Triethylamine → HCID 15524178, compound

1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoropyrrolidine (400 mg, 1.06 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 500 mg) and stirred for 18 hours under a hydrogen atmosphere. 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 (8 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (289 mg, 0.88 mmol) and triethylamine (2 ml) and stirred for 26 hours at 100° C. in a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (80 ml) and washed-with a 10% citric acid aqueous solution (80 ml) and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with a mixture of chloroform:methanol=9:1, and the eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 20 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml×2), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (200 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Thereafter, the resulting residue was purified by recrystallization from ethanol and then dried under reduced pressure to obtain 170 mg (42.6%) 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 (8 ml)
4. stirringstirred for 26 hours at 100° C. in a nitrogen atmosphere
5. temperatureAfter cooling
6. customdimethyl sulfoxide was evaporated under reduced pressure
7. dissolutionthe thus obtained residue was dissolved in chloroform (80 ml) and washed-with a 10% citric acid aqueous solution (80 ml)
8. dry with materialthe organic layer was dried over anhydrous sodium sulfate
9. filtrationAfter filtration
10. concentrationthe filtrate was concentrated under reduced pressure
11. washeluted with a mixture of chloroform
12. concentrationmethanol=9:1, and the eluate was concentrated under reduced pressure
13. temperatureTo the thus obtained residue, which was cooled in an ice bath
14. additionwas added dropwise concentrated hydrochloric acid (5 ml)
15. waitfollowed by 20 minutes
16. stirringof stirring at room temperature
17. additionAfter adding 1 N hydrochloric acid (30 ml) to the reaction solution
18. washthe aqueous solution was washed with chloroform (50 ml×2)
19. washThe aqueous solution was washed with chloroform (100 ml×2)
20. extractionextracted with chloroform (200 ml×3)
21. dry with materialdried over anhydrous sodium sulfate
22. filtrationfiltered
23. concentrationthe filtrate was concentrated under reduced pressure
24. customThereafter, the resulting residue was purified by recrystallization from ethanol
25. customdried under reduced pressure

ORD record

ord-22fdfc7e21dc497cb545396de19b8cf7

Source dataset

uspto-grants-2000_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06121285