KR100885677B1 - Process for purification of Diacerein - Google Patents

Abstract

Purification methods are disclosed for obtaining high purity diacerane from crude diacerein synthesized by various routes. The method for purifying diacerane may include dissolving crude diacerane in an organic solvent using a silylating agent; Decolorizing the reaction solution by adding activated carbon to the reaction solution in which the crude diacerane is dissolved; And adding an organic acid to the reaction solution to crystallize diacerane.

Diacerane, arthritis medicine, tablets

Description

Process for purification of Diacerein

The present invention relates to a method for purifying diacerane, and more particularly, to a method for purifying diacerane of high purity from crude diacerane synthesized by various routes.

Diacerein is widely used as a therapeutic agent for arthritis and is synthesized by various pathways. Among them, the best known synthetic methods are disclosed in French Patent 2,508,798 and Belgian Patent 875,945. However, in most diacerane production methods, in order to obtain a high-purity diacerane, a purification process must be performed. Therefore, various purification methods of crude diacerane have also been developed. For example, European Patent No. 636,602, published by Medidom, Italy, discloses a method for purifying crude diacerane using 2-methoxymethanol or dimethylacetamide. However, the above method has a disadvantage in that the boiling point of the solvent used is very high, an additional purification step for removing residual solvent is required, and the overall yield is lowered by this added step. US Patent No. 5,756,782 discloses a method for purifying diacerane using an organic base in a mixed solvent of an organic solvent and water. However, as is well known in the chemical literature, two acetyl groups protecting the hydroxy group of diacerane are reversibly hydrolyzed under weakly acidic or basic conditions. In addition, as disclosed in WO 00/68179, an acetyl group protecting the hydroxy group of diacerane exists stably when changed from neutral to acidic conditions, but rapidly deacetylated in a slightly basic medium. do. Therefore, the said purification method using organic base in aqueous solution may deacetylate diacelein, and is not suitable for a mass production process.

In addition, WO 01/96276 discloses a method for purifying diacerane using acetic anhydride and acetic acid at high temperature. The process uses high temperature acetic anhydride and acetic acid to filter the mixture while maintaining a high temperature, thus making the process dangerous and not suitable for commercial mass production and further removing the remaining acetic anhydride and acetic acid. There is a disadvantage that a cleaning process is required. On the other hand, Korean Patent Laid-Open Publication No. 2005-0086864 discloses a method for purifying diacerane, which comprises a step of dissolving dicerane using an organic base under water and an organic solvent and extracting the same with a solvent such as toluene. have. The method also includes a process capable of inducing deacetylation, and has a disadvantage in that a complicated extraction process using a solvent such as toluene, xylene, etc. must be repeated. Therefore, there is an urgent need for the development of a dicerane refining process that can be applied to commercial mass production.

Accordingly, it is an object of the present invention to provide a method for purifying diacerane that can ameliorate the various problems described above, which may occur during commercial mass production.

It is another object of the present invention to provide a simple purification method capable of obtaining high purity diacerane from crude diacerane synthesized by various routes.

In order to achieve the above object, the present invention, using a silylating agent, dissolving crude diacerane in an organic solvent; Decolorizing the reaction solution by adding activated carbon to the reaction solution in which the crude diacerane is dissolved; And adding an organic acid to the reaction solution to crystallize diacerane. Wherein the silylating agent is selected from the group consisting of N, O-bis (trimethylsilyl) acetamide, hexamethyldisilane and mixtures thereof, the organic solvent being dichloromethane, dichloroethane, acetone, ethyl acetate, toluene and It is preferably selected from the group consisting of mixtures thereof, and the organic acid is preferably selected from the group consisting of acetic acid, formic acid, methanesulfonic acid and mixtures thereof.

Hereinafter, the present invention will be described in more detail.

According to the present invention, in order to purify diacerane, first, the crude diacerane is dissolved in an organic solvent using a silylating agent. The crude diacerane can be prepared by a variety of synthetic routes, for example by the method disclosed in French Patent No. 2,508,798. The crude diacerane is an impurity and includes an unreacted substance, other impurities, and the like. As the organic solvent, aprotic nonpolar organic solvents such as dichloromethane, dichloroethane, acetone, ethyl acetate, toluene can be used alone or in combination, and dichloromethane is preferable. It is preferable that the usage-amount of the said organic solvent is 3-20 times with respect to crude diacerane, and it is more preferable if it is 5-10 times. In this case, when the amount of the organic solvent used is too small, there is a fear that the diacerane may not be completely dissolved. When the amount of the organic solvent is too high, there is no particular advantage as it causes a decrease in yield.

As the silylating agent used to dissolve the crude diacerane, a compound selected from the group consisting of N, O-bis (trimethylsilyl) acetamide, hexamethyldisilane and mixtures thereof may be used. It is preferable that the usage-amount of the said silylating agent is 0.5-2.0 equivalent by weight ratio with respect to crude diacerane, and it is more preferable to use 1.0 equivalent by weight equivalent with respect to crude diaserine. If the amount of the silylating agent used is too small, the crude diacerane may be incompletely dissolved. If the amount of the silylating agent is too small, the yield decreases and is economically disadvantageous, and there is no particular benefit. The process of dissolving the crude diacerein can be carried out at room temperature, in which the crude diacerein is almost completely dissolved.

When crude diacerane is dissolved, activated carbon is added to the reaction solution to decolorize the reaction solution. The process of decolorizing the reaction solution can be carried out using conventional activated carbon until the reaction solution becomes substantially colorless. In addition, if necessary, after the decolorization process is completed, the activated carbon used for decolorization can be removed by filtration.

When the reaction solution is decolorized, an organic acid is added to the reaction solution to crystallize the dicerane, thereby obtaining high purity diacerane in the form of a crystal. As the organic acid used in the crystallization step, a compound such as acetic acid, formic acid, methanesulfonic acid, or the like can be used alone or in combination. The amount of the organic acid is preferably 1.0 to 3.0 equivalents, based on the silylating agent, and 2.0. It is more preferable to use equivalents. If the amount of the organic acid used is too small, there is a concern that the protonation of diacerane is lessened and the yield and purity are lowered. If the amount is too large, the organic acid is only economically disadvantageous without any particular benefit.

Hereinafter, the present invention will be described in more detail with reference to Comparative Examples and Examples, but the present invention is not limited to the following Examples.

[Comparative Example] Purification of Diacerane according to Korean Patent Publication No. 2005-0086864

4.27 Kg of triethylamine was added to the suspension containing 15.6 Kg of crude diacerane in a mixture of 80 L of acetone and 80 L of water. The resulting solution was extracted with butyl acetate (4 times using 100 L each), but the organic phase was separated and butyl acetate was recovered and reused in the extraction process. The diacerane salt solution was acidified with dilute hydrochloric acid, and the precipitated diacerane was centrifuged, washed with water and dried to obtain 14.8 Kg of dicerane.

Example 1 Purification of Diacerane

10 Kg of crude diacerane was added to 100 L of dichloromethane, and the mixture was stirred at room temperature. 6.63 L of N, O-bis (trimethylsilyl) acetamide was added to the mixture, stirred for 30 minutes to completely dissolve it, and then 1 Kg of activated carbon was added thereto, followed by stirring for 1 hour. The mixture was filtered, washed with a small amount of dichloromethane, and 3.1 L of acetic acid was added to the filtrate, and when crystals formed, the mixture was stirred at room temperature for 2 hours. The resulting solid was filtered and washed with dichloromethane to give 9.0 kg (HPLC purity = 99.5% or more) of high purity diacerane.

Example 2 Purification of Diacerane

10 Kg of crude diacerane was added to 100 L of dichloromethane, and the mixture was stirred at room temperature. 5.56 L of hexamethyldisilane was added to the mixture, and stirred for 30 minutes to completely dissolve it. Then, 1 Kg of activated carbon was added thereto, and the mixture was stirred for 1 hour. The mixture was filtered, washed with a small amount of dichloromethane, and then 3.1L of acetic acid was added to the filtrate, and when crystals formed, the mixture was stirred for 2 hours at room temperature. The resulting solid was filtered and washed with dichloromethane to obtain 8.7 kg (HPLC purity = 99.5% or more) of high purity diacerane.

From the above examples and comparative examples, the method for purifying diacerane according to the present invention does not induce a deacetylation reaction of diacerane, does not require the use of a high boiling point solvent, and a high temperature reaction or a complex extraction process. As it is not carried out, it can be seen that it is particularly suitable for commercial mass production processes.

As described above, the method for purifying diacerane according to the present invention has solved various problems that may occur during commercial mass production, and it is possible to simplify diasperane of high purity from crude diacerein synthesized by various routes. You can get it by

Claims (3)

Dissolving crude diacerane in an organic solvent using a silylating agent; Decolorizing the reaction solution by adding activated carbon to the reaction solution in which the crude diacerane is dissolved; And Adding an organic acid to the reaction solution, the method of purifying diacerane comprising the step of crystallizing the dicerane. The method of claim 1, wherein the silylating agent is a compound selected from the group consisting of N, O-bis (trimethylsilyl) acetamide, hexamethyldisilane, and mixtures thereof. The method of claim 1, wherein the organic solvent is an aprotic nonpolar organic solvent selected from the group consisting of dichloromethane, dichloroethane, acetone, ethyl acetate, toluene and mixtures thereof, wherein the organic acid is acetic acid, formic acid, methanesulfonic acid. And a compound selected from the group consisting of a mixture thereof.