Structure of 1039948-89-4
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CAS No. : | 1039948-89-4 |
Formula : | C11H14O3 |
M.W : | 194.23 |
SMILES Code : | O=CC1=CC(C)=C(OCCO)C(C)=C1 |
MDL No. : | MFCD11188381 |
InChI Key : | PBIWVVONGPLSAJ-UHFFFAOYSA-N |
Pubchem ID : | 28932578 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.36 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 54.22 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.97 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.4 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.15 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.69 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.74 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.98 |
Solubility | 2.04 mg/ml ; 0.0105 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.98 |
Solubility | 2.03 mg/ml ; 0.0104 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.1 |
Solubility | 0.155 mg/ml ; 0.000796 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.49 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.62 |
* 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 |
---|---|---|
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In ethanol; for 24.0h;Heating / reflux; | 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%). |
95% | With potassium carbonate; In ethanol; for 24.0h;Reflux; | 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 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), 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%). |
95% | With potassium carbonate; In ethanol; for 24.0h; | 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%). |
95% | With potassium carbonate; In ethanol; for 24.0h;Heating / reflux; | 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%). |
94% | With potassium carbonate; In ethanol; for 24.0h;Reflux; | In a 50 ml single-neck round bottom flask, 1.05 g (7 mmol) of the starting material B-1 4-hydroxy-3,5-dimethylbenzaldehyde was added.14 ml of ethanol, 3.87 g of anhydrous potassium carbonate (28 mmol) and 2.8 ml of 2-chloroethanol (3.40 g, 42 mmol),The reaction was refluxed for 24 h.The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to dryness.Wash with water (20 ml) and saturated brine (20 ml) and dry over anhydrous sodium sulfate. Column chromatography,Petroleum ether/ethyl acetate (v/v, 3:1) elution,1.25 g of compound B-2 was obtained in a yield of 94%. |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 60.0h; | 3,5-dimethyl-4-hydroxybenzaldehyde (3,5-dimethyl-4-hydroxybenzaldehyde, 13.8 g, 91.9 mmol),2-chloroethanol (15.0 g, 187 mmol)Then, N, N-dimethylformamide (DMF) (130 mL) was added to potassium carbonate (24.2 g, 175 mmol), and the mixture was stirred at 100 C. for 2.5 days.Raw material (Rf: 0.6) by TLC (ethyl acetate / hexane = 1/2 (v / v))After confirming disappearance of the solvent, the solvent was distilled off. After dissolving the residue in dichloromethane and removing inorganic salts by filtration,Washing (1M HClaq. ? 2 times aqueous sodium bicarbonate ? saturated saline)This gave crude product 21 (14.8 g). |
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 |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; | Intermediate 2 is obtained from 1 according to the procedure in Example 1. To a mixture of 2 and diisopropylethyiamine in CH2CI2 at 0 0C is added Ms2O. The reaction mixture is stirred until the reaction is complete, as determined by thin layer chromatography (TLC). The reaction mixture is diluted with ethyl acetate and washed with cold sat. NaHCOs and brine. The organic layer is dried over Na2SO4, filtered and concentrated to provide mesylate 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; | To a solution of 3, 5-dimethyl-4-hydroxybenzaldehyde (1.50 g, 10 mmol) in DMF (30 mL) was added ethylene carbonate (0.88 g, 10 mmol) and K2CO3, and warmed to 110 for refluxing overnight. The reaction mixture then was added water (20 mL), extracted for 3 times with CHCl3, and organic phase was dried overnight, filtered, vacuum distillated, purified by column chromatography (2:1, petroleum ether/ethyl acetate) to afford 14 (1.86 g, 96 %) as yellow oil liquid. 1H NMR (600 MHz, CDCl3) delta: 9.88 (s, 1H), 7.57 (s, 2H), 5.30 (s, 1H), 4.00-3.98 (m, 2H), 3.96 (d, J = 4.9, 3.5 Hz, 2H), 2.36 (s, 6H). MS (ESI) m/z: 217.1 [M + Na]+. |
78.8% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃;Inert atmosphere; | The starting material 4-hydroxy-3,5-dimethylbenzaldehyde (1; 70 kg), K2CO3 (9.8 kg) and DMF (133 kg) were mixed and stirred at 110 0C under nitrogen. Ethylene carbonate (45.6 kg) in DMF (46 kg) was added to the mixture over a period of 4 hours, using a diaphragm pump. The reaction mixture was stirred at 110 0C for 12 hours, until less than 5% of the starting material 1 remained. The reaction mixture <n="17"/>was cooled to 25 0C and water (1300 kg) was added followed by a mixture of dichloromethane and heptane (3V/2V; 1300 kg). The mixture was agitated for 30 minutes. The organic layer was isolated and the aqueous layer was back extracted with a mixture of dichloromethane and heptane (3V/2V; 1300 kg). The combined organic layers were washed with aqueous sodium hydroxide (3 M; 460 kg), followed by three washes with water (3 x 710 kg), and dried over sodium sulfate (60 kg). Dichloromethane was removed from the dried organic layer by distillation, keeping the temperature below 40 0C. Heptane (260 kg) and seed crystals were added to initiate crystallization and the mixture was stirred at 20 0C for 2 hours. The mixture was filtered, washed with heptane (60 kg), and dried under vacuum until constant weight to afford intermediate 2 (71.3 kg, 78.8%). 1H-NMR (DMSO-d6): delta 9.82 (1 H), 7.54 (2H), 4.96 (1 H), 3.85 (2H), 3.74 (2H), 2.29 (6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 155℃; for 14.0h; | Example 7. Preparation of 3-(4-fluorophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)quinazolin-4(3H)-one; [0162] To a solution of 4-fluoroaniline (2.40 ml_, 24.5 mmol) in N, N- dimethylformamide (30 mL) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115C for 14 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give 2-amino-Lambda/-(4-fluoro-phenyl)-benzamide as white solid. Yield: 2.00 g (35%).[0163] To a mixture of <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.420 g, 2.17 mmol) and 2-amino-Lambda/-(4-fluoro-phenyl)-benzamide (0.500 g, 2.17 mmol) in Lambda/,Lambda/-dimethylacetamide (5 mL) was added sodium hydrogen sulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155C for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 ml_) to produce the precipitate. The yellow solid was filtered, washed with cold water (2 x 20 ml_), methanol, and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.10 g (11 %). MP 95-970C. 1H-NMR (400 MHz, CDCI3): delta 8.35 (d, 1 H), 7.81-7.78 (d, 2H), 7.58-7.40 (m, 1 H), 7.20-7.15 (m, 2H), 7.15- 7.01 (m, 4H), 3.98-3.80 (m, 4H), 2.21 (s, 6H), 2.01 (t, 1 H). MS (ES+) m/z: 405.01 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 155℃; for 14.0h; | Example 10. Preparation of 3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)quinazolin-4(3H)-one; [0169] To a solution of 4-chloroaniline (3.13 g, 24.5 mmol) in N, N- dimethylformide (20 ml_) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115C for 14 h, cooled to room temperature and diluted with ethyl acetate (100 ml_). The organic layer was washed with 1 N NaOH (200 mL), water (100 ml_), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; EtOAc/hexane = 1 :9) to give 2- amino-Lambda/-(4-chloro-phenyl)-benzamide as white solid. Yield: 1.67 g (28%).[0170] To a mixture of 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.420 g, 2.17 mmol) and 2-amino-/V-(4-chloro-phenyl)-benzamide (0.500 g, 2.17 mmol) in Lambda/,Lambda/-dimethylacetamide (5 mL) was added sodium hydrogensulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155C for 14 hours, cooled to room temperature, and diluted with cold water (20 mL), to produce the precipitate. The yellow solid was filtered, washed with cold water, then methanol, and dried under vacuum to provide crude product, which was purified by preparative HPLC (0.1 % TFA in CH3CN / H2O as eluent) to give the title compound as a white solid. Yield: 0.23 g (14%). MP 101- 1030C. 1H-NMR (400 MHz, CDCI3): delta 8.38 (d, 1 H), 7.81-7.78 (m, 2H), 7.59-7.51 (m, 1 H), 7.31-7.20 (m, 2H), 7.15-7.12 (m, 2H), 7.01-6.98 (d, 2H), 3.98-3.80 (m, 4H), 2.20 (S, 6H), 2.01 (t, 1 H). MS (ES+) m/z: 421.05 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper dichloride; In ethanol; for 16.0h;Reflux; Inert atmosphere; | Example 3. Preparation of 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)quinazolin-4(3H)-one (K); [0147] 1H-Benzo[c/J[1 ,3]oxazine-2,4-dione (A) (3.26 g, 20.0 mmol) and 4- bromo-aniline (H) (3.23 g, 18.8 mmol) were mixed together as a neat mixture (both solids), and the reaction mixture was stirred at 1300C for 4 hours, and then cooled to room temperature. The crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-Lambda/-(4-bromo-phenyl)- benzamide (J) as white solid. Yield: 4.35 g (75%).[0148] To a solution of 2-amino-/V-(4-bromo-phenyl)-benzamide (3.75 g, 12.9 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (D) (2.50 g, 12.9 mmol) in anhydrous ethanol (75 ml_) was added anhydrous copper (II) chloride (5.19 g, 38.6 mmol). The reaction mixture was stirred under reflux for 16 hours under nitrogen, then cooled to room temperature. The ethanol was evaporated under reduced pressure. The residue was taken in dichloromethane (300 ml_) and the organic phase was washed with water (200 ml_). The aqueous phase was then extracted with CH2CI2 (2 * 200 ml_). The combined organic phase was washed with brine (200 ml_) and dried over anhydrous Na2SO4. The solvent was evaporated. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 30-50% ethyl acetate in hexanes as eluent) to give the title compound (K) as white solid. Yield: 3.84 g (64%). MP 164-1650C. 1H-NMR (400 MHz, DMSO-d6): delta 8.33 (d, J = 7.80 Hz, 1 H), 7.82-7.80 (m, 2H), 7.55-7.45 (m, 3H), 7.04 (d, J = 8.58 Hz, 2H), 6.98 (S, 2H), 3.94-3.90 (m, 2H), 3.82 (t, J = 4.68 Hz1 2H), 2.17 (s, 6H), 2.13 (t, J = 3.51 Hz, 1 H). MS (ES+) m/z: 465.42 (97%) (M+1), 467.43 (100%) (M+3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With copper dichloride; In ethanol; for 16.0h;Reflux; Inert atmosphere; | Example 11. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4- (trifluoromethyl)phenyl)quinazolin-4(3H)-one; [0171] To a solution of IH-benzoIcfHI .Sloxazine^-dione (1.63 g, 10.0 mmol) in anhydrous DMF (20 mL) was added 4-trifluoromethyl-aniline (1.61 g, 10.0 mmol) and the reaction mixture was stirred at 115C for 16 hours. It was then cooled to room temperature, diluted with ethyl acetate (150 mL), and the organic phase was washed with water (100 mL), 10% aq. NaOH solution (100 mL), water (150 mL), brine (150 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and the crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-Lambda/-(4-trifluoromethyl-phenyl)- benzamide as an off-white solid. Yield: 0.2 g (7%).[0172] To a solution of 2-amino-Lambda/-(4-trifluoromethyl-phenyl)-benzamide (0.19 g, 0.68 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.16 g, 0.81 mmol) in anhydrous ethanol (15 mL) was added anhydrous copper (II) chloride (0.273 g, 2.03 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen and then cooled to room temperature. Ethanol was evaporated under reduced pressure. The residue was taken in ethyl acetate (100 ml_). The organic phase was washed with water (2 * 75 ml_), then brine (75 ml_), and dried over anhydrous Na2SO4. Solvent was evaporated; crude compound was purified by column chromatography (silica gel 230-400 mesh; 2:3:5 ethyl acetate, hexanes and CH2CI2 as eluent) to give the title compound as a white solid. Yield: 0.17 g (55%). MP 160-1610C. 1H-NMR (400 MHz, CDCI3): delta 8.34 (d, J = 8.00 Hz, 1 H), 7.84-7.82 (m, 2H), 7.62-7.53 (m, 3H), 7.31 (d, J = 8.40 Hz, 2H), 6.97 (s, 2H), 3.93-3.89 (m, 2H), 3.80 (t, J = 5.20 Hz, 2H), 2.15 (s, 6H), 2.07 (t, J = 6.40 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With copper dichloride; In ethanol; for 16.0h;Reflux; | Example 20. Preparation of 3-(4-bromophenyl)-8-chloro-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)quinazolin-4(3H)-one; [0195] To a stirred solution of 3-chloro-2-nitrobenzoic acid (2.01 g, 10.0 mmol) in anhydrous methanol (100 ml_) nickel(ll)chloride hexahydrate (4.75 g, 20.0 mmol) was added, and the reaction mixture was cooled to room temperature. To this green solution was added NaBH4 (2.27 g, 60.0 mmol) in small portions over a period of 20 min. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The solvents were removed under vacuum and water (100 ml_) was added, before neutralization to pH approximately equal to 4 with aqueous 2 N HCI. After extraction with methylene chloride (2 x 100 ml_), the organic phase was separated, washed with water (100 ml_), then brine (100 ml_), and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 2-amino-3- chlorobenzoic acid as an off-white solid. Yield 0.90 g (52%).[0196] To a stirred solution of 2-amino-3-chlorobenzoic acid (0.86 g, 5.00 mmol) in anhydrous acetonitrile (10 ml_), a solution of triphosgene (0.49 g, 1.65 mmol) in anhydrous CH2CI2 (5 ml_) and anhydrous pyridine (0.79 g, 10.0 mmol) were added, drop-wise at 55C, simultaneously over a period of 10 minutes. After the addition was complete, the reaction mixture was stirred at 550C for another 2 hours. The solvents were removed under vacuum and water (50 ml_) was added. The separated solid was filtered, washed with water, followed by chilled CH2CI2 (10 ml_) and dried under vacuum to give 8-chloro-1 H-benzo[d][1 ,3]oxazine-2,4-dione as an off-white solid. Yield 0.82 g (83%).[0197] A mixture of 8-chloro-1H-benzo[c/][1 ,3]oxazine-2,4-dione (0.80 g, 4.05 mmol) and 4-bromoaniline (0.70 g, 4.05 mmol) with anhydrous DMF (1 ml_) was heated at 1300C for 2 hours. Water (50 mL) was added, and the product was extracted with ethyl acetate (200 mL). The organic phase was separated, washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the crude material was washed with ether, to give 2-amino-Lambda/-(4-bromophenyl)-3-chlorobenzamide as an off-white solid. Yield 1.17 g (89%).[0198] To a solution of 2-amino-Lambda/-(4-bromophenyl)-3-chlorobenzamide (0.52 g, 1.60 mmol) and <strong>[1039948-89-4]4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde</strong> (0.31 g, 1.60 mmol) in anhydrous ethanol (20 mL), anhydrous copper (II) chloride (0.86 g, 6.40 mmol) was added and the reaction mixture was refluxed for 16 hours. The solvent was evaporated in vacuo, water (100 mL) was then added, and the product was extracted with ethyl acetate (200 ml_). The organic phase was separated, washed with water (2 * 100 ml_), then brine (100 ml_), and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude compound was purified by the Simpliflash system (20-40% ethyl acetate in hexanes as eluent), to give the title compound as a white solid. Yield 0.37 g (46%). MP 185-186C. 1H-NMR (400 MHz, CDCI3) delta 8.25 (d, J = 8.20 Hz, 1 H) 7.89 (d, J = 7.42 Hz, 1 H) 7.56-7.34 (m, 3H) 7.03 (t, J = 4.29 Hz, 4H), 4.06-3.87 (m, 2H) 3.87-3.74 (m, 2H) 2.18 (s, 6H) 2.11-1.95 (m, 1 H). MS (ES+) m/z: 499.36, 501.38 (100%), 503.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 16.0h; | Example 4. Preparation of 3-(4-sec-butylphenyl)-7-fluoro-2-(4-(2-hydroxyethoxy)- 3,5-dimethylphenyl)quinazolin-4(3H)-one (Q); [0149] To a stirred solution of 2-amino-4-fluoro benzoic acid (L) (1.15 g, 7.40 mmol) in anhydrous acetonitrile (8 ml_) at 55C were simultaneously added anhydrous pyridine (1.2 ml_, 15 mmol) and a solution of triphosgene (0.73 g, 2.5 mmol) in anhydrous CH2CI2 (5 ml_) via syringe over a period of 15-20 minutes. After the addition was completed, the reaction mixture was stirred at 55C for another 2 hours. Much solid precipitated out. The solvent was distilled off. After cooling down to room temperature, water was added and the solid was filtered off, washed with water, followed by chilled CH2CI2. The solid was dried under vacuum to give 7-fluoro-1/-/-benzo[d][1 ,3]oxazine-2,4-dione (M) as grayish solid. Yield: 1.02 g (76%).[0150] To a solution of 7-fluoro-1 H-benzo[d][1 ,3]oxazine-2,4-dione (LOO g, 5.52 mmol) in anhydrous DMF (15 ml_), 4-(sec-butyl)-aniline (B) (0.824 g, 5.52 mmol) was added and the reaction mixture was heated at 116C for 16 hours. The product was extracted with ethyl acetate and washed with brine. The solvent was evaporated in vacuo to leave a crude material which was purified by column chromatography (silica gel; 230-400 mesh; ethyl acetate / hexane = 1 :9) to give 2- amino-Lambda/-(4-sec-butyl-phenyl)-4-fluoro-benzamide (N) as white solid. Yield: 0.92 g (58%).[0151] A mixture of 2-amino-/V-(4-sec-butyl-phenyl)-4-fluoro-benzamide (0.920 g, 3.21 mmol), 3,5-dimethyl-4-(2-hydroxy-ethoxy)-benzaldehyde (0.627 g, 3.21 mmol), sodium bisulfite (0.640 g, 3.53 mmol), and p-toluenesulfonic acid (60 mg, 0.32 mmol) in Lambdaf,Lambda/-dimethylacetamide (20 ml_) was heated at 12O0C for 16 hours. The solvent was evaporated in vacuo and water was added to the flask. The precipitate was filtered off and washed with water. The solid was triturated with ether and filtered off to give 3-(4-sec-butyl-phenyl)-7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5- dimethyl-phenyl]-2,3-dihydro-1/-/-quinazolin-4-one (P) (0.11 g). The filtrate was evaporated under vacuum to give second crop of (1.02 g). The combined yield: 1.13 g (quantitative).[0152] To a solution of 3-(4-sec-butyl-phenyl)-7-fluoro-2-[4-(2-hydroxy- ethoxy)-3,5-dimethyl-phenyl]-2,3-dihydro-1/-/-quinazolin-4-one (0.11 g, 0.24 mmol) in anhydrous THF (30 ml_) was added DDQ (0.09 g, 0.4 mmol) and the reaction mixture was stirred for 72 hours at room temperature. The solvent was evaporated in vacuo and the crude material was purified by column chromatography (silica gel; 230-400 mesh; 0.5% methanol/CH2Cl2 as eluent) to give the title compound (Q) as white solid. Yield: 0.06 g (50%). MP 53.9-54.4C. 1H-NMR (400 MHz, CDCI3): delta 8.38 (dd, 1 H), 7.43 (dd, 1 H), 7.22-7.05 (m, 5H), 6.99 (s, 2H), 3.90 (m, 2H), 3.78 (m, 2H), 2.59 (m, 1 H), 2.16 (s, 6H), 2.05 (t, 1 H), 1.59 (m, 2H), 1.20 (d, 3H), 0.71 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 155℃; for 14.0h; | Example 8. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4- iodophenyl)quinazolin-4(3H)-one; [0164] To a solution of 4-iodoaniline (4.03 g, 18.4 mmol) in N1N- dimethylformamide (20 mL) was added isatoic anhydride (3.00 g, 18.4 mmol), and the reaction mixture was heated at 115C for 14 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give 2-amino-Lambda/-(4-iodo-phenyl)-benzamide as white solid. Yield: 1.50 g (24%).[0165] To a mixture of <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.570 g, 2.96 mmol) and 2-amino-Lambda/-(4-iodo-phenyl)-benzamide (1.00 g, 2.96 mmol) in Lambda/,Lambda/-dimethylacetamide (10 ml_) was added sodium hydrogen sulfite (0.470 g, 4.44 mmol) and p-toluenesulfonic acid (0.280 g, 1.48 mmol). The reaction mixture was heated at 155C for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 ml_) to produce the precipitate. The yellow solid was filtered, washed with cold water (2 x 20 mL), methanol and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.20 g (13%). MP 101-1030C. 1H-NMR (400 MHz, CDCI3): delta 8.38 (d, 1 H), 7.81-7.78 (m, 2H), 7.75 (d, 2H), 7.59-7.48 (m, 1 H), 7.01-6.85 (m, 4H), 3.98-3.81 (m, 4H), 2.40 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 513.09 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With copper dichloride; In ethanol; for 3.0h;Reflux; | Example 9. Preparation of 3-(4-sec-butylphenyl)-6-fluoro-2-(4-(2-hydroxyethoxy)- 3,5-dimethylphenyl)quinazolin-4(3H)-one; [0166] To a solution of 2-amino-5-fluorobenzoic acid (1.00 g, 6.40 mmol) in acetonitrile (8 mL) was added a solution of triphosgene (0.64 g, 2.1 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.0 mmol) simultaneously within 5 min. The resulting pale yellow suspension was heated at 55C for 2 hours. The solvents were evaporated under vacuum, and the residue was stirred with water (5 ml_). The precipitate obtained was filtered and dried to afford delta-fluoro-IH-benzotcdti .Sloxazine^-dione. Yield: 1.06 g (91 %).[0167] To a suspension 6-fluoro-1 H-benzo[d][1 ,3]oxazine-2,4-dione (1.06 g, 5.90 mmol) in DMF (5 ml_) was added 4-sec-butylphenylamine (1.95 ml_, 11.8 mmol) at room temperature. The suspension was heated at 700C for 2 days, and cooled to room temperature. The reaction mixture was poured into crushed ice (150 ml_), and extracted with dichloromethane. The organic layer was dried over Na2SO4, and evaporated under vacuum. The residue was purified by flash column chromatography on a Biotage (40 M silica column), using a gradient of hexane:ethyl acetate (9:1 to 8:2) mixture as eluent to afford 2-amino-Lambda/-(4-sec-butylphenyl)-5- fluorobenzamide. Yield: 1.16 g (69%).[0168] Anhydrous CuCI2 (0.21 g, 1.6 mmol) was added to a solution of 2- amino-Lambda/-(4-sec-butylphenyl)-5-fluorobenzamide (0.15 g, 0.52 mmol), and 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.12 g, 0.63 mmol) in ethanol (30 ml_). The resulting green solution was heated at reflux for 3 hours. After cooling to room temperature , the mixture was concentrated under vacuum. The residue was stirred with water (20 mL), and extracted with ethyl acetate (2 * 25 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography on a Biotage (25 M silica column) using a gradient of hexane:ethyl acetate (8:2 to 5:5) mixture as eluent to afford the title compound. Yield: 0.19 g (77%). MP 70-720C. 1H-NMR (400 MHz, CDCI3): delta 7.99 (m, 1H), 7.82 (m, 1 H), 7.53 (m, 1H), 7.15 (m, 2H), 7.09 (d, 2H)1 6.97 (s, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 2.59 (m, 1 H), 2.15 (s, 6H), 2.02 (t, 1 H), 1.54 (m, 2H), 1.21 (d, 2H), 0.73 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; | Example 1. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)quinazolin-4(3H)-one (E); [0142] 4-sec-butyl aniline (B) (1.49 g, 10.0 mmol) was added to a solution of isatoic anhydride (A) (1.63 g, 10.0 mmol) in anhydrous DMF (40 ml_) and the reaction mixture was stirred at 115C for 16 hours under nitrogen. It was then cooled to room temperature and poured into water (200 ml_), and extracted with ethyl acetate (200 ml_). The organic phase was washed with water (100 ml_), 10% aqueous NaOH solution (100 ml_), water (100 ml_) and dried over anhydrous Na2SO4. Removal of solvent gave 2-amino-N-(4-sec-butylphenyl)benzamide (C) as a brown solid. Yield: 1.27 g (47%).[0143] To a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (1.27 g, 4.73 mmol) in Lambda/,Lambda/-dimethyl acetamide (20 ml_) were added 4-(2-hydroxy-ethoxy)- 3,5-dimethyl-benzaldehyde (D) (0.92 g, 4.7 mmol), sodium hydrogen sulphite (58.5 wt%) (0.95 g, 5.2 mmol) and p-toluenesulfonic acid (0.18 g, 0.95 mmol). The reaction mixture was stirred at 1200C overnight, and cooled to room temperature. The solvent was removed under reduced pressure and water (100 ml_) was added. The mixture was extracted with ethyl acetate (200 ml_). The organic phase was washed with water (2 * 100 ml_), then brine (100 ml_), and dried over anhydrous Na2SO4. Removal of solvent gave crude compound, which was purified by the Simpliflash system (30% ethyl acetate in hexanes as eluent) to give the title compound (E) as a white solid. Yield: 0.34 g (16%). MP 152-153C. 1H-NMR (400 MHz, CDCI3): delta 8.36-8.34 (m, 1 H), 7.81-7.80 (m, 2H), 7.54-7.50 (m, 1 H), 7.13 (d, J = 6.26 Hz, 2H), 7.06 (d, J = 8.21 Hz, 2H)1 6.98 (s, 2H), 3.92-3.88 (m, 2H), 3.78-3.76 (m, 2H), 2.56-2.54 (m, 1 H), 2.13 (s, 6H), 2.06 (t, J = 6.26 Hz, 1 H), 1.60-1.48 (m, 2H), 1.20 (d, J = 7.04 Hz, 3H), 0.727 (t, J = 7.43 Hz, 3H). MS (ES+) m/z: 443.01 (M+1) (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper dichloride; In ethanol; for 24.0h;Reflux; | Example 12. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-7-(methylsulfonyl)quinazolin-4(3H)-one; [0173] To a suspension of 2-amino-4-methanesulfonyl-benzoic acid (1.00 g, 4.64 mmol) in acetonitrile (15 ml_) at 55C were simultaneously added pyridine (0.75 ml_, 9.3 mmol) and a solution of triphosgene (0.455 g, 1.53 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at 55C for 2 hours and the solvent was removed using a rotary evaporator. The residue was diluted with water (50 mL) and the precipitate was filtered, and air dried to provide 7- methanesulfonyl-1H-benzo[d][1 ,3]oxazine-2,4-dione. Yield: 0.98 g (82%).[0174] A solution of 7-methanesulfonyl-1H-benzo[c/][1 ,3]oxazine-2,4-dione (0.98 g, 3.8 mmol) and 4-sec-butylaniline (0.57 g, 3.8 mmol) in N, N- dimethylformamide (30 mL) was stirred at 115C for 16 hours, cooled to room temperature , diluted with water (50 ml_), extracted with ethyl acetate (2 * 100 ml_), and concentrated using a rotary evaporator. The residue was further purified by column chromatography (SiO2, hexane / ethyl acetate = 2:1) to provide 2-amino-/V- (4-sec-butyl-phenyl)-4-methanesulfonyl-benzamide. Yield: 0.466 g (33%).[0175] To a solution of 2-amino-Lambda/-(4-sec-butyl-phenyl)-4-methanesulfonyl- benzamide (0.20 g, 0.55 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl- benzaldehyde (0.13 g, 0.66 mmol) in ethanol (15 ml_) was added anhydrous copper (II) chloride (0.222 g, 1.65 mmol). The resulting mixture was stirred at reflux for 24 hours and the solvent was removed using a rotary evaporator. The residue was then diluted with water (50 ml_), extracted with ethyl acetate (2 * 100 mL), and concentrated on using a rotary evaporator. The crude product was made into a slurry in diethyl ether (20 mL) and filtered to provide the title compound as white solid. Yield: 0.20 g (70%). MP 235-237C. 1H-NMR (400 MHz, CDCI3): delta 8.53 (d, 1 H), 8.41 (d, 1 H), 8.00 (dd, 1 H), 7.16 (d, 2H), 7.06 (d, 2H)1 7.00 (s, 2H), 3.91 (m, 2H), 3.80 (m, 2H), 3.15 (s, 3H), 2.59 (m, 1 H), 2.13 (s, 6H), 2.04 (m, 1 H), 1.58 (m, 2H), 1.22 (d, 3H), 0.73 (t, 3H). MS (ES+) m/z: 521.22 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With copper dichloride; In ethanol; for 4.0h;Reflux; Inert atmosphere; | Example 13. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; [0176] To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 mL) at 50-550C were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g , 2.96 mmol) in anhydrous dichloromethane (20 mL) over 20 min span, and the reaction was stirred at 50-550C for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude was further washed with ether (20 mL) to give 6-methoxy-1/-/- benzo[c/][1 ,3]oxazine-2,4-dione. Yield: 1.55 g (89%).[0177] To a flask (100 mL) with magnetic stirrer was added 6-methoxy-1H- benzo[c/][1 ,3]oxazine-2,4-dione (1.55 g, 8.00 mmol), 4-sec-butylaniline (1.19 mL, 8.0 mmol) and anhydrous DMF (10 mL). The reaction mixture was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give 2-amino-Lambda/-(4-sec-butyl-phenyl)-5-methoxy-benzamide. Yield: 0.90 g (37%).[0178] To a solution of 2-amino-Lambda/-(4-sec-butyl-phenyl)-5-methoxy- benzamide (0.450 g, 1.51 mmol) and 4-(2-hydroxy-ethoxy)-3, 5-dimethyl- benzaldehyde (0.290 g, 1.51 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.610 g, 4.53 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (100 mL) and water (100 mL). After separation, the organic phase was further washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give the title compound as white solid. Yield: 260 mg (36%). MP 152-154C. 1H-NMR (400 Hz, CDCI3): delta 7.78 (d, 1 H)1 7.74 (s.1H), 7.40 (m, 1H), 7.14 (m, 2H), 7.08 (m, 2H), 6.94 (s,2H), 3.96 (s, 3H), 3.90 (m, 2H), 3.78 (t, 2H), 2.56 (m, 1 H)1 2.12 (s, 6H), 2.08 (t, 1 H), 1.60 (m, 1 H), 1.50 (m, 2H), 1.20 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.29 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With copper dichloride; In ethanol; at 100℃; for 5.0h;Inert atmosphere; | Example 14. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-8-methoxyquinazolin-4(3H)-one; [0179] A solution of 8-methoxy-1 H-benzo[c/][1 ,3]oxazine-2,4-dione (0.50 g, 2.6 mmol) and 4-sec-butylaniline (0.42 g, 2.8 mmol) in DMF (4.0 ml_) were stirred at 1100C under N2 for 24 hours. The mixture was concentrated to dryness then purified by column chromatography on silica gel using 1/2 EtOAc/hexane as eluent to afford 2-amino-Lambda/-(4-sec-butyl-phenyl)-3-methoxy-benzamide as white solid. Yield: 0.533 g (69%).[0180] To a 100-mL round bottom flask were added 2-amino-Lambda/-(4-sec-butyl- phenyl)-3-methoxy-benzamide (0.533 g, 1.79 mmol), 4-(2-hydroxy-ethoxy)-3,5- dimethyl-benzaldehyde (0.382 g, 1.96 mmol), anhydrous copper (II) chloride (0.722 g, 5.37 mmol), and anhydrous ethanol (40 ml_). The mixture was refluxed at 1000C under N2 for 5 hours . The mixture was concentrated to dryness. Water (approximately 20 ml_) was added and extracted with EtOAc (3 * 50 mL). The EtOAc solutions were combined and dried over Na2SO4. The crude product was purified by column chromatography on silica gel using hexane / EtOAc (1 :1 to 1 :2) as eluent. The product fractions were concentrated to dryness then re-crystallized in ether to afford the title compound as white solid. Yield: 0.460 g (54%). MP 158-159C. 1H- NMR (400 MHz1 CDCI3): delta 7.93 (d, 1 H), 7.46 (t, 1 H), 7.24 (d, 1H), 7.12 (d, 2H), 7.05 (d, 2H), 7.00 (s, 2H), 4.03 (s, 3H), 3.89 (m, 2H), 3.75 (m, 2H), 2.56 (m, 1 H), 2.11 (s, 6H), 1.52 (m, 2H), 1.19 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.27 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With copper dichloride; In ethanol; for 48.0h;Reflux; | Example 15. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-(methylsulfonyl)quinazolin-4(3H)-one; [0181] To a solution of 2-chloro-4-methylsulfonyl aniline (1.0 g, 4.9 mmol) in /V-methylpyrrolidine (10 ml_) was added copper (I) cyanide (4.35 g, 48.6 mmol) under nitrogen. The reaction mixture was stirred at 1800C for 72 hours, cooled to room temperature, poured to a 1 :1 mixture of ammonia and water (200 ml_), stirred for 1 hour, and then filtered off. The residue was washed with CH2CI2 (50 ml_) and filtrate was extracted with CH2CI2 (3 * 20 ml_). The combined organic layers were backwashed with water (50 ml_), dried over sodium sulfate, and concentrated to provide crude material, which was purified by flash column chromatography (silica gel; 230-400 mesh; ethyl acetate / hexanes = 1 :5) to obtain 2-amino-5- methanesulfonyi-benzonitrile as a white solid. Yield: 0.1 g (13%). A suspension of potassium hydroxide (2.05 g, 36.7 mmol) in ethylene glycol (9 ml_) was heated to 800C. KOH was dissolved completely at this stage. 2-Amino-5-methanesulfonyl- benzonitrile (0.900 g, 4.59 mmol) was added to the reaction mixture and the bath temperature was increased to 185C and stirred for 16 hours. The resultant reaction mixture was cooled to room temperature , diluted with water (20 ml_), and extracted with CH2CI2 (3 x 30 ml_). The aqueous layer was acidified with 2 N HCI to pH 4-5, extracted with EtOAc (3 * 30 ml_), and the combined organic layers were backwashed with water (30 ml_), then brine (30 mL), dried over sodium sulfate, and evaporated, to obtain 2-amino-5-methanesulfonyl-benzoic acid. Yield: 0.750 g (75%).[0182] To a suspension of 2-amino-5-methanesulfonyl-benzoic acid (0.750 g, 3.48 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.730 g, 3.83 mmol), 1-hydroxybenzothazole (0.510 g, 3.83 mmol), and 4-methylmorpholine (0.380 g, 3.83 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then 4-sec-butyl-aniline (0.780 g, 5.22 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, water was added, and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was washed with ether to obtain 2-amino-Lambda/-(4-sec-butyl- phenyl)-5-methanesulfonyl-benzamide as white solid. Yield: 0.75 g (62%).[0183] To a solution of 2-amino-/V-(4-sec-butyl-phenyl)-5-methanesulfonyl- benzamide (0.21 g, 0.58 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl- benzaldehyde (0.13 g, 0.64 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.440 g, 3.27 mmol) and the reaction mixture was refluxed for 48 hours. The solvent was evaporated in vacuo and the product was extracted with dichloromethane. The solvent was evaporated in vacuo and the residue was triturated with ether and methanol / ethyl acetate and filtered off, to obtain the title compound as a white solid. Yield: 0.13 g (43%). MP 258.8-260.20C. 1H-NMR (400 MHz1 CDCI3): delta 8.94 (s, 1 H)1 8.28 (d, 1 H), 7.94 (d, 1 H), 7.19 (m, 2H), 7.03 (m, 2H), 7.01 (s, 2H), 3.91 (m, 2H), 3.79 (d, 2H), 3.17 (s, 3H), 2.58 (m, 1 H), 2.18 (S1 3H), 2.03 (m, 1 H), 1.60 (m, 2H), 1.21 (d, 3H), 0.78 (t, 3H). MS (ES+) m/z: 521.66 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With copper dichloride; In ethanol; for 4.0h;Inert atmosphere; Reflux; | Example 16. Preparation of 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; [0184] To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 ml_) at 50-550C were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g , 2.96 mmol) in anhydrous dichloromethane (20 ml_) over 20 minute span, and the reaction was stirred at 50- 55C for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 ml_) and dried. The crude product was further washed with ether (20 mL) to give 6-methoxy-1 H- benzo[cO[1 ,3]oxazine-2,4-dione. Yield: 1.40 g (81 %).[0185] A solution of 6-methoxy-1 H-benzo[c/][1 ,3] oxazine-2, 4-dione (0.800 g, 4.10 mmol) and 4-bromoaniline (0.750 g, 4.30 mmol) in anhydrous DMF (10 mL) was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated, backwashed with brine (50 mL), and concentrated. The residue was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 : 1 ) to give 2- amino-Lambda/-(4-bromo-phenyl)-5-methoxy-benzamide. Yield: 0.240 g (18%).[0186] To a solution of 2-amino-/V-(4-bromo-phenyl)-5-methoxy-benzamide (0.240 g, 0.740 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.145 g, 0.740 mmol) in anhydrous ethanol (20 ml_) was added anhydrous copper (II) chloride (0.298 g, 2.22 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 ml_) and water (100 ml_). After separation the organic phase was further backwashed with water (100 ml_), brine (100 mL), dried over sodium sulfate, and concentrated. The crude was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 : 1 ) to give the title compound as white solid. Yield: 120 mg (33%). MP 160-1620C. 1H-NMR (400 Hz, CDCI3): delta 7.74 (d, 1 H), 7.69 (s, 1 H), 7.46 (d, 2H), 7.40 (m, 1 H), 7.03 (d, 2H), 6.96 (s, 2H)1 3.94 (s, 3H)1 3.91 (m, 2H), 3.82 (t, 2H), 2.17 (s, 6H), 2.05 (t, 1 H). MS (ES+) m/z: 497.41 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With copper dichloride; In ethanol; for 16.0h;Reflux; Inert atmosphere; | Example 17. Preparation of 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-8-methoxyquinazolin-4(3H)-one; [0187] To a solution of 2-amino-3-methoxy-benzoic acid (2.50 g, 14.9 mmol) in anhydrous acetonitrile (25 mL) at 50-550C were simultaneously added pyridine (2.36 g, 29.8 mmol) and a solution of triphosgene (1.46 g , 4.90 mmol) in anhydrous dichloromethane (10 mL) over 20 minutes, the reaction was stirred at 50-550C for 2 hours. The solvent was removed and the residue was mixed with water (100 ml_), the solid was filtered and rinsed with cold water (30 ml_) and dried. The crude was further washed with ether (20 ml_) to give 6-methoxy-1/-/-benzo[dJ[1 ,3]oxazine-2,4- dione. Yield: 2.56 g (89%).[0188] A solution of 8-methoxy-1H-benzo[c/][1 ,3] oxazine-2,4-dione (1.50 g, 7.70 mmol) and 4-bromoaniline (1.40 g, 8.10 mmol) in anhydrous DMF (10 ml_) was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 ml_) and ethyl acetate (150 ml_). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 : 1 ) to give 2-amino-Lambda/-(4-bromo-phenyl)-3-methoxy-benzamide. Yield: 1.49 g (60%).[0189] To a solution of 2-amino-Lambda/-(4-bromo-phenyl)-3-methoxy-benzamide (0.600 g, 1.86 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.360 g, 1.86 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.750 g, 5.58 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). After separation, the organic phase was further backwashed with water (100 mL), then brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 :1) to give the title compound as a white solid. Yield: 250 mg (27%). MP 100-1020C. 1H-NMR (400 Hz, CDCI3): delta 7.90 (d, 1 H), 7.47 (m, 3H), 7.25 (m, 1 H), 7.03 (d, 2H)1 7.00 (s, 2H), 4.02 (s, 3H), 3.91 (m, 2H), 3.80 (t, 2H), 2.15 (s, 6H), 2.06 (t, 1 H). MS (ES+) m/z: 497.41 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.6% | With copper dichloride; In ethanol; for 4.0h;Inert atmosphere; Reflux; | Example 18. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethyiphenyl)-3-(4- isopropylphenyl)quinazolin-4(3H)-one; [0190] A solution of 1/-/-benzo[d][1 ,3]oxazine-2,4-dione (2.0 g, 12.2 mmol) and 4-isopropylaniline (1.92 ml_, 13.5 mmol) in anhydrous DMF (10 ml_) was stirred at 115C for 6 hours under nitrogen. DMF was removed and the residue was mixed with water (100 ml_) and dichloromethane (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was washed with ether (50 mL) to give 2-amino-Lambda/-(4-isopropyl-phenyl)-benzamide as a solid. Yield: 0.80 g (25.8%).[0191] To a solution of 2-amino-Lambda/-(4-isopropylphenyl)benzamide (0.400 g, 1.57 mmol) and <strong>[1039948-89-4]4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde</strong> (0.30 g, 1.57 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.63 g, 4.71 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (150 mL) and water (100 mL). The organic phase was separated and further washed with water (100 mL), brine (100 mL), and dried over sodium sulfate. The crude mixture was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate (1 :1) as eluent to give the title compound as a white solid. Yield: 100 mg (15.6%). MP 160-1620C. 1H-NMR (400 Hz, CDCI3): delta 8.34 (d, J=7.6 Hz1I H), 7.80 (m, 2H), 7.52 (m, 1 H), 7.17 (d, J= 8.4 Hz, 2H), 7.05 (d, J= 8.4 Hz, 2H), 6.97 (s, 2H), 3.90 (m, 2H), 3.78 (t, J= 4.8 Hz, 2H), 2.86 (m, 1 H), 2.13 (s, 6H), 2.06 (t, J=6.4 Hz, 1 H), 1.20 (d, J=7.2 Hz1 3H). MS (ES+) m/z: 429.52 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Example 19. Preparation of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one hydrochloride [0228] Bromine (33.7 ml_, 657 mmol) and 1,4-dioxane (56.0 mL, 657 mmol) was mixed at room temperature to provide fresh dioxane dibromide, which was then diluted with ethyl ether (900 mL). To a solution of 2,6-dimethoxytoluene (50.0 g, 328 mmol) in ether (450 mL) was added the freshly prepared dioxane dibromide in ether (900 mL) over 30 minutes while stirring at room temperature. After the addition, the mixture was stirred at room temperature for an additional 1.5 hours, and was poured into a beaker containing water (500 mL) and partitioned. The aqueous was discarded and the ethereal layer was washed sequentially with water (2 * 500 mL), saturated sodium bicarbonate aqueous (2 x 500 mL), dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator, to afford 3-bromo-2,6-dimethoxytoluene as a colorless oil. Yield: 76 g, (100%). [0229] A cooling well was used to collect 300 mL of ammonia at -78C, which was then mixed with 0.5 g potassium and 0.5 g ferric nitrate. After the initial blue color discharged, potassium (14.2 g, 364 mmol) was added at -78C, portion- wise so that the blue color discharged before to each addition. After complete addition of potassium, the solution was stirred at -78C for 15 minutes. To this solution was slowly added 3-bromo-2,6-dimethoxytoluene (42.0 g, 182 mmol) in THF (100 mL). The resulting mixture was stirred at -78C for 3 hours and then 00C for 1 hour. The reaction was quenched by adding water (150 mL) and was extracted with CH2CI2 (3 x 200 mL) to afford a brown oil as the crude product. The product was further purified by column chromatography (SiO2, hexanes / ethyl acetate = 1 :1) to yield 3,5-dimethoxy-4-methylaniline. Yield: 22.1 g (73%).[0230] A solution of 3,5-dimethoxy-4-methylaniline (22.1 g, 132 mmol) in 1 ,4-dioxane (380 mL) and water (380 mL) was mixed with potassium carbonate (45.6 g, 331 mmol) and (Boc)2theta (34.6 g 159 mmol) and stirred at room temperature for 14 hours. The reaction mixture was then extracted with CH2CI2 (3 x 100 ml_) and concentrated on a rotary evaporator. The resulting solid residue was purified by column chromatography (SiO2, hexanes / ethyl acetate = 2:1) to yield a solid. A mixed solvent of CH2CI2-hexanes (20 ml_ / 300 ml_) was used to make a slurry and the solid was collected by filtration and washed with hexanes to provide (3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester as a light yellow needle-like solid. Yield: 28.6 g (81%).[0231] A solution of (3,5-dimethoxy-4-methylphenyl)-carbamic acid tert- butyl ester (28.6 g, 107 mmol) in carbon tetrachloride (450 ml_) was mixed with NBS (19.05 g, 107.1 mmol) and AIBN (1.55 g, 9.37 mmol) and was stirred at 800C under irradiation from a medium-pressure mercury lamp for 2 hours. The reaction was then quenched by adding water (150 ml_) and extracted with CH2CI2 (3 x 100 ml_), and concentrated on a rotary evaporator to afford a solid residue. Further purification on column (SiO2, hexanes / ethyl acetate = 2:1) yielded (2-bromo-3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester. Yield: 34.9 g (94%). [0232] solution of (2-bromo-3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester (34.9 g, 101 mmol) in carbon tetrachloride (450 ml_) was mixed with N-bromosuccinimide (21.5 g, 121 mmol) and AIBN (1.55 g, 9.37 mmol) and was stirred at 800C under irradiation from a medium-pressure mercury lamp for 4 hours. The reaction was then quenched by adding water (150 ml_) and extracted with CH2CI2 (3 x 100 ml_), and concentrated on a rotary evaporator to afford a solid residue. Further purification on a column (SiO2, hexanes / ethyl acetate = 2:1) yielded (2-bromo-4-bromomethyl-3,5-dimethoxyphenyl)-carbamic acid tert-butyl ester. Yield: 39.0 g (91 %).[0233] A solution of (2-bromo-4-bromomethyl-3,5-dimethoxyphenyl)-carbamic acid tert-butyl ester (39.0 g, 91.8 mmol) in THF (600 ml_) was mixed with morpholine (45.0 ml_, 515 mmol) and stirred at room temperature for 7 hours. The reaction was diluted with water (300 ml_), extracted with CH2CI2 (3 * 200 ml_), and concentrated on a rotary evaporator. The residue was further purified by column (SiO2, dichloromethane / methanol = 20:1) to provide (2-bromo-3,5-dimethoxy-4- morpholin-4-ylmethylphenyl)-carbamic acid tert-butyl ester. Yield: 35 g (88%). [0234] A solution of (2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethylphenyl)-carbamic acid tert-butyl ester (3.0 g, 6.9 mmol) in THF (150 ml_) was mixed with sodium hydride (0.333 g, 8.33 mmol) and stirred at room temperature for 1.5 hours. The resulting mixture was then cooled to -78C and mixed with nBuLi (3.33 ml_, 8.33 mmol). The reaction was stirred for 1.5 hours at -78C before addition of tBuLi (8.16 ml_, 13.9 mmol). After addition of tBuLi, the reaction was stirred at -78C for 1 hour and carbon dioxide gas was then bubbled through for 8 hours, a... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | Example 17. Preparation of 2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one [0219] To a solution of 5-methyl-2-nitrobenzoic acid (25.0 g, 138 mmol) in ethanol (200 ml_) was slowly added concentrated sulfuric acid (30 ml_). The resulting solution was stirred at reflux for 48 hours. The reaction mixture was then poured into icy water (300 ml_), extracted with CH2CI2 (3 x 100 ml_), and concentrated on a rotary evaporator, to afford 5-methyl-2-nitrobenzoic acid ethyl ester. Yield: 28.9 g (100%).[0220] A solution of 5-methyl-2-nitrobenzoic acid ethyl ester (28.9 g, 138 mmol), N-bromosuccinimide (24.6 g, 138 mmol), and benzoyl peroxide (7.41 g, 30.6 mmol) in carbon tetrachloride (400 ml_) was stirred at 800C under irradiation from a medium pressure mercury lamp for 3 hours. The lamp was then removed and the reaction was cooled to 400C. To this solution was slowly added morpholine (14.6 ml_, 168 mmol) and triethylamine (43.0 mL, 306 mmol). The resulting mixture was stirred at 400C for 14 hours, diluted with saturated sodium bicarbonate aqueous (300 mL), extracted with CH2CI2 (3 x 100 mL), and concentrated on a rotary evaporator. The residue was subjected to column chromatography (SiO2, hexanes / ethyl ether = 1 :2) to afford 5-morpholin-4-ylmethyl-2-nitrobenzoic acid ethyl ester as an oil. Yield: 20 g (49%). [0221] To a solution of 5-morpholin-4-ylmethyl-2-nitrobenzoic acid ethyl ester (20 g, 68 mmol) in acetic acid (100 mL) was added iron powder (13.0 g, 231 mmol). The resulting suspension was stirred at 600C for 3 hours, cooled to room temperature, and diluted with water (200 mL) and CH2CI2 (200 mL). The solid was filtered off, and the filtrate was extracted with CH2CI2 (3 * 100 mL) and concentrated on a rotary evaporator to remove all solvent. The residue was re-dissolved in CH2CI2 (400 mL), and backwashed with 2 N potassium hydroxide aqueous (2 x 200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated, to afford 2-amino-5-morpholin-4-ylmethylbenzoic acid ethyl ester as an oil. Yield: 17.7 g (100%). [0222] A solution of 2-amino-5-morpholin-4-ylmethylbenzoic acid ethyl ester (3.82 g, 15.3 mmol) and lithium hydroxide (0.733 g, 30.6 mmol) in THF (25 mL), methanol (15 mL), and water (10 mL) was stirred at reflux for 2.5 hours. The reaction mixture was then concentrated to dryness on a rotary evaporator and further dried under high vacuum for 24 hours to afford lithium 2-amino-5-morpholin-4-ylmethylbenzoate. Complete conversion was assumed and the solid obtained was used in the next step without further purification.[0223] A solution of lithium 2-amino-5-morpholin-4-ylmethylbenzoate (3.70 g, 15.3 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.87 g, 30.6 mmol), HOBt (4.54 g, 33.6 mmol), and 4-methylmorpholine (5.0 ml_, 46 mmol) in THF (200 ml_) was stirred at room temperature for 40 minutes. 50% (v/v) aqueous ammonia (20 ml_) was then added. The resulting solution was stirred at room temperature for 14 hours, diluted with water (200 ml_), extracted with CH2CI2 (3 x 100 ml_), and concentrated on a rotary evaporator, to afford 2-amino-5-morpholin-4-ylmethylbenzamide as a light yellow solid. Yield: 1.2 g (33%).[0224] A solution of 2-amino-5-morpholin-4-ylmethylbenzamide (0.60 g, 2.6 mmol), <strong>[1039948-89-4]4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde</strong> (0.58 g, 3.9 mmol), sodium bisulfite (1.14 g, 6.44 mmol), and p-toluenesulfonic acid (0.88 g, 4.6 mmol) in dimethyl acetamide (10 ml_) was stirred at 1500C for 12 hours. Extra solvent was evaporated on a rotary evaporator and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 ml_) and extracted with CH2CI2 (3 x 100 ml_). The residue obtained on concentration was subjected to column chromatography (SiO2, hexanes / ethyl acetate / dichloromethane / methanol = 4:4:8:1 ) to afford 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one as a light yellow solid. Yield: 0.15 g (14%).[0225] A solution of 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.15 g, 0.37 mmol) in CH2CI2 (10 ml_) was mixed with 1 N HCI in ethyl ether (3 ml_, 3 mmol) and was stirred at room temperature for 10 minutes to form a suspension. The solid was filtered, and washed with CH2CI2 to afford the title compound as a light yellow solid. Yield: 52 mg (29%). 1H NMR (400 MHz, CD3OD): delta 8.49 (s, 1 H), 8.13 (d, 1H), 7.93 (d, 1 H), 7.77 (s, 2H), 4.58 (s, 2H), 4.05 (m, 2H), 3.98 (t, 2H), 3.91 (t, 2H), 3.80 (m, 2H), 3.41 (m, 2H), 3.30 (m, 2H), 2.44 (s, 6H). MS (ES+) m/z: 410.05 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.9% | Example 16. Preparation of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one [0210] To a solution of 3,5-dihydroxybenzoic acid (10.0 g, 64.9 mmol) in anhydrous ethanol (100 ml_) at room temperature was slowly added concentrated sulfuric acid (10 ml_). The resulting mixture was stirred at reflux for 36 hours. The reaction was cooled to room temperature, diluted with water (200 ml_), extracted with CH2Cb (3 x 100 ml_), and concentrated on a rotary evaporator, to afford 3,5- dihydroxybenzoic acid ethyl ester as a colorless oil. Yield: 8.2 g (69%).[0211] A solution of 3,5-dihydroxybenzoic acid ethyl ester (6.0 g, 33 mmol) and 2-iodo-propane (9.9 ml_, 99 mmol) in DMF (200 ml_) was mixed with potassium carbonate (13.7 g, 98.9 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then diluted with water (300 ml_), and extracted with ethyl acetate (3 x 100 ml_). The residue obtained upon concentration was subjected to column chromatography (SiO2, hexanes / ethyl acetate = 3:1) to afford 3,5-diisopropoxybenzoic acid ethyl ester. Yield: 8.8O g (100%).[0212] A solution of 3,5-diisopropoxybenzoic acid ethyl ester (8.80 g, 33.1 mmol) and lithium hydroxide (3.18 g, 132 mmol) in water (100 ml_), methanol (50 ml_), and THF (50 ml_) was stirred at reflux for 3 hours. It was then cooled to room temperature, diluted with water (200 mL), acidified with 2 N hydrochloric acid, to pH approximately 2, extracted with CH2Cb (3 chi 100 mL), and concentrated on a rotary evaporator, to afford 3,5-diisopropoxybenzoic acid as a white solid. Yield: 7.60 g (97%).[0213] A solution of 3,5-diisopropoxybenzoic acid (7.60 g, 31.9 mmol), triethylamine (5.3 mL, 38 mmol), and diphenylphosphoroyl azide (8.3 mL, 38 mmol) in 1,4-dioxane (120 mL) and tert-butanol (30 mL) was stirred at reflux for 16 hours. The reaction mixture was then cooled to room temperature, diluted with 0.2 N sodium bicarbonate aqueous (200 mL), extracted with CH2CI2 (3 x 100 mL), and concentrated on a rotary evaporator. The residue obtained was subjected to column chromatography (SiO2, hexanes / ethyl acetate = 3:1) to afford 3,5-diisopropoxyphenyl)-carbamic acid tert-butyl ester as a white solid. Yield: 5.60 g (57%). [0214] A solution of 3,5-diisopropoxyphenyl)-carbamic acid tert-butyl ester (5.60 g, 18.2 mmol) in trifluoroacetic acid (30 mL) was stirred at reflux for 30 minutes and concentrated on a rotary evaporator to dryness to afford 3,5-diisopropoxyphenylamine trifluoroacetic acid salt as an oil. Yield: 5.27 g (90%).[0215] To a round-bottomed flask contained 3,5-diisopropoxyphenylamine trifluoroacetic acid salt (5.27 g, 16.4 mmol) was slowly added oxalyl chloride (20 mL) and the mixture was stirred at reflux for 1 hour. Extra oxalyl chloride was removed by distillation and methanol (100 mL) was added to the residue. It was then stirred at room temperature for 30 minutes and concentrated to dryness on a rotary evaporator to afford 4,6-diisopropoxy-1H-indole-2,3-dione as a semi-solid. Yield: 4.33 g (100%).[0216] A solution of potassium hydroxide (15.3 g, 273 mmol) in water (60 mL) was mixed with 4,6-diisopropoxy-1H-indole-2,3-dione (4.33 g, 16.4 mmol). To this mixture was slowly added hydrogen peroxide. The resulting mixture was stirred at 700C for 30 minutes and cooled to 00C. The mixture was acidified at 0C with 2 N hydrochloric acid to pH approximately 4, extracted with CH2CI2 (3 x 100 mL), and concentrated on a rotary evaporator to afford 2-amino- 4,6-diisopropoxy-benzoic acid as a semi-solid. Yield: 2.91 g | |
6.9% | With sodium hydrogen sulfate; toluene-4-sulfonic acid; In N,N-dimethyl acetamide; at 150℃; for 12.0h; | A solution of 2-amino-4,6-diisopropoxybenzamide (0.30 g, 1.2 mmol), <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethylbenzaldehyde</strong> (0.28 g, 1.4 mmol), sodium bisulfite (0.25 g, 1.4 mmol), and p-toluenesulfonic acid (20 mg, 0.11 mmol) in dimethyl acetamide (10 mL) was stirred at 150 C. for 12 hours. Extra solvent was evaporated on a rotary evaporator and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with CH2Cl2 (3*100 mL). The residue obtained upon concentration was subjected to column chromatography (SiO2, ethyl acetate/dichloromethane/hexanes/methanol=4:4:4:1) to afford the title compound as a light yellow solid. Yield: 35 mg (6.9%). 1H NMR (400 MHz, CDCl3): delta 9.78 (br s, 1H), 7.66 (s, 2H), 6.78 (d, 1H), 6.42 (d, 1H), 4.72 (m, 1H), 4.63 (m, 1H), 3.97 (t, 3H), 3.92 (t, 2H), 2.33 (s, 6H), 1.45 (d, 3H), 1.41 (d, 3H). MS (ES+) m/z: 427.13 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 23.0h;Inert atmosphere; | <strong>[1039948-89-4]4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde</strong> (0.70 g, 3.58 mmol), 2-amino-6-chlorobenzamide (0.60 g, 3.51 mmol), sodium bisulfite (0.71 g, 3.86 mmol) and p-toluenesulfonic acid monohydrate (0.133 g, 0.699 mmol) in anhydrous N,N-dimethyl acetamide (14 mL) were heated at 120 C. under nitrogen for 23 hours. The solvent was evaporated and the white solid was triturated with water (50 mL), filtered, and washed with water (20 mL). The solid was dried in vacuo and triturated with Et2O (20 mL), filtered, and dried to give 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one as a white solid. Yield: 0.77 g, (64%) |
64% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 23.0h;Inert atmosphere; | 4-(2-Hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.70 g, 3.58 mmol), 2-amino-6-chlorobenzamide (0.60 g, 3.51 mmol), sodium bisulfite (0.71 g, 3.86 mmol) and p-toluenesulfonic acid monohydrate (0.133 g, 0.699 mmol) in anhydrous N,N-dimethyl acetamide (14 mL) were heated at 120 C. under nitrogen for 23 hours. The solvent was evaporated and the white solid was triturated with water (50 mL), filtered, and washed with water (20 mL). The solid was dried in vacuo and triturated with Et2O (20 mL), filtered, and dried to give 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one as a white solid. Yield: 0.77 g, (64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 20.0h; | To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115 C. for 20 hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, filtered, and dried under vacuum to give 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.1 g (55%) |
55% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 20.0h; | To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115 C. for 20 hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, filtered, and dried under vacuum to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.1 g (55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 16.0h; | To a solution of 2-amino-4-methoxy-benzamide (1.00 g, 6.01 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was stirred at 115 C. for 16 hours, and cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 hour, filtered, and dried under vacuum, to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.20 g (58%). |
58% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 16.0h; | To a solution of 2-amino-4-methoxy-benzamide (1.00 g, 6.01 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was stirred at 115 C. for 16 hours, and cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 hour, filtered, and dried under vacuum, to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.20 g (58%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 145 - 148℃; for 16.0h; | To a solution of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.00 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.59 g, 3.00 mmol) in N,N-dimethylacetamide (8 mL) was added NaHSO3 (58.5 wt %, 0.59 g, 3.30 mmol) and p-TSA (0.22 g, 1.20 mmol). The reaction mixture was heated to 145-148 C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.50 g (49%) |
49% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 145 - 148℃; for 16.0h; | Example 85 Preparation of 2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one To a solution of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.00 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (0.59 g, 3.00 mmol) in N,N-dimethylacetamide (8 mL) was added NaHSO3 (58.5 wt %, 0.59 g, 3.30 mmol) and p-TSA (0.22 g, 1.20 mmol). The reaction mixture was heated to 145-148 C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.50 g (49%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 16.0h; | A mixture of 2-amino-4,6-difluoro-benzamide (0.96 g, 5.60 mmol), <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.09 g, 5.60 mmol), NaHSO3 (58.5 wt %, 1.00 g, 5.60 mmol) and p-toluenesulfonic acid monohydrate (1.44 g, 7.06 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 120 C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The solid separated was filtered and washed with water and dried under vacuum to give 5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one as a white solid. Yield: 1.55 g (79%) |
79% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 16.0h; | Example 86 Preparation of 2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-1-yl)quinazolin-4(3H)-one A mixture of 2-amino-4,6-difluoro-benzamide (0.96 g, 5.60 mmol), <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.09 g, 5.60 mmol), NaHSO3 (58.5 wt %, 1.00 g, 5.60 mmol) and p-toluenesulfonic acid monohydrate (1.44 g, 7.06 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 120 C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The solid separated was filtered and washed with water and dried under vacuum to give 5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one as a white solid. Yield: 1.55 g (79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 16.0h;Inert atmosphere; | To a solution of 2-amino-4,6-dichloro-benzamide (1.54 g, 7.50 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.46 g, 7.50 mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.51 g, 8.25 mmol) and p-toluenesulfonicacid monohydrate (0.28 g, 1.50 mmol). The reaction mixture was stirred at 120 C. for 16 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was further washed with ether and dried under vacuum to give 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one as a white solid. Yield: 2.42 g (85%) |
85% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 16.0h;Inert atmosphere; | To a solution of 2-amino-4,6-dichloro-benzamide (1.54 g, 7.50 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.46 g, 7.50 mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.51 g, 8.25 mmol) and p-toluenesulfonic acid monohydrate (0.28 g, 1.50 mmol). The reaction mixture was stirred at 120 C. for 16 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was further washed with ether and dried under vacuum to give 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one as a white solid. Yield: 2.42 g (85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 16.0h; | To a stirred solution of 2-amino-5-methoxy-benzamide (2.62 g, 15.80 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (3.23 g, 16.60 mmol) in N,N-dimethyl acetamide (20 mL), were added sodium hydrogen sulfite (58.5 wt %, 3.44 g, 19.00 mmol) and p-toluenesulfonic acid monohydrate (0.60 g, 3.20 mmol) and the reaction mixture was stirred at 115 C. for 16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was triturated with ether to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one as a white solid. Yield: 3.56 g (66%). |
Tags: 1039948-89-4 synthesis path| 1039948-89-4 SDS| 1039948-89-4 COA| 1039948-89-4 purity| 1039948-89-4 application| 1039948-89-4 NMR| 1039948-89-4 COA| 1039948-89-4 structure
A123001 [39250-90-3]
4-Methoxy-3,5-dimethylbenzaldehyde
Similarity: 0.93
A228358 [67639-61-6]
2-Methoxy-3-methylbenzaldehyde
Similarity: 0.91
A123001 [39250-90-3]
4-Methoxy-3,5-dimethylbenzaldehyde
Similarity: 0.93
A228358 [67639-61-6]
2-Methoxy-3-methylbenzaldehyde
Similarity: 0.91
A123001 [39250-90-3]
4-Methoxy-3,5-dimethylbenzaldehyde
Similarity: 0.93
A228358 [67639-61-6]
2-Methoxy-3-methylbenzaldehyde
Similarity: 0.91
A107227 [22042-73-5]
4-(2-Hydroxyethoxy)benzaldehyde
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A114894 [14814-17-6]
(4-(2-Hydroxyethoxy)phenyl)(phenyl)methanone
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A143214 [54287-99-9]
5-Hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde
Similarity: 0.79
A798911 [6665-86-7]
7-Hydroxy-2-phenyl-4H-chromen-4-one
Similarity: 0.78
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P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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