Acetonitrile → 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 triethylamine (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 room 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 as alkaline liquid property by 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 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. 1H-NMR (400 MHz, 0.1 mol/1 NaOD) δ: 1.45-1.47 (2 H, m), 1.75-1.17 (1 N, m), 2.25-2.27 (1 H, m), 2.48-2.50 (1 H, m), 2.97-3.00 (1 H, m), 3.30-3.83 (5 H, m), 4.76 (1 H, br. d, J=62.50 Hz), 7.35-7.44 (2 H, m), 8.52 (1 H, t, J=7.81 Hz), 8.12 (1 H, s), 8.46 (1 H, d, J=4.39 Hz). Melting point: 194-196° C. Elemental analysis: for 0.5H2O. 0.5EtOH.C23H22F3N5O3 Calcd.: C, 57.03; H, 5.18; N, 13.85. Found: C, 57.03; H, 5.11; N, 13.85.

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

ORD-Eintrag

ord-e58ac82b08d2482189a00b2ff4752ef3

Quelldatensatz

uspto-grants-2004_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06762181B1