阅读说明：本技术 一种消旋酮异亮氨酸钙及其中间体的制备方法 (Preparation method of racemic ketone isoleucine calcium and intermediate thereof ) 是由 刘志东 霍玉魁 李志刚 吕振远 李正杰 于 2020-05-30 设计创作，主要内容包括：本发明涉及一种消旋酮异亮氨酸钙及其中间体的制备方法,采用海因,丁酮在氨水中反应,得到亚仲丁基海因,再加入强碱反应,不需要经过复杂的后处理步骤,即可得到高产率、高纯度的消旋酮异亮氨酸盐。利用上述方法制得的消旋酮异亮氨酸盐制备消旋酮异亮氨酸钙,也可得到高产率、高纯度的消旋酮异亮氨酸钙,并且上述反应溶剂可回收循环套用,绿色环保,解决对环境产生的污染问题。(The invention relates to a preparation method of racemic ketone isoleucine calcium and an intermediate thereof, which adopts hydantoin and butanone to react in ammonia water to obtain sec-butylhydantoin, and then adds strong base to react, and racemic ketone isoleucine salt with high yield and high purity can be obtained without complex post-treatment steps. The racemic ketone isoleucine calcium prepared by the method can also be used for preparing the racemic ketone isoleucine calcium with high yield and high purity, and the reaction solvent can be recycled, so that the method is green and environment-friendly, and the problem of environmental pollution is solved.)

1. A preparation method of a racemic ketone isoleucine calcium intermediate is characterized by comprising the following steps:

(1) reacting hydantoin with butanone in ammonia water to obtain a reaction mixture containing a racemic ketoisoleucine calcium intermediate sec-butylhydantoin;

(2) adding a strong base into the reaction mixture obtained in the step (1) to react to obtain a racemic ketoisoleucine calcium intermediate racemic ketoisoleucine salt.

2. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 1, wherein the mass fraction of ammonia in the ammonia water in step (1) is 10-28%.

3. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 1, wherein in the step (1), the molar ratio of the hydantoin, the butanone and the ammonia is 1: 1.0-1.5: 0.5-1.5.

4. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 1, wherein the catalytic reaction temperature in step (1) is 50-70 ℃.

5. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 4, wherein the catalytic reaction temperature in step (1) is 55-60 ℃.

6. The method for preparing the intermediate of racemic ketoisoleucine calcium as described in claim 1, wherein said sec-butylhydantoin is reacted with the base under a micro-negative pressure of-0.1 MPa to-0.05 MPa in step (2).

7. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 1, wherein the reaction temperature in step (2) is 60 to 85 ℃.

8. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 1, wherein in the step (2), the reaction solvent comprises one or more of water, ethanol, isopropanol and methanol.

9. The method for preparing the racemic ketoisoleucine calcium intermediate as described in claim 1, wherein in step (2), said strong base comprises one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

10. The method for preparing the racemic ketoisoleucine calcium intermediate according to claim 1, wherein in the step (2), the molar ratio of the hydantoin to the strong base is 1: 1.5-3.

11. A method for preparing racemic ketoisoleucine calcium, which is characterized in that racemic ketoisoleucine salt obtained by the method of claim 1-10 is reacted with calcium salt to obtain racemic ketoisoleucine calcium.

12. The method of claim 11, wherein the calcium salt is selected from the group consisting of calcium chloride, calcium acetate, and calcium citrate.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of racemic ketone isoleucine calcium and an intermediate thereof.

Background

In recent years, Chronic Kidney Disease (CKD) has been receiving increasing attention in a situation of high incidence and a trend toward youthful condition. CKD progression is insidious and once advanced, the cost of treatment and care is dramatically increased. The compound alpha-ketonic acid tablet can delay the progression of renal failure by matching with low-protein diet, has important value in CKD treatment, and gradually becomes a core means of CKD treatment.

Racemic ketoisoleucine calcium is one of the main components of the compound alpha-keto acid tablet, the compound alpha-keto acid tablet is firstly marketed in Germany by German Feedes Yuskesbane company in 1996, the trade name is the same, and the medicine is a compound preparation containing 1 calcium hydroxyamino acid, 4 calcium ketoamino acids and 5 amino acids, and can increase glomerular filtration and urinary albumin excretion. The medicine has obvious curative effect on chronic kidney diseases, and is clinically used for treating the damage of chronic renal failure patients caused by protein metabolism disorder due to chronic renal insufficiency.

In the prior art, the methods for preparing the racemic ketoisoleucine calcium have certain defects.

CN106045843A discloses a process for producing racemic ketone isoleucine calcium, which comprises the steps of taking hydantoin and butanone as raw materials, reacting under the action of monoethanolamine to obtain sec-butylhydantoin, separating, hydrolyzing, acidifying, extracting, decolorizing with activated carbon, filtering under the strong alkali condition, adding calcium chloride to react to obtain a crude product of racemic ketone isoleucine calcium, and refining the crude product of racemic ketone isoleucine calcium with acetone water to obtain a finished product of racemic ketone isoleucine calcium. In the method, a large amount of monoethanolamine organic alkali is used for the reaction of hydantoin and butanone to generate more organic solid wastes; the total yield of the process is only about 50 percent, the yield is lower, and the production cost is high.

CN103044238B discloses a method for preparing racemic ketone isoleucine calcium, which comprises the steps of dripping diethyl oxalate into an alcohol solution of metal alkoxide, then dripping 2-methyl butyraldehyde, carrying out heat preservation and stirring, adding an alkali solution, carrying out acid regulation and extraction after heat preservation is finished, then adding an extract into the alkali solution, carrying out acid regulation and alkali regulation, reacting with calcium salt to obtain a crude product of racemic ketone isoleucine calcium, and then refining the crude product in a mixed solvent of water and an organic solvent to obtain a finished product of racemic ketone isoleucine calcium. The method has complicated process and is not easy to operate; a large amount of inorganic base is used for catalysis, so that more solid wastes are generated, and the environmental pollution is easily caused; the process uses a large amount of dangerous material sodium methoxide, and the process safety risk is high.

CN110627637A discloses a one-step method for preparing racemic ketoisoleucine calcium, which comprises the steps of taking hydantoin and butanone as raw materials, reacting in the presence of a solvent and monoethanolamine, adding sodium hydroxide after the reaction for hydrolysis, salifying and crystallizing to obtain a crude product wet product of racemic ketoisoleucine calcium, and dissolving, filtering, crystallizing and drying to obtain the racemic ketoisoleucine calcium. The method also uses a large amount of ethanolamine as a catalyst in the reaction of hydantoin and butanone, generates more organic solid wastes, and is easy to cause environmental pollution.

With the development of economy in China, the transition from development of simply pursuing economic benefits to economy and environment coordination development in China is made, which is also a great challenge for drug manufacturing enterprises, and in the research and development of a drug synthesis route, not only high yield is pursued, but also the reduction of waste discharge and the recycling of waste are emphasized.

The prior method for preparing the racemic ketoisoleucine calcium has the defects of high cost, low yield, complex process and post-treatment, more generated wastes and environmental pollution. Therefore, a simple, environment-friendly method for preparing the racemic ketoisoleucine calcium is needed.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of racemic ketone isoleucine calcium and an intermediate thereof, which comprises the steps of reacting hydantoin and butanone in ammonia water to obtain sec-butylhydantoin, adding strong base for reaction, and obtaining the racemic ketone isoleucine salt with high yield and high purity without complex post-treatment steps. The racemic ketone isoleucine calcium prepared by the method can also be used for preparing the racemic ketone isoleucine calcium with high yield and high purity, and the reaction solvent can be recycled, so that the method is green and environment-friendly, and the problem of environmental pollution is solved.

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

a preparation method of a racemic ketone isoleucine calcium intermediate comprises the following steps:

(1) reacting hydantoin with butanone in ammonia water to obtain a reaction mixture containing a racemic ketoisoleucine calcium intermediate sec-butylhydantoin;

(2) adding a strong base into the reaction mixture obtained in the step (1) to react to obtain a racemic ketoisoleucine calcium intermediate racemic ketoisoleucine salt.

In the step (1), the mass fraction of ammonia in the ammonia water is 10-28%. The ammonia water is used in the reaction, and the molar ratio of the hydantoin, the butanone and the ammonia is 1: 1: 1.0-1.5: 0.5-1.5.

In some embodiments, in step (1), the reaction temperature is 50 to 70 ℃. Preferably, the catalytic reaction temperature is 55-60 ℃.

In the step (1), ammonia water is used for replacing ethanolamine commonly used in the prior art as a catalyst for generating sec-butylidene hydantoin from hydantoin and butanone, and the method has the following advantages: (1) when the hydantoin and the butanone are subjected to catalytic reaction under an alkaline condition, the hydantoin is easily heated and hydrolyzed to generate impurities, the generation of the impurities is effectively controlled by catalyzing with ammonia water, condensation reaction can be performed at a lower temperature, the risk of high-temperature degradation of the hydantoin is avoided, and thus the generation of the impurities is reduced; (2) ammonia water is used as a catalyst, and after the catalytic reaction is finished, the ammonia in the reaction liquid can be recovered and reused.

In the step (2), the sec-butylhydantoin and the alkali react under the condition of micro negative pressure, and the pressure of the micro negative pressure is-0.1 MPa to-0.05 MPa.

In the step (2), the reaction temperature is 60-85 ℃, and preferably 75-85 ℃.

In the step (2), the strong base comprises one of sodium hydroxide, potassium hydroxide and lithium hydroxide, and potassium hydroxide is preferred. The molar ratio of the hydantoin to the strong base is 1: 1.5-3. The racemic ketone isoleucine salt is racemic ketone isoleucine potassium, racemic ketone isoleucine sodium or racemic ketone isoleucine lithium.

In the step (2), the reaction solvent comprises one or more of water, ethanol, isopropanol and methanol, and the preferable molar ratio of the strong base to the ethanol is 0.3-0.5: 1.

After the reaction in the step (1) is finished, the sec-butylidene hydantoin exists in the form of white solid in the reaction system, the step (2) is directly carried out without filtration and washing, alkali is added for alkaline hydrolysis, and the high-purity racemic ketone isoleucine salt is directly obtained by a one-pot method, so that the operation is simplified, and the yield is improved. The yield of the racemic ketone isoleucine salt is 93.7-95.2%, the HPLC purity is more than or equal to 99.5%, and the single impurity content is less than or equal to 0.1%.

In the step (2), the sec-butylhydantoin is reacted with the alkali under the condition of slight negative pressure. When the sec-butylidene hydantoin reacts with the alkali under the condition of slight negative pressure, the ammonia gas generated by the reaction quickly overflows from the reaction liquid in the environment of slight negative pressure, so that the reaction is promoted to be carried out in the positive reaction direction, and the reaction speed of the sec-butylidene hydantoin and the alkali is accelerated. Meanwhile, the produced ammonia gas can be collected by another container filled with water, and the prepared ammonia water can also be used for reaction catalysis of hydantoin and butanone, so that reaction byproducts are efficiently utilized, and the aim of circular economy is fulfilled.

In another embodiment of the invention, a method for preparing the racemic ketoisoleucine calcium is provided.

The method for preparing the racemic ketoisoleucine calcium comprises the step of reacting the racemic ketoisoleucine salt obtained by the method with a calcium salt to obtain the racemic ketoisoleucine calcium.

In some embodiments, the calcium salt may be one of calcium chloride, calcium acetate, and calcium citrate.

In some embodiments, after the reaction of the racemic ketoisoleucine salt and the calcium salt, the method further comprises the step of heat-preservation crystallization at the temperature of 20-30 ℃.

The method for preparing the racemic ketone isoleucine calcium does not need further post-treatment and refining steps, and can achieve the yield of 94.2-95.7%, the HPLC purity is more than or equal to 99.9%, the single impurity content is less than or equal to 0.1%, and the pharmaceutical standard is met.

The preparation method of the racemic ketoisoleucine calcium provided by the application has the following advantages:

(1) in the step of preparing the sec-butylidene hydantoin, the sec-butylidene hydantoin is directly hydrolyzed by adding alkali into a reaction system without separation, and the high-purity racemic ketone isoleucine salt is directly obtained by a one-pot method, so that the operation is simplified, and the yield is improved;

(2) ammonia generated in the alkaline hydrolysis step is collected to prepare ammonia water, and the ammonia water can be recycled to the catalytic reaction of hydantoin and butanone, so that the discharge of three wastes is reduced, and the recycling of reaction materials is realized;

(3) the high-purity racemic ketone isoleucine salt is directly used to obtain the high-quality racemic ketone isoleucine calcium meeting the medicinal standard in one step, the product does not need to be refined, and the operation steps are simple and easy to implement;

(4) the three wastes generated by the process are less, and the recycling of the alcohol solvent can be realized; the potassium chloride, sodium chloride and lithium chloride recovered from the mother liquor after the product is filtered can also be used as industrial byproducts, the process realizes resource recycling, is green and environment-friendly, and basically realizes zero emission.

Detailed Description

The following examples are provided to further illustrate the technical solutions of the present invention, but not to limit the present invention.

Example 1

1. Preparation method of racemic ketone isoleucine calcium intermediate

(1) Adding 100.1g of hydantoin into a 5L four-mouth bottle, sequentially adding 93.7g of 2-butanone and 68.1g of 25% ammonia water into a reaction bottle, heating to 60 ℃, keeping the temperature, reacting for 8 hours, and separating out a large amount of white solids, namely sec-butylhydantoin, from the reaction system;

(2) 112.2g of potassium hydroxide and 307.5.0g of ethanol are added into the reaction system, after the feeding is finished, the temperature is raised to 75 ℃, ammonia gas is recovered under the micro negative pressure of-0.1 MPa, and the reaction is stopped after 4 hours of reaction. After the reaction is finished, cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 160.1g of racemic ketone isoleucine potassium salt, wherein the yield is 95.2%, and HPLC: 99.65 percent. The ammonia gas generated in the step is absorbed by water to form ammonia water which can be reused in the step (1).

2. Preparation method of racemic ketoisoleucine calcium

Adding about 500g of purified water and 160.1g of racemic ketone isoleucine potassium into a 5L four-mouth bottle, stirring, dissolving, filtering, controlling the filtrate at 20-30 ℃, slowly dropwise adding a filtered calcium chloride aqueous solution (225.0 g of water and 40g of calcium chloride), keeping the temperature and crystallizing for 4 hours after dropwise adding, and filtering. Obtaining wet products of the racemic ketone isoleucine calcium, drying at 50-60 ℃ to obtain 135.9g of white crystalline racemic ketone isoleucine calcium, wherein the yield is 95.7%, and HPLC: 99.94 percent.

Example 2

1. Preparation method of racemic ketone isoleucine calcium intermediate

(1) Adding 100.1g of hydantoin into a 5L four-mouth bottle, sequentially adding 93.7g of 2-butanone and 54.5g of 22% ammonia water into a reaction bottle, heating to 55 ℃, keeping the temperature, reacting for 8 hours, and separating out a large amount of white solids, namely sec-butylhydantoin, from the reaction system;

(2) 140.25g of potassium hydroxide and 230.5g of ethanol are added into the reaction system, after the feeding is finished, the temperature is raised to 80 ℃, ammonia gas is recovered under the micro negative pressure of-0.1 MPa, and the reaction is stopped after 4 hours of reaction. After the reaction is finished, cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 159.9g of racemic ketone isoleucine potassium salt, wherein the yield is 95.1%, and HPLC: 99.73 percent.

2. Preparation method of racemic ketoisoleucine calcium

Adding about 500g of purified water and 159.9g of racemic ketone isoleucine potassium into a 5L four-mouth bottle, stirring, dissolving, filtering, controlling the filtrate at 20-30 ℃, slowly dropwise adding a filtered calcium chloride aqueous solution (225.0 g of water and 40g of calcium chloride), after dropwise adding, keeping the temperature, crystallizing for 4 hours, and filtering. Obtaining wet product of racemic ketone isoleucine calcium, drying at 50-60 ℃ to obtain 134.6g of white crystalline racemic ketone isoleucine calcium, wherein the yield is 94.9%, and HPLC: 99.94 percent.

Example 3

1. Preparation method of racemic ketone isoleucine calcium intermediate

(1) Adding 100.1g of hydantoin into a 5L four-mouth bottle, sequentially adding 72.1g of 2-butanone and 54.7g of 28 mass percent ammonia water into a reaction bottle, heating to 57 ℃, keeping the temperature, reacting for 8 hours, and separating out a large amount of white solids, namely sec-butylhydantoin, from the reaction system;

(2) adding 80g of sodium hydroxide, 230.5g of ethanol and 50g of water into the reaction system, starting to heat to 85 ℃ after the feeding is finished, simultaneously recovering generated ammonia gas under the micro-negative pressure of-0.05 MPa, and stopping the reaction after the reaction is carried out for 4 hours. After the reaction is finished, cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 144.6g of racemic ketone isoleucine sodium with the yield of 95.1%, HPLC: 99.71 percent.

2. Preparation method of racemic ketoisoleucine calcium

Adding about 500g of purified water and 144.6g of racemic ketoisoleucine sodium into a 5L four-mouth bottle, stirring, dissolving, filtering, controlling the filtrate at 20-30 ℃, slowly dropwise adding a filtered calcium chloride aqueous solution (225.0 g of water and 40g of calcium chloride), keeping the temperature for crystallization for 4h after dropwise adding, and filtering. Obtaining wet products of the racemic ketone isoleucine calcium, drying the wet products at 50-60 ℃ to obtain 134.9g of white crystalline racemic ketone isoleucine calcium, wherein the yield is 95.0%, and HPLC: 99.96 percent.

Example 4

1. Preparation method of racemic ketone isoleucine calcium intermediate

(1) Adding 100.1g of hydantoin into a 5L four-mouth bottle, sequentially adding 79.3g of 2-butanone and 119.1g of ammonia water with the mass fraction of 10% into a reaction bottle, heating to 50 ℃, keeping the temperature, reacting for 8 hours, and separating out a large amount of white solids, namely sec-butylhydantoin, from the reaction system;

(2) and adding 120g of sodium hydroxide and 320.4g of methanol into the reaction system, starting to heat to 60 ℃ after the charging is finished, and stopping the reaction after the reaction is carried out for 5 hours. After the reaction is finished, cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 143.5g of racemic ketone isoleucine sodium, wherein the yield is 94.4%, and HPLC: 99.63 percent.

2. Preparation method of racemic ketoisoleucine calcium

Adding about 500g of purified water and 143.5g of racemic ketoisoleucine sodium into a 5L four-mouth bottle, stirring, dissolving, filtering, controlling the filtrate at 20-30 ℃, slowly dropwise adding a filtered calcium chloride aqueous solution (225.0 g of water and 40g of calcium chloride), keeping the temperature for crystallization for 4h after dropwise adding, and filtering. Obtaining wet products of the racemic ketone isoleucine calcium, drying at 50-60 ℃ to obtain 132.7g of white crystalline racemic ketone isoleucine calcium, wherein the yield is 94.2%, and HPLC: 99.92 percent.

Example 5

1. Preparation method of racemic ketone isoleucine calcium intermediate

(1) Adding 100.1g of hydantoin into a 5L four-mouth bottle, sequentially adding 72.1g of 2-butanone and 42.6g of ammonia water with the mass fraction of 20% into a reaction bottle, heating to 70 ℃, keeping the temperature, reacting for 8 hours, and separating out a large amount of white solids, namely sec-butylhydantoin, from the reaction system;

(2) adding 35.9g of lithium hydroxide and 360.6g of isopropanol into the reaction system, starting to heat to 70 ℃ after the feeding is finished, simultaneously recovering generated ammonia gas under the micro negative pressure of-0.07 MPa, and stopping the reaction after the reaction is carried out for 4 hours. After the reaction is finished, cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 127.6g of racemic ketone isoleucine lithium, wherein the yield is 93.8%, and HPLC: 99.68 percent.

2. Preparation method of racemic ketoisoleucine calcium

Adding about 500g of purified water and 127.6g of racemic ketone isoleucine lithium into a 5L four-mouth bottle, stirring, dissolving, filtering, controlling the filtrate at 20-30 ℃, slowly dropwise adding a filtered calcium chloride aqueous solution (225.0 g of water and 40g of calcium chloride), keeping the temperature for crystallization for 4 hours after dropwise adding, and filtering. Obtaining wet products of the racemic ketone isoleucine calcium, drying at 50-60 ℃ to obtain 133.8g of white crystalline racemic ketone isoleucine calcium, wherein the yield is 95.6%, and HPLC: 99.95 percent.

Example 6

1. Preparation method of racemic ketone isoleucine calcium intermediate

(1) Adding 100.1g of hydantoin into a 5L four-mouth bottle, sequentially adding 108.2g of 2-butanone and 127.7g of ammonia water with the mass fraction of 20% into a reaction bottle, heating to 70 ℃, keeping the temperature, reacting for 8 hours, and separating out a large amount of white solids, namely sec-butylhydantoin, from the reaction system;

(2) and adding 35.9g of lithium hydroxide and 320.4g of methanol into the reaction system, starting to heat to 70 ℃ after the feeding is finished, recovering generated ammonia gas under the micro negative pressure of-0.05 MPa, and stopping the reaction after the reaction is carried out for 4 hours. After the reaction is finished, cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 127.6g of racemic ketone isoleucine lithium, wherein the yield is 93.7%, and HPLC: 99.70 percent.

2. Preparation method of racemic ketoisoleucine calcium

Adding about 500g of purified water and 127.6g of racemic ketone isoleucine lithium into a 5L four-mouth bottle, stirring, dissolving, filtering, controlling the filtrate at 20-30 ℃, slowly dropwise adding a filtered calcium chloride aqueous solution (225.0 g of water and 40g of calcium chloride), keeping the temperature for crystallization for 4 hours after dropwise adding, and filtering. Obtaining wet products of the racemic ketone isoleucine calcium, drying at 50-60 ℃ to obtain 133.7g of white crystalline racemic ketone isoleucine calcium, wherein the yield is 95.7%, and HPLC: 99.95 percent.

Comparative experiment:

in the prior art, monoethanolamine is used as a catalyst to synthesize sec-butylhydantoin, but the reaction temperature is high, in the comparative experiment, ammonia water and ethanolamine with the same molar weight are respectively used as catalysts to synthesize sec-butylhydantoin, the reaction is carried out at 55-60 ℃, and the yield of racemic ketone isoleucine potassium is compared.

Experimental example: example 1 (1) preparation of a calcium racemic ketoisoleucine intermediate.

Comparative example 1: 100g of hydantoin, 93.7g of butanone, 55.0g of monoethanolamine and 300g of water are added into a 5L four-mouth bottle, the temperature is raised to 60 ℃, the reaction is carried out for 8.0 hours, 112.2g of potassium hydroxide is added into the reaction system, the temperature is raised to 75 ℃ continuously, and the reaction time is 4 hours. After the reaction is finished, cooling the reaction liquid to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 138.7g of racemic ketone isoleucine potassium salt with the yield of 82.5%. Comparative example 2: 100g of hydantoin, 93.7g of butanone, 55.0g of monoethanolamine and 300g of water are added into a 5L four-mouth bottle, the temperature is raised to 55 ℃, the reaction is carried out for 8.0 hours, 112.2g of potassium hydroxide is added into the reaction system, the temperature is raised to 75 ℃ continuously, and the reaction time is 4 hours. After the reaction is finished, cooling the reaction liquid to 0 ℃, carrying out heat preservation and crystallization for 5 hours, and filtering to obtain 124.9g of racemic ketone isoleucine potassium salt with the yield of 74.3%.

The comparative experiment proves that the reaction can be carried out at a lower temperature by using the ammonia water as the catalyst, and the obtained racemic ketoisoleucine potassium has high yield and obvious superiority.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.