Method for preparing key intermediate of Alalisset
By employing a four-step reaction involving triphenylmethyl etherification and Raney nickel-catalyzed hydrogenation, the problems of high palladium catalyst usage and benzyl instability were solved, enabling the efficient and low-cost preparation of ellaxis group intermediates and improving yield and purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANGHAI GELINKAI BIOTECHNOLOGY CO LTD
- Filing Date
- 2025-12-31
- Publication Date
- 2026-05-12
Smart Images
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthetic chemistry. Specifically, it relates to a method for preparing a key intermediate of ellastatin. Background Technology
[0002] Elacestrant is a novel, orally administered selective estrogen receptor degrader that binds to estrogen receptor α (ERα) and induces ERα protein degradation via the proteasome pathway, inhibiting 17β-estradiol-mediated cell proliferation. In 2023, the European Commission approved elacestrant for the treatment of patients with ER+, HER2- locally advanced or metastatic breast cancer who have activating ESR1 mutations. The structural formula of elacestrant is shown in Formula I.
[0003]
[0004] Formula I
[0005] The N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)acetamide intermediate involved in this invention is a key intermediate in the synthesis of ellastatin, and its structure is shown in Formula II below:
[0006]
[0007] Formula II
[0008] The original process for the allergic rash group was reported in patent document CN113348163A, in which the synthetic route of compound (5) is shown in formula III below:
[0009]
[0010] Formula III
[0011] This patent document describes the process of borylation and coupling of benzyl-protected alkenyl bromide followed by hydrogenation catalyzed by palladium hydroxide to obtain the intermediate compound of formula (5). The presence of the benzyl group increases the amount of palladium hydroxide metal catalyst required, thereby increasing the safety risks and costs of the reaction.
[0012] Patent document WO2004058682A1 discloses a method for synthesizing ellaxizone, wherein the synthesis of compound (5) is shown in formula IV below:
[0013] Formula IV
[0014] This patent document describes a process involving the introduction of a nitro group, followed by hydrogenation to simultaneously remove the benzyl group, reduce the double bond, and reduce the nitro group, resulting in compound (5). This route also presents challenges related to the large amount of palladium used on carbon and safety risks. Therefore, avoiding or reducing the amount of palladium catalyst used is crucial for large-scale production.
[0015] The modification of the phenolic hydroxyl group on the naphthalene ring plays a crucial role in the reaction. If an acyl group is used to form an ester compound with the phenolic hydroxyl group, the ester is easily hydrolyzed under alkaline conditions; if an alkane silyl ether is formed, it is inherently unstable; if a benzyl ether compound is formed, the ether bond cleavage requires a palladium catalyst, which inevitably leads to safety risks, and palladium catalysts are expensive. Therefore, finding a suitable phenolic hydroxyl modification group and avoiding the use of expensive palladium catalysts is of great significance for the efficient and simple preparation of the drug ellaxistatin. Summary of the Invention
[0016] This invention discloses a method for preparing a key intermediate of ellastatin. The method uses 6-bromo-7,8-dihydronaphth-2-ol as a starting material and prepares the ellastatin intermediate N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)acetamide through a four-step reaction involving etherification, coupling, nickel-catalyzed hydrogenation, and ether bond cleavage. This method avoids the use of expensive palladium-based metal catalysts by etherifying the 2-position alcohol with triphenylmethyl groups and employing Raney nickel-catalyzed hydrogenation, thus reducing hydrogenation costs and offering advantages such as high yield and convenient post-processing.
[0017] Benzyl groups, used as protecting groups for phenolic hydroxyl groups, are employed in most patent literature for the preparation of alasic intermediates. However, during coupling, the instability of the benzyl group leads to low reaction yields and numerous impurities. Therefore, this invention proposes for the first time the use of triphenylmethyl groups as protecting groups for phenolic hydroxyl groups, which can stably prepare coupling products, improve yields, and facilitate purification.
[0018] There are no reports of nickel-catalyzed hydrogenation in the preparation of alasic intermediates because the presence of the benzyl group inevitably necessitates the use of a palladium catalyst for benzyl removal. Removing the benzyl protecting group under acidic conditions leads to numerous side reactions with many impurities in the coupled structure, which is detrimental to the reaction. Therefore, the introduction of the triphenylmethyl protecting group not only significantly reduces the reduction cost but also facilitates and cleans the removal process, improving the quality standards of the product. This is the innovative technical point of this invention.
[0019] This invention provides a method for preparing a key intermediate of the alastrane group. The method uses 6-bromo-7,8-dihydronaphth-2-ol as a raw material and prepares the alastrane group intermediate N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)acetamide through the steps of triphenylmethyl etherification of the 2-hydroxyl group, coupling, nickel-catalyzed hydrogenation, and ether bond cleavage.
[0020] The reaction process of the method is as follows, as shown in the synthetic route (a):
[0021]
[0022] Synthesis route (a);
[0023] Where Tr stands for triphenylmethyl.
[0024] The method of the present invention includes the following steps:
[0025] Step (1) Etherification: The compound of formula (1) is dissolved in a first solvent, and triphenylmethyl chloride and an organic base are added to undergo an etherification reaction to prepare the compound of formula (2). The reaction process is shown in reaction formula (A):
[0026]
[0027] Reaction formula (A);
[0028] Where Tr stands for triphenylmethyl.
[0029] Step (2) Coupling reaction: Compound (2) is dissolved in a second solvent, and potassium carbonate, pinacol ester of 2-acetamido-5-methoxyphenylboronic acid, and a catalyst are added to induce a coupling reaction, thereby preparing compound (3). The reaction process is shown in reaction formula (B):
[0030]
[0031] Reaction formula (B);
[0032] Where Tr stands for triphenylmethyl.
[0033] Step (3) Hydrogenation reaction: The compound of formula (3) is dissolved in a third solvent, a metal catalyst is added, and a hydrogenation reaction occurs under a hydrogen atmosphere to prepare the compound of formula (4). The reaction process is shown in reaction formula (C):
[0034]
[0035] Reaction formula (C);
[0036] Where Tr stands for triphenylmethyl.
[0037] Step (4) Ether bond cleavage: Compound (4) is dissolved in a fourth solvent, and lithium chloride is added to prepare compound (5). The reaction process is shown in reaction (D):
[0038]
[0039] Reaction formula (D);
[0040] Where Tr stands for triphenylmethyl.
[0041] In step (1) of this invention, the etherification reaction specifically involves dissolving the compound of formula (1) in a first solvent, adding triphenylmethyl chloride and an organic base, and conducting an etherification reaction at a certain reaction temperature to prepare the compound of formula (2).
[0042] Wherein, the weight ratio of the compound of formula (1): triphenylmethyl chloride: organic base is 1:(0.5-2):(0.5-2); preferably, it is 1:1.2:0.5;
[0043] The etherification reaction is maintained at a temperature of 10-100°C; preferably, it is 40°C.
[0044] The etherification reaction takes 1 to 12 hours; preferably, it takes 4 hours.
[0045] The organic base includes any one or more of triethylamine, pyridine, and trimethylpyridine; preferably, it is trimethylpyridine.
[0046] The first solvent includes any one or more of dichloromethane, acetonitrile, etc.; preferably, it is dichloromethane.
[0047] In step (2) of this invention, the coupling reaction specifically involves dissolving the compound of formula (2) in a second solvent, adding potassium carbonate, pinacol 2-acetamido-5-methoxyphenylboronic acid, and a catalyst, and conducting a coupling reaction under nitrogen protection at a certain reaction temperature to prepare the compound of formula (3).
[0048] Wherein, the weight ratio of the compound of formula (2), potassium carbonate, pinacol ester of 2-acetamido-5-methoxyphenylboronic acid, and catalyst is 1:(0.3-2):(0.3-2):(0.01-0.05); preferably, it is 1:0.62:0.75:0.01;
[0049] The catalyst includes any one or more of PdCl2(PPh3)2, Pd(PPh3)4, etc.; preferably, it is PdCl2(PPh3)2.
[0050] The second solvent is selected from one or two of dioxane, tetrahydrofuran, etc.; preferably, it is dioxane.
[0051] The coupling reaction is carried out at a temperature of 50–100°C; preferably, at 90°C.
[0052] The coupling reaction takes 1 to 12 hours; preferably, it takes 6 hours.
[0053] In step (3) of this invention, the hydrogenation reaction specifically involves dissolving the compound of formula (3) in a third solvent, adding a catalyst, and conducting a hydrogenation reaction at a certain reaction temperature under a hydrogen atmosphere to prepare the compound of formula (4).
[0054] Wherein, the weight ratio of the compound of formula (3) to the catalyst is 1:0.05 to 0.10; preferably, it is 1:(0.01 to 0.1); more preferably, it is 1:0.1;
[0055] The third solvent is selected from one or two of methanol, ethanol, isopropanol, etc.; preferably, it is isopropanol.
[0056] The catalyst includes one or two of Raney nickel, palladium on carbon, and palladium hydroxide; preferably, it is Raney nickel.
[0057] The hydrogenation reaction is carried out at a temperature of 25–100°C; preferably, at 60°C.
[0058] The hydrogenation reaction takes 12 to 48 hours; preferably, it takes 24 hours.
[0059] In step (4) of this invention, the ether bond cleavage reaction specifically involves dissolving the compound of formula (4) in a fourth solvent, adding lithium chloride, and conducting an ether bond cleavage reaction at a certain reaction temperature to prepare the compound of formula (5).
[0060] Wherein, the weight ratio of the compound of formula (4) to lithium chloride is 1:(0.1-5); preferably, it is 1:0.2;
[0061] The fourth solvent is selected from one or two of methanol, ethanol, isopropanol, etc.; preferably, it is methanol.
[0062] The temperature for the ether bond cleavage reaction is 25–100°C; preferably, it is 50°C.
[0063] The ether bond cleavage reaction takes 12 to 48 hours; preferably, it takes 12 hours.
[0064] The innovations and beneficial effects of this invention include: employing Raney nickel catalysis for the hydrogenation reduction of double bonds, avoiding the use of expensive palladium-based metal catalysts, reducing hydrogenation costs, and featuring high yield and convenient post-processing. The compound proposed in this invention, through the triphenylmethyl etherification of 2-hydroxyl groups, facilitates subsequent ether bond cleavage, effectively reducing costs. This makes the entire reaction simple, efficient, safe to operate, and convenient for product purification, enabling the efficient preparation of key intermediates for alastam. Attached Figure Description
[0065] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0066] Figure 1 The 1H NMR spectrum of compound (5) is shown.
[0067] Figure 2 The high-resolution mass spectrum of compound (5) is shown. Detailed Implementation
[0068] The invention will be further described in detail below with reference to the specific embodiments and accompanying drawings. The processes, conditions, and experimental methods for implementing the invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the invention does not have any particular limitations. Where specific experimental steps or conditions are not described in the embodiments, they can be performed according to the conventional experimental methods described in publicly available texts in the art. Reagents or equipment whose manufacturers are not specified are all commercially available conventional products.
[0069] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.
[0070] In all examples shown and discussed herein, any specific values should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.
[0071] This invention discloses a method for preparing a key intermediate of the drug ellastatin. The method uses 6-bromo-7,8-dihydronaphth-2-ol as a starting material and prepares the ellastatin intermediate N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)acetamide through a four-step reaction involving triphenylmethyl etherification, coupling, nickel-catalyzed hydrogenation, and ether bond cleavage. The method avoids the use of expensive palladium-based metal catalysts by etherifying the 2-hydroxyl group with triphenylmethyl and employing Raney nickel-catalyzed hydrogenation, thus reducing hydrogenation costs and offering advantages such as high yield and convenient post-processing. This invention has promising prospects for large-scale application.
[0072] Example 1
[0073] Etherification reaction:
[0074] Compound (1) of formula 22.3 g (100 mmol) and 223 g of dichloromethane were mixed in a reaction flask, followed by the addition of triphenylmethyl chloride (27.3 g, 100 mmol) and trimethylpyridine (12.1 g, 100 mmol), respectively. The mixture was stirred and heated to 40 °C and reacted for 4 h. After the reaction was completed, the mixture was washed with water, and the organic phase was concentrated to obtain 45 g of compound (2), with a molar yield of 96%.
[0075] Coupling reaction:
[0076] Compound (2) of formula (2) (26.6 g, 57 mmol) was dissolved in 260 g of dioxane in a reaction flask. Then, 2-acetamido-5-methoxyphenylboronic acid pinacol ester (16.5 g, 57 mmol), potassium carbonate (20 g, 145 mmol), water (100 g), and catalyst Pd(PPh3)2Cl2 (0.26 g) were added. The mixture was protected by N2 displacement, stirred, and heated to 90 °C. The reaction was maintained at this temperature for 6 h. After the reaction was completed, the reaction solution was cooled to 25 °C to remove dioxane. The mixture was filtered and dried to obtain 29 g of compound (3), with a molar yield of 82%.
[0077] Hydrogenation reaction (Raney nickel as catalyst):
[0078] 29g of compound (3), 300g of isopropanol, and 2.9g of Raney nickel were added to the reaction flask. H2 was replaced three times or more. The mixture was stirred and the temperature was controlled at 60℃ for 24 hours. After the reaction was completed, the mixture was cooled to 25℃, filtered, washed with isopropanol, and the filtrate was concentrated to dryness. Isopropanol was added to purify the mixture to obtain 26.5g of compound (4), with a molar yield of 90%. 1 H NMR (400 MHz, CDCl3) δ7.45-7.47 (m, 6H), 7.20-7.31 (m, 9H), 7.00-7.10 (m, 2H), 6.64-7.73 (m, 2H), 6.41-6.49 (m, 2H), 3.77 (s, 3H), 2.59-2.86 (m, 5H), 2.14 (s, 3H), 1.73-1.93 (m, 2H).
[0079] Ether bond cleavage:
[0080] The compound of formula (4) (28 g, 51 mmol) was mixed with 90 g of methanol, and then lithium chloride (6.4 g, 153 mmol) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the mixture was cooled to 25 °C, quenched with water, extracted with ethyl acetate, washed with brine, concentrated the organic phase, and purified with dichloromethane to obtain 15 g of compound of formula (5), with a molar yield of 94%. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.02 (s, 1H), 7.20-7.22 (m, 1H), 6.93 (m, 1H), 6.83-6.85 (m, 1H), 6.75-6.78 (m, 1H), 6.50-6.52(m, 2H), 3.71 (s, 3H), 3.02-3.08 (m, 1H), 2.71-2.80 (m, 3H), 2.56-2.63 (m,1H), 2.01 (s, 3H), 1.70-1.80 (m, 2H).
[0081] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
[0082] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.
[0083] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.
[0084] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Claims
1. A method for preparing N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)acetamide, a key intermediate for alastracetamol, characterized in that, The method uses 6-bromo-7,8-dihydronaphth-2-ol as a starting material and prepares the intermediate N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)acetamide via triphenylmethyl etherification of the 2-hydroxyl group, coupling, nickel-catalyzed hydrogenation, and ether bond cleavage. The synthetic route of the method is as follows: ； Where Tr stands for triphenylmethyl.
2. The method according to claim 1, characterized in that, The method includes the following steps: (1) Etherification: Compound (6-bromo-7,8-dihydronaphth-2-ol) of formula (1) is dissolved in a first solvent, and triphenylmethyl chloride and an organic base are added to undergo an etherification reaction to prepare compound (2); the reaction process is shown in reaction formula (A): ； Reaction (A) (2) Coupling reaction: The compound of formula (2) is dissolved in a second solvent, and potassium carbonate, pinacol ester of 2-acetamido-5-methoxyphenylboronic acid and a catalyst are added to undergo a coupling reaction to prepare the compound of formula (3); the reaction process is shown in reaction formula (B): ； Reaction formula (B) (3) Hydrogenation reaction: The compound of formula (3) is dissolved in a third solvent, a catalyst is added, and a hydrogenation reaction is carried out to prepare the compound of formula (4); the reaction process is shown in reaction formula (C): ； Reaction formula (C) (4) Ether bond cleavage: The compound of formula (4) is dissolved in a fourth solvent, and lithium chloride is added to induce an ether bond cleavage reaction, thereby preparing the compound of formula (5); the reaction process is shown in reaction formula (D): ； Reaction formula (D).
3. The method according to claim 2, characterized in that, In step (1), the weight ratio of the compound of formula (1), triphenylmethyl chloride and organic base is 1:0.5 to 2:0.5 to 2; and or, the organic base includes any one or more of triethylamine, pyridine and trimethylpyridine; and or, the first solvent includes any one or two of dichloromethane and acetonitrile.
4. The method according to claim 2, characterized in that, In step (1), the temperature of the etherification reaction is 10 to 100°C; and / or the etherification reaction time is 1 to 12 hours.
5. The method according to claim 2, characterized in that, In step (2), the weight ratio of the compound of formula (2), potassium carbonate, pinacol ester of 2-acetamido-5-methoxyphenylboronic acid and the catalyst is 1:0.3-2:0.3-2:0.01-0.05; and / or, the catalyst includes any one or two of PdCl2(PPh3)2 and Pd(PPh3)4; and / or, the second solvent includes one or two of dioxane and tetrahydrofuran.
6. The method according to claim 2, characterized in that, In step (2), the temperature of the coupling reaction is 50 to 100°C; and / or the time of the coupling reaction is 2 to 12 hours.
7. The method according to claim 2, characterized in that, In step (3), the weight ratio of the compound of formula (3) to the catalyst is 1:0.05 to 0.10; and or, the catalyst includes any one or more of Raney nickel, palladium on carbon, and palladium hydroxide; and or, the third solvent includes any one or more of methanol, ethanol, and isopropanol.
8. The method according to claim 2, characterized in that, In step (3), the temperature of the hydrogenation reaction is 25-100℃; and / or the time of the hydrogenation reaction is 12-48h.
9. The method according to claim 2, characterized in that, In step (4), the weight ratio of the compound of formula (4) to lithium chloride is 1:0.1 to 5; and / or, the fourth solvent includes one or two of methanol, ethanol, and isopropanol.
10. The method according to claim 2, characterized in that, In step (4), the temperature of the ether bond cleavage reaction is 25–100 °C; and / or the time of the ether bond cleavage reaction is 12–48 h.