A 2,6-naphthidine small molecule derivative and its preparation method

Abstract

This invention relates to a 2,6-naphthidine small molecule derivative and its preparation method. The structural formula of the derivative is shown in Formula 1 and / or Formula 2. The novel 2,6-naphthidine small molecule derivative designed and synthesized by this invention has a relatively simple synthesis step and diverse derivatized structures, including aromatic heterocycles, straight chains or branched alkyl groups, which is conducive to the large-scale promotion and application of 2,6-naphthidine derivative structures.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a 2,6-naphthidine small molecule derivative and its preparation method. Background Technology

[0002] Naphthidine compounds are isomeric heterocyclic systems formed by the fusion of two pyridine rings, also known as diaminonaphthalene and pyridopyridine, and possess a certain degree of aromaticity. Each nitrogen atom has one unbonded sp atom. 2 Its hybrid orbitals and the presence of a lone pair of electrons give it a certain degree of basicity, making it a good electron donor.

[0003] The synthesis of naphthidine compounds mainly follows the methods used for quinoline preparation, including the Friedlaender reaction, Combes reaction, and Gould-Jacobs reaction. The Friedlaender reaction offers mild conditions, high yield and stability, and good regiometry and selectivity, and has been widely used to construct various novel naphthidine compounds. The Combes reaction is a common method for synthesizing quinoline compounds, often using pyridineamines and 1,3-dicarbonyl compounds to prepare naphthidine derivatives. The Gould-Jacobs reaction is one of the classic strategies for the modern synthesis of hydroxyquinolines. For example, the condensation of diethyl 2-(1-ethoxyethyl)malonate with aniline forms an enamine intermediate, which, through an intramolecular Gould-Jacobs cyclization reaction, yields 4-hydroxy-2-methyl-1,6-naphthidine-3-carboxylic acid. This reaction can be used to synthesize various highly functionalized hydroxylated naphthidine compounds. However, these methods are mainly used for 1,8-naphthidine and 1,6-naphthidine derivatives, and their application in the synthesis of 2,6-naphthidine is extremely rare.

[0004] Montreal had previously proposed a complete synthesis of 2,6-naphthidine using ethyl pyridine as a reactant. The process involved oxidation, cyanation, amidation, cyanation, cyclization, and hydrogenation of the product to obtain the target compound. However, the reaction process was overly cumbersome, the synthesis complex, and prone to batch-limiting issues, and the reagents used were highly toxic. In 2010, Liu Jing synthesized 2,6-naphthidine using 2-methylpyrazine as a starting material through condensation, elimination, double bond addition, amino protection, cycloaddition / elimination, and deprotection reactions. This method used more readily available reactants, increased the yield, and eliminated the use of highly toxic cyanide. Alfred Taurins started with 4-cyano-3-pyridylacetonitrile and obtained 4-methyl-2,6-naphthidine through coupling, cyclization, and hydrogenation, but the reaction still involved cyanide, and the derived structure was simple.

[0005] Currently, there is limited research on the synthesis methods of 2,6-naphthoidine derivatives, and the existing 2,6-naphthoidine derivative structures are few and relatively simple, making it difficult to widely promote and apply 2,6-naphthoidine derivatives in various fields. Summary of the Invention

[0006] The purpose of this invention is to overcome the above-mentioned technical deficiencies and provide a 2,6-naphthidine small molecule derivative and its preparation method, thereby solving the technical problems that there are few 2,6-naphthidine derivative structures in the prior art and that the synthesis process usually requires the use of highly toxic cyanides.

[0007] To achieve the above-mentioned technical objectives, the technical solution provided by this invention is as follows:

[0008] In a first aspect, the present invention provides a 2,6-naphthidine small molecule derivative, the structural formula of which is shown in Formula 1 and / or Formula 2 below:

[0009] ;

[0010] Where Ar is selected from , , , , , , , , , , , or ;

[0011] X2 can be any type of halogen atom;

[0012] R1 is a single or multiple substituted functional group, wherein the functional group is any one of the following: a straight-chain alkyl group of C1-C20, a branched alkyl group of C1-C20, an aralkyl group of C5-C20, and an aromatic ether group of C5-C20;

[0013] R2 is a single or multiple substituted functional group, wherein the functional group is any one of the following: straight-chain alkyl group (C1-C20), branched alkyl group (C1-C20), alkoxy group (C1-C20), and aralkyl group (C5-C10).

[0014] Secondly, the present invention provides a method for preparing 2,6-naphthidine small molecule derivatives, comprising the following steps:

[0015] 1) Compound 3 and compound 4 undergo a coupling reaction to generate compound 5;

[0016] 2) Compound 5 and N1,N4-dimethylfumaramide undergo a coupling reaction to generate compound 6;

[0017] 3) Compound 6 undergoes a demethylation reaction with PO(X2)3 to yield compound 7;

[0018] 4) Compound 7 reacts with PO(X2)3 in a pressure-resistant tube to obtain compound 1;

[0019] And / or, also includes the following steps:

[0020] 5) Compound 1 was coupled with an organometallic reagent via transition metal catalysis to obtain compound 2;

[0021] The reaction synthesis route is shown below:

[0022]

[0023]

[0024] In R2MBr, M can be any one of Mg, Cu, Fe, Zn, and Li.

[0025] Compared with the prior art, the beneficial effects of the present invention include:

[0026] This invention synthesizes a novel 2,6-naphthidine derivative through a very simple method involving coupling and demethylation reactions, followed by cyclization and aromatization. This eliminates the need for highly toxic cyanide as a raw material. The synthetic method is simple, and the resulting compound exhibits good solubility (soluble in common solvents such as dichloromethane and chloroform) and absorption energy levels. Compared to other polymer materials, the advantages of small molecule compounds lie in their defined structure, high product purity (above 98%), and high yield. The novel 2,6-naphthidine small molecule derivatives designed and synthesized in this invention have relatively simple synthetic steps and diverse derived structures, including aromatic heterocycles, straight-chain or branched alkyl groups, which is beneficial for the large-scale promotion and application of 2,6-naphthidine derivative structures. Attached Figure Description

[0027] Figure 1 The NMR spectrum of compound 6a in Example 1 of this invention; Figure 1 (a) is the proton spectrum, and (b) is the carbon spectrum.

[0028] Figure 2 The NMR spectrum of compound 7a in Example 1 of this invention; Figure 2 (a) is the proton spectrum, and (b) is the carbon spectrum.

[0029] Figure 3 The NMR spectrum of compound 1a in Example 1 of this invention; Figure 3 (a) is the proton spectrum, and (b) is the carbon spectrum.

[0030] Figure 4 The NMR spectrum of compound 2a-1 in Example 1 of this invention; Figure 4 (a) is the proton spectrum, and (b) is the carbon spectrum.

[0031] Figure 5(a) shows the UV absorption of compound 2a-1 in toluene solvent in Example 1; Figure 5(b) shows the UV absorption of compound 2a-1 in different solvents in Example 1.

[0032] Figure 6(a) shows the oxidation curve of ferrocene in dichloromethane, Figure 6(b) shows the oxidation curve of ferrocene in tetrahydrofuran, Figure 6(c) shows the complete redox curve of compound 2a-1 in Example 1, Figure 6(d) shows the oxidation curve of compound 2a-1 in dichloromethane in Example 1, and Figure 6(e) shows the reduction curve of compound 2a-1 in tetrahydrofuran in Example 1.

[0033] Figure 7(a) is the proton spectrum of compound 6b in Example 2 of the present invention, and Figure 7(b) is the carbon spectrum of compound 6b in Example 2 of the present invention.

[0034] Figure 8(a) is the proton spectrum of compound 1b in Example 2 of the present invention; Figure 8(b) is the carbon spectrum of compound 1b in Example 2 of the present invention.

[0035] Figure 9(a) is the proton spectrum of compound 2b in Example 2 of the present invention; Figure 9(b) is the carbon spectrum of compound 2b in Example 2 of the present invention. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0037] Abbreviation Explanation

[0038] Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium dichloride

[0039] NEt3: Triethylamine

[0040] PO(X2)3: Phosphorus trihalomethane

[0041] DCM: Dichloromethane

[0042] THF: Tetrahydrofuran

[0043] This invention provides a 2,6-naphthidine small molecule derivative, the structural formula of which is shown in Formula 1 and / or Formula 2 below:

[0044] ;

[0045] Where Ar is selected from , , , , , , , , , , , or ;

[0046] X2 can be any type of halogen atom;

[0047] R1 is a single or multiple substituted functional group, wherein the functional group is any one of the following: a straight-chain alkyl group of C1-C20, a branched alkyl group of C1-C20, an aralkyl group of C5-C20, and an aromatic ether group of C5-C20;

[0048] R2 is a single or multiple substituted functional group, wherein the functional group is any one of the following: straight-chain alkyl group (C1-C20), branched alkyl group (C1-C20), alkoxy group (C1-C20), and aralkyl group (C5-C10).

[0049] This invention provides a method for preparing the above-mentioned 2,6-naphthidine small molecule derivatives, which includes the following steps:

[0050] 1) Compound 3 and compound 4 undergo a coupling reaction to generate compound 5;

[0051] 2) Compound 5 and N1,N4-dimethylfumaramide undergo a coupling reaction to generate compound 6;

[0052] 3) Compound 6 undergoes a demethylation reaction with PO(X2)3 to yield compound 7;

[0053] 4) Compound 7 reacts with PO(X2)3 in a pressure-resistant tube to obtain compound 1;

[0054] 5) Compound 1 was coupled with an organometallic reagent via transition metal catalysis to obtain compound 2;

[0055] The reaction synthesis route is shown below:

[0056]

[0057] ;

[0058] In the above process, Ar is selected from , , , , , , , , , , , or ;

[0059] R1 is a single or multiple substituted functional group, wherein the functional group is any one of the following: a straight-chain alkyl group of C1-C20, a branched alkyl group of C1-C20, an aralkyl group of C5-C20, and an aromatic ether group of C5-C20;

[0060] R2 is a single or multiple substituted functional group, wherein the functional group is any one of the following: straight-chain alkyl, branched alkyl, alkoxy and aralkyl groups of C1-C20;

[0061] In PO(X2)3 and compound 3, X2 can be any of the halogen atoms;

[0062] In R2MBr, M can be any one of Mg, Cu, Fe, Zn, and Li.

[0063] Compounds 3, 4, and PO(X2)3 can be purchased as commercially available products or prepared according to literature methods. Compounds 1 and 2 are both yellow solids. Both exhibit excellent solubility and are soluble in common organic solvents such as dichloromethane, chloroform, and tetrahydrofuran.

[0064] Preferably, in the above preparation method, in step 1), compound 3 and compound 4 undergo a coupling reaction under the action of catalyst A and CuI, wherein catalyst A is a palladium catalyst selected from at least one of tetra(triphenylphosphine)palladium, tris(dibenzylideneacetone)palladium, bis(1,4-biphenylphosphine)butylpalladium dichloride, palladium acetate, and bis(triphenylphosphine)palladium dichloride.

[0065] More preferably, in step 1), the molar ratio of compound 3 to compound 4 is 1:1 to 1.5.

[0066] More preferably, in step 1), the molar ratio of compound 3 to catalyst A is 1:0.01 to 0.1; the molar ratio of compound 3 to CuI is 1:0.01 to 0.05, more preferably 1:0.02 to 0.04.

[0067] Preferably, step 2) is a coupling reaction involving the addition of compound 5, N1,N4-dimethylfumaramide, copper acetate, catalyst B, and a base.

[0068] More preferably, the catalyst B is a ruthenium catalyst, selected from at least one of p-cymene ruthenium dichloride dimer, diiodo(p-cymene)ruthenium(II) dimer, (p-cymene)tricyclohexylphosphine ruthenium(II) chloride, and (p-cymene)bis(tristylenylcarboxyl)ruthenium(II);

[0069] More preferably, the alkali is at least one selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, and sodium acetate;

[0070] More preferably, in step 2), the molar ratio of compound 5 to N1,N4-dimethylfumaramide is 2-2.5:1, the molar ratio of compound 5 to catalyst B is 1:0.001-0.1, the molar ratio of compound 5 to base is 1:1-10, and the molar ratio of compound 5 to copper acetate is 2-2.5:4.

[0071] Preferably, the raw materials for the demethylation reaction in steps 3) and 4) further include tetrabutylammonium halide and an organic solvent; the molar ratio of compound 6 or compound 7 to tetrabutylammonium halide is 1:5 to 10; the ratio of compound 6 or compound 7 to organic solvent is (3 to 10) mmol: (100 to 150) mL.

[0072] PO(X2)3 includes phosphorus oxychloride or phosphorus tribromooxychloride;

[0073] When phosphorus oxychloride is used, it is a liquid and serves as both a reactant and a solvent. The volume ratio of phosphorus oxychloride to the organic solvent is 1:1 to 100, more preferably 1:1.1 to 100, and even more preferably 1:1.9 to 2.1.

[0074] When using phosphorus tribromooxyphosphorus, the molar ratio of compound 6 or compound 7 to phosphorus tribromooxyphosphorus is 1:1 to 100;

[0075] Preferably, in the demethylation reactions of steps 3) and 4), the halogen atoms in tetrabutylammonium halide are the same as those in PO(X2)3, to avoid generating mixed products with different halogenation states.

[0076] Preferably, in step 5), the molar ratio of compound 1 to R2MBr is 1:2 to 48;

[0077] Preferably, in step 5), compound 1 and R2MBr solution undergo a coupling reaction under the action of catalyst C.

[0078] More preferably, catalyst C is selected from at least one of tetra(triphenylphosphine)palladium, tris(dibenzylideneacetone)palladium, bis(1,4-biphenylphosphine)butylpalladium dichloride, palladium acetate, and bis(triphenylphosphine)palladium dichloride; the molar ratio of compound 1 to catalyst C is 1:0.01 to 0.15.

[0079] Preferably, the reaction temperature of all reactions is 0 to 160°C and the reaction time is 4 to 120 h; and the demethylation reaction temperature in step 3) is lower than the demethylation reaction temperature in step 4).

[0080] Further preferably, the demethylation reaction in step 3) is carried out at atmospheric pressure and 80–120°C for 2.5–3.5 h;

[0081] Further preferred, the demethylation reaction in step 4) is carried out in a pressure-resistant tube at 150–160°C for 3–5 days.

[0082] More preferably, the coupling reactions in steps 1) and 5) are both carried out at 15–45°C for 10–36 h; the coupling reaction in step 2) is carried out at 110–140°C for 15–25 h.

[0083] All reactions were carried out in organic solvents;

[0084] The organic solvent mentioned in step 1) is selected from at least one of triethylamine, ethylenediamine, and diisopropylamine;

[0085] The organic solvents described in steps 2), 3), 4) and 5) are selected from at least one of toluene, diethyl ether, N,N-dimethylformamide, N-methylpyrrolidone, 1,2-dichloroethane, tetrahydrofuran, dichloromethane, carbon tetrachloride and chloroform.

[0086] This invention provides a novel, highly soluble, and easily synthesized conjugated 2,6-naphthidine derivative. Different aromatic heterocyclic-terminated and alkyl-chain-modified 2,6-naphthidine derivatives were designed and synthesized. The flexible introduction of different aromatic heterocyclic termini alters the LUMO and HOMO energy levels of the molecule, thus changing its photoelectric properties to some extent. Simultaneously, the introduction of alkyl chains of varying lengths improves the molecule's solubility, making it readily soluble in most organic solvents and facilitating purification. Furthermore, the simple synthetic method of the target molecule in this invention is beneficial for the large-scale accumulation of the product.

[0087] In the preparation method of this invention, compounds 3 and 4 are used as starting materials, which are widely available. Compound 4 has an alkynyl end group, and compound 5 is obtained in a coupling reaction catalyzed by cuprous salt and transition metals such as Pd. The reaction can be carried out at room temperature, which is relatively mild. Then, compound 6 is generated by a coupling reaction with N1,N4-dimethylfumaramide. The reaction needs to be carried out in a pressure-resistant tube at a slightly higher temperature and pressure. By reacting at a lower temperature and a shorter reaction time, compound 6 is demethylated with PO(X2)3 to obtain compound 7. Then, under higher temperature and higher pressure conditions, the reaction time is extended to generate compound 1. The purity and yield of the product are high.

[0088] The unique structure of the 2,6-naphthidine derivatives of this invention enables them to be studied and applied in biomedical research, photochemistry, electrochemistry, and luminescent materials. Their complex and diverse synthetic structures, along with their potential pharmacological activities, will undoubtedly play an increasingly important role in the construction of a friendly ecological environment and the development of human society in the near future.

[0089] The present invention will be further described in detail below through specific embodiments.

[0090] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the experimental materials and reagents used in the following examples are all available through conventional commercial channels.

[0091] Example 1

[0092]

[0093] 1) Synthesis of compound 5a

[0094] Pd(PPh3)2Cl2 (1.6 mmol, 0.04 eq) and CuI (0.8 mmol, 0.02 eq) were weighed into a dry 500 mL double-necked flask. 2-Iodothiophene (40 mmol, 1 eq) and NET3 (120 mL) were added, and after purging with argon, 4a (40 mmol, 1 eq) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent in the system was removed by rotary evaporation using diatomaceous earth as a filter aid. The product was purified by silica gel column chromatography to obtain compound 5a in 60% yield, with a purity of 98.13% and a molecular weight of 122.02.

[0095] 2) Synthesis of compound 6a

[0096] N1,N4-dimethylfumaramide (22.3 mmol, 1 eq), copper acetate hydrate (89.2 mmol, 4 eq), potassium carbonate (89.2 mmol, 4 eq), and p-cymene ruthenium dichloride dimer (2.2 mmol, 0.1 eq) were weighed sequentially into a pressure-resistant tube. Compound 5a (49.1 mmol, 2.2 eq) was added to 1,2-dichloroethane (240 mL), and the mixture was reacted at 120 °C for 20 h. After the reaction, the mixture was filtered with diatomaceous earth as an aid, and the solvent was removed by rotary evaporation. Compound 6a was purified by silica gel column chromatography with a yield of 53%, a purity of 99.02%, and a molecular weight of 382.08.

[0097] The NMR spectrum of compound 6a is as follows: Figure 1As shown, the specific values ​​are: 1H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 5.1 Hz, 2H), 7.15 (t, J = 4.4 Hz, 2H), 7.01 (d, J = 4.5 Hz, 2H), 3.30 (s, 6H), 2.39 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 161.58, 135.97, 135.75, 131.03, 129.17, 127.97, 127.55, 116.93, 34.97, 18.85.

[0098] 3) Synthesis of compound 7a

[0099] Compound 6a (7.8 mmol, 1 eq) and tetrabutylammonium chloride (54.6 mmol, 7 eq) were added to a round-bottom flask. 1,2-Dichloroethane (120 mL) and phosphorus oxychloride (60 mL) were added, and the mixture was refluxed at 110 °C for 3 h. Care should be taken to control the moisture content in the container during the addition of reagents; increased moisture content will significantly increase the amount of byproducts and significantly reduce the product yield. Phosphorus oxychloride was used as both a reactant and a solvent, with a volume ratio of 1:1.9–2.1 to 1,2-dichloroethane. Reducing the amount of phosphorus oxychloride will decrease the product yield (the yield decreased to 60% when the volume ratio of phosphorus oxychloride to 1,2-dichloroethane was 1:1). After the reaction, the solvent in the system was removed by rotary evaporation, the dichloromethane was dissolved, the reaction was quenched with saturated sodium bicarbonate solution, and then extracted three times with saturated brine and dichloromethane. After extraction, the solvent in the system was removed by rotary evaporation, and the compound 7a was obtained by purification by silica gel chromatography with a yield of 80%, a purity of 99.23%, and a molecular weight of 386.03.

[0100] The NMR spectrum of compound 7a is as follows: Figure 2As shown, the specific ¹H NMR (400 MHz, Chloroform-d) values ​​are: δ 7.54 (d, J = 6.4 Hz, 1H), 7.45 (t, J = 4.8 Hz, 2H), 7.19 – 7.16 (m, 1H), 7.12 (t, J = 4.4 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 3.28 (s, 3H), 3.05 (s, 3H), 2.36 (s, 3H). The ¹³C NMR (101 MHz, Chloroform-d) values ​​are: δ 160.67, 147.94, 143.52, 141.36, 135.37, 134.41, 132.83, 129.29. 129.15, 128.44, 127.69, 127.24, 126.87, 126.61, 126.47, 111.08, 33.93, 19.27, 18.61.

[0101] 4) Synthesis of compound 1a

[0102] Compound 7a (3.87 mmol, 1 eq) and tetrabutylammonium chloride (38.7 mmol, 10 eq) were added to a dry, pressure-resistant tube. After adding 1,2-dichloroethane (150 mL) and phosphorus oxychloride (75 mL), the reaction mixture was reacted at 150 °C for 4 days. The reaction mixture should be thoroughly stirred and completely immersed in the heating medium; otherwise, the yield of the target product will decrease (from 55% to 35%). The reaction time should be at least 4 days; otherwise, the starting material will not react completely. After the reaction, the solvent in the system was removed by rotary evaporation, dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent in the system was removed by rotary evaporation, and compound 1a was purified by silica gel column chromatography with a yield of 55%, a purity of 98.53%, and a molecular weight of 389.98.

[0103] The NMR spectrum of compound 1a is as follows: Figure 3 As shown, the specific values ​​are: ¹H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 4.9 Hz, 4H), 7.20 – 7.15 (m, 2H), 3.07 (s, 6H); ¹³C NMR (101 MHz, Chloroform-d) δ 147.68, 146.16, 142.25, 132.51, 129.31, 128.58, 127.81, 123.51, 21.88.

[0104] 5) Synthesis of compound 2a-1

[0105] Compound 1a (2.56 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.384 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 100 mL of dry toluene was added to the flask. Since methylmagnesium bromide is extremely sensitive to moisture, the moisture content must be kept at trace levels before adding methylmagnesium bromide. A methylmagnesium bromide solution (40.96 mmol, 16 eq) was slowly added at 40 °C. The reaction solution should be fully preheated before adding methylmagnesium bromide, and the solution should be added slowly dropwise. Otherwise, the rapid expansion of the gas volume due to the excessively fast reaction rate may cause the reaction liquid to spray out. The reaction was allowed to proceed overnight. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the solvent in the system was removed by rotary evaporation of the organic phase. The product was purified by silica gel column chromatography to obtain compound 2a-1 with a yield of 70%, a purity of 98.21%, and a molecular weight of 350.09.

[0106] The NMR spectrum of compound 2a-1 is as follows: Figure 4 As shown, the specific values ​​are: 1H NMR (400 MHz, Chloroform-d) δ 7.44 (dd, J = 8.1, 4.4 Hz, 1H), 3.08 (s, 1H), 2.91 (s, 1H). 13C NMR (101 MHz, Chloroform-d) δ 155.35, 146.28, 144.80, 132.71, 128.04, 127.65, 127.43, 121.73, 29.48, 21.67.

[0107] Synthesis of compound 2a-2

[0108] Compound 1a (2.56 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.384 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 100 mL of dry toluene was added to the flask. A solution of phenylmagnesium bromide (40.96 mmol, 16 eq) was slowly added at 40 °C, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the organic phase was evaporated by rotary evaporation to remove the solvent. The product was purified by silica gel column chromatography to give compound 2a-2 in 63% yield, with a purity of 99.15% and a molecular weight of 474.12.

[0109] Synthesis of compound 2a-3

[0110] Compound 1a (2.56 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.384 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 100 mL of dry toluene was added to the flask. A solution of 2-methoxyphenyl magnesium bromide (40.96 mmol, 16 eq) was slowly added at 40 °C, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the organic phase was evaporated by rotary evaporation to remove the solvent. The product was purified by silica gel column chromatography to give compound 2a-3 in 45% yield, with a purity of 99.01% and a molecular weight of 534.69.

[0111] Performance testing

[0112] The compound 2a-1 in Example 1 above was subjected to optical and electrochemical measurements, as detailed below.

[0113] Optical testing: The optical band gap of compound 2a-1 was measured using a UV-Vis absorption spectrometer. Hexane (HEX), toluene (Tol), chloroform (TCM), dichloromethane (DCM), tetrahydrofuran (THF), and N,N-dimethylformamide (DMF) were used as solvents, and compound 2a-1 was used as the solute to prepare 10... -3 5 mL of mol / L sample solution was used, and a 1×1 cm quartz cuvette was used as the sample cell. The wavelength was set to 250 nm-800 nm. The quartz cuvette was placed in the UV absorption spectrometer for formal testing.

[0114] Results Analysis: As shown in Figure 5(a), by plotting the tangent line to the absorption curve of compound 2a-1 in toluene solution, the wavelength of compound 2a-1 in toluene can be determined. Compound 2a-1 exhibits a strongest absorption peak near 350 nm, corresponding to the π-π* transition in the molecular skeleton. The band gap of the compound was estimated from the cutoff position of the maximum absorption peak in the ultraviolet spectrum. Using the formula Eg=1240 / X, its optical band gap can be calculated to be 3.042 cm. -1 As shown in Figure 5(b), as the polarity of the solvent increases, the polar orientation between the solvent and the molecules increases, resulting in a red shift in the absorption spectrum. The absorption peak of the solvent chloroform is relatively weak, which may be due to the strong polarity of the solvent causing fluorescence quenching.

[0115] Table 1 Optical data for compound 2a-1

[0116]

[0117] Electrochemical testing: Compound 2a-1 was tested using cyclic voltammetry (CV) on a standard commercial electrochemical analyzer (Shanghai Chenhua Instrument Co., Ltd., CHI520E). The three-electrode system consisted of a cylindrical platinum working electrode, a platinum wire counter electrode, and an Ag / AgCl reference electrode. The potential of the Ag / AgCl reference electrode was internally calibrated based on ferrocene. 0.1M tetrabutylammonium hexafluorophosphate (TBAPF6) solutions in deoxydichloromethane and deoxytetrahydrofuran were prepared as electrolyte solutions. After adding the sample to the electrolyte solutions, the samples were placed in dried containers and plugged with three-hole stoppers. The working electrode, reference electrode, and counter electrode were connected with wires and inserted into the three-hole stoppers, and argon gas was purged to remove air. The test was then started, with the range set to 0-2.0V. Oxidation and reduction curves for all solvents were measured.

[0118] Results Analysis: The redox peak positions of the compounds were calibrated using the ferrocene / ferrocene cation (Foc / Foc+) redox system as an internal standard. The LUMO and HOMO energy levels of the compounds were estimated from the initial reduction and oxidation peak potentials. Figures 6(a) and 6(b) show the oxidation curves of ferrocene in DCM and THF, respectively. The corresponding X values ​​can be obtained by plotting the tangents. Figure 6(c) shows the complete redox curve of compound 2a-1. Figures 6(c) and 6(d) show the oxidation curve of compound 2a-1 in DCM and the reduction curve in THF, respectively. The corresponding X values ​​can be obtained by plotting the tangents.

[0119] According to the formula:

[0120] E HOMO =-[4.8-X FocDCM +X (2a-1)DCM ]

[0121] E LUMO =-[4.8-X FocTHF +X (2a-1)THF ]

[0122] The final calculated energy levels are -3.503 eV for the LUMO level and -5.345 eV for the HOMO level. The electrochemical band gap is 1.842 cm. -1 Compound 2a-1 exhibits two pairs of redox peaks, indicating good reversibility. The LUMO level of compound 2a-1 is below -3.4 eV, suggesting it possesses high electron affinity.

[0123] The optical band gap of compound 2a-1 is 3.042 cm, as determined by CV and UV measurements. -1 The electrochemical band gap is 1.842 cm. -1 It can be used as a donor material in optoelectronic materials and semiconductor materials.

[0124] Example 2

[0125]

[0126] 1) Synthesis of compound 5b

[0127] Pd(PPh3)2Cl2 (0.8 mmol, 0.02 eq) and CuI (1.6 mmol, 0.04 eq) were weighed into a dry 500 mL double-necked flask. 2-Iodobenzene (40 mmol, 1 eq) and NET3 (120 mL) were added, and after purging with argon, 4b (60 mmol, 1.5 eq) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent in the system was removed by rotary evaporation using diatomaceous earth as a filter aid. The product was purified by silica gel column chromatography to obtain compound 5b in 78% yield, with a purity of 98.10% and a molecular weight of 116.06.

[0128] 2) Synthesis of compound 6b

[0129] N1,N4-dimethylfumaramide (12 mmol, 1 eq), copper acetate hydrate (48 mmol, 4 eq), potassium carbonate (48 mmol, 4 eq), and p-cymene ruthenium dichloride dimer (0.6 mmol, 0.05 eq) were weighed sequentially into a pressure-resistant tube. Compound 5b (26.4 mmol, 2.2 eq) and 1,2-dichloroethane (240 mL) were added, and the mixture was reacted at 135 °C for 20 h. After the reaction, the mixture was filtered with diatomaceous earth as an aid, and the solvent was removed by rotary evaporation. Compound 6b was purified by silica gel column chromatography in 50% yield, with a purity of 99.31% and a molecular weight of 370.17.

[0130] The NMR spectrum of compound 6b is shown in Figure 7. Specifically, ¹H NMR (400 MHz, Chloroform-d) δ 7.46 (dq, J = 14.3, 7.9, 7.2 Hz, 6H), 7.22 (d, J = 7.5 Hz, 4H), 3.18 (s, 6H), 2.30 (s, 6H). ¹³C NMR (101 MHz, Chloroform-d) δ 161.85, 143.07, 135.89, 130.68, 129.24, 128.84, 113.31, 35.33, 18.65.

[0131] 3) Synthesis of compound 7b

[0132] Compound 6b (8.0 mmol, 1 eq) and tetrabutylammonium bromide (56.1 mmol, 7 eq) were added to a round-bottom flask. 1,2-Dichloroethane (120 mL) and phosphorus tribromooxymonophosphate (80.0 mmol, 10 eq) were added, and the mixture was refluxed at 105 °C for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography to obtain compound 7b in 75% yield, with a purity of 98.20% and a molecular weight of 418.07.

[0133] 4) Synthesis of compound 1b

[0134] Compound 7b (3.87 mmol, 1 eq) and tetrabutylammonium bromide (38.7 mmol, 10 eq) were added to a dry, pressure-resistant tube. 1,2-Dichloroethane (150 mL) and phosphorus tribromooxy (38.7 mmol, 10 eq) were added, and the mixture was reacted at 150 °C for 4.5 days. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography to obtain compound 1b in 45% yield, with a purity of 98.89% and a molecular weight of 467.97.

[0135] The NMR spectrum of compound 1b is shown in Figure 8, specifically: ¹H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 7.7 Hz, 4H), 7.49 (dt, J = 13.4, 6.9 Hz, 6H), 2.92 (s, 6H). ¹³C NMR (101 MHz, Chloroform-d) δ 154.78, 146.89, 139.14, 132.70, 130.08, 128.85, 128.53, 124.91, 21.96.

[0136] 5) Synthesis of compound 2b-1

[0137] Compound 1b (2.63 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.395 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 50 mL of dry toluene was added to the flask. Methyl magnesium bromide solution (21.0 mmol, 8 eq) was slowly added at 45 °C, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the organic phase was rotary evaporated to remove the solvent. The product was purified by silica gel column chromatography to give compound 2b-1 in 60% yield, with a purity of 99.01% and a molecular weight of 338.18.

[0138] The NMR spectrum of compound 2b is shown in Figure 9. Specifically, the ¹H NMR (400 MHz, Chloroform-d) values ​​are δ 7.64 (d, J = 7.5 Hz, 4H), 7.49 (t, J = 7.5 Hz, 4H), 7.42 (t, J = 7.5 Hz, 2H), 3.13 (s, 6H), and 2.75 (s, 6H). The ¹³C NMR (101 MHz, Chloroform-d) values ​​are δ 155.54, 153.33, 141.31, 132.54, 130.03, 128.41, 128.00, 122.58, 29.84, and 21.57.

[0139] Synthesis of compound 2b-2

[0140] Compound 1b (2.63 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.395 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 50 mL of dry toluene was added to the flask. 21.0 mmol, 8 eq of 4-methyl-1-naphthylmagnesium bromide solution was slowly added at 45 °C, and the reaction was allowed to proceed overnight. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the organic phase was rotary evaporated to remove the solvent. The product was purified by silica gel column chromatography to give compound 2b-2 in 37% yield, with a purity of 98.45% and a molecular weight of 590.27.

[0141] Synthesis of compound 2b-3

[0142] Compound 1b (2.63 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.395 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 50 mL of dry toluene was added to the flask. 21.0 mmol, 8 eq of 6-methoxy-2-naphthylmagnesium bromide solution was slowly added at 45 °C, and the reaction was allowed to proceed overnight. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the organic phase was rotary evaporated to remove the solvent. Compound 2b was purified by silica gel column chromatography in 60% yield, with a purity of 99.36% and a molecular weight of 622.26.

[0143] Example 3

[0144]

[0145] 1) Synthesis of compound 5c

[0146] Pd(PPh3)4 (0.4 mmol, 0.01 eq) and CuI (0.8 mmol, 0.02 eq) were weighed into a dry 500 mL double-necked flask. 2-Bromoselenophenol (40 mmol, 1 eq) and diisopropylamine (120 mL) were added, and after purging with argon, 4c (40 mmol, 1 eq) was added. The mixture was stirred overnight at 40 °C. After the reaction was complete, the solvent in the system was removed by rotary evaporation using diatomaceous earth as a filter aid. The product was purified by silica gel column chromatography to obtain compound 5c in 45% yield, with a purity of 98.01% and a molecular weight of 436.26.

[0147] 2) Synthesis of compound 6c

[0148] N1,N4-dimethylfumaramide (22.3 mmol, 1 eq), copper acetate hydrate (89.2 mmol, 4 eq), potassium acetate (89.2 mmol, 4 eq), and (p-cymene)bis(trimethylcarboxy)ruthenium(II) (0.22 mmol, 0.01 eq) were weighed sequentially into a pressure-resistant tube. Compound 5c (46.8 mmol, 2.1 eq) was added to 1,2-dichloroethane (240 mL), and the mixture was reacted at 110 °C for 20 h. After the reaction, the mixture was filtered with diatomaceous earth as an aid, the solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography to obtain compound 6c in 37% yield, with a purity of 99.06% and a molecular weight of 1008.57.

[0149] 3) Synthesis of compound 7c

[0150] Compound 6c (7.8 mmol, 1 eq) and tetrabutylammonium bromide (54.6 mmol, 7 eq) were added to a round-bottom flask. 1,2-Dichloroethane (120 mL) and phosphorus tribromooxymonophosphate (117 mmol, 15 eq) were added, and the mixture was refluxed at 115 °C for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography to obtain compound 7c in 53% yield, with a purity of 99.21% and a molecular weight of 1058.46.

[0151] 4) Synthesis of compound 1c

[0152] Compound 7c (3.87 mmol, 1 eq) and tetrabutylammonium bromide (19.35 mmol, 5 eq) were added to a dry, pressure-resistant tube. 1,2-Dichloroethane (150 mL) and phosphorus tribromooxy (58.05 mmol, 15 eq) were added, and the reaction was carried out at 160 °C for 3.5 days. After the reaction was complete, the solvent in the system was removed by rotary evaporation, the mixture was dissolved in dichloromethane, the reaction was quenched with saturated sodium bicarbonate solution, and then extracted three times with saturated brine and dichloromethane. After extraction, the solvent in the system was removed by rotary evaporation, and the product was purified by silica gel column chromatography to obtain compound 1c in 42% yield, with a purity of 98.51% and a molecular weight of 1106.36.

[0153] 5) Synthesis of compound 2c

[0154] Compound 1c (2.56 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.384 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 100 mL of dry toluene was added to the flask. Ethyl magnesium bromide solution (81.92 mmol, 32 eq) was slowly added at 40 °C, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the organic phase was evaporated by rotary evaporation to remove the solvent. The product was purified by silica gel column chromatography to give compound 2c in 56% yield, with a purity of 98.64% and a molecular weight of 1006.41.

[0155] Example 4

[0156]

[0157] 1) Synthesis of compound 5d

[0158] Pd(O2CCH3)2 (4.0 mmol, 0.1 eq) and CuI (0.8 mmol, 0.02 eq) were weighed into a dry 500 mL double-necked flask. 2-Iodofuran (40 mmol, 1 eq) and NET3 (120 mL) were added, and after purging with argon, 4d (40 mmol, 1 eq) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent in the system was removed by rotary evaporation using diatomaceous earth as a filter aid. The product was purified by silica gel column chromatography to obtain compound 5d, with a yield of 57%, a purity of 98.24%, and a molecular weight of 232.18.

[0159] 2) Synthesis of compound 6d

[0160] N,N-dimethylN1,N4-dimethylfumaramide (22.3 mmol, 1 eq), copper acetate hydrate (89.2 mmol, 4 eq), cesium carbonate (89.2 mmol, 4 eq), and ruthenium(II) diiodide (1.1 mmol, 0.05 eq) dimer were weighed sequentially into a pressure-resistant tube. Compound 5d (49.1 mmol, 2.5 eq) was added to 1,2-dichloroethane (240 mL), and the mixture was reacted at 120 °C for 20 h. After the reaction, the mixture was filtered with diatomaceous earth as an aid, the solvent was removed by rotary evaporation, and the product was purified by silica gel chromatography to obtain compound 6d with a yield of 48%, a purity of 98.31%, and a molecular weight of 602.41.

[0161] 3) Synthesis of compound 7d

[0162] Compound 6d (7.8 mmol, 1 eq) and tetrabutylammonium chloride (54.6 mmol, 7 eq) were added to a round-bottom flask. 1,2-Dichloroethane (120 mL) and phosphorus oxychloride (60 mL) were added, and the mixture was refluxed at 110 °C for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography to obtain compound 7d in 75% yield, with a purity of 99.21% and a molecular weight of 606.36.

[0163] 4) Synthesis of compound 1d

[0164] Compound 7d (3.87 mmol, 1 eq) was added to a dry, pressure-resistant tube with tetrabutylammonium chloride (38.7 mmol, 10 eq). 1,2-Dichloroethane (150 mL) and phosphorus oxychloride (75 mL) were added, and the mixture was reacted at 150 °C for 4 days. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography to obtain compound 1d in 45% yield, with a purity of 99.05% and a molecular weight of 610.31.

[0165] 5) Synthesis of compound 2d

[0166] Compound 1d (2.56 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.384 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 100 mL of dry toluene was added to the flask. C24 was slowly added at 40 °C. 20 H 41 The reaction was carried out overnight in MgBr solution (40.96 mmol, 16 eq). After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the solvent in the system was removed by rotary evaporation of the organic phase. The product was purified by silica gel column chromatography to obtain compound 2d with a yield of 63%, a purity of 99.12%, and a molecular weight of 1103.01.

[0167] Example 5

[0168]

[0169] 1) Synthesis of compound 5e

[0170] Pd(O2CCH3)2 (4.0 mmol, 0.1 eq) and CuI (0.8 mmol, 0.02 eq) were weighed into a dry 500 mL double-necked flask. 5-Iodothiazole (40 mmol, 1 eq) and NET3 (120 mL) were added, and after purging with argon, 4e (60 mmol, 1.5 eq) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent in the system was removed by rotary evaporation using diatomaceous earth as a filter aid. The product was purified by silica gel column chromatography to obtain compound 5e in 43% yield, with a purity of 98.36% and a molecular weight of 213.06.

[0171] 2) Synthesis of compound 6e

[0172] N1,N4-dimethylfumaramide (22.3 mmol, 1 eq), copper acetate hydrate (89.2 mmol, 4 eq), cesium carbonate (89.2 mmol, 4 eq), and ruthenium(II) diiodide dimer (1.1 mmol, 0.05 eq) were weighed sequentially into a pressure-resistant tube. Compound 5e (49.1 mmol, 2.5 eq) was added to 1,2-dichloroethane (240 mL), and the mixture was reacted at 120 °C for 20 h. After the reaction, the mixture was filtered with diatomaceous earth as an aid, the solvent was removed by rotary evaporation, and the product was purified by silica gel chromatography to obtain compound 6e in 37% yield, with a purity of 98.62% and a molecular weight of 564.72.

[0173] 3) Synthesis of compound 7e

[0174] Compound 6e (7.8 mmol, 1 eq) and tetrabutylammonium chloride (54.6 mmol, 7 eq) were added to a round-bottom flask. 1,2-Dichloroethane (120 mL) and phosphorus oxychloride (60 mL) were added, and the mixture was refluxed at 110 °C for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the mixture was purified by silica gel chromatography to obtain compound 7e in 53% yield, with a purity of 98.62% and a molecular weight of 567.12.

[0175] 4) Synthesis of compound 1e

[0176] Compound 7e (3.87 mmol, 1 eq) and tetrabutylammonium chloride (38.7 mmol, 10 eq) were added to a dry, pressure-resistant tube. 1,2-Dichloroethane (150 mL) and phosphorus oxychloride (75 mL) were added, and the mixture was reacted at 150 °C for 5 days. After the reaction was complete, the solvent was removed by rotary evaporation, the mixture was dissolved in dichloromethane, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was then extracted three times with saturated brine and dichloromethane. After extraction, the solvent was removed by rotary evaporation, and the product was purified by silica gel chromatography to obtain compound 1e in 21% yield, with a purity of 98.21% and a molecular weight of 572.01.

[0177] 5) Synthesis of compound 2e

[0178] Compound 1e (2.56 mmol, 1 eq) and Pd(PPh3)2Cl2 (0.384 mmol, 0.15 eq) were placed in a 250 mL single-necked flask. After purging with argon, 100 mL of dry toluene was added to the flask. C20 was then slowly added at 40 °C. 20 H 41The reaction was carried out overnight in MgBr solution (40.96 mmol, 16 eq). After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with saturated brine and dichloromethane, and the solvent in the system was removed by rotary evaporation of the organic phase. The product was purified by silica gel column chromatography to obtain compound 2e in 63% yield, with a purity of 98.47% and a molecular weight of 1064.77.

[0179] Comparative Example 1

[0180] The only difference from Example 1 is that the synthesis step of compound 7a is removed, and compound 6a is directly reacted in the pressure tube to obtain compound 1a. After compound 7a is loaded into the pressure tube, it is first reacted at 110°C for 3 hours, and then the temperature is raised to 150°C for 4 days.

[0181] The results showed that obtaining compound 1a in one step led to a decrease in yield. The total yield of the two-step reaction was 45%, while the yield after the one-step reaction was only 35%. Furthermore, when compound 6a was converted into compound 7a, a small amount of isomerized product was present. The polarity of this byproduct was close to that of compound 1a, making it difficult to separate compound 1a after the one-step reaction.

[0182] Comparative Example 2

[0183] The only difference from Example 1 is that tetrabutylammonium chloride is removed in step 3), while the other steps and conditions are the same as in Example 1.

[0184] The results showed that removing tetrabutylammonium chloride reduced the yield of compound 7a to 40-50%. Similarly, removing tetrabutylammonium chloride in step 4) also resulted in a decrease in yield. This indicates that adding an appropriate amount of tetrabutylammonium chloride in the demethylation reaction is beneficial to increasing the yield.

[0185] This invention relates to novel 2,6-naphthidine small molecule derivatives. By designing and synthesizing 2,6-naphthidine small molecule derivatives modified with different aromatic heterocycles and alkyl chains, the introduction of different aromatic heterocycles into the molecule alters the LUMO and HOMO energy levels of the 2,6-naphthidine small molecule derivatives to a certain extent, and modulates their photoelectric properties. Simultaneously, the flexible introduction of alkyl chains of different lengths into the molecule improves its solubility, making it readily soluble in most organic solvents for easy purification; it also allows for the study of the influence of substituents on the compound's properties. The synthetic method provided by this invention, involving cyclization followed by aromatization, has relatively simple steps and is conducive to the large-scale promotion and application of 2,6-naphthidine derivative structures.

[0186] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a 2,6-naphthidine small molecule derivative, characterized in that, The structural formula of the derivative is shown in Formula 1 and / or Formula 2 below: ； Where Ar is selected from , , , , , , , , , , , or ; X2 can be any type of halogen atom; R1 is a single or multiple substituted functional group, wherein the functional group is any one of the following: a straight-chain alkyl group of C1-C20, a branched alkyl group of C1-C20, an aralkyl group of C5-C20, and an aromatic ether group of C5-C20; R2 is a single or multiple substituted functional group, wherein the functional group is any one of the following: straight-chain alkyl, branched alkyl, alkoxy and aralkyl groups of C1-C20; The preparation method of the 2,6-naphthidine small molecule derivative includes the following steps: 1) Compound 3 and compound 4 undergo a coupling reaction in the presence of catalyst A and CuI to generate compound 5; catalyst A is a palladium catalyst. 2) Compound 5, N1,N4-dimethylfumaramide, copper acetate, catalyst B, and a base are added to undergo a coupling reaction to generate compound 6; the catalyst B is a ruthenium catalyst. 3) Compound 6 undergoes a demethylation reaction with PO(X2)3 to yield compound 7; 4) Compound 7 reacts with PO(X2)3 in a pressure-resistant tube to undergo demethylation reaction to obtain compound 1; And / or, also includes the following steps: 5) Compound 1 undergoes a coupling reaction with R2MBr solution in the presence of catalyst C to obtain compound 2; the catalyst C is a palladium catalyst; The reaction temperatures in steps 1) to 5) are all between 0 and 160°C, and the reaction times are all between 4 and 120 h; and the demethylation reaction temperature in step 3) is lower than that in step 4). The reaction synthesis route is shown below: In R2MBr, M can be any one of Mg, Cu, Fe, Zn, and Li.

2. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 1, characterized in that, In step 1), the molar ratio of compound 3 to compound 4 is 1:1 to 1.5; the molar ratio of compound 3 to CuI is 1:0.01 to 0.

05.

3. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 2, characterized in that, In step 1), the catalyst A is selected from at least one of tetra(triphenylphosphine)palladium, tris(dibenzylideneacetone)palladium, bis(1,4-biphenylphosphine)butylpalladium dichloride, palladium acetate, and bis(triphenylphosphine)palladium dichloride; the molar ratio of compound 3 to catalyst A is 1:0.01 to 0.

1.

4. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 1, characterized in that, In step 2), the molar ratio of compound 5 to N1,N4-dimethylfumaramide is 2 to 2.5:

1.

5. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 4, characterized in that, The catalyst B is selected from at least one of p-cymene ruthenium dichloride dimer, diiodo(p-cymene)ruthenium(II) dimer, (p-cymene)tricyclohexylphosphine ruthenium(II) chloride, and (p-cymene)bis(trimethylcarboxylated)ruthenium(II), and the molar ratio of compound 5 to catalyst B is 1:0.001 to 0.1; the base is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, and sodium acetate, and the molar ratio of compound 5 to base is 1:1 to 10; the molar ratio of compound 5 to copper acetate is 2 to 2.5:

4.

6. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 1, characterized in that, The demethylation reaction in step 3) is carried out at 80–120°C under normal pressure for 2.5–3.5 hours; the demethylation reaction in step 4) is carried out in a pressure-resistant tube at 150–160°C for 3–5 days. In steps 3) and 4), the raw materials for the demethylation reaction also include tetrabutylammonium halide and an organic solvent; the molar ratio of compound 6 or compound 7 to tetrabutylammonium halide is 1:5 to 10; the ratio of compound 6 or compound 7 to organic solvent is (3 to 10) mmol: (100 to 150) mL. PO(X2)3 includes phosphorus oxychloride or phosphorus tribromooxychloride; the volume ratio of phosphorus oxychloride to organic solvent is 1:1 to 100; or, the molar ratio of compound 6 or compound 7 to phosphorus tribromooxychloride is 1:1 to 100.

7. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 1, characterized in that, In step 5), the molar ratio of compound 1 to R2MBr is 1:2 to 48; the molar ratio of compound 1 to catalyst C is 1:0.01 to 0.

15.

8. The method for preparing 2,6-naphthidine small molecule derivatives according to claim 1, characterized in that, All reactions in steps 1) to 5) are carried out in the presence of an organic solvent; and the organic solvent in step 1) is selected from at least one of triethylamine, ethylenediamine and diisopropylamine, and the organic solvent in steps 2) to 5) is selected from at least one of toluene, diethyl ether, N,N-dimethylformamide, N-methylpyrrolidone, 1,2-dichloroethane, tetrahydrofuran, dichloromethane, carbon tetrachloride and chloroform.

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