5-amino-6,7,8-trifluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid → 5-Amino-7-[3-(1-amino-1-cyclopropyl)methylpyrrolidin-1-yl]-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-Benzyloxy carbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (originated from F1 of Reference Example 4; 185 mg, 0.494 mmol) was dissolved in anhydrous methanol (30 ml), and the solution was mixed with 10% palladium on carbon catalyst (water content 50%, 200 mg) and stirred at room temperature for 1 hour in an atmosphere of hydrogen under atmospheric pressure. After filtration of the reaction solution through celite, the resulting filtrate was concentrated under a reduced pressure. The thus obtained residue and triethylamine (2 ml) were added to dry acetonitrile (10 ml), and the mixture was further mixed with 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (130 mg, 0.412 mmol) and heated under reflux for 16 hours. After cooling of the reaction solution, the thus precipitated crystals were collected by filtration, washed with acetonitrile, mixed with concentrated hydrochloric acid (10 ml) under ice-cooling and then stirred at room temperature for 5 minutes. This was mixed with distilled water (15 ml), and the thus obtained acidic aqueous solution was washed with dichloromethane (20 ml×2), adjusted to pH 11 with sodium hydroxide aqueous solution under ice-cooling and then washed with chloroform (10 ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1 N hydrochloric acid and extracted with chloroform (100 ml×4). After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was purified by recrystallizing from ethanol-28% aqueous ammonia and then dried under a reduced pressure, thereby obtaining 160 mg (88.9%) of the title compound as yellow needle crystals.

1. filtrationAfter filtration of the reaction solution through celite
2. concentrationthe resulting filtrate was concentrated under a reduced pressure
3. additionThe thus obtained residue and triethylamine (2 ml) were added to dry acetonitrile (10 ml)
4. temperatureheated
5. temperatureunder reflux for 16 hours
6. temperatureAfter cooling of the reaction solution
7. filtrationthe thus precipitated crystals were collected by filtration
8. washwashed with acetonitrile
9. additionmixed with concentrated hydrochloric acid (10 ml) under ice-
10. temperaturecooling
11. additionThis was mixed with distilled water (15 ml)
12. washthe thus obtained acidic aqueous solution was washed with dichloromethane (20 ml×2)
13. temperaturecooling
14. washwashed with chloroform (10 ml)
15. extractionextracted with chloroform (100 ml×4)
16. dry with materialAfter drying over anhydrous sodium sulfate
17. customthe solvent was evaporated under a reduced pressure
18. customThereafter, the resulting residue was purified
19. customby recrystallizing from ethanol-28% aqueous ammonia
20. customdried under a reduced pressure

ORD record

ord-f25aa3badf8b49eb96bc7f96d880c1f9

Source dataset

uspto-grants-2003_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06573260B1