Triethylamine → 8-Amino-10-[4-(R)-(1-aminocyclopropyl)-3-(S)-fluoro-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid

4-(R)-(1-tert-Butoxycarbonylaminocyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]pyrrolidine (900 mg, 2.58 mmol) was dissolved in ethanol (20 ml). After adding a 10% palladium-carbon catalyst (moisture content: 50.2%, 900 mg), the mixture was stirred under a hydrogen atmosphere for 4 hours. After filtering off the catalyst through celite (washed with ethanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (20 ml) and 8-amino-9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (593 mg, 2.00 mmol) and triethylamine (3 ml) were added thereto. Then the mixture was stirred in a nitrogen atmosphere in an oil bath at 100° C. for 25 hours. After allowing it to cool, dimethyl sulfoxide was evaporated under reduced pressure and the residue was dissolved in chloroform (100 ml.) and washed with a 10% aqueous solution of citric acid (80 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. Under ice cooling, concentrated hydrochloric acid (10 ml) was dropped into the residue followed by stirring at room temperature for 30 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×4) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide. The pH value of this aqueous solution was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (500 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol and dried under reduced pressure to obtain 640 mg (76.0%) of the title compound as a yellow powder.

1. filtrationAfter filtering off the catalyst
2. washthrough celite (washed with ethanol)
3. concentrationthe filtrate was concentrated under reduced pressure
4. customThe residue thus obtained
5. stirringThen the mixture was stirred in a nitrogen atmosphere in an oil bath at 100° C. for 25 hours
6. temperatureto cool
7. customdimethyl sulfoxide was evaporated under reduced pressure
8. dissolutionthe residue was dissolved in chloroform (100 ml.)
9. washwashed with a 10% aqueous solution of citric acid (80 ml)
10. dry with materialThe organic layer was dried over anhydrous sodium sulfate
11. filtrationAfter filtering
12. concentrationthe filtrate was concentrated under reduced pressure
13. additionUnder ice cooling, concentrated hydrochloric acid (10 ml) was dropped into the residue
14. stirringby stirring at room temperature for 30 minutes
15. additionAfter adding 1 N hydrochloric acid (30 ml)
16. customthe liquid reaction mixture
17. washwas washed with chloroform (50 ml×4) and its pH value
18. extractionfollowed by extraction with chloroform (500 ml×3)
19. dry with materialThe combined organic layer was dried over anhydrous sodium sulfate
20. filtrationfiltered
21. concentrationThe filtrate was concentrated under reduced pressure
22. customthe residue was recrystallized from ethanol
23. customdried under reduced pressure

ORD record

ord-71e3d49131a24e32a800d96b474ed8be

Source dataset

uspto-grants-2000_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06121285