C-2苯环上取代基对喹唑啉-4-酮烷基化的影响及化合物抗肿瘤、抗菌活性

引用本文: 王淑霞, 高梦颖, 谭官海, 马海霞, 赵莹莹, 杜鸿源, 王总帅, 陈华, 李小六. C-2苯环上取代基对喹唑啉-4-酮烷基化的影响及化合物抗肿瘤、抗菌活性[J]. 有机化学, 2017, 37(2): 385-393. doi: 10.6023/cjoc201608031 shu

Citation: Wang Shuxia, Gao Mengying, Tan Guanhai, Ma Haixia, Zhao Yingying, Du Hongyuan, Wang Zongshuai, Chen Hua, Li Xiaoliu. Effects of the Substituent at C-2 Phenyl on the N-/O-Alkylation of Quinazolin-4(3H)-one and Anti-Tumor, Antimicrobial Activities of Some Compounds[J]. Chinese Journal of Organic Chemistry, 2017, 37(2): 385-393. doi: 10.6023/cjoc201608031 shu

C-2苯环上取代基对喹唑啉-4-酮烷基化的影响及化合物抗肿瘤、抗菌活性

河北大学化学与环境科学学院河北省化学生物学重点实验室保定 071002

通讯作者: 陈华, E-mail: hua-todd@163.com; 李小六, E-mail: lixl@hbu.cn

基金项目:
国家自然科学基金 21372060

河北省自然科学杰出青年基金（培育） B2015201005

摘要: 邻氨基苯甲酰胺与取代苯甲醛反应，合成了含氨烷基侧链的喹唑啉-4-酮4和5，探讨了C-2位苯环取代基对喹唑啉-4-酮内酰胺N-/O-烷基化的影响，并评价了部分化合物的抗肿瘤细胞增殖活性及抑菌活性.结果表明，当C-2苯环上的取代基在邻位时，N-烷基化反应为主；而在间位或对位时，以O-烷基化为主，立体效应起到了主导作用.4-{2-{{2-[3-（苄氧基）苯基]喹唑啉-4-基}氧基}乙基}吗啉（4h）具有较好的抗肺癌细胞增殖活性，IC₅₀值为13.20 μmol/L.2-（2-氯苯基）-3-[2-（哌啶-1-基）乙基]喹唑啉-4（3H）-酮（5aa）和2-[3-（苄氧基）苯基]-4-[2-（吡咯啉-1-基）乙氧基]喹唑啉（4hb）（50 μg/mL）对大肠杆菌和痢疾杆菌具有显著的抑制活性，抑菌率分别为100%，100%和100%，96%.化合物5aa对链铬孢菌真菌的抑制率为100%.

关键词:

English

Effects of the Substituent at C-2 Phenyl on the N-/O-Alkylation of Quinazolin-4(3H)-one and Anti-Tumor, Antimicrobial Activities of Some Compounds

Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002

Corresponding author: Chen Hua, hua-todd@163.com; Li Xiaoliu, lixl@hbu.cn

Received Date: 31 August 2016
Revised Date: 08 October 2016
Fund Project:
National Natural Science Foundation of China

the Natural Science Fund for Distinguished Young Scholars of Hebei Province (Incubation)

Abstract: A series of quinazolin-4(3H)-one derivatives 4 and 5 possessing amino alkyl side chain were synthesized by the condensation reaction of 2-aminobenzamide with substituted benzaldehyde, followed by S_N2 substitution reaction with haloalkane. The effects of the substituent at C-2 phenyl on the N-/O-alkylated reaction of quinazolin-4(3H)-one were explored. Some compounds were also evaluated for their anti proliferation activities and antimicrobial activities. The results showed that when the substituent was at orth O-position on C-2 phenyl, N-alkylation was the main reaction, while at meta-or para-positions, O-alkylation was predominant, which suggested that the steric factor played a key role on this ambident nuclophilic substitution. 4-(2-((2-(3-(Benzyloxy) phenyl) quinazolin-4-yl) oxy) ethyl) morpholine (4h) showed relatively good anti-proliferative activity against A549 tumor cells with the IC₅₀ value of 13.20 μmol/L. 2-(2-Chlorophenyl)-3-(2-(piperidin-1-yl) ethyl) quinazolin-4(3H)-one (5aa) and 2-(3-(benzyloxy) phenyl)-4-(2-(pyrrolidin-1-yl) ethoxy) quinazoline (4hb) exhibited significant anti Esche-richia coli or Shigella castellani activities, and the inhibition rates were near 100% at the concentration of 50 μg/mL. The inhi-bition rate of compound 5aa against Alternaria alternate was 100%.

Key words:

喹唑啉-4-酮是一类广谱的药效基团, 其衍生物多具有抗菌、抗炎、抗疟疾、抗结核、抗肿瘤和抗病毒等作用^[1~3].其中C-2和N-3取代基的结构各异赋予了喹唑啉-4-酮衍生物多样的生物活性^[4~6].因此, 喹唑啉-4-酮的合成及生物活性研究备受关注^[7].喹唑啉-4-酮环内酰胺的烷基化为两可亲核反应, 通常易发生在N-3位^[8], 但受到C-2位取代基立体效应和电子效应的影响, 常伴随有O-(4-羰基烯醇化) 烷基化产物生成^[9], 同时烷基的大小也会影响到N-/O的烷基化^[10].

在我们之前的研究中发现, 当C-2上取代基是苯^[11]、3-羟基苯、4-甲基香豆素时, 其烷基化反应以O烷基化为主; 而当C-2上是3, 4-苯并香豆素时, 则以N-烷基化为主 (图 1).以上结果显示, C-2位苯环上的取代基不同也会造成喹唑啉-4-酮环内酰胺的N-/O烷基化产物比例不同, 而这方面的研究还鲜有报道^[9].因此, 本工作以不同单取代的苯甲醛为原料, 合成了系列吗啉乙烷基化^[12]的喹唑啉-4-酮衍生物 (Scheme 1), 探讨了C-2位苯环单取代基对N-/O-烷基化的影响.鉴于此类化合物的广谱生物活性, 还对部分化合物的抗肿瘤细胞增殖、抗菌活性进行了初步评价.

图 1 C-2位不同芳环取代对喹唑啉-4-酮N-/O-烷基化的影响 Figure 1. Effects of the different substituents at C-2 phenyl on the N-/O-alkylation of quinazolin-4(3H)-one

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图图式1 N-/O-烷基化产物4和5的合成 Figure 图式1. Synthesis of the N-/O-alkylated products 4 and 5

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1 结果与讨论

1.1 化合物3a~3k的烷基化

如Scheme 1所示, 以邻氨基苯甲酰胺1和不同单取代的苯甲醛2为原料, 在二甲基亚砜 (DMSO) 中^{[13, 14]}, 一步简便合成了连有3, 4-苯并香豆素的喹唑啉-4-酮中间体3, 再经与氯乙基吗啉发生S_N2亲核取代 (烷基化) 反应得到目标产物酰胺O(4-羰基烯醇化)4a~4k和N-(3位) 烷基化产物5a~5k.

由表 1可知, 当C-2苯环上的取代基处在邻位时, 烷基化产物以N-烷基化为主, 尤其是R为2-OCH₃时, 只得到N-烷基化产物, 通过薄层色谱 (TLC) 和核磁共振 (¹H NMR) 未检测到O烷基化产物.当取代基在间位或对位时, 烷基化产物以O烷基化为主.吸电基团或供电基团对N-/O烷基化影响不大.以上结果表明, C-2位苯环单取代基对喹唑啉-4-酮内酰胺N-/O烷基化的影响主要体现在其位置上, 即立体效应的影响比电子效应的影响更大.提示C-2苯环上取代基较大的空间位阻, 如邻位, 有利于N-烷基化反应发生.这也较好地解释了之前的实验中, 当C-2上取代基是4-甲基香豆素 (相当于是苯环有间、对位取代, 图 1), 其烷基化反应以O烷基化为主; 而如果是3, 4-苯并香豆素 (苯环有邻、间位取代, 图 1), 则以N-烷基化产物为主.

表 1 化合物3a~3k的烷基化 Table 1. Alkylation of compounds 3a~3k

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Compd.	R	总产率^a/%	Yield/%		4:5
Compd.	R	总产率^a/%	4	5	4:5
a	2-Cl	62.3	10.7	51.6	1:4.8
b	2-CH₃	93.6	21.8	71.8	1:3.3
c	2-F	36.8	5.2	31.6	1:6.1
d	2-OCH₃	91.0	—^b	91.0	0:1
e	3-Cl	88.9	80.6	8.3	9.7:1
f	3-F	91.3	76.3	15.0	5.1:1
g	3-Br	93.1	81.0	12.1	6.7:1
h	3-OBn	87.0	77.2	9.8	7.9:1
i	4-Cl	82.5	82.5	—	＞10:1^c
j	4-CN	87.3	70.5	—	4.2:1^c
k	4-CH₂CH₃	94.8	71.1	23.7	2.6:1^c
^a分离产率; ^b未分离到; ^c由¹H NMR确定.

表 1 化合物3a~3k的烷基化
Table 1. Alkylation of compounds 3a~3k

1.2 化合物3a和3h的烷基化

出于生物活性筛选的考虑, 进一步改变了氨烷基链上的氨基, 分别合成了以2-氯苯 (3a) 和3-苄氧基苯 (3h) 为底物的N-/O烷基化产物.结果表明, C-2位邻位取代仍以N-烷基化为主, 间位以O烷基化为主 (表 2).仅改变不同的氨基, 可能对此类N-/O烷基化反应影响不大.

表 2 化合物3a和3h的烷基化^a Table 2. Alkylation of compounds 3a and 3h

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Compd.	总产率^b/%	Yield/%		4:5
Compd.	总产率^b/%	4	5	4:5
aa	67.0	11.2	55.8	1:5.0
ha	78.8	62.4	16.4	3.8:1
hb	56.8	49.7	7.1	7.0:1
hc	54.0	46.2	7.8	5.9:1
hd	53.5	41.8	11.7	3.6:1
^aReagents and conditions: acetone, K₂CO₃, R¹CH₂CH₂Cl, KI, reflux, 16 h; ^bisolated yield.

表 2 化合物3a和3h的烷基化^a
Table 2. Alkylation of compounds 3a and 3h

1.3 结构确证

N-/O烷基化产物的结构可以通过化合物的¹H NMR明确区分. N-烷基化化合物4a~4k的NCH₂的H信号峰的化学位移较O烷基化化合物5a~5k的OCH₂的相应信号处于更高场, 且NCH₂在¹H NMR中, 有时会裂分为两组信号峰 (每组积分为一个氢), 而OCH₂不裂分仍为一组峰 (积分为两个氢).相关表征数据见表 3.

表 3 N-, O烷基化产物结构表征 Table 3. Structural characterization of the N-/Oalkylated products

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Compd.	δ_H (NCH₂/OCH₂)
4a/5a	4.38~4.33, 3.62~3.72/4.81
4aa/5aa	4.39~4.34, 3.69~3.64/4.83
4h/5h	4.14/5.14
4ha/5ha	4.27/4.85
4hb/5hb	4.16/4.87
4hc/5hc	4.21/4.81
4hd/5hd	4.21/5.10

表 3 N-, O烷基化产物结构表征
Table 3. Structural characterization of the N-/Oalkylated products

1.4 化合物抗肿瘤活性评价

对所合成化合物4a, 5a, 4aa, 5aa和4h, 5h, 4ha~4hd, 5ha~5hd分别进行了体外抑制人宫颈癌 (hela)、乳腺癌 (MCF-7)、肺癌 (A549) 细胞活性测试, 顺铂为阳性对照 (表 4).总体而言, 所测试化合物对三种肿瘤细胞增殖具有中等偏弱的抑制活性.个别化合物, 如4h, 抑制A549细胞的半抑制浓度 (IC₅₀) 为13.20 μmol/L, 优于阳性对照顺铂相应的活性, 表现出一定的选择性.烷基链上氨基的不同对化合物抗肿瘤细胞增殖活性影响不大.

表 4 部分化合物的抗肿瘤活性 Table 4. Antitumor activities of some compounds

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Compd.	IC₅₀/(μmol•L^-1)
Compd.	Hela	MCF-7	A549
4a	＞50	＞50	＞50
5a	35.45±0.02	＞50	＞50
4aa	＞50	＞50	＞50
5aa	＞50	29.93±0.02	＞100
4h	＞50	＞50	13.20±0.14
5h	＞50	＞50	＞50
4ha	＞50	37.38±0.05	＞50
5ha	＞50	40.30±0.04	27.02±0.12
4hb	＞50	＞50	36.44±0.05
5hb	＞50	＞50	28.84±0.05
4hc	＞50	＞50	27.70±0.14
5hc	＞50	＞50	47.69±0.01
4hd	49.31±0.05	＞50	＞50
5hd	＞50	＞50	＞50
顺铂	9.91±0.01	13.10±0.02	17.00±0.01

表 4 部分化合物的抗肿瘤活性
Table 4. Antitumor activities of some compounds

1.5 化合物抗菌活性评价

对所合成化合物5a, 5aa和4h, 5h, 4ha~4hb分别进行了抑制植物病菌的活性测试 (表 5).所选细菌包括两株革兰氏阴性菌:大肠杆菌 (Escherichia coli) 和痢疾杆菌 (Shigella Castellani).四株植物病原菌 (真菌):链铬孢菌 (Alternaria alternate)、尖孢镰刀菌 (Fusarium oxysporum)、立枯丝核菌 (Rhizoctonia solani) 和大丽轮枝菌 (Verticillium dahliae).诺氟沙星 (Norfloxacin) 和三唑酮 (Triadimefon) 为阳性对照, 测试浓度为50 µg/mL.

表 5 部分化合物的抗菌活性 (抑制率/%)^a Table 5. Antmicrobial activities of some compounds (inhibition rate/%)

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Compd.	Anti-bacteria		Anti-fungi
Compd.	Escherichia coli	Shigella castellani	Alternaria alternate	Fusarium oxysporum	Rhizoctonia solani	Verticillium dahliae
5a	98	13	66	61	14	61
5aa	100	100	100	74	43	42
4h	94	79	44	67	35	77
4ha	74	53	75	58	24	30
4hb	100	96	13	95	14	37
5h	85	—^a	88	90	82	80
Norfloxacin	98	95
Triadimefon			64	58	94	63
^a“—”表示无抑制活性.

表 5 部分化合物的抗菌活性 (抑制率/%)^a
Table 5. Antmicrobial activities of some compounds (inhibition rate/%)

实验结果表明, 化合物对细菌的抑菌效果较好, 对Escherichia coli具有显著的抑制活性, 抑制率在74%以上.个别化合物活性较高, 如5aa和4hb对Escherichia coli抑制率均为100%, 对Shigella Castellani的抑制活性分别为100%和96%, 均略优于阳性对照Norfloxacin的抗菌活性.大部分化合物对真菌也有较好的抑制作用, 如对Alternaria alternate和Fusarium oxysporum具有中等偏上的抑制活性, 且多数高于阳性对照Triadimefon; 而对Rhizoctonia solani和Verticillium dahliae具有中等偏弱的抑制作用.化合物5aa对不同的真菌有较强的选择性抑制活性, 如对Alternaria alternate的抑制率为100%, 而对其它的测试真菌抑制活性中等偏下.化合物5h则对四种所测真菌均具有较好的抑制活性, 抑制率在80%以上, 表现出较好的广谱抗菌活性.

2 结论

合成了系列含氨烷基侧链的喹唑啉-4-酮衍生物4和5, 探讨了C-2位苯环单取代基对N-/O烷基化的影响.结果表明, 当C-2苯环上的取代基处在邻位时, 烷基化产物以N-烷基化为主; 处在间位或对位时, 以O烷基化为主.生物活性测试结果表明, 化合物4h具有较好的抗A549细胞增殖活性, 而化合物5aa和4hb具有良好的抗细菌活性.

3 实验部分

3.1 仪器与试剂

熔点由SGW^® X-4显微熔点仪 (温度计未校正) 测定; 核磁共振谱用BRUKER AC-P600 (600 MHz) 型核磁共振仪测定, TMS为内标; 质谱 (ESI) 用Agilent G6300离子阱液相质谱联用仪; 元素分析用HERAEUS (CHNO, rapid) 型元素分析仪; 光密度用BioRad 3550型酶标仪测定; 层析用硅胶 (200~300目) 为青岛海洋化工厂产品.所用其他试剂均为分析纯, 无水试剂均按常规方法处理, 水为二次蒸馏水.

3.2 实验方法

3.2.4 抗肿瘤细胞毒性测试

抗肿瘤细胞毒性采用改进的Mosmann’s MTT (噻唑蓝) 染色法测定^[19].于96孔板接种细胞悬液, 90 μL/孔, 细胞密度2×10⁴个/mL, 37 ℃, 5% CO₂浓度 (体积分数) 的培养箱中过夜, 加10 μL/孔相应浓度药物 (100 μmol/L), 继续培44 h, 加MTT 10 μL/孔培养4 h, 从培养箱中取出, 倒板, 加DMSO 100 μL/孔溶解MTT, 测量570 nm波长下肿瘤细胞OD值, 代入公式 (OD_control-OD_treated)/OD_control×100%计算抑制率, 顺铂为阳性对照.

3.2.5 抗菌活性测试

细菌测试方法:各吸取10^-6或10^-7梯度菌悬液70 μL, 分别加入到药物浓度为50 μg/mL的药物平板和不加药的营养琼脂 (NA) 培养基平板 (对照) 上, 用灭菌三角刮涂布均匀, 做好标识, 置于37 ℃恒温培养箱中培养24 h. 24 h后, 进行菌落计数, 每组设置三次平行试验.

抑菌率 (%)＝(对照组菌落数-药物平板菌落数)/对照组菌落数×100%

真菌测试方法:将供试化合物用质量分数为5%的二甲基亚砜 (DMSO) 水溶液配制成质量浓度分别为50 µg/mL马铃薯葡萄糖琼脂 (PDA) 培养基, 测试其对4种供试真菌病原菌的抑菌活性.在已培养好供试菌株的平皿中取直径8 mm的菌饼, 置于含药平板内, 每皿3块.以不加药剂者为空白对照.于温度为 (25±1) ℃培养箱内培养5 d, 采用十字交叉法测量菌落直径, 计算菌丝生长抑制率.计算公式如下:

菌落增长直径＝菌落直径-菌饼直径抑制率 (%)＝(对照菌落增长直径-试验菌落增长直径)/(对照菌落增长直径)×100%

辅助材料 (Supporting Information) 化合物4a~4k, 5a~5k, 4aa, 5aa和4ha~4hd, 5ha~5hd的核磁共振氢谱和碳谱.这些材料可以免费从本刊网站 (http://sioc-journal.cn/) 上下载.

3.2.3 化合物4aa, 5aa和4ha~4hd和5ha~5hd的合成

按照上述制备4a~4k和5a~5k同样的方法, 以不同的氯代氨烷链为原料, 可以得到化合物4aa, 5aa和4ha~4hd和5ha~5hd.

2-(2-氯苯基)-4-[2-(哌啶-1-基) 乙氧基]喹唑啉 (4aa):白色固体, m.p. 107.5~109.3 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.21 (d, J＝8.4 Hz, 1H, ArH), 8.01 (d, J＝7.8 Hz, 1H, ArH) 7.86 (t, J＝7.8 Hz, 2H, ArH), 7.59 (t, J＝7.2 Hz, 1H, ArH), 7.52~7.51 (m, 1H, ArH), 7.39~7.38 (m, 2H, ArH), 4.83 (brs, 2H, CH₂), 2.98 (brs, 2H, CH₂), 2.63 (m, 4H, CH₂), 1.64 (m, 4H, CH₂), 1.46 (brs, 2H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 161.9, 153.7, 147.3, 134.6, 134.5, 132.6, 131.3, 130.3, 130.0, 127.7, 127.4, 127.3, 126.9, 121.3, 56.7, 54.6, 42.8, 25.9, 24.2; MS (ESI) m/z: 368.5 ([M+H]⁺). Anal. calcd for C₂₁H₂₂ClN₃O₁: C 68.56, H 6.03, N 11.42; found C 68.62, H 5.98, N 11.43.

2-(2-氯苯基)-3-[2-(哌啶-1-基) 乙基]喹唑啉-4(3H)-酮 (5aa):白色固体, m.p. 113.7~115.3 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.34 (d, J＝7.8 Hz, 1H, ArH), 7.77 (t, J＝7.2 Hz, 1H, ArH), 7.73 (d, J＝7.8 Hz, 1H, ArH), 7.54~7.50 (m, 3H, ArH), 7.47~7.42 (m, 2H, ArH), 4.39~4.34 (m, 1H, CH₂), 3.71~3.66 (m, 1H, CH₂), 2.58~2.54 (m, 1H, CH₂), 2.47~2.42 (m, 1H, CH₂), 2.21 (brs, 2H, CH₂), 2.19 (brs, 2H, CH₂), 1.46~1.42 (m, 4H, CH₂), 1.34 (brs, 2H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 162.0, 153.7, 147.3, 134.6, 134.5, 132.6, 131.3, 130.4, 130.0, 127.7, 127.4, 127.4, 126.9, 121.3, 56.7, 54.7, 42.9, 25.9, 24.2; MS (ESI) m/z: 368.9 ([M+H]⁺). Anal. calcd for C₂₁H₂₂ClN₃O₁: C 68.56, H 6.03, N 11.42; found C 68.59, H 6.05, N 11.46.

2-[3-(苄氧基) 苯基]-4-[2-(哌啶-1-基) 乙氧基]喹唑啉 (4ha):白色固体, m.p. 59.6~60.9 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.24 (s, 1H, ArH), 8.20 (d, J＝7.2 Hz, 1H, ArH), 8.16 (d, J＝7.8 Hz, 1H, ArH), 7.99 (d, J＝8.4 Hz, 1H, ArH), 7.82 (t, J＝7.2 Hz, 1H, ArH), 7.51 (d, J＝7.2 Hz, 3H, ArH), 7.42 (q, J＝7.2 Hz, 3H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.11 (d, J＝7.8 Hz, 1H, ArH), 5.21 (s, 2H, CH₂), 4.85 (t, J＝6.0 Hz, 2H, CH₂), 2.96 (t, J＝6.0 Hz, 2H, CH₂), 2.62 (brs, 4H, CH₂), 1.63 (brs, J＝5.4 Hz, 4H, CH₂), 1.46 (brs, 2H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.7, 159.9, 159.2, 152.0, 139.9, 137.3, 133.6, 129.6, 128.7, 128.2, 128.1, 127.8, 126.6, 123.7, 121.5, 117.5, 115.6, 114.7, 70.3, 64.9, 57.6, 55.2, 26.1, 24.3; MS (ESI) m/z: 439.7 ([M+H]⁺). Anal. calcd for C₂₈H₂₉N₃O₂: C 76.51, H 6.65, N 9.56; found C 76.53, H 6.65, N 9.55.

2-[3-(苄氧基) 苯基]-3-[2-(哌啶-1-基) 乙基]喹唑啉-4(3H)-酮 (5ha):白色固体, m.p. 80.7~81.9 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.31 (d, J＝7.8 Hz, 1H, ArH), 7.80~7.76 (m, 2H, ArH), 7.52 (d, J＝6.6 Hz, 1H, ArH), 7.43~7.38 (m, 5H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.18 (s, 1H, ArH), 7.14~7.11 (m, 2H, ArH), 5.09 (s, 2H, CH₂), 4.66 (s, 2H, CH₂), 4.27 (t, J＝6.0 Hz, 2H, CH₂), 2.57 (t, J＝6.0 Hz, 2H, CH₂), 2.36 (brs, 4H, CH₂), 1.51 (t, J＝6.0 Hz, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.0, 162.2, 159.3, 155.4, 147.4, 136.5, 136.0, 134.9, 130.5, 128.8, 128.3, 127.8, 127.6, 127.4, 127.0, 120.6, 120.4, 117.3, 114.4, 70.3, 63.5, 57.2, 54.8, 47.9, 25.9, 24.2. MS (ESI) m/z: 440.1 ([M+H]⁺). Anal. calcd for C₂₈H₂₉N₃O₂: C 76.51, H 6.65, N 9.56; found C 76.54, H 6.64, N 9.58.

2-[3-(苄氧基) 苯基]-4-[2-(吡咯啉-1-基) 乙氧基]喹唑啉 (4hb):白色固体, m.p. 63.3~64.9 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.24 (s, 1H, ArH), 8.20 (d, J＝7.8 Hz, 1H, ArH), 8.17 (d, J＝8.4 Hz, 1H, ArH), 7.99 (d, J＝8.4 Hz, 1H, ArH), 7.82 (t, J＝7.2 Hz, 1H, ArH), 7.51 (d, J＝7.8 Hz, 3H, ArH), 7.42 (q, J＝7.8 Hz, 3H, ArH), 7.34 (t, J＝7.8 Hz, 1H, ArH), 7.11 (dd, J＝7.8, 2.4 Hz, 1H, ArH), 5.21 (s, 2H, CH₂), 4.87 (t, J＝6.0 Hz, 2H, CH₂), 3.10 (t, J＝6.0 Hz, 2H, CH₂), 2.75 (brs, 4H, CH₂), 1.85~1.83 (m, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 171.3, 166.7, 159.9, 159.2, 152.1, 139.8, 137.3, 133.6, 129.6, 128.7, 128.1, 128.1, 127.8, 126.6, 123.7, 121.5, 117.6, 115.5, 114.6, 70.3, 66.1, 54.9, 54.6, 23.7, 21.2; MS (ESI) m/z: 425.8 ([M+H]⁺). Anal. calcd for C₂₇H₂₇N₃O₂: C 76.21, H 6.40, N 9.87; found C 76.25, H 6.37, N 9.82.

2-[3-(苄氧基) 苯基]-3-[2-(吡咯啉-1-基) 乙基]喹唑啉-4(3H)-酮 (5hb):白色固体, m.p. 81.1~82.7 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.32 (d, J＝7.8 Hz, 1H, ArH), 7.77~7.73 (m, 2H, ArH), 7.51 (d, J＝7.2 Hz, 1H, ArH), 7.44~7.38 (m, 5H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.14 (s, 1H, ArH), 7.10 (t, J＝8.4 Hz, 2H, ArH), 5.12 (s, 2H, CH₂), 4.16 (t, J＝7.8 Hz, 2H, CH₂), 2.66 (t, J＝7.2 Hz, 2H, CH₂), 2.31 (brs, 4H, CH₂), 1.67 (brs, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 162.3, 159.0, 156.2, 147.3, 136.8, 136.7, 134.5, 130.1, 128.8, 128.3, 127.7, 127.6, 127.1, 126.9, 121.1, 120.7, 116.7, 114.8, 70.3, 54.2, 54.1, 44.7, 23.6; MS (ESI) m/z: 426.5 ([M+H]⁺). Anal. calcd for C₂₇H₂₇N₃O₂: C 76.21, H 6.40, N 9.87; found C 76.21, H 6.46, N 9.92.

2-{{2-[3-(苄氧基) 苯基]喹唑啉-4-基}氧基}-N, N-二乙基乙胺 (4hc):白色固体, m.p. 76.7~78.1 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.24 (s, 1H, ArH), 8.20 (d, J＝7.8 Hz, 1H, ArH), 8.16 (d, J＝8.4 Hz, 1H, ArH), 7.99 (d, J＝8.4 Hz, 1H, ArH), 7.82 (t, J＝7.8 Hz, 1H, ArH), 7.51 (d, J＝7.8 Hz, 3H, ArH), 7.42 (q, J＝7.2 Hz, 4H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.11 (dd, J＝7.8, 2.4 Hz, 1H, ArH), 5.21 (s, 2H, CH₂), 4.81 (t, J＝6.0 Hz, 2H, CH₂), 3.10 (t, J＝6.0 Hz, 2H, CH₂), 2.75 (q, J＝7.2 Hz, 4H, CH₂), 1.13 (t, J＝7.2 Hz, 6H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 166.8, 159.9, 159.3, 152.1, 139.9, 137.3, 134.5, 133.6, 129.6, 128.8, 128.7, 128.2, 128.1, 127.8, 127.6, 126.6, 123.7, 121.5, 120.7, 117.5, 115.5, 114.7, 70.3, 65.4, 51.3, 48.1, 12.2, 12.1; MS (ESI) m/z: 427.8 ([M+H]⁺). Anal. calcd for C₂₇H₂₉N₃O₂: C 75.85, H 6.84, N 9.83; found C 75.92, H 6.88, N 9.90.

2-[3-(苄氧基) 苯基]-3-[2-(二乙基氨基) 乙基]喹唑啉-4(3H)-酮 (5hc): m.p. 79.7~81.7 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.31 (d, J＝6.6 Hz, 1H, ArH), 7.78~7.74 (m, 2H, ArH), 7.52 (brs, 1H, ArH), 7.44 (d, J＝4.2 Hz, 3H, ArH), 7.39 (brs, 2H, ArH), 7.33 (brs, 1H, ArH), 7.13 (brs, 3H, ArH), 5.13 (s, 2H, CH₂), 4.21 (brs, 2H, CH₂), 2.80 (brs, 2H, CH₂), 2.60 (brs, 4H, CH₂), 1.02 (brs, 6H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 162.3, 159.2, 147.2, 136.6, 134.8, 130.5, 128.8, 128.3, 127.8, 127.7, 127.4, 126.8, 120.8, 120.4, 116.9, 114.8, 70.4, 47.8, 38.9, 23.9, 22.8; MS (ESI) m/z: 428.1 ([M+H]⁺). Anal. calcd for C₂₇H₂₉N₃O₂: C 75.85, H 6.84, N 9.83; found C 75.87, H 6.86, N 9.81.

2-{{2-[3-(苄氧基) 苯基]喹唑啉-4-基}氧基}-N, N-二甲基乙胺 (4hd):白色固体, m.p. 87.7~89.1 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.19 (brs, 2H, ArH), 8.15 (d, J＝7.8 Hz, 1H, ArH), 8.01 (d, J＝8.4 Hz, 1H, ArH), 7.85 (t, J＝7.2 Hz, 1H, ArH), 7.55 (t, J＝7.8 Hz, 1H, ArH), 7.51 (d, J＝7.8 Hz, 2H, ArH), 7.42 (q, J＝7.8 Hz, 3H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.12 (dd, J＝7.8, 2.4 Hz, 1H, ArH), 5.20 (s, 2H, CH₂), 5.10 (t, J＝4.8 Hz, 2H, CH₂), 3.42 (brs, 2H, CH₂), 2.81 (s, 6H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 165.8, 159.5, 159.3, 152.2, 139.3, 137.2, 134.1, 129.7, 128.8, 128.3, 128.1, 127.8, 127.1, 123.4, 121.4, 117.6, 115.0, 114.8, 70.4, 62.2, 56.8, 44.4; MS (ESI) m/z: 400.0 ([M+H]⁺). Anal. calcd for C₂₅H₂₅N₃O₂: C 75.16, H 6.31, N 10.52; found C 75.09, H 6.36, N 10.55.

2-[3-(苄氧基) 苯基]-3-[2-(二甲基氨基) 乙基]喹唑啉-4(3H)-酮 (5hd): m.p. 81.7~83.3 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.31 (d, J＝7.8 Hz, 1H, ArH), 7.78 (t, J＝7.2 Hz, 1H, ArH), 7.74 (d, J＝7.8 Hz, 1H, ArH), 7.52 (t, J＝7.2 Hz, 1H, ArH), 7.45~7.43 (m, 3H, ArH), 7.39 (t, J＝7.2 Hz, 2H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.13~7.11 (m, 3H, ArH), 5.14 (s, 2H, CH₂), 4.21 (t, J＝7.2 Hz, 2H, CH₂), 2.65 (brs, 2H, CH₂), 2.23 (brs, 6H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 162.3, 159.1, 155.7, 147.3, 136.6, 136.4, 134.7, 130.4, 128.8, 128.3, 127.8, 127.6, 127.4, 126.9, 120.9, 120.5, 116.9, 114.8, 70.4, 56.6, 44.9, 42.7; MS (ESI) m/z: 400.8 ([M+H]⁺). Anal. calcd for C₂₅H₂₅N₃O₂: C 75.16, H 6.31, N 10.52; found C 75.18, H 6.32, N 10.50.

3.2.2 化合物4a~4k和5a~5k的合成

以化合物4a和5a的合成为例, 向50 mL圆底烧瓶中加入140 mg (0.5 mmol) 化合物3a及151 mg (1.1 mmol) 无水碳酸钾, 再加入10 mL新处理的丙酮, 搅拌回流30 min后加入203 mg (0.8 mmol) 2-氯-乙基吗啉盐酸盐和催化量碘化钾, 继续回流搅拌16 h, TLC监测反应完全.冷却抽滤除去碳酸钾, 浓缩滤液, 残留物加20 mL二氯甲烷 (DCM) 溶解, 并用10 mL水洗2次, 有机相在无水硫酸镁中干燥.硅胶 (200~300目) 柱色谱[二氯甲烷/甲醇 (V:V＝30:1)]分离, 得到O烷基化产物4a和N-烷基化产物5a.以同样的方法可以得到4b~4k和5b~5k.

4-{2-{[2-(2-氯苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4a):白色固体, m.p. 119.9~121.7 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.20 (d, J＝8.4 Hz, 1H, ArH), 8.02 (d, J＝8.4 Hz, 1H, ArH), 7.87~7.84 (m, 2H, ArH), 7.59 (t, J＝7.2 Hz, 1H, ArH), 7.52~7.50 (m, 1H, ArH), 7.39~7.38 (m, 2H, ArH), 4.81 (t, J＝6.0 Hz, 2H, CH₂), 3.72 (t, J＝4.8 Hz, 4H, CH₂), 2.95 (t, J＝6.0 Hz, 2H, CH₂), 2.64 (brs, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.4, 161.1, 151.7, 138.5, 133.8, 133.1, 131.8, 130.7, 130.3, 128.2, 127.3, 126.9, 123.6, 115.2, 67.1, 64.9, 57.3, 54.1; MS (ESI) m/z: 392.7 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀ClN₃O₂: C 64.95, H 5.45, N 11.36; found C 64.97, H 5.51, N 11.32.

2-(2-氯苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5a):白色固体, m.p. 126.7~127.5 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.33 (d, J＝7.8 Hz, 1H, ArH), 7.77 (t, J＝7.2 Hz, 1H, ArH), 7.74 (d, J＝8.4 Hz, 1H, ArH), 7.55~7.50 (m, 3H, ArH), 7.47~7.42 (m, 2H, ArH), 4.38~4.33 (m, 1H, CH₂), 3.72~3.67 (m, 1H, CH₂), 3.56 (t, J＝4.8 Hz, 4H, CH₂), 2.58~2.54 (m, 1H, CH₂), 2.51~2.48 (m, 1H, CH₂), 2.23 (t, J＝4.2 Hz, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 162.0, 153.5, 147.3, 134.6, 132.6, 131.3, 130.4, 130.0, 127.7, 127.5, 126.9, 121.2, 66.9, 56.6, 42.5; MS (ESI) m/z: 408.8 ([M+K]⁺). Anal. calcd for C₂₀H₂₀Cl-N₃O₂: C 64.95, H 5.45, N 11.36; found C 64.88, H 5.49, N 11.34.

4-{2-[(2-邻甲苯基喹唑啉-4-基) 氧基]乙基}吗啉 (4b):不定形粉末; ¹H NMR (600 MHz, CDCl₃) δ: 8.16 (d, J＝7.8 Hz, 1H, ArH), 8.00 (d, J＝7.8 Hz, 1H, ArH), 7.92 (d, J＝7.8 Hz, 1H, ArH), 7.84 (t, J＝7.2 Hz, 1H, ArH), 7.56 (t, J＝7.8 Hz, 1H, ArH), 7.30~7.56 (m, 3H, ArH), 4.79 (t, J＝6.0 Hz, 2H, CH₂), 3.73 (t, J＝4.8 Hz, 4H, CH₂), 2.94 (t, J＝6.0 Hz, 2H, CH₂), 2.60~2.67 (m, 7H, CH₂, CH₃); MS (ESI) m/z: 372.4 ([M+Na]⁺). Anal. calcd for C₂₁H₂₃N₃O₂: C 72.18, H 6.63, N 12.03; found C 72.15, H 6.60, N 12.09.

3-(2-吗啉乙基)-2-邻甲苯基喹唑啉-4(3H)-酮 (5b):白色固体, m.p. 64.5~65.9 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.33 (d, J＝7.8 Hz, 1H, ArH), 7.74~7.79 (m, 2H, ArH), 7.52 (d, J＝7.2 Hz, 1H, ArH), 7.39~7.41(m, 2H, ArH), 7.32 (t, J＝7.2 Hz, 1H, ArH), 4.28~4.32 (m, 1H, CH₂), 3.74~3.69 (m, 1H, CH₂), 3.56 (t, J＝4.8 Hz, 4H, CH₂), 2.58~2.45 (m, 2H, CH₂), 2.27 (s, 3H, CH₃), 2.26~2.18 (m, 4H, CH₂); MS (ESI) m/z: 372.8 ([M+ Na]⁺). Anal. calcd for C₂₁H₂₃N₃O₂: C 72.18, H 6.63, N 12.03; found C 72.21, H 6.58, N 12.01.

4-{2-{[2-(2-氟苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4c):不定形粉末; ¹H NMR (600 MHz, CDCl₃) δ: 8.15~8.18 (m, 2H, ArH), 8.02 (d, J＝8.4 Hz, 1H, ArH), 7.85 (t, J＝7.2 Hz, 1H, ArH), 7.57 (t, J＝6.6 Hz, 1H, ArH), 7.46~7.43 (m, 1H, ArH), 7.27 (t, J＝7.2 Hz, 1H, ArH), 7.20 (t, J＝7.8 Hz, ArH), 4.83 (t, J＝6.0 Hz, 2H, CH₂), 3.73 (t, J＝6.6 Hz, 4H, CH₂), 2.98 (brs, 2H, CH₂), 2.66 (brs, 4H, CH₂); MS (ESI) m/z: 376.2 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀FN₃O₂: C 67.97, H 5.70, N 11.89; found C 68.03, H 5.65, N 11.84.

2-(2-氟苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5c):不定形粉末; ¹H NMR (600 MHz, CDCl₃) δ: 8.33 (d, J＝7.8 Hz, 1H, ArH), 7.79 (t, J＝7.2 Hz, 1H, ArH), 7.74 (d, J＝7.8 Hz, 1H, ArH), 7.53~7.58 (m, 3H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.23 (t, J＝9.0 Hz, 1H, ArH), 4.30~4.34 (m, 1H, CH₂), 3.87~3.90 (m, 1H, CH₂), 3.56 (t, J＝4.2 Hz, 4H, CH₂), 2.51~2.55 (m, 2H, CH₂), 2.23 (brs, 4H, CH₂); MS (ESI) m/z: 354.6 ([M+H]⁺). Anal. calcd for C₂₀H₂₀FN₃O₂: C 67.97, H 5.70, N 11.89; found C 68.02, H 5.74; N 11.90.

2-(2-甲氧基苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5d):不定形粉末, ¹H NMR (600 MHz, CDCl₃) δ: 8.33 (d, J＝7.8 Hz, 1H, ArH), 7.74~7.76 (m, 2H, ArH), 7.44~7.52 (m, 3H, ArH), 7.11 (t, J＝7.8 Hz, 1H, ArH), 7.00 (d, J＝8.4 Hz, 1H, ArH), 4.34~4.38 (m, 1H, CH₂), 3.82 (s, 3H, OCH₃), 3.70~3.73 (m, 1H, CH₂), 3.56 (t, J＝4.2 Hz, 4H, CH₂), 2.51 (t, J＝6.6 Hz, 2H, CH₂), 2.23 (brs, 4H, CH₂); MS (ESI) m/z: 388.3 ([M+Na]⁺). Anal. calcd for C₂₁H₂₃N₃O₃: C 69.02, H 6.34, N 11.50; found C 69.04, H 6.38, N 11.55.

4-{2-{[2-(3-氯苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4e):白色固体, m.p. 87.5~89.9 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.55 (s, 1H, ArH), 8.46 (d, J＝7.2 Hz, 2H, ArH), 8.15 (d, J＝7.8 Hz, 1H, ArH), 7.98 (d, J＝8.4 Hz, 1H, ArH), 7.83 (t, J＝7.8 Hz, 1H, ArH), 7.54 (t, J＝7.8 Hz, 1H, ArH), 7.42~7.46 (m, 2H, ArH), 4.86 (t, J＝6.0 Hz, 2H, CH₂), 3.75 (t, J＝4.2 Hz, 4H, CH₂), 2.98 (t, J＝6.0 Hz, 2H, CH₂), 2.67 (brs, 4H, CH₂); MS (ESI) m/z: 392.1 ([M+ Na]⁺). Anal. calcd for C₂₀H₂₀ClN₃O₂: C 64.95, H 5.45, N 11.36; found C 64.92, H 5.48, N 11.35.

2-(3-氯苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5e):白色固体, m.p. 92.5~94.2 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.32 (d, J＝7.8 Hz, 1H, ArH), 7.79 (t, J＝7.2 Hz, 1H, ArH), 7.73 (d, J＝7.8 Hz, 1H, ArH), 7.60 (s, 1H, ArH), 7.43~7.55 (m, 4H, ArH), 4.15 (brs, 2H, CH₂, ), 3.58 (brs, 4H, CH₂), 2.57 (brs, 2H, CH₂), 2.25 (brs, 4H, CH₂); MS (ESI) m/z: 392.6 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀ClN₃O₂: C 64.95, H 5.45, N 11.36; found C 64.99, H 5.48, N 11.36.

4-{2-{[2-(3-溴苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4f):白色固体, m.p. 80.5~81.6 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.70 (s, 1H, ArH), 8.49 (d, J＝7.8 Hz, 1H, ArH), 8.14 (d, J＝7.8 Hz, 1H, ArH), 7.97 (d, J＝8.4 Hz, 1H, ArH), 7.83 (t, J＝7.8 Hz, 1H, ArH), 7.60 (d, J＝7.8 Hz, 1H, ArH), 7.53 (t, J＝7.2 Hz, 1H, ArH), 7.37 (t, J＝8.4 Hz, 1H, ArH), 4.85 (t, J＝6.0 Hz, 2H, CH₂), 3.75 (t, J＝4.8 Hz, 4H, CH₂), 2.97 (t, J＝6.0 Hz, 2H, CH₂), 2.67 (brs, 4H, CH₂); MS (ESI) m/z: 437.5 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀BrN₃O₂: C 57.98, H 4.87, N 10.14; found C 58.06, H 4.92, N 11.13.

2-(3-溴苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5f):白色固体, m.p. 84.7~86.1 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.32 (d, J＝7.8 Hz, 1H, ArH), 7.77 (t, J＝7.2 Hz, 1H, ArH), 7.72~7.75 (m, 2H, ArH), 7.66 (d, J＝7.8 Hz, 1H, ArH), 7.54 (d, J＝7.2 Hz, 1H, ArH), 7.50 (d, J＝7.2 Hz, 1H, ArH), 7.40 (d, J＝7.8 Hz, 1H, ArH), 4.10~4.14 (m, 2H, CH₂, 3.58 (brs, 4H, CH₂), 2.56 (t, J＝6.6 Hz, 2H, CH₂), 2.25 (brs, 4H, CH₂). MS (ESI) m/z: 437.8 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀BrN₃O₂: C 57.98, H 4.87, N 10.14; found C 57.96, H 4.94, N 11.16.

4-{2-{[2-(3-氟苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4g):白色固体, m.p. 154.8~155.3 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.36 (d, J＝7.8 Hz, 1H, ArH), 8.26 (d, J＝10.2 Hz, 1H, ArH), 8.14 (d, J＝7.8 Hz, 1H, ArH), 7.98 (d, J＝8.4 Hz, 1H, ArH), 7.84 (t, J＝7.2 Hz, 1H, ArH), 7.50 (t, J＝7.2 Hz, 1H, ArH), 7.46 (t, J＝7.8 Hz, 1H, ArH), 7.18 (t, J＝8.4 Hz, 1H, ArH), 4.86 (t, J＝6.0 Hz, 2H, CH₂), 3.75 (t, J＝4.2 Hz, 4H, CH₂), 2.98 (t, J＝6.0 Hz, 2H, CH₂), 2.67 (brs, 4H, CH₂); MS (ESI) m/z: 376.0 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀FN₃O₂: C 67.97, H 5.70, N 11.89; found C 68.01, H 5.72, N 11.95.

2-(3-氟苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5g):白色固体, m.p. 173.6~174.9 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.32 (d, J＝7.8 Hz, 1H, ArH), 7.79 (t, J＝7.2 Hz, 1H, ArH), 7.73 (d, J＝8.4 Hz, 1H, ArH), 7.49~7.55 (m, 2H, ArH), 7.08~7.37 (m, 3H, ArH), 4.18 (brs, 2H, CH₂, ), 3.58 (brs, 4H, CH₂), 2.57 (brs, 2H, CH₂), 2.27 (brs, 4H, CH₂); MS (ESI) m/z: 376.8 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀FN₃O₂: C 67.97, H 5.70, N 11.89; found C 68.06, H 5.77, N 11.93.

4-{2-{{2-[3-(苄氧基) 苯基]喹唑啉-4-基}氧基}乙基}吗啉 (4h):黄色固体, m.p. 103.1~103.6 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.18 (s, 1H, ArH), 8.15 (d, J＝7.8 Hz, 1H, ArH), 8.11 (d, J＝7.8 Hz, 1H, ArH), 8.01 (d, J＝8.4 Hz, 1H, ArH), 7.85 (t, J＝7.8 Hz, 1H, ArH), 7.55 (t, J＝7.2 Hz, 1H, ArH), 7.51 (d, J＝7.8 Hz, 2H, ArH), 7.43~7.40 (m, 3H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.12 (d, J＝7.8 Hz, 1H, ArH), 5.20 (s, 2H, CH₂), 5.14 (brs, 2H, CH₂), 4.00 (brs, 4H, CH₂), 3.45 (brs, 2H, CH₂), 3.13~3.12 (brs, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 165.8, 159.6, 159.3, 152.2, 139.3, 137.2, 134.1, 129.7, 128.8, 128.4, 128.1, 127.8, 127.1, 123.2, 121.4, 117.6, 115.0, 114.8, 70.4, 64.9, 62.2, 62.2, 56.8, 53.2; MS (ESI) m/z: 441.8 ([M+H]⁺). Anal. calcd for C₂₇H₂₇N₃O₃: C 73.45, H 6.16, N 9.52; found C 73.48, H 6.20, N 9.58.

2-[3-(苄氧基) 苯基]-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5h):黄色固体, m.p. 120.7~122.5 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.31 (d, J＝7.8 Hz, 1H, ArH), 7.78~7.73 (m, 2H, ArH), 7.51 (d, J＝7.2 Hz, 1H, ArH), 7.43~7.42 (m, 3H, ArH), 7.39 (t, J＝7.8 Hz, 2H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 7.14~7.10 (m, 3H, ArH), 5.13 (s, 2H, CH₂), 4.14 (t, J＝7.2 Hz, 2H, CH₂), 3.55 (t, J＝4.2 Hz, 4H, CH₂), 2.52 (t, J＝7.2 Hz, 2H, CH₂), 2.27 (brs, 4H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 162.4, 158.9, 155.9, 147.3, 136.7, 136.5, 134.5, 130.2, 128.8, 128.3, 127.6, 127.5, 127.2, 126.8, 120.9, 120.7, 116.6, 114.9, 70.3, 66.9, 56.7, 53.7, 42.7; MS (ESI) m/z: 442.4 ([M+H]⁺). Anal. calcd for C₂₇H₂₇N₃O₃: C 73.45, H 6.16, N 9.52; found C 73.52, H 6.13, N 9.49.

4-{2-{[2-(4-氯苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4i):白色固体, m.p. 159.7~161.3 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.49 (d, J＝8.4 Hz, 2H, ArH), 8.11 (d, J＝7.8 Hz, 1H, ArH), 7.95 (d, J＝8.4 Hz, 1H, ArH), 7.81 (t, J＝7.2 Hz, 1H, ArH), 7.51 (t, J＝7.2 Hz, 1H, ArH), 7.44 (d, J＝8.4 Hz, 2H, ArH), 4.82 (t, J＝6.0 Hz, 2H, CH₂), 3.73 (t, J＝4.2 Hz, 4H, CH₂), 2.96 (t, J＝6.0 Hz, 2H, CH₂), 2.65 (brs, 4H, CH₂); MS (ESI) m/z: 392.7 ([M+Na]⁺). Anal. calcd for C₂₀H₂₀ClN₃O₂: C 64.95, H 5.45, N 11.36; found C 65.02, H 5.41, N 11.31.

4-[4-(2-吗啉乙氧基) 喹唑啉-2-基]苯乙腈 (4j):白色固体, m.p. 130.9~132.6 ℃; ¹H NMR (600 MHz, CDCl₃), δ: 8.68 (d, J＝8.4 Hz, 2H, ArH), 8.18 (d, J＝7.2 Hz, 1H, ArH), 8.01 (d, J＝8.4 Hz, 1H, ArH), 7.87 (t, J＝8.4 Hz, 1H, ArH), 7.78 (d, J＝8.4 Hz, 2H, ArH), 7.58 (t, J＝7.8 Hz, 2H, ArH), 4.86 (t, J＝6.0 Hz, 2H, CH₂), 3.75 (t, J＝4.2 Hz, 4H, CH₂), 2.99 (t, J＝6.0 Hz, 2H, CH₂), 2.67 (brs, 4H, CH₂); MS (ESI) m/z: 383.4 ([M+Na]⁺). Anal. calcd for C₂₁H₂₀N₄O₂: C 69.98, H 5.59, N 15.55; found C 70.06, H 5.64, N 15.59.

4-{2-{[2-(4-乙基苯基) 喹唑啉-4-基]氧基}乙基}吗啉 (4k):白色固体, m.p. 58.1~59.2 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.48 (d, J＝8.4 Hz, 2H, ArH), 8.14 (d, J＝7.8 Hz, 1H, ArH), 7.97 (d, J＝8.4 Hz, 1H, ArH), 7.81 (t, J＝7.2 Hz, 1H, ArH), 7.46 (t, J＝7.2 Hz, 1H, ArH), 7.33 (d, J＝8.4 Hz, 2H, ArH), 4.87 (t, J＝6.0 Hz, 2H, CH₂), 3.74 (t, J＝4.8 Hz, 4H, CH₂), 2.98 (t, J＝6.0 Hz, 2H, CH₂), 2.74 (q, J＝7.2 Hz, 2H, CH₂), 2.66 (brs, 4H, CH₂), 1.29 (t, J＝7.8 Hz, 3H, CH₃); MS (ESI) m/z: 389.1 ([M+Na]⁺). Anal. calcd for C₂₅H₂₅N₃O₂: C 72.70, H 6.93, N 11.56; found C 72.78, H 6.97, N 11.59.

2-(4-乙基苯基)-3-(2-吗啉乙基) 喹唑啉-4(3H)-酮 (5k):不定形粉末; ¹H NMR (600 MHz, CDCl₃) δ: 8.31 (d, J＝8.4 Hz, 1H, ArH), 7.73~7.75 (m, 2H, ArH), 7.47~7.50 (m, 3H, ArH), 7.33 (d, J＝8.4 Hz, 1H, ArH), 4.19 (t, J＝6.6 Hz, 2H, ArH), 3.54 (t, J＝4.8 Hz, 4H, CH₂), 2.71 (q, J＝7.2 Hz, 2H, CH₂), 2.53 (t, J＝6.6 Hz, 2H, CH₂), 2.23 (brs, 4H, CH₂), 1.25 (t, J＝7.8 Hz, 3H, CH₃); MS (ESI) m/z: 389.3 ([M+Na]⁺). Anal. calcd for C₂₅H₂₅N₃O₂: C 72.70, H 6.93, N 11.56; found C 72.69, H 6.90, N 11.55.

3.2.1 化合物3的合成

10 mL圆底烧瓶中加入136 mg (1.0 mmol) 邻氨基苯甲酰胺 (1), 169 mg (1.2 mmol, 1.2 equiv.) 2-氯苯甲醛 (2a) 及5 mL二甲基亚砜 (DMSO), 在120 ℃油浴条件下加热搅拌4 h.薄层色谱 (TLC) 监测反应完全后, 反应液冷却至室温, 然后倒入100 mL水中, 搅拌, 静置, 析出白色沉淀.抽滤水洗, 最后用石油醚/乙酸乙酯 (V:V＝1:1) 重结晶得到216 mg化合物3a.

按相同的方法, 以不同取代的苯甲醛为原料, 得到了相应的中间体3b~3k.除3h外, 其余中间体化合物^[13~18]均在析出白色沉淀后, 未经提纯而直接用于化合物4和5的合成.

2-(2-氯苯基) 喹唑啉-4(3H)-酮 (3a):白色固体, 产率84.2%. m.p. 142.3~143.9 ℃(文献值^[15]: 195 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 9.95 (s, 1H, NH), 8.31 (d, J＝7.8 Hz, 1H, ArH), 7.85 (dd, J＝7.2, 1.2 Hz, 1H, ArH), 7.83~7.81 (m, 2H, ArH), 7.55~7.52 (m, 2H, ArH), 7.49 (t, J＝7.2 Hz, 1H, ArH), 7.45 (t, J＝7.8 Hz, 1H, ArH); ¹³C NMR (150 MHz, CDCl₃) δ: 161.9, 151.0, 149.1, 135.0, 132.8, 132.2, 132.0, 131.7, 130.8, 128.2, 127.7, 127.6, 126.7, 121.4; MS (ESI) m/z: 257.8 ([M+H]⁺).

2-[3-(苄氧基) 苯基]喹唑啉-4(3H)-酮 (3h):黄色固体, 产率79.8%. m.p. 203.3~204.5 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 11.37 (s, 1H, NH), 8.30 (d, J＝6.6 Hz, 1H, ArH), 7.93 (t, J＝7.8 Hz, 1H, ArH), 7.84~7.78 (m, 3H, ArH), 7.48~7.51 (m, 3H, ArH), 7.40~7.43 (m, 3H, ArH), 7.36 (t, J＝7.2 Hz, 1H, ArH), 7.20 (dd, J＝7.8, 1.8 Hz, 1H, ArH), 5.25 (s, 2H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆), δ: 162.2, 158.5, 151.9, 148.6, 136.9, 134.6, 134.0, 129.8, 128.5, 127.9, 127.7, 127.5, 126.6, 125.8, 121.0, 120.3, 118.2, 113.6, 69.5; MS (ESI) m/z: 329 ([M+H]⁺). Anal. calcd for C₂₁H₁₆N₂O₂: C 76.81, H 4.91, N 8.53; found C 76.92, H 4.86, N 8.48.

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图 1 C-2位不同芳环取代对喹唑啉-4-酮N-/O-烷基化的影响

Figure 1 Effects of the different substituents at C-2 phenyl on the N-/O-alkylation of quinazolin-4(3H)-one

下载: 全尺寸图片幻灯片

图式1 N-/O-烷基化产物4和5的合成

Scheme 1 Synthesis of the N-/O-alkylated products 4 and 5

Reagents and conditions: (a) DMSO, 120 ℃, 4 h; (b) 4-(2-chlor-O ethyl) morpholine, acetone, KI, K₂CO₃, reflux, 16 h.

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表 1 化合物3a~3k的烷基化

Table 1. Alkylation of compounds 3a~3k

Compd.	R	总产率^a/%	Yield/%		4:5
Compd.	R	总产率^a/%	4	5	4:5
a	2-Cl	62.3	10.7	51.6	1:4.8
b	2-CH₃	93.6	21.8	71.8	1:3.3
c	2-F	36.8	5.2	31.6	1:6.1
d	2-OCH₃	91.0	—^b	91.0	0:1
e	3-Cl	88.9	80.6	8.3	9.7:1
f	3-F	91.3	76.3	15.0	5.1:1
g	3-Br	93.1	81.0	12.1	6.7:1
h	3-OBn	87.0	77.2	9.8	7.9:1
i	4-Cl	82.5	82.5	—	＞10:1^c
j	4-CN	87.3	70.5	—	4.2:1^c
k	4-CH₂CH₃	94.8	71.1	23.7	2.6:1^c
^a分离产率; ^b未分离到; ^c由¹H NMR确定.

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表 2 化合物3a和3h的烷基化^a

Table 2. Alkylation of compounds 3a and 3h


Compd.	总产率^b/%	Yield/%		4:5
Compd.	总产率^b/%	4	5	4:5
aa	67.0	11.2	55.8	1:5.0
ha	78.8	62.4	16.4	3.8:1
hb	56.8	49.7	7.1	7.0:1
hc	54.0	46.2	7.8	5.9:1
hd	53.5	41.8	11.7	3.6:1
^aReagents and conditions: acetone, K₂CO₃, R¹CH₂CH₂Cl, KI, reflux, 16 h; ^bisolated yield.

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表 3 N-, O烷基化产物结构表征

Table 3. Structural characterization of the N-/Oalkylated products

Compd.	δ_H (NCH₂/OCH₂)
4a/5a	4.38~4.33, 3.62~3.72/4.81
4aa/5aa	4.39~4.34, 3.69~3.64/4.83
4h/5h	4.14/5.14
4ha/5ha	4.27/4.85
4hb/5hb	4.16/4.87
4hc/5hc	4.21/4.81
4hd/5hd	4.21/5.10

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表 4 部分化合物的抗肿瘤活性

Table 4. Antitumor activities of some compounds

Compd.	IC₅₀/(μmol•L^-1)
Compd.	Hela	MCF-7	A549
4a	＞50	＞50	＞50
5a	35.45±0.02	＞50	＞50
4aa	＞50	＞50	＞50
5aa	＞50	29.93±0.02	＞100
4h	＞50	＞50	13.20±0.14
5h	＞50	＞50	＞50
4ha	＞50	37.38±0.05	＞50
5ha	＞50	40.30±0.04	27.02±0.12
4hb	＞50	＞50	36.44±0.05
5hb	＞50	＞50	28.84±0.05
4hc	＞50	＞50	27.70±0.14
5hc	＞50	＞50	47.69±0.01
4hd	49.31±0.05	＞50	＞50
5hd	＞50	＞50	＞50
顺铂	9.91±0.01	13.10±0.02	17.00±0.01

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表 5 部分化合物的抗菌活性 (抑制率/%)^a

Table 5. Antmicrobial activities of some compounds (inhibition rate/%)

Compd.	Anti-bacteria		Anti-fungi
Compd.	Escherichia coli	Shigella castellani	Alternaria alternate	Fusarium oxysporum	Rhizoctonia solani	Verticillium dahliae
5a	98	13	66	61	14	61
5aa	100	100	100	74	43	42
4h	94	79	44	67	35	77
4ha	74	53	75	58	24	30
4hb	100	96	13	95	14	37
5h	85	—^a	88	90	82	80
Norfloxacin	98	95
Triadimefon			64	58	94	63
^a“—”表示无抑制活性.

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沈阳化工大学材料科学与工程学院沈阳 110142