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With thionyl chloride; at 75℃; for 3h; |
A-3-Methoxy-2-nitrobenzoyl chlorideA mixture of 10 g of <strong>[4920-80-3]3-methoxy-2-nitrobenzoic acid</strong> in 60 ml of thionyl chloride is heated at 75 C. for 3 hours. The reaction mixture is concentrated under vacuum and 10.9 g of the expected compound are obtained, which product is used as is in the following stage. |
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With thionyl chloride; at 75℃; for 3h; |
A-3-Methoxy-2-nitrobenzoyl chloride A mixture of 10 g of <strong>[4920-80-3]3-methoxy-2-nitrobenzoic acid</strong> in 60 ml of thionyl chloride is heated at 75 C. for 3 hours. The reaction mixture is concentrated under vacuum and 10.9 g of the expected compound are obtained, which product is used as is in the following stage. |
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With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 60℃; for 3h; |
Synthesis of 2-chloro-8-methoxy-4-methyl-quinazoline 5d To a solution of the compound 5 (2.0g, 0.01 mol) in 30 mL of anhydrous CH2CI2 was added SOCI2 (4.4 ml, 0.062 mol) and DMF (0.2 mL), then themixture was stirred at 60C for 3 hours. The resulting mixture was concentratedin vacuum to give compound 5a (2.1 g, yield: 95.5%) as ayellow solid, which was used for next step without further purification.To a solution of Mg (0.26 g, 0.01 1mol) in 30 mL of anhydrous THF was added EtOH (0.4 g) and CCI4 (0.2 mL) at 50C. After being stirred for 30min, a solution of 1A (1 .76 g, 0.01 1 mol)and EtOH (0.65 g) in 10 mL of anhydrous THFwas added, the mixture was stirred at 60C for 2 hours. To this solution wasadded a solution of compound 5a (2.1 g, 0.01mol) in 10 mL of THF, the mixture wasstirred at 60C for 1 hour. The reaction mixture was cooled and quenched with 10 ml of aqueous H2SO4 (10%), the organic layers were concentrate in vacuum to give a yellow oil. To this oil was added a mixture of CH3COOH (15 mL), H2SO4 (2 mL) and H2O (10 mL),the mixture was stirred at reflux for 16 hours. The resulting mixture wasextracted with EtOAc (50 mL chi 3), the organic layers were concentrated toafford crude compound 5b (1 .4 g, yield: 73.7%). m/z = 196 [M + H]+ .To a solution of compound 5b (1 .2 g,6.15 mmol) in 20 mL of CH3COOH was addediron power (1 .0 g, 18.5 mmol), then the suspension was stirred at 70C for 4hours. The resulting mixture was filtered through apad of celite, the filtrate was neutralized with aqueous NaOH till pH = 7,extracted with EtOAc (50 mL x 3), the organic layers were concentrated toafford crude compound 5c (0.9 g, yield: 90%). m/z = 166 [M + H]+ .To a solution of the compound 5c(0.85 g, 5.15 mmol) in 20 mL of THF was added DMAP (0.69 g, 5.67 mmol) andCI3CCOCI (0.63 mL, 5.67 mmol) at 0C, then the mixture was stirred at roomtemperature for 2 hours. The resulting mixture was diluted with ice water (50mL), extracted with EtOAc (50 mL x 3), the organic layers were concentrated invacuum to give compound 5d (1 .2 g, yield: 76%), which was used for next stepwithout further purification. No MS signal.To a solution of the compound 5d (1.5 g, 4.8 mmol) in 20 mL of DMSO was added CH3COONH (1 .85 g, 24 mmol), the mixture was stirred at room temperaturefor 20 hours. The resulting mixture was diluted with H2O (200 mL), extracted with EtOAc (50 mL chi 3),the organic layers were concentrated in vacuum to give 8-methoxy-4-methyl-1H-quinazolin-2-one (0.6 g, yield: 65.2%), which was used for next step withoutfurther purification. 1H NMR (DMSO-c/e400 MHz TMS): 51 1 .0 (s, 1 H), 7.50 (q, J = 8.4 Hz, 1 H), 7.30 (d, J = 7.6 Hz,1 H), 7.15-7.19 (m, 1 H), 3.90 (s, 3 H), 2.67 (s, 3 H). m/z = 191 [M + H]+ .To a solution of the compound8-methoxy-4-methyl-1 H-quinazolin-2-one (200 mg, 1 .05 mmol) in 15 mL oftoluene was added POCI3 (0.2 mL, 2.1 mmol) and DIPEA (0.38 mL, 2.1 mmol), thenthe mixture was stirred at 90C for 4 hours. The resulting mixture wasconcentrated in vacuum, the residue was extracted with Et2O (50 mL), the organic layer was collected anddried to give 2-chloro-8-methoxy-4-methyl-quinazoline (100 mg, yield: 45.8%).m/z = 209 [M + H]+ . |
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With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h; |
Oxalyl chloride (34 mL, 0.395 mol) was added to a solution of <strong>[4920-80-3]3-methoxy-2-nitrobenzoic acid</strong> (60 g, 0.305 mol) in dry dichloromethane (600 mL), followed by N,N-dimethylformamide (0.6 mL, 7.8 mmol), which initiates mild gas evolution. The mixture was stirred at room temperature for two hours, then concentrated under vacuum to remove volatiles. The crude acid chloride was dissolved in dry dichloromethane (150 mL) then added dropwise to a cooled (5 C.) solution of aminoacetaldehyde diethylacetal (48 mL, 0.33 mol) and triethylamine (52 mL, 0.374 mol) in dry dichloromethane (250 mL). The mixture was stirred at room temperature for two hours, then washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organics were dried over sodium sulfate and concentrated to give N-(2,2-diethoxyethyl)-3-methoxy-2-nitrobenzamide (296a, 92 g, 97% yield) as a yellow solid. MS: 335 [M+1]. |
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With thionyl chloride; In toluene; for 20h;Reflux; |
SOCl2 (5mL, 68.8mmol) was added to a solution of <strong>[4920-80-3]3-methoxy-2-nitrobenzoic acid</strong> (0.14g, 0.71mmol) in toluene (5mL). The reaction mixture was refluxed for 20h, allowed to reach room temperature and was then concentrated under reduced pressure. The crude residue was dissolved in pyridine (0.5mL) and the mixture was added to an ice-cooled solution of 2?-hydroxyacetophenone 3 (90mg, 0.355mmol) in pyridine (2.5mL). The reaction mixture was allowed to reach room temperature and was stirred for 2.5h. The crude mixture was concentrated under reduced pressure and purified by column chromatography (toluene/ethyl acetate 4:1) to give 8 (0.14g, 92%) as offwhite crystals. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
Oxalyl chloride (34 mL, 0.395 mol) was added to a solution of <strong>[4920-80-3]3-methoxy-2-nitrobenzoic acid</strong> (60 g, 0.305 mol) in dry dichloromethane (600 mL), followed by N,Ndimethylformamide (0.6 mL, 7.8 mmol), which initiates mild gas evolution. The mixture was stirred at room temperature for two hours, then concentrated under vacuum to remove volatiles. The crude acid chloride was dissolved in dry dichloromethane (150 mL) then added dropwise to a cooled (5 C) solution of aminoacetaldehyde diethylacetal (48 mL, 0.33 mol) and triethylamine (52 mL, 0.374 mol) in dry dichloromethane (250 mL). The mixture was stirred at room temperature for two hours, then washed with saturated aqueous sodium bicarbonate (2 x 100 mL) and brine (100 mL). The organics were dried over sodium sulfate and concentrated to give N-(2,2-diethoxyethyl)-3-methoxy-2-nitrobenzamide (HI, 92 g, 97% yield) as a yellow solid. MS:335 [M+1]. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 60℃; for 2h;Inert atmosphere; |
Under the argon <strong>[4920-80-3]3-methoxy-2-nitro-benzoic acid</strong> (2000 mg, 10 . 15mmol) dissolved in anhydrous tetrahydrofuran (10 ml) in, then add oxalyl chloride (1288 mg, 10 . 15mmol) and a catalytic amount of DMF. The resulting reaction mixture in 60 C lower stirring 2 hours, then concentrated under reduced pressure. The crude product in the argon gas directly dissolved in anhydrous dioxane (8 ml) in, cooling the solution to 0 C. Thereafter, the introduction of the ammonia gas 10 minutes. After the end of the introduction of the gas, the reaction solution is poured into the ice water and repeated extraction with ethyl acetate. Combined organic phase dried with magnesium sulfate, filtered and concentrated under reduced pressure. Furthermore, preparation of the 3-methoxy-2-nitro-benzamide (1950 mg, 9 . 94mmol) dissolved in anhydrous methanol (60 ml) in. The addition of a catalytic amount of palladium on activated carbon (10% content by water wetting form; 543 mg; 0.51mmol) later, introducing hydrogen at room temperature until complete conversion. Then filtering out the catalyst, and the concentration of solvent under reduced pressure. The crude product is not further purified but used directly in the next reaction step, and then the thus obtained 2-amino-3-methoxybenzene formamide (350 mg, 2 . 11mmol) dissolved in anhydrous tetrahydrofuran (5 ml) in. The addition of triethylamine (0.32 ml, 2 . 32mmol) and and at room temperature under stirring 10 minutes, add 4-fluoro-benzoyl chloride (0.28 ml, 2 . 32mmol). The resulting reaction mixture stirred at room temperature for 3 hours, then remove the solvent under reduced pressure, and the water and ethyl acetate is added to the residues. The aqueous phase is extracted repeatedly with ethyl acetate, the combined organic phase is then dried by using magnesium sulphate, filtered and concentrated under reduced pressure. The crude product purification column chromatographying (ethyl acetate/n-heptane gradient) to obtain colorless solid 2 - [(4-fluoro-benzoyl) amino] - 3-methoxybenzene formamide (550 mg, of the theoretical value 91%). The 2 - [(4-fluoro-benzoyl) amino] - 3-methoxybenzene carboxamide (500 mg, 1 . 73mmol) dissolved in the aqueous sodium hydroxide solution (2M, 5 ml) in, and in 60 C stirring under 5 hours. After the cooling to room temperature, filtered and thoroughly drying, to obtain colorless solid 2 - (4-fluoro phenyl) - 8- [...] -4 (3H)-one (462 mg, a 98%). 1 HNMR (400MHz, d 6-DMSOdelta, PPM) 12.60 (br.s, 1H, NH), 8.24 (m, 2H), 7.70 (dd, 1H), 7.46 (d, 1H), 7.42 (d, 1H), 7.38 (m, 2H), 3.96 (s, 3H). |
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