* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With trichlorophosphate In acetonitrile for 8 h; Reflux
7-methoxyquinazoline-2,4(lH,3H)dione (0.31 g; 1.6 mmol) was added to a solution of POC13(10 mL; 107 mmol) in 3 mL of acetonitrile and the mixture was heated to reflux for 8 h. The mixture was poured into ice water and was vigorously stirred and the resulting precipitate was filtered and dried. The precipitate was filtered through silica using dichloromethane to afford 9 as a white powder (0.201 g; 0.88 mmol; 54 percent). 1H NMR (500 MHz; DMSO) δ 8.1 (d, J=9.21 Hz, 1H, Ha4), 7.44 (dd, J=2.08, 9.26 Hz, 1H, Ha5), 7.38 (d, J=2.07 Hz, 1H, Ha7), 3.99 (s, 3H, Hbl). 13C NMR (125 MHz; DMSO) δ 166.2 (Ca6), 162.17 (Ca2), 158 (Cal), 154.9 (Ca8), 127.7 (Ca4), 122.95 (Ca5), 117.2 (Ca3), 106.5 (Ca7), 57 (Cbl). HRMS-ESI (m/z) calculated for C9H6C12N20: 227.9918 [M+H]+ ; found: 227.9935
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 42, p. 6081 - 6083
[2] Patent: WO2016/151144, 2016, A1, . Location in patent: Page/Page column 56
[3] Journal of the Chemical Society, 1948, p. 1759,1765
[4] Journal of the Chemical Society, 1947, p. 890,894
[5] Patent: US5688803, 1997, A,
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
2
[ 62484-12-2 ]
[ 62484-31-5 ]
Yield
Reaction Conditions
Operation in experiment
0.64 g
Reflux
<Step 2> 2,4-dichloro-7-methoxyquinazoline A mixture of 7-methoxyquinazolin-2,4-diol (3 g, 15.6 mmol) prepared in Step 1 and phosphorus oxychloride (10 ml) was stirred at reflux overnight. After cooling the reaction mixture to room temperature, the same was added into ice water, and basified to pH 7-8 by using sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=10/1) to give the titled compound (0.64 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H), 7.37-7.20 (m, 2H), 3.99 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 7021 - 7032
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 1, p. 144 - 158
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1452 - 1465
[4] Patent: US2016/90374, 2016, A1, . Location in patent: Paragraph 0218; 0219
3
[ 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,
4
[ 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
With trichlorophosphate; In acetonitrile; for 8.0h;Reflux;
7-methoxyquinazoline-2,4(lH,3H)dione (0.31 g; 1.6 mmol) was added to a solution of POC13(10 mL; 107 mmol) in 3 mL of acetonitrile and the mixture was heated to reflux for 8 h. The mixture was poured into ice water and was vigorously stirred and the resulting precipitate was filtered and dried. The precipitate was filtered through silica using dichloromethane to afford 9 as a white powder (0.201 g; 0.88 mmol; 54 %). 1H NMR (500 MHz; DMSO) delta 8.1 (d, J=9.21 Hz, 1H, Ha4), 7.44 (dd, J=2.08, 9.26 Hz, 1H, Ha5), 7.38 (d, J=2.07 Hz, 1H, Ha7), 3.99 (s, 3H, Hbl). 13C NMR (125 MHz; DMSO) delta 166.2 (Ca6), 162.17 (Ca2), 158 (Cal), 154.9 (Ca8), 127.7 (Ca4), 122.95 (Ca5), 117.2 (Ca3), 106.5 (Ca7), 57 (Cbl). HRMS-ESI (m/z) calculated for C9H6C12N20: 227.9918 [M+H]+ ; found: 227.9935
10.8 g (91%)
In ice-water; toluene; trichlorophosphate;
b) 10 g (0.052 mol) of <strong>[62484-12-2]7-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione</strong> were suspended in 72 ml (0.78 mol) of phosphorus oxychloride and heated to 105 C. for 4 hrs. The mixture was left to cool to room temperature, treated with toluene, cautiously poured on to ice-water and filtered over Dicalite. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated and the residue was chromatographed over silica gel with dichloromethane as the eluent. Yield: 10.8 g (91%) of 2,4-dichloro-7-methoxy-quinazoline as white crystals; m.p. 123-124 C.
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.
<Step 2> 2,4-dichloro-7-methoxyquinazoline A mixture of 7-methoxyquinazolin-2,4-diol (3 g, 15.6 mmol) prepared in Step 1 and phosphorus oxychloride (10 ml) was stirred at reflux overnight. After cooling the reaction mixture to room temperature, the same was added into ice water, and basified to pH 7-8 by using sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate=10/1) to give the titled compound (0.64 g) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.12 (d, 1H), 7.37-7.20 (m, 2H), 3.99 (s, 3H).
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
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