Reacción #1340616

Ecuación de reacción

7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

triethylamine

(3S,4S)-1-(benzyloxycarbonyl)-3-(tert-butoxycarbonylamino)-4-ethylpyrrolidine

→

title compound

Rendimiento 50.1%

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

Rendimiento 50.1%

Disolventes

methanol

Condiciones de reacción

Tratamiento posterior

1. 1
   FiltraciónAfter filtration
2. 2
   Concentraciónthe filtrate was concentrated under reduced pressure
3. 3
   workup.DISSOLUTIONThe obtained residue was dissolved in dimethyl sulfoxide (3 mL)
4. 4
   ConcentraciónThe reaction mixture was concentrated under reduced pressure
5. 5
   workup.DISSOLUTIONthe residue was dissolved in ethyl acetate (50 mL)
6. 6
   LavadoThe solution was washed sequentially with a 10% aqueous citric acid solution (30 mL), water (30 mL×2), and saturated brine (30 mL)
7. 7
   Secadoby drying over anhydrous sodium sulfate
8. 8
   FiltraciónAfter filtration
9. 9
   Concentraciónthe filtrate was concentrated under reduced pressure
10. 10
    workup.ADDITIONSubsequently, concentrated hydrochloric acid (2 mL) was added to the obtained residue at room temperature
11. 11
    Otrothe resultant mixture was transferred to a separatory funnel with water (20 mL)
12. 12
    Lavadoby washing by chloroform (30 mL×2)
13. 13
    Temperaturaunder cooling with ice
14. 14
    Extracciónthe resultant mixture was extracted with chloroform (100 mL×3)
15. 15
    SecadoThe combined organic layer was dried over anhydrous sodium sulfate
16. 16
    Otrothe solvent was removed under reduced pressure
17. 17
    OtroThe obtained residue was recrystallized from hot ethanol
18. 18
    Otrodried under reduced pressure

Procedimiento

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%).

Fuente