* 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: With 2,2'-iminobis[ethanol] In water for 0.0333333 h; Autoclave Stage #2: at 100℃; for 12 h; Autoclave
Weigh 0.763 g (5 mmol) of 2-amino-4-chlorobenzonitrile was placed in a polytetrafluoroethylene liner of a stainless steel reactor and3 mL of a diethanolamine aqueous solution having a concentration of 1.33 mol / L was added and stirred for 2 minutes , The carbon dioxide was heated and the temperature was raisedto 100 ° C, and the carbon dioxide pressure was adjusted to 1 MPa for the carboxylation reaction under stable conditions for 12 hours.Antiupon end, the reaction system was cooled to room temperature slowly released unreacted carbon dioxide, was added 10mL of deionized water and stirreddispersion product, resulting precipitate was filtered and washed with a small amount of distilled water, and then 15mL / wash three times with methyl tert-butyl ether Andthe product was dried at a temperature of 100 ° C to give the product 7-chloroquinazoline-2,4 (1H, 3H) -dione in a yield of 62percent.
62%
With {Eu[N(SiMe3)2](μ-O:κ2-C6H5C(O)NC6H3(iPr)2)(THF)}2; 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 100℃; for 24 h;
In anhydrous, anaerobic, argon protection,0.0999 g (7.5 x 10-5 mol) of {L2Eu [N (SiMe3) 2] THF} 2 was added to the reaction flask,An additional 11.2 μL (7.5 × 10 -5 mol) of DBU,Under the protection of carbon dioxide bag, add 2mL dimethyl sulfoxide,Further, 0.2949 g (1.5 x 10-3 mol) of 2-amino-4-chlorobenzonitrile was added,The reaction was stirred in a constant temperature bath at 100 ° C.After 24h, add 5mL2mol / L hydrochloric acid to quench the reaction, and then suction filtered,The solid was washed with 3 × 5 mL of hydrochloric acid, then with toluene and then with diethyl ether. The residual solvent was removed and the solid was dried to give the product in 62percent yield.
Reference：
[1] ChemSusChem, 2018, vol. 11, # 24, p. 4219 - 4225
[2] RSC Advances, 2015, vol. 5, # 20, p. 15668 - 15673
[3] Synthesis, 2007, # 16, p. 2524 - 2528
[4] RSC Advances, 2015, vol. 5, # 7, p. 5032 - 5037
[5] Green Chemistry, 2014, vol. 16, # 6, p. 3142 - 3148
[6] Chemistry - An Asian Journal, 2016, vol. 11, # 19, p. 2735 - 2740
[7] Tetrahedron, 2002, vol. 58, # 16, p. 3155 - 3158
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 23, p. 5922 - 5925[9] Angew. Chem., 2014, vol. 53-126, # 23, p. 6032 - 6035
[10] Heteroatom Chemistry, 2012, vol. 23, # 3, p. 276 - 280
[11] Canadian Journal of Chemistry, 2019, vol. 97, # 3, p. 212 - 218
[12] Catalysis Science and Technology, 2014, vol. 4, # 6, p. 1608 - 1614
[13] Green Chemistry, 2013, vol. 15, # 6, p. 1485 - 1489
[14] RSC Advances, 2014, vol. 4, # 92, p. 50993 - 50997
[15] ChemSusChem, 2017, vol. 10, # 6, p. 1080 - 1084
[16] Green Chemistry, 2014, vol. 16, # 1, p. 221 - 225
[17] Tetrahedron Letters, 2004, vol. 45, # 38, p. 7073 - 7075
[18] European Journal of Organic Chemistry, 2016, vol. 2016, # 14, p. 2555 - 2559
[19] Patent: CN106946800, 2017, A, . Location in patent: Paragraph 0026-0027
[20] Patent: CN105153048, 2017, B, . Location in patent: Paragraph 0130; 0131
[21] Tetrahedron, 2010, vol. 66, # 23, p. 4063 - 4067
[22] Inorganic Chemistry, 2012, vol. 51, # 23, p. 13001 - 13008
[23] RSC Advances, 2016, vol. 6, # 112, p. 111079 - 111089
2
[ 57-13-6 ]
[ 89-77-0 ]
[ 13165-35-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 200℃; for 1 h;
Step A: Preparation of 7-chloro-1H-quinazoline-2,4-dione. A mixture of 2-amino-4-chlorobenzoic acid (2.00 g, 11.6 mmol) and urea (2.80 g, 46.6 mmol) was heated to 200° C. for 1 h. The mixture was allowed to cool to room temperature and the resulting mass was triturated well with water. The product was collected by filtration (2.30 g, 100percent). The MS and NMR data are in agreement with those that have been previously described: Organic Process Research and Development, 2003, 7, 700-706. 1H NMR (600 MHz, DMSO-d6): 12.00 (br s, 2H), 8.59-8.53 (m, 1H), 7.93-7.80 (m, 2H).
Reference：
[1] Patent: US2010/204226, 2010, A1, . Location in patent: Page/Page column 22
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7268 - 7274
[3] Tetrahedron, 1997, vol. 53, # 25, p. 8457 - 8478
[4] Patent: DE931845, 1952, ,
[5] Pharmaceutical Chemistry Journal, 1987, vol. 21, # 7, p. 478 - 483[6] Khimiko-Farmatsevticheskii Zhurnal, 1987, vol. 21, # 7, p. 802 - 807
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3075 - 3093
[8] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
3
[ 89-77-0 ]
[ 13165-35-0 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1759,1765
[2] Patent: US5688803, 1997, A,
[3] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 8, p. 824 - 829
4
[ 38487-86-4 ]
[ 68-12-2 ]
[ 13165-35-0 ]
Reference：
[1] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2067 - 2073
5
[ 590-28-3 ]
[ 89-77-0 ]
[ 13165-35-0 ]
Reference：
[1] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 431 - 433
6
[ 214288-97-8 ]
[ 13165-35-0 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1759,1765
[2] Organic Process Research and Development, 2003, vol. 7, # 5, p. 700 - 706
[3] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 8, p. 824 - 829
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In acetonitrile; for 36h;Reflux;
Step B: Preparation of 2,4,7-trichloroquinazoline. A mixture of 7-chloro-1H-quinazoline-2,4-dione (2.0 g, 10 mmol) was suspended in ACN (50 mL), then POCl3 (5.0 mL, 55 mmol) was added. This was followed by addition of DIEA (5.0 mL, 28 mmol). The resulting mixture was heated to reflux for 36 h, and then allowed to cool to rt and concentrated. The residue was carefully treated with ice and sodium bicarbonate. The resulting solid was collected by filtration and dried. Chromatographic purification (EtOAc/hexanes 0:100 to 10:90) provided the titled compound (2.1 g, 89%). The MS and NMR data are in agreement with those that have been previously described: Bioorganic & Medicinal Chemistry, 2003, 11, 2439-2444. 1H NMR (400 MHz, DMSO-d6): 8.32 (d, J=8.7 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.93 (dd, J=9.0, 2.1 Hz, 1H).
In ice-water; trichlorophosphate;
b) 10.5 g (0.053 mol) of 7-chloro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were suspended in 35 ml (0.48 mol) of phosphorus oxychloride and heated to 120 C. for 24 hrs. The reaction mixture was left to cool to room temperature and poured on to ice-water. The brown precipitate was filtered off under suction, dried and chromatographed over silica gel with methylene chloride as the eluent. There were obtained: 7.2 g (58%) of 2,4,7-trichloroquinazoline as yellow crystals; MS: me/e=232, 234 (M+).
3.88 g
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; for 4h;Reflux;
<Step 2> 2,4,7-trichloroquinazoline Diisopropylethylamine (9.21 ml, 52.9 mmol) was added to a mixture of 7-chloroquinazoline-2,4(1H,3H)-dione (5.2 g, 26.5 mmol) prepared in Step 1 and phosphorus oxychloride (26 ml), and they were stirred at reflux for 4 hours. 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 (dichloromethane) to give the titled compound (3.88 g) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.22 (d, 1H), 8.01 (s, 1H), 7.68 (d, 1H).
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