Triethylamine → HCID 67490794, compound

Temperature

75 °C

Triethylamine (0.277 mL, 1.98 mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (185 mg, 0.663 mmol) were added to a solution of (1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (175 mg, 0.728 mmol) in dimethyl sulfoxide (1.33 mL) in a nitrogen atmosphere, and the mixture was stirred at 75° C. for 12 days. The reaction solution was diluted with ethyl acetate (45 mL) and then washed with a 10% citric acid solution (40 mL), water (40 mL), and a saturated sodium hydroxide solution (40 mL). The organic layer was 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). 260 mg (0.578 mmol) of the resulting residue was dissolved in concentrated hydrochloric acid (2.5 mL) under ice-cooling, and the solution was stirred at room temperature for 10 minutes. After washing with chloroform (50 mL×2), the aqueous layer was adjusted to pH 12 with a saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by PTLC (developed with the lower layer of chloroform/methanol/water=7/3/1). After the fluorescent part was collected, the lower layer of chloroform/methanol/water=7/3/1 (70 mL) was added. After ultrasonic treatment, the silica gel was filtered off. The filtrate was concentrated under reduced pressure and then vacuum dried. Ethanol (1 mL), diethyl ether, and 2-propanol were added to the residue. Diethyl ether was added. After repeating ultrasonic treatment and ice-cooling several times, the mixture was stirred at 40° C. for 30 minutes. After stirring at room temperature for two hours, the crystals were collected by filtration and dried under reduced pressure to give 88.7 mg of the title compound as pale yellow crystals.

1. washwashed with a 10% citric acid solution (40 mL), water (40 mL)
2. dry with materialThe organic layer was dried over anhydrous sodium sulfate
3. filtrationfiltered
4. concentrationthe filtrate was concentrated under reduced pressure
5. customThe resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2)
6. temperaturecooling
7. stirringthe solution was stirred at room temperature for 10 minutes
8. washAfter washing with chloroform (50 mL×2)
9. extractionfollowed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (100 mL)
10. dry with materialThe organic layer was dried over anhydrous sodium sulfate
11. filtrationfiltered
12. concentrationthe filtrate was concentrated under reduced pressure
13. customThe resulting residue was purified by PTLC (
14. customAfter the fluorescent part was collected
15. additionthe lower layer of chloroform/methanol/water=7/3/1 (70 mL) was added
16. filtrationAfter ultrasonic treatment, the silica gel was filtered off
17. concentrationThe filtrate was concentrated under reduced pressure
18. customvacuum dried
19. additionEthanol (1 mL), diethyl ether, and 2-propanol were added to the residue
20. additionDiethyl ether was added
21. temperaturecooling several times
22. stirringthe mixture was stirred at 40° C. for 30 minutes
23. stirringAfter stirring at room temperature for two hours
24. filtrationthe crystals were collected by filtration
25. customdried under reduced pressure

ORD record

ord-0efa163d68284e2d825c43daa662f2e4

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618094B2