Triethylamine → 1-(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 (880 mg, 3.25 mmol) and triethylamine (1.0 ml) to dried dimethyl sulfoxide (5 ml), 1-cyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (425 mg, 1.63 mmol) was added thereto and heated under reflux in an oil bath of 70° C. for 38 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in ethyl acetate (200 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 (6 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (12 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 recrystallization from a mixed solvent of methanol/2-propanol, and then dried under a reduced pressure. 331 mg (53%) 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 ethyl acetate (200 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 (6 ml) to the residue
10. temperaturewhile cooling with ice, it
11. additionAfter adding 1 mol/l hydrochloric acid (12 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 recrystallization from a mixed solvent of methanol/2-propanol
17. customdried under a reduced pressure

ORD record

ord-dd88eaf2a328490091774bfc06f3d413

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2