Triethylamine → 5-Amino-7-[4-(R)-(1-aminocyclopropyl)-3-(R)-methoxy-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(R)-methoxypyrrolidine (550 mg, 1.41 mmol) was dissolved in ethanol (40 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 550 mg) and stirred for 4 hours under a pressured hydrogen atmosphere (4.5 kg/cm2). The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (5 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (249.8 mg, 0.80 mmol) and triethylamine (3 ml) and stirred for 2 days in an oil bath of 120° C. under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved-in chloroform (100 ml) and washed with a 10% citric acid aqueous solution (50 ml×2) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After adding water (20 ml) to the reaction solution, the aqueous solution was washed with dichloromethane (50 ml×3), adjusted to pH 11 with sodium hydroxide aqueous solution and then washed with dichloromethane (50 ml×2). This was adjusted to pH 7.4 with concentrated hydrochloric acid and extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative silica gel thin layer chromatography (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1), and the resulting crude product was purified by recrystallizing from ethanol-diisopropyl ether and then dried under a reduced pressure to obtain 57 mg (16%) of the title compound as a yellow powder.

1. customThe catalyst was removed by celite filtration (methanol washing)
2. concentrationthe filtrate was concentrated under reduced pressure
3. dissolutionThe thus obtained residue was dissolved in dimethyl sulfoxide (5 ml)
4. stirringstirred for 2 days in an oil bath of 120° C. under a nitrogen atmosphere
5. temperatureAfter cooling
6. customdimethyl sulfoxide was evaporated under reduced pressure
7. washwashed with a 10% citric acid aqueous solution (50 ml×2) and saturated brine (100 ml) in that order
8. dry with materialthe organic layer was dried over anhydrous magnesium sulfate
9. filtrationAfter filtration
10. concentrationthe filtrate was concentrated under reduced pressure
11. temperatureTo the thus obtained residue, which was cooled in an ice bath
12. additionwas added dropwise concentrated hydrochloric acid (10 ml)
13. waitfollowed by 1 hour
14. stirringof stirring at room temperature
15. additionAfter adding water (20 ml) to the reaction solution
16. washthe aqueous solution was washed with dichloromethane (50 ml×3)
17. washwashed with dichloromethane (50 ml×2)
18. extractionextracted with chloroform (150 ml×3)
19. dry with materialdried over anhydrous sodium sulfate
20. filtrationfiltered
21. concentrationthe filtrate was concentrated under reduced pressure
22. additionwith the bottom layer of a mixture of chloroform
23. custommethanol:water=7:3:1), and the resulting crude product was purified
24. customby recrystallizing from ethanol-diisopropyl ether
25. customdried under a reduced pressure

ORD record

ord-cfbf1fac06b140fca8a2cb38c3785eaa

Source dataset

uspto-grants-2001_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06184388B2