* 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.
Stage #1: at 130℃; for 24 h; Stage #2: With ammonia In 2-methoxy-ethanol; water at 20℃;
6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one: Preparation 9 (5 g,18.3 mmol) was mixed with amidine acetate (3.8 g, 36.6 mmol) in ethylene glycol monomethyl ether (25 mL) and the mixture was heated at 13O0C for 24 h. After cooling to room temperature, part of the solvent was removed in vacuo and ammonium hydroxide (5 mL, 30percent in water) and water (50 mL) were added. The solid was filtered, was washed with water and hexanes, and was then dried under vacuum to afford 4.87 g (94percent yield) of the title compound; MS (AP/CI): 283.1 (M+H)+ .
Reference：
[1] Patent: WO2008/20302, 2008, A2, . Location in patent: Page/Page column 29
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4536 - 4547
2
[ 1494468-50-6 ]
[ 286371-64-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
With peracetic acid; sulfuric acid In ethanol at 60℃; for 10 h;
General procedure: To a solution of 6,7-dimethoxyquinazoline 1a (200.0 mg, 1.05 mmol) in ethanol (20 mL) were added 40percent peracetic acid (1.0mL, 5.26 mmol) and 0.01 mL sulfuric acid (1.8 mmol). After the reaction was stirred at 60°C for 4–12 h (see Table 2) and then cooled to room temperature, excess sodium bisulfite (541.8 mg, 5.26 mmol) was added to get rid of the peroxide. The solid was filtered off after stirring for 20 min, and the filtrate was concentrated under reduced pressure to give the crude product, which was washed by ethanol and petroleum ether to give 2a as a light yellow solid (179.7 mg, 83percent), mp>300°C.
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
5
[ 855793-63-4 ]
[ 3473-63-0 ]
[ 286371-64-0 ]
Yield
Reaction Conditions
Operation in experiment
38.4 g
for 12 h; Reflux
A mixture of iron powder (29 g, 0.527 mol) and acetic acid 270 mL was stirred and heated to 50-60°C till a grey white suspension was formed. The suspension was diluted with 150 mL methanol. Methyl 4-methoxy-3-benzyloxy-6-nitrobenzoate 7 (50g, 0.1575 mol) was added portion wise at regular intervals. The reaction was maintained at the same temperature for 5-6 hr. The mixture was filtered hot and the filtrate was evaporated to a residue mass under reduced pressure. The residue was extracted with ethyl acetate 2 × 300 mL. The combined organic layers were washed with water* and formamidine acetate 28.6 g (0.2747 mol) was added to the organic layer and refluxed for 12 hr. Reaction mass was cooled to 25-30°C and stirred for 1 hr and precipitated solid was collected by filtration. Isolated solid was slurry washed with 250 mL methanol and dried to get the off white powder 9, 38.4 g (yield 91percent, purity 98percent); m.p. 258-60°C; 1HNMR (DMSO-d6, 300 MHz): 12.076 (s, 1H), 7.986 (s, 1H), 7.342-7.545 (m, 6H), 7.152 (s, 1H), 5.206 (s, 2H), 3.913 (s, 3H); MS (EI): m/z 283 (M + 1).
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53B, # 10, p. 1269 - 1274
6
[ 645-08-9 ]
[ 286371-64-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53B, # 10, p. 1269 - 1274
7
[ 634198-01-9 ]
[ 286371-64-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
[2] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487
8
[ 148235-40-9 ]
[ 286371-64-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
6-(benzyloxy)-4-chloro-7-methoxyquinazoline: Preparation 10 (4.85 g, 17.2 mmol) in phosphorous oxychioride (25 mL) was heated to 12O0C for 3 h. After cooling to room temperature, the phosphorous oxychioride was removed in vacuo, the residue was slowly added to saturated aqueous potassium carbonate and the mixture was stirred until bubbling ceased. The aqueous mixture was extracted with chloroform, the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 5.1 g (99% yield) of the title compound; MS (AP/CI): 301.1 , 303.1 (M+H)+.
72%
With sodium hydroxide; N-ethyl-N,N-diisopropylamine; trichlorophosphate;
Production Example 30: 6-(Benzyloxy)-4-chloro-7-methoxyquinazoline Phosphorus oxychloride (3.1 ml) was added to <strong>[286371-64-0]6-(benzyloxy)-7-methoxy-3,4-dihydro-4-quinazolinone</strong> (3.5 g) and diisopropylethylamine (11.5 ml). The mixture was refluxed for 20 min. The reaction solution was cooled to room temperature, and a 10% aqueous sodium hydroxide solution was then added to the cooled reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate. The organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 2.9 g (yield 72%) of the title compound. 1H-NMR (CDCl3, 400 MHz): delta 4.07 (s, 3H), 5.32 (s, 2H), 7.35 - 7.53 (m, 7H), 8.86 (s, 1H)
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; for 0.5h;Heating / reflux;
EXAMPLE 20; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(5,8-Dioxa-10-azadispiro[2.0.4.3]undecane) propoxy]quinazolin-4-amine 2-Amino-4-methoxy-5-benzyloxybenzamide (JMC, 20, 146) (5 g) was mixed with triethylorthoformate (15 ml) and refluxed overnight. The reaction solution was cooled and triturated with EtOAc (40 ml) then filtered to give <strong>[286371-64-0]7-methoxy-6-benzyloxyquinazolone</strong> (3.2 g). This product was mixed with DIPEA (15 ml) and to the solution was added POCl3 (3 ml) slowly. The reaction mixture was refluxed for 30 minutes and cooled, then poured into a stirred mixture of ice and CHCl3. The solution was further extracted with CHCl3 three times and washed with H2O followed by brine, dried over Na2SO4 and evaporated to give a light brown solid as the chloride for next step without further purification. The above chloride (2 g) was mixed with 3-chloro-4-flouroaniline (1.3 g) in 2-propanol (30 ml) and the reaction was refluxed for 2 hours and cooled to RT. The precipitate was filtered and mixed with TFA (4 ml) and refluxed for 1 hour. The solvent was evaporated under reduced pressure and the residue was washed with EtOAc to furnish N-(3-chloro4-fluorophenyl)-7-methoxy-6-hydroxy-quinazolin-4-amine (1.3 g) that was mixed with K2CO3 (1.1 g) and 3-bromopropanol (850 muL) in DMF (5 ml). The reaction was heated at 80 C. overnight and poured into water and the precipitate was filtered to give N-(3-chloro4-fluorophenyl)-7-methoxy-6-(2-hydroxyethoxy)-quinazolin-4-amine (1 g). This hydroxy compound (350 mg) was mixed with DIPEA (350 muL) in DCM (10 ml) and cooled at 0 C, to the mixture was added MsCl (85 muL) and stirred for 2 hours. The reaction was evaporated with silica gel (2 g) and purified with silica gel column, then mixed with 5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (B) (120 mg) and DIPEA (120 muL) in 2-propanol (10 ml). The reaction was refluxed overnight and evaporated then purified with silica gel column to give the titled product. Mass: (M+1), 515
With oxalyl dichloride; N-ethyl-N,N-diisopropylamine; In chloroform; at 60 - 65℃; for 12.0h;
Oxalylchloride (62.9 g, 0.496 mol) was added to a mixture of <strong>[286371-64-0]6-benzyloxy-7-methoxyquinazolin-4(3H)-one</strong> 9 (40 g, 0.1416 mol) and diisopropyl ethyl amine (21 g, 0.1625 mol) in chloroform 200 mL. The reaction was maintained at 60-65C for 12 hr. The solvent was completely removed by vacuum distillation. A solution of 3-chloro-4-fluoroaniline (28.7 g, 0.1982 mol) in isopropanol 480 mL was added to the reaction mass at 25-30C. The reaction mass was heated up to 60-65C followed by slow addition of diisopropylamine (21 g, 0.1625 mol) and maintaining for 2 hr. The mixture was cooled to 0-5C for a period of 1 hr. The solid was collected by filtration, washed with chilled isopropanol and dried to get the light yellow compound 11 (54 g, 93%), purity 98-99% m.p. 258-60C; 1H NMR (Methanol-d4, 300 MHz): delta 8.183 (s, 1H), 8.005-8.036 (m, 1H), 7.709-7.761 (m, 1H), 7.556-7.602 (m, 2H), 7.378-7.531 (m, 5H), 7.321 (s, 1 H), 5.380 (s, 2H), 4.153 (s, 3H); MS (EI): m/z 411 (M + 1).
6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one: Preparation 9 (5 g,18.3 mmol) was mixed with amidine acetate (3.8 g, 36.6 mmol) in ethylene glycol monomethyl ether (25 mL) and the mixture was heated at 13O0C for 24 h. After cooling to room temperature, part of the solvent was removed in vacuo and ammonium hydroxide (5 mL, 30% in water) and water (50 mL) were added. The solid was filtered, was washed with water and hexanes, and was then dried under vacuum to afford 4.87 g (94% yield) of the title compound; MS (AP/CI): 283.1 (M+H)+ .
With hydrogenchloride; sodium hydroxide; sodium methylate; iron; formamide; In methanol; chloroform; water; acetic acid; N,N-dimethyl-formamide;
Production Example 29: 6-(Benzyloxy)-7-methoxy-3,4-dihydro-4-quinazolinone Methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (15.8 g) was dissolved in acetic acid (200 ml) at room temperature. Iron (powder) (13.9 g) was then added to the solution. The mixture was heated to 90C and was stirred for one hr. The resultant gray solid was filtered through Celite and was washed with acetic acid. Concentrated hydrochloric acid was added to the mother liquor, and the solvent was then removed by distillation under the reduced pressure to precipitate a solid. The solid was collected by filtration, was washed with ethyl acetate and ether, and was dried through a vacuum pump. Subsequently, chloroform and methanol were added to the solid to prepare a suspension, and a 10% aqueous sodium hydroxide solution was then added to the suspension to dissolve the solid, followed by extraction with chloroform. The extract was washed with water, and the organic layer was then dried over sodium sulfate. Next, the organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 10.4 g (yield 73%) of a crude product of methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate. Methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (5.0 g) was dissolved in N,N-dimethylformamide (150 ml) and methanol (30 ml). Formamide (3.5 ml) and sodium methoxide (2.8 g) were added to the solution. The mixture was heated to 100C and was then stirred overnight. The reaction solution was then cooled to room temperature, and 10 ml of water was then added. The reaction solution was neutralized with a 1 M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, was washed with waterand ether, and was then dried through a vacuum pump to give 3.7 g (yield 76%) of the title compound. 1H-NMR (DMSO-d6, 400 MHz): delta 3.92 (s, 3H), 5.21 (s, 2H), 7.16 (s, 1H), 7.33 - 7.49 (m, 5H), 7.55 (s, 1H), 7.99 (s, 1H), 12.06 (br, 1H)
EXAMPLE 20; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(5,8-Dioxa-10-azadispiro[2.0.4.3]undecane) propoxy]quinazolin-4-amine 2-Amino-4-methoxy-5-benzyloxybenzamide (JMC, 20, 146) (5 g) was mixed with triethylorthoformate (15 ml) and refluxed overnight. The reaction solution was cooled and triturated with EtOAc (40 ml) then filtered to give 7-methoxy-6-benzyloxyquinazolone (3.2 g). This product was mixed with DIPEA (15 ml) and to the solution was added POCl3 (3 ml) slowly. The reaction mixture was refluxed for 30 minutes and cooled, then poured into a stirred mixture of ice and CHCl3. The solution was further extracted with CHCl3 three times and washed with H2O followed by brine, dried over Na2SO4 and evaporated to give a light brown solid as the chloride for next step without further purification. The above chloride (2 g) was mixed with 3-chloro-4-flouroaniline (1.3 g) in 2-propanol (30 ml) and the reaction was refluxed for 2 hours and cooled to RT. The precipitate was filtered and mixed with TFA (4 ml) and refluxed for 1 hour. The solvent was evaporated under reduced pressure and the residue was washed with EtOAc to furnish N-(3-chloro4-fluorophenyl)-7-methoxy-6-hydroxy-quinazolin-4-amine (1.3 g) that was mixed with K2CO3 (1.1 g) and 3-bromopropanol (850 muL) in DMF (5 ml). The reaction was heated at 80 C. overnight and poured into water and the precipitate was filtered to give N-(3-chloro4-fluorophenyl)-7-methoxy-6-(2-hydroxyethoxy)-quinazolin-4-amine (1 g). This hydroxy compound (350 mg) was mixed with DIPEA (350 muL) in DCM (10 ml) and cooled at 0 C, to the mixture was added MsCl (85 muL) and stirred for 2 hours. The reaction was evaporated with silica gel (2 g) and purified with silica gel column, then mixed with 5,8-Dioxa-10-azadispiro[2.0.4.3]undecane (B) (120 mg) and DIPEA (120 muL) in 2-propanol (10 ml). The reaction was refluxed overnight and evaporated then purified with silica gel column to give the titled product. Mass: (M+1), 515
With peracetic acid; sulfuric acid; In ethanol; at 60℃; for 10.0h;
General procedure: To a solution of 6,7-dimethoxyquinazoline 1a (200.0 mg, 1.05 mmol) in ethanol (20 mL) were added 40% peracetic acid (1.0mL, 5.26 mmol) and 0.01 mL sulfuric acid (1.8 mmol). After the reaction was stirred at 60C for 4-12 h (see Table 2) and then cooled to room temperature, excess sodium bisulfite (541.8 mg, 5.26 mmol) was added to get rid of the peroxide. The solid was filtered off after stirring for 20 min, and the filtrate was concentrated under reduced pressure to give the crude product, which was washed by ethanol and petroleum ether to give 2a as a light yellow solid (179.7 mg, 83%), mp>300C.
A mixture of iron powder (29 g, 0.527 mol) and acetic acid 270 mL was stirred and heated to 50-60C till a grey white suspension was formed. The suspension was diluted with 150 mL methanol. Methyl 4-methoxy-3-benzyloxy-6-nitrobenzoate 7 (50g, 0.1575 mol) was added portion wise at regular intervals. The reaction was maintained at the same temperature for 5-6 hr. The mixture was filtered hot and the filtrate was evaporated to a residue mass under reduced pressure. The residue was extracted with ethyl acetate 2 × 300 mL. The combined organic layers were washed with water* and formamidine acetate 28.6 g (0.2747 mol) was added to the organic layer and refluxed for 12 hr. Reaction mass was cooled to 25-30C and stirred for 1 hr and precipitated solid was collected by filtration. Isolated solid was slurry washed with 250 mL methanol and dried to get the off white powder 9, 38.4 g (yield 91%, purity 98%); m.p. 258-60C; 1HNMR (DMSO-d6, 300 MHz): 12.076 (s, 1H), 7.986 (s, 1H), 7.342-7.545 (m, 6H), 7.152 (s, 1H), 5.206 (s, 2H), 3.913 (s, 3H); MS (EI): m/z 283 (M + 1).
(3aS*,7aS*)-Benzyl 2-(bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate[ No CAS ]
[ 286371-64-0 ]
C32H33N3O6[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8.0h;
General procedure: To a solution of 10a (0.80 g, 2.26 mmol) in anhydrousDMF (15 mL), 4a (0.40 g, 2.74 mmol) and K2CO3 (0.80 g,5.79 mmol) were added. After stirring at 80 C for 10 h, thereactant was poured into brine (100 mL) and extracted withEtOAc (3 x 50 mL). The combined organic layers were thenconcentrated under reduced pressure. The residue was purifiedby column chromatography (silica gel, petroleum ether /EtOAc 1:3) to give 11a (0.46 g, 1.10 mmol, 49%).
(3aS,7aS)-2-Bromomethyl-2-methoxy-hexahydro-furo[3,2-b]pyridine-4-carboxylic acid benzyl ester[ No CAS ]
benzyl-[(6-benzyloxy-7-methoxy-4-oxo-3(4H)-quinazolinyl)methyl]hexahydro-2-methoxyfuro[3,2-b]pyridine-4(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 36.0h;
General procedure: To a solution of 10a (0.80 g, 2.26 mmol) in anhydrousDMF (15 mL), 4a (0.40 g, 2.74 mmol) and K2CO3 (0.80 g,5.79 mmol) were added. After stirring at 80 C for 10 h, thereactant was poured into brine (100 mL) and extracted withEtOAc (3 x 50 mL). The combined organic layers were thenconcentrated under reduced pressure. The residue was purifiedby column chromatography (silica gel, petroleum ether /EtOAc 1:3) to give 11a (0.46 g, 1.10 mmol, 49%).
(3aR,7aR)-2-Bromomethyl-2-hydroxy-hexahydro-furo[3,2-b]pyridine-4-carboxylic acid benzyl ester[ No CAS ]
[ 286371-64-0 ]
benzyl-[(6-benzyloxy-7-methoxy-4-oxo-3(4H)-quinazolinyl)methyl]hexahydro-2-hydroxyfuro[3,2-b]pyridine-4(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24.0h;
General procedure: To a solution of 10a (0.80 g, 2.26 mmol) in anhydrousDMF (15 mL), 4a (0.40 g, 2.74 mmol) and K2CO3 (0.80 g,5.79 mmol) were added. After stirring at 80 C for 10 h, thereactant was poured into brine (100 mL) and extracted withEtOAc (3 x 50 mL). The combined organic layers were thenconcentrated under reduced pressure. The residue was purifiedby column chromatography (silica gel, petroleum ether /EtOAc 1:3) to give 11a (0.46 g, 1.10 mmol, 49%).
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