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| CAS No. : | 13790-39-1 |
| Formula : | C10H9ClN2O2 |
| M.W : | 224.64 |
| SMILES Code : | ClC1=NC=NC2=CC(=C(C=C12)OC)OC |
| MDL No. : | MFCD01570172 |
| InChI Key : | LLLHRNQLGUOJHP-UHFFFAOYSA-N |
| Pubchem ID : | 2769364 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302+H312+H332-H315-H319-H335 |
| Precautionary Statements: | P261-P280-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With thionyl chloride; In N,N-dimethyl-formamide; for 6h;Heating / reflux; | b) Dimethylformamide (0.2 ml) was added dropwise to a solution of 6,7-dimethoxy-3,4-dihydro-quinazolin-4-one (10.0 g, 48.5 mmol) in thionyl chloride (200ml) and the reaction was heated at reflux for 6 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2 x 50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with i) saturated aqueous sodium hydrogen carbonate solution (2 x 250 ml) and ii) brine, and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (10.7 g, 98 % yield) as a white solid: 1H-NMR (DMSO d6): 8.86 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H): MS (+ve ESI): 225 (M-H)+. |
| 98% | With thionyl chloride;N,N-dimethyl-formamide; for 6h;Heating / reflux; | b) Dimethylformamide (0.2 ml) was added dropwise to a solution of 6,7-dimethoxy-3,4-dihydro-quinazolin-4-one (10.0 g, 48.5 mmol) in thionyl chloride (200 ml) and the reaction was heated at reflux for 6 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2*50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (2*250 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (10.7 g, 98% yield) as a white solid: 1H-NMR (DMSO d6): 8.86 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H): MS (+ve ESI): 225 (M-H)+. |
| 98% | In N-methyl-acetamide; thionyl chloride; dichloromethane; | b) Dimethylformamide (0.2 ml) was added dropwise to a solution of 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (10.0 g, 48.5 mmol) in thionyl chloride (200 ml) and the reaction was heated at reflux for 6 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2*50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (2*250 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (10.7 g, 98% yield) as a white solid: 1H-NMR (DMSO-d6): 8.86 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H): MS (+ve ESI): 225 (M-H)+. |
| 96.33% | With thionyl chloride;N,N-dimethyl-formamide; at 78 - 80℃; for 7 - 8h;Heating / reflux; | Example- 1:Ia) Preparation of 4-chloro-6, 7-dimethoxy-quinazolineDMF(Catalytic) compound-IVa720.0 g (6.05 mol) of thionyl chloride and 50.0g(0.243 mol) of 6,7-dimethoxy-3H- quinazoline-4-one were charged into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermometer socket and double surface reflux condenser. Reaction mass temperature was raised to reflux temperature (78-800C). 20.0 ml of dimethyl formamide was added slowly at reflux temperature. Maintained the mass temperature at reflux for 7- 8 hours under stirring. Distilled off thionyl chloride completely under vacuum at below 7O0C. Cooled the mass temperature to 4O0C to 45C under nitrogen atmosphere 1000.0 ml of hexane was charged under stirring. Maintained the mass temperature at 40C to 45C for 30- 45 min. Cooled the mass temperature 25- 300C. Maintained the mass temperature at 25- 30C for 45-60 min under nitrogen atmosphere. Filtered the solid under nitrogen atmosphere. Solid was washed with 250.0 ml of hexane. Compound was dried in vacuum tray drier containing phosphorus pentoxide at 30-35C till the loss on drying is not more than 0.50% w/w. Obtained 52.5Og (yield is 96.33% by theory) of yellow coloured product. Melting range 214-220C. HPLC purity 96.5%.Spectral data : FT-IR (KBr) : 3060, 3041, 2951, 2838, 1618, 1562, 1505, 1429, 1360, 1336, 1232, 1163, 966, 878, 853, 806, 656, 615,493,471.ηNMR(DMSO-dδ):. δ Value(ppm):3.89-3.91(m)2(O-CH3)(6H), 7.37(s)Ar-Ha(lH), 7.46(s)Ar-Hb91H), 9.01(s) Hc (lH). <n="32"/>13CNMR: δ value (ppm): 56.55(2C)5 101.69(1C)5 105.95(1C)5 113.39(1C), 134.28(1C)5 148.01(1C)5 150.15(1C)5 155.68(1C)5 157.30(1C)5 157.80(1C) Mass : 225.6[M+1]5224.6[M] |
| 96.33% | With thionyl chloride;N,N-dimethyl-formamide; at 78 - 80℃; | Example-11a) Preparation of 4-chloro-6,7-dimethoxy-quinazoline 720.0 g (6.05 mol) of thionyl chloride and 50.0 g (0.243 mol) of 6,7-dimethoxy-3H-quinazoline-4-one were charged into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermometer socket and double surface reflux condenser. Reaction mass temperature was raised to reflux temperature (78-80 C.). 20.0 ml of dimethyl formamide was added slowly at reflux temperature. Maintained the mass temperature at reflux for 7-8 hours under stirring. Distilled off thionyl chloride completely under vacuum at below 70 C. Cooled the mass temperature to 40 C. to 45 C. under nitrogen atmosphere 1000.0 ml of hexane was charged under stirring. Maintained the mass temperature at 40 C. to 45 C. for 30-45 min. Cooled the mass temperature 25-30 C. Maintained the mass temperature at 25-30 C. for 45-60 min under nitrogen atmosphere. Filtered the solid under nitrogen atmosphere. Solid was washed with 250.0 ml of hexane. Compound was dried in vacuum tray drier containing phosphorus pentoxide at 30-35 C. till the loss on drying is not more than 0.50% w/w. Obtained 52.50 g (yield is 96.33% by theory) of yellow coloured product.Melting range 214-220 C.HPLC purity 96.5%.Spectral data: FT-IR (KBr): 3060, 3041, 2951, 2838, 1618, 1562, 1505, 1429, 1360, 1336, 1232, 1163, 966, 878, 853, 806, 656, 615, 493, 471.1HNMR (DMSO-d6): δ Value (ppm): 3.89-3.91 (m) 2(O-CH3)(6H), 7.37 (s)Ar-Ha(1H), 7.46 (s)Ar-Hb91H), 9.01 (s) Hc (1H).13CNMR: 8 value (ppm): 56.55 (2C), 101.69 (1C), 105.95 (1C), 113.39 (1C), 134.28 (1C), 148.01 (1C), 150.15 (1C), 155.68 (1C), 157.30 (1C), 157.80 (1C)Mass: 225.6 [M+1], 224.6 [M] |
| 92% | With thionyl chloride; N,N-dimethyl-formamide; for 7h;Reflux; | A mixture of compound 2 (1.82 g, 8.8 mmol) and DMF (30 drops) in SOCl2 (50 mL) was refluxed for 7 h. The excess SOCl2 was removed by vacuum distillation. The residue was stirred with diethyl ether, filtered, washed, and dried to give compound 3 as a beige solid (1.83 g, 92%). A mixture of compound 3 and various amines in 2-propanol or DMF was refluxed. Upon completion of the reaction, it was cooled in an ice bath. The residue was filtered, washed, and dried to isolate the product. |
| 89.2% | With trichlorophosphate; In dichloromethane; at 115℃; for 8h; | To the dried 100mL round bottom flask, 6,7-dimethoxy-quinazolin-4-one (10g, 48.5mmol), POCl3 (25mL), were successively added refluxed under 115 C for 8h, TLC monitoring of the reaction (V ethyl acetate: V petroleum ether = 1: 4). After the reaction was complete. Under reduced pressure, most of the POCl3, was removed, cooled to 0C, dissolved in dichloromethane (DCM). The reaction mixture was poured into an appropriate amount of crushed ice and stirred, an appropriate amount of sodium bicarbonate solution was added and extracted three times twice before maintaining the solution was strongly acidic, the third time extraction, pH value was adjusted to 7, the organic layers combined, dried over anhydrous magnesium sulfate, and the DCM was removed under reduced pressure, to give a yellow flaky solid (9.69 g, yield 89.2% ). Product by thin layer chromatography (V petroleum ether / V ethyl acetate = 4: 1, R f = 0.45) in a purity of qualified. Without further purification, it was used directly in the next reaction. |
| 88% | With thionyl chloride; N,N-dimethyl-formamide;Reflux; | 6,7-Dimethoxyquinazolin-4(3H)-one (20 g, 9.7 mmol) and 0.1 mL of /V,//-dimethylformamide were added to 50 mL of thionyl chloride. The resulting mixture was stirred at reflux for overnight. After cooled to room temperature, the solvent was removed in vacuo and saturated sodium carbonate solution was added to adjust the pH value to 8 at 0 C. The resulting mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 1.96 g (88%) of the tilte compound as a yellow solid. MS (ESIpos): m/z = 225 (M+H)+; LC-MS [Method 1] : Rt = 0.91 min. |
| 86.5% | With trichlorophosphate; In toluene; for 3h;Reflux; | 0.1 mol6,7_ dimethoxy-quinazolin-4-one, 200mL toluene, 140mL phosphorus oxychloride were successively added single jar, magnetic stirrer, heated to reflux for 3h.After the reaction, the solvent and spin phosphorus oxychloride, adding an appropriate amount of crushed ice, ice with vigorous stirring to melt the whole, to give a yellow suspension, filtration, and the resulting solid was recrystallized from ethanol to give a white solid.Yield 86.5%. |
| 85% | With thionyl chloride; In N,N-dimethyl-formamide;Reflux; | The 4.12g (20mmol) 6,7-dimethoxy-quinazolinone by adding 500 ml single port in round low flask, then slowly added containing 1 drop of DMF in thionyl chloride of steams again 120 ml, reflux reaction, TLC detection after the reaction is finished, reducing pressure and evaporating excess of thionyl chloride, residue 300 ml ethyl acetate is dissolved, washing with saturated sodium bicarbonate solution to neutral, the organic layer dried anhydrous sodium sulfate, after concentrating column separation (V petroleum ether: V ethyl acetate: 4:1-2:1) to obtain 6,7-dimethoxy-4-chloro-quinazoline, yield: 85%, 1 HNMR (DMSO-d 6, 400MHz): 4.01 (s, 6H, 2CH 3), 7.38 (s, 1H), 7.45 (s, 1H), 8.88 (s, 1H); ESI-MS (100%): 224 ([M] +, 100). |
| 83.1% | With thionyl chloride; In N,N-dimethyl-formamide; for 2h;Reflux; | To the reactor was added 6,7-dimethoxy-4 (3H) -quinazolinone (5 g, 24.3 mmol)30 mL of thionyl chloride was added, 0.5 mL of N, N-dimethylformamide was added,The temperature was raised to reflux for 2 hours. After completion of the reaction,Rotate and evaporate out of the thionyl chloride, ice bath to the residue by adding saturated sodium bicarbonate solution,Stir until no gas is released. Add dichloromethane extraction, anhydrous sodium sulfate drying.The desiccant was removed by filtration,The solvent was removed by rotary evaporation to give 4.52 g of 4-chloro-6,7-dimethoxy-4 (3H) -quinazoline as a pale yellow solid,Yield 83.1%. |
| 82.2% | With thionyl chloride; In N,N-dimethyl-formamide; for 1h;Reflux; | A solution of compound 5 (1.7 g, 8.2 mmol) in SOCl2 (15 mL) containing 0.05 mL ofN,N-dimethylformamide (DMF) were heated to reflux in 100 mL flask for 1 h. Excess SOCl2 wasdistilled in vacuum and the resulting residue was adjusted to pH value 8-10 with aqueous Na2CO3.1.53 g of product was got after filtered as yellow solid, yield: 82.2%, m.p. 180.4-182.0 C. |
| 82% | With trichlorophosphate; at 120℃; for 6h;Inert atmosphere; | A mixture of compound 6 (4.00 g, 19.40 mmol) and phosphorylchloride (40 mL) was stirred at 120 C for 6 h. Thesolvent was removed in vacuo and the residue was dissolvedin ice-H2O and washed with saturated aqueousNaHCO3 solution (three times) followed by brine. Theorganic layer was dried over MgSO4, filtered, and the solventwas evaporated in vacuo. Recrystallizaton from EtOHafforded the chlorinated product 7 (3.58 g, 82%) as a yellowsolid. Analytical data for compound 7 are in agreement withthe literature (VanBrocklin et al. 2005). |
| 81.7% | With thionyl chloride; In N,N-dimethyl-formamide; for 4h;Reflux; | A stirred mixture of 6 (2.0 g, 0.010 mol), thionyl chloride (30 mL) and N,N-dimethylformamide (0.6 mL) was heated under reflux for 4 h. The solvent was removed in vacuo to obtain the off-white crude product and the crude product was recrystallized in DMF to obtain the compound 7 (1.81g, yield 81.7%), m.p.: 178 C. IR (cm-1): ν 3431, 1618, 1560,1508, 1412, 1348, 1234, 1161, 968, 850, 698; 1H-NMR (DMSO-d6) δ (ppm): 8.88(1H, s, 2-H),7.46(1H, s, 5-H), 7.41 (1H, s, 8-H), 4.00 (6H, s, -OCH3); 13C-NMR (DMSO-d6) δ (ppm): 158.82 (2-C), 155.05 (7-C), 149.34 (6-C), 145.86 (9-C), 138.85 (10-C), 114.73 (5-C), 105.52 (8-C), 104.11 (C-4),56.16 (-OCH3), 55.94 (-OCH3). |
| 80% | With trichlorophosphate; at 105℃; for 2h; | Example 4 4-chloro-6,7-dimethoxy-quinazoline In a 100mL flask equipped with a reflux condenser, 6,7-dimethoxy-quinazolin-4-one 4.5g(20mmol), phosphoryl chloride (45ml) were added. The mixture was stirred at 105 for 2h, and then was poured into 100mL of ice water carefully, and off-white squama solid was deposited slowly, which was filtered, dried and identified as the title compound. Yield: 80%. 1H-NMR (400MHz, DMSO): δ8.89(1H, s), 7.47(1H, s), 7.41(1H, s), 4.02(3H, s), 4.00(3H, s). |
| 80% | With trichlorophosphate; at 105℃; for 2h; | Example 4 4-chloro-6,7-dimethoxy-quinazoline In a 100 mL flask equipped with a reflux condenser, 6,7-dimethoxy-quinazolin-4-one 4.5 g (20 mmol), phosphoryl chloride (45 ml) were added. The mixture was stirred at 105 C. for 2 h, and then was poured into 100 mL of ice water carefully, and off-white squama solid was deposited slowly, which was filtered, dried and identified as the title compound. Yield: 80%. 1H-NMR (400 MHz, DMSO): δ8.89(1H, s), 7.47 (1H, s), 7.41 (1H, s), 4.02 (3H, s), 4.00 (3H, s). |
| 75.8% | With triethylamine; trichlorophosphate; In toluene; for 4h;Inert atmosphere; Reflux; | In a 100 mL three-necked flask, 1.1 g (4.6 mmol) of 6,7-trimethoxyquinazolinone, 2 mL of phosphorus oxychloride (21.8 mmol) and 12 mL of toluene were mixed and then 4 mL of tris Ethylamine, take white smoke, argon reflux began under the protection of the reaction, stop after 4 h, with dilute ammonia water to adjust the pH value to about 7, with dichloromethane (20 mLX3) extraction, after desolventizing yellow-green solid column layer Analysis (PE: ΕΑ = 5: 1, V / V) purified to give a white solid 0.9 g, yield: 75.8%, melting point: 115_1170C. |
| 71% | With trichlorophosphate; at 0℃; for 9h;Reflux; | General procedure: To phosphoryl chloride (30 ml, 0.32 mol), the selected quinazolin-4(3H)-one (10 mmol) was added at 0 C and stirred for 10 min.The resulting mixture was then refluxed for 9 h. After removal ofexcess solvent, the residue was dissolved in ice-water (50 ml)and the solution was neutralized with ammonium hydroxide.The solution was extracted three times with dichloromethane(50 ml). The organic layer was washed with brine (100 ml), driedover MgSO4, and the solvent was removed under reduced pressure.The formed solid was recrystallized from ethanol. For further usethe structure of the compounds were confirmed by NMR. |
| 70% | With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux; | General procedure: A mixture of 4-hydroxyquinazoline (50 mmol, 1.0eq) and thionyl chloride(200mL) containing DMF (0.4mL) was refluxed for 3 h. The reaction was cooled, excess thionyl chloride was removed under reduced pressure and the residue was diluted in dichloromethane (500 mL). The solution was sequentially washed with saturated aqueous sodium hydrogen carbonate solution (2 x 250 mL) and brine, respectively, dried over anhydrous Na2SO4 and then concentrated organic phase under reduced pressure to provide the compound as a white solid (4a) [44]. The procedure described for the synthesis of compound 4a can also be applied to the synthesis of compounds 4b-4c. |
| 70% | With thionyl chloride; In N,N-dimethyl-formamide; for 6h;Reflux; | With a thermometer,6,7-Dimethoxyquinazolin-4(3H)-one (10.3 g, 50 mmol) was dissolved in thionyl chloride (200 mL) in a three-necked flask of a magnetic stirring and reflux condenser.DMF (0.4 ml) was added dropwise, and the mixture was heated under reflux for 6 hours.After cooling, excess thionyl chloride was distilled off under reduced pressure, and the residue was azeotroped with toluene (50 mL) to remove the thionyl chloride, and then dichloromethane (500 mL).It was washed twice with a saturated aqueous solution of sodium hydrogencarbonate and water, and the organic phase was dried over magnesium sulfate.The solvent was evaporated in vacuo to give a white solid IV-2,(7.84g, 70%), |
| 64% | With trichlorophosphate; for 9h;Reflux; | General procedure: The selected quinazolin-4(3H)-one (10 mmol) was mixed with 10 ml phosphoryl chloride and was then stirred under reflux for 9 h. After completion of the reaction the solvent was evaporated under reduced pressure. Ice-water was added to the residue and the formed precipitatewas neutralized with ammonium hydroxide and was filtered off. 5.3.2 4-Chloro-6,7-dimethoxyquinazoline (6) The product was synthesized from compound (2) and recrystallized from ethanol to yield pale yellow solid (64%). 1H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 158.00, 156.88, 152.31, 151.53, 148.72, 118.72, 107.00, 102.37, 56.65, 56.30. |
| 27% | With thionyl chloride; In N,N-dimethyl-formamide; | A mixture of 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (2.06 g), thionyl chloride (20 ml) and DMF (1 drop) was stirred and heated to reflux for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as the eluant to give 4-chloro-6,7-dimethoxyquinazoline (0.6 g, 27%). |
| 27% | With thionyl chloride;N,N-dimethyl-formamide; for 2h;Heating / reflux; | To a portion (2.06g) of the material so obtained were added thionyl chloride (20ml) and DMF (1 drop) and the mixture stirred and heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue was partitioned between ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent to give 4-chloro-6,7-dimethoxyquinazoline (0.6g, 27%). |
| With thionyl chloride; In N,N-dimethyl-formamide; for 2h;Heating / reflux; | Example 6 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (290mg, 1.4mmol) was suspended in thionyl chloride (5ml) and DMF (2 drops) and heated at reflux for 2 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped with toluene three times to give 4-chloro-6,7-dimethoxyquinazoline. | |
| Compound 4 was refluxed with phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline (compound 5) in good yield. | ||
| In dichloromethane; sodium carbonate; trichlorophosphate; | 4-Chloro-6,7-dimethoxyquinazoline 5. A suspension of 6,7-dimethoxyquinazoline-4(3H)-one 4 (12.36 g, 60 mmol) in POCl3 (250 mL) was heated under reflux for 4 hr, when a clear solution was obtained. The POCl3 was removed under reduced pressure, and the residue was dissolved in a mixture of CH2Cl2 and aqueous Na2CO3. The organic layer was dried and the solvent removed to give 4-chloro-6,7-dimethoxyquinazoline 5 (11.2 g, 83%); m.p. 259.0-263.0 C.; 1H NMR (DMSO-d6): d 8.75(s, 1H, 2-H), 7.53(s, 1H, 5-H), 7.25(s, 1H, 8H), 3.91(s, 3H, -OCH3), 3.89(s, 3H, -OCH3); IR (KBr) umax: 2963, 2834, 1880, 1612, 1555, 1503, 1339, 1153, 962 cm-1. GC/MS m/z 224(M+, 100), 209(M+ -CH3, 9.4), 189(19.39), (69(10.55). | |
| Compound 4 was refluxed with phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline (compound 5) in good yield. | ||
| With thionyl chloride;N,N-dimethyl-formamide; | Preparation of the 4-(3-ethynyl-phenyl)amino- 6,7-dimethoxy-quinazoIine 3 was achieved in four steps from the commercially available ester 1. (Knesl et al. (2006) Molecules, 11:286-297; Wright, et al. (2001) Bio-org. Med. Ch em. Lett., 1 /; 17-21. | |
| With trichlorophosphate; In acetonitrile; at 110℃; for 0.0833333h;Microwave irradiation; | General procedure: A solution of 6,7-dimethoxyisoquinolin-1(2H)-one(200 mg, 0.97 mmol), phosphoryl trichloride (0.268 mL, 2.92 mmol) inacetonitrile (5 mL) was stirred at 110 C for 5 minutes under microwaveirradiation. The reaction was quenched with a saturated aqueous sodium bicarbonatesolution and stirred at ambient temperature for 1 h. It was filtered throughcelite and washed with ethyl acetate. The filtrate was concentrated to dryness.The crude material was purified by flash chromatography, eluting with heptanesand ethyl acetate (1:0 to 0:1) to give the desired product as a gum (99 mg,45.4 %). | |
| With thionyl chloride; N,N-dimethyl-formamide; for 2h;Reflux; | To a stirred solution of compound 1 (10 mmol) in thionyl chloride (3 mL), DMF was added (2-3 drops) slowly. The reaction mixture was heated to reflux and stirred for about 2 h. Excess thionyl chloride was distilled off and the reaction mixture was quenched in ice with efficient stirring. The precipitate was filtered, washed with ice-water and the crude material was dissolved in chloroform and filtered to remove insoluble impurities. Organic layer was concentrated under vacuum to obtain compound 2. | |
| With trichlorophosphate; | (9.7 mmol) of phosphorus oxychloride was added. After 4-9 h of reaction, the remaining phosphorus oxychloride was removed by steaming and extracted with water and methylene chloride to give crude product. The silica gel column was used to give compound 3. | |
| With thionyl chloride; N,N-dimethyl-formamide; for 8h;Reflux; | General procedure: A mixture of 4-quinazolone analogues 2a-2j (8.0 mmol) in SOCI2 (27.4 mL) containing DMF (2 drops) was refluxed for 8 h. SOCI2 was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 solution and brine, respectively, dried over anhydrous Na2S04 and then concentrated under reduced pressure to yield the compounds 3a-3j (65.1-88.9percent yield) as white or off-white solid. | |
| 13 g | With thionyl chloride; for 3h;Inert atmosphere; Reflux; | In a 250 mL three-necked flask, 20 g of 6,7-dimethoxyquinazolin-4-one was added, followed by addition of 100 mL of thionyl chloride,Nitrogen protection reaction system, heated to reflux reaction, reaction 3h,The thionyl chloride was distilled off to give 4-chloro-6,7-dimethoxyquinazoline13g. |
| 13 g | With thionyl chloride; for 3h;Inert atmosphere; Reflux; | A 250 mL three-necked flask was charged with 20 g of 6,7-dimethoxyquinazolin-4-one and 100 mL of thionyl chloride, and nitrogenGas protection reaction system, heated to reflux reaction, the reaction 3h, evaporated to give 4-chloro-6,7-dimethoxyquinazole13 g |
| With thionyl chloride; In N,N-dimethyl-formamide; for 5h;Reflux; | General procedure: A mixture of 4-hydroxyquinazoline (0.02 mol) in SOCl2 (20 mL)containing DMF (2 drops) was refluxed for 5 h. SOCl2 was removedunder reduced pressure, and the residue was dissolved in dichloromethane(DCM). The solution was washed with NaHCO3 solutionand brine, dried over anhydrous Na2SO4, and concentrated under reducedpressure to obtain the desired compound as a yellow solid. | |
| 85.1%Chromat. | With thionyl chloride; In N,N-dimethyl-formamide; at 79 - 81℃; for 6h; | add dry 6,7-dimethoxy-3H-quinazolin-4-one (compound 1, 82.43g, 0.4mol), thionyl chloride (300mL), dry DMF (15mL), install a reflux condenser, install a drying tube above the condenser, heat, control the temperature at 79C -81C, stir for 6h, After cooling slightly, the thionyl chloride was removed under reduced pressure, the residue was transferred to a beaker, methanol (100 mL) was slowly added, and after stirring for 10 min, the solvent was removed under reduced pressure to remove the remaining trace of thionyl chloride to obtain a yellow-red solid , Add ether (400mL) to the above solid, stir for 0.5h, filter with suction, wash the filter residue with ether twice, Obtained a beige solid, the product, which was tested by thin layer chromatography TLC, with a purity of 98.5% and a yield of 85.1%. |
| With N,N-dimethyl-aniline; trichlorophosphate; at 20℃; for 5h;Reflux; | To a suspension of the starting material quinazolinone 1a(146 mg, 1 mmol, 1eq) in phosphorus oxychloride (280 μL, 3 mmol,3eq) was added N,N-dimethyl aniline (135 μL, 128 mmol, 1.05 eq)dropwise at ambient temperature. Then the reaction mixture washeated to reflux for 5 h. The excess phosphorus oxychloride wascollected under reduced pressure. To the slurry was added crushedice and stirred for 10 min. The precipitate was collected by filtration,and then dried under vacuum to afford 4-choloroquinazoline(2a) as off-white solid (122 mg, 74%). The product was used for thenext step without further purification. This procedure was alsoapplied to the preparation of intermediates 2b-g. | |
| With trichlorophosphate; at 100℃; for 2h; | General procedure: To a solution of intermediates 7a-7i (1 equiv.) and ammonium formate (3 equiv.) in EtOH was added trimethyl orthoformate (3 equiv.). The mixture was heated under reflux for 5-8h. After the addition was completed, TLC analysis indicated the reaction was complete. After cooled to room temperature, the mixture was filtered, and the solid was collected and dried to give a crude intermediates 8a-8i for the next step. A solution of the corresponding intermediates 8a-8i (1 equiv.) in POCl3 (10 equiv.) was stirred at 100C for 2h. After the addition was completed, TLC analysis indicated the reaction was complete. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to give a crude intermediates 9a-9i for the next step. Then, a solution of corresponding intermediates 9a-9i (1 equiv.), methyl 4-(aminomethyl)-benzoate hydrochloride (1 equiv.) and DIPEA (4 equiv.) in IAP was stirred at 90C for 6-8h, at which time TLC analysis indicated the reaction was completed. After cooled to room temperature, the mixture was filtered, and the solid was collected to give intermediates 10a-10i, which was used directly in the next step without purification. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | In acetonitrile; at 100℃; for 24h; | General Procedure: 4-Aminoquinazolines were prepared according to literature methods with a slight procedural modification. A typical procedure utilized is demonstrated for compound 10 as a representative example. In a 25 mL seal-tube reaction vessel equipped with a magnetic stirrer, 100.0 mg (0.445 mmol) of 4-chloro-6,7-dimethoxy-quinazoline was added followed by 2.0 mL of acetonitrile and 62.5 mg (0.490 mmol) of 4-chloroaniline. The vessel was sealed and heated to 100 C. After stirring at said temperature for a period of one day, the reaction was cooled,solvent evaporated via speed-vac, and tritiated three times with cold acetonitrile. Any remaining solvent was evaporated in vacuo to afford 140 mg (quantitative yield) of 10 as a white crystalline solid. |
| 73% | In isopropyl alcohol; at 90℃; | General procedure: A mixture of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1 mmol), aniline (1 mmol) and 2-propanol (5 ml) was refluxed at 90C with stirring on oil bath for 2-3 h. Upon completion of the reaction as indicated by a single spot in TLC (Chloroform/Methanol 9:1 asmobile phase), the reaction mixture is cooled to ambient temperature and the solid product precipitated out is filtered. The filtered product is washed with cold 2-propanol and dried. 4.2.1. 6,7-Dimethoxy-N-phenylquinazolin-4-amine (3a) C16H15N3O2. Yield: 73%, mp 251-253C,1H NMR (DMSO-d6):d4.04 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 7.33 (t,J= 7.40 Hz, 1H, Ar-H),7.48 (t,J= 8.00 Hz, 2H, Ar-H), 7.67 (d,J= 7.72 Hz, 2H, Ar-H), 8.28 (s,1H, Ar-H), 8.77 (s, 1H, Ar-H), 11.32 (s, 1H, NH). IR (KBr)m(cm1):3200 (N-H), 3050 (C-H), 1633 (CN), 1573 (CC), 1281(C-O),1232(C-N). MS-API (M+H)+m/z282.2 (Calcd 281.12). |
| In acetonitrile; at 100℃; for 1h;Microwave irradiation; | 4-Chloro-6,7-dimethoxy-quinazoline (100 mg, 0.4500 mmol) and 1H-indazol-6-amine (59.27 mg, 0.4500 mmol) were mixed in MeCN (2 mL) and irradiated in a CEM microwave at 100 C for one hour. The reaction mixture was allowed to cool and then passed through a short pad of silica. After concentration of the filtrate, the resultant solid was washed sequentially with acetonitrile and diethyl ether and dried in vacuo to give 16 (0.13g, 81%) as a light brown solid. 1H NMR (DMSO-d6) δ 13.21 (br s, 1H), 11.37 (s, 1H), 8.84 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With trichlorophosphate; In toluene; | Production Example 36: 4-Chloro-6,7-dimethoxyquinazoline Toluene (100 ml) and phosphorus oxychloride (7.4 g, 48.6 mmol) were added to 6,7-dimethoxy-4-quinazolone (10.0 g, 48.5 mmol), and the mixture was stirred at 120C for 6.5 hr. The reaction solution was cooled to room temperature, was then filtered, was washed with toluene (100 ml, 50 ml), and was dried to give 11.5 g (yield 91%) of the target product. |
| 82.15% | With thionyl chloride; In N,N-dimethyl-formamide;Reflux; | 6,7-dimethoxyquinazoline-4(1H)-one (compound 28) (6 g, 29 mmol) was dissolved in 100 mL of thionyl chloride and 10 mL of DMF, and the reaction was refluxed overnight. The solution was cooled to room temperature, the majority of the solvent was spun to dryness, then slowly poured into ice water to precipitate the solid, filtered, washed with water and ether, and drained to obtain 5.34 g (82.15%) of the solid. 1HNMR (500 MHz, d6-DMSO), δ 8.88 (s, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). MS (ESI), m/z: 226[M+H]+. |
| 79% | With thionyl chloride; N,N-dimethyl-formamide; for 3h;Heating / reflux; | Obtainment of 6, 7- Dimethoxy-4-quinazolinone (3a) A 6, 7- dimethoxy-4-quinazolinone suspension (2a) (0.79 g, 3.83 mmol) in thionyl chloride (7.0 mL) containing 10 drops of N, N-dimethylformamide (DME) was agitated and heated under reflux for 3 h, until a solution was obtained. The reaction mixture was left cooling at room temperature. The reaction environment was diluted in dichloromethane and water (160 mL) and left in ice bath. The material was treated under agitation with 30 mL of saturated Na2C03 solution. Na2CO3 was carefully added until pH was adjusted to 7-8 range. Then, the aqueous phase was extracted with CH2C12 (2 x 30 mL), and the organic phase compound was washed with salt solution (2 x 10 mL), dried over magnesium sulfate, filtered, and the solvent was evaporated in a rotatory evaporator in order to provide 6, 7-dimethoxy-4-chloroquinazoline (3a) with a yellow solid (0.68 g, 3.03 mmol, 79%), which was used without purification in the next stage: melting point 185-187C. RMN of 1H [500 MHz, (CD3) 2SO, ppm] so 8.90 (1H, s, H-2), 7. 39 (1H, s, H-5), 7.34 (1H, s, H-8), 4.08 (6H, s, H-6a and H-7a). IV (KBr/ cm-1) v: 2975 (C-H), 1619 (C-N of an aromatic), 1511 (C-C of an aromatic), 1233 (C-O-C), 789 (C-H), 872 (C-Cl). |
| 71.4% | With sodium hydroxide; trichlorophosphate; In tetrahydrofuran; sulfolane; | Production Example 35: 4-Chloro-6,7-dimethoxyquinazoline Sulfolane (250 ml) and phosphorus oxychloride (250 ml = 412.5 g, 2.69 mol) were added to 6,7-dimethoxy-4-quinazolone (50.1 g, 0.24 mol), and the mixture was stirred at 120C for one hr. The reaction mixture was cooled to room temperature, and the excess phosphorus oxychloride was then removed by distillation under the reduced pressure. The residue was poured into ice water (1000 ml), and chloroform (1000 ml) was added thereto. The aqueous layer was adjusted to pH 6.5 by the addition of a 20% sodium hydroxide solution, followed by the separation of the organic layer from the aqueous layer.The separated organic layer was washed with water (1000 ml * six times), was dried over sodium sulfate, and was then concentrated under the reduced pressure. Tetrahydrofuran (470 ml) was added to the residue, and the mixture was refluxed. The reaction solution was cooled to -5C to -10C and was filtered and dried to give 38.5 g (yield 71.4%) of the target product. 1H-NMR (DMSO-d6, 400 MHz): δ 4.09 (s, 3H), 4.09 (s, 3H), 7.14 (s, 1H), 7.34 (s, 1H), 7.61 (s, 1H), 7.97 (s, 1H) |
| With trichlorophosphate; at 115℃; for 8h; | General procedure: General procedures for the preparation of substituted 4-chloroquinazolines (3a and 3b) In a dry flask, quinazolin-4(1H)-one (4.38 g, 30 mmol) and POCl3 (19.2 mL, 210 mmol) were added sequentially, and then the mixture was stirred at 115 C for 8 h. The reaction mixture was concentrated under reduced pressure, cooled to room temperature, and then poured into ice water. Excess saturated sodium hydrogen carbonate solution was added to neutralize the generated acid, and then the mixed solution was extracted with CH2Cl2 (3 * 60 mL).;The product 4-chloroquinazoline (3a) was obtained after the organic phase was combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 3a was directly used in the next step without further purification [18] ;4-Chloro-6,7-dimethoxyquinazoline (3b) was synthesized following the same procedures. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 83% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 110℃; for 2h; | A solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (224 mg, 1.00 mmol), potassium carbonate (152 mg, 1.10 mmol) and 4-iodophenol (244 mg, 1.10 mmol) in dimethylformamide (4 ml) was heated at 110 C for 2 hours before the reaction was allowed to cool to ambient temperature. The reaction was poured into water and the solid which had precipitated was collected by suction filtration and washed with a mixture of diethyl ether (10 ml), ethyl acetate (10 ml) and isohexane (10 ml). Drying of this material yielded, yielded 4-(4-iodophenoxy)-6,7-dimethoxyquinazoline (340 mg, 83 % yield) as a white solid:1H-NMR (DMSO d6) : 8.55 (s, 1H), 7.80 (d, 2H, J = 8 Hz), 7.50 (s, 1H), 7.35 (s, 1H), 7.15 (d, 2H, J = 8 Hz), 3.95 (s, 3H), 3.90 (s, 3H): MS (+ve ESI) : 409 (M-H)+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With hydrogenchloride; In acetonitrile;Heating / reflux; | A mixture of 4- chloro-6,7-dimethoxy-quinazoline (548mg, 2. 4mmol), 2-fluoro-4-nitro-phenylamine (392mg, 2. 5mmol), AcCN (10ML), and conc'd HC1 (O. 050ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered, washed with AcCN and air-dried to give (6,7-dimethoxy- QUINAZOLIN-4-YL)- (2-FLUORO-4-NITRO-PHENYL)-AMINE (673mgs, 80%). |
| 69% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; | Step 1. N-(2-fluoro-4-nitrophenyl)-6,7-dimethoxyquinazolin-4-amine (41) A stirred suspension of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (40) (prepared according to A. J. Bridges et al., J. Med. Chem., 1996, 39, 267) (1.00 g, 4.45 mmol), 2-fluoro-4-nitroaniline (940 mg, 6.02 mmol) and cesium carbonate (3.20 g, 9.82 mmol) in anhydrous DMF (20 mL) was heated at 90 C. overnight under nitrogen. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with AcOEt, successively washed with water and a saturated solution of ammonium chloride, concentrated and triturated with AcOEt/hexanes. After filtration, the cake was adsorbed on silica gel and purified by flash column chromatography on (eluents MeOH/DCM: 2/98→10/90) to afford the title compound 41 (1.06 g, 69% yield) as a yellow-green solid. MS (m/z): 345.0 (M+H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 90℃; for 2h; | 6.7-dimethoxy-4-(3-phenylpiperidin-1-yQquinazoline: 4-chloro-6,7- dimethoxyquinazoline (15 g, 66.8 mmol) was mixed with 3-phenylpiperidine (11.8 g, 73.5 mmol) in isopropanol (300 ml_), then diisopropylethylamine (23 ml_, 133.6 mmol) was added and the mixture was heated at 900C for 2 h. After cooling to room temperature, the solvent was removed in vacuo, the residue was diluted with water and chloroform, and the mixture was made basic by adding sodium hydroxide (pH <12). The mixture was extracted with chloroform, the organic layer was washed with brine and was dried over MgSO4, was filtered, and was concentrated in vacuo. Purification by silica gel chromatography (100% chloroform to 100-1-1 chloroform/methanol/aqu. cone, ammonium hydroxide) afforded 17.5 g (75% yield) of the title compound; MS (AP/CI): 350.2 (M+H)+. |
[ 108-45-2 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | In ethanol; at 80℃; for 2h;Inert atmosphere; | A mixture of compound 7 (2.00 g, 8.90 mmol) and 1,3-phenylenediamine (1.06 g, 9.79 mmol) in EtOH (35 mL)was stirred at 80 C for 2 h. The reaction mixture wasallowed to cool to room temperature and the precipitate wasthen collected by filtration, washed with cold EtOH, coldEt2O, and dried to afford 8 (2.51 g, 95%) as a green solid.Analytical data for compound 8 are in agreement with theliterature (Garske et al. 2011). |
| 89.2% | In isopropyl alcohol; for 2h;Reflux; | To the reactor was added 4-chloro-6,7-dimethoxy-4 (3H) -quinazoline (2.25 g, 10 mmol)Add 50mL isopropanol dissolved, adding m-phenylenediamine (1.19g, 11mmol), stirring evenly,The temperature was raised to reflux for 2 hours. The reaction is completeAfter cooling to room temperature. The resulting solid was recrystallized from ethanol to give 4- (3-amino) phenyl-6,7-dimethoxyquinazoline2.64 g, yield 89.2%. |
| 41% | With hydrogenchloride; sodium hydroxide; In diethyl ether; isopropyl alcohol; | 3-Aminoaniline (4.79 g) was added to a suspension of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1.99 g) in isopropanol (100 ml). A 1M solution of hydrogen chloride in diethyl ether (8.86 ml) was added and the reaction mixture was stirred and heated to 90 C. for 3 hours. The mixture was cooled to ambient temperature and the precipitated solid was isolated, washed with isohexane and diethyl ether and then dried under vacuum. The resulting solid was then stirred with 1M aqueous sodium hydroxide solution and the mixture was extracted with methylene chloride. The methylene chloride extract was evaporated to dryness. There was thus obtained the required starting material (1.07 g, 41%); NMR: 3.91 (s, 3H), 3.93 (s, 3H), 5.03 (s, 2H), 6.31 (d, 1H), 6.87 (d, 1H), 7.00 (m, 2H), 7.13 (s, 1H), 7.81 (s, 1H), 8.39 (s, 1H), 9.20 (s, 1H); m/s: M+H+297. |
| 26% | In ethanol; for 3.5h;Heating / reflux; | [[00149]] a) 720 mg, 2 mM, 4-chloro 6,7-dimethoxy quinazoline, AG [1477,] and [350] mg, 3.2 mM, 1, [3- PHENYLENE DIAMINE] in 20 ml ethanol were refluxed 3.5 hours. Workup (KOH) and chromatography gave 0.245 gr light-brown solid, 26% yield, mp-2400 NMR [CDC13] 8 8.67 [(LH,] s, [H2),] 7.36 [(LH,] s, H5), 7.26 [(LH,] m, [H2,),] 7.17 [(LH,] t, J=8. [0HZ,] [HS),] 7.0 [(LH,] s, [HS),] 6.90 (1H. dd), 6.50 [(LH,] dd), 4.04, 4.02 (6H, 2s, [OCH3).] |
| Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. | |
| In isopropyl alcohol; at 60℃; | To a stirred solution of compound 2 (10 mmol) in isopropyl alcohol (25 mL) meta-phenylenediamine was added (10 mmol). The reaction mass was heated to 60 C and stirred for about 3-4 h. Reaction was monitored by TLC. After completion, the reaction mass was quenched in ice water and sodium bicarbobnate and extracted with ethyl acetate. Organic layer was concentrated under vacuum to obtain compound 3. The obtained crude product was purified by column chromatography to get pure compound 3. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With potassium hydroxide; In dimethyl sulfoxide; at 20℃; | [[00118]] 500 mg, 2.2 mM, 4-chloro 6,7-dimethoxy quinazoline, 400 mg, 2.8 mM, 3-formyl indole and 0.3 gr crushed KOH in 10 ml DMSO were stirred at ambient temperature. Workup and [RECRYSTALIZATION] from benzene gave 550 mg, 75% yield, white solid. NMR [CDC13] [6] 10.21 [(LH,] s, CHO), 9.15 [(LH,] s, [H2),] 8.45 [(LH,] d, J=8.0 Hz, [H7,),] 8. 30 [(LH,] s, [H2,),] 7.49 [(LH,] s, H8), 7. [40] [(3H, M),] 7. [04] [(LH, S,] [H5),] 4. [13, 3.] 80 (6H, [2 S,] OCH3). |
[ 799242-33-4 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | 3-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-benzoic acid hydrochloride: To a suspension of 4-chloro-6,7-dimethoxy-quinazoline (3.0 g, 13.35 mmol) in 1,2-dichloroethane (40 mL) and tert-butyl alcohol (40 mL) was added 3-(4-amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (3.99 g, 13.35 mmol). The reaction was heated at 90 C. for 90 minutes. The reaction was then cooled to room temperature and hydrogen chloride gas was bubbled through the solution for 40 minutes. A small amount of hot methanol was added to solublize the gummed solids. Solids then crashed out upon cooling. The solids were filtered and rinsed with cold ethyl acetate. The solids were further dried at 50 C. in a vacuum oven, yielding light yellow solids as the mono hydrochloride salt (5.79 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (bs, 1H), 8.82 (s, 1H), 8.29 (s, 1H), 7.64 (d, J=7.06 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=8.72 Hz, 1H), 7.50 (t, J=15.78, 7.89 Hz, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.08 (d, J=8.72 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 2.17 (s, 3H), LRMS (M+): 732.3, (M-): 430.3. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | 4-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-benzoic acid hydrochloride: To a suspension of 4-chloro-6,7-dimethoxy-quinazoline (3.0 g, 13.35 mmol) in 1,2-dichloroethane (40 mL) and tert-butyl alcohol (40 mL) was added 4-(4-amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (3.99 g, 13.35 mmol). The reaction was heated at 90 C. for 90 minutes. The reaction was then cooled to room temperature and hydrogen chloride gas was bubbled through the solution for 40 minutes. A small amount of hot methanol was added to solublize the gummed solids. Solids then crashed out upon cooling. The solids were filtered and rinsed with cold ethyl acetate. The solids were further dried at 50 C. in a vacuum oven, yielding light yellow solids (5.99 g, 96%) as the mono hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.40 (s, 1H), 7.93 (d, J=9.14 Hz, 2H), 7.67 (d, J=2.07 Hz, 1H), 7.37 (s, 1H), 7.13 (d, J=8.72 Hz, 1H), 6.94 (d, J=8.72 Hz, 2H), 3.99 (s, 3H), 2.14 (s, 3H), LRMS (M+): 432.3, (M-): 430.2. |
[ 1470-57-1 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | Compound 161: {2-[(6,7-Dimethoxy-4-quinazolyl)oxy]-5-methylphenyl}-(phenyl)methanone; 4-Chloro-6,7-dimethoxyquinazoline (59 mg), 2-hydroxy-5-methylbenzophenone (279 mg), and 4-dimethylaminopyridine (168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160C for 10 min. The reaction solution was cooled to room temperature, the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (97 mg, yield 92%). 1H-NMR (CDCl3, 400 MHz): δ 2.46 (s, 3H), 3.90 (s, 3H), 4.01 (s, 3H), 7.03 (s, 1H), 7.19 (s, 1H), 7.22 - 7.27 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.33 - 7.39 (m, 1H), 7.43 - 7.49 (m, 2H), 7.67 - 7.73 (m, 2H), 8.49 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 401 (M+1)+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With hydrazine; In tetrahydrofuran; at 20℃; for 16h; | To a suspension of 4-Chloro-6,7-dimethoxy-quinazoline (0.20 g, 0.89 mmol) in anhydrous THF (0.5 ml) was added hydrazine (1M in THF, 2.0 ml, 2.0 mmol). The mixture was stirred at room temperature for 16 hours whereupon a precipitate had formed which was removed by filtration and washed with cold THF to give the desired product (177 mg, 91%) as a sticky off white solid which was sufficiently pure to be used without any further purification. m/z (LC-MS, ESP): 221 [M+H]+, R/T=2.48 mins. |
| 70% | With hydrazine hydrate; In tetrahydrofuran; at 20℃; for 16h; | Compound 7 (10 mmol) and hydrazine hydrate 85% (30 mmol) in 50 mL of THF was stirred for 16 h at room temperature. The reaction mixture was concentrated and allowed to cool. The solid product obtained was filtered, washed with water and dried. Recrystallization with ethanol and water afforded the desired solid compound 8, mp. 199-202 C in 70% yield. 1H NMR (DMSO-d6, 600 MHz) δ 3.84 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 4.56 (s, 2H, NH2), 7.08 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 8.37 (s, 1H, CH), 9.19 (s, 1H, NH). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 76% | A mixture of 3,3- dimethoxy-pyrrolidine (2.97 g, 17.8 mmol)and 4-chloro-6,7-dimethoxyquinazoline (4.38 g, 19.5 mmol) in THF (30 ml_)and satd. NaHCO3 (50 ml_) was heated to reflux for 5 h. The mixture was cooled and partitioned between water and ethyl acetate. The extract was washed with brine, and then extracted twice with 1 N HCI. After 20 min the combined acidic extracts were poured carefully into an excess of potassium carbonate in water. The mixture was then extracted three times with methylene chloride and the combined extracts were concentrated to a slurry. The slurry was diluted with an equal volume of hexanes and stirred over night. The EPO <DP n="41"/>resultant solids were collected via filtration and rinsed with ether to provide 3.71 g (76%) of the title compound as a tan powder. MS = 274.2. |
[ 2343-22-8 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | In isopropyl alcohol; | Example 17 4-(5-Fluoro-2,3-dihydro-indol-1-yl)-6,7-dimethoxy-quinazoline Utilizing a procedure analogous to that described in Example 1, this product was prepared in 81% yield from 5-fluoro-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq)in i-PrOH. (M.P. 190-191 C.; LC-MS: 326 (MH+); anal. RP18-HPLC RT: 4.40 min.). |
[ 13790-39-1 ]
[ 114744-51-3 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 11% | Example 103 4-(7-Bromo-3,4-dihydro-2H-quinolin-1-yl)-6,7-dimethoxy-quinazoline Utilizing a procedure analogous to that described in Example 1, this product was prepared in 11% yield from <strong>[114744-51-3]7-bromo-1,2,3,4-tetrahydroquinoline</strong> and 4-chloro-6,7-dimethoxy-quinazoline. (film; LC-MS: 399 (MH+)). |
[ 65826-95-1 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | In isopropyl alcohol; | Example 23 6,7-Dimethoxy-4-(5-methyl-2,3-dihydro-indol-1-yl)-quinazoline Utilizing a procedure analogous to that described in Example 1, this product was prepared in 94% yield from <strong>[65826-95-1]5-methyl-indoline</strong> (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 180-181 C.; GC/MS: 321 (M+); anal. RP18-HPLC RT: 4.37 min.). |
[ 666734-80-1 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | With caesium carbonate; In dimethyl sulfoxide; at 120℃; | Dimethylsulfoxide (2.5 ml) was added to 5,6-dimethyl-[2,2']bipyridinyl-3-ol (50 mg), <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (169 mg), and cesium carbonate (244 mg), and the mixture was stirred at 120C overnight. The reaction mixture was cooled to room temperature, water was added to the cooled mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with an ethyl acetate system to give the title compound (79 mg, yield 81%). 1H-NMR (CDCl3, 400 MHz): δ 2.41 (s, 3H), 2.63 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H), 7.06 (ddd, 7.6, 4.9, 1.2 Hz, 1H), 7.28 (s, 1H), 7.50 (s, 1H), 7.55 (s, 1H), 7.62 (ddd, J = 7.6, 4.9, 1.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 4.1 Hz, 1H), 8.48 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 411 (M+Na)+ |
[ 666734-82-3 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 84% | With dmap; In 1,2-dichloro-benzene; at 130℃; | 1,2-Dichlorobenzene (2.5 ml) was added to 5,6-dimethyl-[2,3']-bipyridinyl-3-ol (50 mg), <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (169 mg), and 4-dimethylaminopyridine(92 mg), and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, water was added to the cooled mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-acetone system to give the title compound (81 mg, yield 84%). 1H-NMR (CDCl3, 400 MHz): δ 2.40 (s, 3H), 2.62 (s, 3H), 4.04 (s, 3H), 4.05 (s, 3H), 7.23 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 7.29 (s, 1H), 7.45 (s, 1H), 7.47 (s, 1H), 8.09 (ddd, J = 7.8, 2.2, 2.2 Hz, 1H), 8.47 (dd, J = 4.9, 1.7 Hz, 1H), 8.55 (s, 1H), 9.04 (dd, J = 2.2, 0.8 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 411 (M+Na)+ |

[ 13790-39-1 ]
[ 71207-08-4 ]| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With potassium carbonate; In acetonitrile; at 90℃; | The piperidine salt 21 (84 mg, 0.346 mmol) was dissolved in acetonitrile (13.5 mL), K2CO3 (59.8 mg, 0.432 mmol), 4-chloro-2,6-dimethoxyquinazoline (64.8 mg, 0.288 mmol) was added and stirred overnight at 90 C. The solvent was removed under vacuum and the product was purified by flash column chromatography using CH2Cl2/CH3OH (95:5) to afford 28 as a beige solid (112 mg, 98%). Mp: 161-163 C; IR (ATR, ZnSe): ν (cm-1) 2908, 2850, 1545, 1474, 1244, 1007, 984, 861, 792, 704; 1H NMR (500 MHz, DMSO-d6): δ (ppm) 8.51 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.97 (t, J = 5.9 Hz, 1NH), 4.13 (d, J = 13.2 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.03-2.98 (m, 4H), 2.90 (s, 3H), 1.81 (d, J = 10.8 Hz, 2H), 1.68 (br s, 1H), 1.48 (q, J = 7.0 Hz, 2H), 1.36 (qd, J = 13.2, 3.7 Hz, 2H); 13C NMR (126 MHz, DMSO-d6): δ (ppm) 163.2, 154.1, 152.5, 148.4, 147.9, 110.5, 107.1, 103.4, 55.8, 55.5, 49.6, 40.0, 39.1, 36.0, 32.9, 31.5; HRMS-ESI calcd for C18H27N4O4 [M+H]+ 395.1748 found 395.1759. |
| With triethylamine; In ethanol; water; | EXAMPLE 1 Preparation of 6,7-Dimethoxy-4-[4-(2- methanesulphonamidoethyl) piperidino]quinazoline STR7 4-Chloro-6,7-dimethoxy quinazoline (1.1 g.), 4- (2-methanesulphonamidoethyl)piperidine hydrochloride (1.5 g.) and triethylamine (1.5 ml.) in ethanol (30 ml.) were heated together under reflux for 1.5 hours. The solution was then cooled to room temperature, concentrated in vacuo, suspended in water (70 ml.) and basified to pH 10 with 10% aqueous sodium carbonate solution. The mixture was extracted with chloroform (2*70 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant pale yellow oil was triturated with ether (70 ml.) to give a white solid which was collected by filtration. Crystallization of this solid from ethanol yielded 6,7-dimethoxy-4-[4-(2-methanesulphonamidoethyl)-piperidino]quinazoline (1.7 g.), m.p. 162-164 C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | 60% Sodium hydride dispersion (0.11 g, 2.7 mmol) was added portionwise to DMSO (3 mL)at 22"C under nitrogen. The resulting slurry was stirred at ambient temperature for 5 minutes.5 4-Amino-3-methoxyphenol (0.37 g, 2.7 mmol) was added to the mixture at 22 - 28C undernitrogen and the resulting grey slurry was stirred at ambient temperature for 5 minutes. 4-Chloro-6,7-dimethoxyquinazoline (0.5 g, 2.2 mmol) was added to the mixture at 22 - 28Cunder nitrogen. The resulting dark mixture was stirred at 60C for 30 minutes then at ambienttemperature for 3 hours. Water (40 mL) was added to the mixture. The resulting precipitate10 was collected by filtration and washed with water (2 x 10 mL). The solid was treated withmethanol (5 mL) and evaporated to afford the title compound as a grey solid (0.54 g, 75%),which was used without further purification. 1H NMR (500 MHz, DMSO, 27 oq 8 3.74 (3H,s), 3.96 (6H, d), 4.67 (2H, s), 6.59 (lH, dd), 6.67 (lH, d), 6.76 (lH, d), 7.35 (lH, s), 7.51 (lH,s), 8.51 (lH, s). m/z: ES+ [M+H]+ 328. | |
| 72% | With dimethyl sulfoxide; In methanol; water; | Production Example 5: 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline Sodium hydride (60 wt%, 3.2 g) was added to dimethyl sulfoxide (50 ml), and the mixture was stirredat 50C for 20 min. 4-Amino-3-methoxyphenol (5.6 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (7.0 g) was added thereto, and the mixture was stirred at 100C overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (7.3 g, yield 72%). Mass spectrometry value (ESI-MS, m/z): 328 (M++1) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 72h; | c. 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester; To a mixture of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (17.1 g, 70.5 mmol), as prepared in the previous step, and <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (15.0 g, 67.0 mmol) (Oakwood Products, Inc.) immersed in a -78 C. bath was added 1.08 M LiHMDS/THF (71 mL, 77 mmol) in 20 mL portions under argon via syringe along the sides of the flask (to allow cooling of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was allowed to sit in the -78 C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 18 h stirring at rt, and an additional 2 d sitting at rt, the mixture was quenched with 0.5 M NaH2PO4 (150 mL) and extracted with DCM (1×150 mL and 1×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide the crude title compound as a translucent yellow oil that was used in the next step without further purification (33 g, “114%” crude yield). A small sample was purified by flash chromatography (1:1 hex/EtOAc) for characterization. 1H-NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.76-3.67 (m, 2H), 3.62-3.49 (m, 2H), 3.61 (s, 3H), 2.50-2.36 (br s, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 431.2, found 432.2 (MH)+. |
[ 73874-95-0 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | To a stirred solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1) (1 g, 4.64 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1 .92 g, 13.92 mmol, 3 eq) and tert-buty piperidin-4-yl carbamate (2) (1 g, 5.35 mmol, 1.2 eq) at 0C. The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water and extracted with Ethyl acetate (2 X 70 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and concentrated under reduced pressure to afford crude. The crude purified by trituration with diethyl ether to afford tert-butyl (l -(6,7-dimethoxyquinazolin-4-yl) piperidin-4-yl) carbamate (01) (1.45 g, yield: 88%) as white solid. TLC system MeOH:DCM (5:95), Rf value:0.25; LCMS (m/z): 389.3 (M+H)+; 'HNMR (400 MHz, DMSO-d6) d 8.52 (s, 1H), 7.20 (s, 1H), 7.08 (s, 1H), 6.92 (d, ./= 7.6 Hz, 1H), 4.1 1-4.07 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.57-3.75 (m, 1 H), 3.15 (t, ./ = 1 1.6 Hz, 2H), 1.91-1.89 (m, 2H), 1 .64-1 .54 (m, 2H), 1.40 (s, 9H). |
| 78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 C. with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na2SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH+). |
| 78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | EXAMPLE 21; N-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-2-(4-isopropyl-phenyl)-acetamide (Compound No. 21); a. [1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester; To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 C. with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na2SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH+). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With potassium carbonate; In ISOPROPYLAMIDE; at 120℃; for 2h; | A mixture of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (0.50 g, 0.0022 mol),6-methoxycarbonyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.660 g, 2.90 mmol), potassium carbonate (0.923 g, 6.68 mmol) and N,N-dimethylacetamide (15 mL) was heated at 120 0C for 2 hours. The solvent was then evaporated, and the residue was diluted with ethyl acetate (100 mL) and washed with sodium bicarbonate (2 x 50 mL). The organics were separated and concentrated and the residue was purified by column chromatography (using 3% methanol in ethyl acetate/hexane 1 :1, ammonia 0.03%) to afford 675 mg (80 %) of methyl 2-(6,7-dimethoxyquinazolin-4-y I)- 1,2,3,4 tetrahydroisoquinoline-6-carboxylate as a pale yellow solid. |
[ 926926-67-2 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 53% | With potassium carbonate;tetra-(n-butyl)ammonium iodide; In ISOPROPYLAMIDE; at 140℃; for 2.5h; | 6-(2-Methoxyethoxy)-l,2,3,4-tetrahydroisoquinoline (29 mg, 0.14 mmol) was dissolved in 1.0 mL N,N-dimethylacetamide to give a clear, colorless solution. 4- Chloro-6,7-dimethoxyquinazoline (43.3 mg, 0.193 mmol) was added, resulting in the formation of a cloudy yellow suspension. Tetra-n-butylammonium iodide (16 mg, 0.043 mmol) and potassium carbonate (57.4 mg, 0.415 mmol) were subsequently added, and the reaction mixture was heated in a sealed tube at 140 0C for 2.5 hours. The reaction was concentrated to yield a brown solid. The brown solid was dissolved in ethyl acetate (30 mL) and the organic layer was washed with water (3 x 10 mL) and with brine (1 x 10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow-orange oil. Purification on a C18 column preparative (30 x 100 mm) HPLC column using a gradient of 20-80% acetonitrile:water (with 0.1% formic acid) and a flow rate of 45 mL/min yielded a yellow oil. The yellow oil was then loaded onto an SCX column (0.25g), washed with methanol, eluted with 4 mL ammonia in methanol (7M)5 and concentrated. Dissolution in dichloromethane, followed by concentration in vacuo afforded 29.3 mg (53 %) of 6,7-dimethoxy-4-[6-(2-methoxyethoxy)-3,4-dihydroisoquinolin-2(lH)-yl]quinazoline as a light yellow foam. MS [M+H] = 396.2, LC/MS (EI) tR 3.81 min (Method B), 1HNMR (CDCl3) δ (ppm) 8.18 (s, IH), 7.19 (s, IH), 7.10 (d, J = 9.0 Hz, IH), 6.82 (m, 2H), 4.78 (s, 2H), 4.13 (t, J = 6Hz5 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.93 (t, J = 6Hz5 2H), 3.77 (t, J = 6Hz, 2H), 3.47 (s, 3H), 3.15 (t, J = 6Hz, 2H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 59% | With caesium carbonate; In dimethyl sulfoxide; at 20 - 140℃; for 3h; | Example 1 Preparation of 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid 6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 38 ml of DMSO were stirred at room temperature while cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140 C. for 3 hours. The mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to 6.5. The deposited solids were collected by vacuum filtration, washed with H2O, dried under vacuum and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1). |
| 59% | Example 1 Preparation of 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid 6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) was dissolved in 38 ml of DMSO, then cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140 C for 3 hours. When the reaction was finished the mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to pH=6.5. The deposited solids were filtered, washed with H2O, dried and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With dmap; In dimethyl sulfoxide; at 80℃; for 3h; | A mixture of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (0.63 g, 2.80 mmol), 6- chloropyridin-3-oi (0.37 g, 2.84 mol), and DMAP (0.35 g, 2.84 mmol) in DMSO (3 mL) was stirred at 80 C for 3 h. The reaction mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and dried over sodium sulfate. The diying agent was filtered off, and the filtrate concentrated under reduced pressure to give a residue, which was purified by chromatography (ethyl acetate/hexanes = 6/4) to provide 4-((6-chloropyridin-3-yl)oxy)-6,7-dimethoxyquinazoline as a white solid (0.8 g,90%). fH NMR (DMSO-de, 300 MHz) 8 57 (s, 1H), 8.50 (d, ./= 3.0 Hz, 1H), 7.95 (dd, J= 8.7, 3.0 Hz, 1H), 7 67 (d, ,/ = 8.7 Hz, 1 1 1). 7 57 (s, 1 1 1). 7.40 (s, 1 1 1). 3.98 (s, 3H), 3.97 (s, 3H) ppm; MS m/e 318.1 (M i l) |
| 83% | Potassium t-butoxide (1 mL, 1 mmol, 1 M in THF) was added to 2-chloro-5-hydroxypyridine (198 mg, 1.5 mmol) under inert atmosphere. The reaction mixture was stirred at room temperature for 15 min, then a solution of 6,7-dimethoxy-4-chloroquinozoline (225 mg, 1 mmol) in DMSO (1 mL) was added. The resulting solution was heated to 75 C for 2 h. The reaction mixture was quenched with H20 (50 mL) and EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eluting with 60-(at)70% EtOAc in hexanes) to give 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinazoline (264 mg; 0.83 mmol; 83% yield) ; MS (APCI) (M+H)+ 318. ¹H NMR (400 MHz, CHLOROFORM-D) 6 ppm 4.04 (s, 3 H) 4.05 (s, 3 H) 7.42 (d, (at)8.6 Az, 1 H) 7.48 (s, 1 H) 7.63 (dd, J=8.6, 3.0 Hz, 1 H) 8.38 (d, JL2.8 Hz, 1 H) 8.57 (s, 1 H). | |
| 9.1g | With dmap; In dimethyl sulfoxide; at 20 - 80℃; for 2h;Inert atmosphere; | Under the argon, the DMAP (4.4g) added to the 4-chloro -6,7-dimethoxyquinazoline (8.0g) and 6-chloro-pyridine-3-ol (4.6g) of suspension in DMSO (20 ml), the bath temperature (80 C) heating and stirring 2 hours, at room temperature and to a cup. Later, the reaction solution is diluted with ethyl acetate, and washing water and saturated sodium bicarbonate aqueous solution. The organic layer is dried with anhydrous sodium sulfate and concentrated. The resulting residue with hexane-ethyl acetate (3:1) washing, to obtain the title compound (9.1g), which has the following physical property value. |
| 9.1 g | With dmap; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere; | Example 7 4-[(6-chloro-3-pyridinyl)oxy]-6,7-dimethoxy quinazoline Under an argon atmosphere, DMAP (4.4 g) was added to a DMSO suspension (20 mL) of 4-chloro-6,7 dimethoxy quinazoline (CAS registration No: 13790-39-1) (8.0 g) and 6-chloropyridine-3-ol (4.6 g), and the mixture was heated and stirred at a bath temperature (80C) for two hours. The mixture was allowed to cool to room temperature. The reaction solution was diluted with ethyl acetate, and washed with water and a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was washed with hexane-ethyl acetate (3:1) to obtain the title compound (9.1 g) having the following physical property values. TLC: Rf 0.16 (hexane: ethyl acetate =1:1); 1H-NMR (DMSO-d6): δ 3.97, 3.99, 7.41, 7.58, 7.69, 7.97, 8.50, 8.57. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 59% | With potassium carbonate; In acetonitrile; at 90℃; for 16h; | The piperidine salt 4 (195 mg, 0.80 mmol) was dissolved in acetonitrile (12 mL), K2CO3 (151 mg, 1.09 mmol), 4-chloro-2,6-dimethoxyquinazoline (163 mg, 0.73 mmol) was added and stirred overnight at 90 C. The solvent was removed under vacuum and the product was purified by flash column chromatography eluting using CH2Cl2/CH3OH (90:10) to afford the desired product QPS1 as a beige solid (170 mg, 59%). Mp: 156-160 C; IR (ATR, ZnSe): ν (cm-1) 3311, 2855, 1577, 1455, 1376, 1263, 861, 794; 1H NMR (500 MHz, DMSO-d6): δ (ppm) 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.50 (s, 2H), 4.14 (d, J = 13.1 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.02 (t, J = 11.8 Hz, 2H), 2.96-2.94 (m, 2H), 1.81 (d, J = 10.9 Hz, 2H), 1.74-1.65 (m, 1H), 1.51-1.47 (m, 2H), 1.41-1.32 (m, 2H); 13C NMR (126 MHz, MeOD-d4): δ (ppm) 165.2, 156.5, 153.4, 150.1, 149.4, 112.3, 107.0, 105.0, 56.6, 56.5, 51.3, 41. 6, 37.2, 34.8, 33.2; HRMS-ESI calcd for C17H26N5O4S [M+H]+ 396.1700 found 396.1710. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | In methanol; at 20℃; | General procedure: A solution of intermediate 2a (82 mg, 0.5 mmol, 1 eq) and 3-ethynylaniline (60 mg, 0.5 mmol, 1 eq) in 5 ml of methanol wasstirred at ambient temperature overnight. The resulting precipitatewas collected by filtration, and then dried under vacuum to givecompound 3d as white solid, yield 88%, m.p. 261.7 C. |
| In isopropyl alcohol; | Preparation of the 4-(3-ethynyl-phenyl)amino- 6,7-dimethoxy-quinazoIine 3 was achieved in four steps from the commercially available ester 1. (Knesl et al. (2006) Molecules, 11:286-297; Wright, et al. (2001) Bio-org. Med. Ch em. Lett., 1 /; 17-21. | |
| In isopropyl alcohol; | 3), lg (4.46 mmol) of compound 3 and lg (8.92 mmol) of 3-aminophenylacetylene were added to isopropanol. After 4_9h reaction, the isopropyl alcohol was spin dried and the compound 4 was isolated by silica gel column using dichloromethane-methanol as eluant |
| 20 g | With potassium carbonate; In acetone;Reflux; | To the reaction flask was added 200 mL of acetone,<strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong>22 g and m-aminophenylacetylene12g, stir and mix well before addingPotassium carbonate 30 g,Heated to reflux reaction, TLC monitoring of raw materials completely complete, the solvent solvent acetoneAfter adding 100 mL of water, the mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined and the organic phase was distilled off to give 20 g of 4-aminophenylacetylene-6,7-dimethoxyquinazoline. |
| 25 g | With potassium carbonate; In acetone;Reflux; | Acetone 200 mL was added to the reaction flask, and 22 g of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong>M-aminophenylacetylene12g, stir and then add potassium carbonate 30g, heated to reflux reaction, TLC monitoring raw material reaction is complete, the solvent CAfter the ketone was added 100mL of water, and then extracted twice with 200mL of ethyl acetate, the organic phases were combined, and the organic phase was evaporated to give 25g of 4-m-aminophenylacetylene-6,7-dimethoxyquinazoline |
| With N-ethyl-N,N-diisopropylamine; In ethanol; for 18h;Reflux; | General procedure: 4-chloroquin(az)olinederivative (1.0 eq.), aniline derivative (1.1 eq.), and iPr2NEt (2.5 eq.) were suspended inethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatographyusing EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solventremoval under reduced pressure, the product was obtained as a free following solid orrecrystallized from ethanol/water. |

[ 6859-99-0 ]
[ 31027-31-3 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | Racemic piperidin-3-ol (15 mg, 0.115 mmol) and <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (23 mg, 0.1 mmol) were dissolved in anhydrous dioxane. PS-NMM (Argonaut, Inc) (100 mg, 0.3 mmol) was added and the mixture was stirred at 100 C. for 3 h and then cooled to rt. PS-isocyanate (Argonaut, Inc) (100 mg, 0.3 mmol) was then added and the mixture was shaken at RT for 3 h. It was then filtered and the resins were washed with dioxane. To the combined filtrate and washings was added 4-isopropylphenylisocyanate (0.15 mmol) and the mixture was stirred at 100 C. for 3 h and then cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-1% MeOH/DCM) to obtain 31 mg (70%) of pure (4-isopropyl-phenyl)-carbamic acid 1-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-3-yl]ester. 1H NMR (300 MHz, CDCl3+CD3OD): δ 8.50 (s, 1H), 7.22 (s, 1H), 7.18-7.00 (m, 5H), 4.98 (m, 1H), 4.14-3.80 (m, 8H), 3.75-3.45 (m, 3H), 2.79 (m, 1H), 2.15-1.70 (m, 3H), 1.16 (d, 6H). LC/MS (ESI): calcd mass 450.2, found 451.4 (MH)+. | |
| 70% | EXAMPLE 31 (4-Isopropyl-phenyl)-carbamic acid 1-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-3-yl]ester (Compound No. 31) Racemic piperidin-3-ol (15 mg, 0. 115 mmol) and <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (23 mg, 0.1 mmol) were dissolved in anhydrous dioxane. PS-NMM (Argonaut, Inc) (100 mg, 0.3 mmol) was added and the mixture was stirred at 100 C. for 3 h and then cooled to rt. PS-isocyanate (Argonaut, Inc) (100 mg, 0.3 mmol) was then added and the mixture was shaken at RT for 3 h. It was then filtered and the resins were washed with dioxane. To the combined filtrate and washings was added 4-isopropylphenylisocyanate (0. 15 mmol) and the mixture was stirred at 100 C. for 3 h and then cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-1% MeOH/DCM) to obtain 31 mg (70%) of pure (4-isopropyl-phenyl)-carbamic acid 1-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-3-yl]ester. 1H NMR (300 MHz, CDCl3+CD3OD): δ 8.50 (s, 1H), 7.22 (s, 1H), 7.18-7.00 (m, 5H), 4.98 (m, 1H), 4.14-3.80 (m, 8H), 3.75-3.45 (m, 3H), 2.79 (m, 1H), 2.15-1.70 (m, 3H), 1.16 (d, 6H). LC/MS (ESI): calcd mass 450.2, found 451.4 (MH)+. |

[ 64-18-6 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | 4-Chloro-6,7-dimethoxyquinazoline (100 mg, 0.0004 mol), bis(triphenylphosphine)palladium(II) chloride (54.7 mg, 0.008 mmol), 1 -benzyl- lH-pyrazole- 4-boronic acid (130 mg, 0.00067 mol), 0.16 mL of 2.00 M of sodium carbonate in water and 2 mL of dimethoxyethane:water:ethanol (7:3:2) were combined in a 10 mL sealed tube. The reaction was subjected to microwave irradiation at 300 watts, 1400C for 600 seconds. The reaction contents were filtered through a pad of celite using methanol and then concentrated. EPO <DP n="96"/>The residue was purified by ISCO chromatography with 50% ethyl acetate:hexane followed by 70:30:1 ethyl acetate/methanol/ammonia to give 111 mg of 4-(l -benzyl- lH-pyrazol-4-y I)- 6,7-dimethoxyquinazoline hydroformate as a yellow solid. An additional 10 mg of crude product was purified by preparative HPLC using a gradient of 20-80% acetonitrile (0.1% formic acid). Overall yield 113 mg (70%). MS [M+H] = 347.2, LC/MS (EI) tR 5.72 min (Method B), 1H NMR (CDCl3) δ (ppm) 1HNMR P1OS (s, 1 H), 8.16 (s, 1 H), 8.07 (s, 1 H), 7.48 (s, 1 H), 7.40-7.34 (m, 5 H)5 7.32 (s, 1 H), 5.42 (s, 2 H), 4.06 (s, 3 H), 3.96 (s, 3 H). |

[ 13790-39-1 ]
[ 926926-29-6 ]| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 40% | 4,5,6,7-Tetrahydro-lH-pyrazolo[3,4-c]pyridine dihydrochloride (0.450 g, 2.29 mmol) in N,N-dimethylacetamide (10.00 rnL) was treated with N,N- diisopropylethylamine (1.74 mL, 9.97 mmol) at 100 0C for 5 minutes. 4-chloro-6,7- dimethoxyquinazoline (0.448 g, 1.99 mmol) and tetra-n-butylammonium iodide (0.0560 g, 0.152 mmol) were then added and the mixture was heated at 120 0C for 6 hours. The solvent was evaporated and the residue was diluted with 10% methanol/dichloromethane (60 mL) and filtered. The filtrate was concentrated and purified by column chromatography (using A- 10% methanol/dichloromethane) to afford 250 mg (40 %) of 6,7-dimethoxy-4-(l, 4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridin-6- yl)quinazoline as a yellow solid. 1HNMR (DMSO) δ (ppm) 8.87 (s, IH), 8.86 (s, IH), 8.52 (s, IH), 7.36 (s, IH), 3.99 (s, 3H), 3.90 (s, 3H), 3.83 (s, 2H), 2.99 (t, J=5.7 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H), [M+H] = 312.1, LC/MS (EI) tR 3.91 min (Method I). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77.9% | A solution of 3-aminophenol (0.35 g, 3.2 mmol) in dry DMF (20 mL) was treated with potassiumtert-butoxide (0.44 g, 3.9 mmol), and the mixture was stirred at room temperature for 1 h undernitrogen atmosphere, then a solution of 6 (0.76 g, 3.4 mmol) in DMF (50 mL) and potassium carbonatewere added respectively. The mixture was heated to 80-85 C for 2 h. After the temperature was cooled to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc(3 100 mL). The extract was washed with brine (2 100 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give light-brown solid 7a 0.74 g, yield: 77.9%,m.p. 183.5-185.0 C. 1H-NMR (400 MHz, DMSO-d6) 3.97 (s, 3H, O-CH3), 3.98 (s, 3H, O-CH3),5.28 (s, 2H, -NH2), 6.98 (dd, J = 1.6 Hz, 9.6 Hz, 1H, Ph-H-6), 7.13 (d, J = 7.6 Hz, 1H, Ph-H-4),7.23 (d, J = 1.6 Hz, 1H, Ph-H-2), 7.43 (t, J = 7.8 Hz, 1H, Ph-H-5), 7.55 (s, 1H, quinazoline H-5), 7.63 (s, 1H,quinazoline H-8), 8.56 (s, 1H, quinazoline H-2). HRMS (AP-ESI) m/z: calcd. for C16H15N3O3 [M + H]+298.1192, found 298.1199. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69% | In isopropyl alcohol;Reflux; | General procedure: A mixture of compound 2 (1.82 g, 8.8 mmol) and DMF (30 drops) in SOCl2 (50 mL) was refluxed for 7 h. The excess SOCl2 was removed by vacuum distillation. The residue was stirred with diethyl ether, filtered, washed, and dried to give compound 3 as a beige solid (1.83 g, 92%). A mixture of compound 3 and various amines in 2-propanol or DMF was refluxed. Upon completion of the reaction, it was cooled in an ice bath. The residue was filtered, washed, and dried to isolate the product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | In acetonitrile; at 100℃; for 24h; | General Procedure: 4-Aminoquinazolines were prepared according to literature methods with a slight procedural modification. A typical procedure utilized is demonstrated for compound 10 as a representative example. In a 25 mL seal-tube reaction vessel equipped with a magnetic stirrer, 100.0 mg (0.445 mmol) of 4-chloro-6,7-dimethoxy-quinazoline was added followed by 2.0 mL of acetonitrile and 62.5 mg (0.490 mmol) of 4-chloroaniline. The vessel was sealed and heated to 100 C. After stirring at said temperature for a period of one day, the reaction was cooled,solvent evaporated via speed-vac, and tritiated three times with cold acetonitrile. Any remaining solvent was evaporated in vacuo to afford 140 mg (quantitative yield) of 10 as a white crystalline solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 74% | General procedure: A solution of 3-aminophenol (0.35 g, 3.2 mmol) in dry DMF (20 mL) was treated with potassiumtert-butoxide (0.44 g, 3.9 mmol), and the mixture was stirred at room temperature for 1 h undernitrogen atmosphere, then a solution of 6 (0.76 g, 3.4 mmol) in DMF (50 mL) and potassium carbonatewere added respectively. The mixture was heated to 80-85 C for 2 h. After the temperature wascooled to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc(3 100 mL). The extract was washed with brine (2 100 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give light-brown solid 7a 0.74 g, yield: 77.9%,m.p. 183.5-185.0 C. |
[ 1154276-93-3 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 35% | With hydrogenchloride; In isopropyl alcohol; at 150℃; under 4500.45 Torr; for 0.25h;Microwave irradiation; | EXAMPLE 1 3-[6J-bis(methyloxy)-4-quinazolinyl]amino}-4-(dimethylmethylbenzenesulfonamide hydrochloride•2 HClTo a mixture of 3-amino-4-(dimethylamino)-//-methylbenzenesulfonamide (0.1 OOg, 0.434mmol) and 4-chloro-6,7-bis(methyloxy)quinazoline (0.075 g, 0.334 mmol) in isopropanol (2 ml.) was added HCl (0.334 ml_, 0.334 mmol). The resulting mixture was then subjected to microwave irradiation (150 C, 6 bar) for 15 minutes. The mixture was then concentrated and purified via column chromatography (5-10% MeOH/Ch^C ) to give an orange solid that was triturated with EtOAc and dried to afford 3-[6,7-bis(methyloxy)-4- quinazolinyl]amino}-4-(dimethylamino)-//-methylbenzenesulfonamide (54 mg, 35% yield) as orange crystals. |
[ 13790-39-1 ]
[ 186544-90-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With trifluoroacetic acid; In isopropyl alcohol; at 85℃; for 0.5h;Inert atmosphere; | General procedure: To a solution of 13a-u (0.4 mmol) and <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (0.09g, 0.4 mmol) in isopropanol (10 mL) were added two drops of trifluoroacetic acid (TFA). The reaction was refluxed at 85 oC for 30 min. Upon completion, the reaction mixture is cooled to 0 oC in an ice bath. The precipitated solid was filtered and washed with cold methanol and dried to give the title compounds 14a-u. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | In isopropyl alcohol;Reflux; | General procedure: A mixture of substituted 4-chloroquinazoline (2 mmol) and 3-or 4-aminoacetophenone (2 mmol) was dissolved in hot 2-propanol (25 ml) and refluxed for 1-2 h. After completion of the reaction the formed precipitate was filtered off and washed with 2-propanol (15 ml). The product was recrystallized from ethanol. 5.4.3 1-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenyl)ethanone (11) The product was synthesized from <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (6) (1.25 mmol, 280 mg) and 4-aminoacetophenone (1.25 mmol, 168 mg) to yield pale yellow solid (94%). 1H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 8.04-8.01 (m, 2H), 7.98-7.94 (m, 2H), 7.41 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 2.59 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 196.95, 158.11, 156.58, 150.42, 148.66, 141.64, 136.19, 133.99, 128.88 (2C), 124.03 (2C), 107.81, 104.37, 99.96, 57.26, 56.59, 26.74. |
| 64% | In isopropyl alcohol; at 90℃; | General procedure: A mixture of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1 mmol), aniline (1 mmol) and 2-propanol (5 ml) was refluxed at 90C with stirring on oil bath for 2-3 h. Upon completion of the reaction as indicated by a single spot in TLC (Chloroform/Methanol 9:1 asmobile phase), the reaction mixture is cooled to ambient temperature and the solid product precipitated out is filtered. The filtered product is washed with cold 2-propanol and dried. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 78% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h; | A solution of Compound 10 (739 mg, 3.3 mmol), 4-Fluoro-2-methyl-1H-indol-5-ol (530 mg, 3.3 mmol), and potassium carbonate (920 mg, 6.7 mmol) in dry dimethyl formamide (10 mL) was heated to 100 C. and stirred for 24 hours. The solution was cooled to room temperature and the solvent evaporated by rotary evaporator. Remaining residue was co-evaporated with methanol (20 mL) and dichloromethane/methanol (50 mL). The product residue was precipitated from water (20 mL) and filtered. Solids were washed with water (20 mL), hexanes (20 mL), and diethyl ether (20 mL). Product was dried under high vacuum to give 910 mg of Compound 11 (yield=78%) as a brown powder |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 110℃; for 0.5h;Microwave irradiation; | General procedure: Preparation of compounds V: 241, V: 243-V: 245 A sample of 3H-spiro [isobenzofuran- 1 ,4?-piperidine] hydrochloride (1.2 equiv), corresponding 4-chloro quinazolines (1 equiv.) and DIEA (2 equiv.) was taken in a microwave vial and was added i-PrOH. The reaction mixture was heated to 110 °C for 30 mm in microwave. The solvents were concentrated in vacuo, the residue partitioned between EtOAc and H20, organic layer separated, washedwith sat. brine solution, dried over anhyd. Na2SO4, solvents removed in vacuo and the crude was purified by column chromatography to obtain desiredproducts in 3 5-70percent yields. |
[ 85926-99-4 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | In acetonitrile;Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. |
[ 13790-39-1 ]
[ 113512-71-3 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. |

[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; | General procedure: Pivaloylacetonitrile 4.07 g (32 mmol) and Phenylhydrazine 3.51 g (32 mmol) were added to40 mL ethanol and the mixture was heated to reflux for 15 h. After the solvent was evaporated,[3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine] was obtained. 138.6 mg (1 mmol) hydroxybenzoic acid in5 mL THF was added three drops of DMF and reacted with oxalyl chloride 0.5 mL in 0 C. After 1.5 hreaction, the reaction liquid was dissolved in THF and HCl, which was dissolved in THF solution of3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine. After 3 h, the reaction mixture was evaporated; the crudeproduct was purified by column chromatography to obtain compound 8. Compound 8 was furtherreacted with compounds 5, 6, 7 in the presence of K2CO3 to obtain the final products 9a-c. Compound 9a: N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-((6,7-dimethoxyquinazolin-4-yl)oxy)benzamide. White solid, yield 88%, m.p. 217-219 C. 1H-NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 8.57 (s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.79 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.57(s, 1H), 7.54 (s, 2H), 7.52 (s, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.40 (s, 1H), 7.31 (t, J = 7.3 Hz, 1H), 6.40 (s, 1H),4.01(s, 3H), 3.97(s, 3H), 1.31 (s, 9H). HRMS (m/z): calcd. for 524.2292 ([M + H]+), obsd. 524.2294. |

[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; | General procedure: 138.6 mg (1 mmol) hydroxybenzoic acid in 5 mL THF was added three drops of DMF and reactedwith oxalyl chloride 0.5 mL in 0 C. After 1.5 h reaction, the reaction liquid was dissolved in THFand HCl, which was dissolved in THF solution of aniline derivatives. After 3 h, the reaction mixturewas evaporated; the crude product was purified by column chromatography to obtain compounds 10.Compounds 10 were further reacted with compounds 5, 6, 7 in the presence of K2CO3 to obtain thefinal products 11a-i. Compound 11a: N-(3,4-dimethoxyphenyl)-3-((6,7-dimethoxyquinazolin-4-yl)oxy)benzamide. Yellowsolid, yield 86%, m.p. 220-222 C. 1H-NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.90 (s, 1H), 7.81 (d,J = 7.4 Hz, 2H), 7.60 (t, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.47 (t, 2H), 7.33 (s, 1H), 6.99 (dd, J = 8.6, 2.3 Hz, 1H),6.84 (d, J = 8.6 Hz, 1H), 4.07 (d, J = 2.8 Hz, 6H), 3.90 (d, J = 5.2 Hz, 3H), 3.87 (s, 3H). 13C-NMR (100 MHz,CDCl3) δ 166.79, 165.05, 154.75, 153.84, 153.57, 149.95, 148.67, 148.21, 138.69, 132.68, 129.19, 126.27,122.57, 122.29, 118.41, 114.98, 113.43, 111.44, 108.20, 107.06, 56.83.HRMS (m/z): calcd. for 462.1660([M + H]+), obsd.462.1665. calcd. for 484.11478 ([M + Na]+), obsd.484.1490. |
[ 73544-82-8 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; | General procedure: 138.6 mg (1 mmol) hydroxybenzoic acid in 5 mL THF was added three drops of DMF and reactedwith oxalyl chloride 0.5 mL in 0 C. After 1.5 h reaction, the reaction liquid was dissolved in THFand HCl, which was dissolved in THF solution of aniline derivatives. After 3 h, the reaction mixturewas evaporated; the crude product was purified by column chromatography to obtain compounds 10.Compounds 10 were further reacted with compounds 5, 6, 7 in the presence of K2CO3 to obtain thefinal products 11a-i. |

[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; | General procedure: 138.6 mg (1 mmol) hydroxybenzoic acid in 5 mL THF was added three drops of DMF and reactedwith oxalyl chloride 0.5 mL in 0 C. After 1.5 h reaction, the reaction liquid was dissolved in THFand HCl, which was dissolved in THF solution of aniline derivatives. After 3 h, the reaction mixturewas evaporated; the crude product was purified by column chromatography to obtain compounds 10.Compounds 10 were further reacted with compounds 5, 6, 7 in the presence of K2CO3 to obtain thefinal products 11a-i. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88.6% | With ammonium hydroxide; In ethanol; at 60℃; for 8h; | General procedure: To a solution of aryl halide (9a-b) (0.446 mmol) in ethanol(5 mL) was added ammonium hydroxide (5 mL), the mixture was heated at 60C overnight. Then the mixture was evaporated under reduced pressure to eliminate ethanol, and placed in the ice water bath for dissociation. Solid precipitation was obtained after filtration. |
| 88.6% | With anmonia source; In ethanol; at 60℃; for 8h; | General procedure: To a solution of aryl halide (9a-b) (0.446 mmol) in ethanol(5 mL) was added ammonium hydroxide (5 mL), themixture was heated at 60C overnight. Then the mixture wasevaporated under reduced pressure to eliminate ethanol, andplaced in the ice water bath for dissociation. Solid precipitationwas obtained after filtration. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With potassium tert-butylate; palladium diacetate; triphenylphosphine; potassium thioacetate; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | Under a nitrogen atmosphere,The substrate <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> 1r (0.2 mmol, 44.8 mg) was added to a 25 mL test tube reactor,KSAc(0.6mmol,68.4mg),DMC(1.0mmol,90mg),Pd(OAc)2(0.01mmol,2.3mg),PPh3(0.02mmol,5.9mg),tBuOK(0.6mmol,69.2mg),and DMSO(2.0mL).were added and the reaction was heated to 120 C to carry out the reaction.After the TLC detection reaction was completed,The system was cooled to room temperature.The reaction was quenched with saturated aqueous ammonium chloride,And extracted with ethyl acetate (3 * 10 mL)Column chromatography gave the product 2 r 40.1 mg (85%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With C45H39BrNiOP2; lithium tert-butoxide; phenylboronic acid; In toluene; at 110℃; for 16h;Inert atmosphere; Glovebox; Sealed tube; | General procedure: In a nitrogen atmosphere glove box C1 (5 mol%, 0.05 mmol),phenylboronic acid (5 mol%, 0.015 mmol), LiOt-Bu (1.5 mmol),(hetero)aryl chloride (1 mmol), amine/azole (1.1 mmol), anddry, degassed toluene (10 mL) were added to an oven-dried 4dram vial containing a magnetic stir bar. The vial was sealedwith a screw cap featuring a PTFE/silicone septum and removedfrom the glove box. The reaction mixture was magneticallystirred in a temperature-controlled aluminum heating block setto 110 C for 16 h (unoptimized). The reaction mixture was thencooled to r.t., taken up in EtOAc (ca. 30 mL) and washed withbrine (3 × 50 mL). The organic layer was separated, dried overNa2SO4, filtered, and concentrated with the aid of a rotary evaporatorto afford the crude product, which was purified via chromatographicmethods (see the Supporting Information for completedetails). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With potassium hydroxide; In tetrahydrofuran; water; at 75℃; for 24h; | To a solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (8.00 g, 35.6 mmol) in 72 mL of H2O and 40 mL of THF was added a solution of KOH (7.0 g, 0.12 mol) in 14 mL of H2O. The mixture was stirred 24 h at 75 C. Acetic acid (6.4 mL) was added and the precipitate was filtrated and rinsed with H2O and Et2O. A yellow solid (6.64 g) was obtained in 91% yield. Mp: 300-302 C; IR (ATR, ZnSe): ν (cm-1) 2822, 1649, 1488, 1272, 1218, 1079, 900, 874, 786, 727; 1H NMR (500 MHz, DMSO-d6): δ (ppm) 12.08 (s, 1H), 7.98 (s, 1H), 7.43 (s, 1H), 7.12 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ (ppm) 160.1, 154.4, 148.5, 144.9, 143.9, 115.6, 108.0, 104.9, 55.9, 55.7. HRMS-ESI calcd for C10H10N2O3 [M+H]+ 207.0764 found 207.0765. |

[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | With potassium carbonate; In acetonitrile; at 90℃; | The piperidine salt 23 (65 mg, 0.314 mmol) was dissolved in acetonitrile (15.7 mL), K2CO3 (54.3 mg, 0.393 mmol), 4-chloro-2,6-dimethoxyquinazoline (58.9 mg, 0.262 mmol) was added and stirred overnight at 90 C. The solvent was removed under vacuum and the product was purified by flash column chromatography using CH2Cl2/CH3OH (95:5) to afford 29 as a beige solid (87 mg, 93%). Mp: 161-163 C; IR (ATR, ZnSe): ν (cm-1) 3202, 2903, 2834, 1618, 1516, 1400, 1154, 985, 930, 678; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.64 (s, 1H), 7.24 (s, 1H), 7.08 (s, 1H), 5.48 (br s, 1H), 4.18 (d, J = 12.5 Hz, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.35 (q, J = 6.7 Hz, 2H), 3.05 (t, J = 12.4 Hz, 2H), 1.99 (s, 3H), 1.90 (d, J = 12.4 Hz, 2H), 1.65 (br s, 1H), 1.58-1.42 (m, 4H); 13C NMR (126 MHz, CDCl3): δ (ppm) 170.2, 164.2, 154.5, 153.0, 148.8, 148.4, 111.5, 107.3, 103.3, 56.3, 56.1, 50.2, 37.2, 36.5, 34.0, 32.2, 23.4; HRMS-ESI calcd for C19H27N4O3 [M+H]+ 359.2078 found 359.2095. |
[ 929302-18-1 ]
[ 13790-39-1 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h; | [0513] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (0.2 g, 0.89 mmol) in DMF (10 mL) was added K2CO3 (0.184 g, 1.33 mmol) followed by <strong>[929302-18-1]2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-ium hydrochloride</strong> (0.221 g, 0.979 mmol). Reaction mixture was stirred for 16 h at 90 °C. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 50mL). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using ethyl acetate in hexaneto afford tert-butyl 7-(6,7- dimethoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3g, 81percent) as an off white solid. LC-MS (ES) m/z =415.2 [M+H]+. |
Tags: 4-Chloro-6,7-dimethoxyquinazoline | Quinazolines | Chlorides | Ethers | Organic Building Blocks | Heterocyclic Building Blocks | 13790-39-1
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