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

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Reaction Steps

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.

Provenance & Evidence