2-(4-Fluorophenyl)acetic acid → 4-(2-Fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine

온도

50 °C

Thionyl chloride (2.0 ml) was added to 2-(4-fluorophenyl)acetic acid (694 mg) under a nitrogen atmosphere, followed by stirring at 50° C. for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue. The residue was dissolved in acetonitrile (100 ml) under a nitrogen atmosphere, and then potassium thiocyanate (875 mg) was added thereto at 50° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then 4-(4-amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (949 mg) was added thereto, followed by stirring for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (20 ml) was added to precipitate crystals. The crystals were filtered off and dried under aeration to provide the titled compound (834.5 mg, 54%) as white crystals.

1. concentrationThe reaction mixture was concentrated under a reduced pressure
2. customto give a residue
3. customat 50° C.
4. stirringby stirring at the same temperature for 2 hrs
5. temperatureThe reaction mixture was cooled down to room temperature
6. stirringby stirring for 1 hr
7. concentrationThe reaction mixture was concentrated under a reduced pressure
8. customto give a residue, which
9. customwas then partitioned between ethyl acetate
10. washThe organic layer was washed with brine
11. dry with materialdried over anhydrous sodium sulfate
12. customThe solvent was evaporated under a reduced pressure
13. customto give a residue, which
14. customwas then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:3)
15. additionFractions containing the target compound
16. concentrationwere concentrated
17. customto give a residue
18. customto precipitate crystals
19. filtrationThe crystals were filtered off
20. customdried under aeration

ORD 기록

ord-00e58ff84773497db325e1e4595318d4

출처 데이터셋

uspto-grants-2009_05

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US07531532B2