CN116120251A - Cyclic diacylhydrazone derivative and synthesis and application thereof - Google Patents

Abstract

A cyclic diacylhydrazone derivative and synthesis and application thereof belong to the field of fluorescent molecular probes. The invention provides a cyclic diacylhydrazone derivative shown in a structural general formula (I) or (II) or pharmaceutically acceptable salt thereof, wherein R, X, Y, Z in the general formula is as described in the claims and the specification. The cyclic diacylhydrazone derivative can be obtained through simple synthesis, has response to phthalate anions in a solution or solid state, and has the advantages of high selectivity, high sensitivity, convenience in operation and the like, and the fluorescence intensity of the combined probe is obviously increased. And because of its strong binding properties, phthalate anions can be removed from water and organic solvents.

Description

Cyclic diacylhydrazone derivatives and their synthesis and application

Technical Field

The invention belongs to the field of fluorescent molecular probes, and relates to cyclic diacylhydrazone derivatives and synthesis and application thereof, and in particular to cyclic diacylhydrazone derivatives and application thereof as fluorescent molecular probes in the field of anions.

Background Art

Dicarboxylates are a class of anions that play an important role both in organisms and in industry. Taking the phthalate anion as an example, it is not only widely used as a plasticizer in the plastics industry, but also has strong carcinogenicity. For this reason, a compound that can not only detect phthalate anions but also remove them from water or organic solvents is needed. The selectivity and strong binding function of this compound are crucial. However, despite a large number of reported dicarboxylate anion probes, probes for phthalate anions have not been reported. Therefore, the task of how to efficiently detect and effectively remove phthalate anions remains a huge challenge.

Fluorescent probes for anions are divided into cationic and neutral molecules. The more common cationic probe molecules show strong binding to anions in both organic and aqueous phases, but due to the interaction between anions and cations, this type of probe molecules lacks selectivity for anions; while neutral probe molecules have weak interactions with anions, and selective identification of anions has been difficult for a long time. Currently, there is no commercial fluorescent probe for identifying phthalate anions.

Summary of the invention

In view of the problems existing in the prior art, the present invention provides a cyclic diacylhydrazone derivative and its synthesis and application. The cyclic diacylhydrazone derivative is simple to synthesize and has a high yield. It can be used as a fluorescent molecular probe to detect and remove dicarboxylate anions, especially phthalate anions, and has a selective and strong binding effect.

The cyclic diacylhydrazone derivatives or pharmaceutically acceptable salts thereof represented by the general structural formula (I) or (II) of the present invention are:

In the formula, R is a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group, a methylcyclohexane, a cyclohexane, a C1-C6 ester group, a substituted or unsubstituted C1-C4 amine, a substituted or unsubstituted 5-10 membered heterocyclic group or heteroaryl group, wherein the heterocyclic group or heteroaryl group contains 1-3 heteroatoms of N, O or S, and the substituents used for the substitution are: C1-C10 alkyl group, C1-C10 alkoxy group, C1-C10 alkylamino group;

X, Y, and Z are independently hydrogen atoms, methyl groups, C1-C6 ester groups, C1-C10 alkoxy groups, substituted or unsubstituted C1-C4 amines, substituted or unsubstituted 5-10 membered heterocyclic groups or heteroaryl groups, wherein the heterocyclic groups or heteroaryl groups contain 1-3 heteroatoms of N, O or S, and the substituents used are: C1-C10 alkyl groups, C1-C10 alkoxy groups, and C1-C10 alkylamino groups;

The pharmaceutically acceptable salt formed by the cyclic diacylhydrazone derivatives of the present invention includes a salt formed by the cyclic diacylhydrazone derivatives and an acid. The acid may be an organic acid or an inorganic acid, the inorganic acid is one of hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid, and the organic acid is one of acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid or malic acid.

The present invention preferably comprises cyclic diacylhydrazone derivatives of the following structures and pharmaceutically acceptable salts thereof:

The synthetic route of the cyclic diacylhydrazone derivatives of the general structural formula (I) of the present invention is as follows:

Specifically include:

(1) Preparation of compound a-2-(4,4'-(hydroxymethyl)dibenzoic acid dimethyl ester

Add methyl 4-iodobenzoate (a-1) to anhydrous tetrahydrofuran, protect with nitrogen, cool at -40 to -30°C, and stir evenly; add isopropyl magnesium chloride tetrahydrofuran solution, continue stirring at -30 to -20°C; add anhydrous tetrahydrofuran solution containing methyl 4-formylbenzoate, react for 30-40 minutes, air cool to room temperature, stir and react overnight to obtain an orange-yellow transparent liquid, purify, and obtain product a-2;

In the above (1), the molar ratio of methyl 4-iodobenzoate: isopropylmagnesium chloride: methyl 4-formylbenzoate is 1:1.5:1. The tetrahydrofuran used can also be replaced by anhydrous ether reagent.

In the above (1), the purification is as follows: add methanol to the orange-yellow transparent liquid to quench the reaction, add water, and extract with dichloromethane. Take the organic phase, dry it with anhydrous sodium sulfate, remove the solvent with a rotary evaporator, and separate it with silica gel column chromatography to obtain product a-2.

(2) Preparation of compound a-34,4'-(bromomethylene) dibenzoic acid dimethyl ester

Compound a-2 is dissolved in dichloromethane, phosphorus tribromide is added dropwise under ice-water bath conditions, and the reaction is continued for 4 to 8 hours, followed by purification to obtain product a-3;

In the step (2), the purification is as follows: slowly dropwise adding ice water to quench the reaction, adding water, extracting with dichloromethane, taking the organic phase, adding anhydrous sodium sulfate to dry, and removing the solvent with a rotary evaporator to obtain the product a-3.

In the step (2), the molar ratio of dimethyl 4,4'-(hydroxymethylene)dibenzoate to phosphorus tribromide is 1:2.

(3) Preparation of compound a-4

According to the group represented by R, take the corresponding compound, heat to 60-120°C, add compound a-3, stir for 3-8h, purify after the reaction is complete, and obtain product a-4;

In the step (3), the purification is as follows: after the solution is cooled, water is added and extracted with dichloromethane. The organic phase is taken, dried over anhydrous sodium sulfate, the dichloromethane solvent is removed using a rotary evaporator, and separated by silica gel column chromatography to obtain product a-4.

In the step (3), the corresponding compound is preferably an alcohol compound. The alcohol compound is selected from one or more of methanol, n-butanol, 1-decanol, triethylene glycol monomethyl ether, 2-thiophene methanol, 2-furan methanol, benzyl alcohol, and cyclohexane methanol.

(4) Preparation of compound a-5

Take compound a-4, add methanol and hydrazine hydrate with a mass concentration of 80%, stir at room temperature overnight, remove the solvent, and separate and purify to obtain product a-5;

When R in the cyclic diacylhydrazone derivative of the general structural formula (I) is H, directly use compound a-2 to replace compound a-4, add methanol and hydrazine hydrate with a mass concentration of 80%, stir at room temperature overnight, remove the solvent, and separate and purify to obtain product a-5;

In the step (4), the solvent removal is performed by removing methanol using a rotary evaporator and concentrating. The separation and purification is performed by directly performing silica gel column chromatography to obtain product a-5.

(5) Preparation of cyclic diacylhydrazone derivatives of general structural formula (I)

Take compound a-5, add ethanol, water, glacial acetic acid, and hydroxyisophthalaldehyde, stir at room temperature, solid precipitates, separate the solid and liquid, take the precipitate, wash it, and obtain a cyclic diacylhydrazone derivative of the general structural formula (I).

Wherein, the molar ratio of compound a-5:hydroxyisophthalaldehyde is 1:1.

In the step (5), methanol, dichloromethane and petroleum ether are used for washing three times each to obtain a cyclic diacylhydrazone derivative of the general structural formula (I).

The synthetic route of the cyclic diacylhydrazone derivative of the general structural formula (II) of the present invention is as follows:

Specifically include:

S1: Preparation of compound b-1

Dissolve triethylene glycol monomethyl ether or decanol in tetrahydrofuran, add sodium hydroxide aqueous solution and p-toluenesulfonyl chloride tetrahydrofuran solution under ice-water bath conditions, stir overnight, and extract the obtained product to obtain product b-1;

In the S1, purification is as follows: adding water, extracting with dichloromethane, taking the organic phase, drying with anhydrous sodium sulfate, removing the solvent using a rotary evaporator, and separating by silica gel column chromatography to obtain product b-1.

S2: Preparation of compound b-2

Take methyl hydroxybenzoate, compound b-1, and potassium carbonate, dissolve them in DMF, heat to 100°C, and purify after the reaction to obtain product b-2;

In molar ratio, methyl hydroxybenzoate: compound b-1: potassium carbonate = 1:1.1:3. According to the groups represented by X, Y, and Z, methyl hydroxybenzoate is selected from methyl 4-hydroxybenzoate, methyl 3,5-dihydroxybenzoate, and methyl 3,4,5-trihydroxybenzoate.

In the S2, purification is as follows: after cooling, water is added, extracted with dichloromethane, the organic phase is taken, dried over anhydrous sodium sulfate, the solvent is removed using a rotary evaporator, and separated by silica gel column chromatography to obtain product b-2.

S3: Preparation of compound b-3

Take compound b-2, dissolve it in anhydrous tetrahydrofuran, add lithium aluminum hydride in an ice-water bath, stir, and purify after the reaction to obtain product b-3;

In the step S3, the purification is as follows: dropwise adding ice water to quench the reaction until no bubbles are generated, adding water, extracting with dichloromethane, taking the organic phase, drying with anhydrous sodium sulfate, and removing the solvent with a rotary evaporator to obtain product b-3.

In terms of molar ratio, compound b-2: lithium aluminum hydride = 1:2.

S4: Preparation of compound b-4

Take compound b-3, dissolve it in dichloromethane, add phosphorus tribromide in an ice-water bath, and purify it after the reaction to obtain product b-4;

In the S4, purification is as follows: dropwise addition of ice water to quench the reaction until no bubbles are generated, water is added, extraction is performed using dichloromethane, the organic phase is taken, dried over anhydrous sodium sulfate, and the solvent is removed using a rotary evaporator to obtain the product b-4.

S5: Preparation of compound c-1

Take compound a-2 and dissolve it in tetrahydrofuran. Add sodium hydride powder in an ice-water bath until no bubbles are generated; dropwise add the tetrahydrofuran solution containing compound b-4; after the reaction is completed, purify and dry to obtain product c-1;

In the S5, purification and drying are as follows: ice water is added dropwise to quench the reaction until no bubbles are generated, water is added, extraction is performed using dichloromethane, the organic phase is taken, dried over anhydrous sodium sulfate, the solvent is removed using a rotary evaporator, and separation is performed using silica gel column chromatography to obtain product c-1.

S6: Preparation of compound c-2

Compound c-1, methanol, and 80% hydrazine hydrate were mixed, stirred at room temperature overnight, the methanol was removed by a rotary evaporator, and separated by silica gel column chromatography to obtain product c-2.

S7: Preparation of cyclic diacylhydrazone derivatives of general structural formula (II)

Take compound c-2, ethanol, water, glacial acetic acid, and then add hydroxyisophthalaldehyde, stir at room temperature. After the reaction is completed, use a rotary evaporator to remove ethanol, concentrate, extract with dichloromethane, take the organic phase, dry it over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and separate it through silica gel column chromatography to obtain a cyclic diacylhydrazone derivative of the general formula (II).

In the above synthesis route, the hydroxyisophthalaldehyde is selected from one of 2-hydroxyisophthalaldehyde, 4-hydroxyisophthalaldehyde and 5-hydroxyisophthalaldehyde.

The present invention can obtain cyclic diacylhydrazone derivatives through simple synthesis, which can be used as carboxylate anion fluorescent probes. The cyclic diacylhydrazone derivatives respond to phthalate anions in solution or solid state. The fluorescence intensity of the probe is significantly increased after binding, and the derivatives have the advantages of good selectivity, high sensitivity, convenient operation, etc.

Moreover, among them, compound 1-20 is a fluorescent molecular probe for carboxylate with a brand-new structure, and has strong fluorescence at 550nm. Hydrogen bonds are formed between the NH on the amide bonds on both sides of the molecular ring and the carboxylate ions of the acetate group, which promotes the binding of the compound to the carboxylate group. Among them, compound 20 has the strongest binding ability with the phthalate anion, and there is a significant fluorescence enhancement phenomenon, high sensitivity, and can be identified in solution and solid state, showing significant changes in color and fluorescence. Moreover, after the molecule is combined with the phthalate group, it will form a better nanosphere, which can realize the function of selectively transporting the phthalate group and achieve the purpose of anion splitting.

The solution color and fluorescence of compound 20 fluorescent probe before and after binding to phthalate are significantly different, making it a potential new type of phthalate fluorescent probe. The significant difference in the binding ability of phthalate and other carboxylates is used to achieve the purpose of separation. At the same time, this fluorescent probe forms stable nanoparticles with phthalate, which are easier to penetrate the cell membrane and may be able to stain living cells, which brings a new option for in vitro staining technology of living cells.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a UV spectrum of compound 1-20 when phthalate is added dropwise.

FIG2 is a fluorescence spectrum of compound 1-20 when phthalate is added dropwise.

FIG3 shows the binding constants of compounds 1-20 and phthalate.

Figure 4 shows the fluorescence changes of compounds 1-20 when different types of anions are added.

Figure 5 shows the job plot of compounds 1-20 and phthalate.

Figure 6 shows the mass spectrum of the complex of compound 1-20 and phthalate.

Figure 7 shows TEM test of compounds 1-20 and phthalate.

DETAILED DESCRIPTION

The specific implementation of the present invention is further described in detail below in conjunction with specific examples. It should be noted that the following examples are used to illustrate the present invention, but are not used to limit the scope of protection of the present invention.

In the following examples, cyclic diacylhydrazone derivatives are used to detect anions, including the following experiments:

(1) UV detection: The compound was dissolved in acetonitrile solution and a certain proportion of tetrabutylammonium acetate, tetrabutylammonium benzoate, ditetrabutylammonium phthalate, ditetrabutylammonium isophthalate, and ditetrabutylammonium terephthalate solutions were gradually added to obtain the UV absorption value of 210 nm–550 nm. The data were substituted into the 1:1 binding equation to obtain the binding energy K.

(2) Fluorescence detection: The spectral range is set at 310 nm-650 nm, the excitation wavelength is 300 nm, and a certain proportion of tetrabutylammonium acetate, tetrabutylammonium benzoate, ditetrabutylammonium phthalate, ditetrabutylammonium isophthalate, and ditetrabutylammonium terephthalate solutions are gradually added to a certain concentration of compound solution to obtain the fluorescence absorption spectrum.

Example 1

Take 0.01 mol (2.6 g) of methyl 4-iodobenzoate, add it to a 100 mL three-necked flask, add 30 mL of anhydrous tetrahydrofuran, protect with nitrogen, and stir in a cold trap at -40 ° C. After 10 minutes, use a syringe to inject 0.015 mol (11.3 mL) of isopropyl magnesium chloride tetrahydrofuran solution with a concentration of 2 mol/L. Continue stirring in a cold trap at -30 ° C for 40 minutes. Add 20 mL of anhydrous tetrahydrofuran solution containing 0.01 mol (1.7 g) of methyl 4-formylbenzoate and react for 30 minutes. Close the cold trap, slowly return to room temperature, and stir the reaction overnight. The solution is an orange-yellow transparent liquid. Add 2 mL of methanol to quench the reaction, add 200 mL of water, and extract with 300 ml of dichloromethane. Take the organic phase, dry it with anhydrous sodium sulfate, use a rotary evaporator to remove the solvent, and separate it by silica gel column chromatography to obtain 1.6 g of the product, with a yield of 56%.

Example 2

Take 0.01 mol (3.0 g) of dimethyl 4,4'-(hydroxymethylene) dibenzoate, dissolve it in 10 mL of methanol, add 5 mL of 80% hydrazine hydrate, and stir at room temperature. After 8 hours, the reaction is complete, and the methanol is removed by rotary evaporator and concentrated. Directly perform silica gel column chromatography to obtain 2.1 g of product, with a yield of 70%.

Example 3

0.3 mmol (90 mg) of 4,4'-(hydroxymethylene)dibenzohydrazide, 70 mL of ethanol, 30 mL of water, and 0.5 mL of glacial acetic acid were added to a 200 mL flask, and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde was added, and stirred at room temperature for 8 h. Filtered, washed with methanol and dichloromethane, and the product compound 4 was obtained, 228 mg, with a yield of 55%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.01 (s, 1H), 11.65 (s, 1H), 11.45 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H) ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):163.13,163.05,152.50,147.63,147.10,145.96,137.32,133.24,132.45,128.28,127.96,127.05,127.01,126.24,106.91,81.31.HRMS(ES I):m/z:[M+ H] ⁺ calc.:415.1406; found:415.1433.

Example 4

Take 0.01 mol (3.0 g) of dimethyl 4,4'-(hydroxymethylene) dibenzoate, dissolve it in 20 mL of dichloromethane, and add 0.02 mol (5.4 g) of phosphorus tribromide dropwise in an ice-water bath. After 5 hours, the reaction is complete, and 0.5 mL of ice water is slowly added dropwise to quench the reaction. Add 50 mL of water, extract with 100 mL of dichloromethane, take the organic phase, add anhydrous sodium sulfate to dry, and use a rotary evaporator to remove the solvent to obtain 2.8 g of product, with a yield of 78%.

Example 5

(1) Take 20 mL of methanol as solvent, add it to a 50 mL flask, heat it to 65 ° C in an oil bath, add 3.6 g (0.01 mol) of compound 4,4'-(bromomethylene) dibenzoic acid dimethyl ester, and react completely after 7 hours. After the solution is cooled, add 50 mL of water and extract with 100 mL of dichloromethane. Take the organic phase, dry it with anhydrous sodium sulfate, use a rotary evaporator to remove the dichloromethane solvent, and separate it by silica gel column chromatography to obtain 2.6 g of product, with a yield of 83%.

(2) Take 3 g (0.01 mol) of dimethyl 4,4'-(methoxymethylene)dibenzoate, dissolve it in 10 mL of methanol, add 5 mL of 80% hydrazine hydrate, and stir at room temperature. After 8 hours, the reaction is complete, and the methanol is removed by rotary evaporator and concentrated. Directly perform silica gel column chromatography to obtain 2.3 g of the product, with a yield of 77%.

Example 6

90 mg (0.29 mmol) of 4,4'-(methoxymethylene)dibenzohydrazide, 70 mL of ethanol, 30 mL of water, and 0.5 mL of glacial acetic acid were added to a 200 mL flask, and 43 mg (0.29 mmol) of 4-hydroxyisophthalaldehyde was added, and stirred at room temperature for 8 h. Filtered, washed with methanol and dichloromethane, and the product compound 1 was obtained in an amount of 75 mg, with a yield of 61%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 11.97 (s, 1H), 11.50 (s, 1H), 11.45 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H) ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):170.01,168.68,163.40,148.92,147.05,132.45,130.21,129.68,128.68,128.35,128.20,128.28,127.96,127.05,127.01,126.24,106 .91,87.76,57.63.HRMS(ESI):m /z:[M+H] ⁺ calc.:429.1563; found:429.1530.

Example 7

Take 90 mg (0.29 mmol) of 4,4'-(methoxymethylene)dibenzohydrazide, 70 mL of ethanol, 30 mL of water, and 0.5 mL of glacial acetic acid and add them into a 200 mL flask, then add 43 mg (0.29 mmol) of 5-hydroxyisophthalaldehyde, and stir at room temperature for 8 hours. Filter by suction, wash with methanol and dichloromethane, and obtain 80 mg of the product, with a yield of 65%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 11.98 (s, 2H), 8.51 (s, 2H), 7.92 (d, J = 27.6Hz, 4H), 7.82 (s, 1H), 7.52 (s,2H),7.46(s,4H),5.83(s,1H),3.38(s,3H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):170.06,163.40,148.92,146.32,133.50,130.21,129.23,128.88,128.35,127.96,127.05,127.01,123.21,101.99,87.71,57.63.HRMS(ESI ):m/z:[M+ H] ⁺ calc.:429.1563; found:429.1577.

Example 8

Take 90 mg (0.29 mmol) of 4,4'-(methoxymethylene)dibenzohydrazide, 70 mL of ethanol, 30 mL of water, and 0.5 mL of glacial acetic acid and add them into a 200 mL flask, then add 43 mg (0.29 mmol) of 2-hydroxyisophthalaldehyde, and stir at room temperature for 8 hours. Filter by suction, wash with methanol and dichloromethane, and obtain 71 mg of the product, with a yield of 58%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 11.70 (s, 2H), 8.32 (s, 2H), 7.92 (d, J = 27.6Hz, 4H), 7.72 (s, 2H), 7.46 (s,4H),7.30(s,1H),6.07(s,1H),5.83(s,1H),3.38(s,3H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):172.36,165.36,148.74,146.39,133.10,132.30,128.41,128.38,128.35,128.66,127.96,127.05,127.01,123.21,101.99,88.78,57.6 3.HRMS(ESI):m/z:[ M+H] ⁺ calc.:429.1563; found:429.1590.

Example 9

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 ml of n-butanol and react to obtain 3.0 g of product with a yield of 86%.

(2) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(butoxymethylene)dibenzoate and 5 mL of 80% hydrazine hydrate and react to obtain 2.9 g of product with a yield of 80%.

Example 10

The synthesis method refers to Example 6: 107 mg (0.3 mmol) of 4,4'-(butoxymethylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 117 mg of the product compound 5, with a yield of 83%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.18(s,1H),5.86(s,1H),3.35( t,2H),1.76(t,2H),1.46(t,2H),0.96(t,3H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,133.20,132.08,128.99,128.85,128.38,128.22,127.96,127.88,127.22,124.20,105.99,88.78,69.0 1,32.55,19.09,14.11.HRMS(ESI) :m/z:[M+H] ⁺ calc.:471.2032; found:471.2008.

Embodiment 11

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of 1-decanol and react to obtain 4.0 g of product with a yield of 91%.

(2) Take 4.4 g (0.01 mol) of dimethyl 4,4'-(decyloxymethylene) dibenzoate and 5 mL of 80% hydrazine hydrate and react to obtain 3.9 g of product with a yield of 88%.

Example 12

The synthesis method refers to Example 6: 132 mg (0.3 mmol) of 4,4'-(decyloxymethylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 134 mg of the product compound 6, with a yield of 81%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.18(s,1H),5.86(s,1H),3.35( t,2H),1.76(s,2H),1.46(t,2H),1.43(t,2H),1.30(t,2H),1.26(t,8H),0.88(t,3H). ¹³ CNMR( 150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,133.20,132.08,128.99,128.85,128.38,128.22,127.96,127.88,127.22,124.20,105.99,88.78,69.4 5,31.98,29.01,22.78,14.15.HRMS( ESI):m/z:[M+H] ⁺ calc.:555.2971; found:555.2998.

Example 13

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of triethylene glycol monomethyl ether and react to obtain 3.3 g of product with a yield of 75%.

(2) Take 4.5 g (0.01 mol) of dimethyl 4,4'-(2,5,8,11-tetraoxadodecane-1,1-diyl)dibenzoate and 5 mL of 80% hydrazine hydrate, and react to obtain 3.7 g of product with a yield of 82%.

Embodiment 14

The synthesis method refers to Example 6: 134 mg (0.3 mmol) of 4,4'-(2,5,8,11-tetraoxadodecane-1,1-diyl)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 141 mg of the product compound 7, with a yield of 84%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.12 (s, 1H), 11.71 (s, 1H), 11.54 (s, 1H), 8.68 (s, 1H), 8.38 (s, 1H) ,8.00–7.82(m,5H),7.66(d,J＝8.4Hz,1H),7.63–7.49(m,4H),7.02(d,J＝8.2Hz,1H),5.72(s,1H), 3.64(s,2H),3.61–3.48(m,8H),3.43(s,2H),3.23(s,3H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ(ppm):163.16,163.09,159.28,147.62,147.10,146.46,146.08,133.17,132.42,130.52,128.31,128.20,127.98,127.01,126.94,126.24,119 .79,117.37,81.98,71.67,70.32,70.17, 70.10,70.01,68.46,58.43.HRMS(MALDI-TOF):m/z:[M+Na] ⁺ calc.:583.21687; found:583.21701.

Embodiment 15

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of cyclohexylmethanol and react to obtain 3.0 g of product with a yield of 77%.

(2) 4.0 g (0.01 mol) of dimethyl 4,4'-((cyclohexylmethoxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 3.4 g of the product with a yield of 85%.

Example 16

The synthesis method refers to Example 6: 119 mg (0.3 mmol) of 4,4'-((cyclohexylmethoxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 129 mg of the product compound 8, with a yield of 84%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.18(s,1H),5.86(s,1H),3.29( d,1H),1.64(t,1H),1.62(t,4H),1.53(t,4H),1.44(t,2H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,133.20,132.08,128.99,128.85,128.38,128.22,127.96,127.88,127.22,124.20,105.99,85.88,39.1 5,29.96,26.03,25.84.HRMS(ESI) :m/z:[M+H] ⁺ calc.:511.2345; found:511.2366.

Embodiment 17

The synthesis method is as shown in Example 5.

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of benzyl alcohol and react to obtain 3.1 g of product with a yield of 80%.

(2) 3.9 g (0.01 mol) of dimethyl 4,4'-((benzyloxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 3.2 g of the product with a yield of 83%.

Embodiment 18

The synthesis method refers to Example 6: 117 mg (0.3 mmol) of 4,4'-(benzyloxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 122 mg of the product compound 11, with a yield of 81%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.32(s,1H),7.31(tt,4H),7.18( s,1H),5.86(s,1H),4.63(s,2H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,133.20,132.08,128.99,128.85,128.55,128.51,128.48,128.39,128.38,128.33,128.22,127.96,127 .88,127.22,124.20,105.99,86.92,75.63. HRMS(ESI):m/z:[M+H] ⁺ calc.:505.1876; found:505.1903.

Embodiment 19

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of benzyl alcohol and react to obtain 2.6 g of product with a yield of 68%.

(2) 3.8 g (0.01 mol) of dimethyl 4,4'-((furan-2-ylmethoxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 3.2 g of the product with a yield of 85%.

Embodiment 20

The synthesis method refers to Example 6: 114 mg (0.3 mmol) of 4,4'-((furan-2-ylmethoxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 122 mg of the product compound 9 with a yield of 82%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.58(d,1H),7.31(tt,4H),7.16(s,1H),6.42( s,1H),6.40(s,1H),5.86(s,1H),4.63(s,2H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,150.74,149.38,133.77,132.65,128.89,128.55,128.51,128.48,128.39,128.38,128.33,128.22,127.96,127.88,127 .22,124.20,105.99,86.92,75.63.HRMS( ESI):m/z:[M+H] ⁺ calc.:495.1668; found:495.1666.

Embodiment 21

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of benzyl alcohol and react to obtain 2.5 g of the product with a yield of 65%.

(2) 4.0 g (0.01 mol) of dimethyl 4,4'-((thiophen-2-ylmethoxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 3.2 g of the product with a yield of 79%.

Example 22

The synthesis method refers to Example 6: 119 mg (0.3 mmol) of 4,4'-((thiophen-2-ylmethoxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 127 mg of the product compound 10, with a yield of 83%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.53(d,1H),7.31(tt,4H),7.16(s,1H),7.06( s,1H),7.01(s,1H),5.86(s,1H),4.90(s,2H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,150.74,149.38,133.33,132.55,128.68,128.55,128.51,128.48,128.39,128.38,128.33,128.22,127.96,127.88,127 .22,124.20,105.99,88.92,78.36.HRMS( ESI):m/z:[M+H] ⁺ calc.:511.1440; found:511.1466.

Embodiment 23

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of p-methoxybenzyl alcohol and react to obtain 3.2 g of the product with a yield of 77%.

(2) 4.2 g (0.01 mol) of dimethyl 4,4'-(((4-methoxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 3.5 g of the product with a yield of 84%.

Embodiment 24

The synthesis method refers to Example 6: 126 mg (0.3 mmol) of 4,4'-(((4-methoxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 128 mg of the product compound 12 with a yield of 80%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.18(s,1H),6.99(d,2H),6.91( d,2H),5.86(s,1H),3.81(s,3H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,133.20,132.08,130.66,130.23,130.11,130.09,128.99,128.85,128.38,128.22,127.96,127.88,127 .22,124.20,105.99,86.68,55.32.HRMS( ESI):m/z:[M+H] ⁺ calc.:535.1918; found:535.1902.

Embodiment 25

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of p-methoxybenzyl alcohol and react to obtain 2.8 g of the product with a yield of 62%.

(2) 4.5 g (0.01 mol) of dimethyl 4,4'-((3,5-dimethoxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 3.6 g of the product with a yield of 80%.

Embodiment 26

The synthesis method refers to Example 6: 135 mg (0.3 mmol) of 4,4'-((3,5-dimethoxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 124 mg of the product compound 13 with a yield of 73%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.18(s,1H),6.65(s,2H),6.36( s,1H),5.86(s,1H),3.81(s,6H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,133.20,132.08,132.96,132.53,129.91,128.85,128.38,128.22,127.96,127.88,127.22,124.20,105 .99,87.65,56.32.HRMS(ESI):m /z:[M+H] ⁺ calc.:564.2009; found:564.2040.

Embodiment 27

The synthesis method is as follows:

(1) Take 3.6 g (0.01 mol) of dimethyl 4,4'-(bromomethylene)dibenzoate and 10 mL of p-methoxybenzyl alcohol and react to obtain 2.8 g of the product with a yield of 59%.

(2) 4.2 g (0.01 mol) of dimethyl 4,4'-((3,4,5-trimethoxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 4.0 g of the product with a yield of 84%.

Embodiment 28

The synthesis method refers to Example 6: 144 mg (0.3 mmol) of 4,4'-((3,4,5-trimethoxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 135 mg of the product compound 14 with a yield of 76%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.18(s,1H),6.65(s,2H),5.86( s,1H),3.71(s,9H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,148.74,147.39,136.21,135.98,135.91,135.63,134.95,128.85,128.38,128.22,127.96,127.88,127.22,124.20,105 .99,83.65,54.54.HRMS(ESI):m /z:[M+H] ⁺ calc.:595.2193; found:595.2208.

Embodiment 29

Take 1.6g (0.01mol) of 1-decanol and dissolve it in 3.5mL of tetrahydrofuran. Under ice-water bath conditions, add 3.5mL of sodium hydroxide aqueous solution (6mol/L). Weigh 2.9g (0.015mol) of p-toluenesulfonyl chloride and dissolve it in 6mL of tetrahydrofuran, add it to the reaction bottle and stir it overnight. Add 50mL of water, extract it with 100mL of dichloromethane, take the organic phase, dry it with anhydrous sodium sulfate, use a rotary evaporator to remove the solvent, separate it by silica gel column chromatography, and obtain 2.3g of product, with a yield of 73%.

Embodiment 30

(1) Take 152 mg (1 mmol) of methyl 4-hydroxybenzoate, 345 mg (1.1 mmol) of 4-methylbenzenesulfonic acid decyl ester, and 412 mg (3 mmol) of potassium carbonate, dissolve in 10 mL of DMF, heat to 100° C. in an oil bath, and react for 3 h. After cooling, add 30 mL of water, extract with 50 mL of dichloromethane, take the organic phase, dry it over anhydrous sodium sulfate, remove the solvent using a rotary evaporator, and separate it by silica gel column chromatography to obtain 266 mg of the product, with a yield of 91%.

(2) Take 292 mg (1 mmol) of methyl 4-decyloxybenzoate and dissolve it in 8 mL of anhydrous tetrahydrofuran. Add 76 mg (2 mmol) of lithium aluminum hydride in an ice-water bath and stir for 3 h. Add ice water dropwise to quench the reaction until no bubbles are generated, add 20 mL of water, extract with 50 mL of dichloromethane, take the organic phase, dry it with anhydrous sodium sulfate, and use a rotary evaporator to remove the solvent to obtain 224 mg of the product, with a yield of 85%.

(3) Take 264 mg (1 mmol) of 4-decyloxyphenylmethanol and dissolve it in 8 mL of dichloromethane. Add 540 mg (2 mmol) of phosphorus tribromide in an ice-water bath and react for 3 h. Add ice water dropwise to quench the reaction until no bubbles are generated, add 20 mL of water, extract with 50 mL of dichloromethane, take the organic phase, dry it over anhydrous sodium sulfate, and use a rotary evaporator to remove the solvent to obtain 276 mg of the product, with a yield of 83%.

Embodiment 31

(1) Take 300 mg (1 mmol) of dimethyl 4,4'-(hydroxymethylene)dibenzoate and dissolve it in 8 mL of tetrahydrofuran. Add sodium hydride powder in an ice-water bath until no bubbles are generated. Add a dichloromethane solution containing 326 mg (1 mmol) of 1-(bromomethyl)-4-(decyloxy)benzene dropwise and react for 2 h. Add ice water dropwise to quench the reaction until no bubbles are generated, add 20 mL of water, extract with 50 mL of dichloromethane, take the organic phase, dry it over anhydrous sodium sulfate, remove the solvent with a rotary evaporator, separate it by silica gel column chromatography, and obtain 399 mg of the product with a yield of 73%.

(2) Take 5.5 g (0.01 mol) of dimethyl 4,4'-(((4-decyloxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate and stir at room temperature. After 8 hours, the reaction is complete, and the methanol is removed by rotary evaporator and concentrated. The product is directly separated by silica gel column chromatography to obtain 4.4 g of the product with a yield of 80%.

(3) 164 mg (0.3 mmol) of 4,4'-(((4-decyloxybenzyl)oxy)methylene)dibenzohydrazide, 70 mL of ethanol, 30 mL of water, and 0.5 mL of glacial acetic acid were added to a 200 mL flask, and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were stirred at room temperature for 8 h. The mixture was filtered and washed with methanol and dichloromethane to obtain 150 mg of the product compound 15, with a yield of 76%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.16(s,1H),6.99(d,2H),6.89( d,2H),4.63(s,2H),4.06(t,2H),1.74(tt,2H),1.43(tt,2H),1.29(tt,2H),1.26(tt,10H),0.88(t ,3H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ(ppm):171.36,165.56,158.74,147.39,136.21,135.98,134.55,129.28,129.15,128.85,128.38,128.22,127.96,127.88,127.22,124.20,105 .99,83.65,71.98,68.75,29.68,25.85, 22.74,14.12.HRMS(ESI):m/z:[M+H] ⁺ calc.:661.3390; found:661.3356.

Embodiment 32

The synthesis method is shown in Example 30:

(1) 168 mg (1 mmol) of methyl 3,5-dihydroxybenzoate and 689 mg (2.2 mmol) of decyl 4-methylbenzenesulfonate were reacted to obtain 340 mg of the product with a yield of 76%.

(2) Take 448 mg (1 mmol) of methyl 3,5-di(decyloxy)benzoate and 76 mg (2 mmol) of lithium aluminum hydride and react to obtain 315 mg of the product. The yield is 75%.

(3) Take 420 mg (1 mmol) of (3,5-di(decyloxy)phenyl)methanol and 540 mg (2 mmol) of phosphorus tribromide and react to obtain 419 mg of the product. The yield is 87%.

Embodiment 33

Synthesis method: see Example 31

(1) 300 mg (1 mmol) of dimethyl 4,4'-(hydroxymethylene)dibenzoate and 482 mg (1 mmol) of 1-(bromomethyl)-3,5-didecyloxybenzene were reacted to obtain 475 mg of the product with a yield of 68%.

(2) 7.0 g (0.01 mol) of dimethyl 4,4'-(((3,5-didecyloxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 6.0 g of the product with a yield of 86%.

(3) 209 mg (0.3 mmol) of 4,4′-(((3,5-didecyloxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 171 mg of the product compound 17 with a yield of 70%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.16(s,1H),7.13(s,2H),7.12( s,1H),4.63(s,2H),4.06(t,4H),1.74(tt,4H),1.43(tt,4H),1.29(tt,4H),1.26(tt,20H),0.88(t ,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ(ppm):171.36,165.56,158.74,147.39,136.21,135.98,134.55,130.29,129.98,129.77,129.57,129.54,127.96,127.88,127.22,124.20,105 .99,83.65,71.98,68.75,29.68,25.85, 22.74,14.12.HRMS(ESI):m/z:[M+H] ⁺ calc.:817.4904; found:817.4940.

Embodiment 34

The synthesis method is shown in Example 30:

(1) Take 184 mg (1 mmol) of methyl gallate, 1096 mg (3.5 mmol) of 4-methylbenzenesulfonic acid decyl ester, and 1242 mg (9 mmol) of potassium carbonate and react to obtain 472 mg of the product. The yield is 78%.

(2) Take 605 mg (1 mmol) of methyl 3,4,5-tri(decyloxy)benzoate and 76 mg (2 mmol) of lithium aluminum hydride and react to obtain 473 mg of product. The yield is 82%.

(3) Take 577 mg (1 mmol) of (3,4,5-tri(decyloxy)phenyl)methanol and 540 mg (2 mmol) of phosphorus tribromide and react to obtain 536 mg of product. The yield is 84%.

Embodiment 35

The synthesis method is as follows:

(1) Take 300 mg (1 mmol) of dimethyl 4,4'-(hydroxymethylene)dibenzoate and 638 mg (1 mmol) of 1-(bromomethyl)-3,4,5-didecyloxybenzene and react to obtain 596 mg of the product with a yield of 70%.

(2) Take 8.5 g (0.01 mol) of dimethyl 4,4'-(((3,4,5-didecyloxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate, and react to obtain 7.9 g of the product, with a yield of 93%.

(3) 256 mg (0.3 mmol) of 4,4'-(((3,4,5-didecyloxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 209 mg of the product compound 19 with a yield of 72%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.16(s,1H),7.09(s,2H),4.63( s,2H),4.06(t,6H),1.74(tt,6H),1.43(tt,6H),1.29(tt,6H),1.26(tt,30H),0.88(t,9H). ¹³ C NMR (150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,158.74,147.39,136.21,135.98,134.55,131.29,130.98,130.75,129.57,129.54,127.96,127.88,127.22,124.20,105 .99,83.65,71.98,68.75,29.68,25.85, 22.74,14.12.HRMS(ESI):m/z:[M+H] ⁺ calc.:973.6418; found:973.6450.

Embodiment 36

Take 1.6g (0.01mol) of triethylene glycol monomethyl ether and dissolve it in 3.5mL of tetrahydrofuran. Under ice-water bath conditions, add 3.5mL of sodium hydroxide aqueous solution (6mol/L). Weigh 2.9g (0.015mol) of p-toluenesulfonyl chloride and dissolve it in 6mL of tetrahydrofuran, add it to the reaction bottle and stir it overnight. Add 50mL of water, extract it with 100mL of dichloromethane, take the organic phase, dry it with anhydrous sodium sulfate, use a rotary evaporator to remove the solvent, separate it by silica gel column chromatography, and obtain 2.6g of product, with a yield of 82%.

Embodiment 37

The synthesis method is shown in Example 30:

(1) 152 mg (1 mmol) of methyl p-hydroxybenzoate, 345 mg (1.1 mmol) of 4-methylbenzenesulfonic acid decyl ester, and 414 mg (3 mmol) of potassium carbonate were reacted to obtain 472 mg of the product, with a yield of 78%.

(2) 298 mg (1 mmol) of methyl 4-(2-(2-(-2-(2-methoxyethoxy)ethoxyethyl)ethoxy)benzoate and 76 mg (2 mmol) of lithium aluminum hydride were reacted to obtain 194 mg of the product. The yield was 75%.

(3) Take 270 mg (1 mmol) of (4-(2-(2-(-2-(2-methoxyethoxy)ethoxyethyl)ethoxy)phenyl)methanol and 540 mg (2 mmol) of phosphorus tribromide and react to obtain 279 mg of the product. The yield is 85%.

Embodiment 38

The synthesis method is as follows:

(1) 300 mg (1 mmol) of dimethyl 4,4'-(hydroxymethylene)dibenzoate and 332 mg (1 mmol) of 1-(bromomethyl)-4-(2-(2-(-2-methoxyethoxy)ethoxyethyl)ethoxy)benzene were reacted to obtain 229 mg of the product with a yield of 69%.

(2) 5.5 g (0.01 mol) of dimethyl 4,4'-((4-(2-(2-(-2-(2-methoxyethoxy)ethoxyphenyl)benzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 4.1 g of the product with a yield of 74%.

(3) 166 mg (0.3 mmol) of 4,4'-((4-(2-(2-(-2-(2-methoxyethoxy)ethoxyphenyl)benzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 114 mg of the product compound 16 with a yield of 57%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.16(s,1H),6.98(d,2H),6.86( d,2H),4.63(s,2H),4.31(t,2H),3.77(tt,2H),3.52(tt,8H),3.40(t,3H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,158.74,147.39,136.21,135.98,134.55,131.29,130.98,130.75,129.57,129.54,127.96,127.88,127.22,124.20,105 .99,83.65,71.97,71.62,70.58,70.45, 70.05,69.37,59.35.HRMS(ESI):m/z:[M+H] ⁺ calc.:667.2768; found:667.2766.

Embodiment 39

The synthesis method is shown in Example 30:

(1) 168 mg (1 mmol) of methyl 3,5-dihydroxybenzoate, 690 mg (2.2 mmol) of 4-methylbenzenesulfonic acid decyl ester, and 828 mg (6 mmol) of potassium carbonate were reacted to obtain 377 mg of the product, with a yield of 82%.

(2) 460 mg (1 mmol) of methyl 3,5-di(2-(2-methoxyethoxy)ethoxybenzoate and 76 mg (2 mmol) of lithium aluminum hydride were reacted to obtain 341 mg of the product, with a yield of 79%.

(3) 432 mg (1 mmol) of 3,5-di(2-(2-methoxyethoxy)ethoxybenzyl alcohol and 540 mg (2 mmol) of phosphorus tribromide were reacted to obtain 430 mg of the product with a yield of 87%.

Embodiment 40

The synthesis method is as follows:

(1) 300 mg (1 mmol) of dimethyl 4,4'-(hydroxymethylene)dibenzoate and 494 mg (1 mmol) of 1-(bromomethyl)-3,5-bis(2-(2-methoxyethoxy)ethoxyethyl)ethoxy)benzene were reacted to obtain 471 mg of the product with a yield of 66%.

(2) 7.1 g (0.01 mol) of dimethyl 4,4'-((3,5-bis(2-(2-methoxyethoxy)ethoxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate were reacted to obtain 5.1 g of the product with a yield of 72%.

(3) 214 mg (0.3 mmol) of 4,4'-((3,5-bis(2-(2-methoxyethoxy)ethoxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 111 mg of the product compound 18 with a yield of 52%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.98 (s, 1H), 11.65 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H) ,8.09(s,1H),7.94(d,J＝27.6Hz,4H),7.72(s,H),7.46(s,4H),7.16(s,1H),6.65(s,2H),6.36( s,1H),4.63(s,2H),4.31(t,4H),3.77(tt,4H),3.52(tt,16H),3.40(t,6H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ(ppm):171.36,165.56,158.74,147.39,136.21,135.98,134.55,131.29,130.98,130.75,129.57,129.54,125.88,125.57,125.33,124.20,105 .99,83.65,71.97,71.62,70.58,70.45, 70.05,69.37,59.35.HRMS(ESI):m/z:[M+H] ⁺ calc.:829.3660; found:829.3687.

Embodiment 41

The synthesis method is shown in Example 30:

(1) Take 184 mg (1 mmol) of methyl 3,4,,5-trihydroxybenzoate, 1098 mg (3.5 mmol) of 4-methylbenzenesulfonic acid decyl ester, and 1242 mg (6 mmol) of potassium carbonate, and react to obtain 491 mg of the product. The yield is 79%.

(2) 622 mg (1 mmol) of methyl 3,4,5-tris(2-(2-(-2-(2-methoxyethoxy)ethoxyethyl)ethoxy)benzoate and 76 mg (2 mmol) of lithium aluminum hydride were reacted to obtain 469 mg of the product, with a yield of 79%.

(3) 594 mg (1 mmol) of 3,4,5-tris(2-(2-(-2-(2-methoxyethoxy)ethoxyethyl)ethoxy)benzyl alcohol and 540 mg (2 mmol) of phosphorus tribromide were reacted to obtain 525 mg of the product with a yield of 80%.

Embodiment 42

The synthesis method is as follows:

(1) 300 mg (1 mmol) of dimethyl 4,4'-(hydroxymethylene)dibenzoate and 656 mg (1 mmol) of 5-(bromomethyl)-1,2,3-tris(2-(2-(-2-(2-methoxyethoxy)ethoxyethyl)ethoxy)benzene were reacted to obtain 552 mg of the product with a yield of 63%.

(2) Take 8.8 g (0.01 mol) of dimethyl 4,4'-((3,4,,5-tris(2-(2-methoxyethoxy)ethoxybenzyl)oxy)methylene)dibenzoate and 5 mL of 80% hydrazine hydrate, and react to obtain 6.3 g of product, with a yield of 72%.

(3) 263 mg (0.3 mmol) of 4,4'-((3,4,5-tris(2-(2-methoxyethoxy)ethoxybenzyl)oxy)methylene)dibenzohydrazide and 45 mg (0.3 mmol) of 4-hydroxyisophthalaldehyde were reacted to obtain 178 mg of the product compound 20 with a yield of 60%.

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 11.74 (s, 1H), 11.56 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H) ,7.93(d,J＝27.6Hz,5H),7.62(s,5H),7.03(s,1H),6.68(s,2H),5.76(s,1H),4.47(s,2H),4.08( s,4H),4.01(s,2H),3.74(s,4H),3.67(s,2H),3.59-3.42(m,24H),3.22(s,9H). ¹³ C NMR(150MHz,DMSO- d ₆ )δ(ppm):163.13,163.05,159.31,158.28,152.50,147.63,147.10,145.96,137.32,133.24,132.45,130.48,128.39,128.28,127.96,127.05,127 .01,126.24,106.91,81.37,81.31,74.58, 72.15,71.66,71.64,70.63,70.34,70.22,70.10,69.97,69.39,68.70,58.39,40.81.HRMS(ESI):m/z:[M+H] ⁺ calc.:991.4552; found:991.4555.

Embodiment 43

UV detection was used to detect the changes in UV absorption of compound 20 and phthalate in the organic phase.

The spectral range was set at 210nm-550nm, 1984μL of acetonitrile solution was added to the cuvette, 16μL of a 5mM compound (DMSO as solvent) was added to make the final concentration reach 40μM, di-tetrabutylammonium phthalate was gradually added, [ _Cphthalate /C _Compound ] was 0, 0.25, 0.5, 0.75, 1, 1.5, 2.0, 3.0, 5.0, 10.0, with the addition of di-tetrabutylammonium phthalate, the peak at 305nm decreased, and the peak at 355nm increased, and the change graph of its ultraviolet absorption value was obtained (see Figure 1).

Embodiment 44

Fluorescence detection was used to detect the change in fluorescence intensity and binding constant k between compound 20 and phthalate in the organic phase.

The spectral range was set at 310nm-650nm, the excitation wavelength was 305nm, 1999μL of acetonitrile solution was added to the cuvette, 0.8μL of a 5mM compound (DMSO was used as the solvent) was added to make the final concentration reach 2μM, di-tetrabutylammonium phthalate was gradually added, [C _phthalate /C _compound ] was 0, 0.25, 0.5, 0.75, 1, 1.5, 2.0, 3.0, 5.0, respectively. With the addition of di-tetrabutylammonium phthalate, the peak value at 550 increased, and the fluorescence emission intensity change graph was obtained (see Figure 2).

By numerically importing a 1:1 binding equation and drawing a graph (see FIG3 ), the binding constant between the probe and phthalate is K=2.6×10 ⁷ M ^-1 .

Embodiment 45

Fluorescence detection was used to detect the change in fluorescence intensity of compound 20 with different anions in the organic phase.

The spectral range was set at 310nm–650nm, the excitation wavelength was 305nm, 1999μL of acetonitrile solution was added to the cuvette, 0.8μL of a 5mM compound (DMSO as solvent) was added to make the final concentration reach 2μM, and different types of anion tetrabutylammonium salts were added, [C _anion /C _compound ] was 1. The histogram of the fluorescence intensity change of the detection probe at 550nm (see Figure 4).

Embodiment 46

Job plot curve was used to determine the binding ratio of compound 20 to phthalate.

The spectral range was set at 210 nm–550 nm, 1984 μL of acetonitrile solution was added to the cuvette, the total concentration of the compound in the solution was set to 40 μM, and the UV absorption was scanned in sequence to obtain the values of the UV absorption change at 355 nm when [C _compound /C _phthalate + C _compound ] was 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and 1. The points were plotted to obtain the Job plot curve (see Figure 5), and the binding ratio was 1/1.

Embodiment 47

HRMS (ESI) was used to determine the binding ratio of compound 20 to phthalate.

0.01 mmol of the probe was dissolved in 3 ml of acetonitrile solution, 0.01 mmol of di-tetrabutylammonium phthalate solid was added, and the mixture was pumped dry with an oil pump to obtain a solid powder complex, which was subjected to mass spectrometry detection. The measured molecular weight was 577.2293, and the calculated value was 577.2297 (see Figure 6), indicating that the binding ratio was 1/1.

Embodiment 48

TEM was used to observe the nanomorphology of compound 20 bound to phthalate.

Take 0.001mmol of the probe and dissolve it in 5ml of acetonitrile solution, add 0.001mmol of di-tetrabutyl ammonium phthalate solid, and after the two are combined with each other, perform TEM test. Then test the morphology of the probe and di-tetrabutyl ammonium phthalate itself as a control (see Figure 7). It is found that the composite can form better nano-spherical particles with better dispersion.

Claims (10)

1. A cyclic diacylhydrazone derivative or a pharmaceutically acceptable salt thereof represented by the general structural formula (I) or (II):

In the formula, R is a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group, a methylcyclohexane, a cyclohexane, a C1-C6 ester group, a substituted or unsubstituted C1-C4 amine, a substituted or unsubstituted 5-10 membered heterocyclic group or a heteroaryl group; X, Y, and Z independently represent a hydrogen atom, a methyl group, a C1-C6 ester group, a C1-C10 alkoxy group, a substituted or unsubstituted C1-C4 amine, a substituted or unsubstituted 5-10 membered heterocyclic group, or a heteroaryl group. 2. The cyclic diacylhydrazone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the heterocyclic group or heteroaryl group contains 1-3 heteroatoms of N, O or S, and the substituent used is: C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylamino. 3. The cyclic diacylhydrazone derivative or the pharmaceutically acceptable salt thereof according to claim 1, characterized in that the pharmaceutically acceptable salt formed by the cyclic diacylhydrazone derivative comprises a salt formed by the cyclic diacylhydrazone derivative and an acid. 4. A cyclic diacylhydrazone derivative and a pharmaceutically acceptable salt thereof, which is one of the following compounds:

5. The synthesis method of the cyclic diacylhydrazone derivative of the general structural formula (I) according to any one of claims 1 to 4 is as follows:

Specifically include: (1) Preparation of compound a-2-(4,4'-(hydroxymethyl)dibenzoic acid dimethyl ester Add methyl 4-iodobenzoate (a-1) to anhydrous tetrahydrofuran, protect with nitrogen, cool at -40 to -30°C, and stir evenly; add isopropyl magnesium chloride tetrahydrofuran solution, continue stirring at -30 to -20°C; add anhydrous tetrahydrofuran solution containing methyl 4-formylbenzoate, react for 30-40 minutes, air cool to room temperature, stir and react overnight to obtain an orange-yellow transparent liquid, purify, and obtain product a-2; (2) Preparation of compound a-34,4'-(bromomethylene) dibenzoic acid dimethyl ester Compound a-2 is dissolved in dichloromethane, phosphorus tribromide is added dropwise under ice-water bath conditions, and the reaction is continued for 4 to 8 hours, followed by purification to obtain product a-3; (3) Preparation of compound a-4 According to the group represented by R, take the corresponding compound, heat to 60-120°C, add compound a-3, stir for 3-8h, purify after the reaction is complete, and obtain product a-4; (4) Preparation of compound a-5 Take compound a-4, add methanol and hydrazine hydrate with a mass concentration of 80%, stir at room temperature overnight, remove the solvent, and separate and purify to obtain product a-5; When R in the cyclic diacylhydrazone derivative of the general structural formula (I) is H, directly use compound a-2, add methanol and hydrazine hydrate with a mass concentration of 80%, stir at room temperature overnight, remove the solvent, and separate and purify to obtain product a-5; (5) Preparation of cyclic diacylhydrazone derivatives of general structural formula (I) Take compound a-5, add ethanol, water, glacial acetic acid, and hydroxyisophthalaldehyde, stir at room temperature, solid precipitates, separate the solid and liquid, take the precipitate, wash it, and obtain a cyclic diacylhydrazone derivative of the general structural formula (I). 6. The method for synthesizing cyclic diacylhydrazone derivatives according to claim 5, characterized in that in the step (3), the corresponding compound is an alcohol compound; the alcohol compound is selected from one or more of methanol, n-butanol, 1-decanol, triethylene glycol monomethyl ether, 2-thiophene methanol, 2-furyl methanol, benzyl alcohol, and cyclohexane methanol. 7. The synthesis method of the cyclic diacylhydrazone derivative of the general structural formula (II) according to any one of claims 1 to 4 is as follows:

Specifically include: S1: Preparation of compound b-1 Dissolve triethylene glycol monomethyl ether or decanol in tetrahydrofuran, add sodium hydroxide aqueous solution and p-toluenesulfonyl chloride tetrahydrofuran solution under ice-water bath conditions, stir overnight, and extract the obtained product to obtain product b-1; S2: Preparation of compound b-2 Take methyl hydroxybenzoate, compound b-1, and potassium carbonate, dissolve them in DMF, heat to 100°C, and purify after the reaction to obtain product b-2; S3: Preparation of compound b-3 Take compound b-2, dissolve it in anhydrous tetrahydrofuran, add lithium aluminum hydride in an ice-water bath, stir, and purify after the reaction to obtain product b-3; S4: Preparation of compound b-4 Take compound b-3, dissolve it in dichloromethane, add phosphorus tribromide in an ice-water bath, and purify it after the reaction to obtain product b-4; S5: Preparation of compound c-1 Take compound a-2, dissolve it in tetrahydrofuran, add sodium hydride powder in an ice-water bath until no bubbles are generated; dropwise add the tetrahydrofuran solution containing compound b-4; after the reaction is completed, purify and dry to obtain product c-1; S6: Preparation of compound c-2 Compound c-1, methanol and hydrazine hydrate with a mass concentration of 80% are mixed, stirred at room temperature overnight, the solvent is removed, and the product c-2 is obtained after separation and purification; S7: Preparation of cyclic diacylhydrazone derivatives of general structural formula (II) Take compound c-2, ethanol, water, glacial acetic acid, and then add hydroxyisophthalaldehyde, stir at room temperature. After the reaction is completed, solid precipitates, the solid-liquid is separated, and the precipitate is taken and washed to obtain a cyclic diacylhydrazone derivative of the general structural formula (II). 8. The method for synthesizing a cyclic diacylhydrazone derivative according to claim 6, characterized in that, according to the groups represented by X, Y, and Z, methyl hydroxybenzoate is selected from one of methyl 4-hydroxybenzoate, methyl 3,5-dihydroxybenzoate, and methyl 3,4,5-trihydroxybenzoate. 9. The method for synthesizing a cyclic diacylhydrazone derivative according to any one of claims 5 to 6, characterized in that the hydroxyisophthalaldehyde is selected from one of 2-hydroxyisophthalaldehyde, 4-hydroxyisophthalaldehyde and 5-hydroxyisophthalaldehyde. 10. Use of the cyclic diacylhydrazone derivative represented by the general structural formula (I) or (II) according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof as a fluorescent probe for carboxylate anions.

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