WO2021012726A1 - 一种苯并咪唑并喹唑啉酮化合物的合成方法 - Google Patents

一种苯并咪唑并喹唑啉酮化合物的合成方法 Download PDF

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WO2021012726A1
WO2021012726A1 PCT/CN2020/085634 CN2020085634W WO2021012726A1 WO 2021012726 A1 WO2021012726 A1 WO 2021012726A1 CN 2020085634 W CN2020085634 W CN 2020085634W WO 2021012726 A1 WO2021012726 A1 WO 2021012726A1
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halogen
unsubstituted
formula
benzimidazoquinazolinone
alkyl
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PCT/CN2020/085634
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English (en)
French (fr)
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邹亮华
施凯
刘标
任飞
闫成
朱帅
朱昊
成宇昊
贾哲康
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江南大学
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Priority to US17/113,444 priority Critical patent/US11098049B2/en
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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

Definitions

  • the invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing a benzimidazoquinazolinone compound.
  • Quinazolinone is an important type of aromatic heterocyclic compound with benzopyrimidinone structure, which has the advantages of low toxicity, high efficiency, and unique mode of action.
  • the design, synthesis and biological activity research of this type of compound has become one of the medical research
  • Many quinazolinone compounds such as methaqualone and praziquantel (anticonvulsant drugs), raltitrexed (anticancer drugs) and ketanserin (antihypertensive drugs) have been widely used in clinical practice.
  • quinazolinone compounds have shown great development potential in the field of antibacterial and antifungal.
  • azole compounds such as imidazole, triazole, tetrazole and benzene ring-fused benzimidazole and benzotriazole and other nitrogen-containing aromatic heterocycles can interact with enzymes and receptors in a variety of organisms due to their unique structure.
  • Targets such as body interact, and can adjust and improve the physicochemical properties and pharmacokinetic properties of active molecules.
  • Benzimidazoquinazolinone compounds are the core skeleton structure of biologically active substances, synthetic drugs and natural drugs, and have a wide range of applications in biological and pharmacological research.
  • this structural unit is widely present in antibacterial agents, antibacterial agent precursors and inhibitors such as cholinesterase, and is also a key intermediate for the synthesis of some important compounds.
  • the present invention provides a method for synthesizing benzimidazoquinazolinone compounds.
  • the method is based on a novel and efficient mechanism of action and uses less catalyst to obtain better Yield, and a wide range of applicable substrates.
  • R 1 and R 3 are independently selected from unsubstituted or halogen-substituted C1-8 alkyl, halogen, C1-8 alkoxy, unsubstituted or halogen-substituted C1-8 cycloalkyl, unsubstituted aryl Group, halogen, alkyl or alkoxy substituted aryl;
  • R 2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclic group, substituent on said aryl or aromatic heterocyclic group Including: halogen, alkyl, alkoxy;
  • the ⁇ -ketoamide compound represented by formula I and the o-phenylenediamine compound represented by formula II react under the action of a catalyst and a base to obtain the benzimidazoquinazoline represented by formula III Ketone compounds.
  • the R 1 is preferably unsubstituted C1-4 alkyl, halogen, or C1-4 alkoxy.
  • the R 2 is preferably a group represented by the following structure:
  • the R 3 is preferably unsubstituted C1-4 alkyl or halogen. More preferred are F, Cl, Br, and Me.
  • the method is to perform the reaction in an air atmosphere under the action of a catalyst and alkali.
  • the organic solvent includes one or more of N,N-dimethylformamide, acetonitrile, ethanol, methanol, or 1,2-dichloroethane.
  • the catalyst is a copper catalyst, including: cuprous iodide, cuprous bromide, copper acetate, copper bromide, copper powder, copper triflate, anhydrous copper sulfate .
  • the catalyst is preferably a divalent copper catalyst. Copper bromide is more preferable.
  • the base is a strong base, including: cesium carbonate, potassium carbonate, and potassium phosphate. Cesium carbonate is preferred.
  • the reaction temperature is 100-150°C
  • the reaction time is 22-26h.
  • the ratio of the amount of the ⁇ -ketoamide represented by formula I to the o-phenylenediamine represented by formula II is 1.0:(0.85 to 0.95).
  • the ratio of the amount of the ⁇ -ketoamide shown in formula I to the amount of the catalyst and alkali is 1:(0.05-0.15):(2.5-3.5).
  • the amount of the organic solvent added is 6-14 mL/mmol based on the amount of the ⁇ -ketoamide represented by formula I.
  • the product is purified by silica gel column chromatography.
  • the purification method is as follows: after the reaction, add column chromatography silica gel, distill under reduced pressure to remove the solvent, spin dry until the silica gel adsorption product is in powder form, and then load the sample through the column. The mixture of petroleum ether and ethyl acetate was eluted and collected and concentrated by evaporation to obtain the benzimidazoquinazolinone compound.
  • the second object of the present invention is to provide a benzimidazoquinazolinone compound having the structure shown in the following formula III:
  • R 1 and R 3 are independently selected from unsubstituted or halogen-substituted C1-8 alkyl, halogen, C1-8 alkoxy, unsubstituted or halogen-substituted C1-8 cycloalkyl, unsubstituted aryl Group, halogen, alkyl or alkoxy substituted aryl.
  • the present invention has the following advantages compared with the previously reported synthesis of such benzimidazoquinazolinone compounds. Firstly, only a single catalyst is needed, the catalyst is cheap and easy to obtain, and the amount used is small. The copper catalyst is only Requires 0.1 equivalent, high catalytic efficiency, product yields are all over 47%, easy separation and purification, and good substrate universality. In this way, a variety of biologically active molecules and their skeleton molecules were synthesized. Therefore, it is of great significance to develop a synthetic method for benzimidazoquinazolinone compounds.
  • the raw material ⁇ -ketoamide compounds used in the present invention can be prepared according to existing literature, such as literature Li, P.-G.; Zhu, H.; Fan, M.; Yan, C.; Shi, K.; Chi , X.-W.; Zou, L.-H. Org. Biomol. Chem. 2019, 17, 5902-5907.
  • the present invention provides the following synthesis method:
  • the synthetic route is:
  • R 1 is H, OMe, F, Cl, Br or CF 3 ;
  • Both o-phenylenediamine compounds and benzisoxazole compounds with substituents used in the present invention can be purchased commercially.
  • the preparation method is: add N-(2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 58.2mg), o-phenylenediamine (0.2mmol, 21.6mg) to 25ml Schlenk Into the tube, add N,N-dimethylformamide (2ml) and stir at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the substance is a white solid.
  • the preparation method is: N-(2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 58.2mg), 4,5-dimethyl-1,2-phenylenediamine ( 0.2mmol, 27.2mg) was added to a 25ml Schlenk tube, N,N-dimethylformamide (2ml) was added, and the mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours.
  • the preparation method is: N-(2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 58.2mg), 4,5-difluoro-1,2-phenylenediamine (0.2 mmol, 28.8mg) was added to a 25ml Schlenk tube, N,N-dimethylformamide (2ml) was added, and the mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours.
  • the preparation method is: N-(2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 58.2mg), 4,5-dibromo-1,2-phenylenediamine (0.2 mmol, 52.8 mg) was added to a 25ml Schlenk tube, N,N-dimethylformamide (2ml) was added, and the mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours.
  • the preparation method is: N-(2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 58.2mg), 3-methyl-1,2-phenylenediamine (0.2mmol, 24.4 mg) was added to a 25 ml Schlenk tube, N,N-dimethylformamide (2 ml) was added, and the mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the material is a yellow solid.
  • the preparation method is: N-(2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 58.2mg), 4,5-dichloro-1,2-phenylenediamine (0.2 mmol, 35.2 mg) was added to a 25ml Schlenk tube, N,N-dimethylformamide (2ml) was added, and the mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours.
  • the preparation method is: add N-(4-chloro-2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 66.0mg), o-phenylenediamine (0.2mmol, 21.6mg) To a 25ml Schlenk tube, add N,N-dimethylformamide (2ml) and stir at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the material is a pale yellow solid.
  • the preparation method is: add N-(3-chloro-2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 66.0mg) and o-phenylenediamine (0.2mmol, 21.6mg) To a 25ml Schlenk tube, add N,N-dimethylformamide (2ml) and stir at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the material is a pale yellow solid.
  • the preparation method is: add N-(3-bromo-2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 76.1mg) and o-phenylenediamine (0.2mmol, 21.6mg) To a 25ml Schlenk tube, add N,N-dimethylformamide (2ml) and stir at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the preparation method is: N-(3-methoxy-2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 65.1mg), o-phenylenediamine (0.2mmol, 21.6mg) ) was added to a 25ml Schlenk tube, added with N,N-dimethylformamide (2ml), and stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the preparation method is: N-(4-methoxy-2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 65.1mg), o-phenylenediamine (0.2mmol, 21.6mg) ) was added to a 25ml Schlenk tube, added with N,N-dimethylformamide (2ml), and stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the preparation method is: add N-(4-bromo-2-formylphenyl)-2-oxo-2-phenylacetamide (0.23mmol, 76.1mg) and o-phenylenediamine (0.2mmol, 21.6mg) To a 25ml Schlenk tube, add N,N-dimethylformamide (2ml) and stir at 110°C for 12 hours. After the reaction, the reaction solution was cooled, copper acetate (0.02 mmol, 4.0 mg) and cesium carbonate (0.6 mmol, 195.5 mg) were added, and the mixture was stirred at 130°C for 12 hours. After the reaction, 200 mesh column chromatography silica gel was added, and the solvent was distilled off under reduced pressure.
  • the substance is a pale white solid.
  • Example 1 the copper acetate was replaced with the copper catalyst shown in Table 1, and other conditions were unchanged, to prepare the benzimidazoquinazolinone compound shown in III-1. The results of the reaction are shown in Table 1.
  • Example 2 the amount of the catalyst was replaced with the amount shown in Table 2, and other conditions were unchanged, to prepare the benzimidazoquinazolinone compound shown in III-1. The results of the reaction are shown in Table 2.
  • Example 1 the amount of DMF was replaced with the amount shown in Table 3, and other conditions were unchanged, to prepare the benzimidazoquinazolinone compound shown in III-1.
  • the results of the reaction are shown in Table 3.

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Abstract

本发明公开了一种苯并咪唑并喹唑啉酮化合物的合成方法，属于有机合成领域。本发明以式（I）所示的α-酮酰胺类化合物、式（II）所示的邻苯二胺类化合物为底物，在催化剂和碱的作用下，反应得到式（III）所示的苯并咪唑并喹唑啉酮化合物。本发明基于一种新颖、高效的作用机制，制备得到苯并咪唑并喹唑啉酮化合物，原料便宜，催化剂廉价易得，高效绿色，而且底物范围广，产率较高，操作简单等优点。

Description

一种苯并咪唑并喹唑啉酮化合物的合成方法 技术领域
本发明属于有机合成领域，具体涉及一种苯并咪唑并喹唑啉酮化合物的合成方法。
背景技术
喹唑啉酮是一类重要的具有苯并嘧啶酮结构的芳香杂环化合物,具有低毒、高效、作用方式独特等优点,该类化合物的设计、合成与生物活性研究已成为医药研究中一个十分活跃的领域,受到人们的广泛关注。许多喹唑啉酮类化合物如甲喹酮和吡甲苯喹酮(抗惊厥药物)、雷替曲塞(抗癌药物)以及酮色林(抗高血压药物)等已被广泛运用于临床。近年来,在抗细菌和抗真菌领域喹唑啉酮类化合物显示出巨大的开发潜力。与此同时,唑类化合物如咪唑、三唑、四唑以及苯环稠合的苯并咪唑和苯并三唑等含氮芳杂环以其独特的结构能和多种生物体内的酶和受体等作用靶点发生相互作用,并且能够调节和改善活性分子的物理化学性质和药代动力学性质。
苯并咪唑并喹唑啉酮化合物是生物活性物质、合成药物和天然药物的核心骨架结构，在生物学和药理学研究中具有广泛的应用。此外，这种结构单元广泛存在于抗菌剂、抗菌剂前体和胆碱酯酶等抑制剂中，同时也是合成一些重要的化合物的关键中间体。
现有合成苯并咪唑并喹唑啉酮化合物已有报道，用靛红与苯二胺在DMSO，O 2，130℃条件下反应得到，分离较难、得率较低。
所以，在此背景下，开发一种具有新型作用机制、能够有效合成且易分离的方法合成苯并咪唑并喹唑啉酮化合物具有很重要的意义。
发明内容
针对现有技术存在的上述不足，本发明提供了一种苯并咪唑并喹唑啉酮化合物的合成方法，该方法基于一种新颖高效的作用机制，使用较少的催化剂即可得到较好的收率，且适用底物范围广。
为实现上述目的，本发明采用如下技术方案：
一种苯并咪唑并喹唑啉酮化合物的合成方法，合成路线如下所示：
Figure PCTCN2020085634-appb-000001
其中，R 1和R 3分别独立地选自未取代或卤素取代的C1-8烷基，卤素，C1-8烷氧基，未取代或卤素取代的C1-8环烷基，未取代的芳基，卤素、烷基或烷氧基取代的芳基；R 2选自未取代或取代的芳基，未取代或取代的芳杂环基，所述芳基或芳杂环基上的取代基包括：卤素、烷基、烷氧基；
在有机溶剂中，式I所示的α-酮酰胺类化合物和式II所示的邻苯二胺类化合物在催化剂和碱的作用下，反应得到式Ⅲ所示的苯并咪唑并喹唑啉酮化合物。
在本发明的一种实施方式中，所述R 1优选未取代的C1-4烷基、卤素、C1-4烷氧基。
在本发明的一种实施方式中，所述R 2优选如下结构所示的基团：
Figure PCTCN2020085634-appb-000002
在本发明的一种实施方式中，所述R 3优选未取代的C1-4烷基、卤素。进一步优选F、Cl、Br、Me。
在本发明的一种实施方式中，所述方法是在催化剂、碱作用下，在空气气氛下进行反应。
在本发明的一种实施方式中，所述有机溶剂包括：N,N-二甲基甲酰胺、乙腈、乙醇、甲醇或1,2-二氯乙烷中的一种或多种。
在本发明的一种实施方式中，所述催化剂为铜催化剂，包括：碘化亚铜、溴化亚铜、醋酸铜、溴化铜、铜粉、三氟甲磺酸铜、无水硫酸铜。
在本发明的一种实施方式中，所述催化剂优选二价铜催化剂。进一步优选溴化铜。
在本发明的一种实施方式中，所述的碱为强碱，包括：碳酸铯、碳酸钾、磷酸钾。优选碳酸铯。
在本发明的一种实施方式中，反应温度为100～150℃，反应时间为22～26h。
在本发明的一种实施方式中，式Ι所示的α-酮酰胺与式II所示的邻苯二胺的物质的量之比为1.0:(0.85～0.95)。
在本发明的一种实施方式中，式Ι所示的α-酮酰胺与催化剂、碱的物质的量之比为1:(0.05～0.15):(2.5～3.5)。
在本发明的一种实施方式中，所述有机溶剂加入的量以式Ι所示的α-酮酰胺的物质的量 计为6～14mL/mmol。
在本发明的一种实施方式中，反应后使用硅胶柱层析分离对产物进行提纯。
在本发明的一种实施方式中，所述提纯方法为：所述反应结束后，加入柱层析硅胶，减压蒸馏除去溶剂，旋干至硅胶吸附产物粉末状后上样过柱，并以石油醚和乙酸乙酯混合液洗脱收集并蒸发浓缩得到苯并咪唑并喹唑啉酮化合物。
本发明的第二个目的是提供一种苯并咪唑并喹唑啉酮化合物，具有如下式III所示的结构：
Figure PCTCN2020085634-appb-000003
其中，R 1和R 3分别独立地选自未取代或卤素取代的C1-8烷基，卤素，C1-8烷氧基，未取代或卤素取代的C1-8环烷基，未取代的芳基，卤素、烷基或烷氧基取代的芳基。
有益效果：
相比现有技术，本发明与现有报道的合成此类苯并咪唑并喹唑啉酮化合物比较，有以下优势，首先是只需要单一催化剂，催化剂廉价易得，用量较少，铜催化剂只需0.1当量，催化效率高，产物收率均达47％以上，易分离提纯，具有较好的底物普适性。以此种方法合成了多种具有生物活性的分子及其骨架分子。因此，开发一种苯并咪唑并喹唑啉酮化合物的合成方法具有很重要的意义。
具体实施方式
下面结合具体实施例对本发明的技术方案做进一步详细说明。
本发明使用的原料α-酮酰胺类化合物可以根据现有文献自行制备，例如文献Li,P.-G.；Zhu,H.；Fan,M.；Yan,C.；Shi,K.；Chi,X.-W.；Zou,L.-H.Org.Biomol.Chem.2019,17,5902-5907。本发明提供如下合成方法：
将2,1-苯并异恶唑(0.3mmol，41.1mg)、苯甲酰甲酸(0.6mmol，90.1mg)、CuBr(PPh 3) 3(0.015mmol，13.9mg)加入到25ml的schlenk管中，在减压下，将反应管置换氩气三次。加入1,2-二氯乙烷(3ml)，在110℃下搅拌12小时。反应结束，加入100-200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝20:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产 物洗脱液，蒸发浓缩得到式I所示的邻位醛基的α-酮酰胺类化合物。
合成路线为：
Figure PCTCN2020085634-appb-000004
在本发明的一些实施例中，R 1为H、OMe、F、Cl、Br或CF 3；
R 2为
Figure PCTCN2020085634-appb-000005
Figure PCTCN2020085634-appb-000006
本发明使用的原料带取代基的邻苯二胺类化合物、苯并异恶唑类化合物均可以通过商业用途购买可得。
实施例1
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000007
制备方法为：将N-(2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,58.2mg)、邻苯二胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-1所示的苯并咪唑并喹唑啉酮化合物，产率81％。该物质为白色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ11.98(s,1H),8.35(dd,J＝18.2,7.6Hz,2H),7.87(d,J＝7.7Hz,1H),7.67(t,J＝7.3Hz,1H),7.54-7.34(m,4H)； 13C NMR(101MHz,DMSO-d 6)δ148.2,146.9,144.0,137.6,132.8,131.1,125.5,124.9,124.1,123.9,119.6,116.4, 115.2,112.3.
实施例2
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000008
制备方法为：将N-(2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,58.2mg)、4,5-二甲基-1,2-苯二胺(0.2mmol,27.2mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-2所示的苯并咪唑并喹唑啉酮化合物，产率47％。该物质为淡黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ11.90(s,1H),8.27(dd,J＝7.8,1.0Hz,1H),8.12(s,1H),7.67-7.59(m,2H),7.36(dd,J＝14.2,7.5Hz,2H),2.40(s,3H),2.38(s,3H)； 13C NMR(101MHz,DMSO-d 6)δ147.3,146.8,142.5,137.3,134.1,133.0,132.4,129.4,124.7,123.8,119.6,116.3,115.2,112.4,20.6,20.6.
实施例3
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000009
制备方法为：将N-(2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,58.2mg)、4,5-二氟-1,2-苯二胺(0.2mmol,28.8mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸 馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-3所示的苯并咪唑并喹唑啉酮化合物，产率76％。该物质为淡黄色固体。
表征数据： 1H NMR(400MHz,DMSO)δ12.08(s,1H),8.32-8.10(m,2H),7.99-7.89(m,1H),7.66(t,J＝7.3Hz,1H),7.49-7.27(m,2H)； 13C NMR(101MHz,CDCl 3)δ154.67,154.55(d,J＝2.9Hz),152.20(d,J＝14.4Hz),152.09(dd,J＝241.1,14.4Hz),151.20,144.50(d,J＝11.1Hz),142.36,137.77,130.38(dd,J＝174.4,10.3Hz),128.75,121.23,112.10(dd,J＝20.1,3.9Hz),116.71,108.11(dd,J＝23.9,10.1Hz)； 19F NMR(376MHz,CDCl 3)δ-135.49(d,J＝15.0Hz),-136.28(d,J＝14.5Hz)；HRMS m/z(ESI-TOF)calcd for C 14H 8F 2N 3O(M +H) +272.0630,found272.0625.
实施例4
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000010
制备方法为：将N-(2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,58.2mg)、4,5-二溴-1,2-苯二胺(0.2mmol,52.8mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-4所示的苯并咪唑并喹唑啉酮化合物，产率60％。该物质为棕黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ12.13(s,1H),8.57(s,1H),8.29-8.19(m,2H),7.74-7.63(m,1H),7.37(t,J＝7.7Hz,2H)； 13C NMR(101MHz,DMSO-d 6)δ150.0,146.4,144.42,137.9,133.4,131.3,125.1,124.1,123.9,120.0,119.2,118.0,116.5,111.8；HRMS m/z(ESI-TOF)calcd for C 14H 7Br 2N 3O(M+H) +391.9029,found 391.9041.
实施例5
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000011
制备方法为：将N-(2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,58.2mg)、3-甲基-1,2-苯二胺(0.2mmol,24.4mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-5所示的苯并咪唑并喹唑啉酮化合物，产率56％。该物质为黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ11.92(s,1H),8.31(d,J＝7.7Hz,1H),8.16(d,J＝7.6Hz,1H),7.63(t,J＝7.6Hz,1H),7.47-7.22(m,4H),2.66(s,3H)； 13C NMR(101MHz,DMSO-d 6)δ147.3,146.9,143.1,137.5,132.5,130.6,129.1,125.6,124.9,124.0,123.7,116.3,112.6,112.4,17.1.
实施例6
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000012
制备方法为：将N-(2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,58.2mg)、4,5-二氯-1,2-苯二胺(0.2mmol,35.2mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱 液，蒸发浓缩得到式III-6所示的苯并咪唑并喹唑啉酮化合物，产率74％。该物质为淡黄色固体。
表征数据： 1H NMR(500MHz,DMSO-d 6)δ12.13(s,1H),8.44(s,1H),8.27(d,J＝7.4Hz,1H),8.14(s,1H),7.69(t,J＝7.4Hz,1H),7.43-7.34(m,2H)； 13C NMR(126MHz,DMSO-d 6)δ150.3,146.4,143.6,137.9,133.4,130.5,128.0,126.1,125.1,124.1,120.8,116.5,116.2,111.8；HRMS m/z(ESI-TOF)calcd for C 14H 8Cl 2N 3O(M +H) +304.0039,found 304.0037.
实施例7
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000013
制备方法为：将N-(4-氯-2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,66.0mg)、邻苯二胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-7所示的苯并咪唑并喹唑啉酮化合物，产率74％。该物质为淡黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ12.10(s,1H),8.36(d,J＝7.4Hz,1H),8.26(d,J＝2.3Hz,1H),7.88(d,J＝7.3Hz,1H),7.71(dd,J＝8.7,2.4Hz,1H),7.55-7.45(m,2H),7.41(d,J＝8.8Hz,1H)； 13C NMR(101MHz,DMSO-d 6)δ147.1,146.6,143.8,136.5,132.6,131.1,127.7,125.7,124.5,123.8,119.8,118.4,115.3,113.8.
实施例8
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000014
制备方法为：将N-(3-氯-2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,66.0mg)、邻苯二 胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-8所示的苯并咪唑并喹唑啉酮化合物，产率62％。该物质为淡黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ12.06(s,1H),8.41-8.21(m,2H),7.86(s,1H),7.62-7.19(m,4H)； 13C NMR(101MHz,DMSO-d 6)δ147.4,146.7,143.9,138.7,136.8,131.0,126.7,125.6,124.4,123.9,119.7,115.7,115.2,111.3.
实施例9
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000015
制备方法为：将N-(3-溴-2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,76.1mg)、邻苯二胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-9所示的苯并咪唑并喹唑啉酮化合物，产率60％。该物质为淡黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ12.04(s,1H),8.34(d,J＝7.5Hz,1H),8.21(d,J＝8.2Hz,1H),7.86(d,J＝7.7Hz,1H),7.58-7.42(m,4H)； 13C NMR(101MHz,DMSO-d 6)δ147.5,146.7,143.9,138.8,131.0,126.7,126.7,125.6,125.4,124.4,119.7,118.7,115.2,111.60.
实施例10
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000016
制备方法为：将N-(3-甲氧基-2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,65.1mg)、邻苯二胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-10所示的苯并咪唑并喹唑啉酮化合物，产率70％。该物质为淡黄色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ11.85(s,1H),8.31(d,J＝7.8Hz,1H),8.19(d,J＝8.8Hz,1H),7.80(d,J＝7.9Hz,1H),7.52-7.35(m,2H),6.96(dd,J＝8.8,2.3Hz,1H),6.88-6.83(m,1H),3.85(s,3H)； 13C NMR(101MHz,DMSO-d 6)δ162.8,148.2,147.0,144.2,139.4,131.0,126.5,125.3,123.6,119.2,115.0,111.9,105.5,99.8,56.0.
实施例11
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000017
制备方法为：将N-(4-甲氧基-2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,65.1mg)、邻苯二胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-11所示的苯并咪唑并喹唑啉酮化合物，产率73％。该物质为淡白色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ11.82(s,1H),8.35(d,J＝7.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.70(d,J＝2.5Hz,1H),7.45(dt,J＝14.9,7.1Hz,2H),7.34-7.27(m,1H),7.27-7.18(m,1H),3.87(s,3H)； 13C NMR(101MHz,DMSO-d 6)δ155.6,148.0,146.6,143.9,131.6,131.2,125.4,124.1,121.5,119.5,117.8,115.3,112.7,106.2,56.0.
实施例12
本实施例制备苯并咪唑并喹唑啉酮化合物的结构式如下：
Figure PCTCN2020085634-appb-000018
制备方法为：将N-(4-溴-2-甲酰基苯基)-2-氧代-2-苯乙酰胺(0.23mmol,76.1mg)、邻苯二胺(0.2mmol,21.6mg)加入到25ml的Schlenk管中，加入N,N-二甲基甲酰胺(2ml)，在110℃下搅拌12小时。反应结束后，冷却反应液，加入醋酸铜(0.02mmol,4.0mg)和碳酸铯(0.6mmol,195.5mg)，在130℃下搅拌12小时。反应结束后，加入200目的柱层析硅胶，减压蒸馏除去溶剂，粗产品进行硅胶柱层析分离，并以石油醚和乙酸乙酯(石油醚：乙酸乙酯＝5:1)混合液洗脱，借助TLC洗脱跟踪检测，收集含有目标产物的洗脱液，合并所述目标产物洗脱液，蒸发浓缩得到式III-12所示的苯并咪唑并喹唑啉酮化合物，产率71％。该物质为淡白色固体。
表征数据： 1H NMR(400MHz,DMSO-d 6)δ12.05(s,1H),8.41-8.27(m,2H),7.85(d,J＝8.0Hz,1H),7.78(dd,J＝8.7,2.2Hz,1H),7.52-7.42(m,2H),7.31(d,J＝8.7Hz,1H)； 13C NMR(101MHz,DMSO-d 6)δ146.9,146.6,143.8,136.8,135.2,131.1,126.7,125.6,124.5,119.8,118.6,115.4,115.2,114.1；HRMS m/z(ESI-TOF)calcd for C 14H 8BrN 3O(M +H) +313.9923,found313.9918.
实施例13催化剂对反应的影响
参照实施例1，将醋酸铜替换为表1所示的铜催化剂，其他条件不变，制备得到III-1所示的苯并咪唑并喹唑啉酮化合物。反应结果如表1所示。
表1 不同催化剂制备苯并咪唑并喹唑啉酮化合物
Figure PCTCN2020085634-appb-000019
实施例14催化剂的用量对反应的影响
参照实施例1，将催化剂的用量替换为表2所示的添加量，其他条件不变，制备得到III-1所示的苯并咪唑并喹唑啉酮化合物。反应结果如表2所示。
表2 不同催化剂用量制备苯并咪唑并喹唑啉酮化合物
Figure PCTCN2020085634-appb-000020
Figure PCTCN2020085634-appb-000021
实施例15底物浓度对反应的影响
参照实施例1，将DMF的用量替换为表3所示的添加量，其他条件不变，制备得到III-1所示的苯并咪唑并喹唑啉酮化合物。反应结果如表3所示。
表3 不同底物浓度制备苯并咪唑并喹唑啉酮化合物
Figure PCTCN2020085634-appb-000022
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。

Claims (10)

  1. 一种苯并咪唑并喹唑啉酮化合物的合成方法，其特征在于，所述合成方法的路线如下所示：
    Figure PCTCN2020085634-appb-100001
    其中，R 1和R 3分别独立地选自未取代或卤素取代的C1-8烷基，卤素，C1-8烷氧基，未取代或卤素取代的C1-8环烷基，未取代的芳基，卤素、烷基或烷氧基取代的芳基；R 2选自未取代或取代的芳基，未取代或取代的芳杂环基，所述芳基或芳杂环基上的取代基包括：卤素、烷基、烷氧基；
    所述方法是在有机溶剂中，式I所示的α-酮酰胺类化合物和式II所示的邻苯二胺类化合物在催化剂和碱的作用下，反应得到式Ⅲ所示的苯并咪唑并喹唑啉酮化合物。
  2. 根据权利要求1所述的合成方法，其特征在于，所述R 1为未取代的C1-4烷基、卤素或C1-4烷氧基。
  3. 根据权利要求1所述的合成方法，其特征在于，所述R 2包括如下结构所示的基团：
    Figure PCTCN2020085634-appb-100002
  4. 根据权利要求1所述的合成方法，其特征在于，所述R 3为未取代的C1-4烷基或卤素。
  5. 根据权利要求1所述的合成方法，其特征在于，所述催化剂包括：碘化亚铜、溴化亚铜、醋酸铜、溴化铜、铜粉、三氟甲磺酸铜、无水硫酸铜。
  6. 根据权利要求1所述的合成方法，其特征在于，反应的温度为100～150℃，时间为22～26h。
  7. 根据权利要求1所述的合成方法，其特征在于，式Ι所示的α-酮酰胺类化合物与式II所示的邻苯二胺类化合物的物质的量之比为1.0:(0.85～0.95)。
  8. 根据权利要求1-7任一所述的合成方法，其特征在于，式Ι所示的α-酮酰胺类化合物与催化剂、碱的物质的量之比为1:(0.05～0.15):(2.5～3.5)。
  9. 根据权利要求1-8任一所述的合成方法，其特征在于，以式Ι所示的α-酮酰胺的物质的量计，所述有机溶剂的添加量为6～14mL/mmol。
  10. 一种苯并咪唑并喹唑啉酮化合物，其特征在于，具有如下式III所示的结构：
    Figure PCTCN2020085634-appb-100003
    其中，R 1和R 3分别独立地选自未取代或卤素取代的C1-8烷基，卤素，C1-8烷氧基，未取代或卤素取代的C1-8环烷基，未取代的芳基，卤素、烷基或烷氧基取代的芳基。
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