Dimethyl Sulfoxide → 5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

Temperature

90 °C

After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (788 mg, 3.48 mmol) and triethylamine (2 ml) to dried dimethyl sulfoxide (1 ml, 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (621 mg, 2.00 mol) was added thereto and stirred at 90° C. for 168 hours while sealing in a sealed tube under a nitrogen atmosphere. After letting the reaction solution cool and then concentrating the reaction solution under a reduced pressure, the residue obtained was dissolved in chloroform (200 ml) and washed with a 10% aqueous citric acid solution (100 ml). The organic layer was then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. After adding dropwise concentrated hydrochloric acid (10 ml) to the obtained residue while cooling with ice, it was stirred at the same temperature for 30 minutes. 1 mol/l Hydrochloric acid (20 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.8 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. The organic layers were then combined and dried over anhydrous sodium sulfate, and then the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from a mixed solvent of ethanol and diethyl ether, and then dried under a reduced pressure. 74 mg (9%) of the title compound was thereby obtained in the form of yellow crystals.

1. additionwas added
2. customwhile sealing in a sealed tube under a nitrogen atmosphere
3. temperaturecool
4. concentrationconcentrating the reaction solution under a reduced pressure
5. customthe residue obtained
6. washwashed with a 10% aqueous citric acid solution (100 ml)
7. dry with materialThe organic layer was then dried over anhydrous sodium sulfate
8. filtrationafter filtering
9. concentrationthe filtrate was concentrated under a reduced pressure
10. additionAfter adding dropwise concentrated hydrochloric acid (10 ml) to the obtained residue
11. temperaturewhile cooling with ice, it
12. stirringwas stirred at the same temperature for 30 minutes
13. addition1 mol/l Hydrochloric acid (20 ml) was then added to the reaction solution
14. washafter washing the yellow acidic aqueous solution with chloroform (50 ml×3)
15. extractionwith 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)
16. dry with materialdried over anhydrous sodium sulfate
17. customThe residue thus obtained
18. customwas purified by recrystallization from a mixed solvent of ethanol and diethyl ether
19. customdried under a reduced pressure

ORD record

ord-417e66de3d50447b8fcb97bd4a29f3dc

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2