CN117700298A - A kind of preparation method of hydroxyadapalene - Google Patents

Abstract

The invention belongs to the field of medical technology, and particularly relates to a method for preparing hydroxy adapalene. The invention provides a new method for synthesizing hydroxy adapalene. The specific steps include 6-(4-methoxyphenyl)- Preparation of 2-naphthoic acid, preparation of 6-(4-methoxyphenyl)-2-naphthoic acid methyl ester, 6-(3-(3-hydroxyadamantane-1-yl)-4-methoxy Preparation of phenyl-2-naphthoic acid methyl ester and hydroxy adapalene. This solution provides a method for preparing hydroxy adapalene, which has wide sources of raw materials, simple process operations, high yield, and low cost. The purity of the final prepared hydroxy adapalene is greater than 96%. The present invention can provide impurity reference substances for the study of adapalene drug impurities, thereby promoting the research of drug impurities, controlling the reaction parameters and impurity limits of key sections, so as to improve the quality standards of adapalene drugs, and facilitate the research and development of adapalene raw materials. Research on impurities and impurities has important medical value and ensures the safety of medication for the general public.

Description

A kind of preparation method of hydroxyadapalene

Technical field

The invention belongs to the field of medical technology, and particularly relates to a preparation method of hydroxy adapalene.

Background technique

Hydroxy adapalene is an impurity of adapalene included in the EP Pharmacopoeia and is also one of the metabolites of adapalene in the body. Its molecular formula is as follows:

When preparing adapalene according to EP Pharmacopoeia standards, all impurities need to be controlled. Hydroxy adapalene is also an impurity that must be controlled. The presence of this impurity will affect the product quality of adapalene. However, there is currently no synthesis process and purchase method for hydroxy adapalene on the market, resulting in the inability to control this impurity during the production process. Therefore, there is an urgent need to provide a new synthetic method to prepare hydroxy adapalene and use it as a standard impurity control. The function of the product is to control the reaction parameters and impurity limits in key sections, assisting the quality control in the production process of adapalene raw materials, thereby improving the quality of adapalene raw materials and avoiding failure due to the inability to control the content of hydroxy adapalene in adapalene. The economic losses caused by substandard quality of raw materials are of great medical value to the research and development of raw materials and impurity research of adapalene.

Contents of the invention

In order to achieve the above object, the present invention provides a preparation method of hydroxy adapalene, which at least includes the following steps:

Step 1. Under nitrogen protection conditions, combine 6-bromo-2-naphthoic acid: 4-methoxyphenylboronic acid: palladium/carbon: sodium carbonate with a molar ratio of 1.0: 1.2~1.5: 0.1~0.2: 3.0~5.0 After mixing, add the solvent, stir and dissolve, and react at 60 to 80°C for 4 to 8 hours; after the reaction, add concentrated hydrochloric acid to a pH of 1 to 2, then reflux for 1 hour, cool the reaction solution to 0 to 10°C, and separate. liquid, concentrate, filter, and collect the filter cake to obtain crude 6-(4-methoxyphenyl)-2-naphthoic acid; suspend the crude 6-(4-methoxyphenyl)-2-naphthoic acid in methanol , add 3 times the molar amount of triethylamine, reflux and filter while it is hot. Add concentrated hydrochloric acid dropwise to the filtrate at 50-60°C to adjust the pH to 2, keep it warm and reflux for 0.5h, cool to room temperature and then filter. Use an appropriate amount of water for the filter cake. After washing with methanol, the filtrate was concentrated to dryness at 50-60°C to obtain 6-(4-methoxyphenyl)-2-naphthoic acid;

Step 2. Under nitrogen protection conditions, add 6-(4-methoxyphenyl)-2-naphthoic acid to anhydrous methanol as the solvent, add concentrated sulfuric acid dropwise, and reflux for 24 hours; the reaction solution is cooled to room temperature. Then, concentrate to dryness at 40-50°C, add an appropriate amount of ice water, stir at room temperature for 1 hour, filter, wash the filter cake with an appropriate amount of water, and dry it at 40-50°C for 4 hours to obtain 6-(4-methoxy Methyl phenyl)-2-naphthoate;

Step 3. Add 6-(4-methoxyphenyl)-2-naphthoic acid methyl ester to chloroform as the solvent, add concentrated sulfuric acid dropwise, and after completely dissolving at -10~0°C, add 1 dropwise , the chloroform solution of 3-adamantanediol reacts at -10~0°C; adjust the pH to 6~7, add water, separate and concentrate to obtain 6-(3-(3-hydroxyadamantane-1 -(yl)-4-methoxyphenyl)-2-naphthoic acid methyl ester crude product; 6-(3-(3-hydroxyadamantan-1-yl)-4-methoxyphenyl)-2- The crude methyl naphthoate is recrystallized for the first time in a mixed solvent of dimethyl sulfoxide and ethyl acetate, and then recrystallized for the second time in a mixed solvent of dimethyl sulfoxide and tetrahydrofuran to obtain 6-( 3-(3-Hydroxyadamantan-1-yl)-4-methoxyphenyl)-2-naphthoic acid methyl ester;

Step 4. Mix 6-(3-(3-hydroxyadamantan-1-yl)-4-methoxyphenyl)-2-naphthoic acid methyl ester:sodium hydroxide in a molar ratio of 1.0:3.0~5.0 Then, add water and tetrahydrofuran, and reflux the reaction at 50-60°C for 2-3 hours; the reaction solution is brought to room temperature, adjust the pH value to 2-3, precipitate the solid, filter and collect the white solid, and use N,N-dimethyl Recrystallize from methyl formamide, ethyl acetate, and water to obtain hydroxy adapalene.

Furthermore, the solvents in step 1 are water and tetrahydrofuran.

Moreover, in step 1, adjust the pH with concentrated hydrochloric acid.

Moreover, the molar ratio of the dropwise concentrated sulfuric acid and 6-(4-methoxyphenyl)-2-naphthoic acid in step 2 is 0.05:1, and the reflux reaction time is 24 h.

Moreover, in step 2, use ammonia water to adjust the pH.

Moreover, the molar ratio of the concentrated sulfuric acid and 6-(4-methoxyphenyl)-2-naphthoic acid methyl ester added dropwise in step 3 is 0.1:1; the chloroform of the 1,3-adamantanediol added dropwise The molar ratio of the solution to methyl 6-(4-methoxyphenyl)-2-naphthoate is 0.9:1.

Furthermore, in step 4, use concentrated hydrochloric acid to adjust the pH.

Compared with the existing technology, the beneficial effects of this technical solution are:

Provided is a preparation method of hydroxy adapalene, which is suitable for industrial production, has wide sources of raw materials, low price, and simple process operation. The purity of the finally prepared hydroxy adapalene is greater than 96%, and can be effectively used as a raw material in the production of adapalene. The standard reference substance for quality control controls the reaction parameters and impurity limits in key sections, assisting the quality control in the production process of adapalene API, thereby improving the quality of adapalene API and avoiding the inability to control hydroxyl adapalene in adapalene. The economic losses caused by substandard quality of raw materials due to the forest content are of important medical value to the research and development of raw materials and impurity research of adapalene.

Description of the drawings

Figure 1 is the HPLC spectrum of the example product hydroxy adapalene;

Figure 2 is a screenshot of the EP standard section of adapalene, which records that hydroxy adapalene is an impurity that must be controlled.

Detailed ways

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

A preparation method of adapalene, comprising the following steps:

(1) Under nitrogen protection, add 8.4g of 6-bromo-2-naphthoic acid, 5.7g of 4-methoxyphenylboronic acid, 8.1g of anhydrous sodium carbonate, 0.1g of 10% Pd/C, 60mL of water, and 60mL of tetrahydrofuran. In a 250 mL three-necked flask, reflux the reaction at 60-70°C for 4 hours. Add 12 mL of concentrated hydrochloric acid until the pH is 1 to 2, and reflux for 1 hour. Cool to 0-10°C, separate the liquid, and filter to obtain a gray solid. Reflux all the gray solids obtained, 130 mL of methanol, and 9.7 g of triethylamine at 60°C for 1 hour, filter while hot to remove insoluble matter, and collect the filtrate. Add 11 mL of concentrated hydrochloric acid dropwise to the filtrate at 50-60°C to adjust the pH to 2, and then keep warm and reflux for 30 minutes. After cooling to room temperature, filter, and the filter cake is washed with 30 mL of water and 30 mL of methanol. The filtrate is concentrated to dryness at 50-60°C to obtain 7.60 g of 6-(4-methoxyphenyl)-2-naphthoic acid, with a purity of 98.9%. The yield is 81.3%.

(2) Add 6.0g of 6-(4-methoxyphenyl)-2-naphthoic acid and 120mL of anhydrous methanol prepared in step (1) into a 250mL three-necked flask, add 2mL of concentrated sulfuric acid dropwise, and raise the temperature to 60-70℃, reflux and stir for 24h. Cool to room temperature, concentrate to dryness at 40-50°C, add 60 mL of ice water, and stir at room temperature for 1 hour. Filter, wash with 30 mL of water, and dry at 40-50°C for 4 hours to obtain 6.0 g of 6-(4-methoxyphenyl)-2-naphthoic acid methyl ester, with a purity of 98.6% and a yield of 95.2%.

(3) Add 5.5g of 6-(4-methoxyphenyl)-2-naphthoic acid methyl ester prepared in step (2), 3mL of concentrated sulfuric acid, and 100mL of chloroform into a three-necked bottle, and place at -10 to 0 After complete dissolution at ℃, 4.3 g of 1,3-adamantanediol in 50 mL of chloroform solution was added dropwise, and the reaction was carried out at -10~0 ℃ for 12 hours. Use ammonia to adjust the pH to 6-7, add an appropriate amount of water, separate the liquids, and concentrate to dryness at 60°C to obtain a crude product. The crude product was recrystallized for the first time in a mixed solvent of dimethyl sulfoxide and ethyl acetate, and then for a second time in a mixed solvent of dimethyl sulfoxide and tetrahydrofuran to obtain 6-(3-(3- Methyl hydroxyadamantan-1-yl)-4-methoxyphenyl)-2-naphthoate, purity 96.6%, yield 79.8%.

(4) Take 6.0g of 6-(3-(3-hydroxyadamantan-1-yl)-4-methoxyphenyl)-2-naphthoic acid methyl ester prepared in step (3) and 1.09g of hydrogen Add sodium oxide, 20 mL water, and 20 mL tetrahydrofuran to a 250 mL three-necked flask, stir and reflux for 2-3 hours at 50-60°C, cool to room temperature, add concentrated hydrochloric acid to adjust the pH to 2-3, keep stirring for 1 hour, and separate the solid, filter, filter The cake was washed with 50 mL of water and 50 mL of methanol, and the white solid was collected and recrystallized with N,N-dimethylformamide, ethyl acetate, and water to obtain hydroxy adapalene with a purity of 96.3% and a yield of 73.8%.

The HPLC spectrum of the final product in this example is shown in Figure 1. The content of hydroxy adapalene recorded in the EP standard is shown in molecular formula B in Figure 2.

Claims (7)

1. A method for preparing hydroxyl adapalene, which is characterized by at least comprising the following steps:

step 1, under the protection of nitrogen, the molar ratio is 1.0:1.2 to 1.5:0.1 to 0.2:3.0 to 5.0 of 6-bromo-2-naphthoic acid: 4-methoxyphenylboronic acid: palladium on carbon: mixing sodium carbonate, adding solvent, stirring to dissolve, and reacting at 60-80 ℃ for 4-8 hours; adding concentrated hydrochloric acid until the pH value is 1-2 after the reaction is finished, refluxing, cooling the reaction liquid to 0-10 ℃, separating the liquid, concentrating, filtering, and collecting a filter cake to obtain a crude 6- (4-methoxyphenyl) -2-naphthoic acid product; suspending the crude 6- (4-methoxyphenyl) -2-naphthoic acid in methanol, adding triethylamine with 3 times molar weight, refluxing and filtering while the solution is hot, dropwise adding concentrated hydrochloric acid into the filtrate at 50-60 ℃ to adjust the pH to 2, preserving heat and refluxing, cooling to room temperature, filtering, washing a filter cake, and concentrating the filtrate to dryness at 50-60 ℃ to obtain 6- (4-methoxyphenyl) -2-naphthoic acid;

step 2, under the protection of nitrogen, adding 6- (4-methoxyphenyl) -2-naphthoic acid into absolute methanol serving as a solvent, dropwise adding concentrated sulfuric acid, and carrying out reflux reaction; cooling the reaction solution to room temperature, concentrating to dryness at 40-50 ℃, adding ice water, stirring for 1h at room temperature, filtering, washing a filter cake, and drying at 40-50 ℃ to obtain 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester;

step 3, adding 6- (4-methoxyphenyl) -2-methyl naphthoate into chloroform serving as a solvent, dropwise adding concentrated sulfuric acid, completely dissolving at the temperature of minus 10-0 ℃, dropwise adding a chloroform solution of 1, 3-adamantane diol, and reacting at the temperature of minus 10-0 ℃; adjusting the pH value to 6-7, adding water, separating liquid, concentrating to obtain a crude product of 6- (3- (3-hydroxyadamantane-1-yl) -4-methoxyphenyl) -2-naphthoic acid methyl ester; carrying out first recrystallization on a crude product of the 6- (3- (3-hydroxyadamantan-1-yl) -4-methoxyphenyl) -2-naphthoic acid methyl ester in a mixed solvent of dimethyl sulfoxide and ethyl acetate, and carrying out second recrystallization in a mixed solvent of dimethyl sulfoxide and tetrahydrofuran to obtain the 6- (3- (3-hydroxyadamantan-1-yl) -4-methoxyphenyl) -2-naphthoic acid methyl ester;

step 4, the molar ratio is 1.0:3.0 to 5.0 of methyl 6- (3- (3-hydroxyadamantan-1-yl) -4-methoxyphenyl) -2-naphthoate: mixing sodium hydroxide, adding water and tetrahydrofuran, and reflux-reacting at 50-60 deg.c for 2-3 hr; cooling the reaction liquid to room temperature, regulating the pH value to 2-3, separating out solid, filtering and collecting white solid, and recrystallizing with N, N-dimethylformamide, ethyl acetate and water to obtain the hydroxyl adapalene.

2. The method for preparing hydroxyl adapalene according to claim 1, wherein: the solvents of step 1 are water and tetrahydrofuran.

3. The method for preparing hydroxyl adapalene according to claim 1, wherein: in step 1, the pH is adjusted with concentrated hydrochloric acid.

4. The method for preparing hydroxyl adapalene according to claim 1, wherein: the molar ratio of the dropwise added concentrated sulfuric acid to the 6- (4-methoxyphenyl) -2-naphthoic acid in the step 2 is 0.05:1, the reflux reaction time is 24h.

5. The method for preparing hydroxyl adapalene according to claim 1, wherein: in step 2, ammonia water is used to adjust the pH.

6. The method for preparing hydroxyl adapalene according to claim 1, wherein: the molar ratio of the concentrated sulfuric acid added dropwise in the step 3 to the methyl 6- (4-methoxyphenyl) -2-naphthoate is 0.1:1, a step of; the molar ratio of the chloroform solution of 1, 3-adamantanediol to the methyl 6- (4-methoxyphenyl) -2-naphthoate added dropwise was 0.9:1.

7. the method for preparing hydroxyl adapalene according to claim 1, wherein: in step 4, the pH is adjusted by concentrated hydrochloric acid.