2-Amino-4-Methoxy-5-(3-Morpholinopropoxy)benzonitrile

Sodium DITHIONITE (89percent, 81.4 kg) was added to a stirred slurry of 4-methoxy- 5-(3-MORPHOLINOPROPOXY)-2-NITROBENZONITRILE (48.8 kg) in water (867 litres) and the resultant mixture was heated to 50°C for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately 70°C and a concentrated aqueous hydrochloric acid solution (36percent, 270 kg) was added over 3 hours. The resultant mixture was cooled to 20-25°C and sodium hydroxide liquor (47percent, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 litres). The organic phase was evaporated to give 2- AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY) benzonitrile (46.3 kg, 99percent yield); mp. 87. 5°C ; NMR Spectrum: (DMSOd6) 1.79 (M, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), 3. 86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H) ; Mass Spectrum : M+H+ 292.Sodium dithionite (89percent, 81.4 kg) was added to a stirred slurry of 4-methoxy- [5- (3-MORPHOLINOPROPOXY)-2-NITROBENZONITRILE] (48.8 kg) in water (867 litres) and the resultant mixture was heated to [50°C] for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately [70°C] and a concentrated aqueous hydrochloric acid solution (36percent, 270 kg) was added over 3 hours. The resultant mixture was cooled to [20-25°C] and sodium hydroxide liquor (47percent, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 litres). The organic phase was concentrated by distillation to remove 800 litres of solvent. There was thus obtained a methylene chloride solution (503.5 kg) containing 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzonitrile (46.3 kg, 99percent yield) suitable for use in the next stage. [A portion of the [2-AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY)] benzonitrile was isolated using the following procedure:- A sample of the methylene chloride solution was evaporated. There was thus obtained [2-AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY)] benzonitrile as a solid, m. p. 87. [5°C] ; NMR Spectrum: [(DMSOD6)] 1.79 (m, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), 3.86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H); Mass Spectrum : [M+HS 292.]]The (11.1g, 64.0mmol) mixed nitro-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (10.0g, 31.1mmol) and sodium thiosulfite , was added 80mL of water, the reaction mixture was stirred at 45 2 hours, warmed to 70 , added dropwise with stirring 36percent concentrated hydrochloric acid 25mL, 30min addition was complete, the reaction was continued to maintain 70 20min, heating was stopped, cooled to room temperature.Was slowly added dropwise under ice-cooling to a mixture of 40percent NaOH, the pH was adjusted to about 10, and extracted with dichloromethane (100mL × 3), combined organic phase was washed with water until neutral, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure dichloromethane to give brown viscous liquid, namely 2-amino-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (8.6g, 95percent yield ).Add 14g (43.6mmol) to a 250mL three-necked flask 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile and 140 mL of anhydrous ethanol, after stirring and dissolving, 5.5 g (87.2 mmol) of ammonium formate 1.4 g palladium carbon (content 15percent) was added.The temperature was raised to 60-65°C and the reaction was carried out for 2 hours. The reaction was monitored by TLC. It is filtered with Celite, Ethyl acetate extraction, the organic layer was concentrated, Obtained 12.1 g (95.3percent) of a yellow oil.(3) In the reaction flask, compound A (0.2 mol), anhydrous ethanol 700 g, and reduced iron powder 45 g were sequentially added.(0.8 mol) and ammonium chloride (4.4 g, 0.08 mol), after the addition is completed, the temperature is raised to reflux, and the reaction is carried out for 2-3 hours.The filter cake was washed with absolute ethanol, and the filtrate was combined. The ethanol was distilled off under reduced pressure, cooled to 20 ° C for 30 min, filtered, and reduced at 60 ° C.Dry to constant weight, brown color acicular solid compound B 55g, yield 95percentTo a suspension compound 4 (2.0 g, 6.2 mmol) in water (30.4 mL), sodium dithionite (3.6 g, 20.7 mmol) was added. The mixture was stirred at 50 °C for 2.5 h. After the mixture was heated to 70 °C, 37percent HCl (25 mL) was added slowly in a period of 2 h. Heating was continued for another 1 h. After cooling to room temperature, the mixture was basified to pH 11 with 50percent NaOH aqueous solution. The mixture was extracted by CH2Cl2 for three times. The solution was evaporated, and the residue was purified by silica gel chromatography with eluent (20:1 CH2Cl2/EtOH) to give a viscous liquid 5 (1.5g, 84percent). For 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 6.89 (s, 1H), 6.40 (s, 1H), 5.63 (s, 2H), 3.84–3.88 (t, 2H), 3.73 (s, 3H), 3.56 (m, 4H), 2.35 (m, 6H), 1.77–1.81 (m, 2H). 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 155.4, 148.9, 139.9, 119.1, 116.4, 99.4, 84.2, 68.1, 66.7, 55.8, 55.3, 53.8, 26.5.Sodium DITHIONITE (89percent, 81.4 kg) was added to a stirred slurry of 4-methoxy- 5-(3-MORPHOLINOPROPOXY)-2-NITROBENZONITRILE (48.8 kg) in water (867 litres) and the resultant mixture was heated to 50°C for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately 70°C and a concentrated aqueous hydrochloric acid solution (36percent, 270 kg) was added over 3 hours. The resultant mixture was cooled to 20-25°C and sodium hydroxide liquor (47percent, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 litres). The organic phase was evaporated to give 2- AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY) benzonitrile (46.3 kg, 99percent yield); mp. 87. 5°C ; NMR Spectrum: (DMSOd6) 1.79 (M, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), 3. 86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H) ; Mass Spectrum : M+H+ 292.Sodium dithionite (89percent, 81.4 kg) was added to a stirred slurry of 4-methoxy- [5- (3-MORPHOLINOPROPOXY)-2-NITROBENZONITRILE] (48.8 kg) in water (867 litres) and the resultant mixture was heated to [50°C] for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately [70°C] and a concentrated aqueous hydrochloric acid solution (36percent, 270 kg) was added over 3 hours. The resultant mixture was cooled to [20-25°C] and sodium hydroxide liquor (47percent, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 litres). The organic phase was concentrated by distillation to remove 800 litres of solvent. There was thus obtained a methylene chloride solution (503.5 kg) containing 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzonitrile (46.3 kg, 99percent yield) suitable for use in the next stage. [A portion of the [2-AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY)] benzonitrile was isolated using the following procedure:- A sample of the methylene chloride solution was evaporated. There was thus obtained [2-AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY)] benzonitrile as a solid, m. p. 87. [5°C] ; NMR Spectrum: [(DMSOD6)] 1.79 (m, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), 3.86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H); Mass Spectrum : [M+HS 292.]]The (11.1g, 64.0mmol) mixed nitro-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (10.0g, 31.1mmol) and sodium thiosulfite , was added 80mL of water, the reaction mixture was stirred at 45 2 hours, warmed to 70 , added dropwise with stirring 36percent concentrated hydrochloric acid 25mL, 30min addition was complete, the reaction was continued to maintain 70 20min, heating was stopped, cooled to room temperature.Was slowly added dropwise under ice-cooling to a mixture of 40percent NaOH, the pH was adjusted to about 10, and extracted with dichloromethane (100mL × 3), combined organic phase was washed with water until neutral, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure dichloromethane to give brown viscous liquid, namely 2-amino-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (8.6g, 95percent yield ).Add 14g (43.6mmol) to a 250mL three-necked flask 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile and 140 mL of anhydrous ethanol, after stirring and dissolving, 5.5 g (87.2 mmol) of ammonium formate 1.4 g palladium carbon (content 15percent) was added.The temperature was raised to 60-65°C and the reaction was carried out for 2 hours. The reaction was monitored by TLC. It is filtered with Celite, Ethyl acetate extraction, the organic layer was concentrated, Obtained 12.1 g (95.3percent) of a yellow oil.(3) In the reaction flask, compound A (0.2 mol), anhydrous ethanol 700 g, and reduced iron powder 45 g were sequentially added.(0.8 mol) and ammonium chloride (4.4 g, 0.08 mol), after the addition is completed, the temperature is raised to reflux, and the reaction is carried out for 2-3 hours.The filter cake was washed with absolute ethanol, and the filtrate was combined. The ethanol was distilled off under reduced pressure, cooled to 20 ° C for 30 min, filtered, and reduced at 60 ° C.Dry to constant weight, brown color acicular solid compound B 55g, yield 95percentTo a suspension compound 4 (2.0 g, 6.2 mmol) in water (30.4 mL), sodium dithionite (3.6 g, 20.7 mmol) was added. The mixture was stirred at 50 °C for 2.5 h. After the mixture was heated to 70 °C, 37percent HCl (25 mL) was added slowly in a period of 2 h. Heating was continued for another 1 h. After cooling to room temperature, the mixture was basified to pH 11 with 50percent NaOH aqueous solution. The mixture was extracted by CH2Cl2 for three times. The solution was evaporated, and the residue was purified by silica gel chromatography with eluent (20:1 CH2Cl2/EtOH) to give a viscous liquid 5 (1.5g, 84percent). For 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 6.89 (s, 1H), 6.40 (s, 1H), 5.63 (s, 2H), 3.84–3.88 (t, 2H), 3.73 (s, 3H), 3.56 (m, 4H), 2.35 (m, 6H), 1.77–1.81 (m, 2H). 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 155.4, 148.9, 139.9, 119.1, 116.4, 99.4, 84.2, 68.1, 66.7, 55.8, 55.3, 53.8, 26.5.

Molecular Weight:291.35
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:6
Exact Mass:291.15829154
Monoisotopic Mass:291.15829154
Topological Polar Surface Area:80.7
Heavy Atom Count:21
Complexity:351
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes