2, 5-dihydrofuran derivative and synthesis method thereof

Abstract

The invention discloses a 2, 5-dihydrofuran derivative, the structure of which is # imgabs0 #, in which R1 is selected from one of H and 4-Cl; r2 is selected from one of C6H4, 4 to ClC6H4, 4 to BrC6H4, 4 to FC6H4, 4 to CH3OC6H4, 4 to CH3C6H4 and n-Bu; r < 3 > is selected from one of C < 6 > H < 4 > and 4-ClC < 6 > H < 4 >; r < 4 > is selected from one of C < 6 > H < 4 >, 4-Cl < 6 > H < 4 >, 4-Br < 6 > H < 4 > and 4-CH < 3 > C < 6 > H < 4 >; r < 5 > is selected from one of t-Bu, C6H4CH2, c-C6H11 and 1-adamyl. The invention also provides a synthesis method of the 2, 5-dihydrofuran derivative, the method has the advantages of simple and easily available raw materials, wide substrate adaptability, mild conditions, few steps and the like, the target product can be obtained by only one pot and two steps, and the invention provides a simple and efficient synthesis method of the 2, 5-dihydrofuran compound. And moreover, the yield of the target product is high, and different from the previous silver-catalyzed free radical cyclization reaction, an additional oxidizing agent does not need to be added, so that the method has potential application value in synthetic chemistry and drug research and development.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a 2,5-dihydrofuran derivative and a synthesis method thereof. Background Art

[0002] Polysubstituted furans play a crucial role as structural units in a series of natural products, bioactive synthetic compounds, drugs, and functional materials. Among them, 2,5-dihydrofuran, as an important class of furan derivatives, has attracted attention due to its wide range of biological activities, such as anti-cytotoxicity, anti-microbial effect, anti-fungal activity, insecticidal activity, etc. In view of this, organic chemists have developed a series of effective methods for synthesizing 2,5-dihydrofuran. For example, in 2015, the Hu research group reported a [4+1] cyclization reaction of Pd(II)-catalyzed diazoacetate and aryl propargyl alcohol, successfully synthesizing 2,5-dihydrofuran derivatives (Chem. Commun., 2015, 51, 15204). Subsequently, Karunakar and his collaborators developed a gold-catalyzed intramolecular rearrangement and cyclization protocol to synthesize 2,5-dihydrofuran derivatives using O-propargyl β-enaminone as a raw material (Org. Biomol. Chem., 2019, 17, 6015-6024). However, the current methods still have some challenges, such as difficult raw material sources, the need for relatively expensive catalysts, harsh reaction conditions, the need for multi-step synthesis, and so on. Therefore, it is still necessary to develop a more simple and efficient method for synthesizing 2,5-dihydrofuran.

[0003] Among them, tandem cyclization reactions, especially those involving radical processes, are considered a class of tools for the rapid synthesis of bioactive skeletons. Silver salts have received extensive attention in radical cyclization reactions due to their easy availability, low toxicity, good biocompatibility, and stability. However, usually, such silver-catalyzed radical cyclization reactions generally require the addition of stoichiometric oxidants. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a 2,5-dihydrofuran derivative and a synthesis method thereof.

[0005] The present invention provides a 2,5-dihydrofuran derivative, and its structure is shown in Formula I:

[0006]

[0007] Wherein,

[0008] R 1 is selected from one of H and 4-Cl;

[0009] R 2Selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu;

[0010] R 3 Selected from one of C6H4, 4-ClC6H4;

[0011] R 4 Selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4;

[0012] R 5 Selected from one of t-Bu, C6H4CH2, c-C6H 11 , 1-adamantyl.

[0013] The present invention also provides a method for synthesizing the 2,5-dihydrofuran derivative as described above, comprising the following steps:

[0014] S1. Dissolve salicylic acid or 5-chlorosalicylic acid, primary amine, alkynyl aldehyde, and isocyanide in methanol, stir the reaction until complete, and then remove the solvent to obtain an intermediate;

[0015] S2. Dissolve the intermediate in acetonitrile, then add silver nitrate and potassium carbonate, and after the reaction is complete, remove the solvent to obtain a crude product;

[0016] S3. The crude product is separated by column chromatography to obtain the 2,5-dihydrofuran derivative.

[0017] Further, the structural formula of the primary amine in step S1 is R 2 NH2, where R 2 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu.

[0018] Further, the structural formula of the alkynyl aldehyde in step S1 is as shown in formula II:

[0019]

[0020] where R 3 is selected from one of C6H4, 4-ClC6H4;

[0021] R 4 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4.

[0022] Further, the structural formula of the isocyanide in step S1 is R 5 NC, where R 5Selected from one of t-Bu, C6H4CH2, c-C6H 11 , and 1-adamantyl.

[0023] Furthermore, in step S1, the reaction temperature is room temperature, and TLC is used to monitor the completion of the reaction.

[0024] Furthermore, in step S1, the molar ratio of salicylic acid or 5-chlorosalicylic acid, primary amine, alkynyl aldehyde, and isocyanide is (0.9 - 1.1):(0.9 - 1.1):(0.9 - 1.1):(0.9 - 1.1).

[0025] Furthermore, in step S2, the molar ratio of the intermediate, silver nitrate, and potassium carbonate is (0.9 - 1.1):(0.09 - 0.11):(0.9 - 1.1).

[0026] Furthermore, the structure of the intermediate is shown in Formula III:

[0027]

[0028] wherein, R 1 is selected from one of H and 4-Cl;

[0029] R 2 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, and n-Bu;

[0030] R 3 is selected from one of C6H4 and 4-ClC6H4;

[0031] R 4 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, and 4-CH3C6H4;

[0032] R 5 is selected from one of t-Bu, C6H4CH2, c-C6H 11 , and 1-adamantyl.

[0033] Furthermore, in step S2, the reaction temperature is 80 °C or higher, and the reaction time is 1 - 2 hours.

[0034] Furthermore, the solvent for column chromatography separation in step S3 is a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether is 1:(6 - 10).

[0035] Furthermore, the route of the synthesis method is as follows:

[0036]

[0037] Among them, 1 is salicylic acid or 5-chlorosalicylic acid, 2 is primary amine, 3 is alkynyl aldehyde, 4 is isocyanide, and 5 is intermediate.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0039] 1. The present invention provides a method for synthesizing 2,5-dihydrofuran derivatives. This method uses salicylic acid or 5-chlorosalicylic acid, amine, alkynyl aldehyde, and isocyanide as raw materials, methanol as a solvent, and undergoes a Ugi four-component reaction at room temperature to obtain an intermediate. Without separation, acetonitrile is used as a solvent, silver nitrate is added to the system as a catalyst, and potassium carbonate is used as a base. The reaction is heated to 80 °C until the reaction ends (monitored by TLC), and then the solvent is removed under reduced pressure. The residue is separated and purified by column chromatography to obtain 2,5-dihydrofuran derivatives (Formula I). It uses simple and readily available raw materials to participate in a continuous Ugi / Ag-catalyzed radical cyclization reaction to synthesize a novel 2,5-dihydrofuran compound.

[0040] 2. The synthesis method provided by the present invention has the advantages of simple and readily available raw materials, wide substrate adaptability, mild conditions, and few steps. The target product can be obtained in only one pot and two steps, providing a simple and efficient method for synthesizing 2,5-dihydrofuran compounds. Moreover, the target product has a high yield, and different from previous silver-catalyzed radical cyclization reactions, no additional oxidant needs to be added. Therefore, it has potential application value in synthetic chemistry and drug research and development. Description of the Drawings

[0041] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments of the present invention. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0042] Figure 1 It is the 1 1H NMR (δ / ppm, TMS / CDCl3) spectrum of product I-m;

[0043] Figure 2 It is the 13 13C NMR (δ / ppm, TMS / CDCl3) spectrum of product I-m;

[0044] Figure 3 It is the single crystal structure diagram of product I-m. Detailed Embodiments

[0045] In order to make the technical problems to be solved, technical solutions and beneficial effects of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with embodiments and drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention. The present invention will be specifically introduced below in conjunction with specific embodiments.

[0046] An embodiment of the present invention provides a 2,5-dihydrofuran derivative, and its structure is shown in Formula I:

[0047]

[0048] Wherein,

[0049] R 1 is selected from one of H and 4-Cl;

[0050] R 2 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, and n-Bu;

[0051] R 3 is selected from one of C6H4 and 4-ClC6H4;

[0052] R 4 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, and 4-CH3C6H4;

[0053] R 5 is selected from one of t-Bu, C6H4CH2, c-C6H 11 and 1-adamantyl.

[0054] An embodiment of the present invention also provides a synthesis method of the 2,5-dihydrofuran derivative as described above, including the following steps:

[0055] S1. Dissolve salicylic acid or 5-chlorosalicylic acid, primary amine, alkynyl aldehyde, and isonitrile in methanol, stir the reaction completely, and then remove the solvent to obtain an intermediate;

[0056] S2. Dissolve the intermediate in acetonitrile, then add silver nitrate and potassium carbonate, react completely, and then remove the solvent to obtain a crude product;

[0057] S3. The crude product is separated by column chromatography to obtain the 2,5-dihydrofuran derivative.

[0058] Specifically, the structural formula of the primary amine in step S1 is R 2 NH2, where R 2Selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu.

[0059] Specifically, the structure of the alkynyl aldehyde described in step S1 is as shown in formula II:

[0060]

[0061] Wherein R 3 Selected from one of C6H4, 4-ClC6H4;

[0062] R 4 Selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4.

[0063] Furthermore, the structural formula of the isocyanide described in step S1 is R 5 NC, wherein R 5 Selected from one of t-Bu, C6H4CH2, c-C6H 11 , 1-adamantyl.

[0064] Specifically, the reaction temperature in step S1 is room temperature, and TLC is used to monitor the completion of the reaction.

[0065] Specifically, the molar ratio of salicylic acid or 5-chlorosalicylic acid, primary amine, alkynyl aldehyde, and isocyanide in step S1 is (0.9 - 1.1):(0.9 - 1.1):(0.9 - 1.1):(0.9 - 1.1), and preferably, it is 1:1:1:1.

[0066] Specifically, the molar ratio of the intermediate, silver nitrate, and potassium carbonate in step S2 is (0.9 - 1.1):(0.09 - 0.11):(0.9 - 1.1), and preferably, it is 1:0.1:1.

[0067] Specifically, the structure of the intermediate is as shown in formula III:

[0068]

[0069] Wherein, R 1 Selected from one of H, 4-Cl;

[0070] R 2 Selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu;

[0071] R 3 Selected from one of C6H4, 4-ClC6H4;

[0072] R 4 selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4;

[0073] R 5 selected from one of t-Bu, C6H4CH2, c-C6H 11 , 1-adamantyl.

[0074] Specifically, the reaction temperature in step S2 is 80 °C or above, preferably 80 °C, and the reaction time is 1 - 2 hours.

[0075] Specifically, the solvent for column chromatography separation in step S3 is a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether is 1:(6 - 10).

[0076] Specifically, the route of the synthesis method is as follows:

[0077]

[0078] where 1 is salicylic acid or 5-chlorosalicylic acid, 2 is primary amine, 3 is alkynyl aldehyde, 4 is isonitrile, and 5 is intermediate.

[0079] Specifically, the 2,5-dihydrofuran derivative obtained in step S3 is as follows:

[0080]

[0081] The present invention will be further described below in conjunction with specific embodiments, and the content of the present invention is not limited thereto at all.

[0082] Example 1

[0083] Prepare 2,5-dihydrofuran derivative I-a according to the following steps:

[0084] (1) Add 2 mmol of salicylic acid (2 mmol), 4-chloroaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and tert-butyl isonitrile 4 (2 mmol) to a 50 mL round-bottom flask, dissolve in methanol, stir at room temperature for 1 day, monitor by TLC until the reaction is complete, and remove the solvent by reduced pressure distillation to obtain intermediate 5a;

[0085]

[0086] (2) Add 5 ml of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir for 1 hour to obtain a crude product;

[0087] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-a (0.992 g, yield 88%, yellow oil): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-N-(4-chlorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0088]

[0089] Example 2

[0090] 2,5-Dihydrofuran derivative I-b was prepared according to the following steps:

[0091] (1) 2 mmol of salicylic acid (2 mmol), 4-bromoaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) were added to a 50 mL round-bottom flask, dissolved in methanol, and stirred at room temperature for 1 day. The reaction was monitored by TLC until completion, and the solvent was removed by distillation under reduced pressure to obtain intermediate 5b;

[0092]

[0093] (2) 5 mL of acetonitrile solution was added to a round-bottom flask, followed by the addition of AgNO3 (0.2 mmol) and potassium carbonate (2 mmol). The temperature was raised to 80 °C and stirred for 2 hours to obtain the crude product;

[0094] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-b (1.032 g, yield 85%, yellow oil): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-N-(4-bromophenyl)-2-hydroxybenzamide, and the structural formula is:

[0095]

[0096] Example 3

[0097] 2,5-Dihydrofuran derivative I-c was prepared according to the following steps:

[0098] (1) Add 2 mmol of salicylic acid (2 mmol), 4-fluoroaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until it is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5c;

[0099]

[0100] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 1 hour to obtain the crude product;

[0101] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-c (0.974 g, yield 89%, yellow oil): ((Z)-4-benzyl-5-((Z)-benzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-N-(4-fluorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0102]

[0103] Example 4

[0104] Prepare 2,5-dihydrofuran derivative I-d according to the following steps:

[0105] (1) Add 2 mmol of salicylic acid (2 mmol), 4-methoxyaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until it is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5d;

[0106]

[0107] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0108] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-d (0.770 g, yield 69%, white solid): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-2-hydroxy-N-(4-methoxyphenyl)benzamide, and the structural formula is:

[0109]

[0110] Example 5

[0111] 2,5-Dihydrofuran derivative I-e was prepared according to the following steps:

[0112] (1) 2 mmol of salicylic acid (2 mmol), n-butylamine (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) were added to a 50 mL round-bottom flask, dissolved in methanol, and stirred at room temperature for 1 day. The reaction was monitored by TLC until completion, and the solvent was removed by distillation under reduced pressure to obtain intermediate 5e;

[0113]

[0114] (2) 5 ml of acetonitrile solution was added to a round-bottom flask, and then AgNO3 (0.2 mmol) and potassium carbonate (2 mmol) were added. The temperature was raised to 80 °C and stirred for 1 hour to obtain the crude product;

[0115] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-e (0.732 g, yield 72%, yellow oil): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-N-butyl-2-hydroxy benzamide, and the structural formula is:

[0116]

[0117] Example 6

[0118] 2,5-Dihydrofuran derivative I-f was prepared according to the following steps:

[0119] (1) Add 2 mmol of salicylic acid (2 mmol), 4-chloroaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and adamantane isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor by TLC until the reaction is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5f;

[0120]

[0121] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0122] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-f (1.116 g, yield 87%, yellow oil): N-((Z)-2-(((1r,3r,5r,7r)-adamantan-2-yl)imino)-4-benzyl-5-((Z)-benzylidene)-2,5-dihydrofuran-3-yl)-N-(4-chlorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0123]

[0124] Example 7

[0125] Prepare 2,5-dihydrofuran derivative I-g according to the following steps:

[0126] (1) Add 2 mmol of salicylic acid (2 mmol), 4-methylaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and adamantane isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor by TLC until the reaction is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5g;

[0127]

[0128] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 1 hour to obtain the crude product;

[0129] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-g (0.906 g, yield 73%, yellow oil): N-((Z)-2-(((1r,3r,5r,7r)-adamantan-2-yl)imino)-4-benzyl-5-((Z)-benzylidene)-2,5-dihydrofuran-3-yl)-2-hydroxy-N-(p-tolyl)benzamide, and the structural formula is:

[0130]

[0131] Example 8

[0132] 2,5-Dihydrofuran derivative I-h was prepared according to the following steps:

[0133] (1) 2 mmol of salicylic acid (2 mmol), aniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and adamantane isocyanide 4 (2 mmol) were added to a 50 mL round-bottom flask, dissolved in methanol, and stirred at room temperature for 1 day. The reaction was monitored by TLC until completion, and the solvent was removed by distillation under reduced pressure to obtain intermediate 5h;

[0134]

[0135] (2) 5 mL of acetonitrile solution was added to a round-bottom flask, and then AgNO3 (0.2 mmol) and potassium carbonate (2 mmol) were added. The temperature was raised to 80 °C and stirred for 2 hours to obtain the crude product;

[0136] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-h (0.982 g, yield 81%, yellow oil): N-((Z)-2-(((3s,5s,7s)-adamantan-1-yl)imino)-4-benzyl-5-((Z)-benzylidene)-2,5-dihydrofuran-3-yl)-2-hydroxy-N-phenylbenzamide, and the structural formula is:

[0137]

[0138] Example 9

[0139] 2,5-Dihydrofuran derivative I-i was prepared according to the following steps:

[0140] (1) Add 2 mmol of salicylic acid (2 mmol), aniline (2 mmol), (E)-2-benzylidene-4-(4-chlorophenyl)-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until it is complete, and remove the solvent by vacuum distillation to obtain intermediate 5i;

[0141]

[0142] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 1 hour to obtain the crude product;

[0143] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-i (0.890 g, yield 79%, yellow oil): N-((Z)-4-benzyl-2-(tert-butylimino)-5-((Z)-4-chlorobenzylidene)-2,5-dihydrofuran-3-yl)-2-hydroxy-N-phenylbenzamide, and the structural formula is:

[0144]

[0145] Example 10

[0146] Prepare 2,5-dihydrofuran derivative I-j according to the following steps:

[0147] (1) Add 2 mmol of salicylic acid (2 mmol), aniline (2 mmol), (E)-2-benzylidene-4-(4-bromophenyl)-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until it is complete, and remove the solvent by vacuum distillation to obtain intermediate 5j;

[0148]

[0149] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0150] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-j (0.972 g, yield 80%, yellow oil): N-((Z)-4-benzyl-5-((Z)-4-bromobenzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-2-hydroxy-N-phenylbenzamide, and the structural formula is:

[0151]

[0152] Example 11

[0153] The 2,5-dihydrofuran derivative I-k was prepared according to the following steps:

[0154] (1) 2 mmol of salicylic acid (2 mmol), 4-chloroaniline (2 mmol), (E)-2-benzylidene-4-(4-chlorophenyl)-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) were added to a 50 mL round-bottom flask, dissolved in methanol, and stirred at room temperature for 1 day. The reaction was monitored by TLC until completion, and the solvent was removed by distillation under reduced pressure to obtain the intermediate 5k;

[0155]

[0156] (2) 5 mL of acetonitrile solution was added to a round-bottom flask, and then AgNO3 (0.2 mmol) and potassium carbonate (2 mmol) were added. The temperature was raised to 80 °C and stirred for 1 hour to obtain the crude product;

[0157] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-k (1.004 g, yield 84%, yellow oil): N-((Z)-4-benzyl-2-(tert-butylimino)-5-((Z)-4-chlorobenzylidene)-2,5-dihydrofuran-3-yl)-N-(4-chlorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0158]

[0159] Example 12

[0160] The 2,5-dihydrofuran derivative I-l was prepared according to the following steps:

[0161] (1) Add 2 mmol of salicylic acid (2 mmol), 4-chloroaniline (2 mmol), (E)-2-benzylidene-4-(4-bromophenyl)-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until completion, and remove the solvent by distillation under reduced pressure to obtain intermediate 5l;

[0162]

[0163] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0164] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-l (1.052 g, yield 82%, yellow oil): N-((Z)-4-benzyl-5-((Z)-4-bromobenzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-N-(4-chlorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0165]

[0166] Example 13

[0167] Prepare 2,5-dihydrofuran derivative I-m according to the following steps:

[0168] (1) Add 2 mmol of 5-chlorosalicylic acid (2 mmol), 4-fluoroaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and adamantyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until completion, and remove the solvent by distillation under reduced pressure to obtain intermediate 5m;

[0169]

[0170] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 1 hour to obtain the crude product;

[0171] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-m (0.988 g, yield 75%, yellow oil): N-((Z)-2-(((1r,3r,5r,7r)-adamantan-2-yl)imino)-4-benzyl-5-((Z)-benzylidene)-2,5-dihydrofuran-3-yl)-5-chloro-N-(4-fluorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0172]

[0173] Figure 1 is the 1 1H NMR (δ / ppm, TMS / CDCl3) spectrum of product I-m, Figure 2 is the 13 13C NMR (δ / ppm, TMS / CDCl3) spectrum of product I-m, Figure 3 is the single crystal structure diagram of product I-m.

[0174] Yellow solid (yield 75%), mp: 169 - 171 °C. 1 1H NMR (400 MHz, CDCl3): δ (ppm) 10.05 (s, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.30 - 7.17 (m, 6H), 7.15 - 7.12 (m, 1H), 7.04 (d, J = 7.2 Hz, 2H), 6.95 (s, 2H), 6.86 (d, J = 8.0 Hz, 2H), 5.80 (s, 1H), 3.66 (s, 2H), 2.09 (d, J = 20.0 Hz, 9H), 1.73 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 162.2, 159.7, 150.7, 148.6, 136.7, 136.6, 135.6, 135.3, 133.5, 132.4, 129.7, 128.8, 128.7, 128.3, 128.1, 127.7, 127.7, 127.2, 127.2, 127.0, 123.8, 119.2, 115.9, 115.6, 107.6, 55.9, 42.2, 36.5, 29.8, 29.7 LCMS (ESI) m / z [M + H] + : 659. Anal. Calcd for C 41 H36 ClFN2O3: C, 74.70; H, 5.50; N, 4.25; Found: C, 74.90; H, 5.65; N, 4.66.

[0175] The report of Product I-m single crystal is as follows:

[0176]

[0177] Example 14

[0178] Prepare 2,5-dihydrofuran derivative I-n according to the following steps:

[0179] (1) Add 2 mmol of 5-chlorosalicylic acid (2 mmol), 4-fluoroaniline (2 mmol), (E)-2-benzylidene-4-(4-methylphenyl)-3-butynal (2 mmol), and adamantane isocyanide 4 (2 mmol) into a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor by TLC until the reaction is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5n;

[0180]

[0181] (2) Add 5 ml of acetonitrile solution into a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0182] (3) The crude product is separated by column chromatography (the solvent is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:6) to obtain the target product 2,5-dihydrofuran I-n (0.942 g, yield 70%, yellow oil): N-((Z)-2-(((1r,3r,5r,7r)-adamantan-2-yl)imino)-4-benzyl-5-((Z)-4-methylbenzylidene)-2,5-dihydrofuran-3-yl)-5-chloro-N-(4-fluorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0183]

[0184] Example 15

[0185] Prepare 2,5-dihydrofuran derivative I-o according to the following steps:

[0186] (1) Add 2 mmol of salicylic acid (2 mmol), 4-chloroaniline (2 mmol), (E)-2-(4-chlorobenzylidene)-4-phenyl-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask. Dissolve them in methanol and stir the reaction at room temperature for 1 day. Monitor the reaction by TLC until it is complete, and then remove the solvent by distillation under reduced pressure to obtain intermediate 5o;

[0187]

[0188] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, and then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol). Raise the temperature to 80 °C and stir the reaction for 1 hour to obtain the crude product;

[0189] (3) The crude product was separated by column chromatography (the solvent is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:6) to obtain the target product 2,5-dihydrofuran I-o (1.004 g, yield 84%, yellow oil): N-((Z)-5-((Z)-benzylidene)-2-(tert-butylimino)-4-(4-chlorobenzyl)-2,5-dihydrofuran-3-yl)-N-(4-chlorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0190]

[0191] Example 16

[0192] Prepare 2,5-dihydrofuran derivative I-p according to the following steps:

[0193] (1) Add 2 mmol of 5-chlorosalicylic acid (2 mmol), 4-bromoaniline (2 mmol), (E)-2-benzylidene-4-(4-bromophenyl)-3-butynal (2 mmol), and cyclohexyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask. Dissolve them in methanol and stir the reaction at room temperature for 1 day. Monitor the reaction by TLC until it is complete, and then remove the solvent by distillation under reduced pressure to obtain intermediate 5p;

[0194]

[0195] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, and then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol). Raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0196] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-p (1.120 g, yield 75%, yellow oil): N-((Z)-4-benzyl-5-((Z)-4-bromobenzylidene)-2-(cyclohexylimino)-2,5-dihydrofuran-3-yl)-N-(4-bromophenyl)-5-chloro-2-hydroxybenzamide, and the structural formula is:

[0197]

[0198] Example 17

[0199] The 2,5-dihydrofuran derivative I-q was prepared according to the following steps:

[0200] (1) 2 mmol of salicylic acid (2 mmol), 4-chloroaniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and cyclohexyl isocyanide 4 (2 mmol) were added to a 50 mL round-bottom flask, dissolved in methanol, and stirred at room temperature for 1 day. The reaction was monitored by TLC until complete, and the solvent was removed by distillation under reduced pressure to obtain the intermediate 5q;

[0201]

[0202] (2) 5 ml of acetonitrile solution was added to a round-bottom flask, and then AgNO3 (0.2 mmol) and potassium carbonate (2 mmol) were added. The temperature was raised to 80 °C and stirred for 1 hour to obtain the crude product;

[0203] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-q (0.848 g, yield 72%, yellow oil): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(cyclohexylimino)-2,5-dihydrofuran-3-yl)-N-(4-chlorophenyl)-2-hydroxybenzamide, and the structural formula is:

[0204]

[0205] Example 18

[0206] The 2,5-dihydrofuran derivative I-r was prepared according to the following steps:

[0207] (1) Add 2 mmol of 5-chlorosalicylic acid (2 mmol), aniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and tert-butyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until it is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5r;

[0208]

[0209] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 2 hours to obtain the crude product;

[0210] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-r (0.992 g, yield 88%, yellow oil): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(tert-butylimino)-2,5-dihydrofuran-3-yl)-5-chloro-2-hydroxy-N-phenylbenzamide, and the structural formula is:

[0211]

[0212] Example 19

[0213] Prepare 2,5-dihydrofuran derivative I-s according to the following steps:

[0214] (1) Add 2 mmol of salicylic acid (2 mmol), aniline (2 mmol), (E)-2-benzylidene-4-phenyl-3-butynal (2 mmol), and benzyl isocyanide 4 (2 mmol) to a 50 mL round-bottom flask, dissolve them in methanol, stir the reaction at room temperature for 1 day, monitor the reaction by TLC until it is complete, and remove the solvent by distillation under reduced pressure to obtain intermediate 5s;

[0215]

[0216] (2) Add 5 mL of acetonitrile solution to a round-bottom flask, then add AgNO3 (0.2 mmol) and potassium carbonate (2 mmol), raise the temperature to 80 °C and stir the reaction for 1 hour to obtain the crude product;

[0217] (3) The crude product was separated by column chromatography (the solvent was a mixed solution of ethyl acetate and petroleum ether, where the volume ratio of ethyl acetate to petroleum ether was 1:6) to obtain the target product 2,5-dihydrofuran I-s (0.788 g, yield 70%, yellow oil): N-((Z)-4-benzyl-5-((Z)-benzylidene)-2-(benzylimino)-2,5-dihydrofuran-3-yl)-2-hydroxy-N-phenylbenzamide, and the structural formula is:

[0218]

[0219] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 2,5-dihydrofuran derivative, the structure of which is shown in Formula I: Wherein, R 1 selected from one of H and 4-Cl; R 2 selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu; R 3 selected from one of C6H4 and 4-ClC6H4; R 4 selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4; R 5 Selected from one of t-Bu, C6H4CH2, c-C6H 11 , and 1-adamantyl.

2. A method for synthesizing a 2,5-dihydrofuran derivative as described in claim 1, characterized in that, Comprising the following steps: S1. Dissolve salicylic acid or 5-chlorosalicylic acid, primary amine, alkynyl aldehyde, and isocyanide in methanol, stir the reaction until complete, and then remove the solvent to obtain an intermediate; S2. Dissolve the intermediate in acetonitrile, add silver nitrate and potassium carbonate, and after the reaction is complete, remove the solvent to obtain a crude product; S3. The crude product is separated by column chromatography to obtain the 2,5-dihydrofuran derivative.

3. The synthesis method according to claim 2, characterized in that, The structural formula of the primary amine described in step S1 is R 2 NH2, where R 2 is selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu.

4. The synthesis method according to claim 2, wherein The structure of the alkynyl aldehyde described in step S1 is shown in Formula II: wherein R 3 is selected from one of C6H4 and 4-ClC6H4; R 4 Selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4.

5. The synthesis method according to claim 2, characterized in that The structural formula of the isocyanide described in step S1 is R 5 NC, where R 5 is selected from one of t-Bu, C6H4CH2, c-C6H 11 , 1-adamantyl.

6. The synthesis method according to claim 2, characterized in that, The reaction temperature in step S1 is room temperature, and TLC is used to monitor the completion of the reaction.

7. The synthesis method according to claim 2, characterized in that, The structure of the intermediate is shown in Formula III: Among them, R 1 is selected from one of H and 4-Cl; R 2 selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-CH3OC6H4, 4-CH3C6H4, n-Bu; R 3 selected from one of C6H4 and 4-ClC6H4; R 4 selected from one of C6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4; R 5 Selected from one of t-Bu, C6H4CH2, c-C6H 11 , and 1-adamantyl.

8. The synthesis method according to claim 2, characterized in that, The reaction temperature in step S2 is 80 °C or above, and the reaction time is 1 - 2 hours.

9. The synthesis method according to claim 2, wherein, The solvent for column chromatography separation in step S3 is a mixed solution of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether is 1:(6 - 10).

10. The synthesis method according to any one of claims 2-9, characterized in that, The molar ratio of salicylic acid or 5-chlorosalicylic acid, primary amine, alkynyl aldehyde, and isocyanide described in step S1 is (0.9 - 1.1):(0.9 - 1.1):(0.9 - 1.1):(0.9 - 1.1), and the molar ratio of the intermediate, silver nitrate, and potassium carbonate described in step S2 is (0.9 - 1.1):(0.09 - 0.11):(0.9 - 1.1).

Images