Phenylacetyl chloride → 4-(Pyrrolidin-1-yl)piperidine-1-carboxylic acid {6-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pirimidin-4-yl}amide

2-Phenylacetyl chloride (0.053 ml) was dissolved in acetonitrile (4 ml) under a nitrogen atmosphere, and then potassium thiocyanate (77.7 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added a solution of 4-(pyrrolidin-1-yl)piperidin-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (49.0 mg) in acetonitrile (5 ml) under a nitrogen atmosphere, followed by stirring at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. 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 (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1). The resultant crude product was purified again by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (0.5 ml)-hexane (1.0 ml). The solid was filtered off and dried under aeration to provide the titled compound (8.1 mg, 11.5%) as a white solid.

1. customat 60° C.
2. custompartitioned between ethyl acetate
3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
4. dry with materialdried over anhydrous sodium sulfate
5. customThe solvent was evaporated
6. customto give a residue
7. stirringby stirring at room temperature for 1 hr
8. customThe reaction mixture was partitioned between ethyl acetate and water
9. washThe organic layer was washed with brine
10. dry with materialdried over anhydrous sodium sulfate
11. customThe solvent was evaporated under a reduced pressure
12. customto give a residue, which
13. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1)
14. customThe resultant crude product was purified again by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1)
15. additionFractions containing the target compound
16. concentrationwere concentrated
17. customto give a residue, which
18. filtrationThe solid was filtered off
19. customdried under aeration

ORD 기록

ord-4493839b3a3d49a599dfdafe7420678a

출처 데이터셋

uspto-grants-2009_05

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US07531532B2