Process for the preparation of the drug centhaquine for the treatment of hemorrhagic shock
By simplifying the synthetic route of Centhaquine, compound I reacts with dibromoethane to obtain compound II, compound III reacts with pinacol diboronate to obtain compound IV, and finally Centhaquine is synthesized under the action of a catalyst and a base. This solves the problems of complex synthesis and low yield in the existing technology and realizes efficient and high-purity industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
- Filing Date
- 2020-12-25
- Publication Date
- 2026-06-09
AI Technical Summary
Existing methods for synthesizing Centhaquine are complex, have long reaction times, and low overall yields, making them unsuitable for industrial production.
Compound II was prepared by reacting compound I with dibromoethane under alkaline conditions, and compound IV was prepared by reacting compound III with pinacol diboron under Grignard reagent. Subsequently, compound II was reacted with compound IV under the action of a catalyst and a base to prepare centhaquine, which simplified the synthetic route and improved the yield.
It achieves the preparation of high-purity (over 99.5%) Centhaquine with a yield of over 80%, is simple to operate, suitable for industrial production, and avoids complex post-processing steps such as chromatographic separation.
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Figure CN114685366B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing Centhaquine, a drug for treating hemorrhagic shock. Background Technology
[0002] Centhaquine, developed by Pharmazz, was approved for marketing in India on May 14, 2020, for the treatment of hemorrhagic shock. Its brand name is [Brand Name Missing]. Currently, this drug is in Phase I clinical trials for the treatment of postoperative pain and cardiac arrest. Centhaquine increases venous blood return by stimulating α-adrenergic receptor 2B, thereby increasing blood pressure and cardiac output; it also promotes arterial dilation and increases tissue perfusion by inhibiting α-adrenergic receptor 1. Clinical studies have shown that treatment with Centhaquine can significantly reduce mortality and blood lactate levels, and increase mean arterial pressure, blood pressure, and cardiac output; its structure is shown below:
[0003]
[0004] The method for synthesizing Centhaquine reported in existing patent WO2014 / 35446A1 is as follows:
[0005]
[0006] Its synthetic route is complex, requires a long reaction time, and the product needs to be analyzed by column chromatography. The overall yield is also low, making it unsuitable for industrialization.
[0007] In summary, there is an urgent need in this field to develop a new method for preparing Centhaquine that is simple to process, has a short number of steps, is easy to operate, has a high overall yield, and is suitable for industrial production. Summary of the Invention
[0008] The purpose of this invention is to provide a new method for preparing Centhaquine that is simple to process, has a short number of steps, is easy to operate, has a high overall yield, and is suitable for industrial production.
[0009] In a first aspect of the invention, a method for preparing Centhaquine as shown in Formula A is provided, comprising the steps of:
[0010]
[0011] (S1) provides compounds II and IV; wherein
[0012] Compound II is prepared by the following method, which includes the following steps:
[0013] (A) In a first solvent, in the presence of base 1, compound I is reacted with 1,2-dibromoethane to give compound II;
[0014] Compound IV is prepared by the following method, which includes the following steps:
[0015] (B) In a second solvent, in the presence of a Grignard reagent, compound III is reacted with pinacol diboronate to obtain compound IV;
[0016] Preparation of compound (S2) A: Compound II and compound IV are reacted in a third solvent in the presence of a catalyst and base 2 to obtain Centhaquine.
[0017] In another preferred embodiment, in step (A), the base 1 is selected from the group consisting of triethylamine, pyridine, piperidine, sodium ethoxide, or combinations thereof; preferably, it is triethylamine.
[0018] In another preferred embodiment, in step (A), the first solvent is selected from the group consisting of halogenated hydrocarbon solvents, ether solvents, aromatic solvents, nitrile solvents, or combinations thereof; preferably, it is an ether solvent.
[0019] In another preferred embodiment, the halogenated hydrocarbon solvent includes dichloromethane; and / or the ether solvent includes tetrahydrofuran; and / or the aromatic solvent includes toluene; and / or the nitrile solvent includes acetonitrile.
[0020] In another preferred embodiment, in step (A), the first solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, acetonitrile, or combinations thereof; preferably, it is tetrahydrofuran.
[0021] In another preferred embodiment, in step (A), the mass-to-volume (g:mL) ratio of compound I to the first solvent is 1:5-20; more preferably, it is 1:8-12; and even more preferably, it is 1:10±1.
[0022] In another preferred embodiment, in step (A), the molar ratio of compound I to the base is 1:(0.5-5); more preferably, 1:(1-5); even more preferably, 1:(1-3); and most preferably, 1:(1.5-3).
[0023] In another preferred embodiment, in step (A), the molar ratio of compound I to 1,2-dibromoethane is 1:(0.5-2); more preferably, 1:(0.8-1.2); and even more preferably, 1:(0.9-1.1).
[0024] In another preferred embodiment, in step (A), the reaction temperature is 0–50°C; more preferably, 15–30°C.
[0025] In another preferred embodiment, in step (A), the reaction temperature is room temperature.
[0026] In another preferred embodiment, in step (A), the reaction time is 1 to 30 hours; more preferably, 3 to 10 hours; and even more preferably, 4 to 8 hours.
[0027] In another preferred embodiment, step (A) further includes a post-processing step for separating and / or purifying compound II.
[0028] In another preferred embodiment, step (A) includes: solvent removal, extraction and separation, and concentration.
[0029] In another preferred embodiment, compound II is prepared by a method comprising the steps of:
[0030] (A1) In a first solvent, in the presence of base 1, compound I is reacted with 1,2-dibromoethane to obtain a mixed system containing compound II; and
[0031] (A2) The mixture containing compound II is post-processed to obtain compound II.
[0032] In another preferred embodiment, in step (B), the format reagent is selected from the group consisting of methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium chloride, or combinations thereof; preferably, it is isopropyl magnesium chloride.
[0033] In another preferred embodiment, in step (B), the second solvent is selected from the group consisting of halogenated hydrocarbon solvents, ether solvents, aromatic solvents, nitrile solvents, or combinations thereof; preferably, it is an ether solvent.
[0034] In another preferred embodiment, the halogenated hydrocarbon solvent includes dichloromethane; and / or the ether solvent includes tetrahydrofuran; and / or the aromatic solvent includes toluene; and / or the nitrile solvent includes acetonitrile.
[0035] In another preferred embodiment, in step (B), the second solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, acetonitrile, or combinations thereof, preferably tetrahydrofuran.
[0036] In another preferred embodiment, in step (B), the mass-to-volume (g:mL) ratio of compound III to the second solvent is 1:(3-40); more preferably, it is 1:(4-30); and even more preferably, it is 1:(5-20).
[0037] In another preferred embodiment, in step (B), the molar ratio of compound III to Grignard reagent is 1:(1.3-2.5); more preferably, 1:(1.5-2.0); and even more preferably, 1:1.6±0.1.
[0038] In another preferred embodiment, in step (B), the molar ratio of compound III to pinacol diboronate is 1:(0.8 to 2.3); more preferably, it is 1:1 ± 0.1.
[0039] In another preferred embodiment, in step (B), the reaction temperature is 0–50°C; more preferably, 20–30°C.
[0040] In another preferred embodiment, in step (B), the reaction time is 1 to 50 hours; more preferably, 5 to 20 hours; and even more preferably, 7 to 11 hours.
[0041] In another preferred embodiment, step (B) further includes a post-processing step for separating and / or purifying compound IV.
[0042] In another preferred embodiment, step (B) includes the post-processing step of extraction and concentration.
[0043] In another preferred embodiment, compound II is prepared by a method comprising the steps of:
[0044] (B1) In a second solvent, in the presence of a Grignard reagent, compound III is reacted with pinacol diborate to obtain a mixed system containing compound IV; and
[0045] (B2) The mixture containing compound IV is post-processed to obtain compound IV.
[0046] In another preferred embodiment, in step (S2), the catalyst is a palladium catalyst; preferably, it is selected from the group consisting of palladium on carbon, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, ferrocene palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2), or combinations thereof; preferably, it is [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.
[0047] In another preferred embodiment, in step (S2), the base 2 is a carbonate; preferably, it is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, or combinations thereof; preferably, it is potassium carbonate.
[0048] In another preferred embodiment, in step (S2), the third solvent is a mixed solvent composed of water and an organic solvent selected from the group consisting of halogenated hydrocarbon solvents, ether solvents, aromatic solvents, nitrile solvents, or combinations thereof; preferably, it is a mixed solvent composed of water and an aromatic solvent.
[0049] In another preferred embodiment, the halogenated hydrocarbon solvent includes dichloromethane; and / or the ether solvent includes tetrahydrofuran; and / or the aromatic solvent includes toluene; and / or the nitrile solvent includes acetonitrile.
[0050] In another preferred embodiment, in step (S2), the third solvent is a mixed solvent consisting of water and an aromatic solvent (preferably toluene).
[0051] In another preferred embodiment, the water content in the third solvent is 20 to 50% by volume (more preferably 30 to 40% by volume), based on the total volume of the third solvent.
[0052] In another preferred embodiment, in step (S2), the molar ratio of compound IV to compound II is 1:(1.1-1.5); more preferably, it is 1:1.2±0.1.
[0053] In another preferred embodiment, in step (S2), the mass ratio of compound IV to catalyst is 1:(0.01 to 0.05); more preferably, it is 1:(0.02 to 0.03).
[0054] In another preferred embodiment, in step (S2), the molar ratio of compound IV to base 2 is 1:(1.5-4); more preferably, it is 1:3±0.5.
[0055] In another preferred embodiment, a phase transfer catalyst is also present in step (S2).
[0056] In another preferred embodiment, in step (S2), the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide.
[0057] In another preferred embodiment, in step (S2), the reaction is carried out in the presence of a catalyst, base 2, and optionally a phase transfer catalyst.
[0058] In another preferred embodiment, in step (S2), the mass ratio of compound IV to the phase transfer catalyst is 1:(0.005-0.03); more preferably, it is 1:(0.01-0.02).
[0059] In another preferred embodiment, in step (S2), the mass-to-volume ratio (g:mL) of compound II to the third solvent is 1:(5-13); more preferably, it is 1:(7-12).
[0060] In another preferred embodiment, in step (S2), the reaction temperature is 0–100°C; more preferably, 50–90°C; and even more preferably, 60–80°C.
[0061] In another preferred embodiment, in step (S2), the reaction time is 1 to 30 hours, more preferably 3 to 10 hours; and even more preferably 3 to 7 hours.
[0062] In another preferred embodiment, step (S2) further includes a post-processing step for isolating and / or purifying Centhaquine.
[0063] In another preferred embodiment, in step (S2), the post-processing does not include separation by chromatography and / or column chromatography.
[0064] In another preferred embodiment, step (S2) includes: separating the organic phase, optionally adding another organic solvent (preferably n-hexane), filtering, and concentrating.
[0065] In another preferred embodiment, compound II is prepared by a method comprising the steps of:
[0066] (S2.1) In a second solvent, in the presence of a Grignard reagent, compound III is reacted with pinacol diborate to obtain a mixed system containing compound IV; and
[0067] (S2.2) The mixture containing compound IV is post-processed to obtain compound IV.
[0068] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation
[0069] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have developed a novel method for preparing Centhaquine, a drug for treating hemorrhagic shock. Specifically, this method provides a novel route for reacting compound II (obtained by reacting compound I with dibromoethane under alkaline conditions) and compound IV (obtained by reacting compound III with pinacol diboron ester under Grignard reagents) as reactants, under the action of a catalyst and a base, to yield Centhaquine. In this route, the yield of each reaction step is higher than 80%, and the final product, Centhaquine, achieves a purity of over 99.5% without requiring complex processing such as chromatographic separation. Furthermore, the preparation method of this invention is simple and safe, operates under mild conditions, uses readily available raw materials, requires simple post-processing, and has a high yield, making it suitable for industrial production.
[0070] the term
[0071] Unless otherwise stated, the terms or abbreviations used herein have their conventional meanings well known to those skilled in the art. For example, "wt%" means weight percentage.
[0072] Preparation method of Centhaquine
[0073] To address the shortcomings of existing technologies, this invention provides a novel method for preparing Centhaquine, a drug used to treat hemorrhagic shock. This method involves reacting compound I with dibromoethane under alkaline conditions to yield compound II, and then reacting compound III with pinacol terpenoid under Grignard reagent conditions to yield compound IV. Subsequently, compound IV reacts with compound II under the action of a catalyst and an alkaline environment to prepare Centhaquine. The preparation method of this invention features a simple and safe synthetic route and operation, readily available raw materials, simple post-processing, and high yield, making it suitable for industrial production. The synthetic route provided by this invention is as follows:
[0074]
[0075] In one specific embodiment, the preparation method provided by the present invention includes the following steps:
[0076] (S1) Preparation of compounds II and IV
[0077] (A) Preparation of Compound II
[0078] Dissolve compound I in a solvent, add a base, add 1,2-dibromoethane, and after the addition is complete, proceed with the reaction (e.g., by stirring at room temperature), and optionally post-treat to obtain compound II;
[0079] (B) Preparation of Compound IV
[0080] Dissolve compound III in a second solvent, add Grignard reagent, and dropwise add a solution of pinacol diboronate (CAS No.: 73183-34-3). After the addition is complete, proceed with the reaction (e.g., stirring at room temperature). Optionally, post-treatment is performed to obtain compound IV.
[0081] (S2) Preparation of Centhaquine
[0082] Compound II, compound IV and optional phase transfer catalyst are dissolved in a third solvent, a catalyst and a base are added, the reaction is carried out by heating, and optional post-treatment is performed to obtain compound IV;
[0083] There is no particular order requirement for steps (A) and (B). Steps (A) and (B) can be performed in any order, such as simultaneously, or step (A) can be performed first and then step (B), or step (B) can be performed first and then step (A).
[0084] In another preferred embodiment, the post-processing steps do not include chromatographic separation or column chromatography separation.
[0085] In another preferred embodiment, in step (A), the solvent is anhydrous dichloromethane, anhydrous tetrahydrofuran, toluene, acetonitrile, or a combination thereof, preferably anhydrous tetrahydrofuran.
[0086] In another preferred embodiment, in step (A), the volume ratio of compound I to solvent is 1:5-20; more preferably, 1:8-12; and even more preferably, 1:10.
[0087] In another preferred embodiment, in step (A), the base is one or more of triethylamine, pyridine, piperidine, sodium ethoxide, etc., preferably triethylamine.
[0088] In another preferred embodiment, in step (B), the solvent is anhydrous dichloromethane, anhydrous tetrahydrofuran, toluene, acetonitrile, or a combination thereof, preferably anhydrous tetrahydrofuran.
[0089] In another preferred embodiment, in step (B), the volume ratio of compound III to solvent is 1:3-16; more preferably, 1:4-7; and even more preferably, 1:5.
[0090] In another preferred embodiment, in step (B), the grammatical reagent may be one of methyl magnesium chloride, ethyl magnesium chloride, and isopropyl magnesium chloride, preferably isopropyl magnesium chloride.
[0091] In another preferred embodiment, in step (B), the molar ratio of compound III to Grignard reagent is 1:1.3-2.5; more preferably, 1:1.5-2.0; and even more preferably, 1:1.6.
[0092] In another preferred embodiment, in step (B), the molar ratio of compound III to pinacol diboronate is 1:0.8-1.3; more preferably, 1:1.0.
[0093] In another preferred embodiment, in step (S2), the solvent is a combination of one or more of water and anhydrous dichloromethane, anhydrous tetrahydrofuran, toluene, and acetonitrile (preferably toluene).
[0094] In another preferred embodiment, in step (S2), the volume ratio of compound II to solvent is 1:5-13; more preferably, 1:10.
[0095] In another preferred embodiment, in step (S2), the molar ratio of compound IV to compound II is 1:1.1-1.5; more preferably, 1:1.2.
[0096] In another preferred embodiment, in step (S2), the catalyst is one or more of palladium on carbon, palladium acetate, tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, ferrocene palladium dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2), preferably [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.
[0097] In another preferred embodiment, in step (S2), the mass ratio of compound IV to catalyst is 1:0.01-0.05; more preferably, 1:0.02-0.03.
[0098] In another preferred embodiment, in step (S2), the alkali is one or more of potassium carbonate, sodium carbonate, and cesium carbonate, preferably potassium carbonate.
[0099] In another preferred embodiment, in step (S2), the molar ratio of compound IV to base is 1:1.5-4; more preferably, 1:3.
[0100] The main advantages of this invention include:
[0101] (a) The method for preparing Centhaquine provided by this invention has a simple route, readily available raw materials, simple operation, and high total yield, making it suitable for industrial production.
[0102] (b) The preparation method provided by the present invention can obtain a high-purity product (e.g., above 99.6%) without complicated post-processing steps (e.g., column chromatography purification).
[0103] (c) The preparation method provided by the present invention has a high yield, and the single-step reaction yield for preparing Centhaquine can reach more than 80%.
[0104] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.
[0105] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.
[0106] Example 1: Synthesis of Compound II
[0107]
[0108] Compound I (10.0 g, 0.0567 mol) was dissolved in anhydrous tetrahydrofuran (100 mL) under stirring and nitrogen protection. Triethylamine (11.5 g, 0.1134 mol) was added, and the mixture was cooled to 0 °C. Dibromoethane (9.7 g, 0.05155 mol) was added dropwise, and the mixture was heated to room temperature for 6 hours after the addition was complete. The liquid was evaporated to dryness, and 100 mL of ethyl acetate and 100 mL of water were added. The mixture was separated, the organic phase was washed with water, dried, and concentrated to give 12.2 g of compound II. Yield: 83.5% (based on compound I). MS (ESI): [M+1] + =284.23.
[0109] Example 2 Synthesis of Compound IV
[0110]
[0111] Compound III (10.0 g, 0.0481 mol) was dissolved in tetrahydrofuran (50 mL) and stirred. The mixture was cooled to below -10 °C, and a tetrahydrofuran solution of 2N isopropyl magnesium chloride (38.4 mL, 0.0770 mol) was added dropwise. After the addition was complete, the temperature was raised to 20 °C, and a 100 mL tetrahydrofuran solution of pinacol diboronate (12.2 g, 0.0481 mol) was added dropwise, maintaining the temperature between 20 °C and 30 °C. The reaction was carried out at room temperature for 9 hours after the addition was complete. 500 mL of ethyl acetate and 500 mL of water were added, and the mixture was stirred for 2 hours. The mixture was separated, dried, and concentrated to give 10.4 g of compound IV. Yield: 84.5% (based on compound III). MS (ESI): [M+1] + =256.26.
[0112] Example 3: Synthesis of compound Centhaquine
[0113]
[0114] Compound II (10 g, 0.0353 mol), compound IV (7.5 g, 0.0294 mol, 1 equivalent), and tetrabutylammonium bromide (0.08 g, 1 wt%, based on the mass of compound IV) were dissolved in 75 mL of toluene and stirred. Nitrogen was used to purge the solution. Potassium carbonate (12.2 g, 0.0882 mol), water (40 mL), and Pd(dppf)Cl2 (0.15 g, 2 wt%, based on the mass of compound IV) were added sequentially. The mixture was heated to 70°C and reacted for 5 hours. The temperature was lowered to 25°C, the aqueous phase was removed, and 40 mL of n-hexane was added. The mixture was stirred for 1 hour, filtered through a diatomaceous earth filter, and concentrated to give 7.9 g (yield: 81.0%, based on compound IV), purity: 99.64%). MS (ESI): [M+1] + =332.51.
[0115] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.
Claims
1. A method for preparing Centhaquine as shown in Formula A, characterized in that, Including the following steps: (S1) provides compounds II and IV; wherein Compound II is prepared by the following method, which includes the following steps: (A) In a first solvent, in the presence of base 1, compound I is reacted with 1,2-dibromoethane to give compound II; in, The first solvent is an ether solvent; The base 1 is triethylamine; The molar ratio of compound I to the base is 1:(1.5~3); The molar ratio of compound I to 1,2-dibromoethane is 1:(0.8~1.2); The reaction temperature is 0~50℃; and The reaction time is 4-8 hours; Furthermore, step (A) also includes a post-processing step for the separation and / or purification of compound II, the post-processing step including: solvent removal, extraction and separation, and concentration; Compound IV is prepared by the following method, which includes the following steps: (B) In a second solvent, in the presence of a Grignard reagent, compound III is reacted with pinacol diboronic acid to obtain compound IV; in, The second solvent is an ether solvent; The Grignard reagent is isopropyl magnesium chloride; The molar ratio of compound III to Grignard reagent is 1:(1.5-2.0); The molar ratio of compound III to pinacol diboronic acid ester is 1: (0.8~2.3); The reaction temperature is 0~50℃; and The reaction time is 7-11 hours; Furthermore, step (B) also includes a post-processing step for the separation and / or purification of compound IV, the post-processing step including: extraction and concentration; Preparation of compound (S2) A: Compound II and compound IV are reacted in a third solvent in the presence of a catalyst, base 2 and a phase transfer catalyst to obtain Centhaquine; in, The third solvent is a mixed solvent composed of water and aromatic solvents; The catalyst is palladium, specifically [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. The phase transfer catalyst comprises tetrabutylammonium bromide; The alkali 2 is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, or combinations thereof; The molar ratio of compound IV to compound II is 1:(1.1-1.5); The mass ratio of compound IV to the catalyst is 1:(0.01~0.05); The molar ratio of compound IV to base 2 is 1:(1.5-4); The reaction time is 3 to 7 hours; The mass ratio of compound IV to the phase transfer catalyst is 1:(0.005~0.03); and step (S2) further includes a post-treatment step for the separation and / or purification of Centhaquine, the post-treatment step including: separating the organic phase, optionally adding another organic solvent, filtering and concentrating.
2. The preparation method according to claim 1, characterized in that, In step (A), the molar ratio of compound I to 1,2-dibromoethane is 1:(0.9~1.1).
3. The preparation method according to claim 1, characterized in that, In step (B), the molar ratio of compound III to Grignard reagent is 1:1.6±0.
1.
4. The preparation method according to claim 1, characterized in that, In step (B), the molar ratio of compound III to pinacol diboronic acid ester is 1:1 ±0.
1.
5. The preparation method according to claim 1, characterized in that, In step (S2), the alkali 2 is potassium carbonate.
6. The preparation method according to claim 1, characterized in that, In step (S2), the molar ratio of compound IV to compound II is 1:1.2±0.
1.
7. The preparation method according to claim 6, characterized in that, In step (S2), the mass ratio of compound IV to catalyst is 1: (0.02~0.03).
8. The preparation method according to claim 7, characterized in that, In step (S2), the molar ratio of compound IV to base 2 is 1:3±0.
5.
9. The preparation method according to claim 1, characterized in that, The preparation method described herein has one or more of the following characteristics: (i) In step (A), the first solvent is tetrahydrofuran; (ii) In step (B), the second solvent is tetrahydrofuran; (iii) In step (S2), the third solvent is a mixed solvent composed of water and toluene; (iv) In step (A), the reaction temperature is 15~30°C; (v) In step (B), the reaction temperature is 20~30℃; (vi) In step (S2), the reaction temperature is 60~80℃.
10. The preparation method according to claim 1, characterized in that, In step (S2), the post-processing does not include column chromatography separation.