A compound containing a triphenylamine skeleton, and a preparation method and application thereof

Abstract

This application relates to a terphenylamine skeleton compound, its preparation method, and its application, belonging to the field of chemical synthesis technology. The preparation method of the terphenylamine skeleton compound of this application includes the following steps: dissolving 2,4,6-triphenylaniline with thiazole-4-carboxaldehyde or thiophene-3-carboxaldehyde in a solvent, conducting a reductive amination reaction under reducing agent conditions, quenching, extraction, washing, concentration to remove solvent, and purification to obtain the terphenylamine skeleton compound. This application provides a simple and mild synthetic method for the natural active products 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine, which can only be extracted from the secondary metabolites of the marine fungus Aspergillus sp. Furthermore, this method utilizes widely available raw materials, which is beneficial for large-scale industrial production of these natural active products.

Description

Technical Field

[0001] This application relates to the field of chemical synthesis technology, and in particular to a compound containing a terphenylamine skeleton, its preparation method, and its application. Background Technology

[0002] Synthetic methods for 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine. The first method involved extracting representative terphenylamine skeleton compounds from secondary metabolites of the marine fungus *Aspergillus* sp. Among these, 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine (compound A) exhibited significant anti-dengue virus activity (EC50 = 18 ± 1.05 μM; CC50 > 100 μM). Currently, there is no specific treatment for dengue virus. Therefore, compounds such as 5'-phenyl-N-(thiazolyl-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine may become lead compounds for drug discovery and hold promise for the development of effective new natural drugs.

[0003] ;

[0004] However, currently, 5'-phenyl-N-(thiazolyl-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine can only be extracted from the secondary metabolites of the marine fungus Aspergillus sp., which is a very limited source and has always been a major obstacle for scientists to conduct research. Summary of the Invention

[0005] In view of this, this application provides a terphenylamine skeleton compound, its preparation method and application, which can effectively overcome the shortcomings and deficiencies of existing 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophen-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine, which can only be extracted from the fermentation broth of marine fungi Aspergillus sp., resulting in very limited sources.

[0006] The first aspect of this application provides a method for preparing a compound containing a terphenylamine skeleton, comprising the following steps:

[0007] 2,4,6-Triphenylaniline was dissolved in a solvent with thiazole-4-carboxaldehyde or thiophene-3-carboxaldehyde, and a reductive amination reaction was carried out under reducing agent conditions. After quenching, extraction, washing, concentration to remove solvent, and purification, a compound containing the triphenylaniline skeleton was obtained.

[0008] Specifically, the synthetic route for compounds containing the terphenylamine skeleton is as follows:

[0009] ;

[0010] S1. Compound 1 is used as a raw material and reacts with compound 2 (thiazole-4-carboxaldehyde) under the condition of a reducing agent to undergo a reducing amination reaction. After quenching, extraction, washing, concentration to remove solvent, and purification, compound A is obtained.

[0011] S2. Compound 1 was used as a raw material and reacted with compound 3 (thiophene-3-carboxaldehyde) under the condition of a reducing agent to undergo a reducing amination reaction. After quenching, extraction, washing, concentration to remove solvent, and purification, compound B was obtained.

[0012] Preferably, the specific conditions for the reductive amination reaction are as follows: the reductive amination reaction is carried out at room temperature under conditions that are controlled by a weak acid and adjusted to a weak acid environment. Specifically, the room temperature is 25°C; the reductive amination reaction is promoted in a weakly acidic environment, which is conducive to the formation of the intermediate imine.

[0013] Preferably, the weak acid is selected from at least one of acetic acid, propionic acid, benzoic acid, and citric acid. More preferably, the weak acid is acetic acid.

[0014] Preferably, the reducing agent is selected from sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride. More preferably, the reducing agent is sodium cyanoborohydride.

[0015] Preferably, the solvent is selected from at least one of methanol, ethanol, isopropanol, trifluoroethanol, dichloromethane, and water. More preferably, the solvent is methanol or dichloromethane.

[0016] Preferably, the specific process of quenching, extraction, washing, and concentration to remove solvent is as follows: after the reaction is completed, quenching is performed under ice bath cooling, and saturated sodium bicarbonate aqueous solution is slowly added until the solution is weakly alkaline, so that the product amine changes from a salt state to a free base, which facilitates extraction; extraction is performed with dichloromethane, washing is performed with saturated brine, the organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by rotary evaporation at 45°C, followed by depressurization to remove the solvent.

[0017] Preferably, the purification process is carried out using 200-300 mesh silica gel column chromatography.

[0018] A second aspect of this application also provides a terphenylamine skeleton compound, which is prepared by the above method. The terphenylamine skeleton compound includes 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophen-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine.

[0019] The third aspect of this application also provides the use of the above-mentioned triphenylamine skeleton compounds in dengue virus drugs.

[0020] Compared with the prior art, this application has the following advantages:

[0021] This application provides a method for synthesizing the natural active products 5'-phenyl-N-(thiazolyl-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine (i.e., compound A) and 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine (i.e., compound B), which can only be obtained from marine fungi of the genus *Aspergillus*. Extracting the naturally active products 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine from the secondary metabolites of sp) provides a simple and mild synthetic method. Furthermore, the method utilizes widely available raw materials, facilitating large-scale industrial production of these naturally active products and laying a solid foundation for related bioactivity studies. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in this application or the prior art, the drawings used in the description of this application or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0023] Figure 1 The 1H NMR spectrum of compound A, namely 5'-phenyl-N-(thiazolyl-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine;

[0024] Figure 2The carbon spectrum of compound A, namely 5'-phenyl-N-(thiazolyl-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine;

[0025] Figure 3 The 1H NMR spectrum of compound B, namely 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine;

[0026] Figure 4 The carbon spectrum of compound B, namely 5'-phenyl-N-(thiophene-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0028] Unless otherwise specified, the experimental methods used in the embodiments of this application are all conventional methods.

[0029] In the following examples, unless otherwise specified, all raw materials can be obtained by commercial purchase or conventional methods.

[0030] Example 1 Synthesis of Compound A

[0031] ;

[0032] S1. Compound A was obtained by reductive amination of compound 1 (2,4,6-triphenylaniline) with thiazol-4-carboxaldehyde. 100 mg (311.12 μmol) of compound 1 (2,4,6-triphenylaniline) and 38.72 mg (342.23 μmol) of compound 2 (thiazol-4-carboxaldehyde) were placed in a 10 g beaker and dissolved in DCM:methanol at a ratio of 1:1. After stirring for 10 minutes, 81.45 mg (1.28 mmol) of sodium cyanoborohydride and 3-4 drops of acetic acid were added, and the reaction was allowed to proceed at room temperature for 10 hours. The reaction was monitored by thin-layer chromatography (TLC, PE / EA = 15:1). After the reaction was completed, the mixture was quenched under ice bath cooling, and saturated sodium bicarbonate aqueous solution was slowly added until the solution became weakly alkaline, converting the product amine from a salt state to a free base for easier extraction. Extracted with 50 ml of dichloromethane, washed with 3 × 50 ml of saturated brine, the organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation at 45 °C, and the solvent was removed by vacuum evaporation to obtain a white solid. The solid was purified by rapid column chromatography (using a 200-300 mesh silica gel column) to obtain 106.78 mg of compound A (yield 82%).

[0033] Following the above method, compound A was prepared using different reaction systems, and the results are shown in Table 1.

[0034] Table 1. Preparation of compound A under different conditions

[0035]

[0036] As shown in Table 1, product compound A can be prepared under all the above conditions. However, when sodium triacetoxyborohydride is used as the reducing agent, the yield is lower than that of sodium cyanoborohydride; when DCM / methanol is used as the solvent, the yield is higher; when the temperature is 0℃, reduction is inhibited, and the yield is significantly lower than that at room temperature (25℃).

[0037] 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 8.12 (d, J = 7.8 Hz,2H), 7.64 (dd, J = 8.4, 1.7 Hz, 1H), 7.50-7.41 (m, 3H), 7.06 (d, J = 3.1 Hz,1H), 6.99 (d, J = 8.9 Hz, 1H), 6.89 (dd, J = 8.9, 3.1 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H).

[0038] 13CNMR (101 MHz, Chloroform-d) δ 153.87, 150.99, 139.86, 138.73,132.65, 129.81, 127.67, 125.84, 123.57, 123.36, 121.20, 120.40, 119.48,117.18, 112.88, 112.56, 110.63, 110.05, 56.51, 55.86.

[0039] Example 2 Synthesis of Compound B

[0040] ;

[0041] S2. Compound B was obtained by reductive amination of compound 1 (2,4,6-triphenylaniline) with compound 3 (3-thiophene-3-carboxaldehyde). 100 mg (311.12 µmol) of compound 1 (2,4,6-triphenylaniline) and 38.38 mg (342.23 µmol) of compound 3 (thiophene-3-carboxaldehyde) were placed in a 10 g beaker and dissolved in DCM:methanol at a ratio of 1:1. After stirring for 10 minutes, 81.45 mg (1.28 mmol) of sodium cyanoborohydride and 3-4 drops of acetic acid were added, and the reaction was allowed to proceed at room temperature for 10 hours. The reaction was monitored by thin-layer chromatography (TLC, PE / EA = 15:1). After the reaction was completed, the mixture was quenched under ice bath cooling, and saturated sodium bicarbonate aqueous solution was slowly added until the solution became weakly alkaline, converting the product amine from a salt state to a free base for easier extraction. Extracted with 50 ml of dichloromethane, washed with 3 × 50 ml of saturated brine, the organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation at 45 °C, and the solvent was removed by vacuum evaporation to obtain a white solid. The solid was purified by rapid column chromatography (using a 200-300 mesh silica gel column) to obtain 106.78 mg of compound B (yield 85%).

[0042] Compound B was prepared under different conditions using the method described above, and the results are shown in Table 2.

[0043] Table 2. Preparation of compound B under different conditions

[0044]

[0045] As shown in Table 2, product compound B can be prepared under all the above conditions. Table 2 also shows that the yield decreases when the amount of sodium cyanoborohydride (the reducing agent) is reduced. The yield is higher when DCM / methanol is used as the solvent.

[0046] 1H NMR (400 MHz, Chloroform-d) δ 7.67 – 7.63 (m, 2H), 7.55 (d, J =7.0 Hz, 4H), 7.51 – 7.37 (m, 11H), 7.31 (t, J = 7.4 Hz, 1H), 7.12 (dd, J =4.9, 3.0 Hz, 1H), 6.74 (d, J = 2.9 Hz, 1H), 6.60 (dd, J = 4.9, 1.3 Hz, 1H), 3.68 (s, 2H).

[0047] 13 C NMR (101 MHz, Chloroform-d) δ 143.29, 140.81, 140.76, 140.63,133.63, 133.60, 129.32, 129.12, 128.84, 128.81, 127.44, 127.40, 126.84,126.71, 125.60, 121.70, 47.26.

[0048] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for preparing a compound containing a terphenylamine skeleton, characterized in that, Includes the following steps: 2,4,6-Triphenylaniline was dissolved in a solvent with thiazole-4-carboxaldehyde or thiophene-3-carboxaldehyde, and a reductive amination reaction was carried out under reducing agent conditions. After quenching, extraction, washing, concentration to remove solvent, and purification, a compound containing the triphenylaniline skeleton was obtained.

2. The method for preparing a compound containing a terphenylamine skeleton according to claim 1, characterized in that, The specific conditions for the reductive amination reaction are: the reductive amination reaction is carried out at room temperature under conditions that are controlled by a weak acid and adjusted to a weak acid.

3. The method for preparing a compound containing a terphenylamine skeleton according to claim 2, characterized in that, The weak acid is selected from at least one of acetic acid, propionic acid, benzoic acid, and citric acid.

4. The method for preparing a compound containing a terphenylamine skeleton according to claim 1, characterized in that, The reducing agent is selected from one of sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride.

5. The method for preparing a compound containing a terphenylamine skeleton according to claim 1, characterized in that, The solvent is selected from at least one of methanol, ethanol, isopropanol, trifluoroethanol, dichloromethane, and water.

6. The method for preparing a compound containing a terphenylamine skeleton according to claim 1, characterized in that, The specific process of quenching, extraction, washing, and concentration to remove solvent is as follows: After the reaction is completed, quenching is performed under ice bath cooling, and saturated sodium bicarbonate aqueous solution is slowly added until the solution is weakly alkaline, so that the product amine changes from a salt state to a free base, which facilitates extraction; extraction is performed with dichloromethane, washing is performed with saturated brine, the organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by rotary evaporation at 45°C, followed by depressurization to remove the solvent.

7. The method for preparing a compound containing a terphenylamine skeleton according to claim 1, characterized in that, The specific purification process is as follows: 200-300 mesh silica gel column chromatography is used.

8. A compound containing a terphenylamine skeleton, characterized in that, A terphenylamine skeleton compound prepared by the method according to any one of claims 1 to 7, wherein the terphenylamine skeleton compound comprises 5'-phenyl-N-(thiazol-4-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine and 5'-phenyl-N-(thiophen-3-ylmethyl)-[1,1':3',1''-terphenyl]-2'-amine.

9. The use of the triphenylamine skeleton compound of claim 8 in dengue virus drugs.

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