Preparation method of androgen receptor N-terminal structural domain inhibitor Raaniten triacetate and intermediate Raaniten thereof

Abstract

The invention discloses a synthetic method of an androgen receptor N-terminal domain (AR NTD) inhibitor, namely, Raaniten triacetate (EPI-506), and relates to a synthetic method of the Raaniten triacetate (EPI-506). The preparation method comprises the following steps: firstly, preparing high-purity bisphenol A disodium salt by taking bisphenol A as an initial raw material; the preparation method comprises the following steps: reacting bisphenol A disodium salt with (R)-p-toluenesulfonic acid-2, 2-dimethyl-1, 3-dioxolanyl-4-methyl ester and (R)-p-toluenesulfonic acid glycidyl ester in sequence, and carrying out catalytic reflux ring opening to obtain an intermediate Raanite (EPI-002); and reacting the intermediate with acetyl chloride, triethylamine and 4-dimethylaminopyridine to obtain a target product EPI-506. The synthesis method disclosed by the invention is simple in process, mild in operation condition and relatively high in yield, and provides reliable technical support for preclinical research, process amplification and industrial application of the EPI-506.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing Ralanitentriacetate, an inhibitor of the N-terminal domain of the androgen receptor, and particularly to a synthetic process and method for Ralaniten triacetate, an inhibitor targeting the N-terminal domain (AR NTD) of the androgen receptor, and its key synthetic intermediate Ralaniten. Background Technology

[0002] The development and progression of prostate cancer are highly dependent on the androgen receptor (AR)-mediated signaling pathway. AR belongs to the nuclear receptor superfamily and is structurally composed of multiple functional regions, among which the ligand binding domain (LBD) is the primary target for current clinical anti-androgen therapy. Among currently used drugs, enzalutamide, as a typical AR-LBD antagonist, competitively binds to androgens with LBD, thereby blocking AR activation and downstream gene transcription, significantly delaying prostate cancer progression. It has been widely used to treat advanced pathological types such as metastatic castration-resistant prostate cancer (mCRPC).

[0003] However, with prolonged treatment, some patients develop resistance to enzalutamide and other LBD-targeting drugs. This is primarily due to structural variations in the AR domain, especially splice variants including AR-V7. These variants lack the LBD region but retain transcriptional activity, leading to the ineffectiveness of traditional LBD-targeting drugs. Therefore, there is an urgent need to develop innovative treatment strategies targeting other AR domains to overcome the resistance bottleneck of existing drugs.

[0004] Against this backdrop, the N-terminal domain (NTD) of the androgen receptor, due to its high conservation and crucial role in AR transcriptional activation, has become an important target for next-generation anti-AR therapies. Ralaniten (also known as EPI-002) is a first-in-class small-molecule AR-NTD inhibitor with good oral activity, effectively blocking the interaction between AR NTD and transcriptional coactivators (such as VAV3 and FOXA1), thereby inhibiting the AR signaling pathway. Ralanitentriacetate (EPI-506) is its prodrug, which significantly improves intestinal absorption through triacetate modification. Upon hydrolysis in vivo, it releases the active ingredient Ralaniten, effectively enhancing its bioavailability. Both exhibit inhibitory activity against full-length AR (AR-FL) and clinically resistant AR-V7 variants, representing a new direction for AR-NTD targeted therapy.

[0005] Although ralaniten triacetate, as the first AR-NTD inhibitor to enter clinical trials, showed some efficacy, it did not achieve the desired reduction in prostate-specific antigen (PSA) in Phase I clinical trials and exhibited dose-limiting toxicities (such as nausea and vomiting), hindering its clinical progress. Therefore, research on structural optimization and more efficient synthetic methods for this class of compounds has become a hot topic in current drug development.

[0006] Currently, numerous domestic and international publications and patents disclose methods for synthesizing Ralaniten and its prodrugs. Typical processes, such as those described in international patent WO2014179867 A1 and US patent US20130045204 A1, typically use bisphenol A as the starting material. Under nitrogen protection, a strong base (such as NaH) and a polar solvent (such as DMF) are introduced sequentially to perform nucleophilic substitution reactions with (R)-(+)-3-chloro-1,2-propanediol acetal acetone and (R)-p-toluenesulfonic acid glycidyl ester. After separation and purification, the mixture is refluxed in acetonitrile under CeCl3·7H2O catalysis for ring-opening, and the target intermediate Ralaniten (EPI-002) is obtained by preparative liquid chromatography. Subsequently, this intermediate reacts with acetic anhydride in anhydrous pyridine under DMAP catalysis to complete triacetate esterification, preparing the prodrug Ralaniten triacetate (EPI-506). The synthetic route is shown below:

[0007]

[0008] Although the above synthesis method is feasible under laboratory conditions, it still has many shortcomings, including: 1. The synthesis steps are cumbersome, requiring multiple separation and purification processes, resulting in a long process flow and complex operation; 2. The reaction conditions are harsh, requiring nitrogen protection and a strictly anhydrous environment, and the experiment has high requirements; 3. The use of pyridine, a solvent with a high boiling point, a strong pungent odor, and difficulty in removal, increases the difficulty of post-processing and environmental safety risks; 4. The overall yield is low, which is not conducive to laboratory scale-up or industrial production; 5. The reaction takes a long time, which increases the preparation cycle and cost.

[0009] Therefore, there is an urgent need to develop a green, simple, and controllable new process for the synthesis of Ralaniten triacetate. This process should be environmentally friendly, low-cost, have mild reaction conditions, and achieve high yields to promote further clinical research and application of this innovative drug. Summary of the Invention

[0010] Currently, Ralaniten and its triacetate prodrug Ralaniten triacetate, as novel small molecule drugs targeting the N-terminal domain of the androgen receptor, have shown unique advantages in overcoming resistance to LBD-targeted anti-androgen drugs. However, existing synthetic processes still face many challenges, such as harsh reaction conditions, cumbersome operation steps, low yields, and high synthesis difficulty. Furthermore, some key reactions rely on highly toxic reagents and complex separation methods, which are not conducive to large-scale laboratory preparation and subsequent industrialization.

[0011] Therefore, this invention aims to provide a synthetic method for Ralanitentriacetate, an inhibitor of the N-terminal domain of the androgen receptor. This method, through rational optimization of raw material selection, reaction conditions, and catalytic system, establishes a synthetic route that is simple in procedure, has good yield, is environmentally friendly, and has promising application prospects. It improves the reaction yield of the target product and provides technical support for subsequent efficacy evaluation, clinical development, and commercial production.

[0012] The synthetic process of Ralaniten triacetate constructed in this invention mainly includes the following three key steps: Step 1: Preparation of disodium bisphenol A In a reaction flask equipped with a condenser and a water separator, bisphenol A, sodium hydroxide, and deionized water are added. After heating and stirring to dissolve, organic solvent I is added dropwise. The mixture is then reacted under reflux for 4-5 hours, achieving dehydration of the system through a water-organic solvent azeotropic reaction. After the reaction is complete, the organic solvent is removed by rotary evaporation to obtain a white solid of disodium bisphenol A, which serves as a raw material for subsequent reactions.

[0013] Step 2: Synthesis of intermediate Ralaniten

[0014] The obtained disodium bisphenol A was dissolved in organic solvent II and heated to 70–80°C. (R)-2,2-dimethyl-1,3-dioxolane-4-methyl methyl ester was added stepwise to initiate the first step of nucleophilic substitution, lasting 24–48 hours. After monitoring the reaction progress by TLC, (R)-glycidyl toluenesulfonic acid and a basic catalyst were added to initiate the second step of nucleophilic substitution, lasting 12–16 hours. After the reaction was complete, the inorganic salt was removed by filtration, and the resulting diether compound was post-processed. Next, the diether compound was dissolved in acetonitrile, and cerium chloride heptahydrate was added. An epoxy ring-opening reaction was carried out under reflux for 8–12 hours to generate the intermediate Ralaniten.

[0015] Step 3: Synthesis of the target product Ralaniten triacetate

[0016] The intermediate Ralaniten was dissolved in organic solvent III, and an acid-binding agent (triethylamine or N,N-diisopropylethylamine) and catalyst 4-dimethylaminopyridine (DMAP) and acetyl chloride were added. The mixture was stirred at room temperature for 2–3 hours to carry out the acetylation reaction. After the reaction was completed, the solvent was evaporated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate) to finally obtain the target product Ralaniten triacetate.

[0017] The synthetic process route of this invention is as follows:

[0018]

[0019]

[0020] As one of the preferred technical solutions for the synthesis process of Ralaniten triacetate, in step one, the molar ratio of bisphenol A to sodium hydroxide is 1:2-2.01. The volume ratio of organic solvent I to deionized water is 1:1; wherein organic solvent I is toluene or cyclohexane.

[0021] As one of the preferred technical solutions for the synthesis process of the above-mentioned Ralaniten triacetate, in step two, the molar ratio of bisphenol A disodium salt, (R) p-toluenesulfonic acid-2,2-dimethyl-1,3-dioxolanecycloyl-4-methyl ester, and (R)-p-toluenesulfonic acid glycidyl ester is 1:0.9-1:0.8-1.

[0022] Preferably, the alkaline catalyst comprises potassium carbonate and cesium carbonate. The molar ratio of the alkaline catalyst to disodium bisphenol A is 0.5-1.05:1.

[0023] Preferably, the organic solvent II is N,N-dimethylformamide or N-methylpyrrolidone.

[0024] Preferably, in step two, the amount of CeCl3·7H2O is added according to the amount of disodium bisphenol A, wherein the molar ratio of CeCl3·7H2O to disodium bisphenol A is 0.99-1.01:1.

[0025] As one of the preferred technical solutions for the synthesis process of the above-mentioned Ralaniten triacetate, in step three, the organic solvent III is dichloromethane or N,N-dimethylformamide.

[0026] Preferably, the acid-binding agent is triethylamine or N,N-diisopropylethylamine, and the molar ratio of the acid-binding agent, acetyl chloride, and catalyst DMAP is 1:2:2.4-2.6.

[0027] Preferably, the molar ratio of acetyl chloride to ralaniten used in the esterification reaction in step three is 5:1, and the reaction is carried out at room temperature (20–25°C).

[0028] The purity of the target product, Ralaniten triacetate, is not less than 98.0%.

[0029] Overall, this process, through optimization of the reaction pathway, improves the overall synthesis efficiency while maintaining high reaction selectivity. It is suitable for scale-up from laboratory trials to pilot-scale production and has good scalability and industrialization potential.

[0030] This invention, based on comprehensive considerations of reaction safety, environmental friendliness, ease of operation, and scalability, develops a green synthesis process suitable for Ralaniten triacetate. Compared to existing technologies, it has the following advantages: 1. High integration of processes and simple flow: The overall synthesis route adopts a series design, integrating multiple reactions into a one-pot process, reducing the separation and purification of intermediates, reducing operating costs and time consumption, and improving synthesis efficiency.

[0031] 2. Mild reaction conditions and significantly improved safety: This invention uses sodium hydroxide instead of the highly reactive strong alkali NaH, effectively avoiding the risk of violent reactions; the reaction temperature is controlled within an adjustable range (70–80℃), suitable for conventional laboratory and scale-up process conditions, making the overall operation safer and more stable.

[0032] 3. Green and environmentally friendly, with an optimized reagent system: The acetylation reaction uses an acetyl chloride / triethylamine / DMAP system to replace the traditional acetic anhydride / pyridine system, reducing odor and toxicity, simplifying post-processing, and being environmentally friendly, thus meeting the concept of green chemistry development.

[0033] 4. High economic benefits and reduced production costs: This synthetic route uses disodium bisphenol A as a raw material for nucleophilic substitution reaction, which reduces the amount of catalyst used, and avoids the use of anhydrous DMF solvent, thus reducing production costs.

[0034] 5. Excellent scale-up adaptability and process reproducibility: This synthetic route avoids the use of reaction conditions requiring special equipment, and the overall process has good reproducibility and scale-up adaptability, making it suitable for the entire process from laboratory research and development to industrialization.

[0035] 6. Facilitating the industrialization of AR-NTD-targeted new drugs: Ralaniten triacetate, as the first oral AR-NTD inhibitor to enter the clinical stage, has provided an important impetus for the development of new targets for anti-androgen drugs through the establishment of its efficient and scalable synthesis method, and has broad clinical application prospects and market transformation potential.

[0036] The synthetic process for Ralaniten triacetate constructed in this invention has advantages in terms of technical feasibility, environmental friendliness, and feasibility of scale-up production. It provides synthetic support for the development of AR-NTD new drugs and lays the foundation for the innovation and transformation of tumor targeted therapy drugs, thus having social value and application prospects. Attached Figure Description

[0037] Figure 1 This is Ralaniten hydrogen spectrum data.

[0038] Figure 2 The data are for the hydrogen spectrum of Ralaniten triacetate.

[0039] Figure 3 HPLC for Ralaniten triacetate. Detailed Implementation

[0040] To more comprehensively and systematically demonstrate the core technical path and practicality of this invention, the synthesis principle, reaction process, reagent selection, and condition control of Ralaniten triacetate are described in detail below with reference to several typical embodiments. Through the exploration of reaction conditions, this invention establishes a synthesis process with good reproducibility and industrial transformation potential, which can be flexibly applied to meet different research and development stages and preparation needs. Based on an understanding of the core concept of this invention, those skilled in the art can optimize and adjust the raw material sources, reaction time, catalyst ratios, and other aspects according to specific research objectives or industrialization requirements. Such equivalent changes or derivative improvements should be considered reasonable extensions of this invention and are protected accordingly.

[0041] All reagents used in the following embodiments of the present invention are of analytical grade and have been dried or dehydrated before use to ensure the stability and reliability of the reaction system. The reagents used are as follows: Bisphenol A (99%); Sodium hydroxide; Toluene / Cyclohexane; N,N-Dimethylformamide (DMF) / N-Methylpyrrolidone (NMP); (R)-2,2-dimethyl-1,3-dioxolane-4-methyl p-toluenesulfonic acid; (R)-glycidyl p-toluenesulfonic acid; Potassium carbonate / Cesium carbonate; Cerium chloride heptahydrate (CeCl3·7H2O); Acetonitrile; Ethyl acetate; Anhydrous sodium sulfate; Acetyl chloride / Acetic anhydride; Pyridine / Triethylamine / N,N-Diisopropylethylamine (DIPEA); 4-Dimethylaminopyridine (DMAP); Dichloromethane (DCM).

[0042] Example 1

[0043] The preparation of Ralaniten (EPI-002) includes the following steps: Step 1: Preparation of disodium bisphenol A Bisphenol A (5.0 g, 21.9 mmol) and sodium hydroxide (1.76 g, 44.0 mmol) were added to deionized water (15 mL) and heated with stirring until completely dissolved. A water separator was connected, and toluene (15 mL) was slowly added dropwise. The mixture was refluxed at azeotropic conditions (105 ± 5 °C) for 4 hours to remove water. After cooling, the toluene was evaporated to dryness, yielding 5.95 g of white powdered disodium bisphenol A, yield: 99.6%.

[0044] Step 2: Two nucleophilic substitution reactions

[0045] 5.0 g of disodium bisphenol A (5.0 g, 18.3 mmol) was dissolved in DMF (20 mL), and (R)-2,2-dimethyl-1,3-dioxolanecycloyl-4-methyl ester (4.7 g, 16.4 mmol) was added dropwise at 75°C ± 5°C, and the reaction was continued for 36 hours. Subsequently, (R)-glycidyl p-toluenesulfonate (3.35 g, 14.6 mmol) and potassium carbonate (2.6 g, 18.9 mmol) were added, and the reaction was continued for another 16 hours. After terminating the reaction, insoluble inorganic salts were removed by filtration, followed by extraction with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the intermediate.

[0046] Step 3: Epoxy ring-opening reaction

[0047] The intermediate obtained in step two was dissolved in acetonitrile (20 mL), and CeCl3·7H2O (6.8 g, 18.2 mmol) was added. The mixture was refluxed for 8 hours. After cooling, the mixture was filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:2) to give 1.95 g of Ralaniten (EPI-002), with a yield of 26.9%.

[0048] 1H NMR (400 MHz, DMSO-d6) δ: 7.10 (dd, J = 8.6, 3.7 Hz, 4H), 6.82 (t, J = 8.2 Hz, 4H), 5.54 (d, J = 5.2 Hz, 1H), 4.92 (d, J = 4.9 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.01 (qt, J = 10.1, 5.1 Hz, 1H), 3.98 – 3.86 (m, 3H), 3.77(ddd, J = 15.8, 13.4, 5.3 Hz, 3H), 3.65 (dd, J = 11.1, 5.4 Hz, 1H), 3.42 (t, J = 5.4 Hz, 2H), 1.57 (s, 6H).

[0049] Example 2

[0050] The preparation of Ralaniten triacetate (EPI-506) includes the following steps: Steps 1-3 are the same as in Example 1. In this example, the intermediate Ralaniten prepared in Example 1 is used as the substrate for the subsequent acetylation reaction.

[0051] Step 4: The intermediate Ralaniten (1.95 g, 4.94 mmol) was dissolved in dichloromethane (12 mL), and acetyl chloride (1.9 g, 24.7 mmol), triethylamine (1.25 g, 12.4 mmol), and catalyst DMAP (0.60 g, 4.9 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the dichloromethane was evaporated to dryness, and the reaction mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 2.3 g of the pale yellow oily target product Ralaniten triacetate (EPI-506), with a purity of 98.1%, a yield of 89.1%, and a calculated overall yield of 23.87%.

[0052] 1 H NMR (400 MHz, CDCl3) δ: 7.13 (dd, J = 8.7, 1.3 Hz, 4H), 6.84 – 6.78(m, 4H), 5.33 (dp,J = 15.4, 5.1 Hz, 2H), 4.43 (dd, J = 12.0, 3.9 Hz, 1H), 4.29 (dd, J = 12.0, 6.0 Hz, 1H), 4.17 – 4.11 (m, 2H), 4.09 (d, J = 5.1 Hz, 2H), 3.81 (ddd, J = 27.9, 11.7, 5.2 Hz, 2H), 2.17 – 2.03 (t, 9H), 1.63 (s, 6H).

[0053] Example 3

[0054] The preparation of Ralaniten triacetate (EPI-506) includes the following steps: Steps 1-3 are the same as in Example 1. In this example, the intermediate Ralaniten prepared in Example 1 is used as the substrate for the subsequent acetylation reaction.

[0055] Step 4: The intermediate Ralaniten (1.95 g, 4.94 mmol) was dissolved in anhydrous dichloromethane (12 mL), and acetic anhydride (2.52 g, 24.7 mmol), pyridine (2.92 g, 36.9 mmol), and catalyst DMAP (0.60 g, 4.9 mmol) were added. The reaction was carried out under nitrogen protection and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was quenched with water, extracted three times with dichloromethane (18 mL), and washed twice with saturated brine (30 mL). After the dichloromethane was evaporated, the reaction mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 1.9 g of the pale yellow oily target product Ralaniten triacetate (EPI-506), with a purity of 97.2% and a yield of 73.6%. The calculated overall yield was 19.7%.

[0056] Example 4

[0057] The preparation of Ralaniten triacetate (EPI-506) includes the following steps: Steps 1-3 are the same as in Example 1. In this example, the intermediate Ralaniten prepared in Example 1 is used as the substrate for the subsequent acetylation reaction.

[0058] Step 4: The intermediate Ralaniten (1.95 g, 4.94 mmol) was dissolved in DMF (12 mL), and acetyl chloride (1.9 g, 24.7 mmol), N,N-diisopropylethylamine (1.6 g, 12.4 mmol), and catalyst DMAP (0.60 g, 4.9 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was quenched with water, extracted three times with dichloromethane (18 mL), washed twice with saturated brine (30 mL), and the reaction mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 2.2 g of the pale yellow oily target product Ralaniten triacetate (EPI-506), with a purity of 98% and a yield of 85.2%. The calculated overall yield was 22.8%.

[0059] Example 5

[0060] The scale-up process for preparing Ralaniten triacetate (EPI-506) includes the following steps: Step 1: Preparation of disodium bisphenol A Bisphenol A (11.4 g, 49.9 mmol) and sodium hydroxide (4.0 g, 100 mmol) were added to deionized water (32 mL) and heated with stirring until completely dissolved. A water separator was connected, and cyclohexane (32 mL) was slowly added dropwise. The mixture was refluxed for 5 hours to remove excess water. After cooling, the cyclohexane was evaporated to dryness, yielding 13.3 g of white powdered disodium bisphenol A, with a yield of 98.0%.

[0061] Step 2: Secondary nucleophilic substitution reaction

[0062] Bisphenol A disodium salt (10 g, 36.7 mmol) was dissolved in N-methylpyrrolidone (35 mL), and (R)-2,2-dimethyl-1,3-dioxolane-4-methyl p-toluenesulfonic acid (10.5 g, 36.7 mmol) was added dropwise at 100 ± 5°C, and the reaction was allowed to proceed for 24 hours. Subsequently, (R)-glycidyl p-toluenesulfonic acid (7.5 g, 33.0 mmol) and cesium carbonate (6.0 g, 18.4 mmol) were added, and the reaction was continued for another 12 hours. After the reaction was terminated, insoluble inorganic salts were removed by filtration, followed by extraction with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the intermediate.

[0063] Step 3: Epoxy ring opening to generate intermediate Ralaniten

[0064] The intermediate obtained in step two was added to acetonitrile (35 mL), followed by CeCl3·7H2O (13.5 g, 36.7 mmol), and refluxed for another 8 hours. After cooling, filtration, and rotary evaporation to dryness of the organic phase, the intermediate Ralaniten was obtained and used directly in the next reaction without purification.

[0065] Step 4: Preparation of Ralaniten triacetate

[0066] The crude intermediate Ralaniten was dissolved in dichloromethane (25 mL), and acetyl chloride (3.1 g, 39.4 mmol), triethylamine (2.0 g, 19.7 mmol), and the catalyst DMAP (0.96 g, 7.9 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the dichloromethane was evaporated to dryness, and the reaction mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1). The final purified product, Ralaniten triacetate (4.95 g), was obtained as a pale yellow oil with a purity of 98.1% and an overall yield of approximately 25.9%.

[0067] This invention establishes a synthetic process for synthesizing Ralaniten triacetate from bisphenol A, which has the following technical advantages: The reaction pathway is clear and the process flow is simple; the synthesis steps are rationally designed, with good reaction selectivity and yield; the solvent system can be flexibly replaced (DMF / NMP) to meet the requirements of green and low-toxicity processes; it is economically efficient and easy to operate, taking into account both laboratory research and industrial applications; the final product has a clear structure, high purity, and good NMR consistency, making it suitable for subsequent drug efficacy optimization and drug development.

[0068] Furthermore, the influence of solvent systems, reaction conditions, and purification steps involved in different embodiments on the yield and quality of the target product provides a solid technological foundation and theoretical support for subsequent structural modification, prodrug optimization, and dosage form development. Any reasonable adjustments, variations, and alternatives made without departing from the basic principles of this invention should be included within the scope of protection of this invention.

[0069] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing Ralaniten triacetate, characterized in that, Includes the following steps: Step 1: In the reaction flask with the condenser and water separator, add bisphenol A, sodium hydroxide and deionized water, heat and stir to dissolve, then add organic solvent I dropwise, and react under water-organic solvent azeotropic reflux conditions for 4-5 hours. Remove the solvent to obtain disodium bisphenol A. Step 2: Dissolve the obtained disodium bisphenol A in organic solvent II, heat to 70–80°C, and add (R)-2,2-dimethyl-1,3-dioxolane-4-methyl ester of p-toluenesulfonic acid dropwise to carry out the first step of nucleophilic substitution reaction; after the reaction is completed, add (R)-glycidyl p-toluenesulfonic acid and a basic catalyst to carry out the second step of nucleophilic substitution reaction; after the reaction is completed, the diether compound is obtained by post-treatment; dissolve the diether compound in acetonitrile, add cerium chloride heptahydrate, and carry out an epoxy ring-opening reaction under reflux conditions to generate the intermediate Ralaniten; Step 3: Dissolve intermediate Ralaniten in organic solvent III, add acid-binding agent, 4-dimethylaminopyridine, and acetyl chloride, and stir at room temperature for 2–3 hours to carry out acetylation reaction. After the reaction is completed, evaporate the solvent, separate and purify to obtain the target product Ralaniten triacetate.

2. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, In step one, the molar ratio of bisphenol A to sodium hydroxide is 1:2-2.

01.

3. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, In step one, the volume ratio of organic solvent I to deionized water is 1:1; the organic solvent I is toluene or cyclohexane.

4. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, In step two, the molar ratio of bisphenol A disodium salt, (R) p-toluenesulfonic acid-2,2-dimethyl-1,3-dioxolanecycloyl-4-methyl ester, and (R)-p-toluenesulfonic acid glycidyl ester is 1:0.9-1:0.8-1.

5. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, In step two, the alkaline catalyst includes potassium carbonate and cesium carbonate; and / or, the molar ratio of the alkaline catalyst to disodium bisphenol A is 0.5-1.05:

1.

6. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, The organic solvent II is N,N-dimethylformamide or N-methylpyrrolidone.

7. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, In step two, the amount of cerium chloride heptahydrate is added according to the amount of disodium bisphenol A salt, wherein the molar ratio of cerium chloride heptahydrate to disodium bisphenol A salt is 0.99-1.01:

1.

8. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, In step three, organic solvent III is dichloromethane or N,N-dimethylformamide.

9. The method for preparing Ralaniten triacetate according to claim 1, characterized in that, The acid-binding agent is triethylamine or N,N-diisopropylethylamine, and the molar ratio of the acid-binding agent, acetyl chloride, and catalyst DMAP is 1:2:2.4-2.

6.

10. A method for preparing a Ralaniten intermediate, characterized in that, Includes the following steps: Step 1: In the reaction flask with the condenser and water separator, add bisphenol A, sodium hydroxide and deionized water, heat and stir to dissolve, then add organic solvent I dropwise, and react under water-organic solvent azeotropic reflux conditions for 4-5 hours. Remove the solvent to obtain disodium bisphenol A. Step 2: Dissolve the obtained disodium bisphenol A in organic solvent II, heat to 70–80°C, and add (R)-2,2-dimethyl-1,3-dioxolane-4-methyl ester of p-toluenesulfonic acid dropwise to carry out the first step of nucleophilic substitution reaction; after the reaction is completed, add (R)-glycidyl p-toluenesulfonic acid and a basic catalyst to carry out the second step of nucleophilic substitution reaction; after the reaction is completed, the diether compound is obtained by post-treatment; dissolve the diether compound in acetonitrile, add cerium chloride heptahydrate, and carry out an epoxy ring-opening reaction under reflux conditions to generate the intermediate Ralaniten.

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