4-AMINO-3-FURAZANECARBOXAMIDOXIME

Raw material malononitrile(50.0 g, 0.76 mol, 1.0 eq) was added to a four-necked bottle and dissolved by heating (about 50 ° C).Add water (0.5 L), ice water bath at about 10 ° C, and add sodium nitrite (57.72 g, 0.83 mol, 1.1 eq) in portions.After the addition, hydrochloric acid (6N, 8.5 mL) was added dropwise at 10 ° C or lower.The mixture was stirred for 0.5 h in an ice water bath until the temperature was constant, and the above reaction solution was designated as A.H2NOH·HCl (158.4 g, 2.28 mol, 3.0 eq) was dissolved in water (255 mL).A solution of potassium hydroxide (127.9 g, 2.28 mol, 3.0 eq) in water (255 mL) was added thereto, and the mixture was added.The mixture was stirred at room temperature (25 ° C) for 10 min, and the above reaction solution was designated as B.The reaction liquid of A was cooled to 0 ° C - 10 ° C with an ice water bath, and the B reaction liquid was added dropwise to the A reaction liquid, and the mixture was dropped.After stirring for 0.5 h in an ice water bath, the temperature was kept constant, the ice water bath was removed, and the mixture was heated to reflux for 12 h.After the reaction is completed, hydrochloric acid (6N, 120 mL) is added dropwise in an ice water bath (0 ° C) to adjust the pH = 7.Stirring was continued for 40 min, the reaction solution was suction filtered, the filter cake was washed with water, and the filter cake was drained.The target compound (101 g, yield: 93.5percent) was obtained.Malononitrile (20g, 303mmol)Soluble in 350ml water, Heat at 45 ° C for 5 minutes, Then sodium nitrite (23 g, 333.3 mmol) was added under ice bath.When the temperature rises to 10 ° C 6N HCl (3.4ml), The temperature rose to 16 ° C, Keep the temperature at 16-18 ° C for 1.5 hours.Cooled to 13 ° C, A 50percent aqueous solution of hydroxylamine (61.7 g, 909 mmol) was added in one portion.The temperature rose sharply to 27 ° C, Stir at this temperature for one hour and then reflux for another 2 hours.Cool to room temperature and stir overnight, and add 6N HCl (49 ml). Adjust the pH to 7, continue stirring in an ice bath, and precipitate a solid.Filtration, the filter cake was washed with water and dried to give compound 4-amino-N'-hydroxy-1, 2, 5-oxadiazol-3-carboximidamide 1b (40 g, 92percent).20 Malononitrile (13.2 g, 200mmol) was added to preheated water (280 mL, 45°C) and stirred for 5 mm. The resulting solution was cooled in an ice/water bath, and sodium nitrite (15.18 g, 22Ommol) was added and stirred for 5 mm. Then, HC1 (10 N, 13.2 mL) was added to start the mild exothermic reaction, while bubbles were observed. After 3 mm, the ice/water bath was removed, and the reaction mixture was stirred 1.5 h at room25 temperature. The hydroxylamine (39.6 g, 600mmol) was added to the light yellow reaction mixture in an ice/water bath. After being stirred at room temperature for 1 h, the reaction mixture was refluxed for 2 h and then cooled in an ice/water bath. HC1 (10 N, 32.0 mL) was added in portions to the reaction mixture till neutral (pH = 7.0 via a pH meter). The precipitate was collected by filtration, washed well with water, and dried in a30 vacuum (oil pump) to afford the desired product 2 (26.0 g, 9 1percent). Rf (ethyl acetate/hexanes: 1/1 (v/v)): 0.22.‘H-NMR (400 MHz, DMSO-d6): 0 10.46 (s, 1 H, OH), 6.27(s, 2H, NH2), and 6.19 (s, 2H, NH2).‘3C-NMR (100 MHz, CD3OD): ö 155.86, 145.73, and 141.13.HRMS Calcd for C3H6N5O2Na [M + Na], 166.0336, found, 166.0337.Step 1: 4-Amino-N'-hydroxy-l, 2, 5-oxadiazole-3-carboximidamide [00184] Malononitrile (320.5 g, 5 mol) was added to water (7 L) preheated to 45 °C and stirred for 5 min. The resulting solution was cooled in an ice bath and sodium nitrite (380 g, 5.5 mol) was added. When the temperature reached 10 °C, 6 N hydrochloric acid (55 mL) was added. A mild exothermic reaction ensued with the temperature reaching 16 °C. After 15 min the cold bath was removed and the reaction mixture was stirred for 1.5 hrs at 16-18 °C. The reaction mixture was cooled to 13 °C and 50percent aqueous hydroxylamine (990 g, 15 mol) was added all at once. The temperature rose to 26 °C. When the exothermic reaction subsided the cold bath was removed and stirring was continued for 1 hr at 26-27 °C, then it was slowly brought to reflux. Reflux was maintained for 2 hrs and then the reaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice bath and 6 N hydrochloric acid (800 mL) was added in portions over 40 min to pH 7.0. Stirring was continued in the ice bath at 5 °C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (50 °C) to give the desired product (644 g, 90percent). LCMS for C3H6N5O2 (M+H)+: m/z = 144.0. Step A: In a 1 L three-necked flask, malononitrile (33.0 g, 0.5 mol) was dissolved in 6 mol/L hydrochloric acid (40 mL), and a solution of NaNO2 (69.0 g, 1.0 mol) in water (100 mL) was added dropwise at 0-15 °C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, cooled to 0 ° C, and a solution of hydroxylamine hydrochloride (104.2 g, 1.5 mol) dissolved in water (75 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes, and slowly heated to reflux for 2 hours. Cool to 20 ° C or less with 10mol / LSodium hydroxide solution adjusts the pH to 7-8, Stir at 0-5 ° C for 1 hour, filter, 62.4 g of a white powder was obtained, the yield was 87.5percent, Malononitrile (3.2 kg, 50 mol) was added to water (70 L) preheated to 45°C and stirred for 5 mm. The resulting solution was cooled in an ice bath and sodium nitrite (3.8 kg, 55 mol) was added. When the temperature reached 10°C, 6N hydrochloric acid (550 mL) was added. A mild exothermicreaction ensued with the temperature reaching 16°C. After 15 mm the cold bath was removed and the reaction mixture was stirred for 1.5 hrs at 16-18°C. The reaction mixture was cooled to 13°C and50percent aqueous hydroxylamine (9.9 kg, 150 mol) was added all at once. The temperature rose to 26°C.When the exothermic reaction subsided the cold bath was removed and stirring was continued forhr at 26-27 °C, then it was slowly brought to reflux. Reflux was maintained for 2 hrs and then thereaction mixture was allowed to cool overnight. The reaction mixture was stirred in an ice bath and6N hydrochloric acid (8 L) was added in portions over 40 mm to pH 7.0. Stirring was continued in theice bath at 5°C. The precipitate was collected by filtration, washed well with water and dried in avacuum oven (50°C) to give the desired product (5.6 kg, 78percent) as an off-white solid. LCMS (M+H):m/z = 144.1. 1H NMR (400MHz, DMSO-d6): 6 10.46 (s, 1H), 6.27 (s, 2H), 6.18 (s, 2H).To a solution containing H2O (120 mL)1L three-necked flask was added NaNO2 (62.67 g, 0.91 mol)Room temperature (25 ) stirring dissolved, A solution of malononitrile (II) (30 g, 0.45 mol)Dissolved in 450mL of 2mol / L hydrochloric acid solution, Stirred overnight at room temperature, cooled to 0 ° C, A solution of hydroxylamine hydrochloride (69.74 g, 1.0 mol) dissolved in 80 mL of water was added dropwise, Add after stirring for 30 minutes, 20 below 10mol / L sodium hydroxide solution to adjust the pH to 10, The temperature was raised to 35 ° C for 2 hours, And heated to reflux for 2 hours.The mixture was cooled to room temperature and the reaction was extracted with ethyl acetate (100 mL x 3)Saturated with NaCl twice (30 mL x 2)Anhydrous Na2SO4 dried overnight, The solvent was distilled off under reduced pressure to obtain 46.8 g of a white powder, Yield 72percentThe malononitrile (25.0g, 378.4mmol) was added 500mL three-necked flask was added water (75mL), 45 was heated with stirring to dissolve, then placed in an ice bath was added glacial acetic acid (21.6mL, 378.4mmol), cooled to when 0 , solution of NaNOSodium nitrite (20.7 g, 300 mmol) and 40 mL of water were added to a 500 mL reaction flask, Stirring dissolved, A solution of malononitrile (9.9 g, 150 mmol) in hydrochloric acid (2N) was slowly added dropwise at room temperature, The mixture was stirred at room temperature overnight, cooled to 0 °C, an aqueous solution of hydroxylamine hydrochloride (23 g, 340 mmol)Stirring 30min, 20°C below 10N sodium hydroxide to adjust the pH to 10, rose to 35°C reaction 2h, And then heated to reflux 2h. Cooled to room temperature and the reaction was extracted with 20 mL of ethyl acetate. The solvent was evaporated under reduced pressure to give a white solid which was left overnight to precipitate a solid, The filter cake was distilled under reduced pressure and the white solid was combined and dried to give a white powdery solid (14.9 g, 69.5percent).Sodium nitrite (20.7 g, 300 mmol) and 40 mL of water were added to a 500 mL reaction flask, stirred and dissolved at room temperature(9.9 g, 150 mmol) in hydrochloric acid (2N) was slowly added dropwise, stirred at room temperature overnight, cooled to 0 ° C, and an aqueous solution of hydroxylamine hydrochloride (23 g, 340 mmol) was added dropwise, stirred for 30 min, Sodium adjusted to pH 10, rose to 35 ° C reaction 2h, and then heated to reflux 2h.Cooled to room temperature and the reaction was extracted with 20 mL of ethyl acetate. The solvent was evaporated under reduced pressure to give a white solid. The aqueous layer was allowed to stand overnight. The solid was precipitated, filtered, washed with water and the filtrate was distilled under reduced pressure to give a white solid Solid (14.9 g, 69.5percent).First step.Take 5.0g of malononitrile, Add 10 ml of water to dissolve, then cool to below 0 ° C, add 6.0 g of sodium nitrite, After stirring for 1.0 h, the refrigeration was turned off, and 1.35 ml of 4N hydrochloric acid was added.Move to room temperature and stir for 2.0 h.Then, the temperature was lowered to below 0 ° C, and 15.5 g of a 50percent aqueous solution of hydroxylamine was slowly added dropwise.After the completion of the dropwise addition, the temperature was raised to reflux, and after refluxing for 3 hours, the temperature was lowered to 6 ° C.Stir overnight, below 0 °C, Slowly add diluted hydrochloric acid to adjust PH=5 or so.A large amount of solid precipitated, and suction filtration gave 10.0 g of compound 1;The malononitrile (3.2g, 48.5mmol) was dissolved in 70mL water, heated until complete dissolution. An ice-water bath cooled solution of sodium nitrite (3.8g, 55mmol) and 6N hydrochloric acid (0.6mL). After the reaction was 0.5 hours in an ice bath, the reaction was warmed to room temperature for 2 hours. The reaction was continued ice bath cooling, 50percent aqueous solution of hydroxylamine hydrochloride (9.9g, 150mmol) was added dropwise to the reaction solution, after stirring for half an hour, the reaction was raised to room temperature for 1 hour. The reaction was heated to reflux for 2 hours, the reaction was complete, the ice bath, adjusted with hydrochloric acid to pH 7.0 8mL6N. The precipitate was filtered, washed with water and ethyl acetate each time, and dried to give 6.0 g of a white compound, yield 93percent.Malononitrile [Aldrich, product No.M1407] (320.5 g, 5 mol) was added to water (7 L) preheated to 45° C. and stirred for 5 min. H2O (960 ml), AcOH (515 ml, 540 g, 9.00 mol), and malononitrile (600 g, 9.09 mol) were placed into a 12-l, three-neck, round-bottom flask equipped with a mechanicalstirrer, thermometer, and liquid addition funnel. Whilevigorously stirring, the reaction mixture was cooled to with an ice water bath, and a solution of NaNO2 (660 g, 9.57 mol) in H2O (1 l) was added dropwise at complete addition, the clear reddish solution was stirred atthis temperature for 1 h and then allowed to warm to roomtemperature overnight.The reaction mixture was cooled to water bath, and a solution of NaOH (360 g, 9.00 mol) inH2O (2.4 l) was added dropwise over ~2.5 h to neutralizeAcOH, controlling the rate of addition to maintain thereaction temperature at with vigorous stirring over a 2.5 h period. After two thirdsof hydroxylamine was added, a precipitate formed. The icewater bath was replaced with a water bath, and the mixture was stirred at room temperature for 1 h. The additionfunnel was replaced with a reflux condenser. With stirring, the reaction mixture was heated slowly to 50°C. Initially, the solution had a pH ~9 that increased to pH ~11 uponheating. The reaction mixture was slowly brought to refluxand heated at this temperature for 1.5 h. During heating, thepH should be monitored regularly (every 5 min) and adjustedto pH 9–10 with AcOH (total volume ~50 ml). The reactionmixture was allowed to cool down to room temperatureovernight. The resulting precipitate was filtered off, washedwith H2O (3×1 l), and dried by suction for 24 h to giveproduct 1.Yield 1.08 kg (84percent), pale-yellow solid, mp 190–192°C (mp 190–191°C (H2O)29). 1H NMR spectrum(90 MHz, DMSO-d6), δ, ppm: 10.46 (1H, s, OH); 6.26 (2H, s, furazan NH2); 6.17 (2H, s, NH2). 13C NMR spectrum(22.5 MHz, DMSO-d6), δ, ppm: 154.7; 144.4; 140.3.A solution of compound 6a (2.0 g, 9 mmol) in MeOH(10 ml) was heated to 50°C and treated with N2H4·H2O (0.5 ml, 10 mmol). The mixture was stirred for 30 min at 40–45°C, then diluted 2 times with water, and methanol was removed in vacuo until the product started to crystallize. The mixture was cooled to 10–15°C, the precipitate that formed was filtered off. IR spectrum of the obtained compound was identical to that of 4-aminofurazan-3-carboxylic acid amidoxime (4). Yield 0.84 g (65percent), beige needles, mp 190–191°C.A suspension of 5 g (35 mmol) of AFA was suspended in 25 mL of ethanol, and 4 g (40 mmol) of KHCO330 mL of water. Then, cyanogen bromide (3.71 g, 35 mmol) was added portionwise with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 24 h, filtered, and the resulting precipitate was washed with water and dried to give 3-amino-4- (5-amino-1, 2, 4-oxadiazol-3-yl) furazan (AAOF).4.78g

Molecular Weight:143.10
XLogP3:-0.6
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:143.04432442
Monoisotopic Mass:143.04432442
Topological Polar Surface Area:124
Heavy Atom Count:10
Complexity:148
Undefined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes