7-Methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one

To a slurry of compound 2 (10.0 g, 0.044 mol) and anhydrous potassium carbonate (18.2 g, 0.1317 mol) in acetonitrile (100 ml), 4-(3-chloropropyl)morpholine hydrochloride (10 g, 0.05 mol) was added and refluxed for 2.5 h. The solvent was distilled under reduced pressure to give residue which was diluted with water(60 ml) and extracted with ethyl acetate (100 ml) after completion of reaction. The organic layer was distilled under vacuum and dried to obtain 13.65 g (87.50percent) of the compound 3; m. p. 231-233 °C. 1HNMR (DMSO'd6, 400 MHz): delta 7.62 (s, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 4.18 (t, 2H), 4.17 (s, 2H), 4.16 (s, 3H), 2.37 (d, 1H), 1.91 (d, 2H). IR (numax, cm-1): 3134, 1695, 1601. The compound 3 (10 g, 0.0282 mol) was hydrogenated using 10percent palladium on carbon (1.0 g) in methanol (100 ml) at 3-4 kg/cm3 atambient temperature for 5 h. After completion of the reaction, the catalyst was removed by filtration. The filtrate was distilled off completely to obtain 8.27 g (90.38percent) of compound 4. Compound 4 (8.0 g, 0.0247 mol) was added to formamidine acetate (2.68 g, 0.0257 mol) in methanol (64 ml) and heated at 50-60 °C for 6 h. The reaction mass was cooled to room temperature and stirred for 3 h after completion of reaction. The resulting solid was filtered, washed with methanol (10 ml) and dried to obtain 6.44 g (81.73percent) of the title compound 1; m. p. 267-269 °C 1HNMR (DMSO'd6, 400 MHz): delta 12.06 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 7.12 (s, 1H), 4.11 (t, 2H), 3.91 (s, 3H), 3.58 (t, 4H), 3.58 (t, 4H), 1.92 (t, 1H). HRMS (ESI+): m/z: calcd for C16H22N3O4: 343.1508 [M + Na]+;found: 343.1532. IR (numax, cm-1): 2909, 1639, 1607.Step II: preparation of 7-methoxy-6-(3-morpholin-4-ylpropoxy)-3//-quinazolin-4-one; 2-Amino-4-methoxy-5-(3-mophiholin-4-yfpropoxy)benzoic acid methyl ester (4 g) was added to formamidine acetate (1.34 g) in methanol (32 ml) and heated at 50-60 0C for 6 hours. After completion of reaction, the reaction mass was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with methanol and dried to obtain 3.5 g of the title compound.e -Metnoxy- - -mophi o n- -y propoxy - -qu naZo n- -one i w u w phosphorous oxychloride (13.5ml) in a mixture of dichloromethane (150ml), acetonitrile (15ml) and N1N- dimethylformamide (15ml) for 6 hours. After completion of reaction, the reaction mass was quenched in ice (20Og) and the pEta of the resulting reaction mass was adjusted to neutral with potassium carbonate. The layers were separated. The separated organic layer was washed with water and distilled. The resulting compound was crystallized from isopropanol (75 ml) to give 13.5g (85%) of the title compound having purity 99.79% by EtaPLC 200g, 2000mL of dichloromethane, 200 ml of N, N-dimethylformamide, 200mL of acetonitrile to the reaction mixture was added phosphorus oxychloride (POCl3) 192g by stirring for 3 hours at 40 ~ 45 C prepare a reactant. Preparative cooling the reaction to -10 ~ 0 C and was added dropwise to 25% aqueous potassium carbonate solution was slowly so that the pH is 6-8. After the layers were separated and the organic layer was washed twice with water. After treatment the organic layer over anhydrous magnesium sulfate and activated charcoal, filtered, concentrated and recrystallized isopropanol was added to 2000mL. The resulting solid was filtered and dried under reduced pressure at 50C to 4-chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazoline was obtained 171g. (Yield 80.3%)4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine (S3): Take a 100 ml round bottom flask, Put a magnetic charge and add the reactant A solution of 7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazolin4-one (990 mg, 3.1 mmol) in thionyl chloride (10 ml) and DMF (0.1 ml) was heated at 80 C. for 1.5 hours. The mixture was allowed to cool, toluene was added and the solvent was removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 2M sodium hydroxide solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluding with methylene chloride/methanol (119 followed by 95/5). The purified solid was triturated with hexane, collected by filtration and washed with ether to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (614 mg, 58%). 1H NMR Spectrum: (CDCl3) 2.12(m, 2H); 2.50(br s, 4H); 2.59(t, 2H); 3.73(t, 4H); 4.05(s, 3H); 4.27(t, 2H); 7.33(s, 1H); 7.40(s, 1H); 8.86(s, 1H).Elemental analysis: Found C, 58.6; H, 6.5; N, 12.7% C16H21N3O4 0.5H2O Requires C, 58.5; H, 6.7; N, 12.8% A solution of The 4-amino-7-methoxy-6-(3-morpholinopropoxy)quinazolile used as a starting material was prepared as follows :- A mixture of 4-(3-chloro-4-fluoroanhino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (International Patent Application WO 96/33 980, therein; 6 g) and 6N aqueous hydrochloric acid solution (120 ml) was stirred and heated to reflux for 6 hours. The mixture was cooled to 0 C. and carefully, with cooling, was neutralised by the addition of concentrated aqueous ammonium hydroxide solution. The No. resultant precipitate was isolated, washed in turn with a dilute aqueous ammonium hydroxide solution and with water and dried under vacuum. There was thus obtained i) Preparation of 4-Chloro-6-[3-(4-morpholinyl)propoxy-4-quinazoline (Ilia); Into a clean and dried 5-Litre four necked round bottomed flask equipped with a mechanical stirrer, reflux-condenser, pressure equalizing addition funnel, and thermometer socket were charged chloroform (3000 ml), dimethyl formamide (30 ml) followed by 7-methoxy-6-(3-morpholino propoxy)-3, 4-dihydro-quinazolin-4-one (Ha) (15Og), obtained according to the process given in Example-l of PCT international application published as WO.2005/070909Ai. Oxalyl Chloride (120 g) was slowly added and the reaction mass was heated to reflux temperature and maintained at reflux temperature for about 5 hours. Reaction was found to be completed by HPLC test. The solvent chloroform and excess oxalyl chloride were distilled off by applying mild vacuum. The reaction mass was cooled to about 4O0C and added chloroform (300 ml) and again distilled out the solvent by applying mild vacuum . The reaction mixture was cooled to room temperature and acetonitrile (3000 ml) was added and stirred for 10-15 minutes and kept under nitrogen atmosphere to proceed to the next step.A mixture of a portion (0.99 g) of the material so obtained, thionyl chloride (10 ml) and DMF (0.1 ml) was stirred and heated to 80 C. for 1.5 hours.. The mixture was cooled to ambient temperature, toluene (10 ml) was added and the mixture was evaporated.. The residue was partitioned between ethyl acetate and water (the acidity of the aqueous layer being adjusted to PH 7.5 by the addition of 2N aqueous sodium hydroxide solution).. The organic layer was washed with brine, dried over magnesium sulphate and evaporated.. The residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent.. The solid so obtained was triturated under hexane, re-isolated and washed with diethyl ether.. There was thus obtained 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.614 g); NMR Spectrum: (CDCl3) 2.12 (m, 2H), 2.5 (br s, 4H), 2.59 (t, 2H), 3.73 (t, 4H), 4.05 (s, 3H), 4.27 (t, 2H), 7.33 (s, 1H), 7.4 (s, 1H), 8.86 (s, 1H).EXAMPLE-1Preparation of N-(3-ethylnylphenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine (I, NRC-2694); i) Preparation of 4-Chloro-6-[3-(4-morpholinyl)propoxy-4-quinazoline (IIIa)Into a clean and dried 5-Litre four necked round bottomed flask equipped with a mechanical stirrer, reflux-condenser, pressure equalizing addition funnel, and thermometer socket were charged chloroform (3000 ml), dimethyl formamide (30 ml) followed by 7-methoxy-6-(3-morpholino propoxy)-3, 4-dihydro-quinazolin-4-one (IIa) (150 g), obtained according to the process given in Example-1 of PCT international application published as WO.2005/070909A1. Oxalyl Chloride (120 g) was slowly added and the reaction mass was heated to reflux temperature and maintained at reflux temperature for about 5 hours. Reaction was found to be completed by HPLC test. The solvent chloroform and excess oxalyl chloride were distilled off by applying mild vacuum. The reaction mass was cooled to about 40 C. and added chloroform (300 ml) and again distilled out the solvent by applying mild vacuum. The reaction mixture was cooled to room temperature and acetonitrile (3000 ml) was added and stirred for 10-15 minutes and kept under nitrogen atmosphere to proceed to the next step.1mmol7-methoxy-6 - [3 - (4-morpholinyl) propoxy] quinazoline-4-one with 2mmol chlorination reagent and 2mmol microwave the presence of a base to obtain the intermediate 4-chloro-7-methoxy-6 - [3 - (4-morpholinyl) propoxy] quinazoline. Wherein the reagent is thionyl chloride, the catalyst is K 2 CO 3, the reaction temperature is 80 C, microwave power 150W. After the reaction cooled to room temperature, filter to get the solid powder.The compound (IV) (10 g, 31.31 mmol) and thionyl chloride (20 mL) were stirred well and slowly added dropwiseDMF (2.25 g, 34.44 mmol). After completion of the addition, stirring was continued and the temperature was raised to 80 C. The reaction was completed after 2 h. After cooling to room temperature, most of the thionyl chloride and DMF were removed under reduced pressure, and then 30 mL of toluene was added to the mixture under reduced pressure to give the residue as Compound (V) without further purification and transferred directly to another clean Isopropanol (150 mL) and compound (VI) (9.12 g, 62.62 mmol) were sequentially added and the mixture was heated to reflux. After 1.5 h, the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The cake was dried under reduced pressure. The resulting pale yellow solid was stirred with water (200 mL) and heated to 60 C. The pH was adjusted to 9-10 by the addition of a saturated solution of sodium hydroxide. The resulting filter cake was recrystallized to give the title compound (I) (11.90 g, 85%) as a white solid of high purity.