HOAt → N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide

Participants

Reaction Steps

To a solution of (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (4.0 g) and triethylamine (6 ml) in dry acetonitrile (50 ml) at room temperature were added successively a 1-hydroxy-7-azabenzotriazole (2.39 g) and O-(1H Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (5.64 g) and a solution of 2-amino-3-hydroxy-2-methyl-propionitrile (1.76 g) in dry acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 18 hrs and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then, dried over sodium sulphate. After filtration and concentration under reduced pressure, the crude residue was dissolved in 50 ml of THF/H2O (1/1) and treated with 260 mg of LiOH monohydrate at room temperature for 1 hr. The crude mixture was extracted (pH=11) thrice with ethyl acetate. The organic layers were combined, washed with water, with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure, the crude residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:4, 0:1) to provide 2.02 g of N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (m.p. 78-80° C.).

Provenance & Evidence