阅读说明：本技术 一种二元萘胺类化合物及其制备方法与应用 (Dinaphthylamine compounds, and preparation method and application thereof ) 是由 陈修文 徐盛挺 师建毅 李雅雯 罗小利 杨志海 邓亦秋 李亦彪 于 2020-06-30 设计创作，主要内容包括：本发明公开了一种二元萘胺类化合物及其制备方法与应用,所述二元萘胺类化合物的化学通式如下式I所示：<Image he="160" wi="700" file="DDA0002562501740000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sup>1</Sup>选自取代或未取代的苄胺、取代或未取代的苯乙胺；R<Sup>2</Sup>和R<Sup>3</Sup>分别独立的选自氢、烷基或苯基。将二羟基萘类化合物、伯胺类化合物、催化剂、弱酸盐、氢源和水混合,在加热条件下反应,得到所述二元萘胺类化合物。本发明方案的化合物结构新颖,具有高的生物活性；该类化合物对人白血病细胞K562、人早幼粒急性白血病细胞HL60、BGC-823细胞和人宫颈癌Hela细胞具有良好的抑制作用,因此,该类化合物既作为抗肿瘤试剂用于体外抗肿瘤活性筛选中,也可用于防治肿瘤的药物制备中。(The invention discloses a dinaphthylamine compound, a preparation method and application thereof, wherein the chemical general formula of the dinaphthylamine compound is shown as the following formula I: wherein R is 1 Selected from substituted or unsubstituted benzylaminesSubstituted or unsubstituted phenethylamines; r 2 And R 3 Each independently selected from hydrogen, alkyl or phenyl. Mixing a dihydroxynaphthalene compound, a primary amine compound, a catalyst, a weak acid salt, a hydrogen source and water, and reacting under a heating condition to obtain the dinaphthylamine compound. The compound of the scheme of the invention has novel structure and high biological activity; the compounds have good inhibition effect on human leukemia cells K562, human promyelocytic acute leukemia cells HL60, BGC-823 cells and human cervical cancer Hela cells, so the compounds are used as antitumor agents for in vitro antitumor activity screening and can also be used in preparation of medicaments for preventing and treating tumors.)

1. A dinaphthylamine compound is characterized in that: the chemical general formula of the dinaphthylamine compounds is shown as the following formula I:

wherein R is¹Selected from substituted or unsubstituted benzylamine, substituted or unsubstituted phenethylamine; r²And R³Each independently selected from hydrogen, alkyl or phenyl.

2. The dinaphthylamine compound of claim 1, wherein: the substituted substituent is selected from halogen or alkoxy; preferably, the substituents are selected from fluoro or methoxy.

3. The dinaphthylamine compound of claim 1, wherein: the alkyl is selected from alkyl with 1-4 carbon atoms; preferably, the alkyl group is methyl.

4. A preparation method of a dinaphthylamine compound is characterized by comprising the following steps: the method comprises the following steps:

will twoMixing a hydroxynaphthalene compound, a primary amine compound, a catalyst, a weak acid salt, a hydrogen source and water, and reacting under a heating condition to obtain a dinaphthylamine compound; wherein the primary amine compound is selected from R¹-NH₂OrR¹Selected from substituted or unsubstituted benzylamine, substituted or unsubstituted phenethylamine; r²And R³Each independently selected from hydrogen, alkyl or phenyl.

5. The method of claim 4, wherein: the heating temperature is 80-160 ℃; preferably 100-150 ℃; more preferably 100 to 120 ℃.

6. The method of claim 4, wherein: the dihydroxynaphthalene compound is selected from at least one of the following structural formulas:

preferably, the molar ratio of the primary amine compound to the dihydroxynaphthalene compound is (1-5): (1-5); preferably (2-4): (2-5).

7. The method of claim 4, wherein: the catalyst is selected from Pd/C, PdCl₂、Pd(PPh₃)₄Or Pd (dba)₂At least one of; preferably, the molar ratio of the primary amine compound to the catalyst is 1 (0.03-0.20); preferably 1: (0.03-0.10); more preferably 1: (0.03-0.50).

8. The method of claim 4, wherein: the weak acid salt is at least one of bisulfite or pyrobisulfite; preferably, the weak acid salt is selected from at least one of potassium salt, sodium salt or ammonium salt; preferably, the molar ratio of the primary amine compound to the weak acid salt is 1: (0.5 to 2); preferably 1: (1-2); more preferably 1 (1.5-2).

9. Use of a compound according to any one of claims 1 to 3 for the preparation of an anti-tumor screening agent or an anti-tumor medicament; preferably, the tumour comprises leukaemia, gastric carcinoma and/or cervical carcinoma.

10. Use of a compound according to any one of claims 1 to 3 in the preparation of inhibitors of human leukemia cell K562, human promyelocytic acute leukemia cell HL60, gastric cancer cell BGC-823 and/or human cervical cancer cell Hela.

Technical Field

The invention relates to the technical field of synthesis, in particular to a dinaphthylamine compound and a preparation method and application thereof.

Background

The naphthylamine compound has wide application in various aspects of medicinal chemistry, electronic performance materials and the like, such as (a) sertraline which is firstly marketed in the United kingdom in 1990, is approved as the only medicine for preventing the recurrence of melancholia, has no sedative or excitant effect, has no inhibitory effect on choline resistance or monoamine oxidase, and can improve the compliance effect; (b) n-phenyl-1-naphthylamine (1-NPN) is a novel hole transport material, has good thermal stability, and can be used as an organic electroluminescent material or a blue luminescent material. Wherein the structural formulas of sertraline and NPN are as follows:

the wide application of the naphthylamine compounds has attracted great interest in the development of naphthylamine compounds with novel structures and the research on the process synthesis of the naphthylamine compounds. In the prior art, the naphthylamine compound is usually prepared by coupling reaction of aryl halide and nitrogen-containing compound, namely copper-catalyzed improved Ullmann reaction and palladium-catalyzed Buhward-Hartvich reaction, wherein the two reactions use the aryl halide compound as a substrate and need copper or palladium as a catalyst, and the pure metal catalyst is expensive, and most of the solvents used in the catalysis process are organic solvents such as toluene and the like, so that the naphthylamine compound has the defects of strong toxicity, volatility, difficulty in recovery and the like, and is easy to pollute the environment and hurt the human body.

With the gradual increase of environmental pollution, the green chemistry concept gradually becomes an important trend of social development. In order to fit the green chemistry concept, researchers first need to continuously explore and use environment-friendly reaction solvents, and safe, green, cheap and easily available water is the most conceivable solvent and the most economical and environment-friendly solvent. Therefore, the method for synthesizing the naphthylamine compound by taking water as a reaction medium to search for the optimal reaction condition and high synthesis efficiency has important significance for the naphthylamine compound and the application industry thereof.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a dinaphthylamine compound which is novel in structure and has high biological activity.

The invention also provides a green preparation method of the dinaphthylamine compounds.

The invention also provides application of the compound.

The dinaphthylamine compounds according to the first aspect of the invention have a chemical general formula shown in formula I below:

wherein R is¹Selected from substituted or unsubstituted benzylamine, substituted or unsubstituted phenethylamine; r²And R³Each independently selected from hydrogen, alkyl or phenyl.

According to some embodiments of the invention, the substituted substituent is selected from halogen or alkoxy; preferably, the substituents are selected from fluoro or methoxy.

According to some embodiments of the invention, the alkyl group is selected from alkyl groups of 1 to 4 carbon atoms; preferably, the alkyl group is methyl.

The compounds according to embodiments of the present invention have at least the following beneficial effects: the compound of the scheme of the invention has novel structure and high biological activity; the compounds have good inhibition effect on human leukemia cells K562, human promyelocytic acute leukemia cells HL60, BGC-823 cells and human cervical cancer Hela cells, so the compounds are used as antitumor agents for in vitro antitumor activity screening and can also be used in preparation of medicaments for preventing and treating tumors.

The preparation method according to the second aspect embodiment of the present invention comprises the steps of:

mixing a dihydroxynaphthalene compound, a primary amine compound, a catalyst, a weak acid salt, a hydrogen source and water, and reacting under a heating condition to obtain a dinaphthylamine compound; wherein the primary amine compound is selected from R¹-NH₂OrR¹Selected from substituted or unsubstituted benzylamine, substituted or unsubstituted phenethylamine; r²And R³Each independently selected from hydrogen, alkyl or phenyl.

In the preparation process, the reaction equation is as follows:

according to some embodiments of the invention, the temperature of the heating conditions is between 80 and 160 ℃; preferably 100-150 ℃; more preferably 100 to 120 ℃.

According to some embodiments of the invention, the reaction time is 1 to 24 hours; preferably 3-18 h; more preferably 14 to 17 hours.

According to some embodiments of the invention, the dihydroxynaphthalene compound is selected from at least one of the following structural formulas:

according to some embodiments of the invention, the weak acid salt is selected from at least one of a bisulfite or a metabisulfite; preferably, the weak acid salt is selected from at least one of potassium salt, sodium salt or ammonium salt.

According to some embodiments of the invention, the hydrogen source is selected from at least one of an alcohol, an organic acid salt, or hydrogen gas; preferably, the alcohol is selected from 1-4 carbon alcohols; more preferably, the alcohol is selected from methanol or isopropanol; preferably, the organic acid or the organic acid salt contains 1-4 carbons; more preferably, the organic acid is selected from formic acid.

According to some embodiments of the invention, the catalyst is selected from Pd/C, PdCl₂、Pd(PPh₃)₄Or Pd (dba)₂At least one of (1).

According to some embodiments of the invention, the molar ratio of the primary amine compound to water is 1 (10-20); preferably 1 (10-15); more preferably 1: 10.

According to some embodiments of the invention, the molar ratio of the primary amine compound to the weak acid salt is 1: (0.5 to 2); preferably 1: (1-2); more preferably 1 (1.5-2).

According to some embodiments of the invention, the molar ratio of primary amine-based compound to hydrogen source is 1: (1-4); preferably 1: (1-2).

According to some embodiments of the invention, the molar ratio of the primary amine compound to the catalyst is 1 (0.03-0.20); preferably 1: (0.03-0.10); more preferably 1: (0.03-0.50).

According to some embodiments of the invention, the molar ratio of the primary amine compound to the dihydroxynaphthalene compound is (1-5): (1-5); preferably (2-4): (2-5).

According to some embodiments of the invention, the preparation method further comprises a step of purifying the product after the reaction; preferably, the purification is column chromatography; more preferably, the purification process comprises: diluting the reaction solution, filtering, decompressing, rotary steaming and removing the solvent to obtain a crude product, and purifying the crude product by column chromatography; further preferably, the eluent used for the column chromatography purification is a mixture of petroleum ether, dichloromethane and ethyl acetate; still further preferably, the volume ratio of the petroleum ether, the dichloromethane and the ethyl acetate is (0.5-50): (0-20): 1.

the preparation method according to the embodiment of the invention has at least the following beneficial effects: according to the scheme of the invention, water is used as a solvent in the preparation process, an organic solvent is not required, the preparation condition is mild, the preparation method is green and environment-friendly, the steps are simple, the operation is safe, the raw materials are cheap and easy to obtain, and the preparation method has good selectivity and high atom economy and can well accord with the green chemical development concept.

According to the application of the third aspect of the invention, the compound is applied to preparing an anti-tumor screening reagent or an anti-tumor medicine.

According to some embodiments of the invention, the tumor comprises leukemia, gastric cancer and/or cervical cancer.

According to the application of the third aspect of the invention, the compound is applied to the preparation of inhibitors of human leukemia cells K562, human promyelocytic acute leukemia cells HL60, gastric cancer cells BGC-823 and/or human cervical cancer cells Hela.

The application of the embodiment of the invention has at least the following beneficial effects: the binary naphthylamine compound prepared by the invention has a certain inhibiting effect on K562 cells, HL-60 cells, HeLa cells and BGC-823 cells, and shows that the compound has a certain anti-tumor cell activity and has a potential application value in anti-tumor cell medicines.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

FIG. 1 is a hydrogen spectrum of compound 3a obtained in example 1 of the present invention;

FIG. 2 is a carbon spectrum of compound 3a obtained in example 1 of the present invention;

FIG. 3 is a hydrogen spectrum of compound 3b obtained in example 2 of the present invention;

FIG. 4 is a carbon spectrum of compound 3b obtained in example 2 of the present invention;

FIG. 5 is a hydrogen spectrum of compound 3c obtained in example 3 of the present invention;

FIG. 6 is a carbon spectrum of compound 3c obtained in example 3 of the present invention;

FIG. 7 is a hydrogen spectrum of compound 3d obtained in example 4 of the present invention;

FIG. 8 is a carbon spectrum of compound 3d obtained in example 4 of the present invention;

FIG. 9 is a hydrogen spectrum of compound 3e obtained in example 5 of the present invention;

FIG. 10 is a carbon spectrum of compound 3e obtained in example 5 of the present invention;

FIG. 11 is a hydrogen spectrum of compound 3f obtained in example 6 of the present invention;

FIG. 12 is a carbon spectrum of compound 3f obtained in example 6 of the present invention;

FIG. 13 is a hydrogen spectrum of 3g of the compound obtained in example 7 of the present invention;

FIG. 14 is a carbon spectrum of 3g of the compound obtained in example 7 of the present invention;

FIG. 15 is a hydrogen spectrum of compound 3h obtained in example 7 of the present invention;

FIG. 16 is a carbon spectrum of compound 3h obtained in example 7 of the present invention.

Detailed Description

In order to explain technical contents, achieved objects, and effects of the present invention in detail, the following description is made with reference to the accompanying drawings in combination with the embodiments. The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available reagents and materials unless otherwise specified.

The first embodiment of the invention is as follows: dinaphthylamine compounds, N²,N⁷-diphenylnaphthalene-2, 7-diamine (3a) has the following structure:

N²,N⁷the preparation method of-diphenylnaphthalene-2, 7-diamine (3a) is as follows:

uniformly mixing 2, 7-dinaphthol (2mmol,0.32g), phenethylamine (3mmol,0.36g), Pd/C (0.1mol,0.01g), potassium bisulfate (1mmol,0.14g), ammonium formate (4mmol,0.25g) and water (10mL) in a reaction vessel, reacting at 80 ℃ for 24 hours, cooling to room temperature after the reaction is finished, filtering, decompressing and carrying out rotary evaporation to remove unreacted substances to obtain a crude product, and purifying the crude product by column chromatography to obtain N²,N⁷-diphenylenenaphthalene-2, 7-diamine, compound 3 a. Compound 3a was a yellow oil in 72% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3a are respectively shown in fig. 1 and fig. 2, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.48(d,J＝8.7Hz,2H),7.38–7.34(m,4H),7.30–7.27(m,6H),6.71(s,2H),6.61(d,J＝8.6Hz,2H),3.52(t,J＝7.0Hz,4H),3.01(t,J＝7.0Hz,4H).

¹³C NMR(126MHz,CDCl₃)146.2,139.4,136.9,128.9,128.8,128.6,126.4,121.7,114.0,103.5,45.1,35.4.

the molecular weight of the resulting compound 3a was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₂₆H₂₇N₂[M+H]⁺Theoretical value of (Calcd): 367.2169, respectively; actual measured value (found): 367.2167.

the second embodiment of the invention is as follows: dinaphthylamine compounds, N²,N⁷-bis (4-fluorophenethyl) naphthalene-2,7-diamine (3b) has the following structure:

N²,N⁷the preparation method of bis (4-fluorophenethyl) naphthalene-2,7-diamine (3b) is as follows:

in a reaction vessel, 2, 7-dinaphthol (2mmol,0.32g), 4-fluorophenylethylamine (3mmol,0.42g), PdCl₂(0.1mol,0.02g), sodium bisulfite (2mmol,0.21g), isopropanol (4mmol,0.24g) and water (10mL) are mixed uniformly, reacted at 160 ℃ for 3 hours, cooled to room temperature after the reaction is finished, filtered, decompressed and evaporated to remove unreacted substances to obtain a crude product, and the crude product is purified by column chromatography to obtain N²,N⁷Bis (4-fluorophenethyl) naphthalene-2,7-diamine (3b), compound 3 b. Compound 3b was a yellow oil in 68% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3b are respectively shown in fig. 3 and 4, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.57(d,J＝8.5Hz,2H),7.29–7.21(m,4H),7.09(dd,J＝10.7,6.5Hz,4H),6.78(s,2H),6.67(dd,J＝8.6,1.9Hz,2H),3.70(s,2H),3.52(t,J＝7.0Hz,4H),2.99(t,J＝7.0Hz,4H).

¹³C NMR(126MHz,CDCl₃)161.7(d,J＝244.2Hz),146.2,137.1,135.2(d,J＝2.9Hz),130.3(d,J＝8.0Hz),128.9,121.8,115.5(d,J＝21.1Hz),114.2,103.6,45.2,34.6.

the molecular weight of the resulting compound 3b was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₂₆H₂₅F₂N₂[M+H]⁺Theoretical value of (Calcd): 403.1980, respectively; actual measured value (found): 403.1968.

the third embodiment of the invention is as follows: dinaphthylamine compounds, N²,N⁷-bis (4-methoxyphenethyl) naphthane-2, 7-diamine (3c) having the following structure:

N²,N⁷the preparation method of-bis (4-methoxyphenethyl) naphthalene-2,7-diamine (3c) is as follows:

in a reaction vessel, 2, 7-dinaphthol (2mmol,0.32g), 2- (4-methoxyphenyl) ethylamine (4mmol,0.60g), Pd (PPh)₃)₄(0.2mmol,0.23g), sodium metabisulfite (3mmol,0.57g), sodium formate (5mmol,0.34g) and water (10mL) are uniformly mixed, reacted at 100 ℃ for 4 hours, cooled to room temperature after the reaction is finished, filtered, decompressed and evaporated to remove unreacted substances to obtain a crude product, and the crude product is purified by column chromatography to obtain N²,N⁷Bis (4-fluorophenethyl) naphthalene-2,7-diamine (3c), compound 3 c. Compound 3c was a yellow oil in 75% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3c are respectively shown in fig. 5 and 6, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.55(d,J＝8.7Hz,1H),7.24(d,J＝8.5Hz,2H),6.96(d,J＝8.6Hz,2H),6.78(s,1H),6.66(dd,J＝8.7,1.9Hz,1H),3.87(s,3H),3.52(t,J＝7.0Hz,2H),2.98(t,J＝7.0Hz,2H)；

¹³C NMR(126MHz,CDCl₃)158.3,146.4,137.1,131.5,129.9,128.9,121.7,114.2,114.1,103.6,55.4,45.4,34.5.

the molecular weight of the resulting compound 3c was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₂₈H₃₁N₂O₂[M+H]⁺Theoretical value of (Calcd): 427.2380, respectively; actual measured value (found): 427.2391.

the fourth embodiment of the invention is as follows: dinaphthylamine compounds, N²,N⁶-bis (4-methylphenylthio) naphthalene-2,6-diamine (3d) having the following structure:

N²,N⁶the preparation method of (4-methylphenylthio) naphthalene-2,6-diamine (3d) is as follows:

in a reaction vessel, 2, 6-dinaphthol (2mmol,0.32g), 2- (4-methylphenyl) ethylamine (3mmol,0.70g), Pd (dba)₂(0.3mmol,0.17g), potassium metabisulfite (2mmol,0.44g), methanol (4mmol,0.13g) and water (10mL) are uniformly mixed, the mixture reacts at the temperature of 100 ℃ for 14 hours, the reaction product is cooled to room temperature after the reaction is finished, crude products are obtained by filtering and decompressing rotary evaporation to remove unreacted substances, and the crude products are purified by column chromatography to obtain N²,N⁶Bis (4-methylphenylthio) naphthalene-2,6-diamine (3d), Compound 3 d. Compound 3d was a brown oil in 67% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3d are respectively shown in fig. 7 and 8, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.55(d,J＝8.5Hz,2H),7.31–7.21(m,8H),6.78(d,J＝1.8Hz,2H),6.66(dd,J＝8.3,2.0Hz,2H),3.55(t,J＝6.7Hz,4H),3.02(t,J＝6.7Hz,4H),2.44(s,6H)；

¹³C NMR(126MHz,CDCl₃)146.3,137.0,136.4,136.0,129.4,128.8,121.7,114.2,103.6,45.3,34.9,21.2。

the molecular weight of the resulting compound 3d was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₂₈H₃₁N₂[M+H]⁺Theoretical value of (Calcd): 395.2482, respectively; the actual measured value (found) 395.2493.

The fifth embodiment of the invention is as follows: dinaphthylamine compounds, N²,N⁶-dibenzylnaphthalene-2,6-diamine (3e) having the following structure:

N²,N⁶-dibenzylnaphthalene-2,6-diamine (3e) was prepared as follows:

uniformly mixing 2, 6-dinaphthol (2mmol,0.32g), benzylamine (2mmol,0.21g), Pd/C (0.2mmol,0.02g), ammonium sulfite (3mmol,0.35g), formic acid (6mmol,0.28g) and water (10mL) in a reaction vessel, reacting at 120 ℃ for 4 hours, cooling to room temperature after the reaction is finished, filtering, carrying out reduced pressure rotary evaporation to remove unreacted substances to obtain a crude product, and carrying out column chromatography purification on the crude product to obtain N²,N⁶-dibenzylnaphthalene-2,6-diamine (3e), compound 3 e. Compound 3e was a brown oil in 67% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3e are respectively shown in fig. 9 and fig. 10, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.51(d,J＝8.5Hz,2H),7.43(d,J＝7.4Hz,4H),7.37(t,J＝7.5Hz,4H),7.32(d,J＝7.3Hz,2H),6.76–6.67(m,2H),4.43(s,4H)；

¹³C NMR(126MHz,CDCl₃)145.6,138.8,136.6,128.9,128.7,127.9,127.4,122.3,114.4,104.5,48.8。

the molecular weight of the resulting compound 3e was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₂₄H₂₃N₂[M+H]⁺Theoretical value of (Calcd): 339.1856, respectively; actual measured value (found): 339.1868.

the sixth embodiment of the invention is as follows: a binaphthylamine compound, 1,2,3, 4-tetrahydrobenzol [ g ] quinoxaline (3f), having the following structural formula:

the 1,2,3, 4-tetrahydrobenzol [ g ] quinoxaline (3f) is prepared as follows:

in a reaction vessel, 2, 3-dinaphthol (2mmol,0.32g), ethylenediamine (3mmol,0.18g), Pd (PPh)₃)₄(0.4mmol,0.46g), sodium bisulfite (4mmol,0.42g), sodium formate (8mmol,0.54g) and water (10mL) are mixed uniformly, reacted for 15 hours at 150 ℃, cooled to room temperature after the reaction is finished, filtered, decompressed and evaporated to remove unreacted substances to obtain a crude product, and the crude product is purified by column chromatography to obtain 1,2,3, 4-tetrahydrobenzol [ g ]]quinoxaline (3f), compound 3 f. Compound 3f was a brown oil in 72% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3f are respectively shown in fig. 11 and 12, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.48(dd,J＝6.1,3.3Hz,2H),7.14(dd,J＝6.2,3.2Hz,2H),6.81(s,2H),3.51(s,4H)；

¹³C NMR(126MHz,CDCl₃)135.1,129.0,125.1,122.5,107.9,41.1。

the molecular weight of 3g of the compound obtained was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₁₂H₁₃N₂[M+H]⁺Theoretical value of (Calcd): 185.1073, respectively; actual measured value (found): 185.1066.

the seventh embodiment of the invention is: a dinaphthylamine compound, 2-methyl-1,2,3, 4-tetrahydrobenzol [ g ] quinoxaline (3g), has the following structure:

the preparation method of 2-methyl-1,2,3, 4-tetrahydrobenzol [ g ] quinoxaline (3g) is as follows:

in a reaction vessel, 2, 3-dinaphthol (2mmol,0.32g), 1, 2-propanediamine (4mmol,0.30g), Pd/C (0.4mol,0.04g), potassium bisulfite (2mmol,0.24g), ammonium formate (5mmol,0.32g) and water (10mL) are uniformly mixed, the mixture reacts at 120 ℃ for 7 hours, after the reaction is finished, the mixture is cooled to room temperature, crude products are obtained by filtering and reduced pressure rotary evaporation to remove unreacted substances, and the crude products are purified by column chromatography to obtain 2-methyl-1,2,3, 4-tetrahydrobenozo [ g ] quinoxaline (3g), namely 3g of compounds. Compound 3g was a brown oil in 66% yield.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3g are respectively shown in fig. 13 and 14, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.52–7.43(m,2H),7.17–7.12(m,2H),6.80(d,J＝1.7Hz,2H),3.64(ddd,J＝8.6,6.3,3.0Hz,1H),3.40(dd,J＝10.6,3.1Hz,1H),3.15(dd,J＝10.6,8.5Hz,1H),1.26(d,J＝6.3Hz,3H)；

¹³C NMR(126MHz,CDCl₃)135.1,134.8,129.0,128.9,125.2,125.1,122.5,122.4,107.6,107.4,47.9,45.7,19.9。

the molecular weight of 3g of the compound obtained was determined by High Resolution Mass Spectrometry (HRMS) by electrospray ionization (ESI): c₁₃H₁₅N₂[M+H]⁺Theoretical value of (Calcd): 199.1230, respectively; actual measured value (found): 199.1222.

the eighth embodiment of the present invention is: a dinaphthylamine compound, 2,3-diphenyl-1,2,3, 4-tetrahydrobenzol [ g ] quinoxaline (3h), has the following structure:

the preparation method of 2,3-diphenyl-1,2,3, 4-tetrahydrobenzol [ g ] quinoxaline (3h) is as follows:

in a reaction vessel, 2, 3-dinaphthol (5mmol,1.3g), 1, 2-diphenylethylenediamine (2mmol,0.42g), PdCl₂(0.1mol,0.02g), sodium metabisulfite (2mmol,0.38g), sodium formate (6 m)Uniformly mixing 0.41g of mol and 10mL of water, reacting for 18 hours at 150 ℃, cooling to room temperature after the reaction is finished, filtering, decompressing and rotary distilling to remove unreacted substances to obtain a crude product, and purifying the crude product by column chromatography to obtain the 2,3-diphenyl-1,2,3, 4-tetrahydrobenzol [ g []quinoxaline (3h), compound 3 h. Compound 3h was a brown oil with a yield of 65%.

The reaction route is as follows:

the hydrogen spectrum and the carbon spectrum of the obtained compound 3h are respectively shown in fig. 15 and 16, and the structural characterization data are as follows:

¹H NMR(500MHz,CDCl₃)7.52–7.43(m,2H),7.17–7.12(m,2H),6.80(d,J＝1.7Hz,2H),3.64(ddd,J＝8.6,6.3,3.0Hz,1H),3.40(dd,J＝10.6,3.1Hz,1H),3.15(dd,J＝10.6,8.5Hz,1H),1.26(d,J＝6.3Hz,3H)；

¹³C NMR(126MHz,CDCl₃)139.8,135.0,128.9,128.3,128.1,127.9,125.3,122.8,107.6,62.1。

the molecular weight of the resulting compound was determined by electrospray ionization (ESI) High Resolution Mass Spectrometry (HRMS) for 3 h: c₂₄H₂₁N₂[M+H]⁺Theoretical value of (Calcd): 337.1699, respectively; actual measured value (found): 337.1693.

the products obtained in examples 1 to 8 were tested for antitumor cell activity.

(1) The test method comprises the following steps: each compound was prepared to 100. mu.g/mL^-1The methanol solution, positive control drugs of 5-fluorouracil (5-FU) and docetaxel (docetaxel) are respectively prepared into 100 mu g/mL^-1The DMSO solution is prepared by taking methanol and DMSO solvents as blank controls respectively, and testing the inhibition effect of each compound on K562 cells, HL-60 cells, HeLa cells and BGC-823 cells by adopting an MTT method.

(2) Preparing a cell culture solution: a bag of RPMI-1640 medium powder (Net wt 10.4g) was poured into a clean beaker, dissolved with 900mL of ultra-pure water, and 100 mg. mL _ was added^-11mL streptomycin, 0.5mL penicillin and NaHCO₃2g of the total weight. After magnetic stirring, the mixture was sterilized in a super clean bench by filtration through a 0.22 μm filter using an autoclaved Zeiss filter, and the filtrate was directly stored in a moist heat-sterilized glass bottle (450 mL/bottle). Before the culture medium is used, the frozen and preserved serum is taken, inactivated at 56 ℃ for 30min, added into the prepared RPMI-1640 culture solution (50 mL of serum is added into 450mL of culture medium), and covered, sealed by tinfoil paper and stored in a refrigerator at 4 ℃. Preparing an MTT solution: 50mg of MTT (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide) powder was dissolved in 10mL of PBS solution, filtered through a 0.22 μm filter, and stored in a refrigerator at 4 ℃.

(3) Anti-tumor activity test: respectively taking K562 cells, HL-60 cells, HeLa cells and BGC-823 cells in logarithmic phase, centrifuging at 4 deg.C and 3000rpm for 3min, removing supernatant, adding fresh RPMI-1640 culture medium, and diluting to 1 × 10⁵Cell suspension per ml. 200. mu.L per well were inoculated in a 96-well plate at 37 ℃ with 5% CO₂After culturing for 1h in the cell culture box, 2 μ L of sample solution is added to each well, each sample is provided with 3 parallel wells, two groups of blank controls with three wells are additionally arranged, and after sample addition, the cells are cultured for 24h under the same conditions. And after 24h, observing whether the cells have morphological changes under an optical microscope, preliminarily judging whether the samples have cytotoxic activity, and photographing if necessary. 5 mg/mL of the solution was added to each well^-120. mu.L of each MTT solution was cultured in an incubator for 4 hours. The supernatant was removed by centrifugation (20 min at 2000rpm at 4 ℃) using a 96-well plate, 150. mu.L DMSO was added to each well, and the plate was shaken well to dissolve the purple precipitate completely. The optical density OD was measured at 570nm on a microplate reader, and the average value of each sample was calculated as IR% (OD)_{Blank space}-OD_{Sample (I)})/OD_{Blank space}X 100% formula the inhibition ratio (IR%) was calculated.

The MTT method was used to test the proliferation inhibitory activity of compounds 3a-3h on four tumor cells, and the results are shown in Table 1 below:

TABLE 1 MTT assay results of proliferation inhibitory Activity of Compounds 3a-3h on four tumor cells

As can be seen from Table 1, the binary naphthylamine compound prepared by the invention has a certain inhibition effect on K562 cells, HL-60 cells, HeLa cells and BGC-823 cells, and shows that the compound has a certain antitumor cell activity and has potential application value in antitumor cell medicines. Wherein, the proliferation inhibition effect of the compounds such as 3e, 3g and 3h on K562 cells is equivalent to that of the existing drugs such as 5-fluorouracil and docetaxel.

The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent changes made by using the contents of the present specification and the drawings, or applied directly or indirectly to the related technical fields, are included in the scope of the present invention.