Tetrahydrofuran → HCID 16118939, compound

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogen atmosphere, and triethylamine (0.0724 ml) and phenyl chloroformate (0.0652 ml) were added while stirring and cooling in an ice water bath, followed by stirring at the same temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added N,N-dimethylformamide (2.5 ml), and 4-piperidinemethanol (109 mg) and triethylamine (0.132 ml) were added, followed by stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethyl acetate:methanol=95:5). Crude fractions containing the target compound were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and to the residue were added tert-butyl methyl ether (2 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (98.1 mg, 73.5%).

1. temperaturecooling in an ice water bath
2. stirringby stirring at the same temperature for 1 hr
3. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
4. washThe separated organic layer was washed with brine (30 ml)
5. dry with materialdried over anhydrous sodium sulfate
6. customThe solvent was removed under reduced pressure
7. additionTo the residue was added N,N-dimethylformamide (2.5 ml), and 4-piperidinemethanol (109 mg) and triethylamine (0.132 ml)
8. additionwere added
9. stirringby stirring at room temperature overnight
10. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
11. washThe separated organic layer was washed with brine (30 ml)
12. dry with materialdried over anhydrous sodium sulfate
13. customThe solvent was removed under reduced pressure
14. customthe residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
15. additionCrude fractions containing the target compound
16. concentrationwere concentrated under reduced pressure
17. customthe residue was purified by silica gel column chromatography (eluent
18. additionFractions containing the target compound
19. concentrationwere concentrated under reduced pressure
20. additionto the residue were added tert-butyl methyl ether (2 ml) and heptane (4 ml)
21. filtrationThe solid was collected by filtration
22. customdried under aeration

ORD record

ord-279fdcea70804960a3cbe4e7d9f88101

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07855290B2