* 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.
Intermediate A4: 2-amino-5-(methyloxy)benzamide; 6-methoxy-2/-/-3,1-benzoxazine-2,4(1H)-dione (3.Og, 16 mmol, Trans World Chemicals) was treated directly with 27percent aqueous ammonium hydroxide. After one hour the organic phase was diluted with ethyl acetate, washed twice with aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over sodium sulfate. Filtration and removal of the residual solvent gave 2-amino-5-(methyloxy)benzamide as a white solid (1.42g, 53percent Yield);. 1 H NMR (400 MHz, DMSOd6) δ ppm 3.63 (s, 3 H), 6.07 (s, 2 H), 6.60 (d, J=8.97 Hz, 1 H), 6.79 (dd,J=8.79, 2.93 Hz, 1 H), 7.03 (s, 1 H), 7.06 (d, J=2.93 Hz, 1 H), 7.71 (s, 1 H).
With hydrogenchloride; bis(trichloromethyl) carbonate In water at 20℃; for 4 h;
The 5-methoxyanthranilic acid 2 (30 g,179 mmol)was dissolvedin a mixture of H2O (1.2 L) and conc. HCl (15 mL), and this wasfollowed by the addition of triphosgene (63.8 g, 215 mmol). Thecontents were stirred at rt for 3-4 h until the completion of thereaction (TLC, silica gel). A white solid precipitated from the solutionafter completion. The solids were collected by filtration andwashed with H2O (4 L). The solids were dried under vacuum to givepure anhydride 3 in 89percent (30.7 g) yield: M.p 237-239 °C; 1H NMR(300 MHz, CDCl3) δ 3.65 (s, 3H), 7.11 (d, 1H, J 8.9 Hz), 7.35 (dd, 1H,J 8.9 Hz, 2.7 Hz), 7.19 (d, 1H, J 2.7 Hz),11.61 (bs, 1H). The spectraldata were identical with the reported values [27]. This material wasemployed directly in the next step. Triphosgene is toxic; care mustbe exercised.
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1492 - 1500
[2] Organic Process Research and Development, 2013, vol. 17, # 8, p. 1042 - 1051
[3] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 550 - 560
3
[ 32315-10-9 ]
[ 6705-03-9 ]
[ 37795-77-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 18 h;
General procedure: Toa solution of amino-benzoic acid (2.90 mmol, 1 eq) in anhydrous THF (25 mL), triethylamine (2.90 mmol, 1 eq) was added and the mixture was cooled down to 0°C. Then triphosgene (0.97 mmol, 1 eq) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. 1mL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording pure product.
96%
With triethylamine In tetrahydrofuran at 0 - 20℃;
6-Methoxy-lH-benzo[d] [l,3]oxazine-2,4-dioneTo a solution of 2-amino-5-mefhoxy-benzoic acid (1.2 g, 7 mmol) in anhydrous THF (50 mL) triethylamine (1.0 mL, 7 mmol) was added and the mixture was cooled down to 0°C. Then triphosgene (2.0 g, 7 mmol) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. lmL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording 1.3 g of the titled compound (96percent yield).1H-NMR (d6-DMSO): 3.78 (3H, s); 7.09 (1H, d, J=8.9 Hz); 7.31 (1H, d,J=2.9 Hz); 7.35 (1H, dd, J,= 2.9 Hz, J2= 8.8 Hz); 1 1.59 (1H, s).
90%
for 1 h; Cooling; Reflux
Example Synthesis of 6-Methoxy- lH-benzo [d] [ 1 ,3] oxazine-2 ,4-dione (2); Commercially-available 2-Amino-5-methoxybenzoic acid (20 g, 120 mmol) was dissolved in dioxane (200 mL). Triphosgene (15 g, 50.6 mmol) was added with cooling (during the addition a thick precipitate formed). Dioxane (50 mL) was added to aid mobility. The mixture was heated under reflux for 1 h and then allowed to cool. The resulting precipitate was collected by filtration to afford intermediate 2 as a beige powder (20.8 g, 90percent).1H NMR (D6-DMSO): δ 3.81 (3H, s, CH3), 7.1 1 (1H, d, J= 9 Hz, NHCCHCHCOCH3), 7.34 (1H, d, J= 3 Hz, CH3OCCHCCO), 7.39 (1H, dd, J= 9 and 3 Hz, CHCOCH3CH), 11.6 (1H, 6r s, NH).
90%
for 1 h; Cooling; Reflux
2-Amino-5-methoxy-benzoic acid (20 g, 120 mmol) was dissolved in dioxane (200 mL). Triphosgene (15 g, 50.6 mmol) was added with cooling. During the addition a thick precipitate formed so dioxane (50 mL) was added to aid mobility. The mixture was heated under reflux for 1 h and then allowed to cool. The resulting precipitate was collected by filtration to afford the product as a beige powder (20.8 g, 90percent). 1H NMR (300 MHz, DMSO-d6): δH 3.81 (3H, s, CH3), 7.11 (1H, d, J = 9.0 Hz, NHCCHCHCOCH3), 7.34 (1H, d, J = 3.0 Hz, CH3OCCHCCO), 7.39 (1H, dd, J = 9.0 and 3.0 Hz, CHCOCH3CH), and 11.6 (1H, br s, NH).
89%
With pyridine In dichloromethane; acetonitrile at 50 - 55℃; for 2.33333 h;
Example 13. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; [0176] To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 mL) at 50-550C were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g , 2.96 mmol) in anhydrous dichloromethane (20 mL) over 20 min span, and the reaction was stirred at 50-550C for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude was further washed with ether (20 mL) to give 6-methoxy-1/-/- benzo[c/][1 ,3]oxazine-2,4-dione. Yield: 1.55 g (89percent).[0177] To a flask (100 mL) with magnetic stirrer was added 6-methoxy-1H- benzo[c/][1 ,3]oxazine-2,4-dione (1.55 g, 8.00 mmol), 4-sec-butylaniline (1.19 mL, 8.0 mmol) and anhydrous DMF (10 mL). The reaction mixture was stirred at 115°C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give 2-amino-Λ/-(4-sec-butyl-phenyl)-5-methoxy-benzamide. Yield: 0.90 g (37percent).[0178] To a solution of 2-amino-Λ/-(4-sec-butyl-phenyl)-5-methoxy- benzamide (0.450 g, 1.51 mmol) and 4-(2-hydroxy-ethoxy)-3, 5-dimethyl- benzaldehyde (0.290 g, 1.51 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.610 g, 4.53 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (100 mL) and water (100 mL). After separation, the organic phase was further washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give the title compound as white solid. Yield: 260 mg (36percent). MP 152-154°C. 1H-NMR (400 Hz, CDCI3): δ 7.78 (d, 1 H)1 7.74 (s.1H), 7.40 (m, 1H), 7.14 (m, 2H), 7.08 (m, 2H), 6.94 (s,2H), 3.96 (s, 3H), 3.90 (m, 2H), 3.78 (t, 2H), 2.56 (m, 1 H)1 2.12 (s, 6H), 2.08 (t, 1 H), 1.60 (m, 1 H), 1.50 (m, 2H), 1.20 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.29 (M+1).
88%
at 0 - 20℃; for 5 h; Inert atmosphere
Step 2 6-methoxy-1H-benzo[d][1,3] oxazine-2,4-dione To a solution of 2-amino-5-methoxybenzoic acid (0.9 g, 5.38 mmol) in THF (15 mL) at 0°C was added triphosgene (638 mg, 2.15 mmol). The reaction was stirred at RT for 5h then filtered the insoluble solid. The solid was washed with THF (6 mL) and dried to give 6-methoxy-lH- benzo[d][l,3]oxazine-2,4-dione (0.92 g, 88percent yield) as a light yellow solid. LCMS: MH+ 194 and TR = 1.027 min. Used without further purification
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 526 - 545
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2311 - 2319
[3] Patent: WO2011/42145, 2011, A1, . Location in patent: Page/Page column 48
[4] Organic Letters, 2005, vol. 7, # 23, p. 5285 - 5288
[5] Patent: WO2011/42550, 2011, A1, . Location in patent: Page/Page column 16-17
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 821 - 826
[7] Patent: WO2010/79431, 2010, A2, . Location in patent: Page/Page column 61-63
[8] Patent: WO2016/23826, 2016, A1, . Location in patent: Page/Page column 40; 41
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8858 - 8875
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 16, p. 6434 - 6456
[11] Patent: US2002/103371, 2002, A1,
[12] Patent: WO2015/9930, 2015, A2, . Location in patent: Paragraph 00273-00274
[13] ACS Chemical Neuroscience, 2017, vol. 8, # 5, p. 1004 - 1010
[14] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2006 - 2017
4
[ 75-44-5 ]
[ 6705-03-9 ]
[ 37795-77-0 ]
Yield
Reaction Conditions
Operation in experiment
40%
for 1 h;
To a solution of 2-amino-5-methoxybenzoic acid (HA, 1.34g, 8.00mmol) in 1,4- dioxane (12mL) was added phosgene (20percent in toluene, 1.04g, 10.5mmol). The resulting solution was allowed to stir for 1 hour. A solid precipitate formed and was filtered, rinsed with Et2O, and dried to yield compound 1 IB as a purple solid (0.63g, 40percent).
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1679 - 1688
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 2, p. 295 - 303
[3] Journal of Medicinal Chemistry, 1981, vol. 24, # 6, p. 735 - 742
[4] Medicinal Chemistry Research, 2002, vol. 11, # 9, p. 504 - 537
[5] Patent: WO2009/143049, 2009, A1, . Location in patent: Page/Page column 140
[6] Journal of medicinal chemistry, 1971, vol. 14, # 12, p. 1233 - 1235
[7] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 2075 - 2088
5.00 g (21.6mmol) 2-Bromo-5-methoxy-benzoic acid, 620 mg (4.32mmol) copper (I) bromide and 2.63 g (32.4 mmol) potassium cyanate were dissolved in pyridine and boiled for 30 min. The solvent was removed and the residue was dissolved in 150 ml 2N hydrogen chloride acid and 150 ml ethyl acetate. The organic solvent was treated with water and brine, dried over magnesium sulfate and removed. The residue was digested with methanol. Yield: 2.50 g= 61percent Grey powder
With potassium <i>tert</i>-butylate In tetrahydrofuran at 20 - 25℃; for 1 h; Inert atmosphere
General procedure: Under nitrogen in 500mL dry two-necked flask was added 2-amino-5-chloropyridine (11.98g, 93.19mmol), potassium tert-butoxide (20.91g, 186.38mmol), anhydrous tetrahydrofuran (300mL) at 23 after stirring at 27 ~ clear solution, three times added 5-methoxy-isatoic anhydride (18.00g, 93.19mmol), after the addition was completed, at 23 ~ 27 reaction was stirred 1.0 ~ 1.5h, TLC (V petroleum ether: V ethyl acetate = 2: 1) after completion of the reaction is monitored; was added purified water (50mL) was stirred for 0.5 ~ 1.0h, the reaction solvent was distilled off under reduced pressure, evaporated after completion, ethyl acetate (400mL), saturated sodium carbonate solution ( 400mL), stirred for 10 ~ 15min, phases were separated, the aqueous phase was extracted with ethyl acetate (300mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate was added (100g), dried 2h. By filtration, the filtrate was collected, the solvent evaporated under reduced pressure to give a pale yellow solid (22.05g, 85.20percent).
Reference：
[1] Patent: CN105732490, 2016, A, . Location in patent: Paragraph 0012; 0024; 0025; 0054; 0055; 0056; 0057
To a solution of 2-amino-5-methoxybenzoic acid (HA, 1.34g, 8.00mmol) in 1,4- dioxane (12mL) was added phosgene (20% in toluene, 1.04g, 10.5mmol). The resulting solution was allowed to stir for 1 hour. A solid precipitate formed and was filtered, rinsed with Et2O, and dried to yield compound 1 IB as a purple solid (0.63g, 40%).
2.00 g (10.4 mmol) 6-Methoxy-lH-benzo(d)(l,3)oxazine-2,4-dione were dissolved in dried dimethylformamide and cooled to 0 0C. 324 mg (13.5 mmol) sodium hydride was slowly added (Argon) and the mixture was stirred for 30 min at room temperature. After cooling again to 0 0C 1.92 g (0.85 ml, 13.5 mmol) iodomethane were added. After stirring for 1 h at room temperature the residue was filtrated and washed with water and ethyl ether. Yield: 1.62 g= 75% Grey Powder
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 18h;
General procedure: Toa solution of amino-benzoic acid (2.90 mmol, 1 eq) in anhydrous THF (25 mL), triethylamine (2.90 mmol, 1 eq) was added and the mixture was cooled down to 0C. Then triphosgene (0.97 mmol, 1 eq) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. 1mL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording pure product.
96%
With triethylamine; In tetrahydrofuran; at 0 - 20℃;
6-Methoxy-lH-benzo[d] [l,3]oxazine-2,4-dioneTo a solution of 2-amino-5-mefhoxy-benzoic acid (1.2 g, 7 mmol) in anhydrous THF (50 mL) triethylamine (1.0 mL, 7 mmol) was added and the mixture was cooled down to 0C. Then triphosgene (2.0 g, 7 mmol) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. lmL of H2O was carefully added to the mixture and the solvent was removed under reduced pressure. The residue was precipitated from H2O, affording 1.3 g of the titled compound (96% yield).1H-NMR (d6-DMSO): 3.78 (3H, s); 7.09 (1H, d, J=8.9 Hz); 7.31 (1H, d,J=2.9 Hz); 7.35 (1H, dd, J,= 2.9 Hz, J2= 8.8 Hz); 1 1.59 (1H, s).
90%
In 1,4-dioxane; for 1h;Cooling; Reflux;
Example Synthesis of 6-Methoxy- lH-benzo [d] [ 1 ,3] oxazine-2 ,4-dione (2); Commercially-available 2-Amino-5-methoxybenzoic acid (20 g, 120 mmol) was dissolved in dioxane (200 mL). Triphosgene (15 g, 50.6 mmol) was added with cooling (during the addition a thick precipitate formed). Dioxane (50 mL) was added to aid mobility. The mixture was heated under reflux for 1 h and then allowed to cool. The resulting precipitate was collected by filtration to afford intermediate 2 as a beige powder (20.8 g, 90%).1H NMR (D6-DMSO): delta 3.81 (3H, s, CH3), 7.1 1 (1H, d, J= 9 Hz, NHCCHCHCOCH3), 7.34 (1H, d, J= 3 Hz, CH3OCCHCCO), 7.39 (1H, dd, J= 9 and 3 Hz, CHCOCH3CH), 11.6 (1H, 6r s, NH).
90%
In 1,4-dioxane; for 1h;Cooling; Reflux;
2-Amino-5-methoxy-benzoic acid (20 g, 120 mmol) was dissolved in dioxane (200 mL). Triphosgene (15 g, 50.6 mmol) was added with cooling. During the addition a thick precipitate formed so dioxane (50 mL) was added to aid mobility. The mixture was heated under reflux for 1 h and then allowed to cool. The resulting precipitate was collected by filtration to afford the product as a beige powder (20.8 g, 90%). 1H NMR (300 MHz, DMSO-d6): deltaH 3.81 (3H, s, CH3), 7.11 (1H, d, J = 9.0 Hz, NHCCHCHCOCH3), 7.34 (1H, d, J = 3.0 Hz, CH3OCCHCCO), 7.39 (1H, dd, J = 9.0 and 3.0 Hz, CHCOCH3CH), and 11.6 (1H, br s, NH).
89%
With pyridine; In dichloromethane; acetonitrile; at 50 - 55℃; for 2.33333h;Product distribution / selectivity;
Example 13. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; [0176] To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 mL) at 50-550C were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g , 2.96 mmol) in anhydrous dichloromethane (20 mL) over 20 min span, and the reaction was stirred at 50-550C for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude was further washed with ether (20 mL) to give 6-methoxy-1/-/- benzo[c/][1 ,3]oxazine-2,4-dione. Yield: 1.55 g (89%).[0177] To a flask (100 mL) with magnetic stirrer was added 6-methoxy-1H- benzo[c/][1 ,3]oxazine-2,4-dione (1.55 g, 8.00 mmol), 4-sec-butylaniline (1.19 mL, 8.0 mmol) and anhydrous DMF (10 mL). The reaction mixture was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give 2-amino-Lambda/-(4-sec-butyl-phenyl)-5-methoxy-benzamide. Yield: 0.90 g (37%).[0178] To a solution of 2-amino-Lambda/-(4-sec-butyl-phenyl)-5-methoxy- benzamide (0.450 g, 1.51 mmol) and 4-(2-hydroxy-ethoxy)-3, 5-dimethyl- benzaldehyde (0.290 g, 1.51 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.610 g, 4.53 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (100 mL) and water (100 mL). After separation, the organic phase was further washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give the title compound as white solid. Yield: 260 mg (36%). MP 152-154C. 1H-NMR (400 Hz, CDCI3): delta 7.78 (d, 1 H)1 7.74 (s.1H), 7.40 (m, 1H), 7.14 (m, 2H), 7.08 (m, 2H), 6.94 (s,2H), 3.96 (s, 3H), 3.90 (m, 2H), 3.78 (t, 2H), 2.56 (m, 1 H)1 2.12 (s, 6H), 2.08 (t, 1 H), 1.60 (m, 1 H), 1.50 (m, 2H), 1.20 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.29 (M+1).
88%
In tetrahydrofuran; at 0 - 20℃; for 5h;Inert atmosphere;
Step 2 6-methoxy-1H-benzo[d][1,3] oxazine-2,4-dione To a solution of 2-amino-5-methoxybenzoic acid (0.9 g, 5.38 mmol) in THF (15 mL) at 0C was added triphosgene (638 mg, 2.15 mmol). The reaction was stirred at RT for 5h then filtered the insoluble solid. The solid was washed with THF (6 mL) and dried to give 6-methoxy-lH- benzo[d][l,3]oxazine-2,4-dione (0.92 g, 88% yield) as a light yellow solid. LCMS: MH+ 194 and TR = 1.027 min. Used without further purification
20.9 g (94%)
In 1,4-dioxane;
Step 1 6-Methoxy-2H-3,1-benzoxazine-2,4(1H)-dione This intermediate is known3 and may be prepared by methods, known in the art, for example in the following way: 2-Amino-5-methoxybenzoic acid (19.3 g, 115 mmol) was dissolved in dioxane (200 mL), treated with bis(trichloromethyl)carbonate (11.3 g, 38 mmol) and refluxed for 1 h. The suspension was cooled to rt, the crystals filtered off and washed with dioxane (20 mL). The mother liquor was evaporated and the residue crystallized from ethyl acetate. Yield: 20.9 g (94%). mp 244 C. (dec). m/z 193 (M).
In 1,4-dioxane; at 0 - 90℃; for 2h;
6-methoxy-2H-benzo[(i][l,3]oxazine-2,4(lH)-dione 39 [00274] (Cl3CO)2CO (1.0 mmol) was added to a suspension of 2-amino-5-methoxybenzoic acid 38 (3.0 mmol) in 1 ,4-dioxane (3 mL) at 0 C. The homogeneous reaction mixture was heated to 90 C for 2h and then cooled down. The resulting precipitate 39 was isolated by filtration. . MS ESI (m/z) 192 (M-l); 1H NMR (400 MHz, DMSO-d6) delta 11.61 (s, IH), 7.38 (dd, IH, Ji=2.8, J2=8.4 Hz), 7.34 (d, IH, J=2.4 Hz), 7.11 (d, IH, J=8.4 Hz), 3.80 (s, 3H)
In tetrahydrofuran; at -5 - 20℃; for 15h;
General procedure: A mixture of anthranilic acid (40 mmol) and tetrahydrofuran (THF, 100 mL) was stirred at -5 C for 30 min. Then, triphosgene (40 mmol) was dissolved in THF (20 mL) and added dropwise to the above mixture. After that, the mixture was stirred for 5 h at -5C, followed by 10 h at room temperature. The solvent was removed under reduced pressure, and the residue was washed with ether, and dried to afford compound 2 in yield of 85-95%.
[12-1] Synthesis of 6-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (Compound <12-2>) To the solution of 2-amino-5-methoxybenzoic acid (0.5 g, 3 mmol) dissolved in 1,4-dioxane (5 ml), triphosgene (0.3 g, 1 mmol) was added, and the solution was refluxed for 2 hours. The reaction mixture was cooled in an ice container. The solid was washed with hexane and was under vacuum drying to obtain a pure compound of 0.53 g (92%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) delta 11.61 (s, 1H), 7.38 (dd, J=8.8, 2.9 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 3.80 (s, 3H).
A mixture of 5-methoxyisotoic anhydride 3 (30.7 g, 158.9 mmol)and L-proline (20.2 g, 174.8 mmol) in dry DMSO (300 mL) washeated with stirring at 160 C for 2 h. The white turbid reactionmixture which resulted, became a clear brown solution as thetemperaturewas increased above 80 C. After the completion of thereaction on examination by TLC (silica gel), the solution was cooledto rt. The mixture was poured into 250 mL of ice water to yieldbenzodiazepine 4 as a white solid. The solids were collected by vacuum filtration and washed with ice cold water (2 50 mL). Thefiltrate was extracted with ethyl acetate and the solvent wasremoved under reduced pressure to yield solid diazepine 4. Thecombined solids were dried in a vacuum oven at 80 C for 4 h. Theyield of 4 was 96% (37.9 g): M.p 214-216 C; [a]D25 444.40 (c1%, in CH2Cl2); 1H NMR (300 MHz, CDCl3) delta 1.82e2.01 (m, 3H),2.50-2.51 (m, 1H), 3.40-3.49 (m, 1H), 3.56-3.63 (m, 1H), 3.78 (s,3H), 4.07-4.10 (m, 1H), 7.07 (d, 1H, J 8.7 Hz), 7.13 (dd, 1H,J 8.7 Hz, 3.0 Hz), 7.26 (d, 1H, J 3.0 Hz), 10.30 (bs, 1H). Thespectral data were identical to the reported values [27]. This materialwas employed directly in the next step.
With cetyltrimethylammonim bromide; triphenylphosphine; In acetonitrile; at 60℃; under 760.051 Torr; for 24h;
General procedure: First of all, water of 0.5mL (In the case of Ex. No. 1) oran organic solvent ( In the case of Ex. Nos. 2 to 17) was charged into thereaction vessel, and orthoazide benzoate used in the reaction (81.6mg :0.0005mol), Orthoazide benzoic acid withan equivalent amount (0.0005mol) triphenylphosphine (131.2mg: 0.0005mol) and1.5 times equivalent amount(0.00075mol) CTMABr of orthoazide benzoic acid wereadded to this solvent and the mixture wasstirred for 5 minutes at 20 .Thereafter, water or pH7.6 potassium dihydrogen phosphate (KH2P04)/ sodium hydroxide (NaOH) buffer solution 4.5mL was added and the reactionsystem was made as an aqueous solvent, and reaction vessel was degassed, and after the reaction vessel was made as a carbondioxide atmosphere using a balloon inflated with carbon dioxide, it was allowed to react with stirring under the conditions of 20, 18 hours.
In the same manner, from the appropriate amino benzoic acids, the following compounds are synthesised: 6-methylisatoic anhydride, 6-methoxyisatoic anhydride, and 6-trifluoromethylisatoic anhydride, 5-methylisatoic anhydride, 5-methoxyisatoic anhydride, and 5-trifluoromethylisatoic anhydride. 3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione
64
[ 20839-79-6 ]
[ 37795-77-0 ]
4-(2,4-Dimethoxy-benzyl)-7-methoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39 g (92%)
In para-xylene;
Step 2 4-(2,4-Dimethoxy-benzyl)-7-methoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione 6-Methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (23 g, 119 mmol) and (2,4-dimethoxy-benzylamino)-acetic acid 1 (27 g, 120 mmol) were suspended in p-xylene (500 mL) and heated under argon at reflux (140 C.) for 2 h. The hot solution was allowed to cool to rt, while spontaneous crystallization occurred. The crystals were filtered off and washed with p-xylene (50 mL). Yield: 39 g (92%). mp 196 C. m/z 356 (M).
3-[4-(1H-Imidazol-1-yl)butyl]-6-methoxy-1,2,3-benzotriazin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 45 3-[4-(1H-Imidazol-1-yl)butyl]-6-methoxy-1,2,3-benzotriazin-4(3H)-one The above compound is obtained when 5-methoxyisatoic anhydride is reacted with imidazole-1-butanamine by the procedure of Example 41.
Example 103 3-[4-(1H-Imidazol-1-yl)butyl]-6-methoxy-1,2,3-benzotriazin-4(3H)-one The above compound is obtained when 5-methoxyisatoic anhydride is reacted with imidazole-1-butanamine by the procedure of Example 99.
With hydrogenchloride; potassium hydroxide; triethylamine; In water ethanol; N,N-dimethyl-formamide;
EXAMPLE 4 2-Amino-6-methoxy-4-hydroxyquinoline To a solution of malononitrile (6.0 g., 0.91 mole) and triethylamine (9.2 g., 0.091 mole) in N,N-dimethylformamide (50 ml.) at 55-60 C. is added rapidly, and with stirring, a solution of 5-methoxy isatoic anhydride in N,N-dimethylformamide (100 ml.). The reaction mixture is maintained at 55-60 C. during addition. Carbon dioxide is evolved and the reaction mixture is stirred for a half-hour following completion of addition without application of further heating. The clear solution is poured into 0.2 N of cold hydrochloric acid (1015 ml.) and the resulting precipitate separated by filtration and dried: 16.5 g.; m.p. >370 C. A portion of said product (1.08 g.) is added to 6 N potassium hydroxide solution (20 ml.) and the mixture heated to reflux for about 18 hours. The clear, dark solution formed is cooled and acidified with acetic acid. The dark brown solid which precipitates is filtered, taken up in ethanol-water (1:2, 30 ml.) and the solution made alkaline with ammonium hydroxide. The resulting solid is filtered and dried. Yield=710 mg. (69%); m.p. 298-300 C. MS: m/e=190 (m+). Analysis: Calc'd for C10 H10 N2 O2: C, 63.14; H, 5.30; N, 14.73%. Found: C, 62.85; H, 5.23; N, 14.56%.
With hydrogenchloride; potassium hydroxide; triethylamine; In water ethanol; N,N-dimethyl-formamide;
EXAMPLE 4 2-Amino-6-methoxy-4-hydroxyquinoline To a solution of malononitrile (6.0 g., 0.91 mole) and triethylamine (9.2 g., 0.091 mole) in N,N-dimethylformamide (50 ml.) at 55-60 C. is added rapidly, and with stirring, a solution of 5-methoxy isatoic anhydride in N,N-dimethylformamide (100 ml.). The reaction mixture is maintained at 55-60 C. during addition. Carbon dioxide is evolved and the reaction mixture is stirred for a half-hour following completion of addition without application of further heating. The clear solution is poured into 0.2 N of cold hydrochloric acid (1015 ml.) and the resulting precipitate separated by filtration and dried; 16.5 g.; m.p. >370 C. A portion of said product (1.08 g.) is added to 6 N potassium hydroxide solution (20 ml.) and the mixture heated to reflux for about 18 hours. The clear, dark solution formed is cooled and acidified with acetic acid. The dark brown solid which precipitates is filtered, taken up in ethanol-water (1:2, 30 ml.) and the solution made alkaline with ammonium hydroxide. The resulting solid is filtered and dried. Yield=710 mg (69%); m.p. 298-300 C. MS: m/e=190 (m+). Analysis: Calc'd for C10 H10 N2 O2: C, 63.14; H, 5.30; N, 14.73%. Found: C, 62.85; H, 5.23; N, 14.56%.
copper(I) bromide; In pyridine; for 3h;Heating / reflux;
5.00 g (21.6mmol) 2-Bromo-5-methoxy-benzoic acid, 620 mg (4.32mmol) copper (I) bromide and 2.63 g (32.4 mmol) potassium cyanate were dissolved in pyridine and boiled for 30 min. The solvent was removed and the residue was dissolved in 150 ml 2N hydrogen chloride acid and 150 ml ethyl acetate. The organic solvent was treated with water and brine, dried over magnesium sulfate and removed. The residue was digested with methanol. Yield: 2.50 g= 61% Grey powder
Intermediate A4: 2-amino-5-(methyloxy)benzamide; 6-methoxy-2/-/-3,1-benzoxazine-2,4(1H)-dione (3.Og, 16 mmol, Trans World Chemicals) was treated directly with 27% aqueous ammonium hydroxide. After one hour the organic phase was diluted with ethyl acetate, washed twice with aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over sodium sulfate. Filtration and removal of the residual solvent gave 2-amino-5-(methyloxy)benzamide as a white solid (1.42g, 53% Yield);. 1 H NMR (400 MHz, DMSOd6) delta ppm 3.63 (s, 3 H), 6.07 (s, 2 H), 6.60 (d, J=8.97 Hz, 1 H), 6.79 (dd,J=8.79, 2.93 Hz, 1 H), 7.03 (s, 1 H), 7.06 (d, J=2.93 Hz, 1 H), 7.71 (s, 1 H).
With ammonium carbonate; In 1,4-dioxane; at 60℃; for 8h;
General procedure: A suspension of isatoic anhydride (35 mmol), ammonium carbonate (140 mmol), and 1,4-dioxane (150 mL) was heated at 60 C. After stirring for 8 h, the reaction mixture was cooled to room temperature and evaporated underreduced pressure, and then water (200 mL) was added to the residue, which was extracted with DCM (80 mL × 3). The organic layerwas dried over anhydrous Na2SO4, and concentrated to give compound 3 in yield of 84%.
With ammonium carbonate; In 1,4-dioxane; at 60℃; for 8h;
General procedure: A suspension of substituted isatoic anhydride (35 mmol), ammonium carbonate (140 mmol), and 1,4-dioxane (150 mL) was heated at 60 C. After stirring for 8 h, the reaction mixture was cooled to room temperature and evaporated under reduced pressure, and then water (200 mL) was added to the residue, which was extracted with CH2Cl2 (380 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give compounds 9 in yields of 63-94%.
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 10: (S)-2-[l-(l,4-Dimethyl-lH-indol-3-ylmethyl)-6-methoxy-2,4-dioxo-l,4- dihydro-2H-quinazolin-3-yl] -hexanoic acidTo a mixture of 5-methoxy-isatoic anhydride (1.0 g, 5.18 mmol) and (S)-2-amino-hexanoic acid methyl ester hydrochloride (1.4 g, 7.71 mmol) (prepared according to example A) in DMF (10 <n="50"/>mL) is added triethylamine (2.0 niL, 11.48 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and washed with H2O (50 mL x3). The organic layer is dried over sodium sulfate, concentrated and the residue is purified by flash chromatography with 60% EtOAc in Hexane as the eluent to afford (S)-2-(2-amino-5- methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 27%).
To a solution of 1 IB (0.63g, 3.3mmol) in acetonitrile (10 mL) was added aminodiphenylmethane (0.7 Ig, 3.9mmol), and the solution was heated to 80 0C for 2.5 hours. The reaction was allowed to cool to room temperature, then partitioned between EtOAc (4OmL) and 5% aqueous citric acid (40 mL). The EtOAc layer was separated, washed with H2O, washed with saturated aqueous NaHCO3, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to yield compound 11C as a tan solid (0.86g, 78%).
In N,N-dimethyl-formamide; at 115℃; for 16h;Inert atmosphere;
Example 16. Preparation of 3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; [0184] To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 ml_) at 50-550C were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g , 2.96 mmol) in anhydrous dichloromethane (20 ml_) over 20 minute span, and the reaction was stirred at 50- 55C for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 ml_) and dried. The crude product was further washed with ether (20 mL) to give 6-methoxy-1 H- benzo[cO[1 ,3]oxazine-2,4-dione. Yield: 1.40 g (81 %).[0185] A solution of 6-methoxy-1 H-benzo[c/][1 ,3] oxazine-2, 4-dione (0.800 g, 4.10 mmol) and 4-bromoaniline (0.750 g, 4.30 mmol) in anhydrous DMF (10 mL) was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated, backwashed with brine (50 mL), and concentrated. The residue was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 : 1 ) to give 2- amino-Lambda/-(4-bromo-phenyl)-5-methoxy-benzamide. Yield: 0.240 g (18%).[0186] To a solution of 2-amino-/V-(4-bromo-phenyl)-5-methoxy-benzamide (0.240 g, 0.740 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.145 g, 0.740 mmol) in anhydrous ethanol (20 ml_) was added anhydrous copper (II) chloride (0.298 g, 2.22 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 ml_) and water (100 ml_). After separation the organic phase was further backwashed with water (100 ml_), brine (100 mL), dried over sodium sulfate, and concentrated. The crude was purified by column chromatography (SiO2, hexane / ethyl acetate = 1 : 1 ) to give the title compound as white solid. Yield: 120 mg (33%). MP 160-1620C. 1H-NMR (400 Hz, CDCI3): delta 7.74 (d, 1 H), 7.69 (s, 1 H), 7.46 (d, 2H), 7.40 (m, 1 H), 7.03 (d, 2H), 6.96 (s, 2H)1 3.94 (s, 3H)1 3.91 (m, 2H), 3.82 (t, 2H), 2.17 (s, 6H), 2.05 (t, 1 H). MS (ES+) m/z: 497.41 (M+1).
In N,N-dimethyl-formamide; at 115℃; for 16h;Inert atmosphere;
Example 13. Preparation of 3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; [0176] To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 mL) at 50-550C were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g , 2.96 mmol) in anhydrous dichloromethane (20 mL) over 20 min span, and the reaction was stirred at 50-550C for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude was further washed with ether (20 mL) to give 6-methoxy-1/-/- benzo[c/][1 ,3]oxazine-2,4-dione. Yield: 1.55 g (89%).[0177] To a flask (100 mL) with magnetic stirrer was added 6-methoxy-1H- benzo[c/][1 ,3]oxazine-2,4-dione (1.55 g, 8.00 mmol), 4-sec-butylaniline (1.19 mL, 8.0 mmol) and anhydrous DMF (10 mL). The reaction mixture was stirred at 115C for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give 2-amino-Lambda/-(4-sec-butyl-phenyl)-5-methoxy-benzamide. Yield: 0.90 g (37%).[0178] To a solution of 2-amino-Lambda/-(4-sec-butyl-phenyl)-5-methoxy- benzamide (0.450 g, 1.51 mmol) and 4-(2-hydroxy-ethoxy)-3, 5-dimethyl- benzaldehyde (0.290 g, 1.51 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.610 g, 4.53 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (100 mL) and water (100 mL). After separation, the organic phase was further washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel (230-400 mesh) using hexane / ethyl acetate = 1 :1 to give the title compound as white solid. Yield: 260 mg (36%). MP 152-154C. 1H-NMR (400 Hz, CDCI3): delta 7.78 (d, 1 H)1 7.74 (s.1H), 7.40 (m, 1H), 7.14 (m, 2H), 7.08 (m, 2H), 6.94 (s,2H), 3.96 (s, 3H), 3.90 (m, 2H), 3.78 (t, 2H), 2.56 (m, 1 H)1 2.12 (s, 6H), 2.08 (t, 1 H), 1.60 (m, 1 H), 1.50 (m, 2H), 1.20 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.29 (M+1).
trans-1-[4-(4-aminomethylcyclohexanecarbonyl)piperazin-1-yl]-2-methylpropan-1-one[ No CAS ]
[ 37795-77-0 ]
trans-2-amino-N-[4-(4-isobutyrylpiperazine-1-carbonyl)cyclohexylmethyl]-5-methoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In acetonitrile; at 50℃; for 16h;
2-Amino-N-[ir /i5-4-(4-isobutyryl-piperazine-l-carbonyl)cyclohexyl methyl]-5-methoxy-benzamideTo a solution of 6-Methoxy- lH-benzo[d][l,3]oxazine-2,4-dione (96 mg, 0.5 mmol) in CH3CN (5 mL) K2CO3 (140mg, 1 mmol) and l-[ trans-A-{A- Aminomethyl-cyclohexanecarbony l)-piperazin- 1 -y l]-2-mefhyl-propan- 1 -one (148 mg, 0.5 mmol) were added and the reaction was heated at 50C for 16h. The solvent was removed under reduced pressure, 5 mL of 0.4M Na2CO3 solution were added and the mixture was stirred for lh. Then 5 mL of DCM were added, the organic phase collected, dried over Na2SO4 and the solvent removed under reduced pressure. 156 mg of the titled product were obtained (yield = 68%).C24H36N4O4 Mass (calculated) [444.6]; found [M+H+]=445.3Lc RT=3.55 (method a)
With potassium carbonate; In acetonitrile; at 50℃; for 16h;
General procedure: To a solution of isatoic anhydride (0.5 mmol) in CH3CN(5 mL), K2CO3 (1 mmol) and the desired primary amine (0.5mmol) were added and the reaction was heated at 50C for 16h. The solvent wasremoved under reduced pressure, 5 mL of 0.4M Na2CO3solution were added and the mixture was stirred for 1h. Then 5 mL of DCM wereadded, the organic phase collected, dried over Na2SO4 andthe solvent removed under reduced pressure.
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