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CAS No. : | 21544-81-0 | MDL No. : | MFCD09031988 |
Formula : | C10H9NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FAMGTYWNHVETJC-UHFFFAOYSA-N |
M.W : | 207.18 | Pubchem ID : | 11557522 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 55.14 |
TPSA : | 64.63 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.1 cm/s |
Log Po/w (iLOGP) : | 1.19 |
Log Po/w (XLOGP3) : | 0.66 |
Log Po/w (WLOGP) : | 0.27 |
Log Po/w (MLOGP) : | -0.35 |
Log Po/w (SILICOS-IT) : | 1.5 |
Consensus Log Po/w : | 0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.7 |
Solubility : | 4.09 mg/ml ; 0.0198 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.59 |
Solubility : | 5.28 mg/ml ; 0.0255 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.04 |
Solubility : | 0.189 mg/ml ; 0.000914 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.95 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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% | at 0 - 170℃; for 2.75 h; Heating / reflux | A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10° C., the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45° C. to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170° C. external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0° C. and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64° C.) increased (to a maximum temp of 80° C). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70° C., and the mixture was allowed to stir overnight while cooling to room temperature. The mixture was heated to 70° C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70° C. for a further 2 h until the reaction was complete. After cooling to 10° C. (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCl (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol), and NMM (51.3 mL), and the mixture was allowed to stir at room temperature for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at room temperature for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2.x.250 mL). The combined extracts were then washed with water (2.x.500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57percent) as a brown solid.2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C. for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293° C. |
79% | at 170℃; for 2 h; | A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10° C., the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45° C. to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170° C. external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0° C. and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64° C.) increased (to a maximum temp of 80° C.). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70° C., and the mixture was allowed to stir overnight while cooling to room temperature. The mixture was heated to 70° C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70° C. for a further 2 h until the reaction was complete. After cooling to 10° C. (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCl (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol), and NMM (51.3 mL), and the mixture was allowed to stir at room temperature for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at room temperature for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2×250 mL). The combined extracts were then washed with water (2×500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57percent) as a brown solid. [0454] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C. for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293° C |
79% | at 170℃; for 2 h; | 3,5-dimethoxy aniline (199g, 1.30mol) in diethyl ether (5.0 L) was added inthe flask 5L3 Cooled to 0° C. After 45 minutes the HCl gas (227g)introduced into the solution.at 10°C 45 Minutes the mixture was filtered, (4L) and washed withisopropyl acetate, under high vacuum, dried at 45 ° C Night to give the hydrochloride as a white solid (242.3g, 98percent). Under stirring the above hydrochloride (20g, 0The mixture.105mol) and oxalyl chloride (33 mL of) isequipped with a reflux condenser, 3-neck flask was heated 2 Hour (170 ° C externaltemperature), oxalyl chloride was distilled off from the reactionmixture. The flask was cooled to 0° C, was added methanol (40mL). The reactionmixture was heated at reflux for 45 minutes, filtered while hot, with A Alcohol(80mL) and washed to give a yellow-green solid4,6-dimethoxy isatin (17.2g, 79percent). After 2 Hour to isatin (162g,0.78mol) was heated in aqueous NaOH solution(40percent, 1.5L) in (externalTemperature 70 ° C) was slowly added to H 2 O 2(35percent, 405mL). H 2 O 2 was added after each batch, the internal temperature of the reaction Degree(initially 64 ° C) increase (to a maximum temperature of 80 ° C). Afterthe addition was complete, then at 70 ° C will blister The reaction mixture wasstirred for an additional 2hours, the mixture was stirred overnight while cooling to roomtemperature. The mixtureIt was heated to 70 ° C. An additional H 2 O 2 (75mL), at 70 ° C and themixture was stirred for an additional 2 Hours until the reaction was complete.Cooled to 10 ° C (bath temperature), a solution of Na 2 S 2 O 3 solution (150mL, saturation). The mixture was washed with HCl (37percent, 1.6L) was adjusted to pH8, with acetic acid(glacial acetic acid, 75mL) transfer To pH6, while not allowing thereaction mixture was warmed exceed 40 ° C. The reaction mixture was filtered,washed with water (4L) and washed to give the desired brownsolid amino acid (83.7g, 55percent). The amino acid (82.7g, 0.42mol) (4.2L) was added in dry THF EDCl (89.2g, 0.48mol), HOBT(65g, 0.48mol) and NMM (51.3mL), and the mixturewas stirred at roomtemperature for 3 hours. Adding NH3 Aqueoussolution (83mL, 50percent), and the mixture was stirred at room temperature for 16 hours.Was added water (1.25L), the The mixture (2 × 250mL) and extracted with DCM.Then the combined extracts were washed with water (2 × 500mL) washed Fandi.Concentrated, slurried with ethyl ether (550mL), filtered, and dried under highvacuum to afford a brown The solid4,6-dimethoxy-2-amino-benzamide (46.7g, 57percent).2-Amino-4,6-dimethoxy - benzamide (1.06g, 5.4mmol), 3,5- dimethyl-4-hydroxy Benzaldehyde (0.810g,5.4mmol), K 2 CO 3 (0.747g, 5.4mmol) and I 2(1.645g, 6.5mmol) DMF (20mL) in mixing, at 80 ° C and the reaction mixture was heated for 12 hours. It was cooledto Room temperature, poured onto crushed ice. The solid was collected, whichwas purified by column chromatography to give a white solid State of 2- (4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-quinazolin -4 (3H) - one (0.9g, 51percent). Selected data:MP291-293 ° C. |
79% | at 0 - 170℃; for 2.75 h; Heating / reflux | A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0°C. HCI gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10°C, the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45°C to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170°C external <n="58"/>temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0°C and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70°C) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64°C) increased (to a maximum temp of 80°C). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70°C, and the mixture was allowed to stir overnight while cooling to RT. The mixture was heated to 70°C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70°C for a further 2 h until the reaction was complete. After cooling to 10°C (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCI (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40°C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCI (89.2 g, 0.48 mol), HOBT (65 g, 0.48 rnol), and NMM (51.3 mL), and the mixture was allowed to stir at RT for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at RT for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2x250 mL). The combined extracts were then washed with water (2x500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g,57percent) as a brown solid. <n="59"/>[0111] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl- 4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 ml_) and the reaction mixture was heated at 80°C for 12 h. It was cooled to RT and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy- 3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4<3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: With hydrogenchloride In diethyl ether at 0 - 10℃; for 1.75 h; Stage #2: at 70℃; for 2 h; Stage #3: at 0℃; for 1 h; Reflux |
Aniline 9 (6.0 g, 47.2mmol) wasdissolved in ether(250 mL) and stirred at 0 °C. HCl (gas) wasbubbled into the reaction mixturefor 1 h. The reaction mixturewas warmed to 10 °C for 45 min and then filtered;the filtrant waswashed with cooled ethyl acetate and dried in vacuo to givethecorresponding hydrochloride salt (7.5 g, 94percent). The hydrochloridesalt ofaniline 9 (7.5 g, 39.6mmol) wasdissolved in oxalylchloride (15 mL), and the reaction mixture was heated to 70°Cfor 2 h. The solvent was removed under reduced pressure. Thereaction mixturewas diluted with MeOH (30 mL) at 0 °C andthen heated to reflux for 1 h. Thereaction mixture was hot filtered,and the precipitate was washed with MeOH togive 4,6-dimethoxyindoline-2,3-dione (6.1 g, 72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.7 g | Stage #1: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran; water at 70℃; Stage #2: With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 3 h; Stage #3: With ammonia In tetrahydrofuran; water at 20℃; for 16 h; |
A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10° C., the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45° C. to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170° C. external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0° C. and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64° C.) increased (to a maximum temp of 80° C.). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70° C., and the mixture was allowed to stir overnight while cooling to room temperature. The mixture was heated to 70° C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70° C. for a further 2 h until the reaction was complete. After cooling to 10° C. (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCl (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol), and NMM (51.3 mL), and the mixture was allowed to stir at room temperature for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at room temperature for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2×250 mL). The combined extracts were then washed with water (2×500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57percent) as a brown solid. [0454] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C. for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293° C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dihydrogen peroxide; sodium hydroxide In water at 64 - 80℃; for 4 h; | 3,5-dimethoxy aniline (199g, 1.30mol) in diethyl ether (5.0 L) was added inthe flask 5L3 Cooled to 0° C. After 45 minutes the HCl gas (227g)introduced into the solution.at 10°C 45 Minutes the mixture was filtered, (4L) and washed withisopropyl acetate, under high vacuum, dried at 45 ° C Night to give the hydrochloride as a white solid (242.3g, 98percent). Under stirring the above hydrochloride (20g, 0The mixture.105mol) and oxalyl chloride (33 mL of) isequipped with a reflux condenser, 3-neck flask was heated 2 Hour (170 ° C externaltemperature), oxalyl chloride was distilled off from the reactionmixture. The flask was cooled to 0° C, was added methanol (40mL). The reactionmixture was heated at reflux for 45 minutes, filtered while hot, with A Alcohol(80mL) and washed to give a yellow-green solid4,6-dimethoxy isatin (17.2g, 79percent). After 2 Hour to isatin (162g,0.78mol) was heated in aqueous NaOH solution(40percent, 1.5L) in (externalTemperature 70 ° C) was slowly added to H 2 O 2(35percent, 405mL). H 2 O 2 was added after each batch, the internal temperature of the reaction Degree(initially 64 ° C) increase (to a maximum temperature of 80 ° C). Afterthe addition was complete, then at 70 ° C will blister The reaction mixture wasstirred for an additional 2hours, the mixture was stirred overnight while cooling to roomtemperature. The mixtureIt was heated to 70 ° C. An additional H 2 O 2 (75mL), at 70 ° C and themixture was stirred for an additional 2 Hours until the reaction was complete.Cooled to 10 ° C (bath temperature), a solution of Na 2 S 2 O 3 solution (150mL, saturation). The mixture was washed with HCl (37percent, 1.6L) was adjusted to pH8, with acetic acid(glacial acetic acid, 75mL) transfer To pH6, while not allowing thereaction mixture was warmed exceed 40 ° C. The reaction mixture was filtered,washed with water (4L) and washed to give the desired brownsolid amino acid (83.7g, 55percent). The amino acid (82.7g, 0.42mol) (4.2L) was added in dry THF EDCl (89.2g, 0.48mol), HOBT(65g, 0.48mol) and NMM (51.3mL), and the mixturewas stirred at roomtemperature for 3 hours. Adding NH3 Aqueoussolution (83mL, 50percent), and the mixture was stirred at room temperature for 16 hours.Was added water (1.25L), the The mixture (2 × 250mL) and extracted with DCM.Then the combined extracts were washed with water (2 × 500mL) washed Fandi.Concentrated, slurried with ethyl ether (550mL), filtered, and dried under highvacuum to afford a brown The solid4,6-dimethoxy-2-amino-benzamide (46.7g, 57percent).2-Amino-4,6-dimethoxy - benzamide (1.06g, 5.4mmol), 3,5- dimethyl-4-hydroxy Benzaldehyde (0.810g,5.4mmol), K 2 CO 3 (0.747g, 5.4mmol) and I 2(1.645g, 6.5mmol) DMF (20mL) in mixing, at 80 ° C and the reaction mixture was heated for 12 hours. It was cooledto Room temperature, poured onto crushed ice. The solid was collected, whichwas purified by column chromatography to give a white solid State of 2- (4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-quinazolin -4 (3H) - one (0.9g, 51percent). Selected data:MP291-293 ° C. |
55% | Stage #1: With sodium hydroxide; dihydrogen peroxide In water at 20 - 80℃; Stage #2: With hydrogenchloride; acetic acid In water at 10 - 40℃; |
A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0°C. HCI gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10°C, the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45°C to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170°C external <n="58"/>temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0°C and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70°C) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64°C) increased (to a maximum temp of 80°C). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70°C, and the mixture was allowed to stir overnight while cooling to RT. The mixture was heated to 70°C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70°C for a further 2 h until the reaction was complete. After cooling to 10°C (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCI (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40°C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCI (89.2 g, 0.48 mol), HOBT (65 g, 0.48 rnol), and NMM (51.3 mL), and the mixture was allowed to stir at RT for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at RT for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2x250 mL). The combined extracts were then washed with water (2x500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g,57percent) as a brown solid. <n="59"/>[0111] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl- 4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 ml_) and the reaction mixture was heated at 80°C for 12 h. It was cooled to RT and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy- 3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4<3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293°C. |
33% | With dihydrogen peroxide; sodium hydroxide In water at 70℃; | A solution of 4,6-dimethoxyindoline-2,3-dione(0.6g, 2.89 mmol) in NaOH (33percent in water, 38 mL) was headedto 70 °C. H2O2(30percent in water, 9.4 mL) was added to the solutiondropwise. Themixture was maintained at 70 °C for 40 min. Saturated Na2S2O3solution (30 mL) was added to the abovemixture at 10 °C. The reactionmixture was adjusted to pH 8with HCl and then to pH 5 with AcOH. Theprecipitate thatformed was collected, washed with water, and dried to give compound11 (188 mg, 33percent). |
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