4-Methoxy-5-[3-(4-morpholinyl)propoxy]-2-nitrobenzonitrile

13.0 g (47.0 mmol) of 4-methoxy-3-(3-morpholinopropoxy)benzonitrile, 17mL concentrated nitric acid (65percent) (376mmol)mixed into a 250 mL single-mouth flask with 17 mL of glacial acetic acid, after stirring for about 2 hours at room temperature, a large amount of solids precipitated and stirring was continued for 1 hour. Stop the reaction, add 52g ice water, stir for 30min, suction filtration, The filter cake was washed with ice water to a pH of about 7 and dried to give a white solid, 14.4 g (95.3percent).4-methoxy-3- [3- (4-morpholinyl) propoxy] benzonitrile (10.0g, 36.2mmol) was dissolved in glacial acetic acid (50 mL), and added dropwise at 0 ~ 5 98percent concentrated sulfuric acid (9.2 mL), was slowly warmed to 40 , stirred for 30min, cooled, concentrated nitric acid was slowly added dropwise 67percent (3.7mL, 54.3mmol), and stirring was continued for 6 hours at 40 . After completion of the reaction, the mixture was added 100mL of ice water, adjusted with 40percent NaOH pH 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 the filtrate dichloromethane was distilled off to give a yellow solid, that is, 2-nitro-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (11.1 g of, yield 88percent )Compound 3 (2.6 g, 9.4 mmol) was dissolved in HOAc (6.5 mL) at room temperature. A mixture of H2SO4 (70percent, 6.5 mL) and HNO3 (70percent, 1.3 mL) was cooled to room temperature, then was added slowly to the above solution in an ice/water bath. The mixture was slowly warmed to room temperature and stirred for 50 h. After an addition of water(40 mL), the mixture was basified to pH 11 with addition of 50percent NaOH aqueous solution. CH2Cl2 was added to the mixture, which dissolved the solid. The aqueous phase was further extracted with CH2Cl2. The combined organic phase was washed with water, dried by MgSO4, and evaporated to give a yellow solid 4 (2.5 g, 84percent). For 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 7.86 (s, 1H), 7.70 (s, 1H), 4.29–4.22 (t, 2H), 3.98 (s, 3H), 3.59–3.58 (t, 4H), 2.40–2.38 (m, 6H), 1.94–1.92 (m, 2H).(2) Adding 250 g of acetonitrile to 48 g (0.25 mol) of 2-nitro-4-methoxy-5-hydroxybenzonitrile, while stirringAfter mixing, N-(3-chloropropyl)morpholine (49 g, 0.3 mol), potassium carbonate (69 g, 0.5 mol), potassium iodide (2.1 g, 0.005 mol) were added, and after the addition, the temperature was raised to 85 ° C, and stirred under reflux. 4 hrs After the reaction was completed, the reaction mixture was cooled to room temperature, and the mixture was filtered and washed with acetonitrile, and the filtrate was mixed, and the acetonitrile was evaporated under reduced pressure to give a yellow solid. 150 g of absolute ethanol was added, stirred and refluxed for 15 min at room temperature, cooled to 10 ° C for 30 min, filtered, and dried under reduced pressure at 60 ° C to constant weight to give a white solid compound A 75 g, yield 94percentAdd morpholine (6.43g, 0.07mol), DMF (20.0mL), Compound 3 (10.00g, 0.04mol), KI (0.48g, 2.89mmol), heated to 70 C with stirring for 9h.Cool to room temperature, pour into 150mL ice water, Stir and let stand, a yellow solid precipitates.Suction filtration, filter cake was washed three times with water, dried, Obtained as a yellow solid (9.39 g), Purify by recrystallization from ethyl acetate (requires yellow insoluble impurities to remove by hot filtration) to obtain yellow solid 4 (7.21 g, 0.02 mol). yellow solid, yield: 56.15%, (2) Adding 250 g of acetonitrile to 48 g (0.25 mol) of 2-nitro-4-methoxy-5-hydroxybenzonitrile, while stirringAfter mixing, N-(3-chloropropyl)morpholine (49 g, 0.3 mol), potassium carbonate (69 g, 0.5 mol), potassium iodide (2.1 g, 0.005 mol) were added, and after the addition, the temperature was raised to 85 C, and stirred under reflux. 4 hrs After the reaction was completed, the reaction mixture was cooled to room temperature, and the mixture was filtered and washed with acetonitrile, and the filtrate was mixed, and the acetonitrile was evaporated under reduced pressure to give a yellow solid. 150 g of absolute ethanol was added, stirred and refluxed for 15 min at room temperature, cooled to 10 C for 30 min, filtered, and dried under reduced pressure at 60 C to constant weight to give a white solid compound A 75 g, yield 94%100.00 g of 4-methoxy-5- (3-morpholino propoxy) -2-nitrobenzonitrileInto a reaction flask containing 1000ml of dioxane and 300ml of water, Stirring, heating to 50 , Then add 162.67g slowlyHydrosulfite, Insulation reaction 5h, 100mL concentrated hydrochloric acid was added dropwise, Dropping is completed, the solution is clear.The reaction solution was cooled to room temperature, Add 120 g of sodium hydroxide solution (40%), Adjust pH to strong alkaline, Extraction with methylene chloride (800 ml x 3)The combined dichloromethane phases, The methylene chloride phase is washed with water, Then washed with saturated saline, Anhydrous Na2SO4 dried, filtered, Concentrated to get2-Amino-4-methoxy-5- (3-morpholino propoxy) benzonitrile crude product.The crude product was dissolved in 700ml of absolute ethanol, At room temperature, concentrated hydrochloric acid was added dropwise, Adjust pH to 3, In this process a large number of precipitation precipitation, About 83.36 g of a yellow solid was collected by filtration, Yield 82%.

Gefitinib intermediate

Molecular Weight:321.33
XLogP3:1.4
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:6
Exact Mass:321.13247072
Monoisotopic Mass:321.13247072
Topological Polar Surface Area:101
Heavy Atom Count:23
Complexity:427
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes