CN103204817B - 4‑氰基喹唑啉衍生物的制备方法 - Google Patents

4‑氰基喹唑啉衍生物的制备方法 Download PDF

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CN103204817B
CN103204817B CN201310129952.9A CN201310129952A CN103204817B CN 103204817 B CN103204817 B CN 103204817B CN 201310129952 A CN201310129952 A CN 201310129952A CN 103204817 B CN103204817 B CN 103204817B
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quinazoline
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tolysulfonyl
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CN103204817A (zh
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彭以元
赵旭
杨琴
丁秋平
卢乃浩
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Jiangxi Normal University
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Abstract

本发明是一种4‑氰基喹唑啉衍生物的制备方法。该方法步骤为：采用以喹唑酮为原料先与对甲苯磺酰氯反应生成4‑对甲苯磺酸喹唑啉酯，然后以氰化亚铜为氰基源，在醋酸钯及1,1'‑双(二苯基膦)二茂铁配体作用下反应高效制得4‑氰基喹唑啉衍生物。本发明方法反应条件温和，操作简便，成本较低，副反应少，产品纯度高，便于分离提纯，可适合于较大规模的制备，产物结构骨架具有广谱的生物活性，这类化合物在新药研发中具有非常好的应用前景。

Description

4-氰基喹唑啉衍生物的制备方法
技术领域
本发明属有机化学技术领域，具体涉及一种4-氰基喹唑啉衍生物的制备方法。
背景技术
众所周知，喹唑啉及其衍生物具有广谱生物活性，在农药和医药等领域得到了广泛的关注与应用，得到了广大研究者的追捧。喹唑啉衍生物存在两种分子骨架，三种结构形式(Figure 1) ：喹唑啉 A、4( 3H)- 喹唑啉酮B及4- 羟基喹唑啉C，其中 B 和C 是互变异构体。结构上在2，3，4，5，6 ，7，8- 位可以有不同的取代基，它们构成了一大类含喹唑啉骨架的衍生物；天然的生物碱分子中很多都含有喹唑啉骨架。研究发现喹唑啉衍生物表现出多种生物活性，如有催眠、镇静、止痛、抗惊厥、止咳嗽、消炎、降血压、抗菌、抗过敏症、抗肿瘤等（(a) Johne, S. Rodd’s Chemistry of Carbon Compounds (second supplementsto the 2nd ed.); Sainsbury, M., Ed.; Elsevier: Amsterdam, 2000; Vol. IV I/J,pp 203–2 31; (b) Brown, D. J. Quinazolines. In The Chemistry of HeterocyclicCompounds (supplement I); Wiley: New York, NY, 1996 ; Vol. 55; (c) Connolly,D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61,10153; (d) Mhaske, S. B. Argade, N. P. Tetrahedron 2006, 62, 9798; (e)Michael, J. P. Nat. Prod. Rep. 2003, 20, 476; (f) Michael, J. P. Nat. Prod.Rep. 2005, 22, 627)。最近发现这类化合物可望用作有机小分子探针，用于对帕金森症和老年痴呆症等神经退化疾病的治疗、诊断、分类和程度的分析(Okamura, N.; Suemoto,T.; Furumoto, S.; Suzuki, M.; Shimadzu, H.; Akstsu, H.; Yamamoto, T.;Fujiwara, H.; Nemoto, M.; Maruyama, M.; Arai, H.; Yanai, K.; Sawada, T.;Kudo, Y.; J. Neurosci. 2005, 25, 10857）。长期以来喹唑啉酮的改性一直吸引了广大的研究者的广泛关注。早在1869年Griess, P. 合成了第一个喹唑啉酮化合物：2-氰基喹唑啉酮（(a) Griess, P. Ber. 1869, 2 , 415; (b) Griess, P. Ber. 1878, 11, 1985）,经过研究发现其为组织蛋白酶K抑制剂并且在医学上可用于治疗其中牵涉组织蛋白酶K的疾病或医学状况，例如各种病症，包括炎症，类风湿关节炎，骨关节炎，骨质疏松症或肿瘤（Heteroaryl nitrile derivatives, US2009/0227596 A1, Sep. 10, 2009, patent），经过改性的喹唑啉可以有不同的生物活性。
基于此，本发明旨在使用醋酸钯为催化剂，从4-对甲苯磺酰喹唑啉与CuCN出发，经过亲核取代首次合成2-烃基-4-氰基喹唑啉衍生物，提供了一种高效合成的新技术。
发明内容
本发明目的在于提供一种4-氰基喹唑啉衍生物的制备方法。
本发明内容为在甲苯中使用Pd(OAc)2为催化剂，1,1'-双(二苯基膦)二茂铁为配体，Cs2CO3为碱，在80 o C条件下4-对甲苯磺酰喹唑啉与CuCN发生取代加成反应生成4-氰基喹唑啉衍生物。该方法高效制得4-氰基喹唑啉衍生物。反应方程式如下：
其中，化合物4-对甲苯磺酰喹唑啉的R1为H、CH3，R2为烷基、芳基、杂环芳基等基团。
具体操作为：在氮气保护下依次将原料化合物4-对甲苯磺酸喹唑啉酯、CuCN、醋酸钯、碳酸铯、以及配体1,1'-双(二苯基膦)二茂铁置于一干燥洁净的试管中，加入甲苯做溶剂，将反应液置于80℃油浴中，在氮气保护下反应10-16 h, TLC检测原料完全消失；减压条件下将溶剂旋干，采用石油醚与乙酸乙酯体积比为30:1，经硅胶柱层析分离，得到所需产物；其中4-对甲苯磺酰喹唑啉与CuCN的摩尔比为1:2；4-对甲苯磺酰喹唑啉与催化剂的摩尔比为1:0.05；其中4-对甲苯磺酰喹唑啉与配体的摩尔比为1:0.1；4-对甲苯磺酰喹唑啉与碱的摩尔比为1:2。
反应体系所使用的配体为1,1'-双(二苯基膦)二茂铁。
反应所使用的催化剂体系为醋酸钯及1,1'-双(二苯基膦)二茂铁的物质的量的摩尔比为1:2。
反应所使用的碱为Cs2CO3，其用量为4-对甲苯磺酰喹唑啉的两倍。
反应所使用有机溶剂为甲苯。
在本发明中，反应效率可高达94%。反应的原子经济性很高，体现出了良好的绿色化过程。本发明反应操作简便，底物的适用性良好，条件很温和，产物的收率高而且纯度也高，有利于分离和提纯，可适用于较大规模的生产和制备。产物结构骨架具有广泛的生物活性，因此在新药的研发中有非常好的应用前景。
具体实施方式
实例1
在氮气保护下将原料化合物2-(4-甲基)-4-对甲苯磺酰喹唑啉、CuCN、醋酸钯、碳酸铯、以及配体1,1'-双(二苯基膦)二茂铁置于一干燥洁净的试管中，加入甲苯做溶剂，将反应液置于80℃油浴中，在氮气保护下反应10-16 h, TLC检测原料完全消失；减压条件下将溶剂旋干，采用石油醚与乙酸乙酯体积比为30:1硅胶柱层析分离。得到纯净的目标产物(2a)：2-(4-甲基)-4氰基喹唑啉(2-p-tolylquinazoline-4-carbonitrile)。产率: 92%。
1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.4 Hz, 2H), 8.23 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.01 (t, J = 7.7 Hz, 1H), 7.75 (t, J = 7.7H z, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ161.1, 151.8, 143.4, 141.9, 135.6, 133.7, 129.6, 129.4, 129.1 , 128.7, 124.9,122.9, 114.5, 21.56; HRMS calcd for C16H11N3 + [M + H]+ 246.1031, found 246.1042.
同样的方法得到实例2-20
实例2
2b. 2-m-tolylquinazoline-4-carbonitrile
化合物2b为黄色固体，熔点 154-156 ℃; 收率 86 %; 1H NMR (400 MHz, CDCl3)δ 8.29-8.28 (m, 2H), 8.15 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.92(dd, J = 8.0,7.2 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H),7.25 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.0,151.7, 143.4, 138.6, 136.2, 135.7, 132.4, 129.4, 129.3, 129.2, 128.8, 125.9,124.9, 122.9, 114.5, 21.6; IR (KBr) ν 2922, 2237, 1616, 1546, 1462, 789, 768,726 cm-1；HRMS calcd for C16H12N3 + [M + H]+ 246.1031, found 246.1046.
实例3
2c. 2-o-tolylquinazoline-4-carbonitrile
化合物2c为黄色固体，熔点 156-157 ℃; 收率 78 %; 1H NMR (400 MHz, CDCl3)δ 8.30 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 7.6 Hz,1H), 8.02 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.44-7.35 (m, 3H),2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ163.7, 151.4, 143.1, 138.1, 136.6,135.8, 131.7, 131.2, 130.2, 129.8, 129.5, 126.2, 124.9, 122.4, 114.5, 21.5;HRMS calcd for C16H12N3 + [M + H]+ 246.1031, found 246.1042.
实例4
2d. 2-phenylquinazoline-4-carbonitrile
化合物2d为黄色固体，熔点 171-172 ℃; 收率 78%; 1H NMR (400 MHz, CDCl3)δ 8.63 – 8.62 (m, 2H), 8.26 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H),8.04 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.57-7.53 (m, 3H); 13C NMR(100 MHz, CDCl3) δ 161.0, 151.8, 143.5, 136.4, 135.7, 131.6, 129.5, 129.4,128.8, 128.8, 125.0, 123.1, 114.5; IR (KBr) ν 2924, 2236, 1599, 1485, 767,704 cm-1; HRMS calcd for C15H10N3 + [M + H]+ 232.0875, found 232.0880.
实例5
2e. 2-(benzo[d][1,3]dioxol-5-yl)quinazoline-4-carbonitrile
化合物2e为黄色固体，熔点 229-230 ℃; 收率 80%; 1H NMR (400 MHz, CDCl3)δ 8.25-8.20 (m, 2H), 8.13-8.09 (m, 2H), 8.01 (d, J = 7.2Hz, 1H), 7.74 (t, J =7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.08 (s, 2H); 13C NMR (100 MHz, CDCl3)δ 160.5, 151.8, 150.7, 148.5, 143.3, 135.7, 130.9, 130.8, 129.3, 129.0,128.8, 124.9, 124.1, 122.8, 114.5, 101.7; IR (KBr) ν 3072, 2925, 2235, 1598,1274, 1026, 875, 769, 574 cm-1. HRMS calcd for C16H10N3O2 + [M + H]+ 276.0773,found 276.0794.
实例6
2f. 2-(4-(dimethylamino)phenyl)quinazoline-4-carbonitrile
化合物2f为红色固体，熔点 194-195 ℃; 收率 85%; 1H NMR (400 MHz, CDCl3)δ8.48 (d, J = 8.8 Hz, 2H), 8.15 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.8 Hz,1H), 7.93 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 9.2 Hz,2H), 3.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.5, 152.7, 152.0, 143.3,135.3, 130.2, 129.0, 128.0, 124.9, 123.9, 122.4, 114.7, 111.7, 40.2; IR (KBr)ν 2919, 2236, 1606, 1371, 1187, 824, 776 cm-1; HRMS calcd for C17H15N4 + [M + H]+275.1297, found 275.1274.
实例7
2g. 2-(pyridin-4-yl)quinazoline-4-carbonitrile
化合物2g为黄色固体，熔点 177-178 ℃; 收率 94%; 1H NMR (400 MHz, CDCl3)δ 8.91 (brs, 2H), 8.48 (s, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4Hz, 1H), 8.11 (t, J = 7.8 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz,CDCl3) δ 158.9, 151.6, 150.8, 143.7, 143.5, 136.2, 130.6, 129.8, 125.1,123.6, 122.3, 114.1; IR (KBr) ν 2919, 2241, 1613, 1394, 847, 774, 538 cm-1;HRMS calcd for C14H9N4 + [M + H]+ 233.0827, found 233.0805.
实例8
2h. 2-(furan-2-yl)quinazoline-4-carbonitrile
化合物2h为黄色固体，熔点 192-192 ℃; 收率 86%; 1H NMR (400 MHz, CDCl3)δ 8.21 (d, J = 8.4 Hz, 2H), 8.05-8.00 (m, 1H), 7.78-7.72 (m, 2H), 7.54-7.53(m, 1H), 6.65 (t, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.8, 151.5,151.2, 146.3, 143.7, 136.2, 129.3, 129.2, 125.2, 122.7, 116.0, 114.1, 112.7;IR (KBr) ν 2924, 2239, 1615, 1414, 845 cm-1; HRMS calcd for C13H8N3O+ [M + H]+222.0667, found 222.0668.
实例9
2i. 2-(4-chlorophenyl)quinazoline-4-carbonitrile
化合物2i为黄色固体，熔点 182-183 ℃; 收率 70%; 1H NMR (400 MHz, CDCl3)δ 8.56 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz,1H), 8.04 (t, J = 7.8 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz,2H); 13C NMR (100 MHz, CDCl3) δ 160.0, 151.7, 143.5, 137.9, 135.9, 134.8,130.1, 129.6, 129.5, 129.1, 125.0, 123.0, 114.34; IR (KBr) ν 2919, 2237,1596, 1406, 841 cm-1. HRMS calcd for C15H9ClN3 + [M + H]+ 266.0485, found266.0504.
实例10
2j. 2-(4-fluorophenyl)quinazoline-4-carbonitrile
化合物2j为黄色固体，熔点 171-172 ℃; 收率 65%; 1H NMR (400 MHz, CDCl3)δ 8.64 (dd, J = 8.4, 6.0 Hz, 2H), 8.25 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.8Hz, 1H), 8.04 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 8.8Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 165.2 (d, 1 J C-F = 251 Hz), 160.1, 151.7,143.5, 135.9, 132.6, 131.0 (d, 3 J C-F = 9 Hz), 129.5, 129.4, 125.0, 123.0,115.9 (d, 2 J C-F = 22 Hz), 114.4. IR (KBr) ν 2919, 2236 1602, 1406, 1235, 845,800, 766, 531 cm-1; HRMS calcd for C15H9FN3 + [M + H]+ 250.0781, found 250.0763.
实例11
2k. 2-(3-chlorophenyl)quinazolone-4-carbonitrile
化合物2k为白色固体，熔点 187-188 ℃; 收率 63%; 1H NMR (400 MHz, CDCl3)δ 8.61 (s, 1H), 8.50 (d, J = 6.4 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.18 (d,J = 8.4 Hz, 1H), 8.06 (t, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.50-7.48 (m,2H); 13C NMR (100 MHz, CDCl3) δ 159.1, 151.1, 143.0, 137.6, 135.5,134.6, 131.0, 129.6, 129.3, 129.0, 128.2, 126.3, 124.5, 122.7, 113.8; IR(KBr) ν 2924, 2236, 1614, 1545, 1430, 890, 786, 766, 724 cm-1;HRMS calcd forC15H9ClN3 + [M + H]+ 266.0485, found 266.0506.
实例12
2l. 2-(2,5-dichlorophenyl)quinazoline-4-carbonitrile
化合物2l为白色固体，熔点 190-191℃; 收率 54%; 1H NMR (400 MHz, CDCl3) δ8.35 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.13 (t, J = 7.8 Hz, 1H),7.95 - 7.87 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.4, 2.4 Hz,1H); 13C NMR (100 MHz, DMSO) δ 160.4, 151.4, 143.3, 137.7, 136.2, 133.0,132.1, 132.0, 131.7, 131.1, 130.7, 129.6, 125.0, 122.9, 114.1; IR (KBr) ν2924, 2237, 1613, 1542, 1338, 1048, 889, 814, 769 cm-1; HRMS calcd forC15H8Cl2N3 + [M + H]+ 300.0095, found 300.0118.
实例13
2m. 2-styrylquinazoline-4-carbonitrile
化合物2m为黄色固体，熔点 151-153 ℃; 收率 65%; 1H NMR (400 MHz, CDCl3)δ8.21 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.99 (t, J= 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.44 –7.35 (m, 3H), 7.35 (s, 1H); 13C NMR (100 MHz, CDCl3)δ 161.3, 151.6, 143.3,140.5, 135.8 135.7, 129.6, 129.2, 129.0, 128.9, 127.9, 126.3, 125.1, 122.7,114.3; IR (KBr) ν 2922, 2236, 1613, 1543, 1366, 755, 685 cm-1; HRMS calcd forC17H12N3 + [M + H]+ 258.1031, found 258.1044.
实例14
2n. 2-propylquinazoline-4-carbonitrile
化合物2n为黄色固体，熔点 67-68 ℃; 收率 72%; 1H NMR (400 MHz, CDCl3) δ8.23 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.02 (t, J = 7.6 Hz, 1H),7.77 (t, J = 7.6 Hz, 1H), 3.15 (t, J = 7.6, 2H), 2.17 – 1.87 (m, 2H), 1.04(t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 150.8, 142.8, 135.1,128.7, 128.3, 124.4, 122.2, 113.9, 40.9, 21.5, 13.4; IR (KBr) ν 3035, 2925,2872, 2234, 779 cm-1; HRMS calcd for C12H12N3 + [M + H]+ 198.1031, found 198.1046.
实例15
2o. 7-methyl-2-phenylquinazoline-4-carbonitrile
化合物2o为白色固体，熔点 194-195 ℃; 收率 80%; 1H NMR (400 MHz, CDCl3)δ 8.58 (s, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.58-7.54 (m, 4H); 13CNMR (100 MHz, CDCl3) δ161.0, 152.0, 147.3, 142.8, 136.5, 131.8, 131.4, 128.8,128.7, 128.2, 124.5, 121.4, 114.6, 22.5; IR (KBr) ν 3058, 2234, 1600, 1487,825, 771, 703cm-1; HRMS calcd for C16H12N3 + [M + H]+ 246.1031, found 246.1028.
实例16
2p. 2-(4-fluorophenyl)-7-methylquinazoline-4-carbonitrile
化合物2p为白色固体，熔点 214-215 ℃; 收率 85%; 1H NMR (400 MHz, CDCl3)δ 8.59 (t, J = 8.0 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.58 (d,J = 8.4 Hz, 1H), 7.21 (t, J = 8.0 Hz, 2H), 2.65 (s, 3H); 13C NMR (100 MHz,CDCl3) δ 165.1 (d, 1 J C-F = 251 Hz), 160.0, 151.9, 147.5, 142.8, 132.7, 131.9,130.8 (d, 3 J C-F = 8 Hz), 128.1, 124.6, 121.3, 115.8 (d, 2 J C-F = 22 Hz), 114.5,22.5; IR (KBr) ν 3067, 2927, 2239, 1601, 1452, 1225, 848, 788, 504cm-1; HRMScalcd for C16H11FN3 + [M + H]+ 264.0937, found 264.0949.
实例17
2q. 7-methyl-2-(pyridin-4-yl)quinazoline-4-carbonitrile
化合物2q为黄色固体，熔点 174-175 ℃; 收率 90%; 1H NMR (400 MHz, CDCl3)δ 8.83 (brs, 2H), 8.40 (s, 2H), 8.13 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.66(d, J = 8.4 Hz, 1H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 151.7,150.7, 148.1, 143.6, 142.9, 132.9, 128.4, 124.6, 122.2, 121.9, 114.3, 22.5;IR (KBr) ν 3061, 2923, 2234, 1600, 1394, 847, 774, 538 cm-1; HRMS calcd forC15H11N4 + [M + H]+247.0984 found 247.0975.
实例18
2r. 5-fluoro-2-(pyridin-4-yl)quinazoline-4-carbonitrile
化合物2r为棕色固体，熔点 166-168 ℃; 收率 91%; 1H NMR (400 MHz, CDCl3)δ 8.90 (brs, 2H), 8.48 (s, 2H), 8.08-8.03 (m, 2H), 7.54-7.49 (m, 1H); 13C NMR(100 MHz, CDCl3) δ 159.6, 156.1 (d, 1 J C-F = 262 Hz), 152.6, 150.5, 142.6,138.9, 136.3 (d, 2 J C-F = 9 Hz), 125.9 (d, 3 J C-F = 4 Hz), 115.2, 114.6 (d, 2 J C-F =19 Hz), 114.5, 114.3.
实例19
2s. 2-(4-cyanophenyl)quinazoline-4-carbonitrile
化合物2s为黄色固体，熔点 226-227 ℃; 收率 57%; 1H NMR (400 MHz, CDCl3)δ 8.76 (d, J = 8.4 Hz, 2H), 8.31 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.4 Hz,1H), 8.10 (t, J = 7.8 Hz, 1H), 7.87 (t, J = 8.4 Hz, 3H); 13C NMR (100 MHz,CDCl3) δ 159.0, 151.6, 143.7, 140.3, 136.2, 132.6, 130.4, 129.7, 129.2,125.1, 123.3, 118.5, 114.8, 114.2; IR (KBr) ν 2923, 2225, 1610, 1453, 1263,855, 801, 768, 552 cm-1; HRMS calcd for C16H9N4 + [M + H]+ 257.0827, found257.0841.
实例20
2t. 2-(4-methoxyphenyl)quinazoline-4-carbonitrile
化合物2t为黄色固体，熔点 192-193 ℃; 收率 58% ; 1H NMR (400 MHz, CDCl3)δ 8.51 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.8 Hz,1H), 7.95 – 7.90 (m, 1H), 7.66 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H),3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 159.8, 150.8, 142.4, 134.6,129.5, 128.2, 128.1, 127.8, 123.9, 121.7, 113.5, 113.2, 54.4; IR (KBr) ν3066, 2926, 2838, 2225, 1606, 1585, 1254, 1028, 840, 534 cm-1; HRMS calcd forC16H11N3NaO+ [M + Na]+ 284.0800, found 284.0791。

Claims (1)

1.一种4-氰基喹唑啉衍生物的制备方法，其特征在于，具体操作为：在氮气保护下依次将原料化合物4-对甲苯磺酸喹唑啉酯、CuCN、醋酸钯、碳酸铯以及配体1,1'-双(二苯基膦)二茂铁置于一干燥洁净的试管中，加入甲苯做溶剂，将反应液置于80℃油浴中，在氮气保护下反应10-16h，TLC检测原料完全消失；减压条件下将溶剂旋干，采用石油醚与乙酸乙酯体积比为30:1，经硅胶柱层析分离，得到所需产物；其中，4-对甲苯磺酰喹唑啉与CuCN的摩尔比为1:2；4-对甲苯磺酰喹唑啉与醋酸钯的摩尔比为1:0.05；4-对甲苯磺酰喹唑啉与配体的摩尔比为1:0.1；4-对甲苯磺酰喹唑啉与碳酸铯的摩尔比为1:2；
所述的4-对甲苯磺酸喹唑啉酯的结构通式为：
其中，R1为H或CH3，R2为烷基、芳基或杂环芳基。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101717350A (zh) * 2009-12-08 2010-06-02 南京工业大学 水溶液中芳基氰化物的合成方法
CN101878203A (zh) * 2007-10-29 2010-11-03 纳科法尔马有限公司 作为抗癌剂的新的4-(四唑-5-基)喹唑啉衍生物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9238643B2 (en) * 2010-09-06 2016-01-19 Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences Amide compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101878203A (zh) * 2007-10-29 2010-11-03 纳科法尔马有限公司 作为抗癌剂的新的4-(四唑-5-基)喹唑啉衍生物
CN101717350A (zh) * 2009-12-08 2010-06-02 南京工业大学 水溶液中芳基氰化物的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A Mild and Efficient Palladium-Catalyzed Cyanation of Aryl Mesylates in Water or tBuOH/Water;Pui Yee Yeung et al.;《Angew.Chem.Int.Ed.》;20101008;第49卷;第8918-8922页 *
Preparation of Heteroarenecarbonitriles by Reaction of Haloheteroarenes With Potassium Cyanide Catalyzed By Sodium p-Toluenesulflnate;Akira Miyashita et al.;《Heterocycles》;19941231;第39卷(第1期);第345-356页 *

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