A kind of forskolin tetracyclic analogue and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry and pharmacology, and relates to a forskolin tetracyclic analog and a preparation method thereof. The forskolin tetracyclic analog has a chemical structure shown in formula (I), wherein forskolin and sodium methoxide react in methanol to obtain 7-deacetylforskolin 1, then 7-deacetylforskolin 1 reacts with sodium periodate in a DCM-H2O mixed solution to obtain a forskolin rearrangement product 2, the forskolin rearrangement product 2 reacts with DMP and pyridine in acetonitrile to obtain a forskolin rearrangement product 3, and finally the forskolin rearrangement product 3 reacts with an aryl iodide in anhydrous dichloroethane under the catalysis of anhydrous silver acetate, anhydrous copper acetate and palladium acetate to obtain a forskolin tetracyclic analog. #imgabs0#

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry and pharmacology, and in particular to a forskolin tetracyclic analogue and a preparation method thereof. Background Art

[0002] Forskolin is a diterpenoid compound with important medicinal value in anti-cancer, anti-asthma, anti-hypertension and positive inotropic effects. In addition, forskolin can also interact with certain other proteins, such as glucose transporters and ion channels. The results of pharmacodynamic studies have shown that forskolin can effectively promote the differentiation of neurons and the growth of neurites in the central and peripheral nervous systems, thereby having an important impact on the cardiovascular and cerebrovascular systems, respiratory systems and tumors, and has pharmacological effects such as cardiotonic, anti-asthmatic, anti-tumor, anti-thrombotic and lowering intraocular pressure. It is now clinically used for the treatment of cardiovascular and cerebrovascular diseases, tumors and common diseases of the elderly, with obvious pharmacological effects and broad prospects for clinical application. Using cheap and readily available forskolin as a raw material, chemical methods are used to transform the structure, modify its chemical skeleton, obtain new compounds, and develop its application in the fields of medicinal chemistry and pharmacology technology, which is of great significance. Summary of the invention

[0003] In view of this, the purpose of the present invention is to chemically transform forskolin and obtain forskolin tetracyclic analogs with novel structures by adopting a complexity to diversity strategy (CtD strategy) to further develop its pharmaceutical use.

[0004] The present invention provides a forskolin tetracyclic analogue, wherein the forskolin tetracyclic analogue has a structure shown in formula (I):

[0005]

[0006] wherein R represents one of phenyl, p-trifluoromethoxyphenyl, p-tert-butylphenyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and p-cyanophenyl.

[0007] Furthermore, the tetracyclic forskolin analog has a structure as shown in any one of Formulae 4a to 4c:

[0008]

[0009] in,

[0010] When R is phenyl, the forskolin tetracyclic analog is a compound having a structure shown in Formula 4a;

[0011] When R is p-trifluoromethoxyphenyl, the forskolin tetracyclic analog is a compound having a structure shown in Formula 4b;

[0012] When R is p-tert-butylphenyl, the forskolin tetracyclic analog is a compound having a structure shown in Formula 4c;

[0013] The present invention also provides a method for preparing a tetracyclic forskolin analog, comprising the following steps:

[0014] Forskolin is reacted with sodium methoxide in methanol to obtain 7-deacetylforskolin 1, and then 7-deacetylforskolin 1 is reacted with sodium periodate in a DCM-H2O mixed solution to obtain forskolin rearrangement product 2, and forskolin rearrangement product 2 is reacted with DMP and pyridine in acetonitrile to obtain forskolin rearrangement product 3, and finally forskolin rearrangement product 3 is reacted with aryl iodide in anhydrous dichloroethane under the catalysis of anhydrous silver acetate, anhydrous copper acetate and palladium acetate to obtain forskolin tetracyclic analogue 4.

[0015] Wherein, the reaction formula of the reaction is:

[0016]

[0017] wherein R represents one of phenyl, p-trifluoromethoxyphenyl, p-tert-butylphenyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and p-cyanophenyl.

[0018] Specifically, the preparation method comprises the following steps:

[0019] (1) dissolving forskolin in methanol, adding sodium methoxide to react to obtain a first reaction solution, cooling the first reaction solution, concentrating under reduced pressure, diluting with an organic solvent, washing with water, washing with saturated brine, drying over anhydrous MgSO4, concentrating under reduced pressure, and then flash column chromatography to obtain a white solid 7-deacetylforskolin 1, wherein the molar ratio of forskolin to sodium methoxide is 1:2;

[0020] (2) dissolving 7-deacetylforskolin 1 in a mixed solution of dichloromethane and water, adding silica gel and sodium periodate to react to obtain a second reaction solution, cooling the second reaction solution, concentrating under reduced pressure, diluting with an organic solvent, filtering, washing the organic phase with water and saturated brine in sequence, drying over anhydrous MgSO4, concentrating under reduced pressure, and then flash column chromatography to obtain a white solid forskolin rearrangement product 2, wherein the volume ratio of dichloromethane to water is 4:1, the mass ratio of silica gel to 7-deacetylforskolin 1 is 1:1, and the molar ratio of 7-deacetylforskolin 1 to sodium periodate is 1:10;

[0021] (3) dissolving the forskolin rearrangement product 2 in acetonitrile, adding a Dess-Martin oxidant and pyridine to react to obtain a third reaction solution, diluting the third reaction solution with an organic solvent, washing with a saturated sodium carbonate aqueous solution, a saturated sodium thiosulfate aqueous solution, and a saturated saline solution in sequence, drying with anhydrous MgSO4, concentrating under reduced pressure, and then flash column chromatography to obtain a white solid forskolin skeleton rearrangement product 3, wherein the molar ratio of the forskolin rearrangement product 2, the Dess-Martin oxidant, and the pyridine is 1:3:2;

[0022] (4) dissolving the forskolin rearrangement product 3 in anhydrous dichloroethane, and sequentially adding anhydrous silver acetate, anhydrous copper acetate, palladium acetate, and aryl iodide to react to obtain a fourth reaction solution, cooling the fourth reaction solution, diluting it with an organic solvent, filtering it, and concentrating the filtrate under reduced pressure. The white solid is obtained by flash column chromatography, wherein the white solid is the forskolin tetracyclic analog 4, wherein the molar ratio of the forskolin rearrangement product 3, anhydrous silver acetate, anhydrous copper acetate, palladium acetate, and aryl iodide is 1:1.2:2:0.05:2;

[0023] Wherein, the aryl iodide is one of iodobenzene, p-trifluoromethoxy iodobenzene, p-tert-butyl iodobenzene, p-chloroiodobenzene, p-methyl iodobenzene, p-methoxy iodobenzene, p-nitro iodobenzene and p-cyano iodobenzene.

[0024] Furthermore, in step (1) of the above preparation method, the reaction temperature is 40° C. and the reaction time is 2 h.

[0025] Furthermore, in step (2) of the above preparation method, the reaction temperature is 40° C. and the reaction time is 24 h.

[0026] Furthermore, in step (3) of the above preparation method, the reaction temperature is 20° C. and the reaction time is 12 h.

[0027] Furthermore, in step (4) of the above preparation method, the reaction temperature is 80° C. and the reaction time is 18 h.

[0028] Furthermore, in the above preparation method, the organic solvent is at least one of methanol, dichloromethane, ethyl acetate and dichloroethane.

[0029] Compared with the prior art, the present application provides a class of tetracyclic forskolin analogs and a preparation method thereof. Such compounds have novel structures and have inhibitory effects on tumor cell growth, and may be developed into new anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0031] Figure 1 The NMR of the forskolin rearrangement product (3) provided in Example 2 of the present invention 1 H spectrum;

[0032] Figure 2 The NMR of the forskolin rearrangement product (3) provided in Example 2 of the present invention 13 C spectrum;

[0033] Figure 3 The X-ray single crystal diffraction structure diagram of the forskolin rearrangement product (3) provided in Example 2 of the present invention;

[0034] Figure 4 The nuclear magnetic resonance of the tetracyclic forskolin analog (4a) provided in Example 3 of the present invention 1 H spectrum;

[0035] Figure 5 The nuclear magnetic resonance of the tetracyclic forskolin analog (4a) provided in Example 3 of the present invention 13 C spectrum;

[0036] Figure 6 The 1H NMR spectrum of the tetracyclic forskolin analog (4b) provided in Example 3 of the present invention;

[0037] Figure 7 This is the nuclear magnetic resonance 13C spectrum of the forskolin tetracyclic analog (4b) provided in Example 3 of the present invention. DETAILED DESCRIPTION

[0038] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] Example 1

[0040] 410 mg (1.0 mmol) of forskolin was dissolved in methanol (10 ml), and 360 mg of sodium methoxide (30 wt% in MeOH, 2.0 mmol) was added, and the mixture was reacted at 40° C. for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (10 ml), and then washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. 360 mg of a white solid, i.e., 7-deacetylforskolin 1 (yield 98%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 8:1).

[0041] 1H NMR(400MHz,Chloroform-d)δ6.60(m,1H,9-OH),6.13(dd,J=17.4,10.7Hz,1H,H-14),5.20(d,J=

[0042] 17.4Hz,1H,H-15),4.99(d,J=10.6Hz,1H,H-15),4.62(s,1H,H-1),4.48(s,1H,H-6),4.13(t,J=3.5Hz,1H,H-7),3.18(d,J=1 7.2Hz,1H,H-12),2.93(dt,J=9.4,3.1Hz,1H,1-OH),2.70(q,J=3.7Hz,1H,7-OH),2.50(d,J=17.2Hz,1H,H-12),2.42–2.36(m, 1H,H-2e),2.09(d,J=2.7Hz,1H,H-5),1.84–1.79(m,1H,6-OH),1.73(td,J=13.9,3.6Hz,1H,H-3a),1.65(s,3H,CH3),1.42(s ,3H,CH3),1.42-1.41(m,1H,H-2a),1.41(s,3H,CH3),1.27(s,3H,CH3),1.12(dt,J=13.4,3.5Hz,1H,H-3e),1.06(s,3H,CH3).

[0043] Example 2

[0044] 368 mg (1.0 mmol) of 7-deacetylforskolin 1 was dissolved in a mixed solution of dichloromethane-water (10 ml, v:v=4:1), 368 mg of silica gel and 2.14 g (10.0 mmol) of sodium periodate were added, and the mixture was reacted at 40°C for 24 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (10 ml), filtered, and the organic phase was washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. 340 mg of white solid, i.e., forskolin rearrangement product 2 (yield 98%), was obtained by flash column chromatography (petroleum ether: ethyl acetate=10:1); then 366 mg (1.0 mmol) of rearrangement product 2 was dissolved in acetonitrile (10 ml), 158 μL (2.0 mmol) of pyridine and 1.27 g (3.0 mmol) of Dess-Martin periodinane were added, and the mixture was reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure, then diluted with ethyl acetate (10 ml), washed successively with saturated aqueous sodium carbonate solution, saturated aqueous sodium thiosulfate solution, and saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. 122 mg of a white solid was obtained by flash column chromatography, i.e., the forskolin rearrangement product 3 (yield 35%).

[0045] 1 H NMR (400MHz, DMSO-d6) δ9.58(s,1H,H-16),5.91(dd,J=17.4,10.6Hz,1H,H-13),5.40(s,1H,H-11),5.20(dd,J=17. 4,1.3Hz,1H,H-14),4.98(dd,J=10.5,1.2Hz,1H,H-14),4.26(dd,J=6.0,3.4Hz,1H,H-1),2.73(s,1H,H-5),2.06(dd t,J=15.6,6.8,5.1Hz,1H),1.75(dddd,J=15.2,8.9,5.0,3.4Hz,1H),1.57(dddd,J=14.5,9.7,4.9Hz,1H),1.37(s,3 H,CH3),1.32(ddd,J=12.6,5.2,2.0Hz,1H),1.28(s,3H,CH3),1.21(s,3H,CH3),1.10(s,3H,CH3),1.08(s,3H,CH3). 13 C NMR (100MHz, DMSO) δ200.8,172.1,151.1,144.0,112.2,106.8,90.3,81.7,81.6,76.7,52.6,51.1,34.8,31.2,30.4,28.1,24.1,23.5,20.1,13.7.

[0046] Example 3

[0047] 346 mg (1.0 mmol) of forskolin rearrangement product 3 was dissolved in anhydrous dichloroethane (10 ml), and 200 mg (1.2 mmol) of anhydrous silver acetate, 363 mg (2.0 mmol) of anhydrous copper acetate, 12 mg (0.05 mmol) of palladium acetate, and 408 mg (2.0 mmol) of iodobenzene were added in sequence, and the mixture was reacted at 80° C. for 18 hours. The reaction solution was diluted with ethyl acetate (10 ml), filtered, and the filtrate was washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. 238 mg of a white solid, i.e., forskolin tetracyclic analog 4a (yield 69%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 30:1).

[0048] 1H NMR(400MHz,Chloroform-d)δ9.67(s,1H,CHO),7.45–7.10(m,5H,ArH),6.48(d,J=16.1Hz,1H,H- 14),6.26(d,J=16.2Hz,1H,H-13),5.25(s,1H,H-11),4.06(dd,J=6.2,3.5Hz,1H,H-1),2.72(s,1 H,H-5),1.98(dq,J=18.1,6.0Hz,1H),1.84–1.73(m,1H),1.53(td,J=9.8,5.0Hz,1H),1.46(s,3H ,CH3),1.37–1.30(m,1H),1.29(s,3H,CH3),1.21(s,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ201.07,171.83,151.30,136.84,134.89,128.51,127.53,127.36,126.67,107.20,90.1 2,81.95,81.73,76.40,52.84,51.28,34.95,31.21,30.33,28.07,24.36,23.40,20.14,13.69.HRMS(ESI):m / z calcd for C 26 H 30 O5Na:445.1991; found:445.1989[M+Na] + .

[0049] Embodiment 4-5

[0050] According to the method of Example 3 above, iodobenzene was replaced with p-trifluoromethoxyiodobenzene and p-tert-butyliodobenzene, respectively, to prepare compounds 4b and 4c.

[0051] The following are the physicochemical data of compounds 4b-4c:

[0052] 4b: Yield 63%. 11H NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1H, CHO), 7.45–7.29 (m, 2H, ArH), 7.14–7.02 (m, 2H, ArH), 6.48 (d, J = 16.1 Hz, 1H, H-14), 6.24 (d, J = 16.1 Hz, 1H, H-13), 5.24 (s, 1H, H-11), 4.08 (dd, J = 6.1, 3.5 Hz, 1H, H-1), 2.71 (s, 1H, H-5), 1.99 (dtd, J = 15.6, 6.6, 5.0 Hz, 1H), 1.79 (dddd, J = 15.5, 10.0, 5.2, 3.5 Hz, 1H), 1.54 (tt, J = 10.0, 5.0 Hz, 1H), 1.46 (s, 3H, CH3), 1.38–1.31 (m, 1H), 1.29 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.09 (s, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 200.8, 171.8, 151.5, 148.4, 135.9, 135.7, 127.9, 125.9, 121.7, 121.0, 119.2, 106.8, 90.1, 82.0, 81.8, 76.3, 52.8, 51.3, 34.9, 31.2, 30.3, 28.2, 24.4, 23.4, 20.1, 13.7. HRMS (ESI): m / z calcd for C 27 19 29 21H36O6NaF3: 529.1814; found: 529.1815 [M+Na] + .

[0053] 4c: Yield 24%. 1H NMR(400MHz,)δ9.66(d,J=0.8Hz,1H,CHO),7.36–7.21(m,4H,ArH),6.46(d,J=16.1Hz,1H,H-14),6.22( d,J=16.1Hz,1H,H-13),5.24(s,1H,H-11),4.05(dd,J=6.1,3.4Hz,1H,H-1),2.70(s,1H,H-5),2.08–1.9 0(m,1H),1.78(dddd,J=15.7,9.6,5.4,3.7Hz,1H),1.55–1.47(m,1H),1.45(s,3H,CH3),1.40–1.32(m,1 H),1.29–1.26(m,3H,CH3),1.22(s,9H,C(CH3)3),1.21(s,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ201.1,171.8,151.2,150.6,134.2,134.1,127.1,126.3,125.4,107.3,90.1,81 .9,81.7,76.5,52.8,51.3,35.0,34.6,31.3,31.2,30.3,28.2,24.3,23.4,20.1,13.7.HRMS(ESI):m / z calcd for C 30 H 38 O5Na:501.2617; found:501.2625[M+Na] + .

[0054] In order to better understand the essence of the present invention, the pharmacological experimental results of the inhibitory effect of the tetracyclic analogue of forskolin provided by the present invention on the growth of three tumor cell lines are used below to illustrate its new use in the field of anti-tumor drug research. The pharmacological examples provide partial activity data of representative compounds. It must be noted that the pharmacological examples of the present invention are used to illustrate the present invention rather than to limit the present invention. Simple improvements made to the present invention according to the essence of the present invention all belong to the scope of protection claimed by the present invention.

[0055] Drug Experimental Example 1: Cytotoxicity Test of Compounds 4a-4c and Forskolin on Human Esophageal Cancer Cells (TE-13)

[0056] Human esophageal cancer cell TE-13 was cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 U / mL streptomycin. 5×10 cells were plated per well. 3The concentrations were added to a 96-well plate and cultured in an incubator at 37°C containing 5% CO2 in a humidified air atmosphere for 24 hours.

[0057] Compounds 4a-4c were dissolved in DMSO and prepared into 1×10 -2 mol / L stock solution, dilute the stock solution to the corresponding concentration with complete medium, take cells in logarithmic growth phase and inoculate them in 96-well plates, add compound solutions of different concentrations after 24 hours of attachment, set 4 parallel wells for each concentration, add tetramethylthiazolium (MTT) solution after 68 hours of culture, continue to culture for 4 hours, discard the culture medium, add 150μL of dimethyl sulfoxide, shake for 10 minutes, measure the absorbance (A) value at 570nm with an enzyme reader, and calculate the half inhibitory concentration (IC 50 ), as shown in Table 1. According to Table 1, the IC 50 The positive control forskolin has an IC of 4.0 μM for TE-13 cells. 50 It is 52.0μM.

[0058] Drug Experiment Example 2-3: Cytotoxic activity test of compounds 4a-4c and forskolin on human colon cancer cells (HCT-116) and human lung adenocarcinoma cells (A549).

[0059] The pharmacological experiment was carried out on the growth inhibition of human colon cancer cells (HCT-116) and human lung adenocarcinoma cells (A549) using the method shown in Drug Experiment Example 1, and the half inhibitory concentration (IC 50 ), as shown in Table 1.

[0060] Table 1 Cytotoxic activity test results of compounds 4a-4c and forskolin

[0061]

[0062] According to Table 1, the tetracyclic analogs of forskolin provided by the present invention have important biological activities. The cytotoxic activity test on three types of tumor cells, namely human esophageal cancer cells (TE-13), human colon cancer cells (HCT-116), and human lung adenocarcinoma cells (A549) in vitro shows that the tetracyclic analogs of forskolin with the structure shown in formula (1) have an inhibitory effect on the growth of tumor cells and may be developed into new anti-tumor drugs. From the above pharmacological examples, we can see that these compounds show strong cytotoxic activity on these three types of tumor cells, and the cytotoxic activity exceeds that of forskolin, and have the potential to be developed into anti-tumor drugs.

[0063] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A tetracyclic forskolin analogue, characterized in that: The structure of the forskolin tetracyclic analog is shown in the following formula: Here, R represents one of phenyl, p-trifluoromethoxyphenyl, p-tert-butylphenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and p-cyanophenyl.

2. A tetracyclic forskolin analogue according to claim 1, characterized in that: The tetracyclic forskolin analog has a structure as shown in any one of Formulae 4a to 4c:

3. A method for preparing the tetracyclic analogue of forskolin according to claim 1, characterized in that: The reaction formula of the preparation method is shown below: The preparation method comprises the following steps: S1. Forskolin is dissolved in methanol, and sodium methoxide is added to react to obtain a first reaction solution, the reaction temperature is 40° C. After the first reaction solution is cooled, it is concentrated under reduced pressure, diluted with an organic solvent, washed with water, washed with saturated brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography is performed to obtain a white solid 7-deacetylforskolin 1, wherein the molar ratio of forskolin to sodium methoxide is 1:2; S2. 7-deacetylforskolin 1 is dissolved in a mixed solution of dichloromethane and water, and silica gel and sodium periodate are added to react to obtain a second reaction solution, the reaction temperature is 40° C. After the second reaction solution is cooled, it is concentrated under reduced pressure, diluted with an organic solvent, filtered, and the organic phase is washed with water and saturated brine in sequence, dried over anhydrous MgSO4, concentrated under reduced pressure, and then flash column chromatography is performed to obtain a white solid forskolin rearrangement product 2, wherein the volume ratio of dichloromethane to water is 4:1, the mass ratio of silica gel to 7-deacetylforskolin 1 is 1:1, and the molar ratio of 7-deacetylforskolin 1 to sodium periodate is 1:10; S3. Dissolve the forskolin rearrangement product 2 in acetonitrile, add a Dess-Martin oxidant and pyridine to react to obtain a third reaction solution, the reaction temperature is 20° C., dilute the third reaction solution with an organic solvent, wash with a saturated sodium carbonate aqueous solution, a saturated sodium thiosulfate aqueous solution, and a saturated saline solution in sequence, dry with anhydrous MgSO4, concentrate under reduced pressure, and then obtain a white solid forskolin rearrangement product 3 by flash column chromatography, wherein the molar ratio of the forskolin rearrangement product 2, the Dess-Martin oxidant, and the pyridine is 1:3:2; S4. Dissolve the forskolin rearrangement product 3 in anhydrous dichloroethane, add anhydrous silver acetate, anhydrous copper acetate, palladium acetate, and aryl iodide in sequence to react to obtain a fourth reaction solution, the reaction temperature is 80° C. After cooling the fourth reaction solution, dilute it with an organic solvent, filter it, concentrate the filtrate under reduced pressure, and obtain a white solid by flash column chromatography. The white solid is the forskolin tetracyclic analog 4, wherein the molar ratio of the forskolin rearrangement product 3, anhydrous silver acetate, anhydrous copper acetate, palladium acetate, and aryl iodide is 1:1.2:2:0.05:2; Wherein, the aryl iodide is one of iodobenzene, p-trifluoromethoxy iodobenzene, p-tert-butyl iodobenzene, p-methyl iodobenzene, p-methoxy iodobenzene, p-nitro iodobenzene and p-cyano iodobenzene.

4. The preparation method according to claim 3, characterized in that: In the step S1, the reaction time is 2 hours.

5. The preparation method according to claim 3, characterized in that: In step S2, the reaction time is 24 hours.

6. The preparation method according to claim 3, characterized in that: In step S3, the reaction time is 12 hours.

7. The preparation method according to claim 3, characterized in that: In step S4, the reaction time is 18 hours.

8. The preparation method according to claim 3, characterized in that: The organic solvent is at least one of methanol, dichloromethane, ethyl acetate and dichloroethane.

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