Hydroxylamine → 3-(3-Amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo(2.2.1)heptane

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Isophthalonitrile (5.12 g) was added to NMP (20 mL). The mixture was added dropwise with 50% hydroxyl amine (2.64 g) at 40 degrees Celsius. After being stirred at 50 degrees Celsius for four hours, the mixture was added with 100 mL of ethyl acetate, was washed with water, was dried with magnesium sulfate to give an ethyl acetate solution containing monoamidoxime derivative. The solution was added dropwise with 4-chlorobutyric acid chloride (3.7 g) while being cooled with ices, and further was added dropwise with N,N-dimethylaniline (3.7 mL). After being stirred at the room temperature for two hours, the mixture was added with a mixture of NMP (50 mL) and toluene (50 mL), and then was dehydrated by azeotropy for three hours. The resultant was added with 400 mL of ethyl acetate, was washed with dilute hydrochloric acid, saturated sodium bicarbonate water and saturated salt solution, was condensed, and was purified according to column chromatography to give 4.5 g (45% yield constant) of a oxadiazole derivative. The oxadiazole derivative (4.5 g) was added with THF (20 mL), was added dropwise with 50% hydroxylamine (1.2 g), was stirred for four hours, was added with 100mL of ethyl acetate, and was washed with saturated salt solution to give an ethyl acetate layer. The ethyl acetate layer was purified according to column chromatography to give 4.5 g (88% yield constant) of an amidoxime derivative. The amidoxime derivative (4.5 g) was added with NEP (50 mL), was added dropwise with an ethyl acetate solution (10 mL) of isophthalic acid chloride (1.5 g) while being cooled with ices, and was further added dropwise with N,N-dimethyl aniline (2.3 mL). After being stirred at the room temperature for two hours, the mixture was added with toluene (50 mL), and was dehydrated by azeotropy for three hours. The resultant was added with 400 mL of ethyl acetate, and was washed with dilute hydrochloric acid, saturated sodium bicarbonate water and saturated salt solution, and was condensed to give 4.1 g of a dichloride derivative. To the dichloride derivative (700 mg), NMP (10 mL), potassium carbonate (610 mg), acrylic acid (320 mg), sodium Iodide (330 mg) and “IRGANOX1010” (20 mg), provided by Ciba-Geigy, and was stirred at 85 degrees Celsius for three hours. The resultant was poured into dilute hydrochloric, was filtered, was washed with water, was dried, and was purified according to column chromatography to give 714 mg (89% yield constant) of a target compound, that is, Compound (9). The identification of the compound was carried out by 1H-NMR.

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