A kind of preparation method of high-purity adapalene

Abstract

The present application belongs to the technical field of organic synthesis, and specifically discloses a method for preparing high-purity adapalene. In particular, a method for preparing high-purity adapalene is proposed. The main steps of the method are: first, adapalene is pretreated, and then crystallization is performed by forming a crystal nucleus and slowly dripping a hydrophilic solution seed to remove impurities. This preparation method has the advantages of simple process and easy operation, and effectively controls indicators such as solvent residue and heavy metals during the synthesis process. The adapalene product obtained by the method of the present invention is of excellent quality, with a single impurity content of less than 0.05% and a liquid chromatography purity of more than 99.8%.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical synthesis, and in particular to a method for preparing high-purity adapalene. Background Art

[0002] Adapalene, whose chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, belongs to the third generation of retinoic acid drugs, has good anti-inflammatory effects, and has a good therapeutic effect on the treatment of acne.

[0003] The structural formula of adapalene is:

[0004]

[0005] There are many reports on the synthesis of adapalene in the literature, including the technology described in US Patent US4717720 and Chinese Patent CN104003838 A. These two methods generally involve evaporating the organic solvent under normal pressure, followed by acidifying the reaction mixture to a pH of about 1, and then obtaining the final product by direct filtration. In addition, the synthesis of adapalene can also be achieved through two different routes: one is from 2-(1-adamantyl)-4-bromoanisole, and the other is from 4-methoxy-3-adamantylphenylboronic acid. However, these two routes may result in different levels of impurities.

[0006] The impurities are as follows:

[0007]

[0008] It is worth noting that 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester, due to its large molecular weight and low activity, usually needs to be hydrolyzed under strong alkaline conditions in industrial production to be converted into 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, the final form of adapalene. One challenge in this process is that there will be serious impurity encapsulation during the conversion process. In order to improve the purity, existing technical means usually include the use of mixed solvents, heating and refluxing, and then cooling to precipitate the target compound. Even so, it is still quite difficult to achieve a single impurity content of less than 0.05%. The current qualification standard in the industry is to control the total amount of impurities to less than 0.1%. Therefore, there is an urgent need to develop a method for obtaining high-purity adapalene. Summary of the invention

[0009] Purpose of the invention: In view of the deficiencies in the prior art, the present application provides a method for preparing high-purity adapalene.

[0010] Technical solution: The method comprises the following steps: industrially synthesized adapalene is dissolved in 20-30 times of organic solvent 1, insoluble matter is filtered out, a certain amount of organic solvent 1 is concentrated, and organic solvent 2 is added to the residual organic solvent 1 solution to precipitate crystals, thereby achieving a pretreatment effect. Crude adapalene is dissolved in organic solvent 3, and 1-2 times of hydrophilic solvent 4 is added to heat and reflux to form crystal nuclei. Hydrophilic solvent 4 is added dropwise again to crystallize, so that adapalene in the crystallization process is similar to the crystal nucleus to achieve the effect of separating impurities.

[0011] Specifically, 100 parts by weight of industrially synthesized adapalene is added to 20-30 times of organic solvent 1, stirred and heated to dissolve and clarify. Insoluble matter is removed by hot filtration, and the filtrate is collected. The temperature is controlled at 30-40°C, and about 65-85% of organic solvent 1 is concentrated under reduced pressure. In the remaining organic solvent 1, the temperature is controlled at 30-40°C, and the remaining organic solvent 2 of the same volume is added dropwise. Continue stirring to cool down by 0-5°C, slow down the stirring speed, and precipitate crystals. Filter the crystals and control the temperature to 60°C for vacuum drying to complete the pretreatment to obtain crude adapalene. The crude adapalene is added to organic solvent 3, stirred and heated to dissolve and clarify, and then a specified amount of activated carbon is added to decolorize for 1 hour. After filtering the activated carbon, it is filtered through a 0.22um membrane to obtain a clear organic solution. In the decolorizing solution, the same volume of hydrophilic solution 4 is added, and stirring and refluxing are continued. Continue to drop the hydrophilic solution 4 again, so that the crystals crystallize and precipitate adapalene in the direction of forming crystal nuclei. Thus, high-purity adapalene is obtained.

[0012] Specifically, the organic solvent 1 can be tetrahydrofuran, methanol, or acetone. In the present invention, tetrahydrofuran is preferred.

[0013] Specifically, the organic solvent 2 can be toluene, n-heptane, or dichloromethane. In the present invention, toluene is preferred.

[0014] Specifically, the organic solvent 3 may be methanol, ethanol, or isopropanol. In the present invention, methanol is preferred.

[0015] Specifically, the hydrophilic solution 4 can be a mixture of one or more of water, ethanol or acetone. In the present invention, water is preferred.

[0016] A preferred embodiment of the present invention is: add 100 grams of industrially synthesized adapalene to 20 to 30 times of tetrahydrofuran, stir and heat to dissolve and clarify, and filter the insoluble matter while hot. Collect the filtrate and control the temperature to 30-40°C. After reducing pressure and concentrating the tetrahydrofuran, add toluene at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product. Add the crude product to methanol, stir and heat to dissolve, then add 5% activated carbon of the crude product, continue to heat and reflux for 1 hour, and obtain a clarified solution after filtering and membrane filtration. Add water, continue to heat and reflux for 1 hour, after forming a crystal nucleus, continue to drip water, and reflux for 2 hours to complete the crystallization. Filter and vacuum dry to obtain high-purity adapalene.

[0017] Beneficial effects: The high-purity adapalene-related substances prepared by the method of the present invention are all below 0.05%. The present invention effectively handles key indicators such as solvent residues and heavy metals during the synthesis process, and has the characteristics of simple operation and high refining yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the chromatogram of Example 1.

[0019] Figure 2 This is the chromatogram of Example 2.

[0020] Figure 3 This is the chromatogram of Example 3.

[0021] Figure 4 This is the chromatogram of Example 4.

[0022] Figure 5 This is the chromatogram of Example 5. DETAILED DESCRIPTION

[0023] The technical solution of the present application is described in detail below through embodiments, but the protection scope of the present application is not limited to the embodiments.

[0024] Example 1

[0025] Add 100g of industrially synthesized adapalene to 2000ml of tetrahydrofuran, stir and heat to dissolve and clarify, and filter the insoluble matter while hot. Collect the filtrate and control the temperature to 30-40°C, concentrate 1500ml of tetrahydrofuran under reduced pressure, add 500ml of toluene at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product.

[0026] The crude product was added into 500 ml of methanol, stirred and heated to dissolve, then 5% activated carbon of the crude product was added, and the temperature was continued to be raised and refluxed for 1 hour, and a clear solution was obtained after filtration and membrane filtration.

[0027] Add 500 ml of water, continue to heat and reflux for 1 hour, after the crystal nucleus is formed, continue to drop 500 ml of water, reflux for 2 hours to complete the crystallization. Filter and vacuum dry. High-purity adapalene is obtained. The yield is 90%. See the chromatogram Figure 1 .

[0028] Example 2

[0029] Add 100g of industrially synthesized adapalene to 2000ml of tetrahydrofuran, stir and heat to dissolve and clarify, and filter the insoluble matter while hot. Collect the filtrate and control the temperature to 30-40°C, concentrate 1300ml of tetrahydrofuran under reduced pressure, add 700ml of toluene at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product.

[0030] The crude product was added into 700 ml of methanol, stirred and heated to dissolve, then 5% activated carbon of the crude product was added, and the temperature was continued to be raised and refluxed for 1 hour, and a clear solution was obtained after filtration and membrane filtration.

[0031] Add 700 ml of water, continue to heat and reflux for 1 hour, after the crystal nucleus is formed, continue to drop 700 ml of water, reflux for 2 hours to complete the crystallization. Filter and vacuum dry. High-purity adapalene is obtained. The yield is 87%. See the chromatogram Figure 2 .

[0032] Example 3

[0033] Add 100g of industrially synthesized adapalene to 2000ml of tetrahydrofuran, stir and heat to dissolve and clarify, and filter the insoluble matter while hot. Collect the filtrate and control the temperature to 30-40°C, concentrate 1000ml of tetrahydrofuran under reduced pressure, add 1000ml of toluene at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product.

[0034] The crude product was added into 1000 ml of methanol, stirred and heated to dissolve, then 5% activated carbon of the crude product was added, and the temperature was continued to be raised and refluxed for 1 hour, and a clear solution was obtained after filtration and membrane filtration.

[0035] Add 1000ml of water, continue to heat and reflux for 1 hour, after the crystal nucleus is formed, continue to drop 1000ml of water, reflux for 2 hours to complete the crystallization. Filter and vacuum dry. High-purity adapalene is obtained. The yield is 85%. See the chromatogram Figure 3 .

[0036] Example 4

[0037] Add 100g of industrially synthesized adapalene to 2000ml of acetone, stir and heat to dissolve and clarify, and filter the insoluble matter while hot. Collect the filtrate and control the temperature to 30-40°C, reduce the pressure and concentrate 1300ml of acetone, then add 700ml of dichloromethane at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product.

[0038] The crude product was added into 800 ml of ethanol, stirred and heated to dissolve, then 5% activated carbon of the crude product was added, and the temperature was continued to be raised and refluxed for 1 hour, and a clear solution was obtained after filtration and membrane filtration.

[0039] Add 800 ml of water, continue to heat and reflux for 1 hour, after the crystal nucleus is formed, continue to drop 800 ml of water, reflux for 2 hours to complete the crystallization. Filter and vacuum dry. High-purity adapalene is obtained. The yield is 83%. See the chromatogram Figure 4 .

[0040] Example 5

[0041] Add 100g of industrially synthesized adapalene to 2000ml of acetone, stir and heat to dissolve and clarify, and filter the insoluble matter while hot. Collect the filtrate and control the temperature to 30-40°C, concentrate 1500ml of acetone under reduced pressure, add 500ml of n-heptane at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product.

[0042] The crude product was added into 700 ml of isopropanol, stirred and heated to dissolve, then 5% activated carbon of the crude product was added, and the temperature was continued to be raised and refluxed for 1 hour, and a clear solution was obtained after filtration and membrane filtration.

[0043] Add 700 ml of ethanol, continue to heat and reflux for 1 hour, after the crystal nucleus is formed, continue to drop 700 ml of ethanol, reflux for 2 hours to complete the crystallization. Filter and vacuum dry. High-purity adapalene is obtained. The yield is 82%. See the chromatogram Figure 5 .

[0044] The above description is only a preferred embodiment of the present application and is not intended to limit the present application.

Claims

1. A method for preparing high-purity adapalene, characterized in that: Industrially synthesized adapalene is dissolved in 20-30 times of organic solvent 1, insoluble matter is filtered out, a certain amount of organic solvent 1 is concentrated, and organic solvent 2 is added to the residual organic solvent 1 solution to precipitate crystals, thereby achieving a pretreatment effect; crude adapalene is dissolved in organic solvent 3, 1-2 times of hydrophilic solvent 4 is added, and the temperature is refluxed to form crystal nuclei; hydrophilic solvent 4 is added dropwise again for crystallization, so that during the crystallization process, adapalene crystallizes in a manner similar to that of the crystal nuclei to achieve the effect of separating impurities.

2. The method for preparing high-purity adapalene according to claim 1, characterized in that: Add 20-30 times the amount of organic solvent 1 to 100 parts by weight of industrial synthetic adapalene, stir and heat to dissolve and clarify; filter while hot to remove insoluble matter and collect the filtrate; control the temperature to 30-40°C, and reduce the pressure to concentrate about 65-85% of organic solvent 1; control the temperature to 30-40°C in the remaining organic solvent 1, and drop the remaining organic solvent 2 of the same volume; continue stirring to cool down by 0-5°C, slow down the stirring speed, and precipitate crystals; filter the crystals and control the temperature to 60°C for vacuum drying to complete the pretreatment to obtain crude adapalene; add the crude adapalene to organic solvent 3, stir and heat to dissolve and clarify, and then add a specified amount of activated carbon to decolorize for 1 hour; filter the activated carbon and then filter through a 0.22um membrane to obtain a clear organic solution. Add the same volume of hydrophilic solution 4 to the decolorizing solution, and continue stirring and refluxing; The hydrophilic solution 4 is added dropwise again to make the crystals crystallize and precipitate adapalene in the direction of forming crystal nuclei, thereby obtaining high-purity adapalene.

3. The method for preparing high-purity adapalene according to claim 1, characterized in that: The organic solvent 1 can be tetrahydrofuran, methanol or acetone.

4. The method for preparing high-purity adapalene according to claim 3, characterized in that: The organic solvent 1 is tetrahydrofuran.

5. The method for preparing high-purity adapalene according to claim 1, characterized in that: The organic solvent 2 can be toluene, n-heptane or dichloromethane.

6. The method for preparing high-purity adapalene according to claim 5, characterized in that: The organic solvent 2 is toluene.

7. The method for preparing high-purity adapalene according to claim 1, characterized in that: The organic solvent 3 can be methanol, ethanol or isopropanol.

8. The method for preparing high-purity adapalene according to claim 7, characterized in that: The organic solvent 3 is methanol.

9. The method for preparing high-purity adapalene according to claim 1, characterized in that: The hydrophilic solution 4 may be a mixture of one or more of water, ethanol or acetone.

10. The method for preparing high-purity adapalene according to claim 1, characterized in that: Add 100 grams of industrially synthesized adapalene to 20-30 times of tetrahydrofuran, stir and heat to dissolve and clarify, and filter the insoluble matter while hot; collect the filtrate and control the temperature to 30-40°C, reduce pressure and concentrate the tetrahydrofuran, add toluene at this temperature, continue stirring for 30 minutes, slowly cool to 0-5°C, slow down the stirring speed and continue stirring for 1 hour, filter and vacuum dry to obtain a crude product; add the crude product to methanol, stir and heat to dissolve, then add 5% activated carbon of the crude product, continue to heat and reflux for 1 hour, filter and membrane filter to obtain a clear solution. Add water, continue to heat and reflux for 1 hour, after the crystal nucleus is formed, continue to drop water, reflux for 2 hours to complete the crystallization; filter and vacuum dry to obtain high-purity adapalene.

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