* 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.
Reference：
[1] Journal of the American Chemical Society, 1919, vol. 41, p. 2147
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629
[3] Journal of Organic Chemistry, 2014, vol. 79, # 23, p. 11339 - 11348
5
[ 26759-46-6 ]
[ 16712-16-6 ]
[ 13794-72-4 ]
Yield
Reaction Conditions
Operation in experiment
84.7%
at 190 - 200℃; for 2 h;
Example 1Preparation of 2-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyacetamide (Compound 1)Step 1a. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 0102); A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190200° C. for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8 g, 84.7percent): LCMS: m/z 207[M+1]+; 1HNMR (DMSO) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1.
92.1%
at 150℃; for 2 h;
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
88.8%
at 150℃; for 2 h;
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
87.5%
at 150℃; for 2 h;
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
87%
at 140℃; for 24 h;
30 g of methyl 2-amino-4,5-dimethoxybenzoate was suspended in 240 ml of formamide, and the system was heated to 140° C. and reacted for 24 hrs. A large amount of solids was precipitated in the flask. The reaction solution was filtered after cooled. The filter cake was washed with a small amount of water and then dried to obtain 29.3 g of the resulting product (87percent).10087] ‘H NMR (400 MHz, DMSO) ö 12.01 (br., 1H), 7.99 (s, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H)
84.7%
at 190 - 200℃; for 2 h;
Step 1e. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 107) A mixture of compound 106 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 mL) was stirred and heated to 190~200° C. for 2 hours. The mixture was cooled to room temperature and the resulting precipitate was isolated, washed with water and dried to provide the title compound 107 as a brown solid (1.8 g, 84.7percent): LCMS: 207 [M+1]+; 1H NMR (DMSO-d6); δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
84.7%
at 190 - 200℃; for 2 h;
Step 1a. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 0102) A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190~200° C. for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8 g, 84.7percent): LCMS: m/z 207 [M+1]+; 1H-NMR (DMSO.) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
78.7%
With trichlorophosphate In toluene for 5 h; Reflux
In a 100 mL three-necked flask were added 1.5 g (6.2 mmol) of methyl 6-amino-3,4_-dimethoxybenzoate, 3 mL (75.5 mmol) of formamide, 3 mL (32.77 mmol) Oxygen Phosphorus and 25 mL of toluene were mixed and heated to reflux. TLC was carried out for 5 h and the reaction was completed. The mixture was taken out to obtain a brown solid. After adding water, the pH value was neutralized with ammonia water. A precipitate of yellowish brown color was precipitated. : ΕΑ = 5: 1, V / V) to obtain a white flocculent solid 1.2 g, yield 78.7percent, mp: 184-1860C.
67.5%
at 150℃; for 2 h;
Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
54%
at 168 - 170℃; Inert atmosphere
A solution of compound 1a (5.0 g, 23.7 mmol) in formamide (50 mL) was heated to 168–170 °C under N2 atmosphere overnight. The reaction mixture was cooled and the resultant precipitate was filtered, washed with water, ether to afford 2 (2.63 g, 54percent) as a beige solid, mp 300–302 °C. 1H NMR (DMSO-d6): d 12.07 (s, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
36.4%
at 150℃; for 2 h;
Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
Reference：
[1] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6
[2] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[3] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[4] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[5] Patent: US2016/175453, 2016, A1, . Location in patent: Paragraph 0085; 0086; 0087
[6] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 25-26
[7] Patent: US2009/76022, 2009, A1, . Location in patent: Page/Page column 66
[8] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 8089 - 8103
[9] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1189 - 1204
[10] Patent: CN105037279, 2017, B, . Location in patent: Paragraph 0049; 0050
[11] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[12] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[13] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[14] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[15] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[16] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 21, p. 2723 - 2728
[17] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[18] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 45
[19] MedChemComm, 2014, vol. 5, # 9, p. 1290 - 1296
[20] Bioorganic Chemistry, 2018, vol. 80, p. 433 - 443
7
[ 64-18-6 ]
[ 26759-46-6 ]
[ 77287-34-4 ]
[ 13794-72-4 ]
Yield
Reaction Conditions
Operation in experiment
84.22%
at 160℃; for 10 h;
To a 250 mL round bottom flask, 2-amino-4,5-dimethoxybenzoic acid methyl ester (20 g, 94.7 mmol), formamide (160 mL), formic acid (4 mL) were added sequentially, and refluxed at 160 ° C for 10 h. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1: 1). The resulting mixture was poured rapidly into ice-water, stirring, standing for a while, solid precipitation, filtration, followed by washing with distilled water (3 X 15mL), washed with ethyl acetate (3 X 15 mL), dried, recrystallized from ethyl acetate and dried to give off-white granular crystals, (16.44 g, 84.22percent).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
9
[ 75-44-5 ]
[ 26759-46-6 ]
[ 20197-92-6 ]
Reference：
[1] Synthesis, 1981, # 5, p. 391 - 392
10
[ 26759-46-6 ]
[ 917-61-3 ]
[ 20197-92-6 ]
[ 28888-44-0 ]
Reference：
[1] Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345
11
[ 26759-46-6 ]
[ 5722-93-0 ]
Reference：
[1] Journal of the American Chemical Society, 1942, vol. 64, p. 2983,2985
12
[ 26791-93-5 ]
[ 26759-46-6 ]
Yield
Reaction Conditions
Operation in experiment
88.7%
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 24 h;
1.9 g (7.2 mmol) of methyl 6-nitro-3,4-trimethoxybenzoate and 0.2 g of palladium on carbon were added into a 100 mL round bottom flask and dissolved in 50 mL of methanol. Hydrogen was introduced and the mixture was stirred at room temperature for 24 h h, TLC detection reaction was completed, a brown solid was removed. Column chromatography (PE: ΕΑ = 10: 1, V / V) isolated and purified to give a white solid 1.51 g, yield 88.7percent, Ke point: 91-93C
72%
With hydrogenchloride; tin(II) chloride dihdyrate In water at 0 - 20℃; for 3 h;
To a stirred solution of SnCl2*2H2O (30.85 g, 136.7 mmol) in concentrated HCl (100 mL) was added methyl 4,5-dimethoxy-2-nitrobenzoate (10.0 g, 41.4 mmol) portionwise at 0 °C. The reaction mixture was stirred and warmed to room temperature (rt) slowly. After the reaction mixture was stirred at rt for 3 h, it was poured into ice-water, then basified with 6 N NaOH to pH >10. The mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography with EtOAc/hexanes (1:3 to 1:2) to afford 1a (6.28 g, 72percent) as a pale yellow solid, mp 130–132 °C (lit.39 125–128 °C; lit.40 128–133 °C). 1H NMR (CDCl3): d 7.30 (s, 1H), 6.15 (s, 1H), 5.56 (br s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H).
Reference：
[1] Patent: CN105037279, 2017, B, . Location in patent: Paragraph 0047; 0048
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 10, p. 911 - 913
[4] Justus Liebigs Annalen der Chemie, 1896, vol. 293, p. 190
[5] Journal of the American Chemical Society, 1919, vol. 41, p. 2147
[6] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629
[7] Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345
[8] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 45
[9] Patent: US3954748, 1976, A,
13
[ 2150-38-1 ]
[ 26759-46-6 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 10, p. 4154 - 4171
[2] Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345
[3] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629
[4] Justus Liebigs Annalen der Chemie, 1896, vol. 293, p. 190
[5] Patent: CN105037279, 2017, B,
14
[ 93-07-2 ]
[ 26759-46-6 ]
Reference：
[1] Patent: CN105037279, 2017, B,
15
[ 67-56-1 ]
[ 5653-40-7 ]
[ 26759-46-6 ]
Reference：
[1] Scientia Pharmaceutica, 2003, vol. 71, # 4, p. 331 - 356
[2] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 12144 - 12153
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
16
[ 26759-46-6 ]
[ 221698-39-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 267 - 276
17
[ 26759-46-6 ]
[ 179688-53-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 21, p. 2723 - 2728
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[3] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[5] Patent: US2009/111772, 2009, A1,
18
[ 26759-46-6 ]
[ 179688-52-9 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[2] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[4] Patent: US2009/111772, 2009, A1,
19
[ 26759-46-6 ]
[ 788136-89-0 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[2] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
20
[ 26759-46-6 ]
[ 612501-52-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
Step a 6,7-Dimethyl-2-methylquinazolin-4(3H)-one Dry HCl gas was passed (until the clear solution observed) to a solution of methyl 2-amino-4,5-dimethoxybenzoate (3.0 g, 14.21 mmol) in acetonitrile (72 mL) for 30 min at rt. The reaction mixture was refluxed for 3 h and attained to rt. The solid precipitated was filtered and the solid was dissolved in water. The solution was neutralized with 10% aqueous NaHCO3 and the precipitated solid was filtered, washed with ice cold water and dried to give the product as an off-white color solid (2.5 g, 80%), mp 310-312 C. 1H NMR (400 MHz, DMSO-d6): delta 7.40 (1H, s), 7.06 (1H, s), 3.88 (3H, s), 3.85 (3H, s), 2.31 (3H, s); LC-MS (positive ion mode): m/z 221 (M+H)+.
1
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 %; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 %. The result is shown in Table 1.
92.1%
With ammonium acetate at 150℃; for 2h;
3
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 %; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 %. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
91%
With formic acid at 145℃; for 18h;
88.8%
With acetic acid; diethylamine at 150℃; for 2h;
2
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 %; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 %. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
88%
at 170℃; Inert atmosphere;
6,7-Dimethoxyquinazolin-4(3H)-one (6)
A mixture of methyl 2-amino-4,5-dimethoxybenzoate 5(5.00 g, 23.67 mmol) in formamide (50 mL) was stirred at170 °C overnight under a nitrogen atmosphere. Thereaction mixture was cooled to room temperature and theprecipitate was collected by filtration and washed withH2O, Et2O, and dried. Recrystallization from EtOH provided6 (4.29 g, 88% yield) as a beige solid. Analyticaldata for compound 6 are in agreement with the literature(Li et al. 2016).
87.5%
With acetic acid; ethylenediamine at 150℃; for 2h;
3
Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 %; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 %. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
87%
at 140℃; for 24h;
9.1 Synthesis of 6,7-dimethoxyquinazolinone
30 g of methyl 2-amino-4,5-dimethoxybenzoate was suspended in 240 ml of formamide, and the system was heated to 140° C. and reacted for 24 hrs. A large amount of solids was precipitated in the flask. The reaction solution was filtered after cooled. The filter cake was washed with a small amount of water and then dried to obtain 29.3 g of the resulting product (87%).10087] ‘H NMR (400 MHz, DMSO) ö 12.01 (br., 1H), 7.99 (s, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H)
84.7%
With ammonium formate at 190 - 200℃; for 2h;
1.e Step 1e.
Step 1e. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 107) A mixture of compound 106 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 mL) was stirred and heated to 190~200° C. for 2 hours. The mixture was cooled to room temperature and the resulting precipitate was isolated, washed with water and dried to provide the title compound 107 as a brown solid (1.8 g, 84.7%): LCMS: 207 [M+1]+; 1H NMR (DMSO-d6); δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
84.7%
With ammonium formate at 190 - 200℃; for 2h;
1.1a
Step 1a. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 0102) A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190~200° C. for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8 g, 84.7%): LCMS: m/z 207 [M+1]+; 1H-NMR (DMSO.) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
82%
With sodium methylate In methanol; N,N-dimethyl-formamide for 16h; Reflux;
78.7%
With trichlorophosphate In toluene for 5h; Reflux;
1.4 (4) Preparation of 6,7-trimethoxyquinazolinone
In a 100 mL three-necked flask were added 1.5 g (6.2 mmol) of methyl 6-amino-3,4_-dimethoxybenzoate, 3 mL (75.5 mmol) of formamide, 3 mL (32.77 mmol) Oxygen Phosphorus and 25 mL of toluene were mixed and heated to reflux. TLC was carried out for 5 h and the reaction was completed. The mixture was taken out to obtain a brown solid. After adding water, the pH value was neutralized with ammonia water. A precipitate of yellowish brown color was precipitated. : ΕΑ = 5: 1, V / V) to obtain a white flocculent solid 1.2 g, yield 78.7%, mp: 184-1860C.
72%
In methanol; N,N-dimethyl-formamide Inert atmosphere;
67.5%
With formic acid at 150℃; for 2h;
1
Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
54%
at 168 - 170℃; Inert atmosphere;
(d) 6,7-Dimethoxyquinazolin-4(3H)-one (2):
A solution of compound 1a (5.0 g, 23.7 mmol) in formamide (50 mL) was heated to 168-170 °C under N2 atmosphere overnight. The reaction mixture was cooled and the resultant precipitate was filtered, washed with water, ether to afford 2 (2.63 g, 54%) as a beige solid, mp 300-302 °C. 1H NMR (DMSO-d6): d 12.07 (s, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
36.4%
With potassium carbonate at 150℃; for 2h;
2
Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
at 180℃;
at 150 - 160℃;
With ammonium acetate
5
Preparation of the 4-(3-ethynyl-phenyl)amino- 6,7-dimethoxy-quinazoIine 3 was achieved in four steps from the commercially available ester 1. (Knesl et al. (2006) Molecules, 11:286-297; Wright, et al. (2001) Bio-org. Med. Ch em. Lett., 1 /; 17-21.
for 10h; Reflux;
4.1.1. General procedure for the syntheses of intermediate 1
General procedure: A mixture of 2-aminobenzoic acid (0.1 mol) and formamide (20 mL)was refluxed for 10 h. After the mixture was cooled to room temperature,water (200 mL) was added and the precipitate was filtered off. Thecrude product was recrystallized from ethanol (100 mL) to the desiredintermediate 1 as a white solid.
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
1.a
Example 1Preparation of 2-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyacetamide (Compound 1)Step 1a. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 0102); A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190200° C. for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8 g, 84.7%): LCMS: m/z 207[M+1]+; 1HNMR (DMSO) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 2h;
General procedure: 1.5 equiv of PMBONH3+Cl- plus 4.5 equiv of LiHMDS (at 0 C for 2 h) or 4.1 equiv of LDA (from -78 C to -10 C, 0.5 h); yields were similar.
With potassium hexamethylsilazane In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
Typical procedure
General procedure: To a solution of methyl 2-amino-4-chlorobenzoate (300 mg, 1.6 mmol) and ethyl 2-phenoxyacetate (320 mg, 1.8 mmol) in anhydrous THF (9 mL) was added KHMDS (4.8 mL, 1.0 M in THF, 4.8 mmol) in one portion with vigorous stirring under a nitrogen atmosphere. The reaction mixture was stirred at rt until completion of the reaction (10 min) then MeOH was added. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in water and acidified with 1 N HCl until precipitation occurred. The precipitate was filtered, washed with EtOH then dried to give 7-chloro-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Table 2, entry 1) as a pale pink powder (449 mg, 92%).
Stage #1: 3-Carboxyphenol With pyridine; thionyl chloride In dichloromethane at 45℃; for 2h;
Stage #2: methyl 2-amino-4,5-dimethoxybenzoate In toluene at 100℃; for 3h;
Experimental rocedure for the preparation of methyl 2-(3- ydroxybenzamido)-4,5-dimethoxybenzoate:
General procedure: To solution of 3- ydroxybenzoic cid (138.12 mg, 1.0 mmol) in CH2Cl2 10 mL), pyridine (99 mg, 1.25 mmol) and SOCl2 (773 mg, 6.5 mmol) were slowly added. After stirring at 45 _C for 2 h, the solvent was removed under reduced pressure. The reaction mixture was dissolved in toluene, and then methyl 2-amino-4,5- dimethoxybenzoate (264 mg, 1.25 mmol) was added. The reaction mixture was stirred at 100 _C for 3 h. After the reaction was complete (monitored by TLC), the solvent was evaporated, then an aqueous solution of Na2CO3 (10%, 10 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3 _ 10 mL). The combined organic phases were washed with brine (2 _ 20 mL) and dried over Na2SO4. The solvent was evaporated, and the pure product was obtained by crystallization from EtOH. Yield, 71% (235 mg). Experimental procedure for the preparation of 2-(3-hydroxybenzamido)-4,5- dimethoxybenzoic acid (11): To a stirred solution of the methyl 2-(3- hydroxybenzamido)-4,5-dimethoxybenzoate (165 mg, 0.5 mmol) in dioxane/ THF mixture (1:1, 2 mL), 1 M NaOH (1 mL) was added, and the reaction mixture stirred until the starting material had completely reacted (monitored by TLC). The solvent was then evaporated under reduced pressure, the residue diluted with H2O (10 mL), and washed with EtOAc (2 _ 10 mL). The aqueous phase was acidified to pH 2 using 1 M HCl, and extracted with EtOAc (3 _ 10 mL). The combined organic phases were washed with brine (3 _ 10 mL), then dried over Na2SO4, filtered, and evaporated to dryness, to provide compound 11. Yield, 74% (117 mg). Spectroscopic data for 2-(3-hydroxybenzamido)-4,5-dimethoxybenzoic acid (11): White solid; Yield: 51% (2 steps); Rf 0.49 (CH2Cl2/MeOH/AcOH = 9/1/0.1); Mp: 245.0-248.0 _C; 1H NMR (400 MHz, DMSO-d6): d 3.79 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.95-7.03 (m, 1H, Ar-H), 7.32-7.39 (m, 3H, Ar-H), 7.49 (s, 1H, Ar- H), 8.52 (s, 1H, Ar-H), 9.91 (br s, 1H, NHCO), 13.51 (br s, 1H, COOH); 13C NMR (100 MHz, DMSO-d6): d 55.54 (2C), 102.98, 107.47, 112.83, 113.84, 117.15, 119.01, 129.95, 135.95, 136.98, 143.58, 153.25, 157.76, 164.41, 169.72; HRMS (ESI) m/z calcd for C16H15N2O [M+H]+ 318.0978, found 318.0969; HPLC purity: 95.54%, retention time: 14.06 min
Compound (1) (10 g, 47.3 mmol) and (2) (9.5 g 142 mmol) were weighted into reaction flask and 4M HC1 in 1,4-dioxane was added. The mixture was stirred at 100 C for overnight. The mixture was cooled to rt and poured carefully into cold saturated Na2C03 solution (100 mL). The resulting solid was collected by filtration and washed with water to give compound (3) (10.8 g, yield: 93%) as a white solid 'H NMR (300 MHz, DMSO-i/6): delta 12.28 (brs, 1H), 7.37 (s, 1H), 6.93 (s, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.11-2.04 (m, 1H), 1.07-0.95 (m, 4H). MS: m/z 247 (M-H+).
2.A 6,7-dimethoxyquinazolin-4-one
To a 250 mL round bottom flask, 2-amino-4,5-dimethoxybenzoic acid methyl ester (20 g, 94.7 mmol), formamide (160 mL), formic acid (4 mL) were added sequentially, and refluxed at 160 ° C for 10 h. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1: 1). The resulting mixture was poured rapidly into ice-water, stirring, standing for a while, solid precipitation, filtration, followed by washing with distilled water (3 X 15mL), washed with ethyl acetate (3 X 15 mL), dried, recrystallized from ethyl acetate and dried to give off-white granular crystals, (16.44 g, 84.22%).
2.1 Step-1: Synthesis of 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione:
A solid mixture of methyl 2-amino-4,5-dimethoxybenzoate (500 mg, 2.36 mmol, 1 eq) and urea (300 mg) was fused at 180 °C for 1 h. Progress of reaction was monitored by TLC. After completion reaction mixture was cooled to RT, diluted with cold water (100 mL) and allowed to stir for 5 minutes. Solid was filtered, washed with water and dried under vacuum to afford 6,7- dimethoxyquinazoline-2,4(1H,3H)-dione (360 mg, 68 %). LCMS: 222[M+1]+
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