Preparation method of adapalene
The organic zinc reagent is prepared by reacting 6-halo-2-naphthoate with metal zinc, and coupled with 2-(1-adamantyl)-4-haloanisole in the cuprous reagent system, solving the problems of high cost and difficulty in controlling impurities in adapalin synthesis, and achieving efficient and low-cost adapalin production.
Patent Information
- Application Number
- CN202510609336.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-13
- Publication Date
- 2025-08-12
AI Technical Summary
The existing adapalin synthesis route is expensive and difficult to effectively control impurity generation, especially self-coupling and debrominated by-products.
The organic zinc reagent was prepared by reacting 6-halo-2-naphthoate with metal zinc, and the coupling reaction was carried out with 2-(1-adamantyl)-4-haloanisole in the cuprous reagent system, and combined with nickel catalyst, significantly inhibiting the generation of by-products.
The synthesis of adapalin intermediates with high yield and high purity has been achieved, which reduces production costs, simplifies the process route, and is suitable for industrial production.
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Figure CN120463589A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical chemical synthesis, and in particular to a method for preparing adapalene. Background Art
[0002] Adapalene, chemically known as 6-[3-(1-adamantyl)-4-methylphenyl]-2-naphthoic acid, is a third-generation polyaromatic retinoid. It specifically binds to the retinoic acid receptor (RARγ) on epidermal cells, thereby regulating epidermal cell differentiation and proliferation. It also has anti-acne, sebum secretion inhibition, and anti-inflammatory effects. Compared with traditional tretinoin, adapalene is less irritating, better tolerated, and suitable for long-term maintenance treatment.
[0003] There are currently two main synthetic routes for adapalene.
[0004] Route 1:
[0005]
[0006] This route uses an aryl boride as a raw material or intermediate. The aryl boride and methyl 6-bromo-2-naphthoate undergo a Suzuki reaction to produce 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate, which is then hydrolyzed with sodium hydroxide to yield adapalene. However, the preparation of aryl boride requires harsh reaction conditions, is not easily oxidized, and is difficult to store. Furthermore, this route utilizes an expensive transition metal palladium catalyst, resulting in high costs.
[0007] Route 2:
[0008]
[0009] This route first reacts 2-(1-adamantyl)-4-bromoanisole with magnesium to prepare a Grignard reagent. This is then exchanged with zinc chloride to prepare a zinc reagent. The Negishi reaction yields 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate, which is then hydrolyzed with sodium hydroxide to produce adapalene. This route requires the preparation of a Grignard reagent, which is unstable and difficult to store. Furthermore, zinc chloride readily absorbs water, hindering the preparation of the zinc reagent and resulting in a low yield.
[0010] Both of the above methods involve coupling reactions, which are prone to self-coupling and debromination impurities (III, IV, V). In addition, methyl 6-bromo-2-naphthoate (I) is likely to remain in the coupling reaction. These impurities are difficult to remove in subsequent reactions and have low limits in various pharmacopoeias.
[0011]
[0012] Based on this, there is an urgent need for an efficient and low-cost preparation method of adapalene. Summary of the Invention
[0013] To optimize the process, reduce production costs, and minimize impurities, we developed an efficient and low-cost method for preparing adapalene. This method uses 6-bromo-2-naphthoate and an organozinc to directly and efficiently prepare a highly active organozinc reagent, minimizing the risk of residual methyl 6-bromo-2-naphthoate. Furthermore, a trace amount of cuprous agent was introduced to modulate the catalytic system, significantly inhibiting the formation of self-coupling and debromination byproducts, thereby simplifying the synthetic route and reducing the number of related impurities.
[0014] The technical solution of the present invention is achieved as follows: The present invention provides a method for preparing adapalene, comprising:
[0015] Step 1, reacting methyl 6-halo-2-naphthoate with metallic zinc to prepare an organozinc reagent;
[0016] Step 2: In a system containing a cuprous reagent, 2-(1-adamantyl)-4-halogenated anisole is subjected to a coupling reaction with the organozinc reagent prepared in step 1, and adapalene is obtained after hydrolysis.
[0017] Its specific synthetic route is as follows:
[0018]
[0019] In some embodiments, step one further comprises: adding zinc powder, iodinated alkane, trimethylchlorosilane and a reaction solvent under nitrogen, heating to 60-65° C. and stirring for 0.5 h, then adding dropwise a mixed solution of methyl 6-halogenated 2-naphthoate and the reaction solvent, maintaining the reaction temperature at 60-65° C., and after the addition is complete, keeping the temperature for reaction for 2-3 h, and then cooling to 20-30° C. to obtain an organozinc reagent, wherein the molar ratio of zinc powder: iodinated alkane: trimethylchlorosilane: methyl 6-halogenated 2-naphthoate is (1.2-1.5): (0.1-0.2): (0.1-0.2): (1.0-1.2).
[0020] In some embodiments, the reaction solvent is one of tetrahydrofuran, dioxane, methyl furan, methyl tert-butyl ether, isopropyl ether and propyl ether.
[0021] In some embodiments, the iodinated alkane is at least one of methyl iodide, ethyl iodide, 1,2-dibromoethane and 1,2-diiodoethane.
[0022] In some embodiments, the halogen in the methyl 6-halo-2-naphthoate is one of Cl, Br, and I.
[0023] In some embodiments, in step 2, the coupling reaction step comprises: adding 2-(1-adamantyl)-4-halogenanisole, nickel catalyst, and cuprous reagent to the organozinc reagent prepared in step 1 under a nitrogen atmosphere while maintaining the temperature at 20-25° C., continuing the reaction at the same temperature for 3-4 hours, then adding purified water, crystallizing at 0-10° C. for 1 hour, filtering, washing with water, and collecting to obtain a white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate, wherein the molar ratio of 2-(1-adamantyl)-4-halogenanisole:nickel catalyst:cuprous reagent:6-halogenated-2-naphthoic acid methyl ester is (1.2-1.5):(0.1-0.2):(0.1-0.2):(1.0-1.2).
[0024] In some embodiments, the halogen of the 2-(1-adamantyl)-4-haloanisole is one of F, Cl, and Br.
[0025] In some embodiments, the nickel catalyst is at least one of bis(triphenylphosphine)nickel chloride, 1,2(bisdiphenylphosphine)nickel chloride, 1,3-bis(diphenylphosphinopropane)nickel dichloride, and (1,1′-bis(diphenylphosphino)ferrocene)nickel dichloride.
[0026] In some embodiments, the cuprous reagent is at least one of cuprous bromide, cuprous trifluoromethanesulfonate, and cuprous bromide dimethyl sulfide.
[0027] In some embodiments, in step 2, the coupling reaction step comprises: adding 2-(1-adamantyl)-4-halogenanisole, a nickel catalyst, and a cuprous reagent to the organozinc reagent prepared in step 1 under a nitrogen atmosphere while maintaining the temperature at 20-25° C., and continuing the reaction at the same temperature for 3-4 hours, then adding purified water, crystallizing at 0-10° C. for 1 hour, filtering, washing with water, and collecting to obtain a white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate, wherein the molar ratio of 2-(1-adamantyl)-4-halogenanisole:nickel catalyst:cuprous reagent:6-halogenated-2-naphthoic acid methyl ester is (0.9-1.0):(0.01-0.02):(0.001-0.002):(1.0-1.2).
[0028] In some embodiments, the acid used to adjust the pH is one of hydrochloric acid, sulfuric acid, and acetic acid, preferably hydrochloric acid.
[0029] The present invention has the following beneficial effects compared to the prior art:
[0030] The present invention optimizes the preparation process of the organozinc reagent and combines it with a nickel / cuprous synergistic catalytic system to significantly inhibit the generation of by-products such as debromination, self-coupling and raw material residues in the coupling reaction, thereby obtaining a high-purity adapalene intermediate with a yield of more than 87% without relying on expensive palladium catalysts or unstable Grignard reagents. This simplifies the process route, reduces production costs, and solves the problem of difficult impurity control in traditional methods, making the method suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.
[0032] Figure 1 This is a liquid chromatogram of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate prepared in Example 1 of the present invention;
[0033] Figure 2 This is a liquid chromatogram of Adapalene prepared in Example 1 of the present invention;
[0034] Figure 3 The adapalene prepared in Example 1 of the present invention 1 H NMR spectrum. DETAILED DESCRIPTION
[0035] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.
[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the present invention belong. If the definitions set forth in this section are contrary to or otherwise inconsistent with definitions set forth in the patents, patent applications, published patent applications, and other publications incorporated herein by reference, the definitions listed in this section take precedence over the definitions incorporated herein by reference.
[0037] Unless otherwise specified, the methods used in the following examples are conventional methods. The materials, reagents, and instruments used are conventional materials, reagents, and instruments in the art, unless otherwise specified, and can be obtained commercially by those skilled in the art.
[0038] When an amount, concentration or other value or parameter is expressed as a range, a preferred range or a range defined by a series of upper preferred values and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether the range is disclosed alone. For example, when a range "1 to 5" is disclosed, the described range should be interpreted as including the ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within the range. In the present specification and claims, range definitions may be combined and / or interchanged, and if not otherwise stated, such ranges include all subranges contained therein.
[0039] Example 1
[0040] This embodiment provides a method for synthesizing adapalene, and its preparation process is as follows:
[0041] Step a: In a three-necked flask under a nitrogen atmosphere, zinc powder (1.57 g, 24 mmol), iodoethane (0.31 g, 2 mmol), trimethylsilyl chloride (0.22 g, 2 mmol) and tetrahydrofuran were added, and the temperature was controlled at 65°C and stirred for 0.5 h. A solution of 6-bromo-2-naphthoate (5.30 g, 20 mmol) in tetrahydrofuran was added dropwise. The reaction was initiated at 65°C, and the reaction mixture was reacted at the same temperature for 3 h. After that, the reaction solution was cooled to 25°C to obtain a zinc reagent.
[0042] Step b, under a nitrogen atmosphere, the temperature was controlled at 25 ° C. and 2-(1-adamantyl)-4-bromoanisole (5.78 g, 18 mmol), 1,2-(bisdiphenylphosphine)nickel chloride (0.11 g, 0.2 mmol), and cuprous bromide dimethyl sulfide (0.04 g, 0.2 mmol) were added in sequence and the reaction was continued at the same temperature for 4 hours. Purified water was added to the reaction solution, and the temperature was lowered to 0 ° C. Crystallization was carried out for 1 hour. The filter cake was washed with purified water under reduced pressure and filtered to obtain 7.48 g of white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate. The molar yield was 87.64% and the purity was 99.82% (impurities I, III, IV, and V were not detected).
[0043] Step c: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (6.39 g, 15 mmol) prepared in step b was placed in a single-necked flask, tetrahydrofuran and 5% aqueous sodium hydroxide solution (23.8 g) were added, and the mixture was reacted at 60°C for 8 h. Purified water was added, and the pH of the reaction system was adjusted to 3 with aqueous hydrochloric acid. The mixture was stirred to precipitate a solid, and the temperature was lowered to 0°C for crystallization for 1 h. The solid was filtered, and the filter cake was washed with purified water to obtain 5.97 g of adapalene as a white solid with a molar yield of 96.56% and a purity of 99.89% (impurities I, III, IV, and V were not detected).
[0044] Example 2
[0045] This embodiment provides a method for synthesizing adapalene, and its preparation process is as follows:
[0046] Step a: In a three-necked flask under a nitrogen atmosphere, zinc powder (2.35 g, 36 mmol), 1,2-dibromoethane (0.56 g, 3 mmol), trimethylsilyl chloride (0.33 g, 3 mmol) and tetrahydrofuran were added, the temperature was controlled at 65°C and stirred for 0.5 h, and a solution of 6-bromo-2-naphthoate (7.95 g, 30 mmol) in tetrahydrofuran was added dropwise. After initiating the reaction at 65°C, the reaction solution was reacted at the same temperature for 3 h and then cooled to 25°C to obtain a zinc reagent.
[0047] Step b, under a nitrogen atmosphere, the temperature was controlled at 25 ° C. and 2-(1-adamantyl)-4-bromoanisole (8.67 g, 27 mmol), 1,2-(bisdiphenylphosphine)nickel chloride (0.16 g, 0.3 mmol), and cuprous bromide dimethyl sulfide (0.06 g, 0.3 mmol) were added in sequence and the reaction was continued at the same temperature for 4 hours. Purified water was added to the reaction solution, and the temperature was lowered to 0 ° C. Crystallization was carried out for 1 hour. The filter cake was washed with purified water under reduced pressure and filtered to obtain 11.37 g of white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate. The molar yield was 88.86%, and the purity was 99.88% (impurities I, III, IV, and V were not detected).
[0048] Step c: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (8.53 g, 20 mmol) was placed in a single-necked flask, tetrahydrofuran and 5% aqueous sodium hydroxide solution (31.2 g) were added, and the mixture was reacted at 60°C for 8 h. Purified water was added, and the pH of the reaction system was adjusted to 3 with aqueous hydrochloric acid. The mixture was stirred to precipitate a solid, and the temperature was lowered to 0°C for crystallization for 1 h. The solid was filtered, and the filter cake was washed with purified water to obtain 7.91 g of adapalene as a white solid with a molar yield of 95.86% and a purity of 99.94% (impurities I, III, IV, and V were not detected).
[0049] Example 3
[0050] This embodiment provides a method for synthesizing adapalene, and its preparation process is as follows:
[0051] Step a: Under a nitrogen atmosphere, zinc powder (1.57 g, 24 mmol), iodoethane (0.31 g, 2 mmol), trimethylsilyl chloride (0.22 g, 2 mmol) and methyl tert-butyl ether were added to a three-necked flask. The temperature was controlled at 65° C. and stirred for 0.5 h. A methyl tert-butyl ether solution of 6-chloro-2-naphthoate (4.74 g, 20 mmol) was added dropwise. The reaction was initiated at 65° C. and the reaction mixture was reacted at the same temperature for 3 h. The reaction solution was then cooled to 25° C. to obtain a zinc reagent.
[0052] Step b, under a nitrogen atmosphere, the temperature was controlled at 25 ° C. and 2-(1-adamantyl)-4-chloroanisole (5.42 g, 18 mmol), bis(triphenylphosphine)nickel chloride (0.13 g, 0.2 mmol), and cuprous trifluoromethanesulfonate (0.07 g, 0.2 mmol) were added in sequence and the reaction was continued for 4 h at the same temperature. Purified water was added to the reaction solution, and the temperature was lowered to 0 ° C. Crystallization was carried out for 1 h. The filter cake was washed with purified water under reduced pressure and filtered to obtain 7.12 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate as a white solid with a molar yield of 85.3% and a purity of 99.75% (impurities I, III, IV, and V were not detected).
[0053] Step c: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (6.39 g, 15 mmol) prepared in step b was placed in a single-necked flask, tetrahydrofuran and 5% aqueous sodium hydroxide solution (23.8 g) were added, and the mixture was reacted at 60°C for 8 h. Purified water was added, and the pH of the reaction system was adjusted to 3 with aqueous hydrochloric acid. The mixture was stirred to precipitate a solid, and the temperature was lowered to 0°C for crystallization for 1 h. The solid was filtered, and the filter cake was washed with purified water to obtain 5.61 g of adapalene as a white solid with a molar yield of 95.1% and a purity of 99.83% (impurities I, III, IV, and V were not detected).
[0054] Example 4
[0055] This embodiment provides a method for synthesizing adapalene, and its preparation process is as follows:
[0056] Step a: In a three-necked flask under a nitrogen atmosphere, zinc powder (1.57 g, 24 mmol), iodoethane (0.31 g, 2 mmol), trimethylsilyl chloride (0.22 g, 2 mmol) and dioxane were added, the temperature was controlled at 65 ° C and stirred for 0.5 h, and a dioxane solution of 6-iodo-2-naphthoate (6.82 g, 20 mmol) was added dropwise. After initiating the reaction at 65 ° C, the reaction solution was cooled to 25 ° C for 3 h to obtain a zinc reagent.
[0057] Step b, under a nitrogen atmosphere, the temperature was controlled at 25 ° C. and 2-(1-adamantyl)-4-fluoroanisole (5.06 g, 18 mmol), 1,3-bis(diphenylphosphinopropane) nickel dichloride (0.15 g, 0.2 mmol), and cuprous bromide (0.03 g, 0.2 mmol) were added in sequence and the reaction was continued at the same temperature for 4 hours. Purified water was added to the reaction solution, and the temperature was lowered to 0 ° C. Crystallization was carried out for 1 hour. The filter cake was washed with purified water under reduced pressure and filtered to obtain 7.31 g of white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate. The molar yield was 87.9%, and the purity was 99.68% (impurities I, III, IV, and V were not detected).
[0058] Step c: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (6.39 g, 15 mmol) prepared in step b was placed in a single-necked flask, tetrahydrofuran and 5% aqueous sodium hydroxide solution (23.8 g) were added, and the mixture was reacted at 60°C for 8 h. Purified water was added, and the pH of the reaction system was adjusted to 3 with aqueous hydrochloric acid. The mixture was stirred to precipitate a solid, and the temperature was lowered to 0°C for crystallization for 1 h. The solid was filtered, and the filter cake was washed with purified water to obtain 5.89 g of adapalene as a white solid with a molar yield of 96.4% and a purity of 99.84% (impurities I, III, IV, and V were not detected).
[0059] Example 5
[0060] This embodiment provides a method for synthesizing adapalene, and its preparation process is as follows:
[0061] Step a: In a three-necked flask under a nitrogen atmosphere, zinc powder (1.57 g, 24 mmol), iodoethane (0.31 g, 2 mmol), trimethylsilyl chloride (0.22 g, 2 mmol) and tetrahydrofuran were added, and the temperature was controlled at 65°C and stirred for 0.5 h. A solution of 6-bromo-2-naphthoate (5.30 g, 20 mmol) in tetrahydrofuran was added dropwise. The reaction was initiated at 65°C, and the reaction mixture was reacted at the same temperature for 3 h. After that, the reaction solution was cooled to 25°C to obtain a zinc reagent.
[0062] Step b: Under a nitrogen atmosphere, the temperature was controlled at 25° C. and 2-(1-adamantyl)-4-bromoanisole (5.78 g, 18 mmol), (1,1'-bis(diphenylphosphino)ferrocene)nickel dichloride (0.18 g, 0.2 mmol), and cuprous bromide dimethyl sulfide (0.04 g, 0.2 mmol) were added sequentially and the reaction was continued at the same temperature for 4 h. Purified water was added to the reaction solution, and the temperature was lowered to 0° C. for crystallization for 1 h. The filter cake was washed with purified water under reduced pressure and filtered to obtain 7.26 g of a white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate. The molar yield was 86.1%, and the purity was 99.71% (impurities I, III, IV, and V were not detected).
[0063] Step c: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (6.39 g, 15 mmol) prepared in step b was placed in a single-necked flask, tetrahydrofuran and 5% aqueous sodium hydroxide solution (23.8 g) were added, and the mixture was reacted at 60°C for 8 hours. Purified water was added, and the pH of the reaction system was adjusted to 3 with aqueous hydrochloric acid. The mixture was stirred to precipitate a solid, and the temperature was lowered to 0°C for crystallization for 1 hour. The solid was filtered, and the filter cake was washed with purified water to obtain adapalene as a white solid with a molar yield of 95.8% and a purity of 99.82% (impurities I, III, IV, and V were not detected).
[0064] Comparative Example 1
[0065] This comparative example provides a method for synthesizing adapalene, in which cuprous reagent is not used. The preparation process is as follows:
[0066] Step a: Under a nitrogen atmosphere, zinc powder (2.35 g, 36 mmol), 1,2-dibromoethane (0.56 g, 3 mmol), trimethylsilyl chloride (0.33 g, 3 mmol) and tetrahydrofuran were added to a three-necked flask. The temperature was controlled at 65°C and stirred for 0.5 h. A solution of 6-bromo-2-naphthoate (7.95 g, 30 mmol) in tetrahydrofuran was added dropwise. The reaction was initiated at 65°C and allowed to react for 3 h. The reaction solution was then cooled to 25°C to obtain a zinc reagent.
[0067] Step b: Under a nitrogen atmosphere, 2-(1-adamantyl)-4-bromoanisole (8.67 g, 27 mmol) and 1,2-(bis(diphenylphosphine)nickel chloride) (0.16 g, 0.3 mmol) were added sequentially at 25°C, and the reaction was continued at the same temperature for 4 hours. Purified water was added to the reaction solution, and the temperature was lowered to 0°C for crystallization for 1 hour. The filter cake was washed with purified water under reduced pressure to obtain 9.24 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate as a white solid, with a molar yield of 72.20% and a purity of 94.86%.
[0068] Step c: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (8.53 g, 20 mmol) was placed in a single-necked flask, tetrahydrofuran and 5% aqueous sodium hydroxide solution (31.2 g) were added, and the reaction was carried out at 60°C for 8 hours. Purified water was added, and the pH of the reaction system was adjusted to 3 with aqueous hydrochloric acid. The solid was stirred to precipitate, and the temperature was cooled to 0°C for crystallization for 1 hour. The solid was filtered, and the filter cake was washed with purified water to obtain 7.85 g of adapalene as a white solid with a molar yield of 95.14% and a purity of 95.94% (impurities II = 0.59%, IV = 0.85%, and V = 1.28%).
[0069] Comparative Example 2
[0070] In this comparative example, trimethylsilyl chloride was omitted based on Example 1. Other steps were the same as in Example 1. However, the preparation of the zinc reagent failed, 50% of methyl 6-bromo-2-naphthoate remained, the yield of the subsequent coupling reaction was only 42%, and impurity I (residue of the raw material) reached 5.2%.
[0071] Comparative Example 3
[0072] In this comparative example, based on Example 1, the amount of iodoethane was increased to 0.93 g (6 mmol). The other steps were the same as Example 1. However, the zinc reagent was too active, and debrominated impurity V (1.8%) was generated during the coupling reaction. The product yield was 71% and the purity was 93.5%.
[0073] Comparative Example 4
[0074] In this comparative example, based on Example 1, 2-(1-adamantyl)-4-iodoanisole was used in step b. The coupling reaction rate was reduced, the yield was 38%, and the impurity IV reached 6.3%.
[0075] Comparative Example 5
[0076] In this comparative example, based on Example 1, the amount of zinc powder in step a was reduced to 1.0 ep (19.6 mmol), and the other steps were the same as in Example 1. Zinc was not actually completely generated, 22% of methyl 6-bromo-2-naphthoate remained, and the purity of the final product was 88.4% (impurity I = 1.2%).
[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims
1. A method for preparing adapalene, characterized in that, include: Step 1, reacting methyl 6-halo-2-naphthoate with metallic zinc to prepare an organozinc reagent; Step 2: In a system containing a cuprous reagent, 2-(1-adamantyl)-4-halogenated anisole is subjected to a coupling reaction with the organozinc reagent prepared in step 1, and adapalene is obtained after hydrolysis.
2. The method for preparing adapalene according to claim 1, wherein Step one also includes: adding zinc powder, iodinated alkane, trimethylchlorosilane and a reaction solvent under nitrogen, heating to 60-65° C. and stirring for 0.5 h, then dropwise adding a mixed solution of methyl 6-halogenated 2-naphthoate and the reaction solvent, maintaining the reaction temperature at 60-65° C., and after the dropwise addition is completed, the mixture is kept warm for 2-3 h, and then cooled to 20-30° C. to obtain an organozinc reagent, wherein the molar ratio of zinc powder: iodinated alkane: trimethylchlorosilane: methyl 6-halogenated 2-naphthoate is (1.2-1.5): (0.1-0.2): (0.1-0.2): (1.0-1.2).
3. The method for preparing adapalene according to claim 2, wherein The reaction solvent is one of tetrahydrofuran, dioxane, methyl furan, methyl tert-butyl ether, isopropyl ether and propyl ether.
4. The method for preparing adapalene according to claim 2, wherein The iodinated alkane is at least one of methyl iodide, ethyl iodide, 1,2-dibromoethane and 1,2-diiodoethane.
5. The method for preparing adapalene according to claim 2, wherein The halogen in the 6-halogenated-2-naphthoic acid methyl ester is one of Cl, Br and I.
6. The method for preparing adapalene according to claim 1, wherein In step 2, the coupling reaction step comprises: adding 2-(1-adamantyl)-4-halogenated anisole, a nickel catalyst, and a cuprous reagent to the organozinc reagent prepared in step 1 under a nitrogen atmosphere while maintaining the temperature at 20-25° C., continuing the reaction at the same temperature for 3-4 hours, then adding purified water, crystallizing at 0-10° C. for 1 hour, filtering, washing with water, and collecting to obtain a white solid 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate, wherein the molar ratio of 2-(1-adamantyl)-4-halogenated anisole: nickel catalyst: cuprous reagent: 6-halogenated-2-naphthoic acid methyl ester is (0.9-1.0):(0.01-0.02):(0.001-0.002):(1.0-1.2).
7. The method for preparing adapalene according to claim 6, wherein The halogen of the 2-(1-adamantyl)-4-halogenated anisole is one of F, Cl and Br.
8. The method for preparing adapalene according to claim 6, wherein The nickel catalyst is at least one of bis(triphenylphosphine)nickel chloride, 1,2-(bisdiphenylphosphine)nickel chloride, 1,3-bis(diphenylphosphinopropane)nickel dichloride and (1,1'-bis(diphenylphosphino)ferrocene)nickel dichloride.
9. The method for preparing adapalene according to claim 6, wherein The cuprous reagent is at least one of cuprous bromide, cuprous trifluoromethanesulfonate and cuprous bromide dimethyl sulfide.
10. The method for preparing adapalene according to claim 1, wherein In step 2, the hydrolysis method includes: adding tetrahydrofuran to the 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate obtained in step 2, adding 5% sodium hydroxide aqueous solution, heating to 60-65° C. and keeping the temperature for reaction for 6-8 hours, then adding purified water, adjusting the pH value to 1-3, cooling to 0-10° C. and crystallizing for 1 hour, solvent recrystallization, filtering, and washing with water to obtain adapalene. The molar ratio of sodium hydroxide to 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate is (2-3):1.