Structure of 63920-73-0
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CAS No. : | 63920-73-0 |
Formula : | C9H12N2O3 |
M.W : | 196.20 |
SMILES Code : | COC1=CC(OC)=C(C(N)=O)C(N)=C1 |
MDL No. : | MFCD20040374 |
InChI Key : | LSDUYZHWQMMNCO-UHFFFAOYSA-N |
Pubchem ID : | 20349016 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-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 |
---|---|---|
79.9% | With toluene-4-sulfonic acid; sodium hydrogensulfite In ISOPROPYLAMIDE at 115℃; | Intermediate 2 (58.74 kg), ?/,?/-dimethylacetamide (280 kg), and starting material 3 (56.00 kg) were combined and p-toluenesulfonic acid monohydrate (5.90 kg) and 1/3 of the required sodium bisulfite (24.1 kg) were added. The mixture was heated to 115 0C and stirred for 90-105 minutes before the second 1/3 of the required sodium bisulfite (24.1 kg) was added. The remaining sodium bisulfite (24.1 kg) was added after another 90-105 minutes. The reaction mixture was stirred at 115 0C until the reaction was complete as determined by HPLC (approximately 1 hour, less than 4percent of intermediate 2 remaining). The reaction mixture was cooled to 25 0C and added to water (1770 kg). The mixture was stirred at 20 0C for 6 hours to complete the crystallization. The crude material was isolated by filtration, washed with water (234 kg) and dried under vacuum to constant weight. The crude material was dissolved in ?/,?/-dimethylacetamide (252 kg) at 80 0C until all material had dissolved. The solution was cooled to 60 0C and heptane (918 kg) was slowly added over a period of 1 hour, maintaining a temperature above 35 0C.The solution was cooled to 35 0C and stirred at 35 0C for a minimum of 1 hour. The solid was isolated by filtration, washed with heptane (250 kg) and dried to constantweight under vacuum. Yield: 92.5percent; purity: 98.6percent. The dry solid (83.1 kg) was added to a 1 :1 mixture of ethanol and water (1V/1V; 1670 kg), and the mixture was heated to approximately 840C (reflux) until all material was in solution. The solution was cooled to 70 0C and polish-filtered, and then cooled to 30 0C over 2 hours. The solution was cooled to 0 0C. The mixture was stirred at 0 0C for at least 1 hour, before the material was isolated by filtration, washed with ethanol/water (1V/1V; 33 kg) and dried under vacuum to constant weight. The material was passed through a 60-mesh screen to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (4). Yield: 66.4 kg; 79.9percent. |
62.7% | With toluene-4-sulfonic acid; sodium hydrogensulfite In 1-methyl-pyrrolidin-2-one at 130℃; for 3 h; Inert atmosphere | The intermediate H30-3 (15.2 g, 77.5 mol), H30-5 (15.06 g, 77.5 mmol), NAHSO3 (8.9 g, 85.3 mmol), P-TSA(1.34 g, 7.75 mmol), and NMP (140 mL) were added into a flask in the presence of nitrogen gas. The mixture was stirredfor 3 h at 130 °C. After the completion of the reaction detected by TLC, the mixture was extracted by adding water (450mL) and DCM (500 mL). The separated aqueous layer was extracted with DCM (4 3 400 mL). The resulting organiclayers were combined, washed with water (3 3 400 mL), dried by adding sodium sulfate, and filtered. The resultingfiltrate was distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography(eluent: dichloromethane: methanol = 80: 1) to give the intermediate H130: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (18 g, yield 62.7percent). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; for 14 h; | A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyidimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39percent) as a white solid. Selected data: 229-231° C.Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaidehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50percent ethyl acetate in hexane as eluent) to give 33.3 g (95percent) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5percent methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52percent). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; for 14 h; | To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5percent methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52percent). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; for 14 h; | At 70deg.] C 2-Amino-4,6-dimethoxy-benzamide(0.60g, 3.06mmol) and 4- [2- (tert-butyldimethylsilyloxy)ethoxy]-3,5-dimethyl-benzaldehyde(0.856g,2.78mmol)in N, N- dimethylformamide(20 mL) was stirred for 1hour. Was added iodine (0.846g, 3.33mmol)and potassium carbonate (0.384g, 2.78mmol), thereaction mixture was at 70 stirred for 16 hours. The reactionmixture was poured onto ice, extracted with ethyl acetate. With water, theorganic layer was washed with brine, dried over anhydrous Na 2SO 4dry. The solvent was removed to give acrude product, which was purified by column chromatography to give a white solid of 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-methoxy-quinazolin -4 (3H) - one (444mg, 39percent). Selected data: 229-231 . Alternatively, 2- (4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazolin -4 (3H) - onecan be synthesized by the following method. In ethanol (350 mL of) of 3,5-dimethyl-4-hydroxy-benzaldehyde(26.9g, 0.179mol) disposed dried 2L round bottomed flask with refluxcondenser and magnetic stirrer. 2-chloro-ethanol(87.6g, 1.074mol) and K 2CO 3(99g, 0.716mol),the reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled toroom temperature and filtered. The solvent was removed under reduced pressure.The crude product was diluted with ethyl acetate, and the organic layer waswashed with water, brine, Na 2SO 4dry. 45g crude product obtained after removalof the solvent. The crude product was purified by column chromatography (silicagel 230-400 mesh; with 50percent hexanes in ethyl acetate as eluent) to afford 33.3g (95percent) of product. 2-amino-4,6-dimethoxy - benzamide (33.45g, 0.170mol)and 4- (2-hydroxyethoxy) -3,5-dimethyl benzaldehyde(33.3g, 0.170 mol) was added NaHSO3(33.3g,0.187mol) in N,N- dimethylacetamide (300mL) solution of and p-TSA(3.2g, 17.1mmol), at 150 reaction mixturewas heated for 14 hours.The reaction was cooled to room temperature. The solvent was removed underreduced pressure. The residue was diluted with water, followed by stirring at room temperature for30 minutes. The solid was isolated by filtration and dried to give the crudeproduct. The crude product was purified by column chromatography (silica gel230-400 mesh; used in CH 2Cl 25percent methanol as eluent) to afford 2- (4- (2-hydroxyethoxy) -3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazoline -4 (3H) - one (33g, 52percent). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite In ISOPROPYLAMIDE at 150℃; for 14 h; | A solution of 2-amino-4,6-dimethoxyben2amide (0.60 g, 3.06 mmol) and 4-t2-(tert-butyldimethylsflanoxy)ethoxy]-3,5-dfmethylbenzaldehyde (0.856 g, 2.78 mmol) in λ/,/V-dimethyl formamide (20 mL) was stirred at 70°C for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70°C for 16 h, The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-{2- hydroxyethoxy)-3,5-dimethylphenyl)-5.7-dimethoxyquinazolin-4(3H)-one (444 mg, 39percent) as a white solid. Selected data: 229-231°C.[0117] Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was <n="65"/>placed 3, 5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50percent ethyl acetate in hexane as eluent) to give 33.3 g (95percent) of product, To a solution of 2-amino-4, 6- dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3, 5- dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSOs (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150°C for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5 percent methanol in CHzCI2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (33 g, 52percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With iodine; potassium carbonate In N,N-dimethyl-formamide at 70℃; for 17 h; | A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyidimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39percent) as a white solid. Selected data: 229-231° C.Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaidehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50percent ethyl acetate in hexane as eluent) to give 33.3 g (95percent) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5percent methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52percent). |
39% | Stage #1: at 70℃; for 1 h; Stage #2: With iodine; potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16 h; |
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one [0476] A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39percent) as a white solid. Selected data: 229-231° C. |
39% | Stage #1: at 70℃; for 1 h; Stage #2: at 70℃; for 16 h; |
At 70deg.] C 2-Amino-4,6-dimethoxy-benzamide(0.60g, 3.06mmol) and 4- [2- (tert-butyldimethylsilyloxy)ethoxy]-3,5-dimethyl-benzaldehyde(0.856g,2.78mmol)in N, N- dimethylformamide(20 mL) was stirred for 1hour. Was added iodine (0.846g, 3.33mmol)and potassium carbonate (0.384g, 2.78mmol), thereaction mixture was at 70 stirred for 16 hours. The reactionmixture was poured onto ice, extracted with ethyl acetate. With water, theorganic layer was washed with brine, dried over anhydrous Na 2SO 4dry. The solvent was removed to give acrude product, which was purified by column chromatography to give a white solid of 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-methoxy-quinazolin -4 (3H) - one (444mg, 39percent). Selected data: 229-231 . Alternatively, 2- (4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazolin -4 (3H) - onecan be synthesized by the following method. In ethanol (350 mL of) of 3,5-dimethyl-4-hydroxy-benzaldehyde(26.9g, 0.179mol) disposed dried 2L round bottomed flask with refluxcondenser and magnetic stirrer. 2-chloro-ethanol(87.6g, 1.074mol) and K 2CO 3(99g, 0.716mol),the reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled toroom temperature and filtered. The solvent was removed under reduced pressure.The crude product was diluted with ethyl acetate, and the organic layer waswashed with water, brine, Na 2SO 4dry. 45g crude product obtained after removalof the solvent. The crude product was purified by column chromatography (silicagel 230-400 mesh; with 50percent hexanes in ethyl acetate as eluent) to afford 33.3g (95percent) of product. 2-amino-4,6-dimethoxy - benzamide (33.45g, 0.170mol)and 4- (2-hydroxyethoxy) -3,5-dimethyl benzaldehyde(33.3g, 0.170 mol) was added NaHSO3(33.3g,0.187mol) in N,N- dimethylacetamide (300mL) solution of and p-TSA(3.2g, 17.1mmol), at 150 reaction mixturewas heated for 14 hours.The reaction was cooled to room temperature. The solvent was removed underreduced pressure. The residue was diluted with water, followed by stirring at room temperature for30 minutes. The solid was isolated by filtration and dried to give the crudeproduct. The crude product was purified by column chromatography (silica gel230-400 mesh; used in CH 2Cl 25percent methanol as eluent) to afford 2- (4- (2-hydroxyethoxy) -3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazoline -4 (3H) - one (33g, 52percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 5h; | To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 3.4 g of crude product in 83% yield.LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0 C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78 C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78 C. The reaction mixture was stirred for 15 min at -78 C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78 C. and the mixture was stirred at -78 C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude <strong>[82413-63-6]4-morpholin-4-ylmethyl benzaldehyde</strong> (1.6 g, 81%).To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and <strong>[82413-63-6]4-morpholin-4-ylmethyl benzaldehyde</strong> (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150 C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208 C. (at decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.9% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In ISOPROPYLAMIDE; at 115℃; | Intermediate 2 (58.74 kg), ?/,?/-dimethylacetamide (280 kg), and starting material 3 (56.00 kg) were combined and p-toluenesulfonic acid monohydrate (5.90 kg) and 1/3 of the required sodium bisulfite (24.1 kg) were added. The mixture was heated to 115 0C and stirred for 90-105 minutes before the second 1/3 of the required sodium bisulfite (24.1 kg) was added. The remaining sodium bisulfite (24.1 kg) was added after another 90-105 minutes. The reaction mixture was stirred at 115 0C until the reaction was complete as determined by HPLC (approximately 1 hour, less than 4% of intermediate 2 remaining). The reaction mixture was cooled to 25 0C and added to water (1770 kg). The mixture was stirred at 20 0C for 6 hours to complete the crystallization. The crude material was isolated by filtration, washed with water (234 kg) and dried under vacuum to constant weight. The crude material was dissolved in ?/,?/-dimethylacetamide (252 kg) at 80 0C until all material had dissolved. The solution was cooled to 60 0C and heptane (918 kg) was slowly added over a period of 1 hour, maintaining a temperature above 35 0C.The solution was cooled to 35 0C and stirred at 35 0C for a minimum of 1 hour. The solid was isolated by filtration, washed with heptane (250 kg) and dried to constantweight under vacuum. Yield: 92.5%; purity: 98.6%. The dry solid (83.1 kg) was added to a 1 :1 mixture of ethanol and water (1V/1V; 1670 kg), and the mixture was heated to approximately 840C (reflux) until all material was in solution. The solution was cooled to 70 0C and polish-filtered, and then cooled to 30 0C over 2 hours. The solution was cooled to 0 0C. The mixture was stirred at 0 0C for at least 1 hour, before the material was isolated by filtration, washed with ethanol/water (1V/1V; 33 kg) and dried under vacuum to constant weight. The material was passed through a 60-mesh screen to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (4). Yield: 66.4 kg; 79.9%. |
75% | With sodium hydrogen sulfate; toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 120℃; for 16.0h; | NaHSO3 (0.95 g5 mmol) and toluene-4-sulfonic acid (1.25 g, 12 mmol) added to a solution of 13 (1.96 g, 10 mmol) and 14 (2.13 g, 11 mmol) in DMF (30 mL), followed by warm to 120 C and reflux for 16 h. The resulting mixture was added water (20 mL), extracted using ethyl acetate, then RVX-208 (2.78g, 75 %, Mp: 594.2 ) as yellow solid was obtained after organic phase was dried overnight, filtered, vacuum distillated, purified by column chromatography (40:1, CH2Cl2/CH3OH). 1H NMR (500 MHz, CDCl3) delta: 7.79 (s, 2H), 6.89 (s, 1H), 6.45 (d, J = 2.2 Hz, 1H), 5.29 (s, 1H), 3.98 (d, J = 4.3 Hz, 2H), 3.95 (d, J = 3.9 Hz, 5H), 3.93 (s, 3H), 2.38 (s, 6H). 13C NMR (125 MHz, DMSO-d6) delta: 164.88, 161.41, 160.19, 158.89, 153.59, 152.99, 131.20, 128.66, 127.67, 105.11, 101.60, 97.97, 74.44, 60.88, 56.37, 56.04, 55.30, 16.52. MS (ESI) m/z: 369.1 [M - H]-. |
62.7% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In 1-methyl-pyrrolidin-2-one; at 130℃; for 3.0h;Inert atmosphere; | The intermediate H30-3 (15.2 g, 77.5 mol), H30-5 (15.06 g, 77.5 mmol), NAHSO3 (8.9 g, 85.3 mmol), P-TSA(1.34 g, 7.75 mmol), and NMP (140 mL) were added into a flask in the presence of nitrogen gas. The mixture was stirredfor 3 h at 130 C. After the completion of the reaction detected by TLC, the mixture was extracted by adding water (450mL) and DCM (500 mL). The separated aqueous layer was extracted with DCM (4 3 400 mL). The resulting organiclayers were combined, washed with water (3 3 400 mL), dried by adding sodium sulfate, and filtered. The resultingfiltrate was distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography(eluent: dichloromethane: methanol = 80: 1) to give the intermediate H130: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (18 g, yield 62.7%). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 14.0h;Product distribution / selectivity; | A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyidimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70 C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70 C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39%) as a white solid. Selected data: 229-231 C.Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaidehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and <strong>[1039948-89-4]4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde</strong> (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150 C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 14.0h; | To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and <strong>[1039948-89-4]4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde</strong> (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150 C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 14.0h; | At 70deg.] C 2-Amino-4,6-dimethoxy-benzamide(0.60g, 3.06mmol) and 4- [2- (tert-butyldimethylsilyloxy)ethoxy]-3,5-dimethyl-benzaldehyde(0.856g,2.78mmol)in N, N- dimethylformamide(20 mL) was stirred for 1hour. Was added iodine (0.846g, 3.33mmol)and potassium carbonate (0.384g, 2.78mmol), thereaction mixture was at 70 stirred for 16 hours. The reactionmixture was poured onto ice, extracted with ethyl acetate. With water, theorganic layer was washed with brine, dried over anhydrous Na 2SO 4dry. The solvent was removed to give acrude product, which was purified by column chromatography to give a white solid of 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-methoxy-quinazolin -4 (3H) - one (444mg, 39%). Selected data: 229-231 . Alternatively, 2- (4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazolin -4 (3H) - onecan be synthesized by the following method. In ethanol (350 mL of) of 3,5-dimethyl-4-hydroxy-benzaldehyde(26.9g, 0.179mol) disposed dried 2L round bottomed flask with refluxcondenser and magnetic stirrer. 2-chloro-ethanol(87.6g, 1.074mol) and K 2CO 3(99g, 0.716mol),the reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled toroom temperature and filtered. The solvent was removed under reduced pressure.The crude product was diluted with ethyl acetate, and the organic layer waswashed with water, brine, Na 2SO 4dry. 45g crude product obtained after removalof the solvent. The crude product was purified by column chromatography (silicagel 230-400 mesh; with 50% hexanes in ethyl acetate as eluent) to afford 33.3g (95%) of product. 2-amino-4,6-dimethoxy - benzamide (33.45g, 0.170mol)and 4- (2-hydroxyethoxy) -3,5-dimethyl benzaldehyde(33.3g, 0.170 mol) was added NaHSO3(33.3g,0.187mol) in N,N- dimethylacetamide (300mL) solution of and p-TSA(3.2g, 17.1mmol), at 150 reaction mixturewas heated for 14 hours.The reaction was cooled to room temperature. The solvent was removed underreduced pressure. The residue was diluted with water, followed by stirring at room temperature for30 minutes. The solid was isolated by filtration and dried to give the crudeproduct. The crude product was purified by column chromatography (silica gel230-400 mesh; used in CH 2Cl 25% methanol as eluent) to afford 2- (4- (2-hydroxyethoxy) -3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazoline -4 (3H) - one (33g, 52%). |
52% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In ISOPROPYLAMIDE; at 150℃; for 14.0h;Product distribution / selectivity; | A solution of 2-amino-4,6-dimethoxyben2amide (0.60 g, 3.06 mmol) and 4-t2-(tert-butyldimethylsflanoxy)ethoxy]-3,5-dfmethylbenzaldehyde (0.856 g, 2.78 mmol) in lambda/,/V-dimethyl formamide (20 mL) was stirred at 70C for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70C for 16 h, The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-{2- hydroxyethoxy)-3,5-dimethylphenyl)-5.7-dimethoxyquinazolin-4(3H)-one (444 mg, 39%) as a white solid. Selected data: 229-231C.[0117] Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was <n="65"/>placed 3, 5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product, To a solution of 2-amino-4, 6- dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3, 5- dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSOs (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150C for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5 % methanol in CHzCI2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (33 g, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
165 mg | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 5h; | Example 61 to 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-onea solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and <strong>[82413-63-6]4-morpholin-4-ylmethyl benzaldehyde</strong> (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150 C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). |
Tags: 63920-73-0 synthesis path| 63920-73-0 SDS| 63920-73-0 COA| 63920-73-0 purity| 63920-73-0 application| 63920-73-0 NMR| 63920-73-0 COA| 63920-73-0 structure
A353041 [21577-57-1]
2-Amino-4,6-dimethoxybenzoic acid
Similarity: 0.83
A710975 [379228-26-9]
Methyl 2-amino-4,6-dimethoxybenzoate
Similarity: 0.81
A353041 [21577-57-1]
2-Amino-4,6-dimethoxybenzoic acid
Similarity: 0.83
A710975 [379228-26-9]
Methyl 2-amino-4,6-dimethoxybenzoate
Similarity: 0.81
A353041 [21577-57-1]
2-Amino-4,6-dimethoxybenzoic acid
Similarity: 0.83
A710975 [379228-26-9]
Methyl 2-amino-4,6-dimethoxybenzoate
Similarity: 0.81
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