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

Temperature

70 °C

After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (690 mg, 2.25 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (4 ml), 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (250 mg, 850 μmol) was added thereto and heated under reflux in an oil bath of 70° C. for 24 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml) and saturated saline solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and 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 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 70.0 mg (20%) of the title compound was thereby obtained in the form of yellow crystals.

1. additionwas added
2. temperatureheated
3. concentrationAfter concentrating the reaction solution under a reduced pressure
4. dissolutionthe residue was dissolved in chloroform (100 ml)
5. washAfter washing the organic layer with a 10% aqueous citric acid solution (100 ml) and saturated saline solution (100 ml)
6. dry with materialthe organic layer was dried over anhydrous sodium sulfate
7. filtrationAfter filtering
8. concentrationthe filtrate was concentrated under a reduced pressure
9. additionafter adding dropwise concentrated hydrochloric acid (5 ml) to the residue
10. temperaturewhile cooling with ice, it
11. additionAfter adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution
12. washwashing the yellow acidic aqueous solution with chloroform (50 ml×3)
13. extractionwith 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3)
14. dry with materialAfter drying over anhydrous sodium sulfate
15. customThe residue thus obtained
16. customwas then purified by preparative chromatography (
17. additiondeveloped into the lower layer of a 7:3:1 mixture of chloroform
18. custommethanol:water), purified further by recrystallization from ethanol
19. customdried under a reduced pressure

ORD record

ord-7b9127b414aa43fb80c2642fa8ab4c85

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2