Triethylamine → 10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-Carboxylic Acid

Temperature

100 °C

After adding 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (252 mg, 1.12 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (3 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (244 mg, 928 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduce pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 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 4 ml of water to the reaction solution and washing this acidic aqueous solution with chloroform (10 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 purified by recrystallization from ethanol and then dried under a reduced pressure. 125 mg (36.5%) of the title compound was thereby obtained in the form of yellow crystals.

1. additionwas added
2. concentrationAfter concentrating the reaction solution under a reduce pressure
3. dissolutionthe residue was dissolved in chloroform (100 ml)
4. washAfter washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml)
5. dry with materialthe organic layer was dried over anhydrous sodium sulfate
6. filtrationAfter filtering
7. concentrationthe filtrate was concentrated under a reduced pressure
8. additionafter adding dropwise concentrated hydrochloric acid (6 ml) to the residue
9. temperaturewhile cooling with ice, it
10. stirringwas stirred at room temperature for 30 minutes
11. additionAfter adding 4 ml of water to the reaction solution
12. washwashing this acidic aqueous solution with chloroform (10 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 purified by recrystallization from ethanol
17. customdried under a reduced pressure

ORD record

ord-339fd78624334dd4b159093cc3bd0cf2

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902226B2