Triethylamine → HCID 67491161, compound

Temperature

75 °C

Triethylamine (0.0737 ml, 0.528 mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (49.0 mg, 0.175 mmol) were added to a (1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-azabicyclo[4.3.0]nonane (42.2 mg, 0.176 mmol) in dimethyl sulfoxide (0.352 mL) in a nitrogen atmosphere, and the mixture was stirred at 75° C. for two days. Dimethyl sulfoxide (0.352 mL) and triethylamine (0.147 mL, 1.06 mmol) were added to the reaction solution, and the mixture was stirred at 75° C. for four days. Dimethyl sulfoxide (0.352 mL) and triethylamine (0.147 ml, 1.06 mmol) were added to the reaction solution, and the mixture was stirred at 75° C. for two days. 7-Fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (24.6 mg, 0.0881 mmol) and triethylamine (0.147 mL, 1.06 mmol) were added to the reaction solution, and the mixture was stirred for five days. The reaction solution was diluted with ethyl acetate (30 mL) and then washed with a 10% citric acid solution (25 mL), water (25 mL), and a saturated sodium hydroxide solution (25 mL). Further, the organic layer was extracted again from the washing 10% citric acid solution and the washing water with ethyl acetate (40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Trifluoroacetic acid (0.402 mL, 3 v/w) was added to a solution of 67.5 mg of the resulting residue in dichloromethane (1.32 mL) with stirring under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and trifluoroacetic acid was azeotropically distilled with toluene (×3). 6 mol/L hydrochloric acid was added to the resulting residue under ice-cooling, and the mixture was washed with chloroform (30 mL×5). The aqueous layer was adjusted to pH 12 with a 1 mol/L sodium hydroxide solution under ice-cooling. The basic solution was adjusted to pH 7.4 with 1 mol/L hydrochloric acid, followed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (lower layer of chloroform/methanol/water=7/3/1) and concentrated under reduced pressure. The resulting residue was dissolved in hot ethanol, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, dissolved in hot ethanol (1 mL), ultrasonically treated, and cooled with ice water. Then, the slurry was washed with diethyl ether (10 mL). After stirring at room temperature overnight, the precipitated crystals were collected by filtration, washed with ethanol and diethyl ether, and then dried under reduced pressure at 60° C. to give 12.4 mg of the title compound.

1. stirringthe mixture was stirred at 75° C. for four days
2. stirringthe mixture was stirred at 75° C. for two days
3. stirringthe mixture was stirred for five days
4. washwashed with a 10% citric acid solution (25 mL), water (25 mL)
5. extractionFurther, the organic layer was extracted again from the washing 10% citric acid solution
6. dry with materialdried over anhydrous sodium sulfate
7. filtrationfiltered
8. concentrationthe filtrate was concentrated under reduced pressure
9. customThe resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2)
10. additionTrifluoroacetic acid (0.402 mL, 3 v/w) was added to a solution of 67.5 mg of the resulting residue in dichloromethane (1.32 mL)
11. stirringwith stirring under ice-
12. temperaturecooling
13. stirringthe mixture was stirred at room temperature for one hour
14. concentrationThe reaction solution was concentrated under reduced pressure, and trifluoroacetic acid
15. distillationwas azeotropically distilled with toluene (×3)
16. addition6 mol/L hydrochloric acid was added to the resulting residue under ice-
17. temperaturecooling
18. washthe mixture was washed with chloroform (30 mL×5)
19. temperaturecooling
20. extractionfollowed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (50 mL)
21. dry with materialThe organic layer was dried over anhydrous sodium sulfate
22. filtrationfiltered
23. concentrationthe filtrate was concentrated under reduced pressure
24. customThe residue was purified by PTLC (lower layer of chloroform/methanol/water=7/3/1)
25. concentrationconcentrated under reduced pressure
26. dissolutionThe resulting residue was dissolved in hot ethanol
27. customthe insoluble material was removed by filtration
28. concentrationThe filtrate was concentrated under reduced pressure
29. dissolutiondissolved in hot ethanol (1 mL)
30. additionultrasonically treated
31. temperaturecooled with ice water
32. washThen, the slurry was washed with diethyl ether (10 mL)
33. stirringAfter stirring at room temperature overnight
34. filtrationthe precipitated crystals were collected by filtration
35. washwashed with ethanol and diethyl ether
36. customdried under reduced pressure at 60° C.

ORD record

ord-f1ecb45d5b5a4c41ae16b3aaf6310423

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618094B2