* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: for 12 h; Heating / reflux Stage #2: With ammonia In 2-methoxy-ethanol at 25℃; for 0.5 h;
Method 31; 7-Methoxy-3H-quinazolin-4-one; A mixture of 2-amino-4-methoxy benzoic acid (Method 30; 4.85 g, 88.9 mmol) and formamidine acetate (18.49 g, 177.8 mmol) in 2-methoxyethanol (100 ml) was stirred at reflux for 12 h. The reaction mixture was cooled to 25 °C and diluted with 0.01 M ammonia (100 ml). The mixture was then stirred at 25 0C for 30 min and the resulting solid was collected by filtration. The solid was washed with 0.01M ammonia and water. The product was dried by high vacuum to obtain a light brown solid 11.5 g (73percent). NMR: 12.10 (s, br, IH), 8.05 (m, 2H), 7.10 (m, 2H), 3.90 (s, 3H); m/z 167.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 4963 - 4966
[2] Patent: WO2007/71963, 2007, A2, . Location in patent: Page/Page column 52
[3] Patent: CN104447769, 2016, B, . Location in patent: Paragraph 0056-0057
2
[ 77287-34-4 ]
[ 4294-95-5 ]
[ 16064-24-7 ]
Reference：
[1] Yakugaku Zasshi, 1943, vol. 63, p. 445,447[2] Chem.Abstr., 1951, p. 5156
[3] Journal of the Chemical Society, 1947, p. 890,894
[4] Chemistry and Biodiversity, 2018, vol. 15, # 6,
3
[ 4294-95-5 ]
[ 55496-52-1 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 890,894
[2] Patent: US9527885, 2016, B2,
[3] Patent: CN104447769, 2016, B,
4
[ 4294-95-5 ]
[ 62484-31-5 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 890,894
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1452 - 1465
[4] Patent: US2016/90374, 2016, A1,
[5] Patent: WO2016/151144, 2016, A1,
[6] Patent: WO2018/5799, 2018, A1,
5
[ 4294-95-5 ]
[ 62484-12-2 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 48, p. 17605 - 17614
[2] Journal of the Chemical Society, 1947, p. 890,894
[3] Patent: US5688803, 1997, A,
6
[ 57-13-6 ]
[ 4294-95-5 ]
[ 62484-12-2 ]
Yield
Reaction Conditions
Operation in experiment
48%
at 155℃; for 16 h;
A mixture of 2-amino-4-methoxybenzoic acid (1 g; 5.98 mmol) and urea (7.18 g; 120 mmol) was stirred at 155°C for 16 h. The reaction mixture was cooled to 100°C and then 3 mL of water was added. The mixture was cooled to room temperature and was filtered. 30 mL of 1 mol/L NaOH aqueous solution was added to dissolve the precipitate. After one hour, 4.2 mL of acetic acid was added dropwise and the resulting light brown precipitate was filtered and dried. 8 was obtained as a light brown powder (0.55 g; 2.9 mmol; 48 percent). 1H NMR (500 MHz; DMSO) δ 11.10 (brs, 1H, HNH), 10.55 (brs, 1H, HNH), 7.8 (d, J=8.63 Hz, 1H, Ha4), 6.77 (dd, J=2.44, 8.84 Hz, 1H, Ha5), 6.64 (d, J=2.43 Hz, 1H, Ha7), 3.82 (s, 3H, Hbl). 13C NMR (125 MHz; DMSO) δ 164.8 (Ca6), 162.8 (Ca2), 151 (Cal), 143.3 (Ca8), 129.3 (Ca4), 111 (Ca5), 108.2 (Ca3), 98.8 (Ca7), 56.1 (Cbl). HRMS-ESI (m/z) calculated for C9H8N203: 193.0489 [M+H]+ ; found: 193.0511
Reference：
[1] Patent: WO2016/151144, 2016, A1, . Location in patent: Page/Page column 55; 56
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
Intermediate 113: 2-Amino-4-methoxybenzoic acid4-Methoxy-2-nitrobenzoic acid (3 g, 16.4 mmol) was hydrogenated over palladium on carbon (10percent, 300 mg) in methanol (80 mL) at room temperature and normal pressure for 18 hours. The reaction mixture was filtered through celite and concentrated to dryness under reduce pressure to give 2.50 g (100percent) of the product as a colorless solid.1H NMR (DMSO-d^ δ 3.70 (s, 3H); 6.09 (dd, IH); 6.23 (d, IH); 7.59 (d, IH).
99%
With hydrogen In methanol at 20℃; Inert atmosphere
Example 33. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one [0270] A mixture of 2-nitro-4-methoxybenzoic acid (1.00 g, 5.10 mmol) in methanol (10.0 mL) was stirred at room temperature under nitrogen. Palladium on carbon (10percent wt, 50percent wet, 0.559 g, 0.255 mmol) was added. The round- bottomed flask was capped with a new septa and degassed under vacuum. The flask was charged with hydrogen and degassed again. This was repeated twice and a hydrogen-filled balloon was attached to the flask. The mixture was stirred at room temperature for 4 hours. Nitrogen was then bubbled through the mixture to displace any excess hydrogen. The mixture was filtered through celite 521 and the filtrate was concentrated under reduced pressure to provide 2-amino-4- methoxybenzoic acid (0.890 g, >;99percent) as an off-white solid. The crude material was used directly in the next step without characterization.[0271] A mixture of 2-amino-4-methoxybenzoic acid (0.490 g, 3.00 mmol), EDCI (1.12 g, 5.83 mmol), HOBt (0.788 g, 5.83 mmol), Λ/-methylmorpholine (0.590 g, 5.83 mmol) and 14.8 N NH4OH (0.781 ml_, 10.6 mmol) in THF was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, then the residue was diluted with EtOAc (100 ml_), washed with water (2 x 100 mL), then brine (100 ml_), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to provide 2-amino-4- methoxybenzamide as a tan solid.[0272] A mixture of 2-amino-4-methoxybenzamide (0.490 g, 3.00 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (0.925 g, 3.00 mmol), NaHSO3 (94percent, 0.468 g, 4.50 mmol), and p-TsOHΗ2O (0.171 g, 0.900 mmol) in benzene (10.0 mL) was heated at 800C for 36 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with water (50 mL) then brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to provide 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one as a pink solid. The crude material was used directly in the next step without characterization.[0273] A mixture of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (1.09 g, 2.30 mmol) in 1 M TBAF (11.6 mL, 11.6 mmol) was stirred at room temperature for 3 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with saturated aqueous NH4CI (2 x 75 mL), then brine (100 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified over silica gel (12 g, EtOAc/hexanes), triturated in ether, and the product was freeze- dried from MeCN/H2O to yield the title compound (0.0960 g, 12percent) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.18 (s, 1H), 8.02 (d, J = 8.79 Hz, 1H), 7.91 (s, 2H), 7.16 (d, J = 2.46 Hz, 1 H), 7.07 (dd, J = 8.79, 2.46 Hz, 1 H), 4.90 (t, J = 5.53 Hz, 1 H), 3.91 (s, 3H), 3.89-3.82 (m, 2H), 3.77-3.67 (m, 2H), 2.32 (s, 6H), 2.22 (d, J = 6.92 Hz, 1H). MS (APCI) m/z 341 [C19H2oN2O4+H]+.
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 4 h; Inert atmosphere
Example 28 Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one A mixture of 2-nitro-4-methoxybenzoic acid (1.00 g, 5.10 mmol) in methanol (10.0 mL) was stirred at room temperature under nitrogen. Palladium on carbon (10percent wt, 50percent wet, 0.559 g, 0.255 mmol) was added. The round-bottomed flask was capped with a new septa and degassed under vacuum. The flask was charged with hydrogen and degassed again. This was repeated twice and a hydrogen-filled balloon was attached to the flask. The mixture was stirred at room temperature for 4 hours. Nitrogen was then bubbled through the mixture to displace any excess hydrogen. The mixture was filtered through celite 521 and the filtrate was concentrated under reduced pressure to provide 2-amino-4-methoxybenzoic acid (0.890 g, >99percent) as an off-white solid.
87.6%
With hydrogen In methanol at 25℃; for 168 h;
Method 30; 2-Amino-4-methoxy benzoic acid; A mixture of 4-methoxy-2-nitrobenzoic acid (20 g, 101.5 mmol), 10percent Pd/C (1.5 g) in MeOH (200 ml) was stirred at 25 °C under a hydrogen atmosphere for 168 h. The mixture was diluted with MeOH and filtered through diatomaceous earth. The organics were removed under reduced pressure to yield a light brown solid (14.85 g, 87.6percent). NMR: 7.65 (d, IH), 6.30 (s, IH), 6.15 (d, IH), 3.80 (s, 3H); m/z 167.
50%
With hydrogen In NH4OH at 50℃; for 48 h;
Compounds 1-3 were made using similar procedures to those in U. S. Patent No. 4,287, 341 which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein. Compound 3 was reduced using standard hydrogenation conditions of 10percent Pd/C in NH40H at 50 C over 48 hours. The product was precipitated by neutralizing with glacial acetic acid, filtering, and washing with water and ether. Yields were about 50percent. Compound 5 was prepared in a manner similar to that disclosed in U. S. Patent No. 5,716, 993 herein incorporated by reference in its entirety for all purposes as if fully set forth herein.
Reference：
[1] Patent: WO2006/134378, 2006, A1, . Location in patent: Page/Page column 112
[2] Patent: WO2010/123975, 2010, A1, . Location in patent: Page/Page column 101-102
[3] Patent: US2013/281398, 2013, A1, . Location in patent: Paragraph 0493; 0494
[4] Patent: US5599814, 1997, A,
[5] Patent: WO2007/71963, 2007, A2, . Location in patent: Page/Page column 52
[6] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1240 - 1256
[7] Collection of Czechoslovak Chemical Communications, 1985, vol. 50, # 2, p. 519 - 537
[8] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 265
[9] Chemische Berichte, 1918, vol. 51, p. 14
[10] Chemische Berichte, 1956, vol. 89, p. 2174,2178
[11] Journal of the Chemical Society, 1947, p. 1034,1037
[12] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 884,887[13] Chem. Zentralbl., 1939, vol. 110, # I, p. 4324
[14] Journal of Organic Chemistry, 1953, vol. 18, p. 1380,1400
[15] Chemical and pharmaceutical bulletin, 1964, vol. 12, p. 696 - 705
[16] Chemische Berichte, 1961, vol. 94, p. 2295 - 2305
[17] Patent: US5614530, 1997, A,
[18] Patent: US5852035, 1998, A,
[19] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 7021 - 7032
9
[ 38487-91-1 ]
[ 4294-95-5 ]
Reference：
[1] Patent: US5948775, 1999, A,
10
[ 52351-75-4 ]
[ 4294-95-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 21, p. 3261 - 3273
[2] Synthetic Communications, 1994, vol. 24, # 4, p. 533 - 548
[3] Australian Journal of Chemistry, 1958, vol. 11, p. 225,228
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 8, p. 2440 - 2455
11
[ 33844-21-2 ]
[ 7440-05-3 ]
[ 4294-95-5 ]
Reference：
[1] Patent: US5942520, 1999, A,
[2] Patent: US5488055, 1996, A,
12
[ 33844-21-2 ]
[ 118-92-3 ]
[ 4294-95-5 ]
Reference：
[1] Patent: US4287341, 1981, A,
13
[ 27191-09-9 ]
[ 4294-95-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 8, p. 2440 - 2455
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 21, p. 3261 - 3273
[2] Synthetic Communications, 1994, vol. 24, # 4, p. 533 - 548
[3] Australian Journal of Chemistry, 1958, vol. 11, p. 225,228
16
[ 621-42-1 ]
[ 4294-95-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1967, vol. 40, p. 1480 - 1487
17
[ 50868-78-5 ]
[ 4294-95-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1912, vol. 388, p. 34
18
[ 38469-83-9 ]
[ 4294-95-5 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 1034,1037
19
[ 96-96-8 ]
[ 4294-95-5 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 1034,1037
20
[ 17484-36-5 ]
[ 4294-95-5 ]
Reference：
[1] Chemische Berichte, 1918, vol. 51, p. 14
21
[ 50868-75-2 ]
[ 4294-95-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1912, vol. 388, p. 34
22
[ 2836-00-2 ]
[ 4294-95-5 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 464
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 463
23
[ 4294-95-5 ]
[ 74317-85-4 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 13, p. 4445 - 4452
24
[ 4294-95-5 ]
[ 54435-09-5 ]
Reference：
[1] Chemical and pharmaceutical bulletin, 1964, vol. 12, p. 696 - 705
[2] Collection of Czechoslovak Chemical Communications, 1974, vol. 39, # 12, p. 3548 - 3559
[3] Patent: US5942520, 1999, A,
[4] Patent: US5488055, 1996, A,
[5] Patent: US5852035, 1998, A,
[6] Patent: US3996229, 1976, A,
[7] Patent: US3996229, 1976, A,
[8] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 5031 - 5037
[9] Journal of Organic Chemistry, 2017, vol. 82, # 4, p. 2263 - 2268
[10] Organic Letters, 2017, vol. 19, # 7, p. 1578 - 1581
25
[ 7664-93-9 ]
[ 4294-95-5 ]
[ 54435-09-5 ]
Reference：
[1] Patent: US5614530, 1997, A,
26
[ 4294-95-5 ]
[ 21971-21-1 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 884,887[2] Chem. Zentralbl., 1939, vol. 110, # I, p. 4324
27
[ 4294-95-5 ]
[ 169045-04-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 1 h;
To a solution of 2-amino-4-methoxybenzoic acid (4.00 g, 23.93 mmol) in DMF (120 mL) at 0 °C was added NBS (4.68 g, 26.3 mmol). The cooling bath was removedand the reaction mixture was warmed up to room temperature and was stirred at room temperature for 1 h. The mixture was cooled to 0 °C and was treated with saturated sodium sulfite solution (25 mL) and was stirred for 5 mm. The pH of the mixture was adjusted to pH = 3 using conc. HC1 (ca. 10-15 mL was added). The reaction mixture was transferred to a separatory funnel containing water (100 mL). Theaqueous layer was extracted with ether (1 x 250 mL then 4 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to afford 2-amino-5-bromo-4- methoxybenzoic acid (5.90 g, 100percent yield) as a solid: ‘H NMR (400 MHz, DMSOd6) ö 7.78 (s, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.90 (s, 1H), 2.74 (s, 1H); MS (ESI) m/e228.0 [(M+H-H2O), calcd for C8H7BrNO2 228.0].
77%
at 20 - 40℃; for 18 h;
2-amino-5-bromo-4-methoxybenzoic acid 2-amino-4-methoxybenzoic acid (5 g, 30 mmol) was suspended in acetic acid (100 mL) and bromine (0.57 mL, 11.25 mmol) added at RT. The mixture was stirred approx. 15 h at RT, then additional bromine (0.2 mL, 3.75 mmol) was added and the reaction mixture held at 40° C. for 3 hours. The reaction course was tracked by thin-film chromatography, the product filtered out and washed with a little water. (Yield: 5.63 g, 77percent)
1.3 g
With N-Bromosuccinimide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 4 h;
To a mixture of 4-methoxyanthranilic acid (0.67 g, 4.0 mmol) in DCM (10 mL) and DMF (3 mL) was added NBS (0.71 g, 4.0 mmol) at 0 °C. The mixture was stirred at room temperature for 4 h, then concentrated and subjected to silica gel chromatography (5-100percent EtOAc/Heptane) to provide 2-amino-5-bromo-4-methoxybenzoic acid as a beige solid (1 .30 g, containing 1 equivalent succinamide). MS (M-1 ) = 244.3/246.3. 1H NMR (DMSO-d6) δ 7.76 (s, 1 H), 6.42 (s, 1 H), 3.79 (s, 3H). This material was used without further purification.
To a solution of 4-methoxyanthranilic acid (5.0 g, 30.0 mmol) in a mixtue of 10percent methanol in tetrahydrofuran (100 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 18.0 mL, 36.0 mmol) at 0 °C. The reaction mixture was stirred for 16 hours at room temperature then quenched by the addition of glacial acetic acid (0.1 mL). The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-amino-4-methoxybenzoate as an oil (5.4 g, quantitative). MS (EI) for C9HnNO3: 182 (MH+).
74%
at 0 - 20℃; for 1 h;
To a solution of 2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) wasadded trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred atooc for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in5 vacuo. The crude material was purified by column chromatography (0 to 15percentEtOAC/hexanes) to provide 4.2 g of the title compound (74percent). MS: m/z: 182 [M+H+]
74%
at 0℃; for 1 h;
Step 1. Methyl 2-amino-4-methoxybenzoate: To a solution of 2-amino-4- (methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude material was purified by column chromatography (0 to 15percent EtOAc/hexanes) to provide 4.2 g of the title compound (74percent). MS: m/z: 182 [M+H]+.
74%
at 0℃; for 1 h;
To a solution of 2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude material was purified by column chromatography (0 to 15percent EtOAC/hexanes) to provide 4.2 g of the title compound (74percent). MS: m/z: 182 [M+H]+.
To a solution of 2-amino-4-methoxybenzoic acid 33 (5.0 g,0.03 mol) in methanol (50 mL) was added strong sulphuricacid (9 mL). The solution was stirred at reflux for 24 h. Itwas cooled to room temperature and the pH of the mixturewas adjusted to 5~6 with saturated sodium carbonatesolution. The solution was extracted with EA (100 mL*2).The combined organic layers were washed with brine(50 mL), dried over Na2SO4, filtered and concentrated,affording white powder 34 (4.11 g, 75.92percent). 34: 1H NMR (400 MHz, CDCl3) 7.81 (d, J = 8.9 Hz, 1 H), 6.25 (dd, J =9.0, 2.5 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.80 (s, 2H), 3.86(s, 3H), 3.81 (s, 3H).
37%
Reflux
Step a): Methyl 2-amino-4-methoxybenzoate 1000 mg (6.0 mmol) of 2-amino-4-methoxybenzoic acid are reacted according to General Method I. Yield: 400 mg (37percent of theory) LC-MS (Method 3): Rt=1.96 min; MS (ESIpos): m/z=182 [M+H]+. 5 mmol of the carboxylic acid are dissolved in 50 ml of methanol, and 5 ml of concentrated sulfuric acid are added. The mixture is heated under reflux for 14-24 h. After cooling to room temperature, the solution is poured onto ice and adjusted to pH 6 using sodium bicarbonate. After addition of 100 ml of dichloromethane, the aqueous phase is separated off and reextracted twice with in each case 50 ml of dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reference：
[1] Medicinal Chemistry Research, 2018, vol. 27, # 7, p. 1851 - 1862
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[3] Patent: US2010/4292, 2010, A1, . Location in patent: Page/Page column 12; 15
[4] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 21, p. 3261 - 3273
30
[ 4294-95-5 ]
[ 50413-30-4 ]
Reference：
[1] Patent: US4287341, 1981, A,
[2] Patent: US5599814, 1997, A,
31
[ 4294-95-5 ]
[ 79025-82-4 ]
Reference：
[1] Patent: CN107814792, 2018, A, . Location in patent: Paragraph 0295; 0296
With borane-THF In tetrahydrofuran at 0 - 20℃; for 1.66667 h; Inert atmosphere
General procedure: To a solution of 6-chloroanthranilic acid (1.5 g, 8.74 mmol) in THF (5 mL) was added dropwise 1.08 M borane–tetrahydrofuran complex in THF (24.3 mL, 26.2 mmol) at 0 °C under an Ar atmosphere for 10 min. After 1.5 h with stirring at 30 °C, the solution was cooled at 0 °C, added aqueous THF (THF/H2O = 1:1, 60 mL) and potassium carbonate, and extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was crystallized from AcOEt to give 1a (1.2 g, 88percent) as a white needle crystal.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Patent: WO2014/11900, 2014, A2, . Location in patent: Page/Page column 72
[3] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9603 - 9607,5[4] Angewandte Chemie, 2014, vol. 126, # 36, p. 9757 - 9761,5
[5] Patent: US2015/119405, 2015, A1, . Location in patent: Paragraph 0476; 0477; 0478
[6] Angewandte Chemie - International Edition, 2016, vol. 55, # 49, p. 15272 - 15276[7] Angew. Chem., 2016, vol. 128, # 49, p. 15498 - 15502,5
[8] Canadian Journal of Chemistry, 2016, vol. 94, # 4, p. 305 - 311
[9] Organic and Biomolecular Chemistry, 2018, vol. 16, # 12, p. 2039 - 2042
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 760.051 Torr; for 18h;
Intermediate 113: 2-Amino-4-methoxybenzoic acid4-Methoxy-2-nitrobenzoic acid (3 g, 16.4 mmol) was hydrogenated over palladium on carbon (10%, 300 mg) in methanol (80 mL) at room temperature and normal pressure for 18 hours. The reaction mixture was filtered through celite and concentrated to dryness under reduce pressure to give 2.50 g (100%) of the product as a colorless solid.1H NMR (DMSO-d^ delta 3.70 (s, 3H); 6.09 (dd, IH); 6.23 (d, IH); 7.59 (d, IH).
> 99%
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃;Inert atmosphere;
Example 33. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one [0270] A mixture of <strong>[33844-21-2]2-nitro-4-methoxybenzoic acid</strong> (1.00 g, 5.10 mmol) in methanol (10.0 mL) was stirred at room temperature under nitrogen. Palladium on carbon (10% wt, 50% wet, 0.559 g, 0.255 mmol) was added. The round- bottomed flask was capped with a new septa and degassed under vacuum. The flask was charged with hydrogen and degassed again. This was repeated twice and a hydrogen-filled balloon was attached to the flask. The mixture was stirred at room temperature for 4 hours. Nitrogen was then bubbled through the mixture to displace any excess hydrogen. The mixture was filtered through celite 521 and the filtrate was concentrated under reduced pressure to provide 2-amino-4- methoxybenzoic acid (0.890 g, >;99%) as an off-white solid. The crude material was used directly in the next step without characterization.[0271] A mixture of 2-amino-4-methoxybenzoic acid (0.490 g, 3.00 mmol), EDCI (1.12 g, 5.83 mmol), HOBt (0.788 g, 5.83 mmol), Lambda/-methylmorpholine (0.590 g, 5.83 mmol) and 14.8 N NH4OH (0.781 ml_, 10.6 mmol) in THF was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, then the residue was diluted with EtOAc (100 ml_), washed with water (2 x 100 mL), then brine (100 ml_), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to provide 2-amino-4- methoxybenzamide as a tan solid.[0272] A mixture of 2-amino-4-methoxybenzamide (0.490 g, 3.00 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (0.925 g, 3.00 mmol), NaHSO3 (94%, 0.468 g, 4.50 mmol), and p-TsOHEta2O (0.171 g, 0.900 mmol) in benzene (10.0 mL) was heated at 800C for 36 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with water (50 mL) then brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to provide 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one as a pink solid. The crude material was used directly in the next step without characterization.[0273] A mixture of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (1.09 g, 2.30 mmol) in 1 M TBAF (11.6 mL, 11.6 mmol) was stirred at room temperature for 3 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with saturated aqueous NH4CI (2 x 75 mL), then brine (100 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified over silica gel (12 g, EtOAc/hexanes), triturated in ether, and the product was freeze- dried from MeCN/H2O to yield the title compound (0.0960 g, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6): delta 12.18 (s, 1H), 8.02 (d, J = 8.79 Hz, 1H), 7.91 (s, 2H), 7.16 (d, J = 2.46 Hz, 1 H), 7.07 (dd, J = 8.79, 2.46 Hz, 1 H), 4.90 (t, J = 5.53 Hz, 1 H), 3.91 (s, 3H), 3.89-3.82 (m, 2H), 3.77-3.67 (m, 2H), 2.32 (s, 6H), 2.22 (d, J = 6.92 Hz, 1H). MS (APCI) m/z 341 [C19H2oN2O4+H]+.
> 99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;Inert atmosphere;
Example 28 Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one A mixture of <strong>[33844-21-2]2-nitro-4-methoxybenzoic acid</strong> (1.00 g, 5.10 mmol) in methanol (10.0 mL) was stirred at room temperature under nitrogen. Palladium on carbon (10% wt, 50% wet, 0.559 g, 0.255 mmol) was added. The round-bottomed flask was capped with a new septa and degassed under vacuum. The flask was charged with hydrogen and degassed again. This was repeated twice and a hydrogen-filled balloon was attached to the flask. The mixture was stirred at room temperature for 4 hours. Nitrogen was then bubbled through the mixture to displace any excess hydrogen. The mixture was filtered through celite 521 and the filtrate was concentrated under reduced pressure to provide 2-amino-4-methoxybenzoic acid (0.890 g, >99%) as an off-white solid.
98.6%
In palladium on charcoal; ethanol;
b. 2-Amino-4-methoxybenzoic acid A solution of <strong>[33844-21-2]2-nitro-4-methoxybenzoic acid</strong> (14.0 g, 71.0 mM) in 300 mL of ethanol was hydrogenated in the presence of 10% palladium on charcoal using a Parr apparatus. After reduction was completed, the mixture was filtered and the liltrate concentrated to leave the title amino acid (11.7 g, 98.6%) as a lavender crystalline solid; MS(CI): 168 (M+H).
87.6%
With hydrogen;palladium 10% on activated carbon; In methanol; at 25℃; for 168h;
Method 30; 2-Amino-4-methoxy benzoic acid; A mixture of <strong>[33844-21-2]4-methoxy-2-nitrobenzoic acid</strong> (20 g, 101.5 mmol), 10% Pd/C (1.5 g) in MeOH (200 ml) was stirred at 25 C under a hydrogen atmosphere for 168 h. The mixture was diluted with MeOH and filtered through diatomaceous earth. The organics were removed under reduced pressure to yield a light brown solid (14.85 g, 87.6%). NMR: 7.65 (d, IH), 6.30 (s, IH), 6.15 (d, IH), 3.80 (s, 3H); m/z 167.
~ 50%
With hydrogen;palladium 10% on activated carbon; In NH4OH; at 50℃; for 48h;
Compounds 1-3 were made using similar procedures to those in U. S. Patent No. 4,287, 341 which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein. Compound 3 was reduced using standard hydrogenation conditions of 10% Pd/C in NH40H at 50 C over 48 hours. The product was precipitated by neutralizing with glacial acetic acid, filtering, and washing with water and ether. Yields were about 50%. Compound 5 was prepared in a manner similar to that disclosed in U. S. Patent No. 5,716, 993 herein incorporated by reference in its entirety for all purposes as if fully set forth herein.
30.7 g (84%)
In water; palladium; N,N-dimethyl-formamide;
(a) 2-Nitro-4-methoxybenzoic acid (43.4 g, 0.22 mol) in DMF (250 ml) was hydrogenated at 55 psi in the presence of 10% palladium on carbon (5.8 g) for 2.5 hours. The reaction mixture was filtered through SUPERCELL, the filter cake was rinsed with ethanol and then the filtrate was poured into ice/water (3.5 L). A precipitate formed which was collected by filtration, washed with water and dried in an oven at 60 C. to afford 30.7 g (84%) of 4-methoxyanthranilic acid, m.p. 176-178 C. (dec.).
30.7 g (84%)
In palladium; N,N-dimethyl-formamide;
(a) 2-Nitro-4-methoxybenzoic acid (43.4 g, 0.22 mol) in DMF (250 ml) is hydrogenated at 55 psi in the presence of 10% palladium on carbon (5.8 g) for 2.5 hours. The reaction mixture is filtered through SUPERCELL, the filter cake is rinsed with ethanol, and then the filtrate is poured into ice water (3.5 L). A precipitate forms which is collected by filtration, washed with water and dried in an oven at 60 C. to afford 30.7 g (84%) of 4-methoxyanthranilic acid, m.p. 176-178 C. (dec.).
With sulfuric acid; sodium iodide; sodium nitrite; In water;
(b) To a mixture of 50% sulfuric acid (150 ml) and 4-methoxyanthranilic acid (12 g) at 5-10 C. is added sodium nitrite (5.5 g) in water, followed 10 minutes later by NaI (16.5 g) in water (30-50 ml). The reaction mixture is warmed to room temperature and stirred for 2 hours, then is heated at 60-70 C. for 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is extracted with ether (4*125 ml) and the combined ether extracts are washed with water (50 ml*2), dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography on silica gel eluding with ether to afford 12 g of 2-iodo-4-methoxybenzoic acid.
With sulfuric acid; sodium iodide; sodium nitrite; In water;
(b) To a mixture of 50% sulfuric acid (150 ml) and 4-methoxyanthranilic acid (12 g) at 5-10 C. was added sodium nitrite (5.5 g) in water, followed 10 minutes later by NaI (16.5 g) in water (30-50 ml). The reaction mixture was warmed to room temperature and stirred for 2 hours, then was heated at 60-70 C. for 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted with ether (4*125 ml) and the combined ether extracts were washed with water (50 ml*2), dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel eluding with ether to afford 12 g of 2-iodo-4-methoxybenzoic acid.
With hydrogenchloride; potassium iodide; sulfuric acid; In water; toluene;
(b) A mixture of 4-methoxyanthranilic acid (30.5 g, 0.18 mol), water (274.5 ml), and concentrated HCl (36.6 ml) is heated at 75 C. to effect solution and then is cooled to 0 C. The mixture is then treated with NaNO2 (13.3 g) in water (27.5 ml), followed by potassium iodide (45.75 g) in a water (75 ml)/H2SO4 (10.1 ml) solution. The reaction mixture is heated on a steam bath for 2 hours, then excess iodine is steam distilled. The reaction mixture is then cooled, and the product is collected by filtration and dried in an oven at 75 C. to afford 39.28 g (78.6%) of crude product. The crude product is treated with toluene, the mixture is filtered, and the filtrate is concentrated to afford 26.03 g of 2-iodo-4-methoxybenzoic acid.
With hydrogenchloride; potassium iodide; sodium nitrite; In 5-N sulfuric acid; water;
The dihydrochloride melts at 195-197 C. The 10-chloro-10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin used as the starting material can be prepared as follows: 150 G. of 4-methoxy-anthranilic acid are suspended at 0 C. in 2 liters of water and 80 ml. of concentrated hydrochloric acid. A solution of 62 g. of sodium nitrite in 130 ml. of water is added dropwise thereto with stirring at 0-5 C. over a period of 30 minutes. The resulting diazonium salt solution is stirred for an additional 15 minutes at 0-5 C. A solution of 164 g. of potassium iodide in 700 ml. of 5-N sulfuric acid is subsequently added dropwise at 3-6 C. over a period of 45 minutes. The entire mixture is stirred at room temperature for 30 minutes and subsequently warmed slowly to reflux temperature. After boiling at reflux temperature for 2 hours, the mixture is cooled to room temperature. The separated brown crystals are removed by filtration and washed neutral with water. The filter cake is dried under reduced pressure, and there is obtained 2-iodo-4-methoxy-benzoic acid in the form of brown crystals having a melting point of 174 C.
With hydrogenchloride; potassium iodide; sodium nitrite; In 5-N sulfuric acid; water;
150 G. of 4-methoxy-anthranilic acid are suspended at 0 C. in 2 liters of water and 80 ml. of concentrated hydrochloric acid. To this solution is added dropwise with stirring at 0-5 C. over a period of 30 minutes a solution of 62 g. of sodium nitrite in 130 ml. of water. The resulting diazonium salt solution is stirred for an additional 15 minutes at 0-5 C. A solution of 164 g. of potassium iodide in 700 ml. of 5-N sulfuric acid is subsequently added dropwise at 3-6 C. over a period of 45 minutes. Then, the mixture is stirred at room temperature for 30 minutes and heated slowly to reflux. After boiling at reflux for 2 hours, the mixture is cooled to room temperature. The precipitated brown crystals are removed by filtration and washed neutral with water. The filter cake is dried under reduced pressure, and there is obtained 2-iodo-4-methoxy-benzoic acid as brown crystals having a melting point of 174 C.
Prepared according to literature procedure. A solution of 2-amino-4-methoxybenzoic acid (501.5 mg, 3.0 mmol) in Conc. HCl ( 4.00 mL) was stirred at 0 C. Then a solution of sodium nitrite (310.5 mg, 4.5 mmol) in water (1.00 mL) was added. The reaction mixture became orange yellow. After that a solution of potassium iodide (996.0 mg, 6.00 mmol) in water (2.40 mL) was added slowly. The reaction mixture continued to stir at 0 C for 30 minutes. The reaction mixture changed to dark brown, stirred at room temperature, and heated at 90 C for 2 hours. The reaction was completed then cooled at room temperature. The mixture was diluted with water and extracted with EtOAc. The organic extracts were washed iodine with Sat. Na2S2O3 and followed by brine, dried over anhydrous Na2SO4, filtered and concentrated to afford orange solid. 1H NMR (300 MHz, DMSO-d6) delta 7.82 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.08 (dd, J = 8.7, 1.9 Hz, 1H), 3.89 (s, 3H); 13C NMR (75 MHz, DMSO-d6) delta 166.9, 161.4, 132.1, 127.2, 126.2, 113.7, 96.0, 55.7. Other data was identical to the literature values.
A solution of sodium nitrite (105 mg, 1.52 mmol) in water (0.76 mL) was added dropwise to a solution of 2-amino-4-methoxybenzoic acid (127 mg, 0.76 mmol) in a mixture of water (1.9mL), acetone (0.6 mL), and concentrated HCl (0.4 mL) at 0 C. After stirring for 2 h, potassium iodide (252 mg, 1.52 mmol) was added to the mixture. The resulting solution was stirred at 0 C for 0.5 h, heated at 90 C for 10 min, and then allowed to cool to room temperature. The mixture was extracted with CHCl3. The organic layer was washed with saturated aqueous Na2S2O3 and water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-iodo-4-methoxybenzoic acid (829 mg) as a colorless solid, which was suspended in thionyl chloride (1.6 mL). The mixture was heated at reflux with stirring for 2 h. The resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (2.2 mL). To the mixture were added isopropylamine (46 mg, 0.78 mmol) and triethylamine (197 mg, 1.95 mmol) at 0 C under a nitrogen atmosphere. After stirring at room temperature for 17 h, the resulting solution was diluted with EtOAc. The mixture was washed with 10%HCl, saturated aqueous NaHCO3, water, and brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl3 to give 24 (97 mg, 40% in 3 steps) as colorless needles.
To a solution of 2-amino-4-methoxybenzoic acid 33 (5.0 g,0.03 mol) in methanol (50 mL) was added strong sulphuricacid (9 mL). The solution was stirred at reflux for 24 h. Itwas cooled to room temperature and the pH of the mixturewas adjusted to 5~6 with saturated sodium carbonatesolution. The solution was extracted with EA (100 mL*2).The combined organic layers were washed with brine(50 mL), dried over Na2SO4, filtered and concentrated,affording white powder 34 (4.11 g, 75.92%). 34: 1H NMR (400 MHz, CDCl3) 7.81 (d, J = 8.9 Hz, 1 H), 6.25 (dd, J =9.0, 2.5 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.80 (s, 2H), 3.86(s, 3H), 3.81 (s, 3H).
37%
With sulfuric acid;Reflux;
Step a): Methyl 2-amino-4-methoxybenzoate 1000 mg (6.0 mmol) of 2-amino-4-methoxybenzoic acid are reacted according to General Method I. Yield: 400 mg (37% of theory) LC-MS (Method 3): Rt=1.96 min; MS (ESIpos): m/z=182 [M+H]+. 5 mmol of the carboxylic acid are dissolved in 50 ml of methanol, and 5 ml of concentrated sulfuric acid are added. The mixture is heated under reflux for 14-24 h. After cooling to room temperature, the solution is poured onto ice and adjusted to pH 6 using sodium bicarbonate. After addition of 100 ml of dichloromethane, the aqueous phase is separated off and reextracted twice with in each case 50 ml of dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure.
a) A solution of 1.0 g (0.015 mol) of sodium cyanate in 10 ml of water was added dropwise at 70 C. within 10 minutes to a suspension of 1.7 g (0.010 mol) of 2-amino-4-methoxy-benzoic acid in 17 ml of acetic acid. After stirring for a further 10 minutes the white suspension obtained was cooled to room temperature, diluted with water and subsequently suction filtered. The crystals obtained were boiled under reflux for 30 minutes in 15 ml of 37 per cent aqueous hydrochloric acid, cooled, diluted with 75 ml of water, filtered off under suction, rinsed with water and dried in a vacuum. Yield: 0.73 g (37%) of 7-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione as white crystals; m.p. 320-323 C.
(a) A mixture of <strong>[33844-21-2]2-nitro-4-methoxybenzoic acid</strong> (21.9 g, 0.111 mol), 2N ammonium hydroxide (250 ml) and 5% palladium on strontium carbonate (2.5 g) is shaken under 45 psi of hydrogen pressure for 3-4 hours. The reaction mixture is filtered, and the filtrate is acidified with acetic acid. A solid forms which is collected by filtration, washed with water and dried to afford 16 g of 4-methoxyanthranilic acid, m.p. 194-195 C.
With ammonium hydroxide; hydrogen;
(a) A mixture of <strong>[33844-21-2]2-nitro-4-methoxybenzoic acid</strong> (21.9 g, 0.111 mol), 2N ammonium hydroxide (250 ml) and 5% palladium on strontium carbonate (2.5 g) was shaken under 45 psi of hydrogen pressure for 3-4 hours. The reaction mixture was filtered, and the filtrate was acidified with acetic acid. A solid formed which was collected by filtration, washed with water and dried to afford 16 g of 4-methoxyanthranilic acid, m.p. 194-195 C.
With hydrogenchloride; potassium iodide; sodium nitrite; In water; toluene;
(b) A mixture of 4-methoxyanthranilic acid (30.5 g, 0.18 mol), water (274.5 ml), and concentrated HCl (36.6 ml) was heated at 75 C. to effect solution and then was cooled to 0 C. The mixture was then treated with NaNO2 (13.3 g) in water (27.5 ml), followed by potassium iodide (45.75 g) in a water (75 ml)/H2 SO4 (10.1 ml) solution. The reaction mixture was heated on a steam bath for 2 hours, then excess iodine was steam distilled. The reaction mixture was then cooled and the product was collected by filtration and dried in an oven at 75 C. To afford 39.28 g (78.6 %) of crude product. The crude product was treated with toluene, the mixture was filtered and the filtrate was concentrated to afford 26.03 g of 2-iodo-4-methoxybenzoic acid.
ii. Methyl-4-methoxyanthranilate Esterification of 4-methoxy anthranilic acid as described above afforded methyl-4-methoxyanthranilate, M.P. 77-79 C., in 77% yield.
72.6%
In methanol;
c. Methyl 2-amino-4-methoxybenzoate A solution of 2-amino-4-methoxybenzoic acid (11.7 g, 70.0 mM) in methanol (170 mL) was cooled in an ice bath and saturated with hydrogen chloride gas. The resulting solution was refluxed for 18 hr, cooled to room temperature and concentrated. The residue was diluted with saturated agueous bicarbonate and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave the title amino ester (9.2 g, 72.6%) as a tan crystalline solid; MS(CI): 182 (M+H).
iii. 4-Methoxy anthranilic acid (XXII) A solution of <strong>[33844-21-2]4-methoxy-2-nitrobenzoic acid</strong> (19.3 g., 97.9 mmole) in 200 ml. 1 N NH4 OH was reduced overnight in presence of 5% Pd/BaCO3. The reaction mixture was filtered and acidified with acetic acid to yield 15.8 g. (96%) of the anthranilic acid, M.P. 186-188 C.
Method 31; 7-Methoxy-3H-quinazolin-4-one; A mixture of 2-amino-4-methoxy benzoic acid (Method 30; 4.85 g, 88.9 mmol) and formamidine acetate (18.49 g, 177.8 mmol) in 2-methoxyethanol (100 ml) was stirred at reflux for 12 h. The reaction mixture was cooled to 25 C and diluted with 0.01 M ammonia (100 ml). The mixture was then stirred at 25 0C for 30 min and the resulting solid was collected by filtration. The solid was washed with 0.01M ammonia and water. The product was dried by high vacuum to obtain a light brown solid 11.5 g (73%). NMR: 12.10 (s, br, IH), 8.05 (m, 2H), 7.10 (m, 2H), 3.90 (s, 3H); m/z 167.
In ethanol; for 3h;Microwave irradiation;
1), lg (mmol) and 1Og (mmol) of formamidine were added to 20 ml of ethanol, and the microwave reaction3h. After completion of the reaction, the ethanol was dried and extracted with dichloromethane and water to give the crude product. And the compound 2 was isolated by column chromatography on silica gel using dichloromethane-methanol as eluent.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;
To a solution of 2-amino-4-methoxybenzoic acid (4.00 g, 23.93 mmol) in DMF (120 mL) at 0 C was added NBS (4.68 g, 26.3 mmol). The cooling bath was removedand the reaction mixture was warmed up to room temperature and was stirred at room temperature for 1 h. The mixture was cooled to 0 C and was treated with saturated sodium sulfite solution (25 mL) and was stirred for 5 mm. The pH of the mixture was adjusted to pH = 3 using conc. HC1 (ca. 10-15 mL was added). The reaction mixture was transferred to a separatory funnel containing water (100 mL). Theaqueous layer was extracted with ether (1 x 250 mL then 4 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to afford 2-amino-5-bromo-4- methoxybenzoic acid (5.90 g, 100% yield) as a solid: ?H NMR (400 MHz, DMSOd6) oe 7.78 (s, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.90 (s, 1H), 2.74 (s, 1H); MS (ESI) m/e228.0 [(M+H-H2O), calcd for C8H7BrNO2 228.0].
77%
With bromine; acetic acid; at 20 - 40℃; for 18.0h;
2-amino-5-bromo-4-methoxybenzoic acid 2-amino-4-methoxybenzoic acid (5 g, 30 mmol) was suspended in acetic acid (100 mL) and bromine (0.57 mL, 11.25 mmol) added at RT. The mixture was stirred approx. 15 h at RT, then additional bromine (0.2 mL, 3.75 mmol) was added and the reaction mixture held at 40 C. for 3 hours. The reaction course was tracked by thin-film chromatography, the product filtered out and washed with a little water. (Yield: 5.63 g, 77%)
With bromine; In acetic acid; at 0 - 20℃; for 8.0h;
Step 1: 2-Amino-5-bromo-4-methoxybenzoic acidTo a stirred suspension of 2-amino-4-methoxybenzoic acid (5 g, 0.029 mol) in acetic acid (100 mL) was added bromine (1.23 mL, 0.023 mol) dropwise at 0C. The reaction mixture was stirred at room temperature for 8 h. The separated solid was filtered, washed with water (30 mL) and dried under vacuum to afford the product as white solid (6.3 g, 86 %). As per the LC-MS data this solid contains 14% of starting material, 22% of dibromo byproduct and 61% of desired compound.1H NMR (400 MHz, DMSO-de) : delta 7.76 (s, 1H), 6.42 (s, 1H), 3.72 (s, 3H); ESI-MS: Calculated mass: 244.97; Observed mass LC-MS: 246.0 [M + H]+RT: 2.07 min.
1.3 g
With N-Bromosuccinimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 4.0h;
To a mixture of 4-methoxyanthranilic acid (0.67 g, 4.0 mmol) in DCM (10 mL) and DMF (3 mL) was added NBS (0.71 g, 4.0 mmol) at 0 C. The mixture was stirred at room temperature for 4 h, then concentrated and subjected to silica gel chromatography (5-100% EtOAc/Heptane) to provide 2-amino-5-bromo-4-methoxybenzoic acid as a beige solid (1 .30 g, containing 1 equivalent succinamide). MS (M-1 ) = 244.3/246.3. 1H NMR (DMSO-d6) delta 7.76 (s, 1 H), 6.42 (s, 1 H), 3.79 (s, 3H). This material was used without further purification.
With bromine; acetic acid; In acetonitrile; at 0 - 20℃; for 1.0h;Inert atmosphere;
2-Amino-4-methoxybenzoic acid (5.00 g, 29.91 mmol) was dissolved in acetic acid (10 mL) and acetonitrile (100 mL), slowly added dropwise with liquid bromine (4.78 g, 29.91 mmol) at 0 C and under nitrogen protection,, and stirred at 20 C for 1 hour. TLC showed that the reaction was complete. After the reaction solution was concentrated, water (100 ml) and petroleum ether (100 ml) were successively used for making a slurry, which was vaccum dried to obtain compound 1A. 1H NMR (400MHz, DMSO-d6) delta= 7.76 (s, 1H), 6.41 (s, 1H), 3.79 (s, 3H).
In tetrahydrofuran; methanol; diethyl ether; at 0 - 20℃; for 16h;
To a solution of 4-methoxyanthranilic acid (5.0 g, 30.0 mmol) in a mixtue of 10% methanol in tetrahydrofuran (100 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 18.0 mL, 36.0 mmol) at 0 C. The reaction mixture was stirred for 16 hours at room temperature then quenched by the addition of glacial acetic acid (0.1 mL). The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-amino-4-methoxybenzoate as an oil (5.4 g, quantitative). MS (EI) for C9HnNO3: 182 (MH+).
74%
In methanol; toluene; at 0 - 20℃; for 1h;
To a solution of 2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) wasadded trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred atooc for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in5 vacuo. The crude material was purified by column chromatography (0 to 15%EtOAC/hexanes) to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H+]
74%
In methanol; toluene; at 0℃; for 1h;
Step 1. Methyl 2-amino-4-methoxybenzoate: To a solution of 2-amino-4- (methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0C for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude material was purified by column chromatography (0 to 15% EtOAc/hexanes) to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H]+.
74%
In methanol; toluene; at 0℃; for 1h;
To a solution of 2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0C for 1 h. The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude material was purified by column chromatography (0 to 15% EtOAC/hexanes) to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H]+.
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 1.66667h;Inert atmosphere;
General procedure: To a solution of 6-chloroanthranilic acid (1.5 g, 8.74 mmol) in THF (5 mL) was added dropwise 1.08 M borane-tetrahydrofuran complex in THF (24.3 mL, 26.2 mmol) at 0 C under an Ar atmosphere for 10 min. After 1.5 h with stirring at 30 C, the solution was cooled at 0 C, added aqueous THF (THF/H2O = 1:1, 60 mL) and potassium carbonate, and extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was crystallized from AcOEt to give 1a (1.2 g, 88%) as a white needle crystal.
With borane-THF; In tetrahydrofuran; at 0 - 20℃;
Synthesis of (2-amino-4-methoxyphenyl)methanol. To a solution of 2-amino-4-methoxybenzoic acid (15.0 g, 89.8 mmol) in THF (300 mL) was added borohydride in THF (450 mL, 450 mmol) at 0 C, and the reaction mixture was stuffed at RT overnight. LCMS showed the reaction was completed. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (500 mL x3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filteredand concentrated to afford the title compound. MS (ES+) C8H11N02 requires: 153, found: 154 [M+H].
With borane-THF; In tetrahydrofuran; at 0 - 20℃;
To a solution of 2-amino-4-methoxybenzoic acid (15.0 g, 89.8 mmol) in THF (300 mL) was added borohydride in THF (450 mL, 450 mmol) at 0 C., and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (500 mL×3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound. MS (ES+) C8H11NO2 requires: 153, found: 154 [M+H]+.
A mixture of 2-amino-4-methoxybenzoic acid (1 g; 5.98 mmol) and urea (7.18 g; 120 mmol) was stirred at 155C for 16 h. The reaction mixture was cooled to 100C and then 3 mL of water was added. The mixture was cooled to room temperature and was filtered. 30 mL of 1 mol/L NaOH aqueous solution was added to dissolve the precipitate. After one hour, 4.2 mL of acetic acid was added dropwise and the resulting light brown precipitate was filtered and dried. 8 was obtained as a light brown powder (0.55 g; 2.9 mmol; 48 %). 1H NMR (500 MHz; DMSO) delta 11.10 (brs, 1H, HNH), 10.55 (brs, 1H, HNH), 7.8 (d, J=8.63 Hz, 1H, Ha4), 6.77 (dd, J=2.44, 8.84 Hz, 1H, Ha5), 6.64 (d, J=2.43 Hz, 1H, Ha7), 3.82 (s, 3H, Hbl). 13C NMR (125 MHz; DMSO) delta 164.8 (Ca6), 162.8 (Ca2), 151 (Cal), 143.3 (Ca8), 129.3 (Ca4), 111 (Ca5), 108.2 (Ca3), 98.8 (Ca7), 56.1 (Cbl). HRMS-ESI (m/z) calculated for C9H8N203: 193.0489 [M+H]+ ; found: 193.0511
Multi-step reaction with 3 steps
1.1: tetrahydrofuran / 19 h / -10 - 20 °C
2.1: ammonium carbonate / 1,4-dioxane / 60 °C
3.1: sodium nitrite; hydrogenchloride / water; N,N-dimethyl-formamide / 1.67 h / 0 °C
3.2: 0.25 h / pH 10
Multi-step reaction with 3 steps
1.1: tetrahydrofuran / 15 h / -5 - 20 °C
2.1: ammonium carbonate / 1,4-dioxane / 8 h / 60 °C
3.1: hydrogenchloride / 0.33 h / 0 °C
3.2: 2.66 h / 0 °C
3.3: 0.25 h / pH 8
Multi-step reaction with 3 steps
1.1: tetrahydrofuran / 5 h / -5 °C
2.1: ammonium carbonate / 1,4-dioxane / 8 h / 60 °C
3.1: hydrogenchloride / water / 0.33 h / 0 °C
3.2: 2.67 h / 0 °C
3.3: 0.25 h / pH 8
7-methoxy-3-(4-aminosulphonylphenyl)-2-mercapto-3H-quinazolin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With triethylamine; In ethanol; for 3h;Inert atmosphere; Reflux;
General procedure: A suspention of anthranilic acid A1-A17 (0.001mol), a catalytic amount of triethylamine and <strong>[51908-29-3]4-isothiocyanato-benzenesulfonamide</strong> B17b (0.169g, 0.001mol) in absolute ethanol (25ml) was refluxed for 3. The reaction mixture was filtered while hot, left to cool and the solvent was removed under reduced pressure. The obtained residue was triturated from diethyl ether, filtered and dried under vacuo to obtain titled compound C: 1-17 as a whitish solid.
With N-chlorophthalimide; In acetonitrile; at 75.0℃; for 1.0h;
Step 1: N-chlorophthalimide (1.1 equivalent) was added to a solution of the compound 31a (1 equivalent) in acetonitrile, and the mixture was refluxed at 75 C for 1 hour, and the reaction was terminated by TLC.The solvent was directly dried to give a crude product 31c, which was directly used for the next reaction.
With potassium carbonate; In acetone; at 20℃; for 3h;Inert atmosphere;
To a suspension of compound 2-amino-4-methoxybenzoic acid (10 g, 59.8 mmol) in acetone (110 ml) was added K2003 (12.3 g, 89.7 mmol) followed by dimethyl sulfide (7.1 ml, 71.7 mmol) under argon atmosphere. The reaction mixture was stirred at room temperature for 3h. It was diluted with H20 then extracted with ethyl acetate (2 x 200 ml). The combined organic layer was dried over Na2SO4 then concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh), (eluent 0-30% EtOAc in petroleum ether) to afford the title compound If-I as a pale brown solid (7 g, 68% yield). LCMS [M+H] 182.
7-methoxy-2-propyl-4H-benzo[d][1,3]oxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
at 100℃; for 0.75h;Microwave irradiation; Inert atmosphere;
General procedure: A solution of the anthranilic acid (1.0 mmol) in the orthoester (0.45 mL, 2.0-2.7 equivalents) wasprepared in a 5-mL microwave tube and stirred for 30 s prior to irradiation at the "high absorption"setting. The reaction was performed under N2 at 100 C (400 W) for 0.75-3 h. Upon cooling, the crudeproduct crystallized from the reaction mixture and was purified by trituration from 5% ether in pentane.The following compounds were prepared:2-Methyl-4H-benzo[d][1,3]oxazin-4-one (11a): 130 mg (81%, method 1) and 132 mg (82%, method 2)
Multi-step reaction with 9 steps
1.1: triethylamine / dichloromethane / 3 h / 20 °C
2.1: sulfuric acid; nitric acid / 2 h / 20 °C
3.1: water; sodium hydroxide / methanol / 3.5 h / 40 °C
4.1: thionyl chloride / dichloromethane / 2 h / Reflux
4.2: 1 h / 20 °C
5.1: trichlorophosphate / acetonitrile / 4 h / 50 °C
6.1: N,N-dimethyl-formamide / 3.5 h / 70 °C
7.1: 5%-palladium/activated carbon; hydrogen / acetonitrile / 7 h / 30 °C
8.1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / acetonitrile / 0.5 h / 20 °C
8.2: 12 h / 20 °C
9.1: acetic acid / 24 h / 20 °C
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