Preparation method of adapalene key intermediate
By using low-toxicity methylating agents and phase transfer catalysts, the problem of highly toxic reagents in the synthesis of adapalene has been solved, enabling the efficient and low-cost preparation of key intermediates for adapalene, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU LIANHUAN PHARMA
- Filing Date
- 2026-02-03
- Publication Date
- 2026-05-12
AI Technical Summary
The methylating agents and solvents used in the existing adapalene synthesis process have high genotoxicity, resulting in high risks to occupational safety and post-processing during production, as well as high costs.
The key intermediate adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane, is prepared via methylation using a low-toxicity methylating agent and a phase transfer catalyst. This method avoids the use of highly genotoxic reagents, incorporates a base reagent and a phase transfer catalyst, controls the reaction conditions, simplifies post-processing, and achieves high yield.
This method enables the efficient and low-cost preparation of key intermediates for adapalene, avoiding the use of highly toxic reagents. The operation is simple and safe, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, and more specifically, relates to a method for preparing a key intermediate of adapalene. Background Technology
[0002] Adapalene, chemical name 6 [3 (1 adamantyl) 4 [Methoxyphenyl] 2 Naphthoic acid, with the molecular formula C 28 H 28 O3 is a white or off-white crystalline powder at room temperature, insoluble in water or ethanol, and slightly soluble in tetrahydrofuran. This drug belongs to the third-generation retinoid class of drugs. It regulates epidermal cell differentiation by selectively binding to RARβ and RARγ receptors, and has inhibitory effects on follicular keratinization, comedonalization, and anti-inflammatory properties. Clinically, it is mainly used to treat mild to moderate acne vulgaris on the face, chest, and back, characterized primarily by comedones, papules, and pustules. The common dosage form is a 0.1% gel. Trade name "Differin," it was first launched in France in 1996, approved by the US FDA in July 2000, and first launched as an over-the-counter (OTC) drug in the US in November 2000. It has anti-inflammatory effects during the treatment of acne and can effectively improve dermatitis lesions, thus gaining widespread clinical application.
[0003] Several methods for synthesizing adapalene have been reported in the literature. In recent years, there have been patents or literature reports on adapalene synthesis technology, such as the Chinese patent CN111333496A, which describes the synthesis of adapalene from methyl 6-(4-methoxyphenyl)-2-naphthoic acid and 1-adamantaneol via Friedel-Crafts reaction and hydrolysis. However, the reaction process uses two types of solvents such as dichloroethane and expensive catalysts such as nickel bis(triphenylphosphine) chloride, resulting in high risks of solvent residue, metal residue control, and personnel protection during the production of the active pharmaceutical ingredient. Mainstream production processes include those described in US patent US4717720A and Chinese patent CN104003838A, both involving the key intermediate 1-(5-bromo-2-methoxyphenyl)adamantane. However, the methylating agents used in these patents, such as dimethyl sulfate and iodomethane, are highly genotoxic impurities, increasing the risks in terms of labor protection and post-processing during production.
[0004] Therefore, there is an urgent need to develop an efficient and low-cost method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene. Summary of the Invention
[0005] To address the aforementioned technical problems, this invention provides an efficient and low-cost method for preparing adapalene's key intermediate, 1-(5-bromo-2-methoxyphenyl)adamantane. This method minimizes the use of highly genotoxic reagents and Class I and II solvents during the basicization process. Furthermore, the process is simple, uses readily available raw materials, has a high yield, and is low in cost, while achieving satisfactory adapalene production quality.
[0006] This invention is achieved through the following technical solution:
[0007] A method for preparing a key intermediate of adapalene, wherein 2-(1-adamantyl)-4-bromophenol (AD-a) is used as a raw material, and 1-(5-bromo-2-methoxyphenyl)adamantane (AD-b) is obtained by methylation reaction. The methylation reaction uses a low-toxicity methylating agent, and the molar ratio of the low-toxicity methylating agent to AD-a is (1.25~4.00):1, preferably 1.5:1.
[0008] In a preferred embodiment, a phase transfer catalyst is also added to the reaction system, wherein the mass ratio of the added phase transfer catalyst to AD-a is (0.02~0.05):1, preferably 0.02:1.
[0009] In a preferred embodiment, the low-toxicity methylating agent is selected from one or more of methyl p-toluenesulfonate, methyl benzenesulfonate, and methyl formate.
[0010] In a preferred embodiment, the phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride, and benzyltriethylammonium chloride.
[0011] As a preferred embodiment, the preparation method specifically includes the following steps: Step 1: Add the alkaline reagent, water and AD-a to the reaction flask, stir and heat to 50°C, and react for 10 min to 3 hours; Step 2: Add an acetone solution containing a methylating agent, and optionally add a phase transfer catalyst, and react for 30 minutes to 3 hours; Step 3: After cooling, separate the aqueous phase and wash the organic phase twice with water, then concentrate to dryness; Step 4: Add alcohol and heat to 50°C, then add water, stir at 20-30°C for 1 hour, filter, and dry the filter cake at 45-55°C for 6 hours to obtain adapalene key intermediate 1-(5-bromo-2-methoxyphenyl)adamantane.
[0012] In a preferred embodiment, the alkaline reagent is selected from one or more of sodium hydroxide, sodium carbonate, and potassium carbonate, and the molar ratio of the alkaline reagent to AD-a is (1.1~1.5):1, preferably 1.2:1.
[0013] In a preferred embodiment, the amount of water added in step 1 is 5 to 10 times the mass-volume ratio of AD-a; the amount of acetone used in step 2 is 2.5 to 5 times the mass-volume ratio of AD-a, and the volume ratio of water to acetone is 1.5 to 2.5:1.
[0014] In a preferred embodiment, the amount of alcohol used in step 4 is 1.5 to 2.5 times the mass-volume ratio of AD-a, and the amount of water added is 1.5 to 2.5 times the mass-volume ratio of AD-a. The volume ratio of alcohol to water in step 4 is 1:1.
[0015] In a preferred embodiment, the alcohol in step 4 is methanol or ethanol, preferably methanol.
[0016] In a preferred embodiment, the yield of 1-(5-bromo-2-methoxyphenyl)adamantane (AD-b) is greater than 90%.
[0017] Compared with existing technologies, the preparation method provided by this invention uses inexpensive and readily available raw materials, avoids highly toxic reagents, is simple and safe to operate, has a high yield, low cost, and has the advantages of high product purity and yield. It is also very environmentally friendly and suitable for industrial scale-up. Detailed Implementation
[0018] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0019] 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 the embodiments of this invention pertain. If any definition stated in this section is contrary to or otherwise inconsistent with a definition stated in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definitions listed here shall prevail over those incorporated herein by reference.
[0020] Unless otherwise specified, the methods used in the following embodiments are conventional methods. The materials, reagents, and instruments used, unless otherwise specified, are all conventional materials, reagents, and instruments in the art, and can be obtained commercially by those skilled in the art.
[0021] Example 1 This embodiment provides a method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene, with the following raw material formulation:
[0022] The specific steps are as follows: Sodium hydroxide, water ①, and AD-a were added to the reaction flask, stirred, and heated to 50°C for 10 minutes. An acetone solution of methyl p-toluenesulfonate was added, and the reaction was carried out for 3 hours. The mixture was then cooled, stirred for 5 minutes, separated to remove the aqueous phase, and the organic phase was washed twice with water and concentrated to dryness. Methanol was added, the temperature was raised to 50°C, water ② was added, and the mixture was stirred at 20–30°C for 1 hour. The mixture was then filtered, and the filter cake was dried at 45–55°C for 6 hours to obtain 4.51 g of AD-b, with a yield of 90.2%.
[0023] Example 2 This embodiment provides a method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene, with the following raw material formulation:
[0024] The specific steps are as follows: Sodium carbonate, water, and AD-a were added to the reaction flask, stirred, and heated to 50°C for 10 minutes. Then, an acetone solution of methyl p-toluenesulfonate and tetrabutylammonium chloride were added, and the reaction was carried out for 30 minutes. The mixture was then cooled, and the aqueous phase was separated. The organic phase was washed twice with water and concentrated to dryness. Methanol was added, and the temperature was raised to 50°C. Water ② was added, and the mixture was stirred at 20–30°C for 1 hour. The mixture was then filtered, and the filter cake was dried at 45–55°C for 6 hours to obtain 4.58 g of AD-b, with a yield of 91.6%.
[0025] Example 3 This embodiment provides a method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene, with the following raw material formulation:
[0026] The specific steps are as follows: Sodium carbonate, water, and AD-a were added to the reaction flask, stirred, and heated to 50°C for 10 minutes. Then, an acetone solution of methyl p-toluenesulfonate and tetrabutylammonium fluoride were added, and the reaction was carried out for 30 minutes. The mixture was then cooled, and the aqueous phase was separated. The organic phase was washed twice with water and concentrated to dryness. Methanol was added, and the temperature was raised to 50°C. Water ② was added, and the mixture was stirred at 20–30°C for 1 hour. The mixture was then filtered, and the filter cake was dried at 45–55°C for 6 hours to obtain 4.63 g of AD-b, with a yield of 92.6%.
[0027] Example 4 This embodiment provides a method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene, with the following raw material formulation:
[0028] The specific steps are as follows: Potassium carbonate, water, and AD-a were added to the reaction flask, stirred, and heated to 50°C for 10 minutes. Then, an acetone solution of methyl p-toluenesulfonate and benzyltriethylammonium chloride were added, and the reaction was carried out for 30 minutes. The mixture was then cooled, and the aqueous phase was separated. The organic phase was washed twice with water and concentrated to dryness. Methanol was added, and the mixture was heated to 50°C. Water ② was added, and the mixture was stirred at 20–30°C for 1 hour. The mixture was then filtered, and the filter cake was dried at 45–55°C for 6 hours to obtain 4.62 g of AD-b, with a yield of 92.4%.
[0029] Example 5 This embodiment provides a method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene, with the following raw material formulation:
[0030] The specific steps are as follows: Potassium carbonate, water, and AD-a were added to the reaction flask, stirred, and heated to 50°C for 10 minutes. Then, an acetone solution of methyl p-benzenesulfonate and benzyltriethylammonium chloride were added, and the reaction was carried out for 30 minutes. The mixture was then cooled, and the aqueous phase was separated. The organic phase was washed twice with water and concentrated to dryness. Methanol was added, and the mixture was heated to 50°C. Water ② was added, and the mixture was stirred at 20–30°C for 1 hour. The mixture was then filtered, and the filter cake was dried at 45–55°C for 6 hours to obtain 4.60 g of AD-b, with a yield of 92.0%.
[0031] Example 6 This embodiment provides a method for preparing 1-(5-bromo-2-methoxyphenyl)adamantane, a key intermediate of adapalene, with the following raw material formulation:
[0032] The specific steps are as follows: Potassium carbonate, water, and AD-a were added to the reaction flask, stirred, and heated to 50°C for 10 minutes. Then, an acetone solution of methyl formate and benzyltriethylammonium chloride were added, and the reaction was carried out for 30 minutes. The mixture was then cooled, and the aqueous phase was separated. The organic phase was washed twice with water and concentrated to dryness. Methanol was added, and the temperature was raised to 50°C. Water ② was added, and the mixture was stirred at 20–30°C for 1 hour. The mixture was then filtered, and the filter cake was dried at 45–55°C for 6 hours to obtain 4.58 g of AD-b, with a yield of 91.6%.
[0033] Comparative Example 1 This comparative example provides a method for preparing the key intermediate adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane, with the following raw material formulation:
[0034] The specific steps are as follows: Potassium carbonate, acetone and AD-a were added to the reaction flask, stirred and heated to 50°C, and dimethyl sulfate was slowly added dropwise. The reaction was carried out for 2 hours. After adding sodium hydroxide aqueous solution and stirring for 1 hour, the mixture was filtered, the filter cake was washed with purified water ②, and dried at 45-55°C for 6 hours to obtain 4.28 g of AD-b, with a yield of 85.6%.
[0035] Comparative Example 2 This comparative example provides a method for preparing the key intermediate adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane, with the following raw material formulation:
[0036] The specific steps are as follows: Potassium carbonate, acetone and AD-a were added to the reaction flask, stirred and heated to 50°C, and iodomethane was slowly added dropwise. The reaction was carried out for 1.5 hours. After adding sodium hydroxide aqueous solution and stirring for 1 hour, the mixture was filtered, the filter cake was washed with purified water ②, and dried at 45-55°C for 6 hours to obtain 4.23 g of AD-b, with a yield of 84.7%.
[0037] Comparative Example 3 This comparative example provides a method for preparing the key intermediate adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane, with the following raw material formulation:
[0038] The specific steps are as follows: Sodium hydroxide, acetone and AD-a were added to the reaction flask, and the mixture was stirred and heated to 50°C. Methyl p-toluenesulfonate was then slowly added, and the reaction was allowed to proceed for 5 hours; no reaction occurred.
[0039] Comparative Example 4 This comparative example provides a method for preparing the key intermediate adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane, with the following raw material formulation:
[0040] The specific steps are as follows: Potassium carbonate, acetone, and AD-a were added to the reaction flask, and the mixture was stirred and heated to 50°C. Methyl p-toluenesulfonate was then slowly added, and the reaction was allowed to proceed for 5 hours; no reaction occurred.
[0041] Comparative Example 5 This comparative example provides a method for preparing the key intermediate adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane, with the following raw material formulation:
[0042] The specific steps are as follows: Potassium carbonate, acetone, and AD-a were added to the reaction flask, and the mixture was stirred and heated to 50°C. Methyl methanesulfonate was then slowly added, and the reaction was allowed to proceed for 5 hours; no reaction occurred.
[0043] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing a key intermediate of adapalene, characterized in that, Using 2-(1-adamantyl)-4-bromophenol (AD-a) as a raw material, the key intermediate of adapalene, 1-(5-bromo-2-methoxyphenyl)adamantane (AD-b), is obtained by methylation reaction. The methylation reaction uses a low-toxicity methylating agent, and the molar ratio of the low-toxicity methylating agent to AD-a is (1.25~4.00):1, preferably 1.5:
1.
2. The preparation method according to claim 1, characterized in that, A phase transfer catalyst is also added to the reaction system, and the mass ratio of the added phase transfer catalyst to AD-a is (0.02~0.05):1, preferably 0.02:
1.
3. The preparation method according to claim 1, characterized in that, The low-toxicity methylating agent is selected from one or more of methyl p-toluenesulfonate, methyl benzenesulfonate, and methyl formate.
4. The preparation method according to claim 1, characterized in that, The phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride, and benzyltriethylammonium chloride.
5. The preparation method according to claim 1, characterized in that, Specifically, the following steps are included: Step 1: Add the alkaline reagent, water and AD-a to the reaction flask, stir and heat to 50°C, and react for 10 min to 3 hours; Step 2: Add an acetone solution containing a methylating agent, and optionally add a phase transfer catalyst, and react for 30 minutes to 3 hours; Step 3: After cooling, separate the aqueous phase and wash the organic phase twice with water, then concentrate to dryness; Step 4: Add alcohol and heat to 50°C, then add water, stir at 20-30°C for 1 hour, filter, and dry the filter cake at 45-55°C for 6 hours to obtain adapalene key intermediate 1-(5-bromo-2-methoxyphenyl)adamantane.
6. The preparation method according to claim 1, characterized in that, The alkaline reagent is selected from one or more of sodium hydroxide, sodium carbonate, and potassium carbonate, and the molar ratio of the alkaline reagent to AD-a is (1.1~1.5):1, preferably 1.2:
1.
7. The preparation method according to claim 1, characterized in that, In step 1, the amount of water added is 5 to 10 times the mass-volume ratio of AD-a; in step 2, the amount of acetone used is 2.5 to 5 times the mass-volume ratio of AD-a, and the volume ratio of water to acetone is 1.5 to 2.5:
1.
8. The preparation method according to claim 1, characterized in that, In step 4, the amount of alcohol used is 1.5 to 2.5 times the mass-volume ratio of AD-a, and the amount of water added is 1.5 to 2.5 times the mass-volume ratio of AD-a. The volume ratio of alcohol to water in step 4 is 1:
1.
9. The preparation method according to claim 1, characterized in that, In step 4, the alcohol is methanol or ethanol, with methanol being preferred.
10. The preparation method according to claim 1, characterized in that, The yield of 1-(5-bromo-2-methoxyphenyl)adamantane (AD-b) is greater than 90%.