A water-soluble Janus arene compound and its preparation method

Abstract

The present invention discloses a water-soluble Janus aromatic hydrocarbon compound and a preparation method thereof. The structural formula Ι of the compound is: wherein, R is COOH or COO ‑ ; the compound is a supramolecular host with a back-to-back double-bowl structure, having a cavity size of nanometer scale, with a diameter of 1.6 nm and a depth of 0.6 nm, and there are 36 carboxylate anions or 36 carboxylic acids on the molecule, having good solubility in water, forming a self-assembled body with a stable structure in the aqueous phase, the particle size of the formed assembly is 383 nm, and the particle size of the assembly can also be regulated by changing the concentration, and it is expected to be applied in the fields of molecular recognition and biomimetic catalysis, etc.

Description

Technical Field

[0001] The present invention relates to the technical field of supramolecular chemistry, and particularly to a water-soluble Janus arene compound and a preparation method thereof. Background Art

[0002] In supramolecular chemistry, the construction of supramolecular hosts is a hot research direction. Reported supramolecular hosts include crown ether, cyclodextrin, calixarene, cucurbituril, and the recently emerging pillararene. Calixarenes and their derivatives have many excellent properties such as good pre-organization, highly accurate interactions, easy regulation, and modularity. Due to these excellent properties, calixarene compounds have been widely used in the field of supramolecular chemistry, including molecular recognition, self-assembly, molecular dynamics, and bionics.

[0003] In 2017, Wang Jiaobing et al. reported a lipophilic Janus arene supramolecular host (Angew. Chem. Int. Ed. 2017, 56, 9473-9477); the back-to-back calixarene structure has two nanoscale cavity structures that can accommodate various guests (spherical fullerenes, pyrene, perylene, and 9,10-dimethylanthracene). Essentially, it is a supramolecular host with two sides of the same body. Single-crystal X-ray diffraction shows that Janus arene has host-guest interactions with fullerenes, pyrene, and perylene. By pairwise encapsulation of polycyclic aromatic hydrocarbon guests with Janusarene, polycyclic aromatic hydrocarbon dimers can be obtained, and their spectral properties are different from those of polycyclic aromatic hydrocarbons in solution or solid state. However, the host-guest interactions all occur in the organic phase.

[0004] In recent years, the synthesis of self-assemblies with nanostructures has attracted much attention in the fields of molecular recognition and bionic catalysis. Great progress has been made in the research of self-assembly structures in the organic phase. However, self-assemblies in the aqueous phase are only limited to those formed by covalent bond interactions, and the exploration of self-assemblies formed by non-covalent bond interactions still poses great challenges. Summary of the Invention

[0005] To solve the above problems, the present invention provides a water-soluble Janus arene compound and a preparation method thereof. This compound forms a self-assembly with a stable structure in the aqueous phase, providing a new method for a deeper understanding of the self-assembly behavior of Janus arene in the aqueous phase and the regulation of the particle size of the self-assembly, and is expected to be applied in the fields of molecular recognition and bionic catalysis.

[0006] To achieve the above object, an embodiment of the present invention provides a Janus arene compound in a first aspect, and its structural formula Ι is:

[0007]

[0008] wherein, R is COOH or COO - .

[0009] A water-soluble Janus arene compound according to an embodiment of the present invention is a back-to-back double-bowl structure, having a cavity size of nanoscale and 36 carboxylate anions or 36 carboxylic acids, with good solubility in water, forming a self-assembled body with a stable structure in the aqueous phase. The particle size of the formed assembly is 383 nm, and the particle size of the assembly can also be regulated by changing the concentration, and it is expected to be applied in the fields of molecular recognition and biomimetic catalysis, etc.

[0010] Optionally, the structural formula Ι is based on Janus arene, with six benzene rings added to the waist of the Janusarene molecule and 36 carboxylic acids or carboxylate anions added to the periphery.

[0011] An embodiment of the present invention provides a preparation method of the above water-soluble Janus arene compound in a second aspect, which includes the following steps:

[0012] (1) Compound II-1, 3,5-bis(methoxycarbonyl)phenylboronic acid pinacol ester, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, and potassium carbonate trihydrate react in toluene and water to obtain compound II-2;

[0013] (2) Compound II-2 reacts with tert-butyl nitrite in dichloromethane to obtain compound II-3;

[0014] (3) Compound II-3 reacts with trimethylsilylacetylene, copper(I) iodide, bis(triphenylphosphine)palladium(II) dichloride, and triethylamine in anhydrous tetrahydrofuran to obtain compound II-4;

[0015] (4) Compound II-4 reacts with tetrabutylammonium fluoride in tetrahydrofuran to obtain compound II-5;

[0016] (5) Compound II-5 reacts with compound II-3 in the presence of copper(I) iodide, bis(triphenylphosphine)palladium(II) dichloride, and triethylamine in anhydrous tetrahydrofuran to obtain compound II-6;

[0017] (6) Compound II-6 reacts with dicobalt octacarbonyl in anhydrous dioxane to obtain compound J-36COOMe;

[0018] (7) Compound J-36COOMe reacts with potassium hydroxide in tetrahydrofuran and water to obtain Compound Ι; wherein, R of Compound Ι is COOH;

[0019]

[0020] According to the preparation method of the embodiments of the present invention, Compound J-36COOMe can be synthesized and hydrolyzed under alkaline conditions to obtain the Janus aromatic hydrocarbon compound shown in Formula Ι. This compound has a back-to-back double-bowl structure, with a cavity size of nanoscale and 36 carboxylate anions or 36 carboxylic acids. Its fluorescence quantum efficiency is relatively low, it has good solubility in water, forms a self-assembled body with a stable structure in the aqueous phase, the particle size of the formed assembly is 383 nm, and the particle size of the assembly can also be regulated by changing the concentration, and it is expected to be applied in the fields of molecular recognition and biomimetic catalysis, etc.

[0021] Optionally, it further includes step (8), adding Compound Ι and sodium hydroxide to deuterated water, and ultrasonically treating until all solids are dissolved to obtain Compound Ι with R being COO - of Compound Ι.

[0022] Optionally, in step (1), the reaction temperature is 100 °C and the reaction time is 3 d;

[0023] And / or, in step (2), the reaction temperature is 100 °C and the reaction time is 3 h;

[0024] And / or, in step (3), the reaction condition is nitrogen protection and overnight reaction;

[0025] And / or, in step (4), the reaction condition is room temperature reaction for 1 h;

[0026] And / or, in step (5), the reaction condition is nitrogen protection and overnight reaction;

[0027] And / or, in step (6), the reaction temperature is 125 °C and the reaction time is 1 d;

[0028] And / or, in step (7), the reaction temperature is 100 °C and the reaction time is 24 h.

[0029] Optionally, in step (1), after the reaction is completed, an appropriate amount of water is added to quench the reaction, extracted three times with ethyl acetate, the organic solvent is concentrated, and column chromatography is carried out to obtain Compound II-2;

[0030] And / or, in step (2), after the reaction is completed, the reaction solution is directly poured onto a silica gel column, and column chromatography is carried out to obtain Compound II-3;

[0031] And / or, in step (3), after the reaction is completed, the reaction solution is concentrated, and column chromatography is carried out to obtain Compound II-4;

[0032] And / or, in step (4), after the reaction is completed, ammonium chloride is added to quench the reaction, and the mixture is extracted three times with dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate, to obtain Compound II-5;

[0033] And / or, in step (5), after the reaction is completed, the reaction solution is concentrated and subjected to column chromatography to obtain Compound II-6;

[0034] And / or, in step (6), after the reaction is completed, the organic solvent is concentrated and subjected to column chromatography to obtain Compound J-36COOMe.

[0035] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention. Description of the Drawings

[0036] Figure 1 is the spatial configuration structure of Janusarene;

[0037] Figure 2 is the spatial configuration structure of Compound Ι according to an embodiment of the present invention;

[0038] Figure 3 is the 1H NMR spectrum of Compound II-2 according to an embodiment of the present invention;

[0039] Figure 4 is the 13C NMR spectrum of Compound II-2 according to an embodiment of the present invention;

[0040] Figure 5 is the 1H NMR spectrum of Compound II-3 according to an embodiment of the present invention;

[0041] Figure 6 is the 13C NMR spectrum of Compound II-3 according to an embodiment of the present invention;

[0042] Figure 7 is the 1H NMR spectrum of Compound II-4 according to an embodiment of the present invention;

[0043] Figure 8 is the 13C NMR spectrum of Compound II-4 according to an embodiment of the present invention;

[0044] Figure 9 is the 1H NMR spectrum of Compound II-5 according to an embodiment of the present invention;

[0045] Figure 10 is the 13C NMR spectrum of Compound II-5 according to an embodiment of the present invention;

[0046] Figure 11 is the 1H NMR spectrum of Compound II-6 according to an embodiment of the present invention;

[0047] Figure 12 13C NMR spectrum of Compound II-6 according to an embodiment of the present invention;

[0048] Figure 13 1H NMR spectrum of Compound J-36COOMe according to an embodiment of the present invention;

[0049] Figure 14 13C NMR spectrum of Compound J-36COOMe according to an embodiment of the present invention;

[0050] Figure 15 Mass spectrum of J-36COOMe according to an embodiment of the present invention;

[0051] Figure 16 1H NMR spectrum of Compound J-36COOH according to an embodiment of the present invention;

[0052] Figure 17 13C NMR spectrum of Compound J-36COOH according to an embodiment of the present invention;

[0053] Figure 18 1H NMR spectrum of Compound J-36COO - according to an embodiment of the present invention;

[0054] Figure 19 Absorption spectrum and fluorescence spectrum of J-36COO - according to an embodiment of the present invention;

[0055] Figure 20 Particle size distribution of J-36COO - (0.03 mg / mL, H 2 O / MeOH = 1 / 10) according to an embodiment of the present invention;

[0056] Figure 21 Particle size distribution of J-36COO - (0.01 mg / mL, H 2 O / MeOH = 1 / 300) according to an embodiment of the present invention. Detailed implementation manners

[0057] The technical solution of the present invention will be described below through specific specific examples. It should be understood that one or more method steps mentioned in the present invention do not exclude the existence of other method steps before and after the combined steps or that other method steps can be inserted between these clearly mentioned steps; it should also be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. Moreover, unless otherwise specified, the numbers of the method steps are only convenient tools for identifying the method steps, rather than limiting the arrangement order of the method steps or the scope in which the present invention can be implemented. The change or adjustment of their relative relationship, without substantial change in the technical content, should also be regarded as the scope in which the present invention can be implemented.

[0058] In order to better understand the above technical solution, the exemplary embodiments of the present invention will be described in more detail below. Although the exemplary embodiments of the present invention are shown, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided in order to more thoroughly understand the present invention and to be able to convey the scope of the present invention completely to those skilled in the art.

[0059] The test materials used in the present invention are all ordinary commercially available products and can all be purchased on the market.

[0060] The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way.

[0061] Example 1

[0062] 6 g of compound 3,5-dibromo-4-iodoaniline (16 mmol), 23.0 g of 3,5-bis(methoxycarbonyl)phenylboronic acid pinacol ester (72 mmol), 1.0 g of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (1.44 mmol), 19.8 g of potassium carbonate trihydrate (144 mmol), 130 mL of toluene and 20 mL of water were added to a 200 mL Schlenk reaction flask, and nitrogen was displaced five times, and the reaction was carried out at 100 °C for 3 d. After the reaction was completed, an appropriate amount of water was added to quench the reaction, and it was extracted three times with ethyl acetate (150 mL). The organic solvent was concentrated, and 5.3 g of compound II-2 (white solid, yield 49%) was obtained by column chromatography. The eluent was dichloromethane and ethyl acetate, and the volume ratio was 20:1. As Figure 3 and Figure 4 , the 1 H NMR (300 MHz, CDCl 3) δ 8.45 (t, J = 1.5 Hz, 2H), 8.29 (d, J = 3.1 Hz, 1H), 7.95 (d, J = 1.6 Hz, 4H), 7.74 (d, J = 1.7 Hz, 2H), 6.84 (s, 2H), 4.08 (s, 2H), 3.87 (s, 12H), 3.82 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ) δ 165.87, 165.78, 146.38, 141.75, 141.24, 139.57, 137.12, 134.95, 130.11, 129.78, 128.98, 128.54, 127.55, 116.18, 52.29, 52.22.

[0063] 5.3 g of compound II-2 (8 mmol) and 20 mL of diiodomethane were added to a 100 mL Schlenk reaction flask. The nitrogen was displaced five times. Under the condition of nitrogen introduction, 1.9 mL of tert-butyl nitrite (16 mmol) was slowly added dropwise, and the reaction was carried out at 100 °C for 3 h. After the reaction was completed, the reaction solution was directly poured onto a silica gel column, and 5.2 g of compound II-3 (white solid, yield 83%) was obtained by column chromatography. The eluent was dichloromethane and ethyl acetate with a volume ratio of 20:1. As Figure 5 and Figure 6 , the 1 H NMR (300 MHz, CDCl 3 ) δ 8.50 (t, J = 1.6 Hz, 2H), 8.35 (t, J = 1.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 4H), 7.89 (s, 2H), 7.77 (d, J = 1.6 Hz, 2H), 3.89 (s, 12H), 3.84 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ) δ 165.61, 165.42, 141.95, 139.82, 138.69, 138.31, 138.02, 137.13, 136.15, 134.79, 130.46, 130.20, 129.54, 129.32, 52.40, 52.35.

[0064] Under a nitrogen atmosphere, 783 mg of compound II-3 (1 mmol), 19 mg of copper(I) iodide (0.1 mmol), 70 mg of bis(triphenylphosphine)palladium(II) dichloride (0.1 mmol), 5 mL of anhydrous tetrahydrofuran, 5 mL of triethylamine, and 414 μL of trimethylsilylacetylene (3 mmol) were added to a 100 mL Schlenk reaction tube. The reaction was carried out under nitrogen protection overnight. After completion of the reaction, the reaction mixture was concentrated, and 680 mg of compound II-4 (pale yellow solid, yield 93%) was obtained by column chromatography. The eluent was dichloromethane and ethyl acetate with a volume ratio of 30:1. As Figure 7 and Figure 8 , the 1 1H NMR (300 MHz, CDCl 3 ) δ 8.49 (t, J = 1.6 Hz, 2H), 8.35 (t, J = 1.6 Hz, 1H), 7.96 (d, J = 1.6 Hz, 4H), 7.77 (d, J = 1.6 Hz, 2H), 7.65 (s, 2H), 3.88 (s, 11H), 3.84 (s, 6H), 0.31 (s, 8H). 13 13C NMR (75 MHz, CDCl 3 ) δ 165.69, 165.48, 140.59, 140.38, 138.63, 137.40, 136.26, 134.89, 133.32, 130.38, 130.14, 129.36, 129.26, 123.79, 103.39, 96.68, 52.36, 52.33, -0.13.

[0065] 680 mg of compound II-4 (0.93 mmol), 1.86 mL of tetrabutylammonium fluoride (1.86 mmol, 1 mol / mL in tetrahydrofuran), and 100 mL of tetrahydrofuran were added to a 250 mL round-bottom flask. The reaction was carried out at room temperature for 1 h. After completion of the reaction, ammonium chloride was added to quench the reaction. The mixture was extracted three times with dichloromethane (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and compound II-5 was obtained without further purification in quantitative yield. As Figure 9 and Figure 10 , the 1 1H NMR (300 MHz, CDCl 3 ) δ 8.50 (t, J = 1.6 Hz, 2H), 8.36 (t, J = 1.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 4H), 7.78 (d, J = 1.6 Hz, 2H), 7.67 (s, 2H), 3.88 (s, 12H), 3.84 (s, 6H), 3.24 (s, 1H). 13 13C NMR (75 MHz, CDCl3 ) δ 165.65, 165.44, 140.80, 140.55, 140.44, 138.52, 136.20, 134.87, 133.48, 130.50, 130.44, 130.17, 129.54, 129.43, 129.31, 102.32, 95.82, 52.36, 52.33。

[0066] 1.56 g of compound II-3 (2 mmol), 1.36 g of compound II-5 (2 mmol), 38 mg of copper(I) iodide (0.2 mmol), 70.2 mg of bis(triphenylphosphine)palladium(II) dichloride (0.1 mmol), 15 mL of anhydrous tetrahydrofuran and 10 mL of triethylamine were added to a 100 mL Schlenk reaction tube. The nitrogen was displaced five times and the reaction was carried out overnight. After the reaction was completed, the reaction solution was concentrated, and 2.4 g of compound II-6 was obtained by column chromatography. However, there was 15% of the alkynyl compound in it. 1.2 g of pure compound II-6 (white solid, 38%) was obtained by recrystallization (adding impure II-6 to ethyl acetate and methanol, heating to 70 °C until the solid was completely dissolved, and then slowly cooling to room temperature to precipitate the solid). As Figure 11 and Figure 12 , for compound II-6 1 H NMR (300 MHz, CDCl 3 ) δ 8.51 (t, J = 1.6 Hz, 4H), 8.37 (t, J = 1.6 Hz, 2H), 8.01 (d, J = 1.6 Hz, 8H), 7.82 (d, J = 1.6 Hz, 4H), 7.76 (s, 4H), 3.89 (s, 24H), 3.85 (s, 12H). 13 C NMR (75 MHz, CDCl 3 ) δ 165.67, 165.47, 140.68, 140.51, 138.58, 137.71, 136.26, 134.91, 133.09, 130.46, 130.20, 129.44, 129.32, 123.35, 89.88, 52.37, 52.34.

[0067] In the glove box, 500 mg of compound II-6 (0.375 mmol), 27 mg of dicobalt octacarbonyl (0.079 mmol) and 6 mL of anhydrous dioxane were added to a 50 mL Schlenk reaction tube dried by flame. The reaction was carried out at 125 °C for 1 day. After the reaction was completed, the organic solvent was concentrated, and 410 mg of compound J-36COOMe (white solid, 82%) was obtained by column chromatography. The eluent was dichloromethane and ethyl acetate with a volume ratio of 1:1. As Figure 13 andFigure 14 , for the compound J-36COOMe 1 H NMR (300 MHz, CDCl 3 ) δ 8.39 (s, 12H), 8.32 (s, 6H), 7.66 (s, 24H), 7.58 (d, J = 7.0 Hz, 24H), 3.59 (s, 108H). 13 C NMR (75 MHz, CDCl 3 ) δ 165.22, 140.31, 140.12, 140.08, 139.82, 138.49, 136.40, 135.87, 134.46, 132.47, 130.51, 130.28, 129.11, 52.02.

[0068] Nuclear magnetic resonance confirmation was carried out on the compound J-36COOMe: The hydrogen in the aromatic region and the hydrogen on the methyl group were assigned by nuclear magnetic resonance. As Figure 13 shown, there are two electron-withdrawing groups beside d and e, at the lowest field position, and the integral ratio of the two is 2:1, so d and e can be judged. The integral ratio of b, c and a is 2:1:1, b can be determined, and then c and a are confirmed by two-dimensional spectrum.

[0069] Mass spectrometry confirmation was carried out on the compound J-36COOMe: As Figure 15 shown, the theoretical and actual isotope peak distributions of J-36COOMe are consistent. The simulated molecular weight is 4015.991, and the measured molecular weight is 4015.997. The [M+Na] + peak and [M+K] + were detected.

[0070] 400 mg of the compound J-36COOMe (0.1 mmol), 1.68 g of potassium hydroxide (30 mmol), 5 mL of tetrahydrofuran and 15 mL of ultrapure water were added to a 50 mL round-bottom flask, and the reaction was carried out at 100 °C for 24 h. After the reaction was completed, it was cooled to room temperature, HCl (6 M) was added, the pH was adjusted to 2, and centrifugation was carried out (8000 rpm, 15 min) to obtain 350 mg of the compound Ι (J-36COOH) (white solid, yield 90%). 1 HNMR (300 MHz, DMSO-d 6 ) δ 8.12 (s, 12H), 7.98 (s, 6H), 7.48 (s, 12H), 7.43 (s, 24H), 7.40 (s, 12H).

[0071] The 1H NMR spectra of J-36COOH and J-36COOMe were compared, and the hydrogen in their aromatic regions was assigned. As Figure 16 shown.

[0072] Example 2

[0073] Add 7.5 mg of J-36COOH and 5 mg of sodium hydroxide to 0.6 mL of deuterated water and sonicate until all solids are dissolved to obtain compound Ι (J-36COO - ). 1 H NMR (300 MHz, D 2 O) δ 7.95 (s, 12H), 7.77 (s, 12H), 7.71 (s, 6H), 7.26 (s, 24H), 7.08 (s, 12H).

[0074] Compare the 1H NMR spectra of J-36COOH and J-36COOMe and assign the hydrogens in their aromatic regions as Figure 18 shown.

[0075] Prepare an aqueous solution of J-36COO - with a concentration of 5×10 -6 mol / L and a volume of 2 mL, and measure the UV absorption spectrum and fluorescence spectrum of J-36COO - in water, as Figure 19 shown. The test results show that it has good solubility in water.

[0076] Process of self-assembly behavior generation: 2.5 mL of water, 7.5 mg of J-36COOH, 5 mg of sodium hydroxide, completely dissolved, put into a dialysis bag (molecular weight cut-off 500), dialyze twice in water, each time for 12 h, and then put into methanol for dialysis for 50 min to form a milky turbid liquid. Take 0.5 mL and put it into 15 mL of methanol, and dilute it 10 times to obtain a 0.01 mg / mL colloid, stable, DLS (259 nm), as Figure 20 shown; take 0.5 mL and put it into 49.5 mL (4.5 mL of water, 45 mL of methanol) to obtain a 0.03 mg / mL colloid, stable, DLS (383 nm), as Figure 21 shown.

[0077] In summary, according to the examples of the present invention, a Janus arene (J-36COO - ) with 36 negative charges (carboxylate anions) was synthesized. This molecule has the following three characteristics: a back-to-back double-bowl structure; a nanoscale cavity size; 36 carboxylate anions, which exhibit self-assembly behavior in water and methanol solutions, and the particle size can be regulated by changing the concentration, and it is expected to be applied in the fields of molecular recognition and biomimetic catalysis, etc.

[0078] In the description of this specification, the descriptions referring to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic descriptions of the above terms should not be understood as necessarily referring to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine the different embodiments or examples described in this specification.

[0079] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A water-soluble Janusarene compound, whose structural formula Ι is: Wherein, R is COOH or COO - .

2. The water-soluble Janusarene compound according to claim 1, characterized in that the structural formula Ι has Janusarene as the backbone, and at the same time, six benzene rings are added to the waist of the Janusarene molecule, and 36 carboxylic acids or carboxylate anions are added to the periphery.

3. A preparation method of the water-soluble Janusarene compound according to claim 1 or 2, characterized in that it includes the following steps: (1) React compound Ⅱ-1 with pinacol 3,5-bis(methoxycarbonyl)phenylborate, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, and potassium carbonate trihydrate in toluene and water to obtain compound Ⅱ-2; (2) React compound Ⅱ-2 with tert-butyl nitrite in dichloromethane to obtain compound Ⅱ-3; (3) React compound Ⅱ-3 with trimethylsilylacetylene, copper(I) iodide, bis(triphenylphosphine)palladium(II) dichloride, and triethylamine in anhydrous tetrahydrofuran to obtain compound Ⅱ-4; (4) React compound Ⅱ-4 with tetrabutylammonium fluoride in tetrahydrofuran to obtain compound Ⅱ-5; (5) React compound Ⅱ-5 with compound Ⅱ-3 in the presence of copper(I) iodide, bis(triphenylphosphine)palladium(II) dichloride, and triethylamine in anhydrous tetrahydrofuran to obtain compound Ⅱ-6; (6) React compound Ⅱ-6 with dicobalt octacarbonyl in anhydrous dioxane to obtain compound J-36COOMe; (7) React compound J-36COOMe with potassium hydroxide in tetrahydrofuran and water to obtain compound Ι; wherein, R of compound Ι is COOH; 4. The preparation method according to claim 3, characterized in that It further includes step (8) of adding compound Ι and sodium hydroxide into deuterated water and ultrasonically treating until all solids are dissolved to obtain compound Ι with R being COO - of compound Ι.

5. The preparation method according to claim 3, characterized in that In step (1), the reaction temperature is 100 °C and the reaction time is 3 d; and / or, in step (2), the reaction temperature is 100 °C and the reaction time is 3 h; and / or, in step (3), the reaction condition is nitrogen protection and overnight reaction; and / or, in step (4), the reaction condition is room temperature reaction for 1 h; and / or, in step (5), the reaction condition is nitrogen protection and overnight reaction; and / or, in step (6), the reaction temperature is 125 °C and the reaction time is 1 d; and / or, in step (7), the reaction temperature is 100 °C and the reaction time is 24 h.

6. The preparation method according to claim 3 or 4, characterized in that In step (1), after the reaction is completed, an appropriate amount of water is added to quench the reaction, and it is extracted three times with ethyl acetate, the organic solvent is concentrated, and column chromatography is carried out to obtain compound Ⅱ-2; and / or, in step (2), after the reaction is completed, the reaction solution is directly poured onto a silica gel column, and column chromatography is carried out to obtain compound Ⅱ-3; and / or, in step (3), after the reaction is completed, the reaction solution is concentrated, and column chromatography is carried out to obtain compound Ⅱ-4; and / or, in step (4), after the reaction is completed, ammonium chloride is added to quench the reaction, and it is extracted three times with dichloromethane, the organic phases are combined, and dried over anhydrous sodium sulfate to obtain compound Ⅱ-5; And / or, in step (5), after the reaction is completed, concentrate the reaction solution and perform column chromatography to obtain compound II-6; And / or, in step (6), after the reaction is completed, concentrate the organic solvent and perform column chromatography to obtain compound J-36COOMe.

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