KR20170023417A

KR20170023417A - Methods for producing L-carnosine zinc complex

Info

Publication number: KR20170023417A
Application number: KR1020150114980A
Authority: KR
Inventors: 육진수; 이용섭; 정재욱; 박정화; 김선미; 이종수; 강병규
Original assignee: 주식회사 엔지켐생명과학
Priority date: 2015-08-14
Filing date: 2015-08-14
Publication date: 2017-03-06
Also published as: KR101788268B1

Abstract

A method for easily synthesizing a crystalline L-carnosine zinc complex useful as an anti-ulcer therapeutic agent in a high purity and a high yield without a separate purification process. The method for producing the L-carnosine zinc complex comprises: suspending L-carnosine and zinc salt in an alcohol or a hydrated alcohol; Dissolving an alkali metal compound in an alcohol or a hydrated alcohol to prepare an alkali metal compound solution; Adding a solution of the alkali metal compound to the suspension of L-carnosine and zinc salt to precipitate an L-carnosine zinc complex; Adding purified water to the reaction solution containing the L-carnosine zinc complex; And filtering the L-carnosine zinc complex crystals.

Description

[0001] The present invention relates to a method for producing L-carnosine zinc complexes,

The present invention relates to a process for preparing L-carnosine zinc complexes, and more particularly, to a process for producing L-carnosine zinc complexes which can be conveniently synthesized in high purity and high yield without further purification, - < / RTI > carnosine zinc complexes.

The L-carnosine zinc complex represented by the following formula (1) is widely used as an anti-ulcer therapeutic agent such as gastric ulcer, and Korean Patent No. 10-0128514 discloses a production method thereof.

According to this document, when a solution obtained by dissolving sodium hydroxide in alcohol, adding L-carnosine to form a homogeneous solution and then dissolving zinc acetate dihydrate in methanol is added dropwise to the homogeneous solution of L-carnosine, crystalline L -Carnosine zinc complexes can be prepared. However, the L-carnosine zinc complex obtained by the above method has a disadvantage in that it is difficult to remove sodium acetate as a by-product, since crystals are fine and have poor filtration properties and are difficult to wash. Japanese Patent No. 04880332 discloses a method of dissolving L-caronosine and an alkali metal compound in an alcohol or a hydrated alcohol and then adding the zinc salt to a zinc salt solution at 40 to 80 캜 in which an anhydrous or hydrated alcohol is dissolved, L-carnosine < / RTI > complexes. However, in the above method, it is troublesome to dissolve L-carnosine in an alkali solution, and an L-carnosine zinc complex containing about 10% by-product sodium acetate is obtained. Therefore, as disclosed in Japanese Patent No. 04936737, there is a disadvantage that a separate purification (reprocessing) process using purified water is necessary.

It is an object of the present invention to provide a process for producing L-carnosine zinc complex which can produce L-carnosine zinc complex in high purity, high yield and large quantity. Another object of the present invention is to provide a method for producing L-carnosine zinc complex which can easily obtain an L-carnosine zinc complex without a separate purification process.

In order to accomplish the above object, the present invention provides a method for preparing L-carnosine, comprising: suspending L-carnosine and zinc salt in an alcohol or a hydrated alcohol; Dissolving an alkali metal compound in an alcohol or a hydrated alcohol to prepare an alkali metal compound solution; Adding a solution of the alkali metal compound to the suspension of L-carnosine and zinc salt to precipitate an L-carnosine zinc complex; Adding purified water to the reaction solution containing the L-carnosine zinc complex; And filtering the L-carnosine zinc complex crystals. The present invention also provides a method for producing L-carnosine zinc complex. Preferably, the amount of the purified water used is 2 to 30 times (ml / g, volume / weight ratio) of L-carnosine, and the purified water dissolves and removes impurities contained in the L-carnosine complex complex lattice It plays a role.

According to the present invention, it is possible to produce L-carnosine zinc complexes in high purity, high yield, and in a large amount without performing a separate purification process.

Hereinafter, the present invention will be described in detail.

According to the present invention, in order to prepare an L-carnosine zinc complex, L-carnosine and a zinc salt represented by the following formula 2 are suspended in an alcohol or a hydrated alcohol.

Examples of the zinc salt include inorganic salts such as zinc chloride, zinc halide such as zinc chloride and zinc sulfate, zinc sulfate, zinc nitrate and zinc perchlorate, and organic salts such as zinc acetate anhydrous, zinc acetate dihydrate and acetylacetone zinc , Preferably anhydrous zinc acetate, zinc acetate dihydrate, or zinc halide can be used. The amount of the zinc salt to be used is preferably 0.8 to 1.2 equivalents, preferably 0.9 to 1.1 equivalents, such as 1 equivalent, based on L-carnosine. If the amount of the zinc salt to be used is too small, there is a problem that the zinc content is lowered, and if it is too much, zinc hydroxide as an insoluble matter is generated and remains in the L-carnosine zinc complex. As the solvent for suspending the L-carnosine and the zinc salt, an anhydrous alcohol solvent such as methanol, ethanol, isopropanol, or a mixture thereof may be used or may be used in an amount of 50% by weight or less, preferably 30% by weight or less, For example, a mixed solvent of water and alcohol consisting of 1 to 20% by weight of water and the remaining alcohol may be used. The amount of the solvent to be used may be 1 to 30 times (ml / g, volume / weight ratio), preferably 2 to 15 times, more preferably 5 to 10 times, to L-carnosine.

Next, an alkali metal compound solution is prepared by dissolving the alkali metal compound in an alcohol or a hydrated alcohol. As the alkali metal compound, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium alcoholate, potassium alcohol and the like can be used, and sodium hydroxide, potassium hydroxide, sodium alcoholate or potassium alcoholate can be preferably used . As the solvent for dissolving the alkali metal compound, an anhydrous alcohol solvent such as methanol, ethanol, isopropanol or a mixture thereof may be used, or 50 wt% or less, preferably 30 wt% or less, for example, 1 To 20% by weight of water and the remaining alcohol may be used. The amount of the solvent to be used may be 2 to 30 times (ml / g, volume / weight ratio), preferably 3 to 20 times, more preferably 5 to 10 times, based on the alkali metal compound.

Next, the alkali metal compound solution is added to a suspension of the L-carnosine and the zinc salt to precipitate the L-carnosine zinc complex represented by the formula (1). The mixing ratio of the L-carnosine and zinc salt suspension and the alkali metal compound solution may be such that the alkali metal compound is 0.8 to 1.5 equivalents, preferably 0.9 to 1.2 equivalents, relative to the L-carnosine. If the amount of the alkali metal compound used is too small, there is a problem that the content of zinc is lowered, and if it is too much, there is a problem that impurities are generated. The reaction between the L-carnosine and the alkali metal compound is a protecting group forming reaction. The reaction temperature is usually from room temperature to the boiling point of the solvent to be used, for example, from 20 to 80 ° C, preferably from 40 to 70 ° C, 2 to 5 hours.

When the L-carnosine zinc complex is formed by the above reaction, purified water is added to the reaction solution in order to dissolve and remove impurities such as sodium acetate, which is a by-product contained in the L-carnosine complex complex lattice. The amount of the purified water used is 2 to 30 times (ml / g, volume / weight ratio), preferably 5 to 20 times, of L-carnosine. The crystalline L-carnosine complex can then be obtained by filtering, washing and drying the L-carnosine zinc complex crystals by conventional methods such as filtration and centrifugation.

According to the present invention, since the crystallinity of the L-carnosine zinc complex is good and the generation and the residue of the by-product sodium acetate can be minimized, the lowering of the content of the target compound and the poor filtration problem can be solved, There is no need to perform a separate process such as a slurry treatment for removing the slurry. Also, through the simple process of adding purified water after the reaction, it is possible to stably mass-produce L-carnosine zinc complex with high purity and high yield.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Comparative Example 1] Production of L-Carnosine Zinc Complex

A 50,000 ml reactor was charged with 12.7 liters of methanol and 1.61 kg of zinc acetate dihydrate, and the mixture was heated to 50 캜 for dissolution. On the other hand, 17.7 liters of methanol and 587 g of sodium hydroxide were added to a 20,000 ml reactor and dissolved by stirring. The solution was cooled to 5 占 폚 and 1.66 Kg of L-carnosine was dissolved therein. This L-carnosine methanol solution was added dropwise to a methanol solution of zinc acetate dihydrate at 50 占 폚 over 1 hour. During the dropwise addition, the reaction temperature was adjusted to the range of 45 to 55 ° C, stirred at the same temperature for 2 hours and filtered to obtain 10.5 Kg of white powdery crystals. The white powder phase crystal was analyzed using NMR to find that the content of sodium acetate was 9.9% by weight.

[Comparative Example 2] Preparation of L-carnosine zinc complex

In a 10,000 ml reactor, 5,020 ml of methanol and 335 g of zinc acetate dihydrate were added and dissolved. On the other hand, in a 10,000 ml reactor, 3,800 ml of methanol and 122 g of sodium hydroxide were added and dissolved by stirring. The solution was cooled to 5 캜, and 345 g of L-carnosine was added thereto and dissolved. A methanol solution of zinc acetate dihydrate was added dropwise to the L-carnosine methanol solution for 30 minutes. The mixture was aged for 2 hours and then filtered to obtain 2050 g of a white powdery crystal. NMR analysis of the white powdery crystal revealed that the content of sodium acetate was 22.59% by weight.

[Example 1] Preparation of L-carnosine zinc complex

100 ml of methanol, 9.71 g of zinc acetate dihydrate and 10 g of L-carnosine were suspended in a 500-ml three-necked flask, and the suspension was gradually heated to maintain the temperature at 60 占 폚. 3.52 g of sodium hydroxide was completely dissolved in 70 ml of methanol to prepare a sodium hydroxide solution, which was then slowly added to the suspension. The reaction solution was stirred at 50 to 60 캜 for 1 hour, then cooled to 30 캜, and 80 ml of purified water was gradually added dropwise for 30 minutes. After the addition of purified water, the mixture was stirred at the same temperature for 1 hour, filtered under reduced pressure, washed sequentially with 80 ml of purified water and 80 ml of methanol, and dried to obtain 12.8 g of a white powdery crystal. NMR analysis of the white powdery crystal revealed that the content of sodium acetate was 0.5% by weight.

[Example 2] Preparation of L-carnosine zinc complex

100 ml of ethanol, 9.71 g of zinc acetate dihydrate and 10 g of L-carnosine were suspended in a 500-ml three-necked flask, and the suspension was gradually heated to maintain the temperature at 60 占 폚. 3.52 g of sodium hydroxide was completely dissolved in 70 ml of ethanol to prepare a sodium hydroxide solution, which was then slowly added to the suspension. The reaction solution was stirred at 50 to 60 캜 for 1 hour, then cooled to 30 캜, and 80 ml of purified water was gradually added dropwise for 30 minutes. After the addition of the purified water, the mixture was stirred at the same temperature for 1 hour and then filtered under reduced pressure. The filtrate was washed with 80 ml of purified water and 80 ml of ethanol successively and dried to obtain 12.8 g of a white powdery crystal. NMR analysis of the white powdery crystal revealed that the content of sodium acetate was 0.9% by weight.

Claims

Suspending L-carnosine and a zinc salt in an alcohol or a functional alcohol;
Dissolving an alkali metal compound in an alcohol or a hydrated alcohol to prepare an alkali metal compound solution;
Adding a solution of the alkali metal compound to the suspension of L-carnosine and zinc salt to precipitate an L-carnosine zinc complex;
Adding purified water to the reaction solution containing the L-carnosine zinc complex; And
And filtering the L-carnosine zinc complex crystals.

The method of claim 1, wherein the zinc salt is selected from the group consisting of zinc acetate anhydrous, zinc acetate dihydrate and zinc halide.

The method of claim 1, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof, and the functional alcohol is a mixture of water and alcohol consisting of 50% by weight or less of water and the remaining alcohol Lt; RTI ID = 0.0 > L-carnosine < / RTI >

The method of claim 1, wherein the purified water is used in an amount of 2 to 30 times (ml / g, volume / weight ratio) of L-carnosine, and the purified water dissolves impurities contained in the L- &Lt; / RTI > wherein the L-carnosine zinc complex is prepared by reacting a compound of formula <