CN106749280B - 5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物及其制备方法 - Google Patents
5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物及其制备方法 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 26
- BBEYSYIVCYJTTE-UHFFFAOYSA-N 5,6-dihydroquinazoline Chemical class N1=CN=C2C=CCCC2=C1 BBEYSYIVCYJTTE-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001854 cinnolines Chemical class 0.000 title claims abstract 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- -1 quinazoline quinoline ketone Chemical class 0.000 claims abstract description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 72
- 238000010438 heat treatment Methods 0.000 claims description 34
- GRWMSCBKWMQPON-UHFFFAOYSA-N 2-aminobenzohydrazide Chemical class NNC(=O)C1=CC=CC=C1N GRWMSCBKWMQPON-UHFFFAOYSA-N 0.000 claims description 18
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- 229910052740 iodine Inorganic materials 0.000 claims description 18
- 239000011630 iodine Substances 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
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- 239000000460 chlorine Substances 0.000 claims description 5
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
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- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
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- 239000011737 fluorine Substances 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
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- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 238000003756 stirring Methods 0.000 description 32
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 27
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- RMNIWQNEYXVILU-UHFFFAOYSA-N 5-phenyl-5,6-dihydroquinazoline Chemical class C1(=CC=CC=C1)C1C=2C=NC=NC=2C=CC1 RMNIWQNEYXVILU-UHFFFAOYSA-N 0.000 description 15
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- 125000005594 diketone group Chemical group 0.000 description 5
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- 0 *C(c1ccccc1N)=* Chemical compound *C(c1ccccc1N)=* 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000551547 Dione <red algae> Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 229910002027 silica gel Inorganic materials 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- JWHYSEDOYMYMNM-QGZVFWFLSA-N 2-[4-[(2r)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid Chemical compound C([C@@H](OCC)CSC=1C=C(C)C(OCC(O)=O)=CC=1)OC1=CC=C(C(F)(F)F)C=C1 JWHYSEDOYMYMNM-QGZVFWFLSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- PIMNFNXBTGPCIL-UHFFFAOYSA-N CC(c1ccccc1Br)=O Chemical compound CC(c1ccccc1Br)=O PIMNFNXBTGPCIL-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
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- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
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- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 description 1
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- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
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- UBZJXAQDXUGXIZ-UHFFFAOYSA-N quinazoline;quinoline Chemical compound N1=CC=CC2=CC=CC=C21.N1=CN=CC2=CC=CC=C21 UBZJXAQDXUGXIZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种5H‑喹唑啉[3,2‑b]噌啉‑7,13‑二酮类化合物及其制备方法，属于新型喹唑啉酮四环化合物的合成技术领域。本发明的技术方案要点为：5H‑喹唑啉[3,2‑b]噌啉‑7,13‑二酮类化合物，具有如下结构：或
Description
技术领域
本发明属于新型喹唑啉酮四环化合物的合成技术领域，具体涉及一种5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物及其制备方法。
背景技术
含有喹唑啉酮结构单元的四环化合物作为一种重要的含氮杂环化合物，不仅广泛存在于具有重要生理活性的天然生物碱中，而且还表现出强大的抗菌、抗癌、UV-A防护及清除DPPH自由基的活性，近年来引起了有机及药物化学家越来越多的关注和研究。尽管人们对喹唑啉酮四环化合物的合成及生物活性进行了系统的研究并取得了丰硕的研究成果，但是已有的研究手段大都集中在对已知的喹唑啉酮四环骨架进行结构修饰和改造上，这在一定程度上制约了该领域的发展。因此，从简单易得的原料出发，设计并开发一类新型喹唑啉酮四环骨架的构建方法，之后将所得产物用于生物活性研究中，这将大大促进含有新型喹唑啉酮四环骨架的药物分子的发现。
发明内容
本发明解决的技术问题是提供了一种5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物及其制备方法。
本发明为解决上述技术问题采用如下技术方案，5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物，其特征在于具有如下结构： 其中R1为氢、甲基、甲氧基、氯或氟；R2为苯基、4-甲基苯基、4-甲氧基苯基、4-氟苯基或4-氯苯基；R3为氢或氯。
本发明所述的5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物的制备方法，其特征在于具体步骤为：(1)将邻溴苯乙酮类化合物1、二甲基亚砜和碘单质置于反应容器中，于110℃加热反应；(2)冷却至室温，加入2-氨基苯甲酰肼类化合物2和碱，于室温搅拌反应，之后升温至100℃搅拌反应至TLC跟踪监测反应完全，最终制得5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物3，制备过程中的反应方程式为：
其中R1、R2和R3是如上述所定义的。
进一步优选，所述的碱为K2CO3、Na2CO3、NaHCO3、K3PO4、Cs2CO3或DBU。
进一步优选，所述的邻溴苯乙酮类化合物、碘单质、2-氨基苯甲酰肼类化合物与碱的投料摩尔比为1-1.5:0.2-1.5:1:3-4.5。
本发明利用邻溴苯乙酮类化合物和2-氨基苯甲酰肼类化合物为起始原料，经由几步简单、高效的化学转化，成功制得一系列新型5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物，该制备方法具有以下显著优点：起始原料价廉易得、底物适用范围广及反应过程中避免使用过渡金属催化剂，合成的5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物具有潜在的抗肿瘤活性。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(221mg,1.6mmol)，于室温搅拌反应5h，之后于100℃加热搅拌反应6h。反应完成后，向反应瓶中加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取，有机相用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝2/1,v/v)，制得黄色固体5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(106mg,78％)。该化合物的表征数据如下：1H NMR(CDCl3,600MHz)δ7.29(t,J＝7.2Hz,1H),7.33(t,J＝7.2Hz,1H),7.37-7.41(m,3H),7.44(d,J＝7.8Hz,2H),7.58(t,J＝7.8Hz,1H),7.63-7.66(m,1H),7.85(t,J＝7.8Hz,1H),8.10(d,J＝8.4Hz,1H),8.23(d,J＝7.8Hz,1H),8.27(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ121.6,122.7,123.5,125.1,126.4,127.2,127.8,128.4,129.0,129.6,134.9,136.4,144.0,145.4,146.5,148.4,157.7,175.0(one 13C signal wasnot observed).HRMS(ESI)calcd for C21H13N3O2Na[M+Na]+362.0900,found362.0910。
实施例2
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(79.6mg,0.4mmol)，二甲基亚砜(3mL)和碘单质(102mg,0.4mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(166mg,1.2mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(92mg,68％)。
实施例3
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(79.6mg,0.4mmol)，二甲基亚砜(3mL)和碘单质(20.3mg,0.08mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(166mg,1.2mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(33mg,24％)。
实施例4
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(79.6mg,0.4mmol)，二甲基亚砜(3mL)和碘单质(50.8mg,0.2mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(166mg,1.2mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(48mg,35％)。
实施例5
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(79.6mg,0.4mmol)，二甲基亚砜(3mL)和碘单质(81.3mg,0.32mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(166mg,1.2mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(61mg,45％)。
实施例6
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(79.6mg,0.4mmol)，二甲基亚砜(3mL)和碘单质(132mg,0.52mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(166mg,1.2mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(88mg,65％)。
实施例7
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(95.5mg,0.48mmol)，二甲基亚砜(3mL)和碘单质(122mg,0.48mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(199mg,1.44mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(98mg,72％)。
实施例8
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(249mg,1.8mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(106mg,78％)。
实施例9
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和Na2CO3(191mg,1.8mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(46mg,34％)。
实施例10
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和NaHCO3(151mg,1.8mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(41mg,30％)。
实施例11
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K3PO4(382mg,1.8mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(52mg,38％)。
实施例12
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和Cs2CO3(586mg,1.8mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(92mg,68％)。
实施例13
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和DBU(274mg,1.8mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(83mg,61％)。
实施例14
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和DABCO(203mg,1.8mmol)，于室温搅拌反应5h，之后于100℃加热搅拌反应6h，未制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a。
实施例15
按实施例1所述的方法，在25mL的反应瓶中依次加入邻溴苯乙酮1a(119mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(166mg,1.2mmol),于室温搅拌反应5h，之后于100℃加热搅拌反应6h，制得产物5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3a(94mg,69％)。
实施例16
以3-甲基-5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3b的合成为例详细地阐述具体的实验步骤：
在25mL的反应瓶中依次加入2-溴-5-甲基苯乙酮1b(127mg,0.6mmol)，二甲基亚砜(3mL)和碘单质(152mg,0.6mmol)，于110℃加热搅拌反应3h，之后冷却至室温，加入2-氨基苯甲酰肼2a(90.8mg,0.4mmol)和K2CO3(221mg,1.6mmol)，于室温搅拌反应5h，之后于100℃加热搅拌反应6h。反应完成后，向反应瓶中加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取，有机相用去离子水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝2/1)，得黄色固体3-甲基-5-苯基-5H-喹唑啉[3,2-b]噌啉-7,13-二酮3b(79mg,56％)。该化合物的表征数据如下：1H NMR(CDCl3,600MHz)δ2.40(s,3H),7.14(d,J＝8.4Hz,1H),7.18(s,1H),7.30(t,J＝7.8Hz,1H),7.39(t,J＝7.8Hz,2H),7.44(d,J＝7.8Hz,2H),7.57(t,J＝7.2Hz,1H),7.84(t,J＝7.2Hz,1H),8.09(d,J＝7.8Hz,1H),8.12(d,J＝8.4Hz,1H),8.27(d,J＝8.4Hz,1H)；13C NMR(CDCl3,150MHz)δ22.4,121.37,121.40,122.6,126.5,126.8,127.1,127.7,128.3,128.8,129.6,134.8,144.1,145.5,146.7,148.3,148.5,157.7,174.6(one 13C signal was not observed).HRMS(ESI)calcd forC22H15N3O2Na[M+Na]+376.1056,found 376.1062。
利用上述的合成步骤可以以35％-76％的分离收率得到相应的5H-喹唑啉[3,2-b]噌啉-7,13-二酮3c-3s，其对应的结构式如下：
5H-喹唑啉[3,2-b]噌啉-7,13-二酮3c-3s的结构表征数据如下：
化合物3c:1H NMR(CDCl3,600MHz)δ3.90(s,3H),7.24-7.27(m,2H),7.35-7.39(m,5H),7.56(d,J＝3.0Hz,1H),7.58(t,J＝7.2Hz,1H),7.86(t,J＝7.8Hz,1H),8.10(d,J＝8.4Hz,1H),8.29(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ56.0,107.0,122.5,123.8,124.6,125.7,126.6,127.2,128.1,128.9,129.59,129.61,134.9,143.0,143.9,145.5,147.0,157.0,157.7,174.9.HRMS(ESI)calcd for C22H16N3O3[M+H]+370.1186,found370.1185。
化合物3d:1H NMR(CDCl3,600MHz)δ7.26-7.28(m,1H),7.33-7.36(m,2H),7.41-7.44(m,2H),7.46-7.47(m,2H),7.59(t,J＝7.2Hz,1H),7.86(t,J＝7.2Hz,1H),8.10(d,J＝8.4Hz,1H),8.18(d,J＝8.4Hz,1H),8.25(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ121.0,121.4,122.6,125.9,126.8,127.2,128.9,129.1,129.3,129.7,129.8,135.0,143.1,143.4,145.3,145.7,149.0,157.4,173.9.HRMS(ESI)calcd for C21H12ClN3O2Na[M+Na]+396.0510,found396.0505。
化合物3e:1H NMR(CDCl3,400MHz)δ7.27-7.32(m,1H),7.35-7.44(m,6H),7.58-7.62(m,1H),7.84-7.89(m,2H),8.10(d,J＝8.0Hz,1H),8.28(dd,J＝1.2,8.0Hz,1H)；13CNMR(CDCl3,150MHz)δ112.6(d,J＝23.0Hz,1C),122.7,124.4(d,J＝7.7Hz,1C),124.76(d,J＝7.7Hz,1C),124.80(d,J＝25.1Hz,1C),126.1,127.2,128.5,129.2,129.7,129.8,135.0,143.4,145.0,145.4,146.6,157.6,159.5(d,J＝247.2Hz,1C),174.4.HRMS(ESI)calcd forC21H13FN3O2[M+H]+358.0986,found 358.0971。
化合物3f:1H NMR(CDCl3,600MHz)δ7.12(t,J＝7.2Hz,1H),7.22(t,J＝7.8Hz,2H),7.30(d,J＝8.4Hz,2H),7.61-7.70(m,3H),7.86(t,J＝7.8Hz,1H),7.92(d,J＝8.4Hz,2H),8.05(d,J＝7.8Hz,1H),8.13(d,J＝8.4Hz,1H),8.45(d,J＝7.8Hz,1H),8.67(d,J＝8.4Hz,1H)；13C NMR(CDCl3,150MHz)δ121.8,122.7,123.5,126.07,126.11,127.0,127.2,127.5,128.1,128.2,128.5,129.4,129.6,129.8,130.4,135.0,137.3,145.6,146.5,146.8,149.2,158.9,177.1.HRMS(ESI)calcd for C25H16N3O2[M+H]+390.1237,found 390.1231。
化合物3g:1H NMR(CDCl3,600MHz)δ6.83(d,J＝5.4Hz,1H),7.37-7.40(m,1H),7.41-7.43(m,2H),7.45-7.47(m,2H),7.57(t,J＝7.2Hz,1H),7.80(d,J＝5.4Hz,1H),7.87(t,J＝7.2Hz,1H),8.14(d,J＝8.4Hz,1H),8.21(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ119.9,120.7,121.7,125.2,127.0,128.6,129.0,129.4,129.8,135.0,139.0,142.5,144.7,145.5,153.8,157.5,167.2.HRMS(ESI)calcd for C19H12N3O2S[M+H]+346.0645,found 346.0642。
化合物3h:1H NMR(CDCl3,600MHz)δ2.32(s,3H),7.18(d,J＝7.8Hz,2H),7.30(t,J＝7.8Hz,1H),7.34-7.37(m,3H),7.57(t,J＝7.2Hz,1H),7.63(t,J＝8.4Hz,1H),7.85(t,J＝7.8Hz,1H),8.10(d,J＝8.4Hz,1H),8.22(d,J＝7.8Hz,1H),8.27(d,J＝8.4Hz,1H)；13CNMR(CDCl3,150MHz)δ21.1,121.3,122.7,123.1,124.8,126.6,127.1,127.7,128.9,129.6,130.2,134.8,136.4,138.6,143.86,143.88,145.4,148.7,157.6,174.9.HRMS(ESI)calcdfor C22H16N3O2[M+H]+354.1237,found 354.1240。
化合物3i:1H NMR(CDCl3,600MHz)δ2.32(s,3H),2.39(s,3H),7.11(d,J＝8.4Hz,1H),7.13(s,1H),7.18(d,J＝8.4Hz,2H),7.34(d,J＝7.8Hz,2H),7.56(t,J＝7.8Hz,1H),7.84(t,J＝7.2Hz,1H),8.09(d,J＝8.4Hz,1H),8.11(d,J＝7.8Hz,1H),8.26(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ21.1,22.4,121.0,121.1,122.6,126.5,126.7,127.1,127.6,128.7,129.5,130.2,134.8,138.6,143.97,144.01,145.5,148.3,148.8,157.7,174.5.HRMS(ESI)calcd for C23H18N3O2[M+H]+368.1394,found 368.1385。
化合物3j:1H NMR(CDCl3,600MHz)δ2.34(s,3H),7.21(d,J＝7.8Hz,2H),7.24(m,1H),7.32(s,1H),7.35(d,J＝8.4Hz,2H),7.57(t,J＝7.8Hz,1H),7.85(t,J＝8.4Hz,1H),8.09(d,J＝7.8Hz,1H),8.17(d,J＝8.4Hz,1H),8.25(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ21.1,120.8,121.1,122.7,125.6,126.9,127.1,129.0,129.2,129.6,130.4,134.9,139.2,143.0,143.1,143.3,145.3,149.3,157.4,173.9.HRMS(ESI)calcd forC22H14ClN3O2Na[M+Na]+410.0667,found 410.0668。
化合物3k:1H NMR(CDCl3,600MHz)δ3.77(s,3H),6.88(d,J＝9.0Hz,2H),7.28-7.30(m,2H),7.42(d,J＝9.0Hz,2H),7.57(t,J＝7.2Hz,1H),7.60-7.63(m,1H),7.83-7.86(m,1H),8.09(d,J＝8.4Hz,1H),8.22-8.23(m,1H),8.27(d,J＝8.4Hz,1H)；13C NMR(CDCl3,150MHz)δ55.5,114.6,121.3,122.7,122.9,124.6,127.1,127.6,128.76,128.83,129.6,134.8,136.4,138.8,143.7,145.4,149.1,157.6,159.4,174.8.HRMS(ESI)calcd forC22H16N3O3[M+H]+370.1186,found 370.1189。
化合物3l:1H NMR(CDCl3,600MHz)δ3.79(s,3H),6.91(d,J＝9.0Hz,2H),7.23-7.25(m,2H),7.42(d,J＝9.0Hz,2H),7.58(t,J＝7.2Hz,1H),7.85(t,J＝7.2Hz,1H),8.09(d,J＝8.4Hz,1H),8.17(d,J＝9.0Hz,1H),8.25(d,J＝8.4Hz,1H)；13C NMR(CDCl3,150MHz)δ55.5,114.8,120.7,120.9,122.7,125.5,127.1,128.97,129.01,129.1,129.6,134.9,137.9,143.0,143.2,145.3,149.6,157.4,159.7,173.8.HRMS(ESI)calcd for C22H14ClN3O3Na[M+Na]+426.0616,found 426.0587。
化合物3m:1H NMR(CDCl3,600MHz)δ7.07(t,J＝8.4Hz,2H),7.29-7.34(m,2H),7.47-7.49(m,2H),7.59(t,J＝7.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.86(t,J＝7.8Hz,1H),8.09(d,J＝8.4Hz,1H),8.23(d,J＝7.8Hz,1H),8.27(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ116.5(d,J＝23.0Hz,2C),121.4,122.6,123.2,125.1,127.1,127.8,129.05,129.11(d,J＝9.9Hz,2C),129.6,135.0,136.5,142.2(d,J＝3.3Hz,1C),143.6,145.4,148.4,157.6,161.9(d,J＝248.4Hz,1C),174.7.HRMS(ESI)calcd for C21H13FN3O2[M+H]+358.0986,found 358.0970。
化合物3n:1H NMR(CDCl3,600MHz)δ2.40(s,3H),7.06-7.09(m,3H),7.14(d,J＝8.4Hz,1H),7.46-7.49(m,2H),7.58(t,J＝7.8Hz,1H),7.85(t,J＝7.2Hz,1H),8.09(d,J＝7.8Hz,1H),8.13(d,J＝7.8Hz,1H),8.26(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ22.4,116.5(d,J＝23.0Hz,2C),121.1,121.2,122.6,126.8,127.1,127.7,128.9,129.2(d,J＝8.9Hz,2C),129.6,134.9,142.3(d,J＝3.3Hz,1C),143.8,145.4,148.4,148.6,157.7,161.1,174.3.HRMS(ESI)calcd for C22H15FN3O2[M+H]+372.1143,found 372.1144。
化合物3o:1H NMR(CDCl3,600MHz)δ7.34-7.36(m,4H),7.39-7.40(m,2H),7.60(t,J＝7.2Hz,1H),7.66(t,J＝8.4Hz,1H),7.87(t,J＝7.2Hz,1H),8.10(d,J＝8.4Hz,1H),8.23(d,J＝7.8Hz,1H),8.28(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ121.5,122.6,123.6,125.4,127.1,127.89,127.91,129.2,129.7,129.8,134.3,135.0,136.5,143.8,144.9,145.4,148.0,157.6,174.8.HRMS(ESI)calcd for C21H13ClN3O2[M+H]+374.0691,found374.0699。
化合物3p:1H NMR(CDCl3,600MHz)δ3.91(s,3H),7.25-7.27(m,1H),7.30-7.34(m,5H),7.56(d,J＝3.0Hz,1H),7.60(t,J＝7.2Hz,1H),7.86(t,J＝7.8Hz,1H),8.09(d,J＝8.4Hz,1H),8.29(d,J＝7.8Hz,1H)；13C NMR(CDCl3,150MHz)δ56.0,107.2,122.4,123.7,124.7,126.6,127.1,127.2,129.1,129.7,129.8,133.9,135.0,142.5,143.7,145.5,157.2,157.7,174.8(one 13C signal was not observed).HRMS(ESI)calcd forC22H14ClN3O3Na[M+Na]+426.0616,found 426.0595。
化合物3q:1H NMR(CDCl3,600MHz)δ7.30-7.35(m,2H),7.38-7.41(m,3H),7.43-7.44(m,2H),7.65(t,J＝7.2Hz,1H),7.78(dd,J＝1.8,8.4Hz,1H),8.04(d,J＝9.0Hz,1H),8.22-8.23(m,2H)；13C NMR(CDCl3,150MHz)δ121.5,123.3,123.6,125.2,126.5,127.8,128.6,129.7,131.2,135.1,135.5,136.5,143.9,144.0,146.3,148.3,156.6,174.6(one13C signal was not observed).HRMS(ESI)calcd for C21H12ClN3O2Na[M+Na]+396.0510,found396.0501。
化合物3r:1H NMR(CDCl3,600MHz)δ2.40(s,3H),7.14-7.16(m,2H),7.31(t,J＝7.2Hz,1H),7.39(t,J＝7.8Hz,2H),7.43-7.44(m,2H),7.77(dd,J＝1.8,8.4Hz,1H),8.03(d,J＝9.0Hz,1H),8.12(d,J＝7.8Hz,1H),8.22(d,J＝2.4Hz,1H)；13C NMR(CDCl3,150MHz)δ22.4,121.22,121.24,123.6,126.5,126.6,126.9,127.7,128.5,129.6,131.1,135.0,135.4,143.9,144.1,146.4,148.4,148.5,156.7,174.2.HRMS(ESI)calcd forC22H14ClN3O2Na[M+Na]+410.0667,found 410.0660。
化合物3s:1H NMR(CDCl3,400MHz)δ7.28(dd,J＝1.6,8.4Hz,1H),7.33-7.38(m,2H),7.41-7.47(m,4H),7.78(dd,J＝2.4,8.8Hz,1H),8.03(d,J＝8.8Hz,1H),8.18(d,J＝8.4Hz,1H),8.21(d,J＝2.4Hz,1H)；13C NMR(CDCl3,100MHz)δ120.9,121.2,123.6,125.9,126.5,126.9,129.1,129.3,129.9,131.2,135.3,135.5,143.2,143.4,143.8,145.5,148.9,156.4,173.6.HRMS(ESI)calcd for C21H11Cl2N3O2Na[M+Na]+430.0121,found430.0120。
以上实施例描述了本发明的基本原理、主要特征及优点，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (3)
1.一种5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物的制备方法，其特征在于具体步骤为：(1)将邻溴苯乙酮类化合物1、二甲基亚砜和碘单质置于反应容器中，于110℃加热反应；(2)冷却至室温，加入2-氨基苯甲酰肼类化合物2和碱，于室温搅拌反应，之后升温至100℃搅拌反应至TLC跟踪监测反应完全，最终制得5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物3，制备过程中的反应方程式为：
其中R1为氢、甲基、甲氧基、氯或氟；R2为苯基、4-甲基苯基、4-甲氧基苯基、4-氟苯基或4-氯苯基；R3为氢或氯。
2.根据权利要求1所述的5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物的制备方法，其特征在于：所述的碱为K2CO3、Na2CO3、NaHCO3、K3PO4、Cs2CO3或DBU。
3.根据权利要求1所述的5H-喹唑啉[3,2-b]噌啉-7,13-二酮类化合物的制备方法，其特征在于：所述的邻溴苯乙酮类化合物、碘单质、2-氨基苯甲酰肼类化合物与碱的投料摩尔比为1-1.5:0.2-1.5:1:3-4.5。
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