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

Temperature

70 °C

After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (643 mg, 2.55 mmol) and triethylamine (0.5 ml) to dried dimethyl sulfoxide (1 ml, 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (250 mg, 850 μmol) was added thereto and stirred at 70° C. for 37 hours while sealing under a nitrogen atmosphere. After letting the reaction solution cool, the reaction solution was concentrated under a reduced pressure, the residue obtained was dissolved in ethyl acetate (100 ml), and washed with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (30 ml). The organic layer was then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. The residue obtained was then applied to a short silica gel chromatography and crude crystals were obtained from a chloroform:methanol=30:1 eluate. After adding dropwise concentrated hydrochloric acid (5 ml) to the crude crystals while cooling with ice, it was stirred at the same temperature for 30 minutes. 1 mol/l Hydrochloric acid (10 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×2), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 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 ethanol and then dried under a reduced pressure. 32 mg (9%) of the title compound was thereby obtained in the form of yellow crystals.

1. additionwas added
2. temperaturecool
3. concentrationthe reaction solution was concentrated under a reduced pressure
4. customthe residue obtained
5. washwashed with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (30 ml)
6. dry with materialThe organic layer was then dried over anhydrous sodium sulfate
7. filtrationafter filtering
8. concentrationthe filtrate was concentrated under a reduced pressure
9. customThe residue obtained
10. temperaturewhile cooling with ice, it
11. stirringwas stirred at the same temperature for 30 minutes
12. washafter washing the yellow acidic aqueous solution with chloroform (50 ml×2)
13. extractionwith 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)
14. dry with materialdried over anhydrous sodium sulfate
15. customThe residue thus obtained
16. customwas purified by recrystallization from ethanol
17. customdried under a reduced pressure

ORD record

ord-473ca61cb76044819b6ec540ea9de50f

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2