ml)
7. dry with materialdried over anhydrous sodium sulfate
8. customthe solvent was evaporated under a reduced pressure
9. additionThe resulting residue was mixed with concentrated hydrochloric acid (10 ml) under ice-
10. temperaturecooling
11. additionfurther mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at roan temperature
12. washwashed with chloroform (50 ml×4)
13. customthe insoluble matter was removed by filtration
14. additionadding 10 mol/l sodium hydroxide aqueous solution
15. additionby adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid
16. extractionextracted with chloroform (150 ml×4)
17. dry with materialThe resulting organic layer was dried over anhydrous sodium sulfate
18. customthe solvent was evaporated under a reduced pressure
19. customto obtain the crude title compound as light yellow crystals
20. customThis was purified
21. customby recrystallizing from ethanol

ORD-Eintrag

ord-abc45d1634404011a7390d6855f6a7fe

Quelldatensatz

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07186843B2