1,1'-Carbonyldiimidazole → N-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)-1-methyl-1H-indazole-3-carboxamide

Beteiligte Stoffe

Reaktionsschritte

A suspension of 1-methyl-1H-indazole-3-carboxylic acid (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (2×30 ml) containing some 2-propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20% methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39%) of the title compound as a pale yellow solid; mp 147°-149° C.

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