A process for the preparation of alpha, beta-unsaturated carboxylic acid esters

Abstract

The application relates to the technical field of organic synthesis, and particularly relates to a preparation method of alpha, beta-unsaturated carboxylic acid ester, which comprises the following steps: mixing a ruthenium catalyst, an organic nitrogen ligand, a 1,2-propadiene compound and an alcohol compound under the condition of carbon monoxide, and then performing reaction to obtain alpha, beta-unsaturated carboxylic acid ester. The application adopts the 1,2-propadiene compound to perform a hydrogen esterification reaction to efficiently prepare alpha, beta-unsaturated carboxylic acid ester; through the regulation of the organic nitrogen ligand on the ruthenium catalyst, the target product can be efficiently and highly selectively synthesized, and the application has a good industrialization prospect; meanwhile, in the preparation method, the reaction condition is relatively mild, excellent conversion of the substrate can be realized at a relatively low reaction temperature, catalyst deactivation can be effectively avoided, and the conversion rate of the substrate and the yield of the product are relatively high. In addition, the application is widely applicable, and can be used to synthesize various types of alpha, beta-unsaturated carboxylic acid ester in one step.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of alpha, beta-unsaturated carboxylate. BACKGROUND

[0002] Carbonylation reactions (such as hydroformylation, hydroesterification, hydrocarboxylation, etc.) are widely used in organic synthesis and industrial production due to their ability to introduce carbonyl groups and easily extend carbon chains. Hydroesterification is a method for synthesizing various ester compounds by transition metal catalysis, using unsaturated hydrocarbons, carbon monoxide (CO) and different alcohols as substrates (Coord. Chem. Rev. 248 (2004) 2165; Chem. Commun. 51 (2015) 12574). Alpha, beta-unsaturated carboxylate derivatives are important intermediates in organic synthesis, and are also important building blocks in the synthesis of drug molecules in medicinal chemistry, and are widely used in the synthesis of drug molecules with cyclic or heterocyclic structures, natural products, and chiral / non-chiral related drug molecules; can also be used as coatings for automobiles and non-ferrous metal materials; and can also be used to prepare adhesives with special functions.

[0003] The existing reported strategies for synthesizing alpha, beta-unsaturated carboxylate mainly include two types: 1. addition reaction of transition metal-catalyzed Baylis-Hillman addition product and different organic metal reagents (Tetrahedron. 66 (2010) 3623); and 2. visible light-catalyzed organic boronic acid (or potassium organotrifluoroborate) to prepare polysubstituted alpha, beta-unsaturated carboxylate derivatives (Tetrahedron Lett. 59 (2018) 2046; Tetrahedron Lett. 60 (2019) 1302). These methods still have some deficiencies: 1. the preparation process of the organic metal reagent in the raw material is complicated; 2. the reaction conditions are relatively harsh, the substrate universality range is limited, and heterocyclic or aliphatic alpha, beta-unsaturated carboxylate cannot be effectively synthesized, resulting in incomplete conversion of the substrate (conversion rate of 60% to 90%); 3. a large amount of by-products (such as biphenyl) are produced in the reaction process, resulting in poor chemical selectivity and difficulty in separation (Tetrahedron. 62 (2006) 6355; J. Chem. Soc., Chem. Commun. (1984) 905), resulting in a low yield (80%). Therefore, it is particularly important to develop a new catalyst system to synthesize alpha, beta-unsaturated carboxylate derivatives with easy-to-obtain starting materials, high atom economy and high chemical / region selectivity. On the other hand, a wider substrate range and a more economical catalyst system are also research hotspots. SUMMARY

[0004] Therefore, the present application aims to provide a method for preparing α,β-unsaturated carboxylic acid ester with high conversion rate of substrate and high yield of product.

[0005] The present application provides a method for preparing α,β-unsaturated carboxylic acid ester, comprising the following steps:

[0006] The ruthenium catalyst, the organic nitrogen ligand, the 1,2-propadiene compound and the alcohol compound are mixed under the condition of carbon monoxide, and then reacted to obtain the α,β-unsaturated carboxylic acid ester.

[0007] Preferably, the ruthenium catalyst comprises at least one of hydrated ruthenium trichloride, triruthenium dodecacarbonyl, 1,5-cyclooctadiene ruthenium dichloride, tris(triphenylphosphine) ruthenium dichloride and bis(triphenylphosphine) dicarbonyl ruthenium dichloride.

[0008] The molar ratio of the ruthenium catalyst to the 1,2-propadiene compound is 1:10-1000.

[0009] Preferably, the molar ratio of the ruthenium catalyst to the 1,2-propadiene compound is 1:100.

[0010] Preferably, the organic nitrogen ligand has the structure shown in Formula I or Formula II.

[0011]

[0012] wherein R1 and R2 are independently selected from hydrogen, C1-C8 alkyl, C6-C18 aryl or nitro; or R1 and R2 independently form a C6-C18 aromatic ring or a C6-C18 aromatic heterocyclic ring with the ring in which they are located.

[0013] R3 and R4 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy or C6-C18 aryl.

[0014] Preferably, the organic nitrogen ligand is selected from one of N1-N10.

[0015]

[0016] The molar ratio of the organic nitrogen ligand to the ruthenium catalyst is 1-500:1.

[0017] Preferably, the molar ratio of the organic nitrogen ligand to the ruthenium catalyst is 6:1.

[0018] Preferably, the 1,2-propadiene compound has the structure shown in Formula III.

[0019]

[0020] R5 and R6 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 cycloalkyl, substituted or unsubstituted C6-C18 aromatic groups; the substituted substituents are selected from halogens, C1-C8 alkyl or C1-C8 alkoxy groups.

[0021] Preferably, the 1,2-propadiene compound is selected from one of 1a to 1h;

[0022]

[0023] Preferably, the alcohol compound includes at least one selected from methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH), and tert-butanol (tBuOH);

[0024] The carbon monoxide pressure of the reaction is 0.1–10 MPa, the reaction temperature is 25–200 °C, and the reaction time is 1–48 h.

[0025] The reaction is followed by column chromatography separation.

[0026] Preferably, the carbon monoxide pressure of the reaction is 1-5 MPa, the reaction temperature is 50-100°C, and the reaction time is 20-30 h.

[0027] This invention provides a method for preparing α,β-unsaturated carboxylic acid esters, comprising the following steps: under carbon monoxide conditions, a ruthenium catalyst, an organic nitrogen ligand, a 1,2-propadiene compound, and an alcohol compound are mixed and reacted to obtain α,β-unsaturated carboxylic acid esters. This invention utilizes the hydrogen esterification reaction of 1,2-propadiene compounds to efficiently prepare α,β-unsaturated carboxylic acid esters. Through the regulatory effect of the organic nitrogen ligand on the ruthenium catalyst, the target product can be synthesized efficiently and selectively, showing good industrialization prospects. Furthermore, the product has important applications in industrial production and daily life, and can be used to prepare important intermediates for drug molecules in medicinal chemistry, as well as coatings for automobiles and non-ferrous metal materials, and adhesives with special functions. Simultaneously, the preparation method provided by this invention uses relatively mild reaction conditions, achieving excellent substrate conversion at a lower reaction temperature, effectively avoiding catalyst deactivation, and resulting in high substrate conversion and product yield. Moreover, this invention has broad applicability, enabling the one-step synthesis of various types of α,β-unsaturated carboxylic acid esters.

[0028] Experimental results show that, in the method for preparing α,β-unsaturated carboxylic acid esters provided by the present invention, the conversion rate of the substrate is not less than 99%, and the yield of the product is not less than 60%. Attached Figure Description

[0029] Figure 1 This is the 1H NMR spectrum of the α,β-unsaturated carboxylic acid ester in Example 1 of the present invention. Detailed Implementation

[0030] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0031] This invention provides a method for preparing α,β-unsaturated carboxylic acid esters, comprising the following steps:

[0032] Under carbon monoxide conditions, a ruthenium catalyst, an organic nitrogen ligand, a 1,2-propadiene compound, and an alcohol compound are mixed and reacted to obtain an α,β-unsaturated carboxylic acid ester.

[0033] In some embodiments of the present invention, the ruthenium catalyst comprises hydrated ruthenium trichloride (RuCl3·3H2O) and dodecylruthenium trichloride (Ru3(CO)). 12 At least one of 1,5-cyclooctadiene ruthenium dichloride (Ru(cod)Cl2), tris(triphenylphosphine) ruthenium dichloride (Ru(PPh3)3Cl2), and di(triphenylphosphine) dicarbonyl ruthenium dichloride (RuCl2(CO)2(PPh3)2); preferably dodecacarbonyl ruthenium (Ru3(CO)2). 12 ).

[0034] The molar ratio of the ruthenium catalyst to the substrate 1,2-propadiene is 1:10 to 1000; preferably 1:100.

[0035] In some embodiments of the present invention, the organic nitrogen ligand is one of a nitrogen ligand having a bipyridine skeleton structure or a 1,10-phenanthroline skeleton structure, specifically having the structure shown in Formula I or Formula II;

[0036]

[0037] Wherein, R1 and R2 are independently selected from hydrogen, C1-C8 alkyl, C6-C18 aromatic or nitro; or R1 and R2 independently form a C6-C18 aromatic ring or a C6-C18 aromatic heterocycle with the ring in which they are located.

[0038] R3 and R4 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, or C6-C18 aromatic groups.

[0039] Specifically, R1 and R2 are independently selected from hydrogen, methyl, tert-butyl, nitro, or R1 and R2 independently form a C6 aromatic ring with their respective rings;

[0040] R3 and R4 are independently selected from hydrogen, phenyl, methyl, or methoxy.

[0041] More specifically, the organic nitrogen ligand is selected from one of N1 to N10;

[0042]

[0043] The organic nitrogen ligand is preferably N9.

[0044] In some embodiments of the present invention, the molar ratio of the organic nitrogen ligand to the ruthenium catalyst is 1 to 500:1; preferably 6:1.

[0045] In some embodiments of the present invention, the 1,2-propadiene compounds have the structure shown in Formula III;

[0046]

[0047] Wherein, R5 and R6 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 cycloalkyl, substituted or unsubstituted C6-C18 aromatic groups; the substituted substituents are selected from halogens, C1-C8 alkyl or C1-C8 alkoxy groups; the halogen is chlorine.

[0048] Specifically, R5 and R6 are independently selected from hydrogen, methyl, phenyl, biphenyl, chlorinated phenyl, methylated phenyl, methoxylated phenyl, or cyclohexyl.

[0049] More specifically, the 1,2-propadiene compound is selected from one of 1a to 1h;

[0050]

[0051] In some embodiments of the present invention, the alcohol compound includes at least one selected from methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH), and tert-butanol (tBuOH). The alcohol compound serves as both a nucleophile and a solvent. The molar ratio of the alcohol compound to the 1,2-propadiene compound is 1.0–10.0 mL : 1.0–10.0 mmol; specifically, it is 1.0 mL : 1.0 mmol.

[0052] In some embodiments of the present invention, the carbon monoxide pressure of the reaction is 0.1 to 10 MPa, specifically 1 to 5 MPa, more specifically 3 MPa; the reaction temperature is 25 to 200°C, specifically 50 to 100°C, more specifically 70°C; and the reaction time is 1 to 48 h, specifically 20 to 30 h, more specifically 24 h.

[0053] In some embodiments of the present invention, the reaction is followed by column chromatography separation.

[0054] The column chromatography separation uses 300-400 mesh silica gel, and the eluent includes n-hexane and ethyl acetate in a volume ratio of 10:1.

[0055] In some embodiments of the present invention, the structure of the α,β-unsaturated carboxylic acid ester is shown in formulas 2a to 2k:

[0056]

[0057] The present invention does not impose any special restrictions on the source of the raw materials used above, and they can be commercially available.

[0058] Beneficial effects:

[0059] 1) This invention utilizes 1,2-propadiene compounds for the efficient preparation of α,β-unsaturated carboxylic acid esters via hydrogen esterification. Through the regulation of ruthenium catalyst by organic nitrogen ligands, the target product can be synthesized efficiently and selectively with a substrate conversion rate of not less than 99%, showing good prospects for industrialization. Furthermore, the product has important applications in industrial production and daily life. It can be used to prepare important intermediates for drug molecules in medicinal chemistry, as well as coatings for automobiles and non-ferrous metal materials, and adhesives with special functions.

[0060] 2) The preparation method provided by the present invention has mild reaction conditions and can achieve excellent conversion of the substrate at a low reaction temperature, which can effectively avoid catalyst deactivation.

[0061] 3) This invention has broad applicability and can synthesize a variety of different types of α,β-unsaturated carboxylic acid esters in one step.

[0062] 4) Ruthenium catalysts are cheaper than metals such as palladium, which can reduce production costs.

[0063] To further illustrate the present invention, the following detailed description of a method for preparing α,β-unsaturated carboxylic acid esters provided by the present invention is provided in conjunction with embodiments, but it should not be construed as limiting the scope of protection of the present invention.

[0064] The chemical reagents used in the examples were purchased from Maclean's Reagents and Aladdin Reagents.

[0065] The gas chromatograph used for the gas chromatography analysis was an Agilent-7820.

[0066] Gas chromatography column and test conditions: 0.25 mm × 30 m HP-5 capillary column, FID detector; vaporization chamber temperature 250 °C, column oven temperature 250 °C, FID detector temperature 300 °C, argon flow rate 2.0 mL / min, hydrogen flow rate 30 mL / min, air flow rate 400 mL / min, injection volume 0.2 μL. The conversion of the alkene and the selectivity of the product were calculated using the area normalization method. Temperature program: Preheat to column temperature 50 °C, hold for 5 min, then increase from 40 °C to 250 °C at a rate of 15 °C / min, hold for 5 min.

[0067] Nuclear magnetic resonance analyzer: Bruker 400M.

[0068] Examples 1-5

[0069] 0.01 mmol of ruthenium catalyst, 0.06 mmol of organic nitrogen ligand (N9), 1.0 mmol of 1,2-propadiene compound (phenyl 1,2-propadiene, i.e., 1a), and 1.0 mL of alcohol compound (methanol) were added sequentially to a reaction flask. The flask was placed in a high-pressure reactor and reacted at 3 MPa of carbon monoxide and 70 °C for 24 h. The substrate conversion and product selectivity were determined by gas chromatography. The yields of α,β-unsaturated carboxylic acid esters were calculated by column chromatography (using 300-400 mesh silica gel, with hexane and ethyl acetate as eluents in a volume ratio of 10:1). Table 1 shows the experimental results of the hydrogen esterification reaction of 1,2-propadiene compounds catalyzed by different ruthenium catalysts.

[0070]

[0071] Table 1. Experimental results of hydrogen esterification reactions of 1,2-propadiene compounds catalyzed by different ruthenium catalysts.

[0072]

[0073] In Table 1, b These are the results of gas chromatography analysis.

[0074] The α,β-unsaturated carboxylic acid ester (2a) obtained in Example 1 was analyzed by nuclear magnetic resonance spectroscopy using a Bruker 400M instrument. The results are as follows: Figure 1 As shown. Figure 1 This is the 1H NMR spectrum of the α,β-unsaturated carboxylic acid ester in Example 1 of the present invention.

[0075] The NMR data of the α,β-unsaturated carboxylic acid ester (2a) are as follows:

[0076] 1H NMR (400MHz, Chloroform-d) δ7.70 (s, 1H), 7.40 (d, J = 4.3Hz, 4H), 7.35-7.30 (m, 1H), 3.84-3.80 (m, 3H), 2.13-2.12 (m, 3H).

[0077] Examples 6-14

[0078] Add 0.01 mmol of ruthenium catalyst (ruthenium dodecacarbonyl, i.e., Ru3(CO)) sequentially to the reaction flask. 12 0.06 mmol of an organic nitrogen ligand, 1.0 mmol of a 1,2-propadiene compound (phenyl 1,2-propadiene, i.e., 1a), and 1.0 mL of an alcohol compound (methanol) were added to a reaction flask placed in a high-pressure reactor. The reaction was carried out at 70°C and 3 MPa for 24 h. The substrate conversion and product selectivity were determined by gas chromatography. The yields of α,β-unsaturated carboxylic acid esters were calculated by column chromatography (using 300–400 mesh silica gel, with hexane and ethyl acetate as eluents in a 10:1 volume ratio). Table 2 shows the yields of ruthenium dodecacarbonyl (Ru3(CO)) regulated by different organic nitrogen ligands. 12 Experimental results of catalytic hydrogen esterification of 1,2-propadiene compounds.

[0079]

[0080] Table 2. Regulation of Ru3(CO) by different organic nitrogen ligands 12 Experimental results of catalytic hydrogen esterification of 1,2-propadiene compounds

[0081]

[0082] In Table 2, b These are the results of gas chromatography analysis.

[0083] Examples 15-24

[0084] Add 0.01 mmol of ruthenium catalyst (ruthenium dodecacarbonyl, i.e., Ru3(CO)) sequentially to the reaction flask. 12 0.06 mmol of an organic nitrogen ligand (N9), 1.0 mmol of a 1,2-propadiene compound, and 1.0 mL of an alcohol (methanol) were added to a reaction flask in a high-pressure reactor. The reaction was carried out at 70°C and 3 MPa for 24 h. Substrate conversion and product selectivity were determined by gas chromatography. α,β-unsaturated carboxylic esters (2b-2k) were separated by column chromatography (using 300-400 mesh silica gel, with hexane and ethyl acetate as eluents in a 10:1 volume ratio) and the yields were calculated. Table 3 shows the regulation of dodecacarbonyltriruthenium (Ru3(CO)) by organic nitrogen ligand N9.12 Experimental results of catalytic hydrogen esterification reactions of different 1,2-propadiene compounds.

[0085] Table 3. Regulation of Ru3(CO) by the organic nitrogen ligand N9 12 Experimental results of catalytic hydrogen esterification reactions of different 1,2-propadiene compounds

[0086]

[0087]

[0088] In Table 3, b These are the results of gas chromatography analysis.

[0089] The α,β-unsaturated carboxylic acid esters (2b-2k) obtained in Examples 15-24 were analyzed by nuclear magnetic resonance spectroscopy using a Bruker 400M instrument.

[0090] The NMR data of the α,β-unsaturated carboxylic acid ester (2b) are as follows:

[0091] 1 H NMR (400MHz, Chloroform-d) δ7.81-7.85(m,5H),7.48-7.46(m,3H),3.79(s,3H),2.17(s,3H).

[0092] The NMR data for the α,β-unsaturated carboxylic acid ester (2c) are as follows:

[0093] 1 H NMR (400MHz, Chloroform-d) δ7.63 (s, 1H), 7.32-7.27 (m, 4H), 3.81 (s, 3H), 2.06 (d, J = 1.5Hz, 3H).

[0094] The NMR data of the α,β-unsaturated carboxylic acid ester (2d) are as follows:

[0095] 1 H NMR (400MHz, Chloroform-d) δ7.75 (s, 1H), 7.19-7.22 (m, 4H), 3.83 (s, 3H), 2.26 (s, 3H), 1.98 (d, J = 1.8Hz, 3H).

[0096] The NMR data for the α,β-unsaturated carboxylic acid ester (2e) are as follows:

[0097] 1H NMR (400MHz, Chloroform-d) δ7.63 (s, 1H), 7.35 (d, J = 8.5Hz, 2H), 6.90 (d, J = 8.5Hz, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 2.63 (s, 3H).

[0098] The NMR data of the α,β-unsaturated carboxylic acid ester (2f) are as follows:

[0099] 1 H NMR (400MHz, Chloroform-d) δ7.65 (s, 1H), 7.35 (d, J = 8.4Hz, 2H), 7.24 (d, J = 8.4Hz, 2H), 3.81 (s, 3H), 2.26 (s, 3H), 2.05 (s, 3H).

[0100] The NMR data of the α,β-unsaturated carboxylic acid ester (2g) are as follows:

[0101] 1 H NMR (400MHz, Chloroform-d) δ7.71 (s, 1H), 7.47-7.38 (m, 5H), 4.25 (q, J = 7.2Hz, 2H), 2.05 (s, 3H), 1.27 (t, J = 7.2Hz, 3H).

[0102] The NMR data of the α,β-unsaturated carboxylic acid ester (2h) are as follows:

[0103] 1 H NMR (400MHz, Chloroform-d) δ7.65 (s, 1H), 7.39-7.38 (m, 4H), 7.31-7.28 (m, 1H), 5.19-5.08 (m, 1H), 2.09 (d, J = 1.2Hz, 3H), 1.31 (d, J = 5.1Hz, 6H).

[0104] The NMR data of the α,β-unsaturated carboxylic acid ester (2i) are as follows:

[0105] 1 H NMR (400MHz, Chloroform-d) δ7.58(s,1H),7.42-7.25(m,5H),2.12(s,3H),1.55(s,9H).

[0106] The NMR data of the α,β-unsaturated carboxylic acid ester (2j) are as follows:

[0107] 1H NMR (400MHz, Chloroform-d) δ7.45-7.16 (m, 5H), 3.79 (s, 3H), 2.28 (d, J = 1.8Hz, 3H), 1.73 (d, J = 1.8Hz, 3H).

[0108] The NMR data for the α,β-unsaturated carboxylic acid ester (2k) are as follows:

[0109] 1 H NMR (400MHz, Chloroform-d) δ7.35-7.30(m,1H),5.43-4.80(m,8H),4.42-4.20(m,2H),4.10-4.05(m,1H),3.84-3.80(m,3H),2.13-2.12(m,3H).

[0110] Experimental results show that, in the method for preparing α,β-unsaturated carboxylic acid esters provided by the present invention, the conversion rate of the substrate is not less than 99%, and the yield of the product is not less than 60%.

[0111] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing an α, β-unsaturated carboxylic acid ester, comprising the steps of: mixing a ruthenium catalyst, an organic nitrogen ligand, a 1,2-propadiene compound, and an alcohol compound under a carbon monoxide condition, and then performing a reaction to obtain an α, β-unsaturated carboxylic acid ester; wherein the ruthenium catalyst is triruthenium dodecacarbonyl; the organic nitrogen ligand is selected from one of N1, N2, N7, N9, and N10; the 1,2-propadiene compound is selected from one of 1a to 1f; and the alcohol compound is selected from at least one of methanol, ethanol, isopropanol, and tert-butanol; and wherein the α, β-unsaturated carboxylic acid ester has a structure as shown in any one of 2a to 2i. 2.The method according to claim 1, wherein a molar ratio of the ruthenium catalyst to the 1,2-propadiene compound is 1: 10 to 1000. 3.The method according to claim 1, wherein a molar ratio of the ruthenium catalyst to the 1,2-propadiene compound is 1:

100. 4.The method according to claim 1, wherein a molar ratio of the organic nitrogen ligand to the ruthenium catalyst is 1 to 500:

1. ； ； 5.The method according to claim 1, wherein a molar ratio of the organic nitrogen ligand to the ruthenium catalyst is 6:

1. ； ； 6.The method according to claim 1, wherein a carbon monoxide pressure of the reaction is 0.1 to 10 MPa, a temperature of the reaction is 25 to 200 ℃, and a time of the reaction is 1 to 48 h. 7.The method according to claim 1, wherein after the reaction, a column chromatography separation is further included. 2a; 2b; 2c; 2d; 2e; 2f; 2g; 2h; 2i。 8.The method according to claim 1, wherein a carbon monoxide pressure of the reaction is 1 to 5 MPa, a temperature of the reaction is 50 to 100 ℃, and a time of the reaction is 20 to 30 h. ​ 3. The preparation method according to claim 1, characterized in that, ​ ​ ​ 5. The preparation method according to claim 1, characterized in that, ​ 6. The method of claim 1, wherein, ​ ​ 7. The preparation method according to claim 1, characterized in that, ​

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