Triethylamine → 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

100 °C

After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (118 mg, 436 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (122 mg, 436 μmol) was added thereto and heated under reflux in an oil bath of 100° C. for 18 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), 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 (2 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 a 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. 72.8 mg (42%) 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)
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 (2 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 a 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-e13cb1c7303e4e67b868c41207ab41c4

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2