Phenylacetyl chloride → 3-{4-[2-Fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea

2-Phenylacetyl chloride (0.032 ml) was dissolved in acetonitrile (3 ml) under a nitrogen atmosphere, and then potassium thiocyanate (46.6 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 then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by stirring for 30 min. The organic layer was separated, 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 acetonitrile (2 ml) to prepare a solution. 3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-[3-(4-methylpiperazin-1-yl)propyl]urea (50.0 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then D-10-camphorsulfonic acid (24.9 mg) was added thereto, followed by stirring for 5 min. To the reaction mixture was added the solution of 2-phenylacetyl isothiocyanate in acetonitrile (2 ml) synthesized above, followed by stirring under a nitrogen atmosphere at room temperature overnight. The reaction mixture was 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, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:5 to 1:8). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1.5 ml)-hexane (1.5 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (35.0 mg, 49.1%) as a white solid.

1. customat 60° C.
2. stirringby stirring for 30 min
3. customThe organic layer was separated
4. washwashed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
5. dry with materialdried over anhydrous sodium sulfate
6. customThe solvent was evaporated
7. customto give a residue
8. customto prepare a solution
9. stirringby stirring for 5 min
10. customsynthesized above,
11. stirringby stirring under a nitrogen atmosphere at room temperature overnight
12. customThe reaction mixture was partitioned between ethyl acetate
13. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order
14. dry with materialdried over anhydrous sodium sulfate
15. customThe solvent was evaporated
16. customto give a residue, which
17. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:5 to 1:8)
18. additionFractions containing the target compound
19. concentrationwere concentrated
20. customto give a residue
21. filtrationThe solid was filtered off
22. customdried under aeration

ORD record

ord-25f02f42fb72400d9860c39bc7de0b0b

Source dataset

uspto-grants-2009_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07531532B2