* 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.
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12 h;
Compound 10A (3.26 g, 10 mmol) was added to a 100 mL single-mouth bottle.Compound 11 is ethylene carbonate (0.88 g, 10 mmol),Add 30 mL of N,N-dimethylformamide to dissolve it.At the same time, potassium carbonate (1.38 g, 10 mmol) was added.Warm the system to 110 ° C,The reaction was refluxed for 12 hours.After the reaction is over,Add 20 mL of water to the reaction system.Extract three times with dichloromethane (3*20 mL),Combine the organic phase,Dry with anhydrous sodium sulfate,filter,Distilling under reduced pressure to obtain a mixture,Purified by column chromatography (the eluent is petroleum ether / ethyl acetate,Volume ratio 2:1),A yellow solid RVX-208 (3.51 g, yield 95percent) was obtained.
Reference:
[1] Patent: CN108484510, 2018, A, . Location in patent: Paragraph 0041
2
[ 1039948-89-4 ]
[ 63920-73-0 ]
[ 1044870-39-4 ]
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).
With ammonium hydroxide; L-valine; caesium carbonate; copper(I) bromide In dimethyl sulfoxide at 100℃; for 24 h; Sealed tube
Take 2-bromo-4,6-dimethoxybenzamide (C-4) (388.5 mg, 1.50 mmol),Cuprous bromide (21.5 mg, 0.15 mmol), cesium carbonate (977.5 mg, 3.00 mmol),L-valine (34.5mg, 0.30mmol) in a thick-walled pressure tube,Add 5 ml of DMSO, intermediate B-3 (930 mg, 3.00 mmol), 1.90 ml of 26percent aqueous ammonia,Seal the pressure tube. The mixture was stirred at 100 ° C for 12 h, and then open for 12 h. Quenched with 6ml saturated ammonium chloride solution,Add 50 ml of ethyl acetate and 50 ml of distilled water.The mixture was separated and the aqueous layer was extracted with ethyl acetate (50ml×3).The organic layer was washed with distilled water (30 ml × 2) and saturated brine (30 ml).Dry over anhydrous sodium sulfate. Column chromatography, eluting with dichloromethane/methanol (v/v, 40:1) afforded 267 mg of Apabetalone.The yield was 48percent.
Reference:
[1] Patent: CN108218798, 2018, A, . Location in patent: Paragraph 0061; 0062
4
[ 1039948-89-4 ]
[ 1545025-44-2 ]
[ 1044870-39-4 ]
Yield
Reaction Conditions
Operation in experiment
81.5%
With sodium hydroxide In tetrahydrofuran for 3.5 h;
2-Amino-4,6-dimethoxybenzonitrile 8.9 g (0.05 mol) and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde 14.6 g were sequentially added to the reaction flask. (0.075mol),50ml of tetrahydrofuran, 0.05g of sodium hydroxide, stirred and refluxed for 3.5h,After the reaction is completed, ethyl acetate and water are successively added, and the organic phase is separated and washed with water.Drying, recovering ethyl acetate under reduced pressure, and the residue was crystallized from ethanol.15.1 g of 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one,The yield is 81.5percent.The purity is 99.7percent (area normalization method).
Reference:
[1] Patent: CN108997226, 2018, A, . Location in patent: Paragraph 0036; 0045; 0054; 0055; 0062; 0063
5
[ 1044872-73-2 ]
[ 63920-73-0 ]
[ 1044870-39-4 ]
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).
With triethylamine; In tetrahydrofuran; at 70℃; for 16h;
A mixture of the compound of Example 20 (0.070 g, 0.19 mmol), propyl isocyanate (0.088 mL, 0.94 mmol), and TEA (0.14 g, 1.1 mmol) in THF (4.0 mL) was stirred at 70 C. for 16 h. The mixture was filtered, washed with THF, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), dried and the solvent was removed under reduced pressure. The resulting solid was chromatographed on silica gel to yield 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate (0.035 g, 41%) as an off-white solid: Selected data: 1H NMR (300 MHz, DMSO-d6) delta 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J=5.27 Hz, 1H), 6.74 (d, J=2.32 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.27 (t, J=4.29 Hz, 2H), 3.99 (t, J=4.29 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J=7.33 Hz, 3H); MS (APCl) m/z 456 [M+H]+.
41%
With triethylamine; In tetrahydrofuran; at 70℃; for 16h;
For 70 C the 2 - (4 - (2-hydroxy-ethoxy) - 3,5-dimethyl-phenyl) - 5,7-dimethoxyquinazoline -4 (3H)-one (0.070g, 0 . 19mmol), propyl isocyanate (0.088 ml, 0 . 94mmol) and TEA (0.14g, 1 . 1mmol) in THF (4.0 ml) stirring the mixture in the 16 hours. The mixture is filtered, with washing THF, solvent is removed under reduced pressure. The residue is dissolved in EtOAc (50 ml) in, with saturated aqueous solution of sodium bicarbonate (50 ml) washing, drying, solvent is removed under reduced pressure. The resulting solid on silica gel for chromatography, to obtain gray solid propyl ammonia formic acid 2 - (4 - (5,7-dimethoxy-4-oxo -3,4-dihydrochinazolines having antiviral properties-2-yl) - 2,6-dimethyl-phenoxy) ethyl ester (0.035g, 41%)
41%
With triethylamine; In tetrahydrofuran; at 70℃; for 16h;
A mixture of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-onbeta (0.070 g, 0.19 mmol), propyl isocyanate (0.088 ml_, 0.94 mmol), and TEA (0.14 g, 1.1 mmol) in THF (4.0 mL) was stirred at 70C for 16 h. The mixture was filtered, washed with THF, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), dried and the solvent was removed under reduced pressure. The resulting solid was chromatographed on silica gel to yield 2-{4-(5,7-Dimethoxy-4-oxo-3,4- dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate (0.035 g, 41%) as an off-white solid: Selected data: 1H NMR (300 MHz, DMSO-d6) delta 11.82 (s, 1H), 7.90 (S, 2H), 7.23 (t, J = 5.27 Hz, 1H), 6.74 (d, J = 2.32 Hz, 1H), 6.52 (d, J <n="82"/>= 2.31 Hz, 1H), 4.27 (t, J = 4.29 Hz, 2H), 3.99 (t. J = 4.29 Hz, 2H), 3.89 (S, 3H), 3.84 (S. 3H), 3.02-2.86 (m. 2H), 2-29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J = 7.33 Hz, 3H); MS (APCI) mtz 456 [M+H]+.
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%).
With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 17h;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 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; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%).
39%
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, 39%) as a white solid. Selected data: 229-231 C.
39%
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%).
With triethylamine; In tetrahydrofuran; for 4h;Heating / reflux;
A mixture of 4-(6,8-dimethoxyisoquinolin-3-yl)-2)6-dimethylphenol (0.100 g, 0.270 mmol), cyclohexylisocyanate (172 mul_, 1.35 mmol), and Et3N (263 muL, 1.89 mmol) in THF (1.00 mL) was stirred at reflux for 4 h then diluted with EtOAc (200 mL) and washed with saturated aqueous ammonium chloride (3 x 75 mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (12 g, CH2CI2ZCH3OH) and the product freeze dried from MeCN/l-feO to provide 2- (4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate (0.0981 g, 73%) as a white solid. 1H NMR (300 MHz, DMSO-Cfedelta ) 11.82 (s, 1H), 7.90 (S, 2H), 7.24-7.05 (m, 1H), 6.73 (d, J = 2.30 Hz, 1H), 6.52 (d, J = 2.31 Hz, 1H), 4.30-4.22 (m, 1H), 4.03-3.95 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 6H), 1.82-1.46 (m, 5H), 1.18 (m, 5H); MS (APCI) m/z 496 [M+H)+.
With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;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%).
To a mixture of 4 (2.00 g, 5.40 mmol) and Et3N (0.977 ml_, 7.02 mmol) in CH2CI2 (27.0 mL) was added slowly MsCI (0.543 ml_, 7.02 mmol) at room temperature. After 1 day, additional Et3N (0.977 mL, 7.02 mmol) and MsCI (0.543 mL, 7.02 mmol) was added and the mixture was stirred for 2 hours, then diluted with EtOAc (300 mL) and washed with 10% aqueous citric acid (3 * 75 mL), saturated aqueous NaHCO3 (75 mL), and brine (75 mL). An insoluble white solid was collected by filtration to provide mesylate 6 (0.890 g, 37%): 1H NMR (300 MHz,DMSO-cfe) delta 11.84 (s, 1 H), 7.91 (s, 2H), 6.74 (d, J = 2.32 Hz, 1 H), 6.52 (d, J = 2.32Hz1 1 H), 4.59-4.48 (m, 2H), 4.15-4.04 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.25 (s, 3H), 2.32 (s, 6H).
37%
With triethylamine; In dichloromethane; at 20℃;
Example 42. Preparation of 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one [0299] To a mixture of <strong>[1044870-39-4]2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one</strong> (2.00 g, 5.40 mmol) and Et3N (0.977 ml_, 7.02 mmol) in CH2CI2 (27.0 ml_) was added slowly MsCI (0.543 ml_, 7.02 mmol) at room temperature. After 1 day, additional Et3N (0.977 ml_, 7.02 mmol) and MsCI (0.543 ml_, 7.02 mmol) was added and the mixture was stirred for 2 hours, then diluted with EtOAc (300 mL) and washed with 10% aqueous citric acid (3 x 75 mL), saturated aqueous NaHCO3 (75 mL), and brine (75 mL). An insoluble white solid was collected by filtration to provide 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methanesulfonate (0.890 g, 37%).[0300] A mixture of compound 2-(4-(5,7-dimethoxy-4-oxo-3,4- dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methanesulfonate (0.200 g, 0.446 mmol) and 33% CH3NH2 in EtOH (5.00 mL) was heated at reflux overnight. The solvent was removed under vacuum and the residue was purified on silica gel (12 g, CH2CI2/CH3OH) and the product freeze-dried from MeCN/H2O to provide the title compound (0.0968 g, 57%) as a light yellow solid. 1H NMR (300 MHz, DMSO-cfe: delta 7.90 (s, 2H), 6.73 (d, J = 2.29 Hz, 1 H), 6.52 (d, J = 2.29 Hz, 1 H), 3.94-3.80 (m, 8H), 2.98 (t, J = 5.46 Hz, 2H), 2.45 (s, 3H), 2.33-2.28 (m, 8H). MS (APCI) m/z 384 [C2iH25N3O4+H]+.
37%
With triethylamine; In dichloromethane; at 20℃; for 26h;
To a mixture of <strong>[1044870-39-4]2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one</strong> (2.00 g, 5.40 mmol) and Et3N (0.977 mL, 7.02 mmol) in CH2Cl2 (27.0 mL) was added slowly MsCl (0.543 mL, 7.02 mmol) at room temperature. After 1 day, additional Et3N (0.977 mL, 7.02 mmol) and MsCl (0.543 mL, 7.02 mmol) was added and the mixture was stirred for 2 hours, then diluted with EtOAc (300 mL) and washed with 10% aqueous citric acid (3*75 mL), saturated aqueous NaHCO3 (75 mL), and brine (75 mL). An insoluble white solid was collected by filtration to provide 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methanesulfonate (0.890 g, 37%)
To a stirred solution of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-3H-quinazolin-4-one (1; RVX-208) (3.0g, 8.1mmol) in DMF (75mL) under nitrogen atmosphere, sodium hydride (60% in mineral oil, 0.39g, 9.7mmol) was added in small portions at room temperature. The reaction mixture was stirred for 1h, then chloromethylpivalate (1.76mL, 12.1mmol) was added, and stirring was continued at room temperature for 24h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The crude material was purified by column chromatography (Silica Gel 230-400mesh; 7/3 methylene chloride/ethyl acetate as eluent; column eluted until compound was isolated as monitored by TLC) to give 2,2-dimethylpropionic acid 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl ester (2) as a white solid. Yield: 2.2g (56%). 1H NMR (400MHz, CDCl3): delta 8.20 (s, 2H), 6.95 (d, J=2.4Hz, 1H), 6.47 (d, J=2.4Hz, 1H), 6.39 (s, 2H), 3.97 (m, 4H), 3.95 (s, 3H), 3.93 (s, 3H), 2.40 (s, 6H), 2.22 (t, J=5.8Hz, 1H), 1.21 (s, 9H)
With glucose-6-phosphate dehydrogenase; D-glucose 6-phosphate; nicotinamide adenine dinucleotide phosphate; magnesium chloride; In aq. phosphate buffer; dimethyl sulfoxide; at 37℃; for 24h;pH 7.4;Enzymatic reaction;
General procedure: A 10mM stock solution of RVX-208 [7] in DMSO was prepared and used in these experiments. The incubation mixtures, prepared in duplicate, consisted of 0.50 mg microsomal protein, 100 mM potassium phosphate buffer, pH 7.4, 100 muM test compound, and the NADPH regenerating system (1.3mM NADP+, 3.3mM glucose-6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, and 3.3 mM magnesium chloride), UDPGA (5mM), and D-saccharic acid lactone (5mM) in a final volume of 0.5mL. The reaction mixture minus the microsomal protein or S9 fraction was pre-warmed for 5 min at 37C. In experiments with S9 fractions, 0.1 mL of the S9 fraction suspension was added directly to the reaction mixture. In experiments with microsomes, prior to addition to the reaction mixture, ice-cold microsomes were pre-incubated for 20 min with alamethicin (4muL of alamethicin stock solution in DMSO, 1.5mg/30muL, were mixed with 0.2mL of microsomal suspension) and then added to initiate the reaction. After 1h, 6h, or 24h incubation in a shaking water bath at 37C, the reactions were stopped by the addition of an equal volume of methanol. After incubation on ice for 15min, samples were centrifuged (10,000g, 15min, 4C) to remove precipitated protein. The supernatants were filtered using a Teflon syringe filter (4mm PTFE, 0.45mum) from Whatman, Inc. (Clifton, NJ) followed by evaporation to dryness in a Centrivap concentrator and Freeze Dry system (both Labconco, Kansas City, MO). Sample residues were resuspended in 80muL of 50% (v/v) methanol, mixed for 15s on a vortex mixer, and sonicated for 30s followed by centrifugation (20,000g, 30s, room temperature). The supernatant was then transferred to HPLC vials for LC/MS analysis
With glucose-6-phosphate dehydrogenase; D-glucose 6-phosphate; nicotinamide adenine dinucleotide phosphate; UDP-glucuronic acid; magnesium chloride; In aq. phosphate buffer; dimethyl sulfoxide; at 37℃; for 4h;pH 7.4;Enzymatic reaction;
General procedure: A 10mM stock solution of RVX-208 [7] in DMSO was prepared and used in these experiments. The incubation mixtures, prepared in duplicate, consisted of 0.50 mg microsomal protein, 100 mM potassium phosphate buffer, pH 7.4, 100 muM test compound, and the NADPH regenerating system (1.3mM NADP+, 3.3mM glucose-6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, and 3.3 mM magnesium chloride), UDPGA (5mM), and D-saccharic acid lactone (5mM) in a final volume of 0.5mL. The reaction mixture minus the microsomal protein or S9 fraction was pre-warmed for 5 min at 37C. In experiments with S9 fractions, 0.1 mL of the S9 fraction suspension was added directly to the reaction mixture. In experiments with microsomes, prior to addition to the reaction mixture, ice-cold microsomes were pre-incubated for 20 min with alamethicin (4muL of alamethicin stock solution in DMSO, 1.5mg/30muL, were mixed with 0.2mL of microsomal suspension) and then added to initiate the reaction. After 1h, 6h, or 24h incubation in a shaking water bath at 37C, the reactions were stopped by the addition of an equal volume of methanol. After incubation on ice for 15min, samples were centrifuged (10,000g, 15min, 4C) to remove precipitated protein. The supernatants were filtered using a Teflon syringe filter (4mm PTFE, 0.45mum) from Whatman, Inc. (Clifton, NJ) followed by evaporation to dryness in a Centrivap concentrator and Freeze Dry system (both Labconco, Kansas City, MO). Sample residues were resuspended in 80muL of 50% (v/v) methanol, mixed for 15s on a vortex mixer, and sonicated for 30s followed by centrifugation (20,000g, 30s, room temperature). The supernatant was then transferred to HPLC vials for LC/MS analysis
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 16h;
To a suspension of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.50 g, 1.35 mmol) in THF (20 mL), were added <strong>[89-24-7]5-phenyl-imidazolidine-2,4-dione</strong> (0.24 g, 1.35 mmol) and triphenyl phosphine (0.35 g, 1.35 mmol), then diethyl azodicarboxylate (0.43 mL, 2.70 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo and the residue was washed with dichloromethane and ether. The residue was dissolved in acetic acid and purified by preparative HPLC. The compound was further washed with dichloromethane and ether (1:1, 20 mL) to obtain the title compound as a white solid. Yield: 0.07 g (10%). MP 219.6-221.4 C. 1H NMR (400 MHz, DMSO-d6): delta 8.81 (s, 1H), 7.86 (s, 2H), 7.37 (m, 5H), 6.71 (s, 1H), 6.48 (s, 1H), 3.94 (m, 4H), 3.86 (s, 3H), 3.82 (s, 3H), 2.18 (s, 6H). MS (ES) m/z: 529.29 (M++1)
10%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 16h;
Example 82 Preparation of 3-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-<strong>[89-24-7]5-phenylimidazolidine-2,4-dione</strong> To a suspension of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.50 g, 1.35 mmol) in THF (20 mL), were added <strong>[89-24-7]5-phenyl-imidazolidine-2,4-dione</strong> (0.24 g, 1.35 mmol) and triphenyl phosphine (0.35 g, 1.35 mmol), then diethyl azodicarboxylate (0.43 mL, 2.70 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo and the residue was washed with dichloromethane and ether. The residue was dissolved in acetic acid and purified by preparative HPLC. The compound was further washed with dichloromethane and ether (1:1, 20 mL) to obtain the title compound as a white solid. Yield: 0.07 g (10%). MP 219.6-221.4 C. 1H NMR (400 MHz, DMSO-d6): delta 8.81 (s, 1H), 7.86 (s, 2H), 7.37 (m, 5H), 6.71 (s, 1H), 6.48 (s, 1H), 3.94 (m, 4H), 3.86 (s, 3H), 3.82 (s, 3H), 2.18 (s, 6H). MS (ES) m/z: 529.29 (M++1).
With N-ethyl-N,N-diisopropylamine; triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 8h;Inert atmosphere;
To a solution of <strong>[1044870-39-4]2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one</strong> (0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenyl phosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02 mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To this stirred solution was added diethylazodicarboxylate (0.35 g, 2.02 mmol). The reaction mixture was stirred at room temperature for 8 hours under nitrogen. Ethyl acetate (400 mL) was added. The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (4:96 methanol:CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.3 g. (49%). 1H NMR (400 MHz, CDCl3): delta 9.30 (br s, 1H), 7.66 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z: 452.51 (M+1) (100%)
49%
With N-ethyl-N,N-diisopropylamine; triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 8h;Inert atmosphere;
Example 102 Preparation of 1-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)pyrrolidine-2,5-dione To a solution of <strong>[1044870-39-4]2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one</strong> (0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenyl phosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02 mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To this stirred solution was added diethylazodicarboxylate (0.35 g, 2.02 mmol). The reaction mixture was stirred at room temperature for 8 hours under nitrogen. Ethyl acetate (400 mL) was added. The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by the Simpliflash system (4:96 methanol:CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.3 g. (49%). 1H NMR (400 MHz, CDCl3): delta 9.30 (br s, 1H), 7.66 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z: 452.51 (M+1) (100%).
With ammonium hydroxide; L-valine; caesium carbonate; copper(I) bromide; In dimethyl sulfoxide; at 100℃; for 24h;Sealed tube;
Take 2-bromo-4,6-dimethoxybenzamide (C-4) (388.5 mg, 1.50 mmol),Cuprous bromide (21.5 mg, 0.15 mmol), cesium carbonate (977.5 mg, 3.00 mmol),L-valine (34.5mg, 0.30mmol) in a thick-walled pressure tube,Add 5 ml of DMSO, intermediate B-3 (930 mg, 3.00 mmol), 1.90 ml of 26% aqueous ammonia,Seal the pressure tube. The mixture was stirred at 100 C for 12 h, and then open for 12 h. Quenched with 6ml saturated ammonium chloride solution,Add 50 ml of ethyl acetate and 50 ml of distilled water.The mixture was separated and the aqueous layer was extracted with ethyl acetate (50ml×3).The organic layer was washed with distilled water (30 ml × 2) and saturated brine (30 ml).Dry over anhydrous sodium sulfate. Column chromatography, eluting with dichloromethane/methanol (v/v, 40:1) afforded 267 mg of Apabetalone.The yield was 48%.
2-(4-(2-nitroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With nitric acid; In water; at 0 - 20℃; for 2h;
The intermediate H130 (370.4 mg, 1 mmol) and concentrated nitric acid (35 mL) were mixed at 0 C. Let themixture stand for 2 h. After the completion of the reaction detected by TLC, the mixture was slowly heated to roomtemperature. Water (100 mL) and DCM (100 mL) were added into the mixture to separate it into layers. The aqueouslayer was separated, and extracted with DCM (3 3 100 mL). The resulting organic layers were combined, dried byadding sodium sulfate, and filtered. The resulting filtrate was distilled under reduced pressure. The crude product waspurified by silica gel column chromatography (eluent: dichloromethane: methanol = 100: 1) to give 120 mg of the targetcompound 2-(4-(2-nitroxy-ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one, yield 29%. Its structure wasconfirmed by 1H NMR and mass spectrometry. 1H NMR (400 MHz, CDCl3) delta: 9.87 (s, 1H), 7.75 (s, 2H), 6.83 (d, J = 2.2Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 4.90 - 4.81 (m, 2H), 4.15 - 4.09 (m, 2H), 3.95 (d, 6H), 2.38 (s, 6H). LC-MS: m/z (ES+),415 [M+1]+.
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethylcarbonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.5%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In tetrahydrofuran; for 48h;
The intermediate H130 (420 mg, 1.1 mmol), BOP (673 mg, 2.3 mmol), and THF (100 mL) were added into a 250 mL flask. The mixture was stirred for 48 h. After the completion of the reaction detected by TLC, the mixture was distilled under reduced pressure. Ether (60 mL) was added. The mixture was stirred, and filtrated. The filtrate was discarded. The resulting product was the intermediate 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-ethylcarbonyl chloride (450 mg, yield 94.5%).
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethyl 4-(2-oxo-3-nitroxymethyl-1,2,5-oxadiazol-3-methyl)oxy-4-oxo-butyrate[ No CAS ]
4-(2-(((2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethoxy)carbonyl)oxy)ethoxy)-3-(phenylsulfonyl)-2-oxo-furazan[ No CAS ]
3-chloro-2,2-di(chloromethyl)propyl 4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]butyl)-4-oxo-2-acetaminobutyrate[ No CAS ]
3-iodo-2,2-di(iodomethyl)propyl 4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]butyl)-4-oxo-2-acetaminobutyrate[ No CAS ]
3-(nitroxy)-2,2-di(nitroxymethyl)propyl4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]butyl)-4-oxo-2-acetaminobutyrate[ No CAS ]
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethyl 3-nitroxymethylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32.7%
With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 3h;
H130 (370 mg, 1 mmol), 3-nitroxymethyl-benzoic acid (211 mg, 1 mmol), DCC (309 mg, 1.5 mmol), HOBt(202.5 mg, 1.5 mmol), DMAP (183 mg, 1.5 mmol) and THF (40 mL) were added into a 100 mL flask. The mixture wasstirred at room temperature for 3 h. After the completion of the reaction detected by TLC, water (30 mL) and DCM (30mL) were added to separate the mixture into layers. The aqueous layer was separated, and extracted with DCM (3 3100 mL). The resulting organic layers were combined, dried by adding sodium sulfate, and filtered. The resulting filtratewas distilled under reduced pressure. The crude product was purified by silica gel column chromatography (eluent:dichloromethane: methanol = 100: 1) to give 180 mg of the target compound 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy]-ethyl 3-nitroxymethyl-benzoate (H102), yield 32.7%. Its structure was confirmedby 1H NMR and mass spectrometry. 1H NMR (400 MHz, DMSO-d6) delta: 11.86 (s, 1H), 8.09 - 8.00 (m, 2H), 7.91 (s, 2H),7.78 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 1.7 Hz, 1H), 5.67 (s, 2H), 4.64 (m,2H), 4.19 (m, 2H), 3.86 (d, 6H), 2.31 (s, 6H). LC-MS: m/z (ES+), 549 [M+1]+.
The intermediate H130 prepared in Example 1 (185 mg, 0.5 mmol), pyridine (130 mg, 1.65 mmol), and DCM(5 ml) were added into a 25 mL flask. P-nitrophenyl chloroformate (110 mg, 0.55 mmol) dissolved in DCM (2 mL) wasadded dropwise into the above mixture at 0 C. The mixture was allowed to naturally warm up to room temperature, andstirred overnight. After the completion of the reaction detected by TLC, the reactant was washed with water. The organiclayer was separated, and distilled under reduced pressure. The residue was purified by silica gel column chromatography(DCM: MeOH = 95: 5) to give the intermediate H04-7 (130 mg, yield 48.6%).
The intermediate H130 prepared in Example 1 (1.5 g, 4.05 mmol), succinic anhydride (810 mg, 8.1 mmol), and DMF (15 mL) were added into a 25 mL flask. The mixture was stirred at 110 C for 2 h. After the completion of thereaction detected by TLC, the mixture was distilled under reduced pressure. Ethyl acetate (30 mL) was then added toobtain a suspension. The suspension was filtered. The filtrate was discarded. The resulting product was the intermediatemono-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}succinate (1 g, yield52.5%).
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethyl (tert-butoxycarbonylamino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1,2-dichloro-ethane; In acetone; at 0 - 20℃; for 2h;
540 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin -4(3H)-one was dissolved in35 mL of acetone. N-Boc-glycine (0.334 g) and 4-dimethylaminopyridine (DMAP, 20 mg) were added. The above mixedsolution was cooled at 0 C. EDC (0.365 g) was added. The mixture was stirred at room temperature. After reacting for2 h, the solvent was evaporated under vacuum. The resulting residue was washed with water (50 mL) and dichloromethane (3 3 50 mL) successively. The organic layer obtained was dried by sodium sulfate, and distilled under reduced pressure.The concentrate was purified by column chromatography (eluent: the ratio of n-hexane to ethyl acetate was 6: 4) to givethe intermediate (d), i.e.2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-ethyl(tert-butoxycarbonylamino)-acetate.
2-(nitroxy)ethyl 2-(tert-butoxycarbonylamino)-3-[4-(4-nitrophenoxycarbonyloxy)phenyl]propionate[ No CAS ]
2-nitroxyethyl 2-(tert-butoxycarbonylamino)-3-(4-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethoxycarbonyloxy}phenyl)propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; scandium tris(trifluoromethanesulfonate); In dichloromethane; at 0 - 20℃; for 70h;
Scandium triflate (0.11 g) and 0.57 g of DMAP were added into the solution of intermediate (i) in dichloromethane(40 mL). The mixed solution was cooled to 0 C. <strong>[1044870-39-4]2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one</strong> (1.07 g) was added. The mixture was stirred at room temperature, allowed to react for 70 h, and distilledunder reduced pressure. The concentrate was purified by column chromatography (eluent: the gradient of n-hexane/ethylacetate was 9: 1 to 3: 7, and 1600 mL of the eluent was used in total) to give the product 2-nitroxy-ethyl 2-(tert-butoxycarbonylamino)-3-(4-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-ethoxycarbonyloxy}-phenyl)-propionate.
2-(nitroxy)ethyl 2-(tert-butoxycarbonylamino)-3-[4-(4-nitrophenoxycarbonyloxy)phenyl]propionate[ No CAS ]
2-nitroxyethyl 2-amino-3-(4-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethoxycarbonyloxy}phenyl)propionate hydrochloride[ No CAS ]
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃;
The intermediate H130 (2.22 g, 59.9 mmol), H18-7 (1.94 g, 59.9 mmol), DCC (1.86 g, 90 mmol), DMAP (1.1g, 1.1 mmol), and THF (60 mL) were added into a 100 mL flask. The mixture was stirred overnight at room temperature.After the completion of the reaction detected by TLC, DCM (50 mL) was added to obtain a suspension. The suspensionwas filtered. The filtrate was washed with water, then dried with sodium sulfate, and suction filtration under reducedpressure. The resulting filtrate was distilled under reduced pressure. The crude product was purified by silica gel columnchromatography (eluent: dichloromethane: methanol = 100: 1) to give H18-8 (4.1 g, 6.07 mmol, yield 100%).
3,4-dinitroxybutyl 2-acetylamino-3-(4-nitrophenoxy)carbonyloxyphenylpropionate[ No CAS ]
3,4-dinitroxybutyl 2-acetamino-3-(4-(((2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethoxy)carbonyl)oxy)phenyl)propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With dmap; scandium tris(trifluoromethanesulfonate); In dichloromethane; at 0 - 20℃; for 18h;
The product from the previous step (453 mg, 0.8 mmol) was dissolved in dichloromethane (15 mL). Thenscandium triflate (0.04 g, 0.09 mmol) and DMAP (0.21 g, 1.8 mmol) were added. The reactants were cooled to 0 C.The intermediate H130 (296 mg, 0.8 mmol) was added. The reactants were stirred at room temperature for 18 h.Dichloromethane (24 mL) was added. The mixture was washed with 5% of sodium dihydrogen phosphate solution, andthen washed with saturated aqueous sodium carbonate solution. The organic layer was dried with sodium sulfate, anddistilled under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution witheluent: n-hexane/ethyl acetate) to give the target compound (204 mg, yield 32%). The structure of the resulting targetcompound was confirmed by 1H NMR and mass spectrometry.1H NMR (400 MHz, DMSO-d6) delta: 11.81 (s, 1H), 7.89 (s, 2H), 7.52 - 6.74 (m, 4H), 6.73 (d, J = 2.8 Hz, 1H), 6.57 (d, J =2.7 Hz, 1H), 4.58 - 4.53 (m, 3H), 4.11 - 4.05 (m, 2H), 3.98(m, 2H), 3.91 (s, 3H), 3.88 - 3.82 (t, 5H), 3.58 - 3.52 (m, 1H),3.49-3.40 (m, 2H), 2.29 (s, 6H), 1.95 (m, 3H). LC-MS: m/z (ES+), 798 [M+1]+.
4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]butyl)-4-oxo-2-acetaminobutyric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetone; at 0 - 20℃; for 24h;
The intermediate H130 (1.3 g, 3.5 mmol) was dissolved in acetone (100 mL) to form a solution. Then <strong>[997-55-7]N-acetylaspartic acid</strong> (1.09 g, 6.25 mmol) and DMAP (catalytic amount) were added. The reactants were cooled to 0 C. EDAC(1.19 g, 6.25 mmol) was added. The reactants were stirred at room temperature for 24 h, and distilled under reducedpressure. The residue was purified by silica gel column chromatography (gradient elution with eluent: dichloromethane/methanol) to give 4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy] butyl)-4-oxo-2-acetamino-butyric acid (0.83 g, yield 45%).
4-(allyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutanoic acid[ No CAS ]
2-allyl 4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]butyloxy)-4-oxo-2-(tert-butoxycarbonylamino)succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12h;
The intermediate H130 (2.11 g, 5.7 mmol) was dissolved in dichloromethane (100 mL) to form a solution.4-(allyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutanoic acid (1.55 g, 5.7 mmol) and DMAP (catalytic amount) wereadded. The reactants were cooled to 0 C. Then EDAC (1.49 g, 7.85 mmol) was added. The reactants were stirred atroom temperature for 12 h, and distilled under reduced pressure. The residue was purified by silica gel column chromatography(gradient elution with eluent: n-hexane/ethyl acetate) to give the intermediate 2-allyl 4-(2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy] butyloxy)-4-oxo-2-(tert-butoxycarbonylamino)succinate (1.92 g,yield 54%).
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
Compound 10A (3.26 g, 10 mmol) was added to a 100 mL single-mouth bottle.Compound 11 is ethylene carbonate (0.88 g, 10 mmol),Add 30 mL of N,N-dimethylformamide to dissolve it.At the same time, potassium carbonate (1.38 g, 10 mmol) was added.Warm the system to 110 C,The reaction was refluxed for 12 hours.After the reaction is over,Add 20 mL of water to the reaction system.Extract three times with dichloromethane (3*20 mL),Combine the organic phase,Dry with anhydrous sodium sulfate,filter,Distilling under reduced pressure to obtain a mixture,Purified by column chromatography (the eluent is petroleum ether / ethyl acetate,Volume ratio 2:1),A yellow solid RVX-208 (3.51 g, yield 95%) was obtained.
With sodium hydroxide; In tetrahydrofuran; for 3.5h;
2-Amino-4,6-dimethoxybenzonitrile 8.9 g (0.05 mol) and <strong>[1039948-89-4]4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde</strong> 14.6 g were sequentially added to the reaction flask. (0.075mol),50ml of tetrahydrofuran, 0.05g of sodium hydroxide, stirred and refluxed for 3.5h,After the reaction is completed, ethyl acetate and water are successively added, and the organic phase is separated and washed with water.Drying, recovering ethyl acetate under reduced pressure, and the residue was crystallized from ethanol.15.1 g of 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one,The yield is 81.5%.The purity is 99.7% (area normalization method).
With copper(l) iodide; caesium carbonate In dimethyl sulfoxide at 80℃; for 12h; Inert atmosphere;
9-10 Example 9 Preparation of Apabetalone (RVX-208) (1)
Weigh 2-bromo-4,6-dimethoxybenzoic acid (1.95g, 7.4mmol), 4-(2-hydroxyethoxy)-3,5-dimethylbenzamidine hydrochloride (2g , 8.2mmol), cuprous iodide (0.14g, 0.75mmol), cesium carbonate (4.89g, 14.8mmol) was added to a 100mL three-necked bottle, dimethyl sulfoxide (15mL) was added, under the protection of inert gas, at 80 Reaction at for 12h. Saturated ammonium chloride solution (50 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation , Column chromatography (mobile phase: dichloromethane: methanol = 40:1).Apabetalone (RVX-208) 2.01g was obtained. The yield was 72.5%.
Stage #1: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-3,4-dihydroquinazoline-4-one With potassium carbonate In acetonitrile at 0℃; for 0.166667h;
Stage #2: tert-butyl 1-bromo-3,6,9,12,15-pentaoxaoctadecan-18-oate In acetonitrile at 0 - 60℃; for 72h;
1
[00229] Synthesis of SynTEF5 is shown in Scheme 3 of FIG.18. For Scheme 3, reagents and conditions are as follows: i) K2CO3, ACN, 60 OC, 72 h; ii) HCOOH, room temperature, 4 days; iii) HATU, DIPEA, DMF, room temperature, 16h. To synthesize RVX-PEG5-COOtBu K2CO3 was added to a stirred solution of RVX208 (50 mg) in acetonitrile (2 ml) at 0 °C and stirred for 10 min at same temperature. After 10 min, the solution of Br-PEG-COOtBu (57 mg) was added to the reaction mixture and then the reaction stirred for 3 days at 60 °C. The reaction was monitored by TLC. After completion of the starting materials, reaction mixture was concentrated and purified by HPLC chromatography to give a pure pale yellow compound as a semi solid (40 mg, yield: 41%).
Multi-step reaction with 3 steps
1: dichloromethane / 12 h / 40 °C
2: potassium carbonate / tetrahydrofuran / 16 h / 70 °C
3: acetic acid / 3 h / 100 °C
Multi-step reaction with 3 steps
1: dichloromethane / 12 h / 40 °C
2: potassium carbonate / tetrahydrofuran / 16 h / 70 °C
3: acetic acid / 3 h / 100 °C
6; 8 Example 6 Preparation of apabetalone of structural formula I
Add 5.5g of compound with structural formula 4, 5.0g of structural formula II compound and 25ml of glacial acetic acid to a 100ml bottle, and heat it to 100 °C for 3h; The solvent was recovered to dry, and the obtained product was recrystallized with isopropanol to obtain 8.4g of compound (light yellow solid) with structural formula I, namely apabetalone, with a yield of 88% and a purity greater than 99.8%.
88 %
In acetic acid at 100℃;
6; 8 Example 6 Preparation of apabetalone of structural formula I
Add 5.5g of compound with structural formula 4, 5.0g of structural formula II compound and 25ml of glacial acetic acid to a 100ml bottle, and heat it to 100 °C for 3h; The solvent was recovered to dry, and the obtained product was recrystallized with isopropanol to obtain 8.4g of compound (light yellow solid) with structural formula I, namely apabetalone, with a yield of 88% and a purity greater than 99.8%.
7; 9 Example 7 Preparation of apabetalone of structural formula I
6.0g compound of structural formula 5, 5.2g compound of structural formula II, and 30ml of glacial acetic acid were added to a 100ml bottle, and the reaction was heated to 100 °C for 3h; The solvent was recovered to dry, and the obtained product was recrystallized with isopropanol to obtain 8.9g of compound (light yellow solid) with structural formula I, namely apabetalone, with a yield of 91% and a purity greater than 99.8%.
91 %
In acetic acid at 100℃;
7; 9 Example 7 Preparation of apabetalone of structural formula I
6.0g compound of structural formula 5, 5.2g compound of structural formula II, and 30ml of glacial acetic acid were added to a 100ml bottle, and the reaction was heated to 100 °C for 3h; The solvent was recovered to dry, and the obtained product was recrystallized with isopropanol to obtain 8.9g of compound (light yellow solid) with structural formula I, namely apabetalone, with a yield of 91% and a purity greater than 99.8%.
Multi-step reaction with 3 steps
1: dichloromethane / 12 h / 40 °C
2: potassium carbonate / tetrahydrofuran / 16 h / 70 °C
3: acetic acid / 3 h / 100 °C
Multi-step reaction with 3 steps
1: dichloromethane / 12 h / 40 °C
2: potassium carbonate / tetrahydrofuran / 16 h / 70 °C
3: acetic acid / 3 h / 100 °C