* 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 hydrazine hydrate In N,N-dimethyl-formamide at 100℃; for 3 h; Green chemistry
General procedure: A mixture of the organic nitro compound (1.0 mmol), NH2NH2·H2O (2.5 equiv.) and H2O2-treated AC powder (50 wtpercent) in DMF (1.5 mL) was stirred vigorously magnetically at 100 °C. The reaction was monitored by LC–MS or GC–MS. On completion the reaction mixture was filtered to remove the catalyst. The combined organic mixture material was dried using anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to obtain the products. All the compounds were known and characterised by their 1H NMR and MS spectra and comparison with literature data.
98.1%
at 30 - 40℃; for 4 h; Green chemistry
The reaction vessel was charged with 260g of Compound II prepared according to the method of Example 1 and 3000ml of absolute ethanol. 50g of sodium borohydride was added under stirring to control the reaction temperature at 30-40 ° C. The progress of the reaction was monitored by TLC. After about 4 hours, Filtration, the filtrate was concentrated under reduced pressure, evaporated and evaporated to recover the set of ethanol to the next batch of reduction reaction section, non-condensing gas into the exhaust absorption device. The concentrate was collected and confirmed by structure to give 232.8 g of compound III in a yield of 98.1percent. The purity was 99.9percent by HPLC.
95.5%
With hydrogen; nickel In ethanol at 40℃; for 20 h;
Compound (iv) (196 · 4g) was dissolved in absolute ethanol (3000mL) was added Raney Ni (39 · 3g), hydrogen gas is setChange three times. In a hydrogen atmosphere, heated to 40 ° C for 20 hours, the HPLC detector material is less than 1percent, cooled to 25 ° C. Filtration,With anhydrous ethanol (701 ^) rinse, spin dry ethanol to give compound (¥) (171.18), yield 95.5percent, purity> 95percent
92%
With hydrogen In methanol at 50 - 60℃; for 6 h;
[Synthesis Example 3]; (Synthesis of ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate); In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 2,328 g (6.78 moles) of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate prepared in the Synthesis Example 2, 2 wt.percent platinum per 118 g of carbon (50 wt.percent product, N.E. Chemcat Corporation, 6.0 mmoles in terms of platinum metallic atom) and 9,440 mL of methanol were placed. The mixture was allowed to react at 50 to 60°C for 6 hours in an atmosphere of hydrogen while stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to obtain 1,960 g of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an orange liquid (isolation yield: 92percent).
92%
With hydrogen In methanol at 20℃; for 1 h;
Subsequently, 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoic acid ethyl ester (3.0 mg) produced by the above process was dissolved in methanol, and platinum oxide (250 mg) was added to the solution at room temperature. The air in the reaction system was replaced by hydrogen, and the mixture was then stirred for one hr. After the completion of the reaction, the atmosphere in the reaction system was replaced by nitrogen. The reaction solution was filtered through Celite to remove platinum oxide. The filtrate was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 2-amino-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (compound A) (2.5 g, yield 92percent).
88.27%
With 10 % platinum on carbon; hydrogen In methanol at 90℃; for 0.00972222 h;
2) catalytic hydrogenation reaction: 200 g of the nitrification product obtained in the previous step is dissolved in 5 L of anhydrous methanol, and then added15g of Pt/C catalyst with Pt content of 10percent is fully stirred and mixed to form material IV, H2 is used as material V, and the slurry pump is adjusted.The flow rate is such that the flow rate of the material IV is 42.0 g/min, the flow rate of the gas flow meter is adjusted to 600 ml/min, the molar ratio of the nitrification product to H2 is 1:3.4, the reaction temperature is 90 ° C, and the temperature of the cooling module is 25 ° C. , the reaction residence time is 35s, the reactionThe pressure is 1.5Mpa, and the reaction liquid flowing out from the outlet of the cooling module is collected for post-treatment, and the post-treatment refers to filtration and recovery.Catalyst Pt/C, the organic solvent was recovered by distillation under reduced pressure, and the residue was added with 1.2 L of acetone to stir the solvent, and 450 ml of concentrated salt was added.Acid, stirring and crystallization for 1h, filtration, the filter cake is put into 2L of water, adding 2mol / L NaOH solution to adjust the pH of the system8.0 or so, 2L of ethyl acetate was added twice, each time 1 L of ethyl acetate was added, and the organic phase was combined and dried over anhydrous sodium sulfateAfter drying solvent is recovered by distillation under reduced pressure to give the product amino 161.12g, yield 88.27percent, purity 99.59percent.
85.1%
With ammonium hydroxide; sodium dithionite; sodium hydroxide In tetrahydrofuran; water; ethyl acetate for 2 h; Reflux
(2) Preparation of Ethyl 2-amino-4,5-dimethoxyethoxybenzoate 15 Ethyl 2-nitro-4,5-dimethoxyethoxybenzoate 14 (7 g, 20.40 mmol) is placed in a two-neck bottle of 500 ml, THF (30 ml), water (140 ml) and NH4OH (4 ml, 28~30percent) are added, then sodium hydrosulfite (3.88 g, 28.04 mmol) is added, and heat refluxing is carried out for 2 hours. Conc.HCl (4 ml) is added to continue heat refluxing for 2 hours. After reaction is completed and cooled to 5° C., NaOH (18 ml, 20percent) is added to adjust pH>9. Extraction is performed by using ethyl acetate (200 ml*2), organic layers are combined to be washed by water (200 ml), and the organic layers is dried by adding anhydrous MgSO4, filtered and concentrated to obtain brown liquid compound 15 (5.34 g, 85.1percent). 1H-NMR (CDCl3) spectrum: 1.33 (t, 2H, J=7.1 Hz), 3.41 (s, 6H), 3.68~3.71 (m, 4H), 4.04~4.25 (m, 4H), 4.26 (q, 2H, J=7.1 Hz), 6.14 (s, 1H), 7.42 (s, 1H).
Reference：
[1] Journal of Chemical Research, 2017, vol. 41, # 9, p. 509 - 512
[2] Patent: CN107382880, 2017, A, . Location in patent: Paragraph 0028
[3] Research on Chemical Intermediates, 2013, vol. 39, # 6, p. 2303 - 2309
[4] Patent: CN103709110, 2016, B, . Location in patent: Paragraph 0065; 0066
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[6] Patent: EP1650196, 2006, A1, . Location in patent: Page/Page column 7
[7] Patent: EP1614676, 2006, A1, . Location in patent: Page/Page column 194-195
[8] Patent: CN108358798, 2018, A, . Location in patent: Paragraph 0052; 0062; 0068; 0071-0072; 0082; 0105-0111; 0122
[9] Patent: US2010/267949, 2010, A1, . Location in patent: Page/Page column 7
[10] European Journal of Medicinal Chemistry, 2008, vol. 43, # 7, p. 1478 - 1488
[11] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[12] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[13] Patent: CN103193722, 2016, B, . Location in patent: Paragraph 0112; 0113; 0114
[14] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
2
[ 183322-16-9 ]
[ 179688-27-8 ]
Reference：
[1] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[3] Research on Chemical Intermediates, 2013, vol. 39, # 6, p. 2303 - 2309
[4] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[5] Patent: CN103193722, 2016, B,
[6] Patent: CN103709110, 2016, B,
[7] Patent: CN107382880, 2017, A,
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
[9] Patent: CN108358798, 2018, A,
3
[ 3943-89-3 ]
[ 179688-27-8 ]
Reference：
[1] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[2] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[4] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
4
[ 819813-71-3 ]
[ 179688-27-8 ]
Reference：
[1] Patent: CN103193722, 2016, B,
5
[ 179688-27-8 ]
[ 149-73-5 ]
[ 179688-29-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With ammonium acetate In methanol at 110℃; for 6 h;
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.02 g (3.3 mmol) of ethyl 4,5-bis(2-methoxyethoxy)anthranilate, 0.96 g (9.1 mmol) of methyl orthoformate, 0.69 g (9.1 mmol) of ammonium acetate, and 5.0 mL of methanol. The reaction was carried out at 110°C for 6 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then, the concentrate was recrystallized from 20 mL of methanol. The crystalline product was collected by filtration and dried under reduced pressure to give 0.87 g (isolated yield: 91percent) of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as a white crystalline product.
91%
With ammonium acetate In methanol at 60 - 70℃; for 7 h;
[Synthesis Example 4]; (Synthesis of 6,7-bis(2-methoxyethoxy)quinazolin-4-one); In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 1,600 g (5.11 moles) of the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate prepared in the Synthesis Example 3, 1,626 g (15.3 moles) of methyl orthoformate, 1,181 g (15.3 moles) of ammonium acetate and 4,800 mL of methanol were placed. The mixture was allowed to react under refluxing conditions (60 to 70°C) for 7 hours while stirring. After the reaction was complete, the reaction solution was cooled to 60°C. To the reaction solution, 4,800 mL of methanol was added. The mixture was stirred for 30 minutes while maintaining the temperature, cooled to 0 to 5°C, and further stirred for 1 hour. The resulting mixture was filtered to obtain 1,373 g of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as white crystals (isolation yield: 91percent).
Stage #1: at 80℃; for 5 h; Inert atmosphere Stage #2: for 1 h; Reflux
Compound (v) (171.1g), formamidine acetate (79.8 g) was dissolved in n-butanol (1027mL), and nitrogen at elevatedTemperature to 80 ° C for 5 hours, the reaction was complete by HPLC. Spin dry n-butanol, was added 1711g of isopropyl acetate heated to reflux for 1Hours, cooled to _5 ° C for 4 hours. Filtered, 50 ° C and dried under blast (vi) (164.0g), yield 98percent, purity>95percent. NMR data identified compound (vi) as follows
98.5%
at 55℃; for 3 h; Green chemistry
2375 ml of absolute ethanol and 255 g of compound III prepared by the method of Example 9 were added to the reaction vessel,After stirring to dissolve, add formamidine acetate 95g, heated to 55°C , temperature control reaction for 3 hours, cooled to 15 crystal out. Filtration, the filtrate evaporated condensate recovery of ethanol applied to the next batch of ring reactor, non-condensable gas into the exhaust absorption device. The filter cake was collected and dried at 40-50 ° C,The structure was confirmed to give the finished product 6,7-bis (methoxyethoxy) quinazolin-4-one 235.7g, the yield was 98.5percent, by HPLC purity of 99.9percent.
Reference：
[1] Patent: CN103709110, 2016, B, . Location in patent: Paragraph 0067; 0068
[2] Patent: CN107382880, 2017, A, . Location in patent: Paragraph 0029-0041
[3] European Journal of Medicinal Chemistry, 2008, vol. 43, # 7, p. 1478 - 1488
7
[ 77287-34-4 ]
[ 179688-27-8 ]
[ 179688-29-0 ]
Yield
Reaction Conditions
Operation in experiment
72%
at 165 - 170℃; for 12 h; Inert atmosphere
1.8 Synthesis of 6,7-bis(methoxyethoxy)quinazolin-4-one 0.18 mol ethyl 6-amino-3,4-bis(methoxyethoxy)benzoate was dissolved in 50 ml formamide, under N 2 protection at 165-170 °C for 12h. After cooling solid precipitate was filtered. The resulting solid was recrystallized from acetonitrile to give white solid. Yield 72percent.
Reference：
[1] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[2] Patent: CN103193722, 2016, B, . Location in patent: Paragraph 0115; 0116; 0117
[3] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
8
[ 16712-16-6 ]
[ 179688-27-8 ]
[ 179688-29-0 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
With hydrazine hydrate; In N,N-dimethyl-formamide; at 100℃; for 3h;Green chemistry;
General procedure: A mixture of the organic nitro compound (1.0 mmol), NH2NH2·H2O (2.5 equiv.) and H2O2-treated AC powder (50 wt%) in DMF (1.5 mL) was stirred vigorously magnetically at 100 C. The reaction was monitored by LC-MS or GC-MS. On completion the reaction mixture was filtered to remove the catalyst. The combined organic mixture material was dried using anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to obtain the products. All the compounds were known and characterised by their 1H NMR and MS spectra and comparison with literature data.
98.1%
With sodium tetrahydroborate; ethanol; at 30 - 40℃; for 4h;Green chemistry;
The reaction vessel was charged with 260g of Compound II prepared according to the method of Example 1 and 3000ml of absolute ethanol. 50g of sodium borohydride was added under stirring to control the reaction temperature at 30-40 C. The progress of the reaction was monitored by TLC. After about 4 hours, Filtration, the filtrate was concentrated under reduced pressure, evaporated and evaporated to recover the set of ethanol to the next batch of reduction reaction section, non-condensing gas into the exhaust absorption device. The concentrate was collected and confirmed by structure to give 232.8 g of compound III in a yield of 98.1%. The purity was 99.9% by HPLC.
95.5%
With hydrogen; nickel; In ethanol; at 40℃; for 20h;
Compound (iv) (196 · 4g) was dissolved in absolute ethanol (3000mL) was added Raney Ni (39 · 3g), hydrogen gas is setChange three times. In a hydrogen atmosphere, heated to 40 C for 20 hours, the HPLC detector material is less than 1%, cooled to 25 C. Filtration,With anhydrous ethanol (701 ^) rinse, spin dry ethanol to give compound (¥) (171.18), yield 95.5%, purity> 95%
92%
With hydrogen;2.2% platinum on carbon; In methanol; at 50 - 60℃; for 6h;
[Synthesis Example 3]; (Synthesis of ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate); In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 2,328 g (6.78 moles) of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate prepared in the Synthesis Example 2, 2 wt.% platinum per 118 g of carbon (50 wt.% product, N.E. Chemcat Corporation, 6.0 mmoles in terms of platinum metallic atom) and 9,440 mL of methanol were placed. The mixture was allowed to react at 50 to 60C for 6 hours in an atmosphere of hydrogen while stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to obtain 1,960 g of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an orange liquid (isolation yield: 92%).
92%
With hydrogen;platinum(IV) oxide; In methanol; at 20℃; for 1h;
Subsequently, 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoic acid ethyl ester (3.0 mg) produced by the above process was dissolved in methanol, and platinum oxide (250 mg) was added to the solution at room temperature. The air in the reaction system was replaced by hydrogen, and the mixture was then stirred for one hr. After the completion of the reaction, the atmosphere in the reaction system was replaced by nitrogen. The reaction solution was filtered through Celite to remove platinum oxide. The filtrate was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 2-amino-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (compound A) (2.5 g, yield 92%).
88.27%
With 10% Pt/activated carbon; hydrogen; In methanol; at 90℃; under 11251.1 Torr; for 0.00972222h;
2) catalytic hydrogenation reaction: 200 g of the nitrification product obtained in the previous step is dissolved in 5 L of anhydrous methanol, and then added15g of Pt/C catalyst with Pt content of 10% is fully stirred and mixed to form material IV, H2 is used as material V, and the slurry pump is adjusted.The flow rate is such that the flow rate of the material IV is 42.0 g/min, the flow rate of the gas flow meter is adjusted to 600 ml/min, the molar ratio of the nitrification product to H2 is 1:3.4, the reaction temperature is 90 C, and the temperature of the cooling module is 25 C. , the reaction residence time is 35s, the reactionThe pressure is 1.5Mpa, and the reaction liquid flowing out from the outlet of the cooling module is collected for post-treatment, and the post-treatment refers to filtration and recovery.Catalyst Pt/C, the organic solvent was recovered by distillation under reduced pressure, and the residue was added with 1.2 L of acetone to stir the solvent, and 450 ml of concentrated salt was added.Acid, stirring and crystallization for 1h, filtration, the filter cake is put into 2L of water, adding 2mol / L NaOH solution to adjust the pH of the system8.0 or so, 2L of ethyl acetate was added twice, each time 1 L of ethyl acetate was added, and the organic phase was combined and dried over anhydrous sodium sulfateAfter drying solvent is recovered by distillation under reduced pressure to give the product amino 161.12g, yield 88.27%, purity 99.59%.
85.1%
With ammonium hydroxide; sodium dithionite; sodium hydroxide; In tetrahydrofuran; water; ethyl acetate; for 2h;Reflux;
(2) Preparation of Ethyl 2-amino-4,5-dimethoxyethoxybenzoate 15 Ethyl 2-nitro-4,5-dimethoxyethoxybenzoate 14 (7 g, 20.40 mmol) is placed in a two-neck bottle of 500 ml, THF (30 ml), water (140 ml) and NH4OH (4 ml, 28~30%) are added, then sodium hydrosulfite (3.88 g, 28.04 mmol) is added, and heat refluxing is carried out for 2 hours. Conc.HCl (4 ml) is added to continue heat refluxing for 2 hours. After reaction is completed and cooled to 5 C., NaOH (18 ml, 20%) is added to adjust pH>9. Extraction is performed by using ethyl acetate (200 ml*2), organic layers are combined to be washed by water (200 ml), and the organic layers is dried by adding anhydrous MgSO4, filtered and concentrated to obtain brown liquid compound 15 (5.34 g, 85.1%). 1H-NMR (CDCl3) spectrum: 1.33 (t, 2H, J=7.1 Hz), 3.41 (s, 6H), 3.68~3.71 (m, 4H), 4.04~4.25 (m, 4H), 4.26 (q, 2H, J=7.1 Hz), 6.14 (s, 1H), 7.42 (s, 1H).
With palladium 10% on activated carbon; hydrogen; In methanol; for 12h;
1.7 Synthesis of ethyl 6-amino-3,4-bis(methoxyethoxy)benzoate0.2 mol ethyl 6-nitro-3,4-bis(methoxyethoxy)benzoate was dissolved in 250 ml methanol, adding 0.5g palladium carbon (10%), into the hydrogen. After 12h the reaction is complete, filtering out palladium-carbon. Revolving off a solvent, be oil, directly used for the next reaction
1.8 Synthesis of 6,7-bis(methoxyethoxy)quinazolin-4-one0.18 mol <strong>[179688-27-8]ethyl 6-amino-3,4-bis(methoxyethoxy)benzoate</strong> was dissolved in 50 ml formamide, under N 2 protection at 165-170 C for 12h. After cooling solid precipitate was filtered. The resulting solid was recrystallized from acetonitrile to give white solid. Yield 72%.
To a stirred solution of 15.7 g (50 mmol) of <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate</strong> (WO-96130347) in 50 ml of DMF at 0C was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55C for 45 m, cooled, diluted with methylene chloride, and treated at 0C with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0C with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) ? 3.02 (s, Me2N).
With ammonium acetate; In methanol; at 110℃; for 6h;
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.02 g (3.3 mmol) of <strong>[179688-27-8]ethyl 4,5-bis(2-methoxyethoxy)anthranilate</strong>, 0.96 g (9.1 mmol) of methyl orthoformate, 0.69 g (9.1 mmol) of ammonium acetate, and 5.0 mL of methanol. The reaction was carried out at 110C for 6 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then, the concentrate was recrystallized from 20 mL of methanol. The crystalline product was collected by filtration and dried under reduced pressure to give 0.87 g (isolated yield: 91%) of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as a white crystalline product.
91%
With ammonium acetate; In methanol; at 60 - 70℃; for 7h;
[Synthesis Example 4]; (Synthesis of 6,7-bis(2-methoxyethoxy)quinazolin-4-one); In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 1,600 g (5.11 moles) of the <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate</strong> prepared in the Synthesis Example 3, 1,626 g (15.3 moles) of methyl orthoformate, 1,181 g (15.3 moles) of ammonium acetate and 4,800 mL of methanol were placed. The mixture was allowed to react under refluxing conditions (60 to 70C) for 7 hours while stirring. After the reaction was complete, the reaction solution was cooled to 60C. To the reaction solution, 4,800 mL of methanol was added. The mixture was stirred for 30 minutes while maintaining the temperature, cooled to 0 to 5C, and further stirred for 1 hour. The resulting mixture was filtered to obtain 1,373 g of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as white crystals (isolation yield: 91%).
With pyridine; In dichloromethane; at 0 - 20℃; for 0.5h;
2-Amino-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (compound A) (2.5 g) produced by the above process was dissolved in anhydrous methylene chloride (40 ml). Pyridine (1.4 ml) and 3-(chloromethyl)-benzoyl chloride (compound B) (1.3 ml) were added dropwise to the solution at 0C, and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3-chloromethylbenzoylamino)-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (2.3 g, yield 62%).
N'-[2-Carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; In N,N-dimethyl-formamide; toluene;
EXAMPLE 113 N'-[2-Carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine To a stirred solution of 15.7 g (50 mmol) of <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate</strong> (Pfizer patent WO 96130347) in 50 ml of DMF at 0 C. was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55 C. for 45 m, cooled, diluted with methylene chloride, and treated at 0 C. with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0 C. with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) delta 3.02 (s, Me2N).
With trichlorophosphate; In N,N-dimethyl-formamide; toluene;
EXAMPLE 113 N'-[2-Carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine To a stirred solution of 15.7 g (50 mmol) of <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate</strong> (Pfizer patent WO 96130347) in 50 ml of DMF at 0 C. was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55 C. for 45 m, cooled, diluted with methylene chloride, and treated at 0 C. with 200 ml of N/i sodium hydroxide during 2 m. The organic layer was separated and washed at 0 C. with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) delta 3.02 (s, Me2 N).
With trichlorophosphate; In N,N-dimethyl-formamide; toluene;
EXAMPLE 62 N'-[2-Carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine To a stirred solution of 15.7 g (50 mmol) of <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate</strong> (WO-96130347) in 50 ml of DMF at 0 C. was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55 C. for 45 m, cooled, diluted with methylene chloride, and treated at 0 C. with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0 C. with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) delta6 3.02 (s, Me2N).
With trichlorophosphate; In N,N-dimethyl-formamide; toluene;
Example 113 N'-[2-Carbethoxy-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine To a stirred solution of 15.7 g (50 mmol) of <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate</strong> (Pfizer patent WO 96130347) in 50 ml of DMF at 0C was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55C for 45 m, cooled, diluted with methylene chloride, and treated at 0C with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0C with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) delta 3.02 (s, Me 2N).
Nitric acid (70%, 75 ml) was stirred and cooled to 0 C. The benzoate so obtained was added portionwise over 30 minutes and the mixture was stirred at 0 C. for 10 minutes. The mixture was diluted into water and extracted with methylene chloride. The organic phase was evaporated to give ethyl 4,5-di-(2-methoxyethoxy)-2-nitrobenzoate (10.4 g). A mixture of the material so obtained, 10% palladium-on-carbon catalyst (2 g), cyclohexane (25 ml) and methanol (125 ml) was stirred and heated to reflux for 9 hours. The mixture was cooled to ambient temperature, filtered and the filtrate was evaporated. There was thus obtained ethyl 2-amino-4,5-di-(2-methoxyethoxy)benzoate.
14
[ 3473-63-0 ]
[ 179688-27-8 ]
[ 179688-29-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
Compound (v) (171.1g), formamidine acetate (79.8 g) was dissolved in n-butanol (1027mL), and nitrogen at elevatedTemperature to 80 C for 5 hours, the reaction was complete by HPLC. Spin dry n-butanol, was added 1711g of isopropyl acetate heated to reflux for 1Hours, cooled to _5 C for 4 hours. Filtered, 50 C and dried under blast (vi) (164.0g), yield 98%, purity>95%. NMR data identified compound (vi) as follows
98.5%
In ethanol; at 55℃; for 3h;Green chemistry;
2375 ml of absolute ethanol and 255 g of compound III prepared by the method of Example 9 were added to the reaction vessel,After stirring to dissolve, add formamidine acetate 95g, heated to 55C , temperature control reaction for 3 hours, cooled to 15 crystal out. Filtration, the filtrate evaporated condensate recovery of ethanol applied to the next batch of ring reactor, non-condensable gas into the exhaust absorption device. The filter cake was collected and dried at 40-50 C,The structure was confirmed to give the finished product 6,7-bis (methoxyethoxy) quinazolin-4-one 235.7g, the yield was 98.5%, by HPLC purity of 99.9%.
To a stirred solution of 15.7 g (50 mmol) of <strong>[179688-27-8]ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate</strong> (Pfizer patent WO 96130347) in 50 ml of DMF at 0C was added phosphorous oxychloride (5.6 ml, 60 mmol) during 15 m. The resulting solution was heated at 55C for 45 m, cooled, diluted with methylene chloride, and treated at 0C with 200 ml of N/1 sodium hydroxide during 2 m. The organic layer was separated and washed at 0C with water. The solution was dried and evaporated with added toluene present to give 18.4 g of amber oil; NMR (CDCl3) delta 3.02 (s, Me2N).
With ammonium formate; In N,N-dimethyl-formamide; at 160℃;
To the reaction flask was added ethyl 2-amino-4,5-di-(2-methoxyethoxy)-benzoate 350 g, dimethyl500 mL of amide and 200 g of ammonium formate. The reaction was heated to 160 C and monitored by TLC until ethyl 2-amino-4,5-di-(2-methoxyethoxy)-benzoate was completely reacted. The temperature is lowered to 0 to 5 C to precipitate, suction filtration, the filter cake is washed with acetone, and dried at 80 C.Compound II (white solid, 232.6 g, yield 79%) was obtained.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
