Preparation method of adapalene

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of adapalene, which comprises the following steps: taking p-bromoanisole as a main raw material, taking acid as a catalyst, carrying out Friedel-Crafts reaction on p-bromoanisole and 1-adamantanol to obtain 2-(1-adamantyl)-4-bromoanisole, reacting 2-(1-adamantyl)-4-bromoanisole with pinacolborane in the presence of the catalyst and a ligand to generate boric acid ester, and carrying out recrystallization to obtain the adapalene. The preparation method comprises the following steps: carrying out Suzuki coupling on 3-(1-adamantyl)-4-methoxyphenyl)-2-methyl naphthoate and 6-bromo-2-methyl naphthoate to generate 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-methyl naphthoate in one pot, and finally carrying out ester hydrolysis to obtain adapalene. The overall yield of the process is nearly 70%, and the total production cost is remarkably reduced by more than 40%; according to the method, boric acid ester is constructed by adopting a one-pot method, a Suzuki reaction is performed, pinacolborane is cheap and easy to obtain, a catalyst and a ligand are repeatedly utilized, the construction of borane and the Suzuki coupling reaction are completed, purification is not needed, and the operation steps are reduced; the process reaction conditions and operation are simple, the method is green and environment-friendly, and a key coupling intermediate with high purity and high yield can be obtained; the adapalene API which is high in purity, high in yield and low in cost and conforms to EP and USP can be obtained.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a preparation method of adapalene. Background Art

[0002] Adapalene is suitable for the skin treatment of acne vulgaris mainly manifested by comedones, papules and pustules. It can also be used to treat acne on the face, chest and back.

[0003] Chinese invention patent "CN111333496A" discloses a preparation method of adapalene, which uses 2-methoxycarbonyl-6-naphthol p-toluenesulfonate and 4-methoxyphenylboronic acid as the main raw materials; first, 4-methoxyphenylboronic acid is used for coupling to construct a carbon-carbon bond, and then 1-adamantanamine is connected through Friedel-Crafts reaction. The disadvantage of this method is that it is difficult to obtain raw materials. The synthesis process of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate is not described in this invention. In fact, when applying this method, the cost and difficulty of synthesizing 2-methoxycarbonyl-6-naphthol p-toluenesulfonate are high when extending forward.

[0004] Its reaction principle is:

[0005]

[0006] US Patent "US4717720" discloses a synthesis method of adapalene. It carries out a Negishi cross-coupling reaction between an organozinc reagent and methyl 6-bromo-2-naphthoate under the catalysis of an organophosphine-supported nickel catalyst (NiCl2 / dppe), and finally hydrolyzes to obtain the target product adapalene. The defects of this method are that the price of methyl 6-bromo-2-naphthoate is expensive, and strict anhydrous and anaerobic operations are required due to the use of organozinc reagents during the coupling reaction; the stoichiometric zinc salts after the reaction cause great pollution to the environment and are difficult to handle. These problems are particularly prominent in industrial production.

[0007] Chinese invention patent 《CN1872829A》 discloses a method for preparing adapalene. In a solvent, a solution of halogen anisole and adamantanol reacts under the action of an acid at -10 to 150 °C for 1 to 24 hours to obtain 2-(1-adamantanol)-4-bromoanisole. Then, in an ether or non-polar solvent, it reacts with magnesium under the initiation of one or more of iodine, iodide or bromide to generate a Grignard reagent, which is then synthesized with methyl 6-bromo-2-naphthoate, and finally hydrolyzed to obtain the adapalene raw material. This method has a relatively complete reaction, increased yield, reduced side reactions, improved product quality, all raw materials are common domestic chemical products, simple operation, reduced three wastes, and reduced costs, making it suitable for large-scale industrial production. However, this method uses a Grignard reaction to construct carbon-carbon bonds, with demanding anhydrous and anaerobic reaction conditions, posing great technical difficulties and production risks in industrial production, having a low overall yield, requiring multiple steps of purification, and high production costs. Additionally, it is difficult to handle the process impurities of self-coupling, and the environmental pollution problem of inorganic metal salts is prominent.

[0008] The reaction principle is as follows:

[0009]

[0010] US patent 《US7345189》 discloses that 4-methoxy-3-adamantylphenylboronic acid and 2-alkoxycarbonyl-6-naphthol p-toluenesulfonate are subjected to Suzuki coupling under the catalysis of a nickel catalyst supported by an organophosphorus ligand to obtain methyl adapalene, which is then hydrolyzed to obtain the target product adapalene. The disadvantages of this method are that arylboronic acid needs to be prepared at a very low temperature (below -50 °C); when the temperature is higher than -30 °C, special technical equipment such as a microreactor is required, otherwise the yield is very low. These harsh synthesis conditions make the production cost of arylboronic acid very high and the price expensive. Due to the high cost of arylboronic acid, the feasibility of implementing this technology industrially is poor. Summary of the Invention

[0011] The object of the present invention is to address the deficiencies of current industrial technologies and to solve the problems of the harsh reaction conditions of the traditional Grignard reaction for synthesizing adapalene and the high requirements for equipment and operation. A method for preparing adapalene by using pinacolborane to construct carbon-carbon bonds is provided. The raw materials involved in the reaction process are widely sourced, inexpensive, have few side reactions, high yields, and safe and simple operations. The quality of the final product meets the pharmacopoeia standards.

[0012] The reaction principle of this technical solution is as follows: Using inexpensive and readily available p-bromoanisole as the main raw material, with an acid as the catalyst, it undergoes a Friedel-Crafts reaction with 1-adamantanol to obtain 2-(1-adamantyl)-4-bromoanisole. In the presence of a catalyst and a ligand, it reacts with pinacol borane to form a boronic acid ester, and relying on the catalyst / ligand for constructing the boronic acid ester, it continues to couple in one pot. Then, it undergoes a Suzuki coupling with methyl 6-bromo-2-naphthoate to generate methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate in one pot. Finally, through ester hydrolysis and purification, the target product adapalene with high purity is obtained.

[0013]

[0014] The specific technical solution adopted is a method for preparing adapalene, which at least includes the following steps:

[0015] Step 1. Mix p-bromoanisole, 1-adamantanol, and acid with a molar ratio of 1.0:1.2 - 1.5:0.1 - 0.2, and then add 5 - 8 times the volume of the solvent. Stir until completely dissolved, and react at 10 - 30°C for 16 - 20 h. Cool the reaction solution to 0 - 10°C, add water, separate the layers, concentrate and filter, collect the filter cake to obtain 2-(1-adamantyl)-4-bromoanisole;

[0016] Step 2. Under nitrogen protection, mix 2-(1-adamantyl)-4-bromoanisole, a palladium catalyst, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and an organic base with a molar ratio of 1.0:0.05 - 0.10:0.6 - 1.0:2.0 - 3.0. Then add 5 - 8 times the volume of an aprotic solvent and stir at 10 - 30°C for 1 - 2 h to form a reaction system. Add 2.0 - 3.0 times the molar amount of pinacol borane to the reaction system and react at 80 - 100°C for 6 - 8 h. Then add 0.8 - 1.0 times the molar amount of methyl 6-bromo-2-naphthoate, 2.0 - 3.0 times the molar amount of base, and water, and react at 80 - 100°C for 4 - 6 h. After the reaction is completed, cool to room temperature and filter to obtain the first part of the product. Concentrate the filtrate obtained by filtration to 1 / 4 - 1 / 3 of the original volume, cool to room temperature and filter to obtain the second part of the product. Combine the first part of the product and the second part of the product, and recrystallize with a mixed solvent of N,N-dimethylformamide and an aprotic solvent to obtain methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate;

[0017] Step 3. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate and a base with a molar ratio of 1.0:3.0 - 4.0 are mixed, then 2 - 5 times the volume of water and 2 - 5 times the volume of tetrahydrofuran are added. The temperature is raised to 60 - 80 °C and refluxed for 2 - 3 h. The reaction solution is cooled to room temperature, and the pH value is adjusted to 2 - 3 with an acid to precipitate a solid. The solid is filtered, and the white solid is collected and recrystallized with N,N-dimethylformamide and an aprotic solvent to obtain adapalene.

[0018] Moreover, the acid in Step 1 is concentrated sulfuric acid or phosphoric acid.

[0019] Moreover, the solvent in Step 1 is chloroform or dichloromethane.

[0020] Moreover, the palladium catalyst in Step 2 is tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium or palladium acetate.

[0021] Moreover, the aprotic solvent in Step 2 is 1,4-dioxane or tetrahydrofuran.

[0022] Moreover, the organic base in Step 2 is triethylamine.

[0023] Moreover, the base in Step 2 is sodium carbonate or potassium carbonate.

[0024] Moreover, the base in Step 3 is sodium hydroxide or potassium hydroxide.

[0025] Moreover, the acid in Step 3 is hydrochloric acid or acetic acid.

[0026] Moreover, the aprotic solvent in Step 3 is tetrahydrofuran or ethyl acetate.

[0027] Compared with the prior art, the beneficial effects of this technical solution are as follows:

[0028] (1) The cost is significantly reduced. The p-bromoanisole and pinacol borane used in this process route are both cheap and easily available. In the prior art, p-bromophenol and 4-methoxyphenylboronic acid are often used as raw materials. Among them, p-bromophenol needs to be methylated with iodomethane or dimethyl sulfate to obtain p-bromoanisole. Whether it is the genotoxicity of iodomethane or the high toxicity of dimethyl sulfate, they are both problems difficult to solve in industry. Now, with the development of industrialization, the cost of p-bromoanisole is 40% lower than that of p-bromophenol, and the synthesis steps are simplified. Among them, the price of pinacol borane is 30% lower than that of 4-methoxyphenylboronic acid, and the dosage is reduced by 50%. After adopting this technical solution and through practical verification, the total production cost of the process is significantly reduced by more than 40%. On the premise of producing the same amount of adapalene, the production cost of the prior art exceeding 15,000 is reduced to less than 10,000.

[0029] (2) Technological innovation: breaking through the borate ester route with the "one-pot method". There are two defects in the existing borate ester route technology: 1. 4-Methoxyphenylboronic acid is used in all cases. Due to material limitations, the Friedel-Crafts reaction can only be placed at the back end of the route, which leads to transesterification reactions, introducing many impurities with polarities close to those of the finished product, increasing the difficulty of purification and raising production costs. 2. The construction of borate esters uses n-butyllithium and diboron, with harsh reaction conditions and high industrial operation difficulty. The Grignard reaction conditions require anhydrous and anaerobic environments, belonging to dangerous processes and being difficult for industrial production. In this route, the borate ester is constructed by the one-pot method and the Suzuki reaction is carried out. The main feature is that based on the readily available and inexpensive pinacol borane, the catalyst and ligand are reused repeatedly, continuously completing the construction of borane and the Suzuki coupling reaction without the need to purify the borate ester, greatly reducing the number of operation steps. The reaction conditions and operations of each unit in the overall process are simple, and the key intermediate with high purity and high yield can be obtained.

[0030] (3) Simple operation, facilitating industrial production. The reaction conditions are simple, with a high tolerance to water. The materials do not require complex pretreatment and do not need the anhydrous and anaerobic conditions that are difficult to achieve industrially. The post-treatment is simple, mainly by crystallization, without multiple complex extraction or washing operations.

[0031] (4) Green and environmentally friendly. In the traditional routes, there are problems such as a large amount of waste liquid caused by repeated refining and purification, or a large amount of metal inorganic salts that are difficult to treat and pollute the environment. In this technical solution, there are few refining steps, solving the problem of purifying impurities from the mechanism and reducing the generation of waste liquid. And only a small amount of inorganic salts are generated during the hydrolysis step. The overall route has less waste in terms of waste gas, waste liquid, and waste residue, being green and environmentally friendly.

[0032] (5) High overall yield and high product quality of the route. The yield of the traditional synthesis route is 30 - 50%, with multiple-step refining. It is difficult to remove inorganic salts, resulting in problems such as unqualified residues. In this technical solution, the purity of each intermediate in the process route is high and the purification is simple; the overall yield is high, approaching 70%, the purity of the finished product is greater than 99.9%, each single impurity is less than 0.10%, and the residues are qualified, meeting the requirements of EP and USP in terms of quality. Description of the Drawings

[0033] Figure 1 The liquid chromatogram of adapalene prepared in Example 1. Detailed Embodiments

[0034] The present invention will be described in detail below with reference to the drawings and examples. The content of the present invention is not limited to the following examples.

[0035] Example 1

[0036] A method for preparing adapalene, comprising the following steps:

[0037] (1) Add 1 kg of p - bromoanisole, 0.81 kg of 1 - adamantanol, 300 mL of concentrated sulfuric acid and 10 L of chloroform into a three - necked flask. Under stirring, react at 10 - 30 °C for 16 - 20 hours. Cool the reaction solution to 0 - 10 °C, add 8 L of water, separate the layers, and collect the organic layer. Concentrate the organic layer at 40 - 50 °C until most of the solvent is removed, then filter, collect the filter cake, wash the filter cake with an appropriate amount of water twice, filter again, and dry to obtain 1.43 kg of 2 - (1 - adamantyl) - 4 - bromoanisole with a purity of 98.6% and a yield of 82.5%;

[0038] (2) Under nitrogen protection, add 1 kg of the prepared 2 - (1 - adamantyl) - 4 - bromoanisole, 50 g of palladium acetate, 130 g of 2 - dicyclohexylphosphino - 2',6' - dimethoxybiphenyl, and 346 g of triethylamine into a three - necked flask, then add 8 L of 1,4 - dioxane. Stir at room temperature for 1 - 2 hours, then add 260 g of pinacol borane into the reaction system, and react at 80 - 100 °C for 6 - 8 hours. Add 800 g of methyl 6 - bromo - 2 - naphthoate, 1.28 kg of sodium carbonate, and 5 L of water, and continue to react at 80 - 100 °C for 4 - 6 hours. After the reaction is completed, cool to room temperature and filter to obtain a part of the product. Concentrate the filtrate to 1 / 4 of the original volume, cool to room temperature and filter, and combine the products. Recrystallize from N,N - dimethylformamide and ethyl acetate to obtain 1.08 kg of methyl 6 - [3 - (1 - adamantyl) - 4 - methoxyphenyl] - 2 - naphthoate with a purity of 99.4% and a yield of 81.1%;

[0039] (3) Add 1 kg of the prepared methyl 6 - [3 - (1 - adamantyl) - 4 - methoxyphenyl] - 2 - naphthoate and 182 g of sodium hydroxide into a three - necked flask, then add 5 L of water and 5 L of tetrahydrofuran, heat to reflux for 2 - 3 hours. Cool the reaction solution to room temperature, adjust the pH value to 2 - 3 with acid, precipitate a solid, filter, collect the white solid, and recrystallize from N,N - dimethylformamide and tetrahydrofuran to obtain 818 g of adapalene with a purity of 99.9% and a yield of 84.5%.

[0040] Example 2

[0041] A method for preparing adapalene, comprising the following steps:

[0042] (1) Add 1 kg of p-bromoanisole, 0.81 kg of 1-adamantanol, 300 mL of concentrated sulfuric acid and 10 L of dichloromethane into a three-necked flask. Under stirring, react at 10 - 30 °C for 16 - 20 hours. Cool the reaction solution to 0 - 10 °C, add 8 L of water, separate the layers, and collect the organic layer. Concentrate the organic layer at 40 - 50 °C until most of the solvent is removed, then filter, collect the filter cake, wash the filter cake with an appropriate amount of water twice, filter again, and dry to obtain 1.47 kg of 2-(1-adamantyl)-4-bromoanisole with a purity of 98.9% and a yield of 84.8%;

[0043] (2) Under nitrogen protection, add 1 kg of 2-(1-adamantyl)-4-bromoanisole, 50 g of tris(dibenzylideneacetone)dipalladium, 130 g of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and 346 g of triethylamine into a three-necked flask, then add 8 L of tetrahydrofuran. Stir at room temperature for 1 - 2 hours, then add 260 g of pinacolborane to the reaction system, and react at 80 - 100 °C for 6 - 8 hours. Add 800 g of methyl 6-bromo-2-naphthoate, 1.33 kg of potassium carbonate, and 5 L of water, and continue to react at 80 - 100 °C for 4 - 6 hours. After the reaction is completed, cool to room temperature and filter to obtain a part of the product. Concentrate the filtrate to 1 / 3 of the original volume, cool to room temperature and filter, and combine the products. Recrystallize from N,N-dimethylformamide and ethyl acetate to obtain 1.05 kg of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate with a purity of 99.9% and a yield of 78.9%;

[0044] (3) Add 1 kg of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate and 255 g of potassium hydroxide into a three-necked flask, then add 3 L of water and 5 L of tetrahydrofuran, and reflux at an elevated temperature for 2 - 3 hours. Cool the reaction solution to room temperature, adjust the pH value to 2 - 3 with acid, precipitate a solid, filter, collect the white solid, and recrystallize from N,N-dimethylformamide and ethyl acetate to obtain 803 g of adapalene with a purity of 99.5% and a yield of 82.9%.

[0045] Example 3

[0046] A method for preparing adapalene, comprising the following steps:

[0047] (1) Add 1 kg of p - bromoanisole, 0.81 kg of 1 - adamantanol, 300 mL of phosphoric acid and 10 L of chloroform into a three - necked flask. Under stirring, react at 10 - 30 °C for 16 - 20 hours. Cool the reaction solution to 0 - 10 °C, add 8 L of water, separate the layers, and collect the organic layer. Concentrate the organic layer at 40 - 50 °C until most of the solvent is removed, then filter, collect the filter cake, wash the filter cake with an appropriate amount of water twice, filter, and dry to obtain 1.48 kg of 2 - (1 - adamantyl) - 4 - bromoanisole with a purity of 98.1% and a yield of 85.6%;

[0048] (2) Under nitrogen protection, add 1 kg of 2 - (1 - adamantyl) - 4 - bromoanisole, 50 g of dichloropalladium [1,1'-bis(diphenylphosphino)ferrocene], 130 g of 2 - dicyclohexylphosphino - 2',6'-dimethoxybiphenyl into a three - necked flask, then add 10 L of 1,4 - dioxane. Stir at room temperature for 1 - 2 hours, then add 260 g of pinacolborane into the reaction system, and react at 80 - 100 °C for 6 - 8 hours. Add 800 g of methyl 6 - bromo - 2 - naphthoate, 1.28 kg of sodium carbonate, and 5 L of water, and continue to react at 80 - 100 °C for 4 - 6 hours. After the reaction is completed, cool to room temperature and filter to obtain a part of the product. Concentrate the filtrate to 1 / 4 - 1 / 3 of the original volume, cool to room temperature and filter, and combine the products. Recrystallize from N,N - dimethylformamide and ethyl acetate to obtain 1.10 kg of methyl 6 - [3 - (1 - adamantyl) - 4 - methoxyphenyl] - 2 - naphthoate with a purity of 99.3% and a yield of 82.6%;

[0049] (3) Add 1 kg of methyl 6 - [3 - (1 - adamantyl) - 4 - methoxyphenyl] - 2 - naphthoate and 182 g of sodium hydroxide into a three - necked flask, then add 5 L of water and 5 L of tetrahydrofuran, heat to reflux for 2 - 3 hours. Cool the reaction solution to room temperature, adjust the pH value to 2 - 3 with acid, precipitate a solid, filter, collect the white solid, and recrystallize from N,N - dimethylformamide and tetrahydrofuran to obtain 818 g of adapalene with a purity of 99.8% and a yield of 86.0%.

[0050] In summary, in order to avoid the contingency of single - experiment data, the synthesis method and parameter conditions of this technical solution were repeatedly verified through multiple experiments with similar conditions. The overall average yield of the experiments was close to 70%, the minimum purity of the finished product was 99.5%, the maximum was 99.9%, each single impurity was less than 0.10%, the residue was qualified, and the quality met the requirements of EP and USP.

Claims

1. A preparation method of adapalene, characterized in that, it at least includes the following steps: Step 1. After mixing anisole bromide: 1-adamantanol: acid with a molar ratio of 1.0: 1.2 - 1.5: 0.1 - 0.2, add a solvent with a volume 5 - 8 times, stir until completely dissolved, and react at 10 - 30 °C for 16 - 20 h; cool the reaction solution to 0 - 10 °C, add water, separate the liquid, concentrate and filter, collect the filter cake to obtain 2-(1-adamantyl)-4-bromoanisole; Step 2. Under nitrogen protection, mix 2-(1-adamantyl)-4-bromoanisole: palladium catalyst: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl: organic base with a molar ratio of 1.0: 0.05 - 0.10: 0.6 - 1.0: 2.0 - 3.0, then add a non-protic solvent with a volume 5 - 8 times, stir at 10 - 30 °C for 1 - 2 h to form a reaction system; add 2.0 - 3.0 times the molar amount of pinacol borane to the reaction system, react at 80 - 100 °C for 6 - 8 h; then add 0.8 - 1.0 times the molar amount of methyl 6-bromo-2-naphthoate, 2.0 - 3.0 times the molar amount of base, and water, mix and react at 80 - 100 °C for 4 - 6 h, after the reaction is completed, cool to room temperature and filter to obtain the first part of the product; concentrate the filtrate obtained by filtration to 1 / 4 - 1 / 3 of the original volume, cool to room temperature and filter to obtain the second part of the product; combine the first part of the product and the second part of the product obtained, and recrystallize with a mixed solvent of N,N-dimethylformamide and non-protic solvent to obtain methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate; Step 3. Mix methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate and base with a molar ratio of 1.0: 3.0 - 4.0, then add 2 - 5 times the volume of water and 2 - 5 times the volume of tetrahydrofuran, heat to 60 - 80 °C and reflux for 2 - 3 h, cool the reaction solution to room temperature, adjust the pH value to 2 - 3 with acid, precipitate solid, filter, collect the white solid, and recrystallize with a mixed solvent of N,N-dimethylformamide and non-protic solvent to obtain adapalene.

2. The preparation method of adapalene according to claim 1, characterized in that: The acid in Step 1 is concentrated sulfuric acid or phosphoric acid.

3. The preparation method of adapalene according to claim 1, characterized in that: The solvent in Step 1 is chloroform or dichloromethane.

4. The preparation method of adapalene according to claim 1, characterized in that: The palladium catalyst in Step 2 is tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium or palladium acetate.

5. The preparation method of adapalene according to claim 1, characterized in that: The non-protic solvent in Step 2 is 1,4-dioxane or tetrahydrofuran.

6. The preparation method of adapalene according to claim 1, characterized in that: The organic base in Step 2 is triethylamine.

7. The preparation method of adapalene according to claim 1, characterized in that: The base in step 2 is sodium carbonate or potassium carbonate.

8. The preparation method of adapalene according to claim 1, characterized in that: The base in step 3 is sodium hydroxide or potassium hydroxide.

9. The preparation method of adapalene according to claim 1, characterized in that: The acid in step 3 is hydrochloric acid or acetic acid.

10. The preparation method of adapalene according to claim 1, characterized in that: The aprotic solvent in step 3 is tetrahydrofuran or ethyl acetate.

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