Uses
4-Amino-N-hydroxyfurazan-3-carboxamidine is used to prepare inhibitors of indoleamine 2,3-dioxygenase. It is also used in the synthesis of 3-azolylpropanohydroxamic acids as procollagen c-proteinase inhibitors.
Synthesis
The general procedure for the synthesis of 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine from malononitrile was as follows: malononitrile (50.0 g, 0.76 mol, 1.0 eq.) was added to a four-necked flask and heated to about 50 °C to dissolve it. Water (0.5 L) was then added and the mixture was cooled in an ice-water bath at about 10°C. Under cooling conditions, sodium nitrite (57.72 g, 0.83 mol, 1.1 eq.) was added in batches. After addition, 6N hydrochloric acid (8.5 mL) was added slowly and dropwise at 10 °C or lower. The reaction mixture was stirred continuously in an ice-water bath for 0.5 h, keeping the temperature constant, and the resulting solution was labeled as A. Separately, H2NOH-HCl (158.4 g, 2.28 mol, 3.0 eq.) was dissolved in water (255 mL), and potassium hydroxide solution (127.9 g, 2.28 mol, 3.0 eq. dissolved in 255 mL of water) was prepared and added to the above solution. This mixture was stirred at room temperature (25 °C) for 10 min, and the resulting solution was labeled B. The solution A was cooled to 0 °C - 10 °C with an ice water bath, and solution B was slowly added dropwise to A. After completion of the dropwise addition, the stirring was continued for 0.5 h, keeping the temperature constant. The ice water bath was removed and the mixture was heated to reflux for 12 hours. Upon completion of the reaction, 6N hydrochloric acid (120 mL) was added slowly and dropwise to pH=7 (0°C) in an ice water bath. Stirring was continued for 40 min, followed by diafiltration, washing the filter cake with water and drying to give 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (101 g, 93.5% yield).
References
[1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10532 - 10535
[2] Patent: CN108727361, 2018, A. Location in patent: Paragraph 0150; 0152-0154
[3] Patent: TW2018/23219, 2018, A. Location in patent: Page/Page column 31; 32
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2015, vol. 58, # 4, p. 156 - 162
[5] Patent: WO2016/40458, 2016, A2. Location in patent: Page/Page column 25; 26
