CN111320664A - A kind of preparation method of ethyl 24-cholenoate - Google Patents

Abstract

The invention discloses a preparation method of ethyl 24-cholenoate. The invention provides a preparation method of ethyl 24-cholenoate as shown in formula 04, which comprises the following steps: step (1), in an organic solvent, in the presence of zinc, a catalyst and an alkaline reagent, The compound shown in formula 02 is subjected to the alkylation reaction shown below with ethyl acrylate to obtain the compound shown in formula 03; step (2), in water and an organic solvent, in the presence of an acidic reagent , the compound shown in formula 03 described in step (1) is subjected to the reaction shown below to obtain the compound shown in formula 04. The preparation method has short reaction steps, high yield (two-step total yield can reach 80%-91%), mild reaction conditions, cheap reagents, low requirements for experimental equipment, and is suitable for large-scale synthesis.

Description

A kind of preparation method of ethyl 24-cholenoate

technical field

The present invention relates to a preparation method of ethyl 24-cholenoate.

Background technique

25-hydroxycholesterol is the metabolite precursor of vitamin _D3 , and 24-cholenoate ethyl ester is a key intermediate in the synthesis of 25-hydroxycholesterol, and 25-hydroxycholesterol can be synthesized in one step.

There are two main routes for the synthesis of 24-cholenoic acid ethyl ester reported in the literature. Route one:

Using lithocholic acid as the starting material, it is prepared through 11 steps of reaction, and has the disadvantages of long route, low yield (total yield is 11.13%), and relatively expensive experimental reagents (steroids 121 (2017) 22-31).

Route two:

Using dehydroepiandrosterone as raw material, the product is obtained through 5-step reaction, two of which are used in Wittig reaction, which requires anhydrous and oxygen-free operation; the three-step reaction needs to be carried out at -78 ℃, and the reagents used in multi-step reaction are expensive. Not suitable for larger scale synthesis (Tetrahedron letters Vol. 23, NO. 20, PP 2077-2080, 1982).

In conclusion, both routes are not suitable for larger scale synthesis.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to overcome the existing preparation methods of ethyl 24-cholenoate, which have long routes, low yields, relatively expensive reagents, or harsh operating conditions, which are not suitable for larger-scale synthesis techniques. However, a method for preparing ethyl 24-cholenoate is provided. The preparation method provided by the invention has the advantages of short reaction steps, high yield, mild reaction conditions, cheap reagents, low requirements for experimental equipment, and is suitable for large-scale synthesis.

The present invention solves the above-mentioned technical problems through the following technical solutions.

The invention provides a preparation method of 24-cholenoic acid ethyl ester shown in formula 04, which comprises the following steps:

In step (1), in an organic solvent, in the presence of zinc, a catalyst and an alkaline reagent, the compound shown in formula 02 is subjected to the alkylation reaction shown below with ethyl acrylate to obtain a compound shown in formula 03 You can;

In step (2), in water and an organic solvent, in the presence of an acidic reagent, the compound shown in formula 03 described in step (1) is subjected to the reaction shown below to obtain the compound shown in formula 04. Can;

In the described step (1), the organic solvent can be a conventional organic solvent in this type of reaction in the field, such as a pyridine solvent (such as pyridine) and/or a cyclic ether solvent (such as tetrahydrofuran); preferably for pyridine.

In the step (1), the catalyst can be a conventional catalyst in this type of reaction in the art, and in the present invention, it is preferably nickel chloride hexahydrate.

In the step (1), the alkaline reagent may be a conventional alkaline reagent in this type of reaction in the art, and preferably an organic base (eg, pyridine) in the present invention.

In the described step (1), the amount of the organic solvent can be not specifically limited, as long as it does not affect the reaction; in the present invention, the mass volume of the compound shown in the formula 02 and the organic solvent is More preferably, it is 0.01 g/mL to 1 g/mL (for example, 0.25 g/mL to 0.4 g/mL).

In the described step (1), the zinc can be conventional zinc in this type of reaction in this area, such as zinc powder; the mol ratio of the zinc and the compound shown in the formula O2 can be 5: 1-10:1, preferably 6:1-8:1 (eg 7.5:1).

In the step (1), the molar ratio of the catalyst to the compound represented by formula 02 is preferably 1:1 to 2:1 (for example, 1:1).

In the step (1), the molar ratio of the basic reagent to the compound represented by formula 02 is preferably 7.5:1 to 25:1 (for example, 22:1).

In the step (1), the molar ratio of the ethyl acrylate to the compound represented by the formula 02 may be 5:1 to 10:1, preferably 6:1 to 8:1 ( eg 7.5:1).

In the step (1), the temperature of the alkylation reaction is preferably 0°C to 80°C (eg, 10°C to 70°C, for example, 10°C to 30°C, 40°C to 70°C).

In the step (1), the progress of the alkylation reaction can be monitored by conventional monitoring methods in the art (such as TLC or NMR), and generally the compound shown in formula 02 disappears or does not. Re-reaction is the end of the reaction.

In the step (1), a post-processing operation may also be included. The post-processing operation includes the following steps: filtering, washing, concentrating, and purifying the reaction system after the alkylation reaction is completed. , to obtain the compound shown in formula 03; the washing, concentrating, and purification by column chromatography can be conventional operations in the field; The brine is washed separately; the column chromatography purification can be a conventional operation in the field, for example, n-hexane:ethyl acetate (volume ratio=20:1) is used for elution.

In the step (2), the organic solvent can be a conventional organic solvent in this type of reaction in the art, preferably a cyclic ether solvent (eg dioxane and/or tetrahydrofuran) in the present invention.

In the step (2), the acid can be a conventional acid in this type of reaction in the art, and in the present invention, it is preferably p-toluenesulfonic acid and/or methanesulfonic acid.

In the step (2), the volume ratio of the water and the organic solvent is preferably 2:1 to 1:2 (for example, 1:1).

In the described step (2), the amount of the described organic solvent may not be specifically limited, as long as it does not affect the reaction; in the present invention, the mass volume of the compound of formula 03 and the organic solvent is preferably It is 0.01 g/mL to 0.5 g/mL (for example, 0.09 g/mL to 0.12 g/mL).

In the step (2), the molar ratio of the acid to the compound represented by formula 03 is preferably 0.05:1 to 0.5:1 (for example, 0.08:1 to 0.1:1).

In the step (2), the temperature of the reaction can be a conventional temperature in this type of reaction in the art, and in the present invention, it is preferably 80°C to 100°C.

In the described step (2), the progress of the reaction can be monitored by conventional monitoring methods (such as TLC or NMR) in the art, generally when the compound shown in Formula 03 disappears or no longer reacts. is the end point of the reaction.

In the described step (2), a post-processing operation may also be included, and the post-processing operation includes the following steps: extracting, washing, and concentrating the reaction system after the reaction ends to obtain the described formula as shown in formula 04. The compound shown; the extraction, washing, and concentration can be conventional operations in the field; for example, the extraction can be performed with ethyl acetate.

The preparation method may further include the following steps: in an organic solvent, in the presence of an alkaline reagent and a ligand, the compound shown in formula 01 is subjected to the iodination reaction shown below with iodine to obtain the Compounds as shown in formula 02 can be;

In the iodination reaction, the organic solvent can be a conventional organic solvent in this type of reaction in the art, such as a halogenated alkane solvent (eg, dichloromethane).

In the iodination reaction, the ligand can be a conventional ligand in this type of reaction in the art, such as a phosphine ligand, preferably triphenylphosphine in the present invention.

In the iodination reaction, the alkaline reagent may be a conventional alkaline reagent in this type of reaction in the art, and in the present invention, it is preferably an organic base (eg, imidazole).

In the described iodination reaction, the amount of the organic solvent can be not specifically limited, as long as it does not affect the reaction; in the present invention, the compound shown in the formula 01 is compared with the mass volume of the organic solvent. Preferably, it is 0.01 g/mL to 0.2 g/mL (eg, 0.07 g/mL to 0.09 g/mL).

In the iodination reaction, the molar ratio of the iodine to the compound represented by the formula 01 may be 2.3:1-1.5:1, preferably 2.3:1-2:1 in the present invention.

In the iodination reaction, the molar ratio of the ligand to the compound represented by the formula 01 may be 2.3:1-1.5:1, preferably 2.3:1-2:1 in the present invention .

In the iodination reaction, the molar ratio of the alkaline reagent to the compound represented by the formula 01 may be 3:1 to 6:1, and preferably 4:1 to 6:1 in the present invention. 1.

The temperature of the iodination reaction is preferably room temperature (for example, 10°C to 30°C).

The progress of the iodination reaction can be monitored by conventional monitoring methods in the art (eg TLC or NMR), and generally the reaction end point is when the compound represented by formula 01 disappears or no longer reacts.

The preparation method of the compound shown in formula 02 can also include post-processing operations, and the post-processing operations include the following steps, the reaction system after the iodination reaction is washed, concentrated, and beaten with an organic solvent. , to obtain the compound shown in _{formula 02} ; the washing, concentrating, and beating can be conventional operations in the field _; The brine is washed separately; the beating can be conventional in the field to remove insolubles such as ligands; in the beating, the organic solvent can be a conventional organic solvent in this type of operation in the field, preferably It is a halogenated alkane solvent (such as dichloromethane) and/or an ether solvent (such as diethyl ether and/or methyl tert-butyl ether).

The preparation method of the compound shown in formula 02 may further include the following steps, after the post-processing operation as described above, preferably without purification, the compound shown in formula 02 is directly used for The alkylation reaction is performed to prepare the compound 03.

》制备得到。The compound shown in the formula 01 can refer to the document "Vitamin D3Metabolites I.Synthesisof 25hydroxycholesterol John J.Partridge Stephanie Faber Milan R.

"Prepared.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive improvement effects of the present invention are: the preparation method provided by the present invention has short reaction steps, high yield (the total yield of two steps can reach 80% to 91%), mild reaction conditions, cheap reagents, and low requirements for experimental equipment, Suitable for larger scale synthesis.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

In the following examples, the HPLC method:

Chromatographic column: Thermo C18 4.6*150mm

Injection volume: 15μL

Wavelength: 205nm

Column temperature: 30℃

Flow rate: 1mL/min

Mobile phase: A: methanol; B: 10% methanol in water; A:B=87:13.

Preparation of compound 02

Example 1

Dissolve 36.17 g of triphenylphosphine and 24.51 g of imidazole in 300 ml of dichloromethane, add 35.03 g of iodine, and after reacting for a period of time, dropwise add the dichloromethane solution of compound 01 (20.78 g of compound 01, 150 ml of dichloromethane), and react at room temperature . The TLC plate showed that the reaction was complete, and the raw materials were basically converted into compound 02; the reaction solution was washed with Na ₂ S ₂ O ₄ aqueous solution, pure water, and brine respectively, dried, filtered, and spin-dried to obtain an off-white solid, which was slurried with 150 ml of n-hexane. , the filtrate was spin-dried to obtain 29.9 g of crude compound 02, (compound 01: triphenylphosphine: imidazole: iodine=1:2.3:6:2.3; since the crude product contained triphenylphosphine, the material yield was 109.22%), no For further purification, it was directly put into the next reaction.

Example 2

Dissolve 131.05 g of triphenylphosphine and 68.08 g of imidazole in 1000 ml of dichloromethane, add 126.9 g of iodine, and after reacting for a period of time, add the dichloromethane solution of compound 01 dropwise (86.67 g of compound 01, 500 ml of dichloromethane), and react at room temperature . The TLC plate showed that the reaction was complete, and the raw materials were basically converted into compound 02; the reaction solution was washed with Na ₂ S ₂ O ₄ aqueous solution, pure water, and brine respectively, dried, filtered, and spin-dried to obtain an off-white solid, and the solid was slurried with 500 ml of n-hexane. , the filtrate was spin-dried to obtain 125.6 g of a crude product of compound 02, (compound 01: triphenylphosphine: imidazole: iodine=1:2:4:2; since the crude product contained triphenylphosphine, the material yield was 110.0%), no For further purification, it was directly put into the next reaction.

Example 3

Dissolve 23.59 g of triphenylphosphine and 12.25 g of imidazole in 300 ml of dichloromethane, add 22.84 g of iodine, and after reacting for a period of time, dropwise add the dichloromethane solution of compound 01 (20.78 g of compound 01, 150 ml of dichloromethane), and react at room temperature . The TLC plate showed that the raw materials remained. The reaction solution was washed with Na ₂ S ₂ O ₄ aqueous solution, pure water, and brine respectively, dried, filtered, and spin-dried to obtain an off-white solid. The solid was slurried with 150 ml of n-hexane, and the filtrate was spin-dried to obtain compound 02. Crude product 27.3g. (Compound 01: triphenylphosphine: imidazole: iodine = 1: 1.5: 3: 1.5; the crude product contains triphenylphosphine, the material yield is 99.73%), and it was directly put into the next reaction without further purification.

Preparation of compound 03

Example 4

8.17g of zinc powder, 5.94g of nickel chloride hexahydrate, 13.31ml of ethyl acrylate were suspended in 30ml of pyridine, heated to initiate (40°C ~ 70°C), cooled to room temperature and added dropwise to compound 02 (obtained in Example 2) 12.54g of the pyridine solution (compound 0212.54g (calculated according to 100% in the previous step, about 11.4g of compound 02), 15ml of pyridine), and stirred after completion of dropping. TLC plate showed that there were more raw materials remaining and a small amount of impurities. The reaction solution was filtered, and the filtrate was washed with 50ml EDTA solution (EDTA: 4g, NaHCO ₃ : 4g, H ₂ O: 50ml), brine, dried, filtered, spin-dried, column Chromatographic purification yielded about 8.47 g of an oil. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:5:5:1; two-step yield 78.76%)

MS: 453.34 [M+Na] ⁺ , 399.33 [M-CH ₃ O] ⁺ ; ¹ HNMR (400 MHz, CD ₃ Cl) δ: 4.01(2H,q), 3.41(3H,s), 3.04(1H,t ),2.35(2H,t),1.90(4H,m),1.60(8H,m),1.50(2H,m),1.38(6H,m),1.19(2H,m),1.07(7H,m) ,0.85(9H,m).

Example 5

8.17g of zinc powder, 5.94g of nickel chloride hexahydrate, 13.31ml of ethyl acrylate were suspended in 15ml of pyridine+15ml of tetrahydrofuran, heated to initiate (40 ° C ~ 70 ° C), cooled to room temperature and added dropwise to compound 02 (Example 2) mixed solution (compound 02 12.54g (calculated according to the 100% of the previous step, about compound 02 11.4g), pyridine 15ml, tetrahydrofuran 15ml), stir after completion of dropping. The TLC plate showed that there were more raw materials remaining, and the impurities were slightly more than that of Example 4. The reaction solution was filtered, and the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 7.92 g of an oily substance. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:5:5:1; two-step yield 73.65%)

Example 6

12.26g of zinc powder, 5.94g of nickel chloride hexahydrate, 13.31ml of ethyl acrylate were suspended in 30ml of pyridine, heated to initiate (40°C ~ 70°C), cooled to room temperature and added dropwise to compound 02 (obtained in Example 2) The pyridine solution (compound 0212.54g (calculated according to 100% of the previous step, about compound 0211.4g), pyridine 15ml), was stirred after the dropping. The TLC plate showed that a small amount of raw material remained, and the impurities were less than that of Example 4. The reaction solution was filtered, and the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 9.79 g of an oily substance. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:7.5:5:1; two-step yield 91.04%)

Example 7

98.09g of zinc powder, 47.54g of nickel chloride hexahydrate, and 159.69ml of ethyl acrylate were suspended in 300ml of pyridine, heated to initiate (40°C to 70°C), cooled to room temperature and added dropwise to compound 02 (obtained in Example 2) The pyridine solution (100.36 g of compound 02 (calculated according to the 100% of the previous step, about compound 0291.24 g), 100 ml of pyridine) was stirred after dropping. The TLC plate showed that the reaction of the raw materials was basically complete, with only trace impurities. The reaction solution was filtered, and the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 86.13 g of an oily substance. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:7.5:7.5:1; two-step yield 100.08%)

Example 8

24.52g of zinc powder, 11.88g of nickel chloride hexahydrate, 39.92ml of ethyl acrylate were suspended in 30ml of pyridine+30ml of tetrahydrofuran, heated to initiate (40℃～70℃), cooled to room temperature and added dropwise to compound 02 (Example 2) mixed solution (compound 02 25.08g (calculated according to the 100% of the previous step, about compound 02 22.8g), pyridine 15ml, tetrahydrofuran 15ml), stirred after the drop was completed. TLC plate showed that the reaction of the raw materials was basically complete, the reaction solution was filtered, the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 21.17 g of oil. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:7.5:7.5:1; two-step yield 98.45%)

Preparation of compound 04

Example 9

About 8.47 g of the oily substance of compound 03 obtained in Example 4 was dissolved in a mixed solvent of 80 ml of 1,4-dioxane and 80 ml of water, 0.34 g of p-toluenesulfonic acid monohydrate was added, and the mixture was heated to reflux (80 ℃～100 ℃). °C) reaction. TLC plate showed that the reaction was complete, extracted with EA, the organic layers were combined, the organic layers were washed with brine, dried, filtered, and spin-dried to obtain 7.29 g of a white solid with a yield of 89.0% (the single-step yield of 03 to prepare 04) (Compound 02 For 100% theoretical yield, the two-step yield is 70%; the HPLC purity is 96.5%).

Example 10

About 7.92 g of the oily compound 03 obtained in Example 5 was dissolved in a mixed solvent of 80 ml of 1,4-dioxane and 80 ml of water, 0.32 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated under reflux. TLC plate showed that the reaction was complete, extracted with EA, combined the organic layers, washed the organic layers with brine, dried, filtered, and spin-dried to obtain 6.73 g of white solid, yield 87.86% (the single-step yield of 03 to prepare 04) (with compound 02 is 100% theoretical yield, two-step yield is 65%; HPLC purity is 96.0%).

Example 11

About 9.79 g of the oily substance of compound 03 obtained in Example 6 was dissolved in a mixed solvent of 90 ml of 1,4-dioxane and 90 ml of water, 0.39 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated and refluxed. TLC plate showed that the reaction was complete, extract with EA, combine the organic layers, wash the organic layers with brine, dry, filter, and spin dry to obtain 8.57 g of white solid, yield 90.48% (the single-step yield of 03 to prepare 04) (with compound 02 is 100% theoretical yield, two-step yield is 82.4%; HPLC purity is 97.5%).

Example 12

About 86.13 g of the oily substance of compound 03 obtained in Example 7 was dissolved in a mixed solvent of 800 ml of 1,4-dioxane and 800 ml of water, 3.46 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated and refluxed. The TLC plate showed that the reaction was complete, extracted with EA, combined the organic layers, washed the organic layers with brine, dried, filtered, and spin-dried to obtain 75.74 g of white solid, the yield was 90.9% (the single-step yield of 03 to prepare 04) (compound 02 is 100% theoretical yield, two-step yield 90.9%; HPLC purity 99.1%).

Example 13

About 21.17 g of the oily substance of compound 03 obtained in Example 8 was dissolved in a mixed solvent of 180 ml of 1,4-dioxane and 180 ml of water, 0.83 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated and refluxed. TLC plate showed that the reaction was complete, extract with EA, combine the organic layers, wash the organic layers with brine, dry, filter, spin dry to obtain 18.48 g of white solid, yield 90.21% (the single-step yield of 03 to prepare 04) (compound 02 is 100% theoretical yield, the two-step yield is 88.8%; the HPLC purity is 98.7%).

Claims (10)

1. a preparation method of ethyl 24-cholenoate as shown in formula 04, is characterized in that, it comprises the steps: In step (1), in an organic solvent, in the presence of zinc, a catalyst and an alkaline reagent, the compound shown in formula 02 is subjected to the alkylation reaction shown below with ethyl acrylate to obtain a compound shown in formula 03. compound; In step (2), in water and an organic solvent, in the presence of an acidic reagent, the compound shown in formula 03 described in step (1) is subjected to the reaction shown below to obtain the compound shown in formula 04. Can;

2. preparation method as claimed in claim 1, is characterized in that, in described step (1), described organic solvent is pyridine solvent and/or cyclic ether solvent; And/or, in described step (1), described zinc is zinc powder; And/or, in described step (1), described catalyzer is nickel chloride hexahydrate; And/or, in the described step (1), the described alkaline reagent is an organic base; And/or, in described step (2), described organic solvent is cyclic ether solvent; And/or, in the step (2), the acid is p-toluenesulfonic acid and/or methanesulfonic acid. 3. preparation method as claimed in claim 2 is characterized in that, in described step (1), when described organic solvent is pyridine solvent, described pyridine solvent is pyridine; And/or, in the described step (1), when the organic solvent is a cyclic ether solvent, the cyclic ether solvent is tetrahydrofuran; And/or, in described step (1), when described basic reagent is organic base, described organic base is pyridine; And/or, in the step (2), when the organic solvent is a cyclic ether solvent, the cyclic ether solvent is dioxane and/or tetrahydrofuran. 4. The preparation method according to claim 1, wherein in the step (1), the mass volume ratio of the compound represented by the formula 02 to the organic solvent is 0.01 g/mL～ 1g/mL; And/or, in the step (1), the molar ratio of the zinc to the compound represented by the formula 02 is 5:1 to 10:1; And/or, in the step (1), the molar ratio of the catalyst to the compound represented by the formula 02 is 1:1 to 2:1; And/or, in the step (1), the molar ratio of the alkaline reagent to the compound represented by the formula 02 is 7.5:1 to 25:1; And/or, in the step (1), the molar ratio of the ethyl acrylate to the compound represented by the formula 02 is 5:1 to 10:1; And/or, in the step (1), the temperature of the alkylation reaction is 0°C to 80°C. 5. The preparation method according to claim 4, wherein in the step (1), the mass volume ratio of the compound represented by the formula 02 to the organic solvent is 0.25g/mL～ 0.4g/mL; And/or, in the step (1), the molar ratio of the zinc to the compound represented by the formula 02 is 6:1 to 8:1; preferably 7.5:1; And/or, in the described step (1), the mol ratio of the catalyst to the compound shown in the formula 02 is 1:1; And/or, in the described step (1), the molar ratio of the alkaline reagent to the compound shown in the formula 02 is 22:1; And/or, in the step (1), the molar ratio of the ethyl acrylate to the compound represented by the formula 02 is 6:1 to 8:1; preferably 7.5:1; And/or, in the step (1), the temperature of the alkylation reaction is 10°C to 70°C; And/or, in the described step (1), a post-treatment operation is also included, and the post-treatment operation includes the following steps, the reaction system after the alkylation reaction is filtered, washed, concentrated, column Chromatographic purification to obtain the compound shown in formula 03. 6. The preparation method of claim 1, wherein in the step (2), the volume ratio of the water to the organic solvent is 2:1 to 1:2; And/or, in the step (2), the mass volume ratio of the compound of formula 03 to the organic solvent is 0.01g/mL～0.5g/mL; And/or, in the step (2), the molar ratio of the acid to the compound represented by the formula 03 is 0.05:1 to 0.5:1; And/or, in the step (2), the temperature of the reaction is 80°C to 100°C. 7. preparation method as claimed in claim 6 is characterized in that, in described step (2), the volume ratio of described water and described organic solvent is 1:1; And/or, in the step (2), the mass volume ratio of the compound of formula 03 to the organic solvent is 0.09g/mL～0.12g/mL; And/or, in the step (2), the molar ratio of the acid to the compound represented by the formula 03 is 0.08:1 to 0.1:1; And/or, in the described step (2), it also includes post-processing operations, and the post-processing operations include the following steps, extracting, washing, and concentrating the reaction system after the reaction finishes to obtain the described The compound of formula 04. 8. The preparation method according to any one of claims 1 to 7, characterized in that, the preparation method further comprises the steps of: in an organic solvent, in the presence of an alkaline reagent and a ligand, formula The compound shown in 01 is subjected to the iodination reaction shown below with iodine to obtain the compound shown in the formula 02;

9. preparation method as claimed in claim 8, is characterized in that, in described iodination reaction, described organic solvent is halogenated alkanes solvent; And/or, in the iodination reaction, the ligand is a phosphine ligand; And/or, in the described iodination reaction, the described alkaline reagent is an organic base; And/or, in the iodination reaction, the mass volume ratio of the compound represented by the formula 01 to the organic solvent is 0.01g/mL～0.2g/mL; And/or, in the iodination reaction, the molar ratio of the iodine to the compound represented by the formula 01 is 2.3:1 to 1.5:1; And/or, in the iodination reaction, the molar ratio of the ligand to the compound represented by the formula 01 is 2.3:1 to 1.5:1; And/or, in the iodination reaction, the molar ratio of the basic reagent to the compound represented by the formula 01 is 3:1 to 6:1; And/or, the temperature of the iodination reaction is 10℃～30℃; And/or, the preparation method also includes a post-processing operation, and the post-processing operation includes the following steps: washing the reaction system after the iodination reaction is finished, concentrating, and beating in an organic solvent to obtain the The compound of formula 02. 10. preparation method as claimed in claim 9 is characterized in that, in described iodination reaction, when described organic solvent is halogenated alkanes solvent, described halogenated alkanes solvent is dichloromethane; And/or, in the iodination reaction, when the ligand is a phosphine ligand, the phosphine ligand is triphenylphosphine; And/or, in the described iodination reaction, when the described alkaline reagent is an organic base, the described organic base is imidazole; And/or, in the iodination reaction, the mass volume ratio of the compound represented by the formula 01 to the organic solvent is 0.07g/mL～0.09g/mL; And/or, in the iodination reaction, the molar ratio of the iodine to the compound represented by the formula 01 is 2.3:1 to 2:1; And/or, in the iodination reaction, the molar ratio of the ligand to the compound represented by the formula 01 is 2.3:1 to 2:1; And/or, in the iodination reaction, the molar ratio of the basic reagent to the compound represented by the formula 01 is 4:1 to 6:1; And/or, the preparation method further includes the following steps: after the post-treatment operation, the compound shown in formula 02 is directly used in the alkylation reaction to prepare the compound 03.