阅读说明：本技术 一种酮苯丙氨酸钙的制备方法 (Preparation method of ketophenylalanine calcium ) 是由 袁明华 章永强 洪荣川 丁东 张�雄 车瑶 罗浩 于 2019-09-25 设计创作，主要内容包括：本发明属于制药技术领域,具体涉及一种酮苯丙氨酸钙的制备方法。酮苯丙氨酸钙的制备方法,包括以下步骤：以海因、苯甲醛为原料,在相转移催化剂四丁基氯化铵的作用下“一锅法”制备粗品。再经成盐,离心,干燥,得到酮苯丙氨酸钙粗品,进一步精制得成品。本发明使用相转移催化剂,溶剂为水,大大减小环保压力,降低成本,减小反应体系体积,缩短生产周期,可得到纯度99％以上的酮苯丙氨酸钙成品。(The invention belongs to the technical field of pharmacy, and particularly relates to a method for preparing ketophenylalanine calcium. The preparation method of the ketophenylalanine calcium comprises the following steps: hydantoin and benzaldehyde are used as raw materials, and a crude product is prepared by a one-pot method under the action of a phase transfer catalyst tetrabutylammonium chloride. Salifying, centrifuging and drying to obtain crude ketophenylalanine calcium product, and further refining to obtain the final product. The invention uses phase transfer catalyst, uses water as solvent, greatly reduces environmental protection pressure, reduces cost, reduces reaction system volume, shortens production period, and can obtain ketophenylalanine calcium finished product with purity of more than 99%.)

1. The preparation method of the ketophenylalanine calcium is characterized by comprising the following steps:

1) preparation of crude ketophenylalanine calcium: hydantoin and benzaldehyde are used as raw materials, a reaction reagent is added, and the mixed solution after reaction is subjected to pH adjustment, calcium salt forming reaction and crystallization to obtain a wet ketophenylalanine calcium crude product;

2) preparation of ketophenylalanine calcium: dissolving, filtering, crystallizing and drying the wet product obtained in the step 1) to obtain ketophenylalanine calcium;

the reaction reagent is a composition of tetrabutylammonium chloride and 20% sodium hydroxide aqueous solution, and the molar ratio of the tetrabutylammonium chloride to the 20% sodium hydroxide is 0.01-2.00: 2.5 to 3.5; the molar ratio of the hydantoin to the benzaldehyde is 1:1 to 2.

2. The method according to claim 1, wherein the reaction solvent in step 1) is water.

3. The method according to claim 1, wherein calcium chloride is used in the step 1) of forming the calcium salt.

4. The method according to claim 1, wherein the ratio of hydantoin to calcium chloride is 1:0.80 to 1.30.

5. The preparation method according to claim 1, wherein the solvent used in the dissolving in step 2) is one or more of water, methanol and ethanol.

6. The preparation method according to claim 1, wherein the molar ratio of the hydantoin to the tetrabutylammonium chloride is 1.0: 0.01-2.00.

7. The method according to claim 1, wherein the ratio of hydantoin to calcium chloride is 1:0.50 to 1.50.

8. The preparation method according to claim 1, wherein the temperature of the mixed solution after the reaction in step 1) is reduced to 0-30 ℃, the pH value is adjusted to 6-7, calcium chloride is added, the temperature is reduced to 0-30 ℃, crystallization is carried out for 1-4 hours, and wet products of crude ketophenylalanine calcium products are obtained by filtration.

9. The preparation method according to claim 1, characterized in that the wet crude product of the ketophenylalanine calcium obtained in step 2) is dissolved in a solvent at 70-100 ℃, then is dissolved and cleared, and is decolored by adding activated carbon, and is filtered, the filtrate is slowly cooled to 10-20 ℃, and is crystallized by heat preservation for 3-4 h, and is filtered, and the filter cake is washed by the solvent, so that the wet product of the ketophenylalanine calcium is obtained; drying for 8 hours under reduced pressure at the temperature of 45-70 ℃; obtaining the ketophenylalanine calcium.

Technical Field

The invention belongs to the technical field of pharmacy, and particularly relates to a method for preparing ketophenylalanine calcium.

Background

Ketophenylalanine Calcium (α -Ketophenylalanine Calcium), 2-oxo-3-phenyl-propionic acid Calcium. Ketobenzalanine calcium is one of the main components of compound alpha-ketonic acid tablets (Ke Yi). The alpha-keto acid and the derivatives thereof show increasingly wide application prospects in the aspects of food, daily chemicals, medicines and the like. In food application, the product can be used as an ingredient of sports nutritional beverage; in functional skin care cosmetics, the skin care cream has good effects of moisturizing, preventing wrinkles, preventing shrinkage, resisting aging and resisting allergy. In medical application, the compound alpha-ketonic acid tablet can treat the damage caused by chronic renal insufficiency and can be used as a specific medicine for treating uremia. The compound alpha-ketonic acid tablet is taken by a patient with renal failure and is matched with low-protein diet, so that the high filtration of glomeruli can be relieved, nephrons can be protected, and symptoms can be relieved and the progress of the disease can be delayed for the patient with light and moderate chronic renal failure; for severe chronic renal failure patients, the nutritional deficiency can be improved, and the amino acid is a substitute for the corresponding amino acid.

The synthesis of ketophenylalanine calcium mainly comprises the following methods: route 1: the alpha-acetamido cinnamic acid hydrolysis method is used for preparing phenylpyruvic acid, firstly, glycine is used for preparing acetyl glycine, then, the acetyl glycine is condensed with benzaldehyde, the generated lactone is hydrolyzed to obtain acetyl cinnamic acid, and the acetyl cinnamic acid is acidified to obtain phenylpyruvic acid, and then, the phenylpyruvic acid is converted into calcium salt, and the conversion rate of the phenylpyruvic acid prepared by the process is about 50 percent. Preparation route 2: the ketophenylalanine calcium is obtained by taking phenylacetic acid as a raw material to react with cyanogen diethyl phosphate and then hydrolyzing, oxidizing and salifying the raw material. The method has the advantages of starting material phenylacetic acid, high price of the reagent diethyl cyanophosphate, low yield and unsuitability for large-scale production. Route 3: directly collecting phenylalanine, and fermenting microorganism by using microorganism, wherein the microorganism consists of Bacillus cereus CGMCC No.7433, Bacillus licheniformis CGMCC No.6102 and Paracoccus denitrificans CGMCC No.3658, and the mass ratio of the Bacillus cereus CGMCC No.7433 to the Bacillus licheniformis CGMCC No.6102 to the Paracoccus denitrificans CGMCC No.3658 is 3-5:1-2: 1. Filtering to remove the compound microorganism, decoloring the filtrate, and adding a salifying assistant to obtain the 2-ketophenylalanine calcium precipitate. The method is not suitable for purification, has harsh reaction conditions and longer time, and also has the problems of environmental protection, pollution and cost.

Therefore, in order to overcome the defects, the invention provides a method for preparing ketophenylalanine calcium by a one-pot method.

Disclosure of Invention

In view of the above, the invention aims to provide a method for preparing ketophenylalanine calcium, which belongs to a method for preparing ketophenylalanine calcium by a one-pot method, uses a high-activity catalyst, and has the advantages of low environmental protection pressure, low cost, low equipment requirement, mild reaction conditions, high conversion rate and high purity.

In order to achieve the purpose, the invention adopts the following scheme:

the preparation method of the ketophenylalanine calcium comprises the following steps:

1) preparation of crude ketophenylalanine calcium: hydantoin and benzaldehyde are used as raw materials, a reaction reagent is added, and the mixed solution after reaction is subjected to pH adjustment, calcium salt forming reaction and crystallization to obtain a wet ketophenylalanine calcium crude product;

2) preparation of ketophenylalanine calcium: dissolving, filtering, crystallizing and drying the wet product obtained in the step 1) to obtain ketophenylalanine calcium;

the reaction reagent is a composition of tetrabutylammonium chloride and 20% sodium hydroxide aqueous solution, and the molar ratio of the tetrabutylammonium chloride to the 20% sodium hydroxide is 0.01-2.00: 2.5 to 3.5; the molar ratio of the hydantoin to the benzaldehyde is 1:1 to 2.

The 20% sodium hydroxide can be replaced by sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and other alkalis. The reason for selecting 20% sodium hydroxide in the invention is that sodium hydroxide is cheap and easy to obtain, no gas is generated, and overpressure danger is avoided.

Further, the molar ratio of the hydantoin, the benzaldehyde and the tetrabutylammonium chloride is 1: 1.0-2.0.

The method selects tetrabutylammonium chloride with higher activity, and is more economic and more environment-friendly compared with a monoethanolamine catalyst. Compared with other phase transfer catalysts, the tetrabutyl ammonium chloride has the advantages of high reaction efficiency, easy removal and less impurities.

Further, the reaction solvent of step 1) is water.

Further, calcium chloride is used in the step 1) of forming calcium salt.

Further, the ratio of the hydantoin to the calcium chloride is 1: 0.80-1.30.

Further, the solvent used in the dissolving in the step 2) is one or more of water, methanol and ethanol.

Preferably, the solvent used is water.

Further, the molar ratio of the hydantoin to the tetrabutylammonium chloride is 1.0: 0.01-2.00.

Further, the ratio of the hydantoin to the calcium chloride is 1: 0.50-1.50.

Preferably, the ratio of the hydantoin to the calcium chloride is 1: 0.50-1.00.

Further, cooling the mixed solution after the reaction in the step 1) to 0-30 ℃, adjusting the pH value to 6-7, adding calcium chloride, cooling to 0-30 ℃, crystallizing for 1-4 hours, and filtering to obtain a wet crude product of the ketophenylalanine calcium.

Further, adding a solvent into the wet crude product of the ketophenylalanine calcium obtained in the step 2) to dissolve at 70-100 ℃, adding activated carbon to decolor after dissolving, filtering, slowly cooling the filtrate to 10-20 ℃, keeping the temperature and crystallizing for 3-4 hours, filtering, and washing a filter cake with the solvent to obtain a wet product of the ketophenylalanine calcium; drying for 8 hours under reduced pressure at the temperature of 45-70 ℃; obtaining the ketophenylalanine calcium.

The invention has the beneficial effects that:

1) the preparation method adopts a one-pot method, and an intermediate does not need to be taken out after the reaction is finished, so that the operation steps are simplified, the use quantity of equipment is reduced, the discharge amount of waste water is reduced, and the method is suitable for commercial production;

2) the wet crude product of the ketophenylalanine calcium does not need to be independently prepared into the benzylidene hydantoin, the wet product does not need to be dried, the degradation of the product in the drying process is reduced, the purity of the final product is high, and the product does not need to be refined subsequently;

3) the process only uses a single solvent (water), and is convenient to recycle;

4) the process equipment of the invention is less in use and convenient for large-scale production.

Drawings

FIG. 1 is an HPLC chromatogram of example 1.

FIG. 2 is an HPLC chromatogram of example 2.

FIG. 3 is an HPLC chromatogram of comparative example 1.

Detailed Description

The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.