* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iron; ammonium chloride In methanol; water at 80℃; for 0.5 h; Inert atmosphere
8.0 g of compound II, 12.0 g of iron powder, 12.0 g of ammonium chloride, 60 ml of water, 120 ml of methylene chlorideThe mixture of alcohols was stirred at 80 ° C for 30 minutes under reflux. TLC analysis showed no starting material and was filtered off with 50 ml of methanol and50 ml of ethyl acetate, the filtrate was spin-dried, the solvent was added to 300 ml of water,Liter of ethyl acetate and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate,Dried to give 7.2 g of a brown solid (Compound 3) in 99.4percent yield;
87%
With hydrogen In 1,2-dimethoxyethane at 20℃; for 7 h;
Example 6 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate); Into a glass vessel having an internal volume of 20 ml and equipped with a stirrer, a thermometer, a reflux condenser, and a balloon filled with hydrogen gas were placed 4.0 g (12.6 mmol) of methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate, 0.2 g of 3percent by mass platinum sulfided carbon powder (60percent moisture content) (manufactured by N.E. CHEMCAT CORPORATION), and 20 ml of dimethoxyethane, and the resultant mixture was reacted in a hydrogen gas atmosphere at room temperature for 7 hours with stirring. After completion of the reaction, the reaction mixture was allowed to stand for 10 days and then filtered, and the reaction mixture was concentrated under reduced pressure to obtain 3.17 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate as a pale brown solid (isolation yield: 87percent). Values of physical properties for the obtained methyl 2-amino-4-benzyloxy-5-methoxybenzoate are as follows. 1 H-NMR(CDCl3 , δ(ppm)); 3.81(3H,s), 3.83(3H,s), 5.09(2H,s), 5.37(2H,brs), 6.15(1H,s), 7.31-7.41(6H,m) CI-MS(m/e); 287(M+)
85%
Stage #1: With iron In ethanol; water for 3 h; Heating / reflux Stage #2: With sodium hydroxide In ethanol; water at 20℃;
Step 2c. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (Compound 204) A mixture of compound 203 (10 g, crude), iron powder (54 g, 0.96 mol), ethanol (100 mL), and H2O (20 mL) was stirred and heated to reflux for 3 hours. The mixture was cooled to room temperature and neutralized with aqueous sodium hydroxide (10percent). The reaction was filtered and the filtrate was concentrated to give a residue which was extracted with dichloromethane (200 mL*2). The combined organic layer was washed with brine and dried over MgSO4, filtered and concentrated to yield the title compound 204 as a grey solid (14.5 g, 85percent): LCMS: 288 [M+1]+.
84.7%
With acetic acid; zinc In methanol; water for 3 h; Reflux
A mixture of compound 5 (2.0g, 6.2mmol), zinc powder (1.2g, 19mmol), glacial acetic acid (3.6mL, 63.3mmol) in methanol: H2O (33: 3mL) was stirred at reflux for 3h. The reaction mixture was filtered while hot and the solid was washed with CH3OH. The solvent was removed from filtrate and the resulting solid was diluted with water (50mL) and subsequently extracted with ethyl acetate. The extracts were combined, washed with saturated sodium bicarbonate and saturated saline solution, and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 6 as a light yellow solid (84.7percent). Mp: 131–133°C; 1H NMR (CDCl3, 300MHz): δ (ppm) 3.83–3.84 (d, J=3.7Hz, 6H), 5.14 (s, 2H), 5.52 (s, 2H), 6.16 (s, 1H), 7.26–7.42 (m, 6H).
84.7%
at 20℃; for 3 h; Reflux
A solution of methyl 2-nitro-4-benzyloxy-5-methoxybenzoate (6.2 mmol, 2.0 g) was added to a 100 ml reaction flask followed by MeOH / H2(63 mmol, 3.6 ml) was slowly added dropwise, and the mixture was heated under reflux for 3 hours. The resulting mixture was stirred for 3 hours at room temperature, followed by addition of zinc powder (19 mmol, 1.2 g).After completion of the reaction, the residue was filtered off, the methanol was removed from the filtrate, and then 50 ml of water was added thereto. The mixture was extracted with ethyl acetate (30 ml x 2), and the organic phase was separated and washed successively with saturated sodium hydrogencarbonate X 2) and saturated sodium chloride (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was dried to give 1.5 g of 2-amino-4- benzyloxy-5-methoxybenzoate, yieldpercent 84.7,
81%
With iron; ammonium chloride In methanol; water at 105℃;
A suspension of 120 (495 g, 1.56 mol), Fe (305.7 g, 5.46 mol) and NH4Cl (337.0 g, 6.24 mol) in a mixture of methanol/H2O (1500 mL/500 mL) was stirred at 105° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (1500 mL), stirred for 3 h at room temperature and filtered. The filtrate was washed with water (500 mL×3) and brine (500 mL×3), then dried over Na2SO4. The solution was concentrated in vacuum to give 121 (363.8 g, yield=81percent) as a light brown solid
67%
With iron; acetic acid In methanol for 4 h; Heating / reflux
Iron powder (46.2 g, 0.828 mol) is added to a suspension of methyl A- (benzyloxy)-5-methoxy-2-nitrobenzoate (52.5g, 165.6 mmol) in acetic acid (95 ml) and MeOH (200 ml). The reaction is then heated to reflux for 4 hours. The hot reaction mixture is then filtered through diatomaceous earth with 10percent MeOH/CH2Cl2. The filtrate is concentrated in vacuo, dissolved in EtOAc, and passed through hydrous magnesium silicate using EtOAc. The organic phase is concentrated in vacuo and triturated with 30percent EtOAc/Hexane to provide methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (31.94 g, 67percent).
Reference：
[1] Patent: CN105541736, 2016, A, . Location in patent: Paragraph 0044; 0047
[2] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[3] Chemical Communications, 2016, vol. 52, # 87, p. 12869 - 12872
[4] Patent: EP2123627, 2009, A1, . Location in patent: Page/Page column 6-7
[5] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 26-27
[6] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[7] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0058; 0059
[8] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[9] Patent: US2014/235634, 2014, A1, . Location in patent: Paragraph 0390; 0393
[10] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
[11] Patent: WO2008/109613, 2008, A1, . Location in patent: Page/Page column 214
[12] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 53
[13] Patent: US2007/208164, 2007, A1, . Location in patent: Page/Page column 14-15
[14] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5342 - 5346
[16] Patent: WO2006/117552, 2006, A1, . Location in patent: Page/Page column 64-65
2
[ 56441-97-5 ]
[ 61032-42-6 ]
Reference：
[1] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[2] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[3] Patent: US2014/235634, 2014, A1,
[4] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[5] Patent: CN105541736, 2016, A,
[6] Chemical Communications, 2016, vol. 52, # 87, p. 12869 - 12872
[7] Patent: CN105884699, 2016, A,
[8] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[9] Patent: WO2006/117552, 2006, A1,
3
[ 1486-53-9 ]
[ 61032-42-6 ]
Reference：
[1] Organic Letters, 1999, vol. 1, # 11, p. 1835 - 1837
[2] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[3] Patent: CN105884699, 2016, A,
With iron; ammonium chloride; In methanol; water; at 80℃; for 0.5h;Inert atmosphere;
8.0 g of compound II, 12.0 g of iron powder, 12.0 g of ammonium chloride, 60 ml of water, 120 ml of methylene chlorideThe mixture of alcohols was stirred at 80 C for 30 minutes under reflux. TLC analysis showed no starting material and was filtered off with 50 ml of methanol and50 ml of ethyl acetate, the filtrate was spin-dried, the solvent was added to 300 ml of water,Liter of ethyl acetate and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate,Dried to give 7.2 g of a brown solid (Compound 3) in 99.4% yield;
87%
With hydrogen;3percent by mass platinum sulfided carbon; In 1,2-dimethoxyethane; at 20℃; for 7h;Product distribution / selectivity;
Example 6 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate); Into a glass vessel having an internal volume of 20 ml and equipped with a stirrer, a thermometer, a reflux condenser, and a balloon filled with hydrogen gas were placed 4.0 g (12.6 mmol) of <strong>[61032-41-5]methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate</strong>, 0.2 g of 3% by mass platinum sulfided carbon powder (60% moisture content) (manufactured by N.E. CHEMCAT CORPORATION), and 20 ml of dimethoxyethane, and the resultant mixture was reacted in a hydrogen gas atmosphere at room temperature for 7 hours with stirring. After completion of the reaction, the reaction mixture was allowed to stand for 10 days and then filtered, and the reaction mixture was concentrated under reduced pressure to obtain 3.17 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate as a pale brown solid (isolation yield: 87%). Values of physical properties for the obtained methyl 2-amino-4-benzyloxy-5-methoxybenzoate are as follows. 1 H-NMR(CDCl3 , delta(ppm)); 3.81(3H,s), 3.83(3H,s), 5.09(2H,s), 5.37(2H,brs), 6.15(1H,s), 7.31-7.41(6H,m) CI-MS(m/e); 287(M+)
85%
Step 2c. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (Compound 204) A mixture of compound 203 (10 g, crude), iron powder (54 g, 0.96 mol), ethanol (100 mL), and H2O (20 mL) was stirred and heated to reflux for 3 hours. The mixture was cooled to room temperature and neutralized with aqueous sodium hydroxide (10%). The reaction was filtered and the filtrate was concentrated to give a residue which was extracted with dichloromethane (200 mL*2). The combined organic layer was washed with brine and dried over MgSO4, filtered and concentrated to yield the title compound 204 as a grey solid (14.5 g, 85%): LCMS: 288 [M+1]+.
84.7%
With acetic acid; zinc; In methanol; water; for 3h;Reflux;
A mixture of compound 5 (2.0g, 6.2mmol), zinc powder (1.2g, 19mmol), glacial acetic acid (3.6mL, 63.3mmol) in methanol: H2O (33: 3mL) was stirred at reflux for 3h. The reaction mixture was filtered while hot and the solid was washed with CH3OH. The solvent was removed from filtrate and the resulting solid was diluted with water (50mL) and subsequently extracted with ethyl acetate. The extracts were combined, washed with saturated sodium bicarbonate and saturated saline solution, and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give 6 as a light yellow solid (84.7%). Mp: 131-133C; 1H NMR (CDCl3, 300MHz): delta (ppm) 3.83-3.84 (d, J=3.7Hz, 6H), 5.14 (s, 2H), 5.52 (s, 2H), 6.16 (s, 1H), 7.26-7.42 (m, 6H).
84.7%
In methanol; water; at 20℃; for 3h;Reflux;
A solution of methyl 2-nitro-4-benzyloxy-5-methoxybenzoate (6.2 mmol, 2.0 g) was added to a 100 ml reaction flask followed by MeOH / H2(63 mmol, 3.6 ml) was slowly added dropwise, and the mixture was heated under reflux for 3 hours. The resulting mixture was stirred for 3 hours at room temperature, followed by addition of zinc powder (19 mmol, 1.2 g).After completion of the reaction, the residue was filtered off, the methanol was removed from the filtrate, and then 50 ml of water was added thereto. The mixture was extracted with ethyl acetate (30 ml x 2), and the organic phase was separated and washed successively with saturated sodium hydrogencarbonate X 2) and saturated sodium chloride (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was dried to give 1.5 g of 2-amino-4- benzyloxy-5-methoxybenzoate, yield% 84.7,
81%
With iron; ammonium chloride; In methanol; water; at 105℃;
A suspension of 120 (495 g, 1.56 mol), Fe (305.7 g, 5.46 mol) and NH4Cl (337.0 g, 6.24 mol) in a mixture of methanol/H2O (1500 mL/500 mL) was stirred at 105 C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (1500 mL), stirred for 3 h at room temperature and filtered. The filtrate was washed with water (500 mL×3) and brine (500 mL×3), then dried over Na2SO4. The solution was concentrated in vacuum to give 121 (363.8 g, yield=81%) as a light brown solid
67%
With iron; acetic acid; In methanol; for 4h;Heating / reflux;
Iron powder (46.2 g, 0.828 mol) is added to a suspension of methyl A- (benzyloxy)-5-methoxy-2-nitrobenzoate (52.5g, 165.6 mmol) in acetic acid (95 ml) and MeOH (200 ml). The reaction is then heated to reflux for 4 hours. The hot reaction mixture is then filtered through diatomaceous earth with 10% MeOH/CH2Cl2. The filtrate is concentrated in vacuo, dissolved in EtOAc, and passed through hydrous magnesium silicate using EtOAc. The organic phase is concentrated in vacuo and triturated with 30% EtOAc/Hexane to provide methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (31.94 g, 67%).
With sodium tetrahydroborate; nickel(II) chloride hexahydrate;
Commercially available methyl 4-hydroxy-3-methoxy-benzoate 1 was converted in 5 steps to 4-(3-fluoroanilino)-6-methoxy-7-benzyloxy-quinazolme 15 (35% overall yield).[17,18] The only significant modification involved an improved workup of the nickel chloride hexahydrate-sodium borohydride reduction of the nitro intermediate. Debenzylation with trifluoroacetic acid to give the 7-hydroxy intermediate 16, followed by alkylation with propargyl bromide in acetonitrile, gave 13 in a 65% yield for 2 steps. This method involved an additional step, and the overall yield was greater. In addition, the final 7-hydroxy intermediate 16 could be used to generate other products [19].
Preparation of 2-amino-4-benzyloxy-5-methoxy-methylbenzoate 6.5 g of 2-nitro-4-benzyloxy-5-methoxy-methylbenzoate was dissolved in 2:1 CH2Cl2/MeOH (138 mL). 1.56 g of nickel chloride hexahydrate was added and the resulting green solution stirred until all solids dissolved. The reaction mixture was then cooled on ice and 2.56 g of sodium borohydride added slowly in 4 portions, with each portion being added at 7-8 minute intervals. After the last addition was complete, all the solvent was removed to result in a gray solid. 150 mL of cold 10% HCl was added and the mixture washed with a 100 mL rinse of 10% HCl. The aqueous phase extracted three more times with ethyl acetate. The organic phases were combined and dried over sodium sulfate. After filtration, the filtrate was concentrated to a pink-orange solid, which was recrystallized from methanol. The final productproduct (2.13 grams) was isolated as a pale orange-brown solid. Proton NMR was consistent with the proposed structure. (lit. ref. Organic Letters 1999 vol 1(11) pp 1835-37).
With iron(III) chloride; iron; acetic acid; In ethanol; water;
A mixture of <strong>[61032-41-5]4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester</strong> (6.00 g, 18.91 mmol), iron powder (5.91 g, 105.9 mmol) and iron (III) chloride (307 mg, 1.89 mmol) in EtOH (12 ml), acetic acid (48 ml) and water (2.4 ml) was heated at reflux for 4 hours. The reaction mixture was cooled, filtered and the solids washed with EtOAc. The filtrate was concentrated and the residue purified by column chromatography (15-70 % EtOAc: Heptane) to provide the title compound as a pale yellow solid (5.09 g).LC/MS purity: 92 %, m/z 288.1 [M+H]+. 1H NMR (300 MHz, CDCI3) delta: 7.53-7.31 (6H, m), 6.33 (1 H, s), 5.10 (2H, s), 3.94 (3H, s), 3.90 (3H, s).
Step 2d. 7-(Benzyloxy)-6-methoxyquinazolin-4(3H)-one (Compound 205) A mixture of compound 204 (7.5 g, 25 mmol), ammonium formate (1.1 g, 22.4 mmol) and formamide (60 mL) was stirred and heated at 180~190 C. (oil bath temperature) for 2 hours. Then the mixture was cooled to room temperature and the resulting precipitate was isolated, washed with water and dried to give the title compound 205 as a brown solid (6.5 g, 95%): LCMS: 283 [M+1]+.
With ammonium formate;
Commercially available methyl 4-hydroxy-3-methoxy-benzoate 1 was converted in 5 steps to 4-(3-fluoroanilino)-6-methoxy-7-benzyloxy-quinazolme 15 (35% overall yield).[17,18] The only significant modification involved an improved workup of the nickel chloride hexahydrate-sodium borohydride reduction of the nitro intermediate. Debenzylation with trifluoroacetic acid to give the 7-hydroxy intermediate 16, followed by alkylation with propargyl bromide in acetonitrile, gave 13 in a 65% yield for 2 steps. This method involved an additional step, and the overall yield was greater. In addition, the final 7-hydroxy intermediate 16 could be used to generate other products [19].
at 190℃; for 5h;
A mixture of 2-amino-4-benzyloxy-5-methoxy-benzoic acid methyl ester (5.09 g, 17.7 mmol) in formamide (50 ml) was heated at 1900C for 5 hours. The reaction mixture was cooled, poured into water and NaCI was added. The precipitate was filtered, washed with water and dried under reduced pressure to provide the title compound as a tan brown solid (4.0 g). LC/MS purity: 98 %, m/z 283 [M+H]+. 1H NMR (300 MHz, DMSO-Cf6) delta: 12.10 (1H, br s), 7.98 (1H1 s), 7.51-7.33 (5H, m), 7.23 (1H, s), 5.26 (2H, s), 3.88 (3H, s).
With hydrogenchloride; sodium hydroxide; sodium methylate; iron; formamide; In methanol; chloroform; water; acetic acid; N,N-dimethyl-formamide;
Production Example 26: 7-(Benzyloxy)-6-methoxy-3,4-dihydro-4-quinazolinone Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15.0 g) was dissolved in acetic acid (200 ml) at room temperature. Iron (powder) (13.2 g) was then added tothe solution. The temperature of the mixture was raised to 90C, and the mixture was then stirred for one hr. The resultant gray solid was filtered through Celite, followed by washing with acetic acid. Concentrated hydrochloric acid was added to the mother liquor. The solvent was then removed by distillation under the reduced pressure. This resulted in the precipitation of 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 dissolve the solid, followed by extraction with chloroform. After washing with water, the organic layer was 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 9.5 g (yield 70%) of a crude product of methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (650 mg) was dissolved in N,N-dimethylformamide (15 ml) and methanol (3 ml). Formamide (0.46 ml) and sodium methoxide (373 mg) were added to the solution. The mixture was heated to 100C and was stirred overnight. The reaction solution was cooled to room temperature, and 10 ml of water was then added to the cooled reaction solution. 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 water and ether, and was then dried through a vacuum pump to give 566 mg (yield 87%) of the title compound. 1H-NMR (DMSO-d6, 400 MHz): delta 3.88 (s, 3H), 5.25 (s, 2H), 7.23 (s, 1H), 7.33 - 7.49 (m, 6H), 7.97 (s, 1H), 12.06 (br, 1H)
In a 3 L volume stainless pressure-resistant vessel equipped with a stirrer, a thermometer and a pressure gauge were placed 121 (363.8 g, 1.267 mol), methyl orthoformate (336.0 g, 3.167 mol), ammonium acetate (243.9 g, 3.167 mol), and methanol (1500 mL). The vessel was closed, and the reaction was carried out at 100 C. overnight. After the reaction was complete, water (1500 mL) was added to the reaction mixture. The mixture was stirred at 0-10 C. for 1 hour to generate a crystalline product. The crystalline product was collected by filtration, washed with water (300 mL×3), and dried to give 122 (247 g, yield=69%) as pale solid
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