Method for preparing elacestrant and intermediate thereof

Abstract

The present invention relates to the technical field of drug synthesis, and specifically relates to a method for preparing elacestrant and an intermediate thereof. The method comprises: 1) subjecting compound A1 and 4-bromo-3-nitroanisole as raw materials to a Suzuki coupling reaction to obtain compound A2; 2) subjecting compound A2 to catalytic hydrogenation and debenzylation reactions to obtain compound A3; 3) subjecting compound A3 to an acetylation reaction under the action of an acetylation reagent to obtain compound A4; 4) subjecting compound A4 to a reduction reaction to obtain compound A5; 5) subjecting compound A5 to chiral resolution to obtain compound A6; 6) subjecting compound A6 to reductive amination with N-ethyl-2-(4-formylphenyl)acetamide to obtain compound A7; and 7) subjecting compound A7 to reaction under the action of a reducing agent to obtain elacestrant. The method for preparing elacestrant and an intermediate thereof, as provided by the present invention, has the characteristics of short synthesis route, high yield, and high purity.

Description

Process for the preparation of elacestrant and intermediates thereof TECHNICAL FIELD The present application belongs to the technical field of drug synthesis, and particularly relates to a process for the preparation of elacestrant and intermediates thereof. BACKGROUND Elacestrant is a new oral selective estrogen receptor degrader, which can bind to estrogen receptor alpha and induce estrogen receptor alpha protein degradation through the proteasome pathway, thereby inhibiting 17beta-estradiol-mediated cell proliferation. In 2023, the European Commission approved Elacestrant (Elacestrant) for the treatment of patients with ER+, HER2- locally advanced or metastatic breast cancer with activated ESR1 mutations. The molecular formula of Elacestrant is C 30 H 38 N2O2, the molecular weight is 458.63, and the structural formula is shown as formula VIII. The original research process of Elacestrant is reported in CN113348163A patent, and the synthetic route is as follows: The original research patent is based on 7-benzyloxy-3-bromo-1,2-dihydronaphthalene as a starting material, which is catalyzed by palladium to form a borane compound, then subjected to Suzuki-Miyaura reaction with compound c to obtain compound d, and then reduced by palladium-carbon hydroxide to obtain compound e, followed by hydrolysis to obtain compound f, and then subjected to tartaric acid resolution to obtain compound g, and then subjected to reductive amination with compound h, and finally subjected to reduction by sodium borohydride and iodine to obtain the product of Elacestrant. In this route, the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (compound f) is produced from 7-benzyloxy-3-bromo-1,2-dihydronaphthalene as a starting material, which is subjected to Suzuki-Miyaura reaction, palladium-carbon hydroxide reduction, and deacetylation. The synthetic process route is long, and a large amount of waste acid is produced by using dilute hydrochloric acid for deacetylation; and compound c is expensive, and the process cost is high. At the same time, compound i is a by-product of reductive amination in the synthetic route, and the main product in the synthesis process is compound i', which is difficult to convert to compound i effectively, and the yield is low. And the peak time of compounds i and i' is similar, which is difficult to purify by crystallization and column chromatography technology, which has a great influence on the overall process yield and product quality. The whole process synthesis cycle is long, and a large amount of waste acid is produced, which is very harmful to the environment. Some existing technologies also report the synthesis method of Elacestrant and its key intermediates. For example: 1)CN116969848A patent discloses a preparation method of an intermediate for treating advanced breast cancer drug, which takes 6-hydroxy-3,4-dihydro-1H-2-naphthalenone as the starting material, and obtains the key intermediate 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol through 4-step reactions. The specific synthesis route is as follows: The starting material 6-hydroxy-3,4-dihydro-1H-2-naphthalenone is expensive, and the supplier is less. It is difficult to form the o-nitro Grignard reagent, even if the Turbo Grignard reagent is added, the yield is low, and it is difficult to realize industrial production. Based on the method for further synthesis of elacestrant, not only the cost is high, but also the operation is complex, and the impurities are more, which is not conducive to realize industrial production. 2)CN117902990A patent discloses a preparation method of elacestrant intermediate (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, and the synthesis route is as follows: The patent uses expensive rhodium metal reagent and chiral ligand, and the low yield leads to high process cost. 3)CN117229157A patent discloses a method for preparing elacestrant by using compound j as raw material. Compound j is subjected to tartaric acid resolution to obtain absolute configuration compound k, then compound l is subjected to reductive amination to obtain compound m, and then compound n is obtained by deprotection, and finally reductive amination with acetaldehyde to obtain elacestrant product. The synthesis route is as follows: The route has at least the following defects: ① needs to be protected, deprotection process, poor economy; ② the first step reaction will produce another configuration; ③ the reaction step will produce more diethyl by-product, which is difficult to remove impurities by recrystallization and other methods; ④ according to CN117229157A patent, the purity of the pure elacestrant prepared in example 1 is 97.2%. According to the "Guiding Principles for the Standardization Process of Chemical Drug Quality Standards", combined with the current regulations and ICH related guidelines, the maximum single impurity is required to be not more than 0.10%, and the total impurity is required to be not more than 0.5%. The purity of the product after the last step of purification in example 1 of the patent is 97.2%, which does not meet the above requirements, and the purity is unqualified. 4)WO2004058682A1 patent discloses a synthesis method of the key intermediate (2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol of elacestrant, and the synthesis route is as follows: The present application has at least the following defects: ① the method for synthesizing the compound of formula J requires strict control of the amount of acetic anhydride, and there are phenyl acetate and diacetylated impurities in the system, resulting in a low yield; and the total yield of the patent from the compound of formula I to the compound of formula J is 60%, which is relatively low by using the chromatographic column technology (loss is less); and the present application is more simple and efficient by using the crystallization beating method; ② the Ulmann coupling reaction for synthesizing the compound H has many coupling impurities and a low yield of about 40%; and the addition of stoichiometric copper increases the solid waste problem; ③ the compound of formula J is reduced by lithium aluminum hydride to obtain the intermediate I, which has certain defects. Firstly, the method involves the use of pyridine, but pyridine has weak basicity, a large amount of pyridine is required for the reaction, and pyridine is toxic, which is not suitable for industrial production; secondly, the aluminum salt generated after the quenching of lithium aluminum hydride can coordinate with the resolution agent in the next step, resulting in invalid resolution; although the column can filter the aluminum salt, the column efficiency is too low to be suitable for industrial production; thirdly, the reaction of lithium aluminum hydride and aluminum chloride produces a large amount of solid which can wrap the raw materials and products, reducing the reaction efficiency; and the reducing property of lithium aluminum hydride is too strong, which can cause hydrolysis reaction to generate a large amount of by-products, resulting in a low yield of 60% under the column. In summary, the existing synthesis process of elacridar has many defects, and it is necessary to study a synthesis method of elacridar and its key intermediate which has high yield, high purity, low cost, few impurities, simple steps and is suitable for industrial production. SUMMARY Therefore, the present application provides a preparation method of a key intermediate compound A4 of elacridar and a method for preparing elacridar by using the intermediate compound. The present application finds a new synthesis route of elacridar, which first uses compound A1 and 4-bromo-3-nitroanisole as raw materials, and then performs Suzuki-Miyaura reaction, catalytic hydrogenation, debenzyl reaction and acetylation reaction to prepare the key intermediate compound A4 of elacridar; and then the compound A4 is sequentially subjected to reduction reaction, chiral resolution, reductive amination and reduction reaction to obtain the finished product of elacridar. The method provided by the present application has a short synthesis route, low impurity content and low cost, and can realize the synthesis of high-quality elacridar, and is more suitable for industrial production. One of the purposes of the present application is to provide a preparation method of the intermediate compound A4 of elacridar, which provides support for the subsequent synthesis of elacridar. To achieve the above-mentioned purposes, the present application adopts the following technical solutions: The preparation method of the intermediate compound A4 of elacridar comprises: acetylation reaction of compound A3 under the action of an acetylation reagent to obtain compound A4; the structural formula of the compound A3 is shown in formula III; and the structural formula of the compound A4 is shown in formula IV; Further, the acetylating agent comprises any one or more of acetyl chloride, acetic anhydride, preferably acetic anhydride. Further, the solvent for the acetylation reaction is any one or more of dichloromethane, tetrahydrofuran; and / or the acetylation reaction is carried out in the presence of 4-dimethylaminopyridine or triethylamine; and / or the acetylation reaction is carried out at a temperature of 22-27℃ for 0.4-1h, more preferably at a temperature of 25℃ for 0.5h; and / or the mass ratio of the compound A3 to the acetylating agent is 1:0.5-1.5, more preferably 1:0.7-1. Further, the 4-dimethylaminopyridine acts as a catalyst to promote acetylation, and the triethylamine acts as a base to promote acetylation and neutralize hydrogen chloride. As a preference, when the acetylating agent is acetic anhydride, the mass-volume ratio of the compound A3 to acetic anhydride is preferably 1:1; when the acetylating agent is acetyl chloride, the mass ratio of the compound A3 to acetyl chloride is preferably 1:0.7. As a preference, the mass ratio of the compound A3 to 4-dimethylaminopyridine is 100:3-10, preferably 100:4.5. As a preference, the mass ratio of the compound A3 to triethylamine is 1:1-3, preferably 1:1.5. As a preference, the mass-volume ratio of the compound A3 to the solvent is 1:3-10, preferably 1:5. Further, after the acetylation reaction is completed, ammonium chloride is added for quenching, saturated sodium bicarbonate solution is added for neutralization, liquid separation is performed, or ethyl acetate is added for extraction; saturated brine is used for washing, drying, filtration, concentration, and crystallization with ethyl acetate and n-hexane to obtain the compound A4. Further, the compound A3 is prepared by the following method: (1) using the compound A1 and 4-bromo-3-nitroanisole as raw materials, a Suzuki coupling reaction is performed to obtain the compound A2; (2) the compound A2 obtained in step (1) is reduced by hydrogen to obtain the compound A3; The structural formula of the compound A1 is shown in Formula I; the structural formula of the compound A2 is shown in Formula II; The present application uses 7-benzyloxy-3-bromo-1,2-dihydronaphthalene as a starting material, and only two steps are required to obtain the key intermediate A3 compound, which has the characteristics of short route, cheap and easily available starting material, safe operation, high yield, environmental friendliness, etc. Further, in step (1), the Suzuki coupling reaction is carried out in the presence of a palladium catalyst, wherein the palladium catalyst is any one or more of dichlorobis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, and palladium acetate; and the amount of the palladium catalyst is 0.3-1.2 mol%. Further, in step (1), the Suzuki coupling reaction is carried out in the presence of a boron reagent, wherein the boron reagent is pinacol diboronic acid ester; and the mass ratio of the compound A1 to the boron reagent is 1:0.8-1.2, preferably 1:1.06. Further, in step (1), the Suzuki coupling reaction is carried out in the presence of a base, wherein the base is any one or more of potassium acetate and KHCO3. Further, in step (1), the Suzuki coupling reaction is carried out in a reaction solvent, wherein the reaction solvent is any one or more of ethylene glycol dimethyl ether and 1,4-dioxane. Further, in step (1), the mass ratio of the compound A1 to 4-bromo-3-nitroanisole is 1:0.5-1, preferably 1:0.74. Preferably, in step (1), the palladium catalyst is 0.6 mol% of dichlorobis(triphenylphosphine)palladium. Preferably, step (1) comprises the following steps: The compound A1 is mixed with ethylene glycol dimethyl ether, potassium acetate, a boron reagent, and a palladium catalyst, and then heated at 85°C after being replaced with nitrogen to obtain a reaction solution; the reaction solution is evaporated to dryness, and then 25 wt% KHCO3 solution, 4-bromo-3-nitroanisole, and 1,4-dioxane are added in sequence, and then replaced with nitrogen for three times and reacted under reflux; after the reaction is completed, the temperature is lowered to 25°C, and then washed with water for three times; the organic phase is heated to reflux, and then ethanol is added, and then crystallized after being cooled; and then filtered, and then washed to obtain the compound A2. Further, in step (1), the reaction is monitored by HPLC. Further, in step (2), the reaction solvent is any one or more of methanol and tetrahydrofuran. Further, in step (2), the hydrogen reduction reaction is carried out in the presence of a catalyst, wherein the catalyst is any one or more of palladium hydroxide / carbon and palladium / carbon; and the amount of the catalyst is 4-8 wt%. Further, in step (2), the hydrogen reduction reaction is carried out under the following conditions: 5-15 MPa of hydrogen, 35-50°C, and 40-60 h; more preferably, 10 MPa of hydrogen, 40°C, and 48 h. Preferably, in step (2), the catalyst is 4-8 wt% of palladium / carbon. As preferred, in step (2), the reaction solvent is composed of methanol and tetrahydrofuran at a volume ratio of 1:1. As preferred, in step (2), the mass-volume ratio of compound A2 to solvent is 1:8-15, preferably 1:10. As a preferred technical solution, step (2) comprises: mixing compound A2 with solvent and catalyst, reacting at 10 MPa of hydrogen at 40℃ for 48h; after the reaction is completed, filtering, concentrating, and recrystallizing in methanol / ethyl acetate to obtain compound A3. The second object of the present application is to provide a compound A4 prepared by the aforementioned method. To achieve the above object, the present application adopts the following technical solution: The compound A4 prepared by the aforementioned method has a structural formula as shown in Formula IV. The third object of the present application is to provide a preparation method of elacridar. To achieve the above object, the present application adopts the following technical solution: The preparation method of elacridar comprises the following steps: S1: preparing compound A4 by the method of any one of claims 1-7; S2: reacting the compound A4 obtained in S1 under the action of a reducing agent to obtain compound A5; S3: reacting the compound A5 obtained in S2 under the action of a resolving agent to obtain compound A6; S4: reducing and aminating the compound A6 obtained in S3 with N-ethyl-2-(4-formylphenyl)acetamide to obtain compound A7; S5: reacting the compound A7 obtained in S4 under the action of a reducing agent to obtain elacridar; The structural formula of the compound A5 is shown in Formula V; the structural formula of the compound A6 is shown in Formula VI; the structural formula of the compound A7 is shown in Formula VII; and the structural formula of the elacridar is shown in Formula VIII. Further, in S2, the reducing agent is any one of sodium borohydride combined with boron trifluoride ether, sodium borohydride combined with iodine, sodium borohydride combined with trifluoroacetic acid, lithium aluminum hydride combined with aluminum chloride; the reducing agent is preferably sodium borohydride, and most preferably any one of sodium borohydride combined with boron trifluoride ether and sodium borohydride combined with iodine; And / or in S2, the reaction solvent is tetrahydrofuran. And / or in S2, the reaction condition is 50-80℃ for 0.5-2h, preferably 65℃ for 1h. And / or in S2, the molar ratio of compound A4 to reducing agent is 1:3-5, more preferably 1:4. As preferred, when the reducing agent contains sodium borohydride, the mass ratio of compound A4 and sodium borohydride is 1:0.4-1, preferably 1:0.48. As preferred, in S2, the mass-volume ratio of compound A4 and the reaction solvent is 1:8-15, preferably 1:10. Further, after the reaction in S2 is completed, dilute hydrochloric acid is added for quenching, saturated sodium bicarbonate solution is added for neutralization, ethyl acetate is added for liquid separation, saturated brine is added for washing, drying, filtration, concentration, crystallization with tetrahydrofuran and n-hexane, to obtain compound A5. Further, in S3, the resolving agent is any one or more of L-(-)-dibenzoyl tartaric acid (L-DBTA), L-(-)-di-p-toluoyl tartaric acid, L-(-)-di-p-methoxybenzoyl tartaric acid, preferably L-(-)-dibenzoyl tartaric acid; and / or in S3, the reaction solvent is acetonitrile; and / or in S3, the mass ratio of compound A5 and the resolving agent is 1:0.5-1.5, preferably 1:0.7; and / or in S3, the reaction condition is to heat to 50-70℃ for dissolution, more preferably to heat to 60℃ for dissolution. As preferred, the mass-volume ratio of compound A5 and the reaction solvent is 1:8-20, preferably 1:10. Further, in S3, after the reaction is completed, slow cooling to 22℃, suction filtration, drying, addition of methanol, water, dropwise addition of 25% potassium bicarbonate solution, stirring at room temperature for 3h, suction filtration, washing, to obtain compound A6. Further, in S4, the reducing agent is triacetyl borohydride sodium; and / or in S4, the reductive amination is carried out under the action of a catalyst, and the catalyst is any one or more of glacial acetic acid, trifluoroacetic acid, tartaric acid, preferably glacial acetic acid; and / or in S4, the reaction solvent is dichloromethane; and / or in S4, the mass ratio of compound A6 and N-ethyl-2-(4-formylphenyl)acetamide is 1:1-2, more preferably 1:1.285; and / or in S4, the mass ratio of compound A6 and the reducing agent is 1:1.8-5, more preferably 1:2.11. and / or in S4, the mass ratio of compound A6 and the catalyst is 1:0.3-1, preferably 1:0.4; As preferred, the mass-volume ratio of compound A6 and the solvent is 1:10-30, preferably 1:15. Further, in S4, the protecting group is ethyl. The ethyl group of the finished product of Irasposagene is protected by ethyl group in the present application, which avoids the operation of adding ethyl group after the deprotection of other protecting groups. Further, in S4, the N-ethyl-2-(4-formylphenyl)acetamide, the reducing agent and the catalyst are added in three batches; after the first two additions, the reaction is carried out at 20℃ for 3h; after the third addition, the reaction is monitored by HPLC until completion. As a preference, the amount of each addition is the same when the addition is carried out in three batches. Further, after the completion of the reaction in S4, saturated ammonium chloride solution is added to quench the reaction, ethyl acetate is added for extraction, the organic phases are combined and concentrated under reduced pressure, concentrated hydrochloric acid is added to adjust the pH to 1, ethyl acetate is added for extraction, saturated brine is used for washing, anhydrous sodium sulfate is used for drying, and the product is concentrated under reduced pressure and crystallized from methanol and ethyl acetate to obtain compound A7. Further, in S5, the reducing agent is any one combination of sodium borohydride and boron trifluoride ether, sodium borohydride and iodine, sodium borohydride and trifluoroacetic acid, lithium aluminum hydride and aluminum chloride, and the reducing agent is preferably sodium borohydride, and most preferably a combination of sodium borohydride and boron trifluoride ether; and / or in S5, the reaction solvent is tetrahydrofuran; and / or in S5, the molar ratio of the compound A7 and the reducing agent is 1:3-5, and more preferably 1:4. and / or in S5, the reaction conditions are 50-80℃ for 0.5-2h, and more preferably 65℃ for 1h. As a preference, when the reducing agent contains sodium borohydride, the sodium borohydride is slowly added at 0℃. As a preference, the mass-volume ratio of the compound A7 and the solvent is 0.1-0.3:1, and more preferably 0.18:1. Further, in S5, the reaction is monitored by HPLC, after the completion of the reaction, the temperature is lowered to 25℃, hydrochloric acid is added, the temperature is raised to 70℃, stirring is maintained for 1h, the temperature is lowered, saturated sodium bicarbonate is added to neutralize the reaction solution, the solution is extracted, dried, filtered, concentrated to obtain the crude irasposagene, and the product is crystallized from methanol and ethyl acetate to obtain irasposagene. In the present application, the mass-volume ratio is calculated as the ratio of "g for the unit of mass and mL for the unit of volume". The present application has the following beneficial effects: 1. The present application significantly improves the yield of the compound A2 by Suzuki coupling, and the yield of the product is about 80%; at the same time, the generation of coupling impurities is reduced, and the purity is greater than 99%. 2. In the preparation of compounds A1-A3, the palladium catalyst used in the present application is low in price, and at the same time, the use of chiral ligand is avoided, which significantly reduces the cost. 3. In the synthetic scheme of the present application, the direct acetyl protection and reduction of the A3 compound to obtain the A5 compound avoids the subsequent deprotection and ethylation operation, reducing the types of impurities. 4. In the synthesis of the A6 compound, the present application preferably uses L-DBTA as the resolving agent, significantly reducing the isomer content. 5. In the synthesis of the A7 compound, the present application preferably uses a process of adding N-ethyl-2-(4-formylphenyl)acetamide, glacial acetic acid, and sodium triacetyl borohydride in three batches, which reduces the amount of N-ethyl-2-(4-formylphenyl)acetamide and the impurities generated by N-ethyl-2-(4-formylphenyl)acetamide. 6. In the synthesis of Elacestrant, the present application preferably uses sodium borohydride and boron trifluoride ether as reducing agents, which has milder reaction conditions, simpler operation, and avoids the generation of a large amount of solid waste, making it more suitable for industrial production. 7. The synthetic route provided by the present application significantly simplifies the process flow, reduces impurity content, improves total synthesis yield, and enables the synthesis of high-quality Elacestrant at low cost, with the characteristics of short synthesis route, low cost, high efficiency, high yield, and more suitable for industrial production. 8. In the preparation of compounds A3-A5, the WO2004058682A1 patent related synthesis step uses pyridine which is toxic; while the present application uses a catalytic amount of 4-dimethylaminopyridine to react, avoiding the use of a large amount of pyridine. At the same time, the present application uses sodium borohydride and boron trifluoride ether / iodine instead of lithium aluminum hydride and aluminum chloride, and through conventional crystallization, 82%-87% can be achieved. BRIEF DESCRIPTION OF DRAWINGS Figure 1 is a synthetic route diagram of Elacestrant; Figure 2 is a chromatogram of the compound A2 prepared in Example 1; Figure 3 is a chromatogram of the compound A3 prepared in Example 6; Figure 4 is a chromatogram of the compound A7 prepared in Example 21; Figure 5 is a chromatogram of Elacestrant prepared in Example 25; Figure 6 is a synthetic route diagram of Elacestrant in CN113348163A patent; Figure 7 is a hydrogen spectrum of the compound A4 prepared in Example 10, where the numbers represent the hydrogen on the numbered carbon atom; Figure 8 is a carbon spectrum of the compound A4 prepared in Example 10, where the numbers represent the numbered carbon atom; Figure 9 is a mass spectrum of the compound A4 prepared in Example 10; Figure 10 is a chromatogram of the A6 compound prepared in Example 17; Figure 11 is a mass spectrum of the diethyl compound in Comparative Example 2; Figure 12 is a chromatogram of the diethyl compound in Comparative Example 2; Figure 13 is a chromatogram of the A6 compound prepared in Comparative Example 3; Figure 14 is a chromatogram of the A6 compound prepared in Comparative Example 4. DETAILED DESCRIPTION The technical solutions of the present application will be further clearly and completely described below in combination with specific examples. Obviously, the described examples are only a part of the examples of the present application, but not all the examples. Therefore, all the other examples obtained by those skilled in the art based on the examples in the present application without creative labor are within the protection scope of the present application. In the examples of the present application, the raw materials and reagents involved can be purchased through the regular channel if no special instructions are given. In the examples of the present application, the compound information is shown in Table 1. Table 1. Compound information table In the examples of the present application, based on the research and development idea of cost optimization and improvement of API quality, a new synthetic method of iralesium is proposed, and the general synthetic route is shown in Figure 1. In the present application, compound A1 and 4-bromo-3-nitroanisole are used as raw materials to obtain compound A2 through Suzuki-Miyaura reaction; compound A2 is subjected to catalytic hydrogenation and debenzyl reaction to obtain compound A3; compound A3 is subjected to O-acetylation and N-acetylation to obtain compound A4; compound A4 is subjected to reduction reaction to obtain compound A5; compound A5 is subjected to chiral resolution to obtain compound A6; compound A6 is subjected to reductive amination reaction to obtain compound A7; finally, compound A7 is reduced to obtain iralesium product. The method has the characteristics of short synthetic route, low cost, high efficiency, high yield, and is more suitable for industrial production. In the present application, the reaction mechanism of compound A3 to compound A4 is as follows: As can be seen from the reaction formula, the dimethylamine structure in DMAP resonates with the pyridine ring, so that the nitrogen on the pyridine of DMAP has strong nucleophilicity, thereby attacking the electrophilic site ester group carbon of acetic anhydride to produce intermediate 3. When the oxygen anion in intermediate 3 is converted into a carbonyl group, acetic anion is removed to produce intermediate 4. The pyridine cation structure in intermediate 4 significantly enhances the positive charge of the carbon of the carbonyl group, which is then attacked by the oxygen anion of the phenol structure, and the pyridine cation structure is removed as a good leaving group to generate compound 5 acetylated with phenol. The following two documents can prove that phenolic compounds can be easily acetylated with acetic anhydride: ①CN111777830A patent specification

[0015] -

[0017] The paragraph shows that phenolic compounds can produce acetylated phenol products after adding acetic anhydride and triethylamine. It is obvious that DMAP can be used as a basic substance instead of triethylamine to acetylate phenolic compounds A4. ② "Efficient iron-catalyzed direct acylation of amines with carboxylic acids and esters under oxygenated Conditions", Catalysis Science & Technology, 2024, 14, p.478-488, its supporting information document S3, "3. Preparation of substrates. Synthesis of phenyl acetate (1b). 3" lists the case: phenol can react with acetic anhydride to produce acetylphenol after adding pyridine. It is proved that phenol can be acetylated under the condition of acetic anhydride and pyridine. The lone pair of electrons carried by the nitrogen atom in the dimethylamino group of the DMAP (chemical name: 4-dimethylaminopyridine) molecule resonates with the aromatic ring, increasing the nucleophilicity of the nitrogen atom in the pyridine ring, making DMAP an acylation transfer reagent. The acylation reaction catalyzed by DMAP is 103-105 times faster than that catalyzed by pyridine. It is obvious that using DMAP as an acid-binding agent and catalyst is more acetylated than pyridine. In the present application, during the reaction of compound A4 to compound A5, the removal of the acetyl group in the acetoxy (ester group) has the following two possibilities: 1) Reductive mechanism: Trifluoroboron has a strong Lewis acidity due to the unoccupied empty orbital of boron. The sodium borohydride and Lewis acid reduction system can reduce the acetoxy (ester group) in the above figure to ethanol and phenolic products. As can be seen from the above reaction formula, trifluoroboron ether coordinates with the ester group (the lone pair of electrons on the oxygen atom fills the empty orbital of the boron atom), causing the electrophilicity of the carbon atom in the ester group to increase, making it more susceptible to attack by the hydride anion of sodium borohydride, generating a hemiacetal intermediate, which is rearranged to generate acetaldehyde and phenolate compounds. Ethyl aldehyde is further reduced by sodium borohydride, and then quenched by acid to obtain ethanol and phenolic compounds A5. This method is similar to the reduction of ester groups by lithium aluminum hydride. In the prior art, "Organic Chemistry Structure and Function", 8th edition, page 985, states: The ester is reduced by a hydride reagent to form an alcohol or an aldehyde: 1 mol of ester is reduced by 0.5 mol of LiAlH4to form 1 mol of alcohol, because only two hydrogens are needed for each ester group. The reaction process is similar to the double Grignard addition: the first hydride undergoes addition-elimination to form an aldehyde, which quickly reacts with the second hydride to form an alcohol (after water treatment). In the above reaction, the alcohol part of the ester is still an alcohol after reduction (the part in the black box), so the ester can be reduced by lithium aluminum hydride to form two alcohols. The lithium aluminum hydride needs to be used in anhydrous conditions. The above reaction is carried out in two steps: the first step is lithium aluminum hydride reduction, which needs to be strictly anhydrous, and the second step is quenching with an acid aqueous solution; in the formula "2) H2O" refers to the addition of an acid aqueous solution in the second step reaction (quenching), not in the first step of lithium aluminum hydride reduction. This technical solution is similar to the prior art, using dilute hydrochloric acid to quench to obtain the target compound. + , H2O" refers to the addition of an acid aqueous solution in the second step reaction (quenching), not in the first step of lithium aluminum hydride reduction. This technical solution is similar to the prior art, using dilute hydrochloric acid to quench to obtain the target compound. 2) Hydrolysis mechanism: Considering that sodium borohydride and boron trifluoride will react to produce borane (Inorg. Chem. 2000, 39, 1795-1802), the preparation of A5 from A4 in this technical solution may go through: 1) borane reduction of amide (borane is relatively difficult to reduce ester group under mild conditions); 2) acid hydrolysis to remove the acetyl protecting group during quenching. In the prior art, it is recorded in Organic Chemistry: Structure and Function, 8th Edition, page 981: The ester is hydrolyzed by acid to obtain an acid and an alcohol. Example 1. Preparation of A2 In a three-necked reaction flask, 100.0 g of A1 compound was added, 700 mL of ethylene glycol dimethyl ether was added, 106.0 g of pinacol diboronic acid, 98.0 g of potassium acetate and 1.0 g of dichlorobis(triphenylphosphine)palladium (0.6 mol%) were added at one time, and then heated at 85°C after replacing nitrogen. HPLC detection showed that the reaction was complete, the solvent was evaporated, 300 mL of 25 wt% KHCO3 solution, 74.0 g of 4-bromo-3-nitrobenzyl ether and 700 mL of 1,4-dioxane were added in turn, and then replaced with nitrogen three times. After refluxing, HPLC detection showed that the reaction was complete, it was cooled to 25°C, washed with water three times, the organic phase was heated to reflux, ethanol was added, cooled to crystallize, filtered, and washed to obtain 101.3 g of A2 compound, with a yield of 83% and a purity of more than 98%. The HPLC spectrum is shown in Figure 2, and the corresponding integral results are shown in Table 2. Table 2. Integral results of Figure 2 Example 2. Preparation of A2 In a three-necked flask, A1 compound 100.0 g, ethylene glycol dimethyl ether 700 mL, pinacol diborane 106.0 g, potassium acetate 98.0 g and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium 1.0 g (0.6 mol%) were added. After three times of nitrogen replacement, the mixture was heated at 85°C. HPLC detection showed that the reaction was complete. The solvent was evaporated, 25 wt% KHCO3 solution 300 mL, 4-bromo-3-nitrobenzyl ether 74.0 g and 1,4-dioxane 700 mL were added in turn, and the reaction was carried out under reflux after three times of nitrogen replacement. HPLC detection showed that the reaction was complete. The temperature was lowered to 25°C, and the organic phase was washed with water three times. The temperature was raised to reflux, and ethanol was added. Crystallization was performed after cooling, and A2 compound 45.2 g was obtained by suction filtration and washing, with a yield of 37% and a purity of more than 98%. Example 3. Preparation of A2 In a three-necked flask, A1 compound 100.0 g, ethylene glycol dimethyl ether 700 mL, pinacol diborane 106.0 g, potassium acetate 98.0 g and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium 1.0 g (0.6 mol%) were added. After three times of nitrogen replacement, the mixture was heated at 85°C. HPLC detection showed that the reaction was complete. The solvent was evaporated, 25 wt% KHCO3 solution 300 mL, 4-bromo-3-nitrobenzyl ether 74.0 g and 1,4-dioxane 700 mL were added in turn, and the reaction was carried out under reflux after three times of nitrogen replacement. HPLC detection showed that the reaction was complete. The temperature was lowered to 25°C, and the organic phase was washed with water three times. The temperature was raised to reflux, and ethanol was added. Crystallization was performed after cooling, and A2 compound 45.2 g was obtained by suction filtration and washing, with a yield of 37% and a purity of more than 98%. Example 4. Preparation of A2 In a three-necked flask, A1 compound 100.0 g, ethylene glycol dimethyl ether 700 mL, pinacol diborane 106.0 g, potassium acetate 98.0 g and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium 1.0 g (0.6 mol%) were added. After three times of nitrogen replacement, the mixture was heated at 85°C. HPLC detection showed that the reaction was complete. The solvent was evaporated, 25 wt% KHCO3 solution 300 mL, 4-bromo-3-nitrobenzyl ether 74.0 g and 1,4-dioxane 700 mL were added in turn, and the reaction was carried out under reflux after three times of nitrogen replacement. HPLC detection showed that the reaction was complete. The temperature was lowered to 25°C, and the organic phase was washed with water three times. The temperature was raised to reflux, and ethanol was added. Crystallization was performed after cooling, and A2 compound 45.2 g was obtained by suction filtration and washing, with a yield of 37% and a purity of more than 98%. Example 5. Preparation of A2 In a three-necked flask, A1 compound 100.0 g, ethylene glycol dimethyl ether 700 mL, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride 2.0 g (1.2 mol%), potassium acetate 98.0 g were added. After three times of nitrogen replacement, the reaction mixture was heated at 85 °C. HPLC detection showed that the reaction was complete. The solvent was evaporated, 25 wt% KHCO3 solution 300 mL, 4-bromo-3-nitrobenzyl phenyl ether 74.0 g and 1,4-dioxane 700 mL were added in turn. After three times of nitrogen replacement, the reaction was refluxed. HPLC detection showed that the reaction was complete. The temperature was lowered to 25 °C, and the organic phase was washed with water three times. The temperature was raised to reflux, and ethanol was added. After cooling, the product was filtered and washed to obtain A2 compound 97.6 g, with a yield of 80% and a purity of more than 98%. Example 6. Preparation of A3 A2 compound was prepared according to the method of Example 1. Then in a reaction kettle, A2 compound 50.0 g, methanol 250 mL and tetrahydrofuran 250 mL, palladium on carbon 2.0 g (4 wt%) were added. The reaction mixture was reacted under 10 MPa hydrogen at 40 °C for 48 h. HPLC detection showed that the reaction was complete. Filtration, concentration and recrystallization in methanol / ethyl acetate gave A3 compound 33.6 g, with a yield of 96% and a purity of more than 99%. The HPLC spectrum thereof is shown in Figure 3, and the corresponding integral results are shown in Table 3. Table 3. Integral results table of Figure 3 Example 7. Preparation of A3 A2 compound was prepared according to the method of Example 1. In a reaction kettle, A2 compound 50.0 g, methanol 250 mL and tetrahydrofuran 250 mL, palladium hydroxide on carbon 2.0 g (4 wt%) were added. The reaction mixture was reacted under 10 MPa hydrogen at 40 °C for 48 h. HPLC detection showed that the reaction was complete. Filtration, concentration and recrystallization in methanol / ethyl acetate gave A3 compound 25.9 g, with a yield of 74% and a purity of more than 99%. Example 8. Preparation of A3 A2 compound was prepared according to the method of Example 1. In a reaction kettle, A2 compound 50.0 g, methanol 250 mL and tetrahydrofuran 250 mL, palladium hydroxide on carbon 2.0 g (4 wt%) were added. The reaction mixture was reacted under 10 MPa hydrogen at 40 °C for 48 h. HPLC detection showed that the reaction was complete. Filtration, concentration and recrystallization in methanol / ethyl acetate gave A3 compound 25.9 g, with a yield of 74% and a purity of more than 99%. Example 9. Preparation of A3 The A2 compound was prepared according to the method of Example 1. In a reaction flask, the A2 compound 50.0 g was added, methanol 250 mL and tetrahydrofuran 250 mL, palladium on carbon 1.0 g (2 wt%), the reaction mixture was reacted under 10 MPa hydrogen at 40 °C for 48 h. The reaction was detected by HPLC to be complete, filtered, concentrated, and recrystallized in methanol / ethyl acetate to obtain the A3 compound 18.9 g, with a yield of 54% and a purity of more than 99%. Example 10. Preparation of A4 The A3 compound was prepared according to the method of Example 6. In a three-necked flask, the A3 compound 100 g and dichloromethane 500 mL were added, acetic anhydride 100 mL and 4-dimethylaminopyridine 4.5 g were added, and the reaction was maintained at 25 °C for 0.5 h, ammonium chloride was added to quench, dilute hydrochloric acid was added to wash away the 4-dimethylaminopyridine, saturated sodium bicarbonate solution was added to neutralize, separated, washed with saturated brine, dried, filtered, concentrated, and crystallized with ethyl acetate and n-hexane to obtain the A4 compound 119.0 g, with a yield of 91% and a purity of more than 98%. The qualitative spectrum of the A4 compound is shown in Figures 7-9. 1 H NMR (500 MHz, CDCl3) δ 7.31 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.90-6.77 (m, 3H), 3.82 (s, 3H), 2.99 (d, J = 14.8 Hz, 4H), 2.86-2.78 (m, 1H), 2.32 (s, 3H), 2.19 (s, 3H), 2.06 (s, 1H), 1.96 (d, J = 9.8 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 169.95, 168.96, 158.21, 148.69, 137.52, 135.13, 134.13, 129.94, 126.98, 121.66, 119.04, 112.60, 110.46, 55.39, 36.72, 34.35, 29.94, 29.42, 24.28, 21.12. First, from the hydrogen spectrum analysis, there are three methyl groups δ H = 2.19 (No. 1); δ H = 2.32 (No. 20); δ H= 3.82 (No. 21), methyl hydrogen of phenol acetyl, methyl hydrogen of acetic amide and methyl hydrogen of methoxyl, respectively. Second, from the carbon spectrum, the chemical shifts of No. 2 and 19 are 169.95 and 168.96, respectively, which are the carbons of ester and amide according to the table of chemical shifts of some characteristic carbons in the page 192 of the first volume of the fourth edition of the book of Basic Organic Chemistry. From the analysis of the high field of the chemical shifts of the carbon spectrum, there are seven alkyl carbons, such as only one acetyl group, there are only six alkyl carbons in the high field of the chemical shifts. Finally, from the mass spectrum analysis, the accurate molecular weight of the A4 compound is 353, and the accurate molecular weight of the monoacetylated compound 311 is not observed in the mass spectrum. + = 354; [M+NH4] + = 371; [M+Na] + = 376; [M+K] + = 392; [2M+H] + = 707; [2M+Na] + = 729; [2M+NH4] + = 724; [2M+K] + = 745, while the accurate molecular weight 311 of the monoacetylated compound is not observed. It can be seen that the A4 compound can be identified as a diacetylated product. Example 11. Preparation of A4 The A3 compound was prepared according to the method of Example 6. In a three-necked flask, A3 compound 100 g and tetrahydrofuran 500 mL were added, triethylamine 150 g was added, and the temperature was lowered to 0°C, acetyl chloride 70 g was slowly added dropwise, the temperature was raised to 25°C and maintained for 5.0 h, ammonium chloride was added to quench, extracted with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and crystallized with ethyl acetate and n-hexane to obtain A4 compound 112.0 g with a yield of 86% and a purity of more than 98%. Example 12. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-necked flask, A4 compound 100 g and tetrahydrofuran 1000 mL were added, sodium borohydride 48.0 g and boron trifluoride etherate 240.0 g were added, the temperature was raised to 65°C and reacted for 1 h, dilute hydrochloric acid was added to quench, neutralized with saturated sodium bicarbonate solution, separated into two layers with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and crystallized with tetrahydrofuran and n-hexane to obtain A5 compound 81.0 g with a yield of 96% and a purity of more than 98%. Example 13. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 100 g and tetrahydrofuran 1000 mL were added, sodium borohydride 48.0 g and iodine 71.9 g were added, and the mixture was heated to 65 °C for 2 h. The reaction was quenched by adding 500 mL of concentrated hydrochloric acid, neutralized by adding saturated sodium bicarbonate solution, partitioned with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and crystallized from tetrahydrofuran and n-hexane to obtain the A5 compound 76.6 g in a yield of 91% and a purity of more than 98%. Example 14. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 100 g and tetrahydrofuran 1000 mL were added, sodium borohydride 48.0 g and iodine 71.9 g were added, and the mixture was heated to 65 °C for 2 h. The reaction was quenched by adding 500 mL of concentrated hydrochloric acid, neutralized by adding saturated sodium bicarbonate solution, partitioned with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and crystallized from tetrahydrofuran and n-hexane to obtain the A5 compound 76.6 g in a yield of 91% and a purity of more than 98%. Example 15. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 100 g and tetrahydrofuran 1000 mL were added, sodium borohydride 48.0 g and iodine 71.9 g were added, and the mixture was heated to 65 °C for 2 h. The reaction was quenched by adding 500 mL of concentrated hydrochloric acid, neutralized by adding saturated sodium bicarbonate solution, partitioned with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and crystallized from tetrahydrofuran and n-hexane to obtain the A5 compound 76.6 g in a yield of 91% and a purity of more than 98%. Example 16. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 100 g and tetrahydrofuran 1000 mL were added, sodium borohydride 48.0 g and iodine 71.9 g were added, and the mixture was heated to 65 °C for 2 h. The reaction was quenched by adding 500 mL of concentrated hydrochloric acid, neutralized by adding saturated sodium bicarbonate solution, partitioned with ethyl acetate, washed with saturated brine, dried, filtered, concentrated, and crystallized from tetrahydrofuran and n-hexane to obtain the A5 compound 76.6 g in a yield of 91% and a purity of more than 98%. Example 17. Preparation of A6 The A5 compound was prepared according to the method of Example 12. In a three-neck flask, the A5 compound 104.0 g was added, acetonitrile 1040 mL was added, and the mixture was heated to 60 °C until clear. L-(-)-dibenzoyl tartaric acid 72.4 g was added, and the mixture was heated to 65 °C until clear. The mixture was slowly cooled to 22 °C, filtered, and dried. Methanol 240 mL and water 480 mL were added, and 25% potassium bicarbonate solution 1000 mL was added dropwise. The mixture was stirred at room temperature for 3 h, filtered, and washed to obtain the A6 compound 48.1 g in a yield of 48%, a purity of more than 99%, and an ee value of 99.8%. The HPLC detection results are shown in FIG. 10, and the integration results are shown in Table 4. Table 4. Table of integration results for Figure 10 Example 18. Preparation of A6 The A5 compound was prepared according to the method of Example 12. In a three necked flask, A5 compound 104.0 g was added, acetonitrile 1040 mL was added, warmed to 60 °C until clear, L-(-)-dimethoxybenzoyl tartaric acid 84.5 g was added, warmed to 65 °C until clear, slowly cooled to 22 °C, suction filtered, dried, methanol 240 mL was added, water 480 mL was added, 25% potassium bicarbonate solution 1000 mL was added dropwise, stirred at room temperature for 3 h, suction filtered, washed to give A6 compound 32.1 g in 32% yield, purity greater than 99%, ee value 96.2%. Example 19. Preparation of A6 The A5 compound was prepared according to the method of Example 12. In a three necked flask, A5 compound 104.0 g was added, acetonitrile 1040 mL was added, warmed to 60 °C until clear, L-(-)-dimethoxybenzoyl tartaric acid 84.5 g was added, warmed to 65 °C until clear, slowly cooled to 22 °C, suction filtered, dried, methanol 240 mL was added, water 480 mL was added, 25% potassium bicarbonate solution 1000 mL was added dropwise, stirred at room temperature for 3 h, suction filtered, washed to give A6 compound 32.1 g in 32% yield, purity greater than 99%, ee value 96.2%. Example 20. Preparation of A6 The A5 compound was prepared according to the method of Example 12. In a three necked flask, A5 compound 104.0 g was added, acetonitrile 1040 mL was added, warmed to 60 °C until clear, L-(-)-dimethoxybenzoyl tartaric acid 84.5 g was added, warmed to 65 °C until clear, slowly cooled to 22 °C, suction filtered, dried, methanol 240 mL was added, water 480 mL was added, 25% potassium bicarbonate solution 1000 mL was added dropwise, stirred at room temperature for 3 h, suction filtered, washed to give A6 compound 32.1 g in 32% yield, purity greater than 99%, ee value 96.2%. Example 21. Preparation of A7 The A6 compound was prepared according to the method of Example 17. In a three-necked flask, A6 compound 60.0 g and dichloromethane 900 mL were added, after the solution was stirred and dissolved, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and glacial acetic acid 8.0 g were added, after reaction for 3 h at 20 °C, then N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and glacial acetic acid 8.0 g were added again, after reaction for 3 h at the same temperature, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and glacial acetic acid 8.0 g were added again, the reaction was monitored by HPLC, after the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added for extraction, the organic phase was combined and concentrated under reduced pressure, concentrated hydrochloric acid was added to adjust pH = 1, ethyl acetate was added for extraction, saturated brine was washed, anhydrous sodium sulfate was dried, concentrated under reduced pressure, and crystallized by methanol and ethyl acetate to obtain A7 compound 86.7 g with a yield of 91% and a purity of more than 99%. The HPLC chromatogram of the reaction liquid is shown in Figure 4, and the corresponding integral results are shown in Table 5. In Figure 4 and Table 5, C10 refers to the A5 compound, C07 refers to the A7 compound, and C09 refers to N-ethyl-2-(4-formylphenyl)acetamide. Table 5. Integral results table of Figure 4 Example 22. Preparation of A7 The A6 compound was prepared according to the method of Example 17. In a three-necked flask, A6 compound 60.0 g and dichloromethane 900 mL were added, after the solution was stirred and dissolved, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and glacial acetic acid 8.0 g were added, after reaction for 3 h at 20 °C, then N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and glacial acetic acid 8.0 g were added again, after reaction for 3 h at the same temperature, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and glacial acetic acid 8.0 g were added again, the reaction was monitored by HPLC, after the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added for extraction, the organic phase was combined and concentrated under reduced pressure, concentrated hydrochloric acid was added to adjust pH = 1, ethyl acetate was added for extraction, saturated brine was washed, anhydrous sodium sulfate was dried, concentrated under reduced pressure, and crystallized by methanol and ethyl acetate to obtain A7 compound 86.7 g with a yield of 91% and a purity of more than 99%. The HPLC chromatogram of the reaction liquid is shown in Figure 4, and the corresponding integral results are shown in Table 5. In Figure 4 and Table 5, C10 refers to the A5 compound, C07 refers to the A7 compound, and C09 refers to N-ethyl-2-(4-formylphenyl)acetamide. Example 23. Preparation of A7 The A6 compound was prepared according to the method of Example 17. In a three-necked flask, A6 compound 60.0 g and dichloromethane 900 mL were added, after the solution was stirred, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and L-(-)-dibenzoyl tartaric acid 47.7 g were added, after reaction for 3 h at 20 °C, then N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and L-(-)-dibenzoyl tartaric acid 47.7 g were added again, after reaction for 3 h at the same temperature, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and L-(-)-dibenzoyl tartaric acid 47.7 g were added again, the reaction was monitored by HPLC, after the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added to extract, the organic phase was combined and concentrated under reduced pressure, concentrated hydrochloric acid was added to adjust pH = 1, ethyl acetate was added to extract, saturated brine was washed, anhydrous sodium sulfate was dried, concentrated under reduced pressure, and crystallized by methanol and ethyl acetate to obtain A7 compound 23.8 g with a yield of 25% and a purity of more than 99%. Example 24. Preparation of A7 The A6 compound was prepared according to the method of Example 17. In a three-necked flask, A6 compound 60.0 g and dichloromethane 900 mL were added, after the solution was stirred, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and L-(-)-dibenzoyl tartaric acid 47.7 g were added, after reaction for 3 h at 20 °C, then N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and L-(-)-dibenzoyl tartaric acid 47.7 g were added again, after reaction for 3 h at the same temperature, N-ethyl-2-(4-formylphenyl)acetamide 25.7 g, sodium triacetylboration hydride 42.2 g and L-(-)-dibenzoyl tartaric acid 47.7 g were added again, the reaction was monitored by HPLC, after the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added to extract, the organic phase was combined and concentrated under reduced pressure, concentrated hydrochloric acid was added to adjust pH = 1, ethyl acetate was added to extract, saturated brine was washed, anhydrous sodium sulfate was dried, concentrated under reduced pressure, and crystallized by methanol and ethyl acetate to obtain A7 compound 23.8 g with a yield of 25% and a purity of more than 99%. Example 25. Preparation of Elacestrant The A7 compound was prepared according to the method of Example 21. In a three-necked flask, A7 compound 72.0 g and tetrahydrofuran 400 mL were added, sodium borohydride 23.3 g was added slowly at 0 °C, boron trifluoride etherate 115.1 g was added dropwise, the temperature was raised to 65 °C and maintained for 1 h, the reaction was monitored by HPLC, after the reaction was completed, the temperature was lowered to 25 °C, 1 M hydrochloric acid 200 mL was added, the temperature was raised to 70 °C, stirring was maintained for 1 h, the temperature was lowered, saturated sodium bicarbonate 350 mL was added to neutralize the reaction solution, it was extracted, dried, filtered, concentrated to obtain the crude elacridar, methanol and ethyl acetate were added to crystallize to obtain elacridar 64.6 g, the yield was 92%, and the purity was greater than 99%. The HPLC chromatogram is shown in Figure 5, and the corresponding integral results are shown in Table 6. Table 6. Integral results table of Figure 5 Example 26. Preparation of elacridar The A7 compound was prepared according to the method of Example 21. In a three-necked flask, A7 compound 72.0 g and tetrahydrofuran 400 mL were added, sodium borohydride 23.3 g was added slowly at 0 °C, boron trifluoride etherate 115.1 g was added dropwise, the temperature was raised to 65 °C and maintained for 1 h, the reaction was monitored by HPLC, after the reaction was completed, the temperature was lowered to 25 °C, 1 M hydrochloric acid 200 mL was added, the temperature was raised to 70 °C, stirring was maintained for 1 h, the temperature was lowered, saturated sodium bicarbonate 350 mL was added to neutralize the reaction solution, it was extracted, dried, filtered, concentrated to obtain the crude elacridar, methanol and ethyl acetate were added to crystallize to obtain elacridar 64.6 g, the yield was 92%, and the purity was greater than 99%. The HPLC chromatogram is shown in Figure 5, and the corresponding integral results are shown in Table 6. Example 27. Preparation of elacridar The A7 compound was prepared according to the method of Example 21. In a three-necked flask, A7 compound 72.0 g and tetrahydrofuran 400 mL were added, sodium borohydride 23.3 g was added slowly at 0 °C, boron trifluoride etherate 115.1 g was added dropwise, the temperature was raised to 65 °C and maintained for 1 h, the reaction was monitored by HPLC, after the reaction was completed, the temperature was lowered to 25 °C, 1 M hydrochloric acid 200 mL was added, the temperature was raised to 70 °C, stirring was maintained for 1 h, the temperature was lowered, saturated sodium bicarbonate 350 mL was added to neutralize the reaction solution, it was extracted, dried, filtered, concentrated to obtain the crude elacridar, methanol and ethyl acetate were added to crystallize to obtain elacridar 64.6 g, the yield was 92%, and the purity was greater than 99%. The HPLC chromatogram is shown in Figure 5, and the corresponding integral results are shown in Table 6. Example 28. Preparation of elacridar The A7 compound was prepared according to the method of Example 21. In a three-necked flask, A7 compound 72.0 g and tetrahydrofuran 400 mL were added, sodium borohydride 23.3 g was added slowly at 0 °C, boron trifluoride etherate 115.1 g was added dropwise, the temperature was raised to 65 °C and maintained for 1 h, the reaction was monitored by HPLC, after the reaction was completed, the temperature was lowered to 25 °C, 1 M hydrochloric acid 200 mL was added, the temperature was raised to 70 °C, stirring was maintained for 1 h, the temperature was lowered, saturated sodium bicarbonate 350 mL was added to neutralize the reaction solution, it was extracted, dried, filtered, concentrated to obtain the crude elacridar, methanol and ethyl acetate were added to crystallize to obtain elacridar 64.6 g, the yield was 92%, and the purity was greater than 99%. The HPLC chromatogram is shown in Figure 5, and the corresponding integral results are shown in Table 6. Example 29. Preparation of elacridar The A7 compound was prepared according to the method of Example 21. In a three-necked flask, lithium aluminum hydride 17.4 g and tetrahydrofuran 400 mL were added, and the temperature was controlled below 10 °C. Aluminum chloride 61.1 g was added, and the temperature was raised to room temperature and stirred for 1 h. The A7 compound in tetrahydrofuran (72.0 g / 200 mL) was added dropwise, and the temperature was raised to 65 °C and stirred for 2 h. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched by the addition of ammonia water. The mixture was filtered and concentrated to give the crude iralesium. The product was crystallized from methanol and ethyl acetate to give iralesium 59.7 g with a yield of 85% and a purity of more than 99%. Example 30. Preparation of A4 The A3 compound was prepared according to the method of Example 6. In a three-necked flask, the A3 compound 1000 g and dichloromethane 5000 mL were added. Acetic anhydride 1000 mL and 4-dimethylaminopyridine 45 g were added, and the temperature was maintained at 25 °C for 1.5 h. Ammonium chloride was added to quench the reaction. Dilute hydrochloric acid was added to wash away the 4-dimethylaminopyridine. The mixture was neutralized by the addition of saturated sodium bicarbonate solution. The mixture was separated, washed with saturated brine, dried, filtered, and concentrated. The product was crystallized from ethyl acetate and n-hexane to give the A4 compound 1249.5 g with a yield of 95.2% and a purity of more than 98%. Example 31. Preparation of A4 The A3 compound was prepared according to the method of Example 6. In a three-necked flask, the A3 compound 10 g and dichloromethane 50 mL were added. Acetic anhydride 10 mL and 4-dimethylaminopyridine 0.45 g were added, and the temperature was maintained at 5 °C for 5 h. Ammonium chloride was added to quench the reaction. Dilute hydrochloric acid was added to wash away the 4-dimethylaminopyridine. The mixture was neutralized by the addition of saturated sodium bicarbonate solution. The mixture was separated, washed with saturated brine, dried, filtered, and concentrated. The product was crystallized from ethyl acetate and n-hexane to give the A4 compound 10.46 g with a yield of 79.7% and a purity of more than 98%. Example 32. Preparation of A4 The A3 compound was prepared according to the method of Example 6. In a three-necked flask, the A3 compound 10 g and dichloromethane 50 mL were added. Acetic anhydride 10 mL and 4-dimethylaminopyridine 0.45 g were added, and the temperature was maintained at 25 °C for 1.5 h. Ammonium chloride was added to quench the reaction. Dilute hydrochloric acid was added to wash away the 4-dimethylaminopyridine. The mixture was neutralized by the addition of saturated sodium bicarbonate solution. The mixture was separated, washed with saturated brine, dried, filtered, and concentrated. The product was crystallized from ethyl acetate and n-hexane to give the A4 compound 10.46 g with a yield of 79.7% and a purity of more than 98%. Example 33. Preparation of A4 The A3 compound was prepared according to the method of Example 6. In a three-neck flask, the A3 compound 10 g and dichloromethane 50 mL were added, acetic anhydride 10 mL and 4-dimethylaminopyridine 0.45 g were added, and the reaction was maintained at 25 °C for 1.5 h. Ammonium chloride was added to quench the reaction, dilute hydrochloric acid was added to wash away the 4-dimethylaminopyridine, saturated sodium bicarbonate solution was added to neutralize, and the mixture was separated, washed with saturated brine, dried, filtered, concentrated, and crystallized from ethyl acetate and cyclohexane to obtain the A4 compound 11.43 g with a yield of 87.1% and a purity of more than 98%. Example 34. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 10 g and tetrahydrofuran 100 mL were added, sodium borohydride 4.8 g and boron trifluoride etherate 24.0 g were added, and the reaction was maintained at 65 °C for 1 h. Dilute hydrochloric acid was added to quench the reaction, saturated sodium bicarbonate solution was added to neutralize, ethyl acetate was added to separate the mixture, saturated brine was added to wash, the mixture was dried, filtered, concentrated, and crystallized from ethyl acetate and n-hexane to obtain the A5 compound 8.05 g with a yield of 95.7% and a purity of more than 98%. Example 35. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 10 g and tetrahydrofuran 100 mL were added, sodium borohydride 4.8 g and boron trifluoride etherate 24.0 g were added, and the reaction was maintained at 45 °C for 1 h. Dilute hydrochloric acid was added to quench the reaction, saturated sodium bicarbonate solution was added to neutralize, ethyl acetate was added to separate the mixture, saturated brine was added to wash, the mixture was dried, filtered, concentrated, and crystallized from ethyl acetate and n-hexane to obtain the A5 compound 7.24 g with a yield of 86.0% and a purity of more than 98%. Example 36. Preparation of A5 The A4 compound was prepared according to the method of Example 10. In a three-neck flask, the A4 compound 10 g and tetrahydrofuran 100 mL were added, sodium borohydride 4.8 g and boron trifluoride etherate 24.0 g were added, and the reaction was maintained at 55 °C for 1 h. Dilute hydrochloric acid was added to quench the reaction, saturated sodium bicarbonate solution was added to neutralize, ethyl acetate was added to separate the mixture, saturated brine was added to wash, the mixture was dried, filtered, concentrated, and crystallized from tetrahydrofuran and n-hexane to obtain the A5 compound 7.83 g with a yield of 93.0% and a purity of more than 98%. Example 37. Experimental results and analysis of Examples 1-36 (1) Examples 1-5 Examples 1-5 are the preparation methods of A2, which are prepared by using different palladium catalysts. The results are shown in Table 7. The A2 compound can be successfully prepared by using dichlorobis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, or tetrakis(triphenylphosphine)palladium as the palladium catalyst. Among them, the product yield is best when dichlorobis(triphenylphosphine)palladium is used as the palladium catalyst. Table 7. Experimental conditions and results table for preparing compound A2 in Examples 1-5 (2) Examples 6-9 Examples 6-9 are the preparation methods of A3, which are prepared by using different catalysts respectively. The results are shown in Table 8, and A3 compounds can be successfully prepared by using palladium hydroxide on carbon or palladium carbon as catalysts. Table 8. Experimental conditions and results table for preparing compound A3 in Examples 6-9 (3) Examples 10-11, 30-33 Examples 10-11, 30-33 are the preparation methods of A4, wherein Examples 10-11 are prepared by using different acetylating reagents respectively. The results are shown in Table 9, and A4 compounds can be successfully prepared by using acetic anhydride or acetyl chloride as acetylating reagent. Examples 30-33 use different reaction temperatures or crystallization solvents, and the reaction temperature of 25℃ has a higher yield, and the yield decreases when the reaction temperature is reduced to 5℃. Table 9. Experimental conditions and results table for preparing compound A4 in Examples 10-11 (4) Examples 12-16, 34-36 Examples 12-16, 34-36 are the preparation methods of A5. Among them, Examples 12-16 are prepared by using different reducing agents respectively. The results are shown in Table 10, and A5 can be prepared by using any one combination of sodium borohydride and boron trifluoride ether, sodium borohydride and iodine, sodium borohydride and trifluoroacetic acid, lithium aluminum hydride and aluminum chloride as reducing agent, wherein the combination of sodium borohydride and boron trifluoride ether, or the combination of sodium borohydride and iodine as reducing agent to prepare A5 has the best yield; and the yield of compound A5 prepared by using single lithium aluminum hydride as reducing agent is lower. Examples 34-36 use different reaction temperatures or crystallization solvents. When the reaction temperature is increased to 55-65℃, the yield is higher; when the reaction temperature is increased to 45℃, the yield decreases. Table 10. Experimental conditions and results table for preparing compound A5 in Examples 12-16 (5) Examples 17-20 Examples 17-20 are the preparation methods of A6, which are prepared by using different resolving agents respectively. The results are shown in Table 11, and A6 can be prepared by using L-(-)-dibenzoyl tartaric acid, L-(-)-di-p-toluoyl tartaric acid or L-(-)-di-p-methoxybenzoyl tartaric acid as resolving agent. Table 11. Experimental conditions and results table for preparing compound A6 in Examples 17-20 (6) Examples 21-24 Examples 21-24 are the preparation methods of A7, which are prepared by using different catalysts respectively; and the feeding mode is three batches. The results are shown in Table 12, and the preparation of compound A7 can be realized by using glacial acetic acid, trifluoroacetic acid or tartaric acid as catalyst, and the yield is the highest when glacial acetic acid is used as catalyst. Table 12. Experimental conditions and results of preparing compound A7 in Examples 21-24 (7) Examples 25-29 Examples 25-29 are the preparation methods of Elacestrant, which are prepared by using different reducing agents respectively. The results are shown in Table 13, Table 13. Experimental conditions and results of preparing compound Elacestrant in Examples 25-29 Comparative Example 1 The present application refers to the technical solution of CN113348163A patent, and Elacestrant is synthesized by using 7-benzyloxy-3-bromo-1,2-dihydronaphthalene as starting material, and the synthesis route is shown in Figure 6. It is found that compound i in the synthesis route is a by-product of reductive amination, and the main product in the synthesis process is compound i'. HPLC content detection finds that the content of compound i is 17.8%; the content of compound i' is 62.5%. This method is difficult to realize effective conversion to compound i, and the yield is low. And the peak time of compounds i and i' is similar, which is difficult to purify by crystallization and column chromatography technology, which has a great influence on the whole process yield and product quality. And the whole process synthesis cycle is long, and a large amount of waste acid is produced, which is very harmful to the environment. Comparative Example 2 CN117229157A patent discloses a method for preparing Elacestrant by using compound j as raw material, and the synthesis route is as follows: Among them, the compound of formula n is reduced and aminated by acetaldehyde, and the finished product will inevitably introduce diethyl impurities, which are difficult to purify due to similar structures. In order to better prove this point, the present application reduces and aminates compound A3 with acetaldehyde to obtain a diethyl compound, whose molecular formula is C 21 H 27 NO2, the accurate mass is 325.2042, and the structural formula is shown as formula IX. The HPLC detection spectrum is shown in Figure 12, and the mass spectrum is shown in Figure 11. From the results, it can be speculated that the compound of formula n is reduced and aminated by acetaldehyde, and the finished product is easy to introduce diethyl impurities. The process route proposed by the present application avoids the generation of this impurity, so that Elacestrant finished product can be obtained in high quality. Comparative Example 3 The synthetic route of CN117229157A patent is shown in Comparative Example 2. In the first step of CN117229157A patent, compound j is resolved by D-(-)-dibenzoyl tartaric acid to obtain compound k with absolute configuration. However, D-(-)-dibenzoyl tartaric acid is used as a resolving agent, which can produce another configuration. The present application is confirmed by the following experiment: A5 compound is prepared according to the method of Reference Example 12. In a three-necked flask, A5 compound 104.0 g is added, acetonitrile 1040 mL is added, and the temperature is raised to 60°C to dissolve the solution. D-(-)-dibenzoyl tartaric acid 72.4 g is added, and the temperature is raised to 65°C to dissolve the solution. The temperature is slowly lowered to 22°C, and the filter is extracted. The filter is dried, and methanol 240 mL and water 480 mL are added. 25% potassium bicarbonate solution 1000 mL is added dropwise, and the temperature is maintained at room temperature for 3h. The filter is extracted, and the product is washed to obtain A6 compound 48.1 g with a yield of 46%, a purity of more than 99%, and an ee value of -98.9%. The HPLC detection results are shown in Figure 13, and the integration results are shown in Table 14. Table 14. Integration results table of Figure 13 Comparative Example 4 The residual trace amount of aluminum salt in the intermediate produced by the reduction of lithium tetrahydrochloride in WO2004058682A1 patent can coordinate with the resolving agent, resulting in no resolving ability of the resolving agent. The present application further confirms this conclusion by the following experiment: A5 compound is prepared according to the method of Reference Example 15. In a three-necked flask, A5 compound 104.0 g is added, acetonitrile 1040 mL is added, and the temperature is raised to 60°C to dissolve the solution. L-(-)-dibenzoyl tartaric acid 72.4 g is added, and the temperature is raised to 65°C to dissolve the solution. The temperature is slowly lowered to 22°C, and the filter is extracted. The filter is dried, and methanol 240 mL and water 480 mL are added. 25% potassium bicarbonate solution 1000 mL is added dropwise, and the temperature is maintained at room temperature for 3h. The filter is extracted, and the product is washed to obtain white solid with an ee value of 2.3%. The HPLC detection results are shown in Figure 14, and the integration results are shown in Table 15. The results prove that the aluminum salt possibly contained in the product reduced by lithium tetrahydrochloride can cause the failure of resolution. The route of the present application improves the yield by synthesizing diacetylated A4 compound, and avoids the influence of aluminum salt on the resolving agent, thereby significantly improving the resolution effect. Table 15. Integration results table of Figure 14

Claims

1. A process for the preparation of intermediate compound A4 of Elacestrant, characterized in that, The method comprises: preparing compound A4 by subjecting compound A3 to acetylation reaction under the action of an acetylation reagent; the structural formula of the compound A3 is as shown in formula III; and the structural formula of the compound A4 is as shown in formula IV.

2. The production method according to claim 1, characterized by, The acetylating agent comprises any one or more of acetyl chloride, acetic anhydride.

3. The preparation method according to claim 1, characterized in that, The solvent of the acetylation reaction is any one or more of dichloromethane, tetrahydrofuran; And / or the acetylation reaction is carried out in the presence of 4-dimethylaminopyridine or triethylamine; And / or the reaction temperature of the acetylation reaction is 22-27℃, and the reaction time is 0.4-1h; And / or the mass ratio of the compound A3 and the acetylating agent is 1:0.5-1.

5.

4. The method of claim 1, wherein, The compound A3 is prepared by the following method: (1) using compound A1 and 4-bromo-3-nitroanisole as raw materials, compound A2 is obtained by suzuki coupling reaction; (2) compound A2 obtained in step (1) is subjected to catalytic hydrogenation and debenzyl reaction to obtain compound A3; The structural formula of the compound A1 is shown as formula I; the structural formula of the compound A2 is shown as formula II; 5. The method of claim 4, wherein, In step (1), the suzuki coupling reaction is carried out in the presence of a palladium catalyst, and the palladium catalyst is any one or more of dichlorobis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, and palladium acetate; the amount of the palladium catalyst is 0.3mol%-1.2mol%; And / or in step (1), the suzuki coupling reaction is carried out in the presence of a boron reagent, and the boron reagent is pinacol diboron; The mass ratio of the compound A1 and the boron reagent is 1:0.8-1.2; And / or in step (1), the suzuki coupling reaction is carried out in the presence of a base, and the base is any one or more of potassium acetate and KHCO3; And / or in step (1), the reaction solvent of the suzuki coupling reaction is any one or more of ethylene glycol dimethyl ether and 1,4-dioxane; And / or in step (1), the mass ratio of the compound A1 and the 4-bromo-3-nitroanisole is 1:0.5-1, preferably 1:0.

74.

6. The method of claim 4, wherein, In step (2), the reaction solvent is any one or more of methanol and tetrahydrofuran; And / or the hydrogen reduction reaction is carried out in the presence of a catalyst, and the catalyst is any one or more of palladium hydroxide / carbon and palladium / carbon, and the amount of the catalyst is 4wt%-8wt%; And / or the reaction conditions of the hydrogen reduction are as follows: 5-15MPa hydrogen, 35-50℃, and 40-60h.

7. Compound A4 produced by the method of claim 1, characterized by, The structural formula of the compound A4 is shown as formula IV.

8. Process for the preparation of irasposim, characterized in that, Comprising the following steps: S1: preparing compound A4 by the method of any one of claims 1-6; S2: obtaining compound A5 by reacting compound A4 obtained in S1 in the presence of a reducing agent; S3: obtaining compound A6 by reacting compound A5 obtained in S2 in the presence of a resolving agent; S4: obtaining compound A7 by subjecting compound A6 obtained in S3 to reductive amination with N-ethyl-2-(4-formylphenyl)acetamide; S5: obtaining irasugrel by reacting compound A7 obtained in S4 in the presence of a reducing agent; The structural formula of the compound A5 is shown in formula V; the structural formula of the compound A6 is shown in formula VI; and the structural formula of the compound A7 is shown in formula VII; The structural formula of said elagolix is shown as formula VIII.

9. The preparation method according to claim 8, characterized in that, In S2, the reducing agent is any one of sodium borohydride combined with boron trifluoride ether, sodium borohydride combined with iodine, sodium borohydride combined with trifluoroacetic acid, lithium aluminum hydride combined with aluminum chloride; In S2, the reaction solvent is tetrahydrofuran; In S2, the reaction condition is 50-80℃ for 0.5-2h; In S2, the molar ratio of compound A4 to reducing agent is 1:3-5.

10. The preparation method according to claim 8, characterized in that, In S3, the resolving agent is any one or more of L-(-)-dibenzoyl tartaric acid, L-(-)-di-p-toluoyl tartaric acid, L-(-)-di-p-methoxybenzoyl tartaric acid; In S3, the reaction solvent is acetonitrile; In S3, the mass ratio of compound A5 to resolving agent is 1:0.5-1.5; In S3, the reaction condition is warming to 50-70℃ until the solution is clear.

11. The preparation method according to claim 8, characterized in that, In S4, the reducing agent is sodium triacetyl borohydride; In S4, the reductive amination is carried out in the presence of a catalyst, which is any one or more of glacial acetic acid, trifluoroacetic acid, tartaric acid; In S4, the reaction solvent is dichloromethane; In S4, the mass ratio of compound A6 to N-ethyl-2-(4-formylphenyl)acetamide is 1:1-2; In S4, the mass ratio of compound A6 to reducing agent is 1:1.8-5. In S4, the mass ratio of compound A6 to catalyst is 1:0.3-1.

12. The method of claim 8, wherein, In S4, the protecting group is ethyl.

13. The preparation method according to claim 8, characterized in that, In S4, N-ethyl-2-(4-formylphenyl)acetamide, reducing agent and catalyst are added in three batches; after the first two additions, the reaction is carried out at 20℃ for 3h; after the third addition, HPLC is used to monitor the reaction until completion.

14. The preparation method according to claim 8, characterized in that, In S5, the reducing agent is any one of sodium borohydride and boron trifluoride ether, sodium borohydride and iodine, sodium borohydride and trifluoroacetic acid, lithium aluminum hydride and aluminum chloride; In S5, the reaction solvent is tetrahydrofuran; In S5, the molar ratio of compound A7 to reducing agent is 1:3-5. In S5, the reaction condition is 50-80℃ for 0.5-2h.

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