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

Cyclopropanecarbonitrile (100 g, 1.49 mol), methanol (59.7 g, 76 mL, 1.86 mol), and diethyl ether (184 mL) were charged to a 2 L three-necked flask. The mixture was cooled to −10° C. while stirring and HCl (g) (232 g, 6.36 mol) was then bubbled through the mixture solution such that the internal temperature was maintained below −5° C. Upon completion of gas addition, the mixture was stirred for 1.5 h at −10° C. Ether (685 mL) was added slowly over a 1-h period while continuing to maintain a the temperature below 0° C. The resulting solids were filtered and rinsed with diethyl ether (3×300 mL). The solids were further dried under vacuum, affording 181.5 g (89.8% yield) of methyl cyclopropanecarboximidoate hydrochloride. mp: 112-114° C. 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.

1. customproducing
2. customa slightly exothermic reaction
3. temperatureAfter cooling
4. customUpon completion of the reaction
5. customthe solvent was slowly evaporated under vacuum
6. washwashed with water (3×500 mL)
7. customThe organic layer was dried
8. filtrationthe salts filtered
9. customthe solvent evaporated carefully under vacuum

ORD record

ord-f1b0553c51464f25a18a1f76d000f99a

Source dataset

uspto-grants-2009_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07622605B2