Dabco → HCID 59306531, compound

A mixture of ethyl 8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (250 mg, 0.785 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (267 mg, 1.18 mmol), 1,4-diazabicyclo[2.2.2]octane (132 mg, 1.18 mmol), and dimethyl sulfoxide (13 ml) was stirred for 2 hours at room temperature under a nitrogen-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (30 ml) and 10% aqueous citric acid solution (30 ml), and the organic layer was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The residue was dissolved in concentrated hydrochloric acid (4 ml) and glacial acetic acid (4 ml) at room temperature and then stirred for 12 hours while heating in an oil bath at 110° C. After evaporating the solvent, concentrated hydrochloric acid (2 ml) and water (20 ml) were added, and the solution was transferred into a separation funnel and then washed with chloroform (50 ml). 10 mol/l Aqueous sodium hydroxide solution was then added to the aqueous layer after washing, thereby adjusting the pH to >12. Then after washing with chloroform (50 ml), the pH was adjusted to 8.3 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid. The aqueous layer obtained was then concentrated to 5 ml under a reduced pressure, subject to extraction into chloroform:methanol=10:1 (50 ml×3), and the combined organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The yellow solids thus obtained were recrystallized in ethanol and then dried under a reduced pressure to obtain 124 mg (40%) of the title compound as a yellow powder.

1. customAfter evaporating the solvent
2. customthe residue was partitioned in chloroform (30 ml)
3. custom10% aqueous citric acid solution (30 ml), and the organic layer was separated
4. customThe organic layer obtained
5. dry with materialwas dried over anhydrous sodium sulfate
6. customafter removing the drying agent
7. filtrationby filtration
8. customthe solvent was evaporated under a reduced pressure
9. dissolutionThe residue was dissolved in concentrated hydrochloric acid (4 ml)
10. stirringglacial acetic acid (4 ml) at room temperature and then stirred for 12 hours
11. temperaturewhile heating in an oil bath at 110° C
12. customAfter evaporating the solvent, concentrated hydrochloric acid (2 ml) and water (20 ml)
13. additionwere added
14. customthe solution was transferred into a separation funnel
15. washwashed with chloroform (50 ml)
16. addition10 mol/l Aqueous sodium hydroxide solution was then added to the aqueous layer
17. washafter washing
18. washThen after washing with chloroform (50 ml)
19. additionby adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid
20. customThe aqueous layer obtained
21. concentrationwas then concentrated to 5 ml under a reduced pressure
22. extractionsubject to extraction into chloroform
23. dry with materialmethanol=10:1 (50 ml×3), and the combined organic layer was dried over anhydrous sodium sulfate
24. customAfter removing the drying agent
25. filtrationby filtration
26. customthe solvent was evaporated under a reduced pressure
27. customThe yellow solids thus obtained
28. customwere recrystallized in ethanol
29. customdried under a reduced pressure

ORD record

ord-eccdf3c68e9e4a41a2f18566d6f5f7eb

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2