Acetonitrile, 2,2-diethoxy- → Methyl 2,2-diethoxyethanecarboximidate

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Reaction Steps

In a 2 L three-neck flask, a solution of diethoxyacetonitrile (125 g, 968 mmol) in methanol (300 mL, anhydrous) was treated with a 25 wt % solution of sodium methoxide (21.0 g, 389 mmol) in methanol, producing a slightly exothermic reaction. After cooling, the mixture was stirred at room temperature for 15 h. Upon completion of the reaction, the solvent was slowly evaporated under vacuum. The remaining brown-colored residue was solvated with diethyl ether (1 L), then washed with water (3×500 mL), followed by brine (1×200 mL). The organic layer was dried using magnesium sulfate, the salts filtered, and the solvent evaporated carefully under vacuum to afford 132 g (85% yield) of methyl 2,2-diethoxyethanimidoate as a colorless liquid. Methyl 2,2-diethoxyethanimidoate (39.0 g, 242 mmol) was dissolved in tetrahydrofuran (345 mL), mixed with methylhydrazine (11.1 g, 242 mmol), then the mixture stirred at room temperature for 5 h, at which point LC/MS analysis confirmed the formation of the amidrazone intermediate. Methyl cyclopropanecarboximidoate hydrochloride (32.8 g, 242 mmol) was added to the reaction mixture, resulting in a suspension. Acetic acid (21.8 g, 363 mmol) was added slowly to the suspension, and the resulting exothermic reaction controlled with a cooling bath. After addition was completed, the reaction mixture was stirred at ambient temperature overnight. After LC/MS analysis indicated that the starting reactants had been consumed, the mixture was diluted with dichloromethane (500 mL) and stirred for 1 h. The solids were filtered and rinsed with dichloromethane (3×200 mL), and the filtrate concentrated in vacuo. The remaining oil was purified by column chromatography on silica gel (mobile phase: ethyl acetate, then with 1, 3, 5, 10% methanol, consecutively). The product-containing fractions were pooled and the solvent evaporated in vacuo. After further drying under high vacuum, 27.4 g of the title acetal was obtained as an oil containing 12.4 weight % of ethyl acetate as an impurity.

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