Triethylamine → 7-[(3S,4S)-3-Amino-4-ethylpyrrolidine-1-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Temperature

65 °C

A 10% palladium carbon catalyst (27 mg) was added to a solution of (3S,4S)-1-(benzyloxycarbonyl)-3-(tert-butoxycarbonylamino)-4-ethylpyrrolidine (270 mg, 775 μmol) in methanol (7.75 mL), and the resultant mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (3 mL), and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (216 mg, 775 μmol) and triethylamine (130 μL, 930 μmol) were added to the solution, followed by stirring in an oil bath at 65° C. for 8 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed sequentially with a 10% aqueous citric acid solution (30 mL), water (30 mL×2), and saturated brine (30 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Subsequently, concentrated hydrochloric acid (2 mL) was added to the obtained residue at room temperature, and the resultant mixture was transferred to a separatory funnel with water (20 mL), followed by washing by chloroform (30 mL×2). The pH of the obtained aqueous layer was adjusted to 12.0 with a 10 mol/L aqueous sodium hydroxide solution under cooling with ice. The pH was adjusted again to 7.4, and the resultant mixture was extracted with chloroform (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was recrystallized from hot ethanol, and dried under reduced pressure, to thereby yield the title compound as pale yellow crystals (145 mg, 50.1%).

1. filtrationAfter filtration
2. concentrationthe filtrate was concentrated under reduced pressure
3. dissolutionThe obtained residue was dissolved in dimethyl sulfoxide (3 mL)
4. concentrationThe reaction mixture was concentrated under reduced pressure
5. dissolutionthe residue was dissolved in ethyl acetate (50 mL)
6. washThe solution was washed sequentially with a 10% aqueous citric acid solution (30 mL), water (30 mL×2), and saturated brine (30 mL)
7. dry with materialby drying over anhydrous sodium sulfate
8. filtrationAfter filtration
9. concentrationthe filtrate was concentrated under reduced pressure
10. additionSubsequently, concentrated hydrochloric acid (2 mL) was added to the obtained residue at room temperature
11. customthe resultant mixture was transferred to a separatory funnel with water (20 mL)
12. washby washing by chloroform (30 mL×2)
13. temperatureunder cooling with ice
14. extractionthe resultant mixture was extracted with chloroform (100 mL×3)
15. dry with materialThe combined organic layer was dried over anhydrous sodium sulfate
16. customthe solvent was removed under reduced pressure
17. customThe obtained residue was recrystallized from hot ethanol
18. customdried under reduced pressure

ORD record

ord-5a67230943a3438da7ec63f1927d82b3

Source dataset

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07977327B2