Benzocrown ether derivative and synthesis method thereof

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a benzocrown ether derivative and a synthesis method thereof. According to the invention, carboxylic acid or substituted carboxylic acid as shown in a general formula I, benzocrown ether as shown in a general formula II and substituted terephthalaldehyde as shown in a general formula IV are used as raw materials, and two kinds of benzocrown ether derivatives as shown in a general formula (A) and a general formula (B) are synthesized through Friedel-Crafts acylation reaction, reduction reaction and substitution reaction. The preparation method provided by the invention has the advantages of simple and easily available raw materials, simple post-treatment, high yield, good universality, environmental friendliness and the like. The two benzocrown ether derivatives as shown in the general formula (A) and the general formula (B), which are disclosed by the invention, serve as important organic synthesis intermediates and have great research values in the aspects of ion recognition, material preparation, medicine synthesis and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic compound synthesis, and particularly relates to a benzocrown ether derivative and a synthesis method thereof. BACKGROUND

[0002] As a macrocyclic host, crown ether has attracted extensive attention in the combination of inorganic or organic guests due to its cyclic cavity and electron-donating property. Chemical modification of crown ether is crucial in ion recognition, material preparation, drug synthesis, etc. The synthesis of benzocrown ether derivatives is rarely reported, and there are disadvantages such as complex post-treatment, low yield, poor universality, etc. Therefore, it is still necessary to develop a synthesis method of benzocrown ether derivatives with simple post-treatment, high yield and wide application reaction.

[0003] Based on this, the present application designs two new synthesis methods of benzocrown ether derivatives, synthesizes a series of novel benzocrown ether derivatives through Friedel-Crafts acylation reaction, reduction reaction and substitution reaction, and has great research value in ion recognition, material preparation, drug synthesis, etc. SUMMARY

[0004] The present application aims to overcome the deficiencies in the prior art, and provides a benzocrown ether derivative and a synthesis method thereof.

[0005] To achieve the above-mentioned purpose, the technical solutions of the present application are as follows: The first aspect of the present application is a benzocrown ether derivative, the structural formula of which is shown in general formula (A) or general formula (B):

[0006] wherein R1 is selected from carbonyl, methylene or hydroxyl-substituted methylene; R2 is selected from any one of hydrogen, fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkynyl, phenyl, hydroxyl, mercapto, alkoxy, alkenyloxy, alkynyloxy, phenyloxy, benzyloxy, alkylthio, alkenylthio, alkynylthio, phenylthio, benzylthio, aldehyde, alkylketone, alkenylketone, alkynylketone, phenylketone, benzylketone, alkylthioketone, alkenylthioketone, alkynylthioketone, phenylthioketone, benzylthioketone, carboxyl, alkoxylketone, alkenyloxylketone, alkynyloxylketone, phenyloxylketone, benzyloxylketone, amido, N-mono-substituted amido, N,N-disubstituted amido, cyano, nitro; R3 is selected from hydrogen, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkynyl, phenyl, benzyl, alkoxy, alkenyloxy, alkynyloxy, phenyloxy, benzyloxy, alkylthio, alkenylthio, alkynylthio, phenylthio, benzylthio, amido, N-mono-substituted amido, N,N-disubstituted amido, nitro or benzocrown ether-4-(R1-alkyleneoxy), wherein R1 represents any one of carbonyl, methylene, hydroxyl-substituted methylene; m is selected from any integer from 0 to 20; n is selected from any integer from 1 to 3.

[0007] Preferably, said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, alkylketone, alkenylketone, alkynylketone, alkylthioketone, alkenylthioketone, alkynylthioketone, alkoxyketone, alkenyloxyketone, alkynyloxyketone, N-mono-substituted amido, N,N-disubstituted amido are independently C1-C20alkyl, C1-C20alkenyl, C1-C20alkynyl, C1-C20alkoxy, C1-C20alkenyloxy, C1-C20alkynyloxy, C1-C20alkylthio, C1-C20alkenylthio, C1-C20alkynylthio, C1-C20alkylketone, C1-C20alkenylketone, C1-C20alkynylketone, C1-C20alkylthioketone, C1-C20alkenylthioketone, C1-C20alkynylthioketone, C1-C20alkoxyketone, C1-C20alkenyloxyketone, C1-C20alkynyloxyketone, C1-C20alkylamido, C1-C20alkenylamido, C1-C20alkynylamido. 10 alkyl, C1-C 10 alkenyl, C1-C 10 alkynyl, C1-C 10 alkoxy, C1-C 10 alkenyloxy, C1-C 10 alkynyloxy, C1-C 10 alkylthio, C1-C 10 alkenylthio, C1-C 10 alkynylthio, C1-C 10 alkylketone, C1-C 10 alkenylketone, C1-C 10 alkynylketone, C1-C 10 alkylthioketone, C1-C 10 alkenylthioketone, C1-C 10 alkynylthioketone, C1-C 10 alkoxyketone, C1-C 10 alkenyloxyketone, C1-C 10 alkynyloxyketone, C1-C 10 N-mono-substituted amido, C1-C 10 N,N-disubstituted amido.

[0008] Preferably, said benzo crown ether-4-(R1-alkyleneoxy) is benzo-12-crown-4-ether-4-(R1-alkyleneoxy), benzo-15-crown-5-ether-4-(R1-alkyleneoxy) or benzo-18-crown-6-ether-4-(R1-alkyleneoxy), wherein R1 is selected from carbonyl, methylene or hydroxy-substituted methylene.

[0009] A second aspect of the present application is a method for synthesizing benzo crown ether derivatives, comprising the following steps: Synthesis of benzo crown ether derivatives as shown in general formula (A): (a) Friedel-Crafts acylation reaction of carboxylic acid or substituted carboxylic acid of general formula I and benzo crown ether of general formula II under the action of catalyst to synthesize benzo crown ether derivative of general formula III; (b) reduction reaction of benzo crown ether derivative of general formula III under the action of reducing agent in nitrogen atmosphere to synthesize benzo crown ether derivative of general formula IV, and the reaction process is shown in formula 1:

[0010] wherein, R2, m, n are defined as any one of claims 1-3; Synthesis of benzo crown ether derivative of general formula (B): Substitution reaction of benzo crown ether derivative of general formula III or general formula IV and substituted terephthaldehyde of general formula V under the action of catalyst to synthesize benzo crown ether derivative of general formula VI, and the reaction process is shown in formula 2:

[0011] wherein, R1, R2, R3, m, n are defined as any one of claims 1-3.

[0012] Preferably, the catalyst in step (a) is one or more of methane sulfonic acid, Eaton's reagent, ethane sulfonic acid, propane sulfonic acid, trifluoromethane sulfonic acid, p-trifluoromethylbenzenesulfonic acid; the solvent in step (b) is trifluoroacetic acid, and the reducing agent is silane or solvent is methanol, and the reducing agent is sodium borohydride, wherein the silane is one or more of trimethylsilane, triethylsilane, tripropylsilane.

[0013] Preferably, the temperature of Friedel-Crafts acylation reaction in step (a) is 10-60℃, and the time is 2-6 hours; the temperature of reduction reaction in step (b) is 0-70℃, and the time is 2-6 hours.

[0014] Preferably, the molar ratio of carboxylic acid or substituted carboxylic acid of general formula I, benzo crown ether of general formula II, catalyst in step (a) is (1-10):1:(0.1-100); the molar ratio of benzo crown ether derivative of general formula III, reducing agent in step (b) is 1:(2-10).

[0015] Preferably, the solvent in the substitution reaction is one or more of acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide; and the catalyst is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, N,N-diisopropyl ethylamine.

[0016] Preferably, the temperature of the substitution reaction is 60-100℃, and the time is 4-24 hours.

[0017] Preferably, the molar ratio of the benzocrown ether derivative of general formula III or general formula IV, the substituted p-xylylene glycol of general formula V, and the catalyst is (1-8):1:(1-8).

[0018] Compared with the prior art, the present application has the following advantages: The present application provides two types of benzocrown ether derivatives which have not been reported before, and the preparation method has the advantages of simple and readily available raw materials, simple post-treatment, high yield, good universality, environmental friendliness, etc. The two types of benzocrown ether derivatives proposed in the present application have great research value as important organic synthesis intermediates in ion recognition, material preparation, drug synthesis, etc. DETAILED DESCRIPTION

[0019] The preferred embodiments of the present application are described in detail below, which are only used to illustrate and explain the present application, and do not limit the present application.

[0020] Example 1: Synthesis of compound III-1 Benzene-12-crown-4-ether 1.000 g and bromoacetic acid 3.717 g were placed in a 100 mL dry reaction bottle, and Eaton reagent 10 mL was added, and the reaction was stirred at 25℃ for 3 hours, and the reaction system finally turned into a deep red color. 50 mL of cold distilled water was poured into the reaction system and stirred for 30 minutes. Then, saturated Na2CO3 solution was added dropwise to adjust the pH value of the reaction mixture to 7. The aqueous solution was extracted with dichloromethane 3 times (3x50 mL), and the combined organic phase was washed with distilled water and 1M NaOH (50 mL) respectively. The combined organic phase was dried with appropriate amount of anhydrous Na2SO4, filtered, and the volatile matter was removed under reduced pressure to obtain the crude product. The separation yield was 42.7%, and white solid III-1 was obtained (see Table 1 for structure).

[0021] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 7.66 (m, 2H), 6.98 (d, J =8.9 Hz, 1H), 4.39 (s, 2H), 4.24 (m, 4H), 3.90 (m, 2H), 3.82 (m, 2H), 3.77 (s,4H); 13C NMR (151 MHz, CDCl3) δ 189.98, 156.27, 150.43, 128.24, 125.48, 119.72, 115.72, 73.11, 71.59, 71.04, 70.75, 69.86, 69.72, 30.73. High resolution mass spectral data: HRMS (FTMS + ESI): 345.0332 [M + H] + .

[0022] Example 2: Synthesis of compound III-2 Bromacetic acid was replaced by 4-bromobutyric acid (2.234 g), and the rest of the required raw materials, reagent types and preparation methods were the same as in Example 1. The isolated yield was 68.4%, and white solid III-2 (see Table 1 for the structural formula) was obtained.

[0023] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 7.65 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 4.23 (m, 4H), 3.90 (m, 2H), 3.83 (m, 2H), 3.78 (s, 4H), 3.54 (t, J = 6.4 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H), 2.29 (m, 2H); 13 C NMR (151 MHz, CDCl3) δ 197.44, 155.57, 150.31, 131.32, 124.35, 118.69, 115.87, 72.93, 71.58, 71.09, 70.85, 69.94, 69.81, 36.35, 33.86, 27.19. High resolution mass spectral data: HRMS (FTMS + ESI): 373.0645 [M + H] + .

[0024] Example 3: Synthesis of compound III-3 Bromacetic acid was replaced by 8-bromooctanoic acid (139 mg), and the rest of the required raw materials, reagent types and preparation methods were the same as in Example 1. The isolated yield was 83.6%, and white solid III-3 (see Table 1 for the structural formula) was obtained.

[0025] NMR data:1 H NMR (600 MHz, Chloroform- d ) δ 7.63 (d, J = 8.0 Hz, 2H),6.96 (d, J = 8.2 Hz, 1H), 4.23 (m, 4H), 3.89 (m, 2H), 3.83 (m, 2H), 3.78 (s,4H), 3.40 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H), 1.85 (m, 2H), 1.71 (m,2H), 1.44 (m, 2H), 1.37 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 199.07, 155.27,150.27, 131.66, 124.28, 118.66, 115.88, 72.84, 71.56, 71.10, 70.89, 69.93,69.83, 38.29, 34.08, 32.86, 29.28, 28.74, 28.13, 24.52. High resolution mass spectral data: HRMS (FTMS + ESI): 429.1275 [M + H] + .

[0026] Example 4: Synthesis of compound III-4 Replace benzo-12-crown-4-ether with benzo-15-crown-5-ether (100 mg), replace bromoacetic acid with 8-bromooctanoic acid (117 mg), and the rest of the required raw materials, reagent types and preparation methods are the same as in Example 1. The isolated yield is 85.2%, and white solid III-4 (see Table 1 for structural formula) is obtained.

[0027] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 7.55 (d, J = 8.3 Hz, 1H),7.50 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.18 (m, 4H), 3.92 (m, 4H), 3.76 (s,8H), 3.40 (t, J = 6.8 Hz, 2H), 2.90 (t, J= 7.4 Hz, 2H), 1.85 (m, 2H), 1.72 (m,2H), 1.44 (m, 2H), 1.37 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 199.22, 153.45,148.96, 130.58, 123.11, 112.85, 111.89, 71.29(overlap), 70.54, 70.44, 69.52,69.40, 69.07, 68.77, 38.17, 34.09, 32.87, 29.31, 28.75, 28.14, 24.66. High resolution mass spectral data: HRMS (FTMS + ESI): 473.1527 [M + H] + .

[0028] Example 5: Synthesis of compound IV-1 Compound III-1 1.235 g was weighed into a 100 mL dry reaction flask and triethylsilane 2.080 g and trifluoroacetic acid 25 mL were added. The reaction was stirred at 60 °C under nitrogen protection for 4 hours. TLC method was used to monitor the reaction completion. Most of the trifluoroacetic acid was removed under reduced pressure. The reaction system was diluted with an appropriate amount of dichloromethane (50 mL), and then saturated Na2CO3 solution was slowly added until the gas bubbles stopped. The organic phase was separated and washed with distilled water (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and the volatile matter was removed under reduced pressure to obtain the crude product. The separation yield was 94.5%, and white solid IV-1 was obtained (see Table 1 for the structural formula).

[0029] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 6.91 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 6.79 (d, J = 8.1 Hz, 1H), 4.17 (m, 4H), 3.85 (m, 4H), 3.79 (s,4H), 3.52 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.7 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 150.70, 149.62, 133.66, 122.85, 118.53, 118.37, 72.04, 71.80, 71.31, 71.25, 70.05, 70.03, 39.05, 33.18. High resolution mass spectral data: HRMS (FTMS + ESI): 331.0539 [M+H] + .

[0030] Example 6: Synthesis of compound IV-2 Compound III-1 was replaced by III-2 (816 mg), and the rest of the required raw materials, reagent types and preparation methods were the same as in Example 5, with an isolation yield of 93.2%, to obtain colorless viscous oil liquid IV-2 (see Table 1 for the structural formula).

[0031] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 6.89 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 4.16 (m, 4H), 3.85 (m, 4H), 3.80 (s,4H), 3.41 (t, J = 6.5 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 1.87 (m, 2H), 1.74 (m,2H); 13 C NMR (151 MHz, CDCl3) δ 150.66, 148.81, 136.72, 122.45, 118.46, 118.11, 72.27, 71.71, 71.37, 71.24, 70.12 (overlap), 34.57, 33.80, 32.31, 29.96. High resolution mass spectral data: HRMS (FTMS + ESI): 359.0853 [M+H] + .

[0032] Example 7: Synthesis of compound IV-3 Compound III-1 was replaced by 4-(6-bromohexanoyl)benzo-12-crown-4-ether (1.155 g), and the rest of the required starting materials, reagent types and preparation methods were the same as in Example 5. The isolation yield was 95.8%, and a colorless viscous oil liquid IV-3 (see Table 1 for the structural formula) was obtained.

[0033] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 6.88 (d, J = 8.1 Hz, 1H),6.78 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 8.1, 2.0 Hz, 1H), 4.16 (m, 4H), 3.86 (m,2H), 3.84 (m, 2H), 3.80 (s, 4H), 3.40 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 7.8 Hz,2H), 1.85 (m, 2H), 1.59 (m, 2H), 1.45 (m, 2H), 1.34 (m, 2H); 13 C NMR (151 MHz,CDCl3) δ 150.59, 148.61, 137.54, 122.41, 118.42, 118.11, 72.31, 71.67, 71.38,71.24, 70.14(overlap), 35.40, 34.09, 32.84, 31.38, 28.43, 28.12. High resolution mass spectrometry data: HRMS (FTMS + ESI): 387.1163 [M + H] + .

[0034] Example 8: Synthesis of compound IV-4 Compound III-1 was replaced by 4-(6-bromohexanoyl)benzo-12-crown-4-ether (1.155 g), and the rest of the required starting materials, reagent types and preparation methods were the same as in Example 5. The isolation yield was 95.8%, and a colorless viscous oil liquid IV-3 (see Table 1 for the structural formula) was obtained.

[0035] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 6.81 (d, J = 7.8 Hz, 1H),6.73 (d, J= 8.5 Hz, 2H), 4.12 (m, 4H), 3.90 (m, 4H), 3.75 (s, 8H), 3.52 (t, J =7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 149.28, 148.26,132.24, 121.46, 114.85, 114.35, 71.22(overlap), 70.68(overlap), 69.78, 69.76,69.29, 69.24, 39.17, 33.35. High resolution mass spectral data: HRMS (FTMS + ESI): 397.0618 [M + Na] + .

[0036] Example 9: Synthesis of compound IV-5 Compound III-1 was replaced by 4-(2-bromoacetyl)benzo-18-crown-6-ether (1.387 g), and the rest of the required starting materials, reagent types and preparation methods were the same as in Example 5. The white solid IV-5 was obtained in 48.1% isolated yield (see Table 1 for the structure).

[0037] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 6.82 (d, J = 8.5 Hz, 1H),6.73 (s, 2H), 4.14 (m, 4H), 3.91 (m, 4H), 3.76 (m, 4H), 3.71 (m, 4H), 3.68(s, 4H), 3.51 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.7 Hz, 2H); 13 C NMR (151 MHz,CDCl3) δ 149.12, 148.12, 132.25, 121.49, 114.99, 114.43, 70.98(overlap),70.91(overlap), 69.82(overlap), 69.33(overlap), 39.15, 33.34. High resolution mass spectral data: HRMS (FTMS + ESI): 419.1061 [M + H] + .

[0038] Example 10: Synthesis of compound VI-1 Compound Ⅳ-1 656 mg and anhydrous potassium carbonate 219 mg were weighed into a 100 mL dry reaction flask, and acetonitrile 16 mL was added. The reaction was stirred at 85°C for 24 hours, and the reaction was determined to be complete by TLC. The reaction was cooled to room temperature, and the acetonitrile was removed under reduced pressure. The reaction was dissolved in dichloromethane (50 mL), and then washed with saturated Na2CO3 solution (50 mL) and distilled water (50 mL), respectively. The organic phase was dried with anhydrous Na2SO4, filtered, and the volatile matter was removed under reduced pressure to obtain the crude product. The separation yield was 53.6%, and yellow solid VI-1 was obtained (see Table 1 for the structural formula).

[0039] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 10.42 (s, 2H), 7.39 (s,2H), 6.93 (s, 1H), 6.91 (s, 1H), 6.87 (s, 2H), 6.85 (d, J = 1.4 Hz, 1H), 6.83(d, J = 1.3 Hz, 1H), 4.26 (t, J = 6.7 Hz, 4H), 4.16 (m, 8H), 3.85 (m, 8H), 3.79(s, 8H), 3.05 (t, J = 6.7 Hz, 4H); 13 C NMR (151 MHz, CDCl3) δ 189.26(overlap),155.10(overlap), 150.78(overlap), 149.55(overlap), 132.40(overlap), 129.39(overlap), 123.19(overlap), 118.85(overlap), 118.46(overlap), 111.88(overlap), 72.05(overlap), 71.87(overlap), 71.27(overlap), 70.07(overlap),69.99(overlap), 35.24(overlap). High resolution mass spectrometry data: HRMS (FTMS + ESI): 667.2747 [M + H] + .

[0040] Example 11: Synthesis of compound VI-2 Compound IV-1 was replaced by IV-2 (250 mg), and the rest of the required starting materials, reagents, and preparation methods were the same as in Example 10. The isolated yield was 72.2% to give VI-2 as a yellow solid (see Table 1 for the structure).

[0041] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 10.50 (s, 2H), 7.41 (s,2H), 6.90 (d, J = 8.0 Hz, 2H), 6.80 (s, 2H), 6.77 (d, J = 7.9 Hz, 2H), 4.16 (m,8H), 4.09 (t, J = 5.5 Hz, 4H), 3.85 (m, 8H), 3.80 (s, 8H), 2.62 (t, J = 7.1 Hz,4H), 1.86 (m, 4H), 1.78 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 189.44(overlap),155.30(overlap), 150.69(overlap), 148.83(overlap), 136.80(overlap), 129.38(overlap), 122.44(overlap), 118.51(overlap), 118.12(overlap), 111.76(overlap), 72.28(overlap), 71.72(overlap), 71.37(overlap), 71.24(overlap),70.12(overlap), 69.11(overlap), 35.10(overlap), 28.72(overlap), 27.93(overlap). High resolution mass spectrometry data: HRMS (FTMS + ESI): 723.3371 [M + H] + .

[0042] Example 12: Synthesis of compound VI-3 Compound IV-1 was replaced by IV-3 (150 mg), and the rest of the required starting material, reagent type and preparation method were the same as in Example 10, with an isolated yield of 54.6%, to obtain yellow solid VI-3 (see Table 1 for structural formula).

[0043] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 10.51 (s, 2H), 7.42 (s,2H), 6.89 (d, J = 8.1 Hz, 2H), 6.79 (d, J = 1.6 Hz, 2H), 6.75 (dd, J = 8.1, 1.6 Hz,2H), 4.16 (m, 8H), 4.08 (t, J = 6.4 Hz, 4H), 3.85 (m, 8H), 3.80 (s, 8H), 2.54(t, J = 7.7 Hz, 4H), 1.83 (m, 4H), 1.62 (m, 4H), 1.50 (m, 4H), 1.39 (m, 4H); 13 CNMR (151 MHz, CDCl3) δ 189.57, 189.51, 155.35(overlap), 150.60(overlap),148.62(overlap), 137.56(overlap), 129.40(overlap), 122.42(overlap), 118.44(overlap), 118.10(overlap), 111.77(overlap), 72.32(overlap), 71.67(overlap),71.40(overlap), 71.25(overlap), 70.15(overlap), 69.30(overlap), 35.47(overlap), 31.53(overlap), 29.13(overlap), 29.03(overlap), 26.06(overlap). High resolution mass spectrometry data: HRMS (FTMS + ESI): 779.4002 [M + H] + .

[0044] Example 13: Synthesis of compound VI-4 When compound IV-1 was replaced with IV-4 (678 mg), the other required raw materials, reagents and preparation methods were the same as in Example 10. The separation yield was 55.0%, and yellow solid VI-4 (structural formula is shown in Table 1) was obtained.

[0045] NMR data: 1 H NMR (600 MHz, Chloroform- d ) δ 10.42 (s, 2H), 7.40 (s, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 6.6 Hz, 4H), 4.26 (t, J = 6.7 Hz, 4H), 4.12 (m, 8H), 3.90 (m, 8H), 3.75 (s, 16H), 3.05 (t, J = 6.7 Hz, 4H); 13 C NMR (151MHz, CDCl3) δ 189.33, 189.24, 155.11(overlap), 149.37(overlap), 148.18(overlap), 130.97(overlap), 129.41, 129.40, 121.82(overlap), 115.16(overlap),114.51(overlap), 111.89(overlap), 71.21(overlap), 70.70(overlap), 70.08(overlap), 69.82(overlap), 69.78(overlap), 69.36(overlap), 69.32(overlap),35.31(overlap). High-resolution mass spectrometry data: HRMS (FTMS+p ESI): 755.3265 [M+H] + .

[0046] Example 14: Synthesis of compound VI-5 When compound IV-1 was replaced with IV-5 (455 mg), the other required raw materials, reagents and preparation methods were the same as in Example 10. The separation yield was 49.8%, and yellow solid VI-5 (structural formula is shown in Table 1) was obtained.

[0047] NMR data: 1 H NMR (600 MHz, Chloroform- d) δ 10.42 (s, 2H), 7.39 (s, 2H), 6.82 (d, J = 8.5 Hz, 2H), 6.78 (s, 4H), 4.26 (t, J = 6.5 Hz, 4H), 4.14 (m,8H), 3.91 (m, 8H), 3.75 (m, 8H), 3.71 (m, 8H), 3.67 (s, 8H), 3.04 (t, J = 6.5Hz, 4H); 13 C NMR (151 MHz, CDCl3) δ 189.29(overlap), 155.10(overlap), 149.14(overlap), 147.97(overlap), 130.92(overlap), 129.38(overlap), 121.80(overlap), 115.14(overlap), 114.45(overlap), 111.87(overlap), 70.93(overlap),70.87(overlap), 70.06(overlap), 69.79(overlap), 69.28(overlap), 35.29(overlap). High-resolution mass spectrometry data: HRMS (FTMS+p ESI): 843.3797 [M+H] + .

[0048] Example 15: Synthesis of Compound VI-6 60 mg of 2-methoxy-5-hydroxyterephthalaldehyde, 276 mg of compound IV-1, and 115 mg of anhydrous potassium carbonate were weighed and placed in a 100 mL dry reaction flask, and 15 mL of acetonitrile was added. The reaction was stirred at 85 °C for 9 hours. The reaction was completed by TLC. The reaction system was cooled to room temperature, and the acetonitrile was removed under reduced pressure. The mixture was dissolved in 50 mL of dichloromethane, and then washed with 50 mL of saturated Na₂CO₃ solution and 50 mL of distilled water, respectively. The organic phase was dried with anhydrous Na₂SO₄, filtered, and the volatiles were removed under reduced pressure to obtain the crude product. The yield was 71.2%, yielding a yellow solid VI-6 (structural formula shown in Table 1).

[0049] NMR data: 1 H NMR (600 MHz, Chloroform- d) δ 10.47 (s, 1H), 10.44 (s,1H), 7.42 (s, 2H), 6.92 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.85 (d, J = 8.1 Hz,1H), 4.28 (t, J = 6.6 Hz, 2H), 4.16 (m, 4H), 3.93 (s, 3H), 3.85 (m, 4H), 3.79(s, 4H), 3.06 (t, J = 6.6 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 189.33 (overlap), 155.85, 155.12, 150.79, 149.54, 132.42, 129.40, 129.23, 123.21, 118.86, 118.47, 112.01, 110.90, 72.05, 71.87, 71.27, 71.26, 70.07, 70.06, 70.01, 56.33, 35.26. High resolution mass spectrometry data: HRMS (FTMS + ESI): 431.1697 [M+H] + .

[0050] Table 1 Structural formula of compounds synthesized in Examples 1-15

[0051] It is apparent that the above examples are merely for the purpose of clearly illustrating the present application, and are not intended to limit the embodiments of the present application. Changes and advantages which are obvious to those skilled in the art are included in the present application, and are protected by the appended claims without departing from the spirit and scope of the present application.

Claims

1. Benzocrown ether derivatives characterized in that, The structural formula is shown in general formula (A) or general formula (B): ； R1 is selected from carbonyl, methylene or hydroxyl-substituted methylene; R2 is selected from any one of hydrogen, fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkynyl, phenyl, hydroxyl, sulfydryl, alkoxy, alkenyloxy, alkynyloxy, phenyloxy, benzyloxy, alkylthio, alkenylthio, alkynylthio, phenylthio, benzylthio, aldehyde, alkylketone, alkenylketone, alkynylketone, phenylketone, benzylketone, alkylthioketone, alkenylthioketone, alkynylthioketone, phenylthioketone, benzylthioketone, carboxyl, alkoxylketone, alkenyloxylketone, alkynyloxylketone, phenyloxylketone, benzyloxylketone, amido, N-monosubstituted amido, N,N-disubstituted amido, cyano, nitro; R3 is selected from hydrogen, hydroxyl, sulfydryl, fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkynyl, phenyl, benzyl, alkoxy, alkenyloxy, alkynyloxy, phenyloxy, benzyloxy, alkylthio, alkenylthio, alkynylthio, phenylthio, benzylthio, amido, N-monosubstituted amido, N,N-disubstituted amido, nitro or benzo crown ether-4-(R1-alkyleneoxy), wherein R1 is any one of carbonyl, methylene or hydroxyl-substituted methylene; m is selected from any integer from 0 to 20; n is selected from any integer from 1 to 3.

2. The benzo crown ether derivative according to claim 1, characterized by The alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynylthio, alkynylthio, alkynylthio, alkynylketyl, alkenylketyl, alkynylthioketyl, alkenylthioketyl, alkynylthioketyl, alkenylthioketyl, alkenyloxyketyl, alkenyloxyketyl, alkynyloxyketyl, alkenyloxyketyl, N-monosubstituted amide, and N,N-disubstituted amide groups are C1-C1 respectively. 10 Alkyl, C1-C 10 alkenyl, C1-C 10 alkynyl group, C1-C 10 Alkoxy, C1-C 10 Alkenyloxy group, C1-C 10 Acryloxy group, C1-C 10 Alkylthio, C1-C 10 Thylene, C1-C 10 Acrylylthio, C1-C 10 Alkyl group, C1-C 10 Enone group, C1-C 10 acetylaceton group, C1-C 10 Alkylthionyl group, C1-C 10 Enthionone group, C1-C 10 Acrylthionyl group, C1-C 10 Alkoxyketone group, C1-C 10 Enoxyketone group, C1-C 10 alkynyloxyketone group, C1-C 10 N-monosubstituted amide group, C1-C 10 N,N-disubstituted amide group.

3. The benzo crown ether derivative according to claim 1, characterized by The benzo crown ether-4-(R1-alkyleneoxy) is benzo-12-crown-4-ether-4-(R1-alkyleneoxy), benzo-15-crown-5-ether-4-(R1-alkyleneoxy) or benzo-18-crown-6-ether-4-(R1-alkyleneoxy), wherein R1 is selected from carbonyl, methylene or hydroxyl-substituted methylene.

4. A process for the synthesis of benzo crown ether derivatives, characterized in that, The method comprises the following steps: Synthesis of benzo crown ether derivative shown in general formula (A): (a) Friedel-Crafts acylation reaction is carried out under the action of catalyst with carboxylic acid or substituted carboxylic acid shown in general formula I and benzo crown ether shown in general formula II as raw materials, and benzo crown ether derivative shown in general formula III is synthesized; (b) reduction reaction is carried out under the action of reducing agent with benzo crown ether derivative shown in general formula III as raw material under nitrogen atmosphere, and benzo crown ether derivative shown in general formula IV is synthesized, and the reaction process is shown in formula 1: ； R2, m and n are defined in any one of claims 1-3; Synthesis of benzo crown ether derivative shown in general formula (B): Substitution reaction is carried out under the action of catalyst with benzo crown ether derivative shown in general formula III or general formula IV and substituted p-benzenedicarboxaldehyde shown in general formula V as raw materials, and benzo crown ether derivative shown in general formula VI is synthesized, and the reaction process is shown in formula 2: ； R1, R2, R3, m and n are defined in any one of claims 1-3.

5. The method of synthesis of benzo crown ether derivatives according to claim 4, wherein, The catalyst in step (a) is one or more of methane sulfonic acid, Eaton's reagent, ethane sulfonic acid, propane sulfonic acid, trifluoromethane sulfonic acid and p-trifluoromethyl benzene sulfonic acid; the solvent in step (b) is trifluoroacetic acid, the reducing agent is silane or the solvent is methanol, and the reducing agent is sodium borohydride, wherein the silane is one or more of trimethylsilane, triethylsilane and tripropylsilane.

6. The method of synthesis of benzo crown ether derivatives as claimed in claim 4 wherein, The Friedel-Crafts acylation reaction in step (a) is carried out at a temperature of 10-60℃ for 2-6 hours; the reduction reaction in step (b) is carried out at a temperature of 0-70℃ for 2-6 hours.

7. The method of synthesis of benzo crown ether derivatives as claimed in claim 4, wherein, The molar ratio of the carboxylic acid or substituted carboxylic acid represented by general formula I, the benzo crown ether represented by general formula II, and the catalyst in step (a) is (1-10):1:(0.1-100); the molar ratio of the benzo crown ether derivative represented by general formula III and the reducing agent in step (b) is 1:(2-10).

8. The method of synthesis of benzo crown ether derivatives as claimed in claim 4, wherein, The solvent in the substitution reaction is one or more of acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; and the catalyst is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, and N,N-diisopropyl ethylamine.

9. The method of synthesis of benzo crown ether derivatives as claimed in claim 4, wherein, The substitution reaction is carried out at a temperature of 60-100℃ for 4-24 hours.

10. The method for synthesizing the benzocrown ether derivative according to claim 4, characterized in that, The molar ratio of the benzo crown ether derivative represented by general formula III or general formula IV, the substituted terephthalaldehyde represented by general formula V, and the catalyst is (1-8):1:(1-8).

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