Synthesis method of alpha-ketoisoleucine calcium intermediate and application of alpha-ketoisoleucine calcium intermediate in preparation of alpha-ketoisoleucine calcium

Abstract

The invention provides a synthesis method of an alpha-ketoisoleucine calcium intermediate and application of the alpha-ketoisoleucine calcium intermediate in preparation of alpha-ketoisoleucine calcium, and belongs to the technical field of medicines. The synthesis method of the alpha-ketoisoleucine calcium intermediate comprises the following steps: 1) hydrolyzing 2-butylidene hydantoin by adopting alkali to prepare an alkaline solution of alpha-ketoisoleucine salt; and 2) adjusting the pH value of the alkaline solution of the alpha-ketoisoleucine salt obtained in the step 1) to be acidic, and distilling to prepare an aqueous solution of alpha-ketoisoleucine, namely the alpha-ketoisoleucine calcium intermediate. Further, the obtained alpha-ketoisoleucine calcium intermediate reacts with calcium salt to prepare the alpha-ketoisoleucine calcium, and the alpha-ketoisoleucine calcium is high in purity and yield and meets the medicinal standard. The whole reaction process is carried out in water without any organic solvent, the reaction route is green and environment-friendly, the problem of three-waste pollution to the environment is effectively avoided, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to a method for synthesizing an α-ketoisoleucine calcium intermediate, and specifically relates to a method for synthesizing an α-ketoisoleucine calcium intermediate and application of the intermediate in preparing α-ketoisoleucine calcium. Background Art

[0002] In recent years, with the increasing incidence and younger age of patients, the treatment of chronic kidney disease (CKD) has received more and more attention. Once chronic kidney disease (CKD) enters the late stage, the cost of treatment drugs and care will skyrocket.

[0003] Compound a-ketoacid tablets (trade name: Kaitong) are compound preparations containing 4 kinds of ketoamino acid calcium, 1 kind of hydroxyamino acid calcium and 5 kinds of amino acids. They are mainly used in conjunction with a low-protein diet to prevent and treat damage caused by protein metabolism disorders due to chronic renal insufficiency (chronic renal failure), and can slow down the progression of kidney disease to a certain extent.

[0004] Calcium α-ketoisoleucine is one of the main ingredients of compound α-ketoacid tablets, and its structural formula is as follows:

[0005]

[0006] According to prior art reports, the existing methods for preparing α-ketoisoleucine calcium or its intermediate α-ketoisoleucine mainly include:

[0007] Route 1: A journal document (J. Org. Chem. 1963, 28 (11): 3088-3092) discloses a preparation route for the intermediate α-ketoisoleucine, which first uses ethyl cyanoacetate and butanone as starting materials, obtains 2-butylene ethyl cyanoacetate through a Knoevenagel-Cope reaction, and then obtains α-ketoisoleucine through oxidation and hydrolysis. This route has a long reaction process (6 steps) and is complicated to operate. The starting material ethyl cyanoacetate is highly toxic, and the use of hydrogen peroxide in the oxidation reaction is not conducive to safe production and industrial production.

[0008] Route 2 (1. Invention patent: Publication No. GB1550993A, Application Date 1977.10.05; 2. Journal Literature: Chemical Industry Times, 2007, 21(12):5-8): Discloses the use of the hydantoin method to prepare calcium α-ketoisoleucine and its intermediate α-ketoisoleucine. Hydantoin and butanone are used as starting materials, and 2-butylenehydantoin is obtained through condensation reaction, and then α-ketoisoleucine is obtained through hydrolysis and acidification reaction, and further α-ketoisoleucine calcium is obtained. This route has a short reaction step (4 steps) and is simple to operate. The starting materials are easily available and have low toxicity. There is no dangerous reaction involved. However, the hydrolysis reaction generates many impurities and the yield is low, and further improvement and optimization are still needed.

[0009] Route 3 (invention patent with publication number CN103044238B, application date 2012.11.26): diethyl oxalate and 2-methylbutyraldehyde react in alcohol under the catalysis of sodium alcoholate to prepare crude racemic ketoisoleucine calcium, which is then refined with water and an organic solvent to obtain a finished racemic ketoisoleucine calcium, wherein the organic solvent is selected from one of methanol, ethanol, isopropanol, n-propanol, acetone, and tetrahydrofuran. The reaction uses sodium alcoholate hazardous reagents, produces a lot of post-treatment waste liquid, and uses organic solvents, which makes it difficult to treat the three wastes, and is not conducive to industrial production.

[0010] It can be seen that compared with routes 1 and 3, route 2 avoids the use of highly toxic materials and the implementation of oxidation reactions, and has a large room for improvement. The prior art also discloses an improved method for the Hein process in route 2.

[0011] Improvement method 1 of route 2:

[0012] Ketoisoleucine salt is firstly prepared, and then calcium salt is added to prepare the finished product of ketoisoleucine calcium.

[0013] The prior art (invention patent with publication number CN113735727B and application date 2020.05.30) discloses a method for preparing racemic ketoisoleucine calcium and its intermediates. The method for preparing racemic ketoisoleucine calcium intermediates comprises the following steps:

[0014] (1) reacting hydantoin with butanone in aqueous ammonia to obtain a reaction mixture containing a racemic ketoisoleucine calcium intermediate, sec-butylhydantoin; (2) adding a strong base to the reaction mixture of step (1) to obtain a racemic ketoisoleucine calcium intermediate, racemic ketoisoleucine salt. In step (2), an organic solvent (one or more of ethanol, isopropanol, and methanol) is used for the reaction. After obtaining the racemic ketoisoleucine calcium intermediate, it is reacted with a calcium salt to obtain racemic ketoisoleucine calcium.

[0015] The prior art (invention patent with publication number CN1117776947A, application date 2023.12.01) discloses a method for preparing sodium racemic ketoisoleucine and calcium racemic ketoisoleucine. The method for preparing sodium racemic ketoisoleucine includes first reacting hydantoin and butanone at low temperature under the action of a solvent, then heating the reaction, adjusting the pH, and obtaining sodium racemic ketoisoleucine. Alcohol (methanol, ethanol or isopropanol) is used in the low-temperature reaction. After obtaining sodium racemic ketoisoleucine, calcium salt is added and reacted with the calcium salt to obtain calcium racemic ketoisoleucine.

[0016] It can be seen that the above technologies all use alcohol organic solvents in the process of preparing racemic ketoisoleucine calcium, the post-treatment steps are cumbersome, and the treatment of three wastes is difficult.

[0017] Improvement method 2 of route 2:

[0018] Firstly, a crude calcium ketoisoleucine product is prepared, and then the crude calcium ketoisoleucine product is refined to obtain a finished calcium ketoisoleucine product.

[0019] The prior art (invention patent with publication number CN106045843B and application date 2016.06.16) discloses a production process of racemic ketoisoleucine calcium, including the preparation of 2-butylene hydantoin, the preparation of racemic ketoisoleucine calcium crude product and the refining of racemic ketoisoleucine calcium crude product. The preparation steps of racemic ketoisoleucine calcium crude product include: mixing 2-butylene hydantoin with sodium hydroxide solution, reflux reaction, stopping heating after 2-butylene hydantoin is completely dissolved, cooling to room temperature, adjusting pH value to 0.5-1.5, extracting with ethyl acetate, decolorizing with activated carbon, filtering, dripping anhydrous calcium chloride aqueous solution into the filtrate, precipitating solid, filtering, washing, and heat preservation at 30-35°C for 4-5h to obtain racemic ketoisoleucine calcium crude product. The purification step of the crude racemic ketoisoleucine calcium product comprises: dissolving the crude racemic ketoisoleucine calcium product in water, and recrystallizing through acetone or ethanol to obtain the racemic ketoisoleucine calcium.

[0020] The prior art (invention patent with publication number CN110627637B and application date September 25, 2019) discloses a one-step method for preparing racemic ketoisoleucine calcium, which uses hydantoin and butanone as raw materials, reacts in the presence of a solvent and monoethanolamine, and after the reaction, adds sodium hydroxide for hydrolysis, salt formation, and crystallization to obtain a crude wet product of racemic ketoisoleucine calcium, which is then dissolved, adsorbed on activated carbon, filtered, crystallized, washed with ethanol, and dried to obtain racemic ketoisoleucine calcium.

[0021] It can be seen that the alkaline reaction liquid of α-ketoisoleucine salt after hydrolysis of 2-butylene hydantoin has many impurities and high concentration. The above technology uses acetone or ethanol recrystallization, activated carbon adsorption, ethanol washing and other further purification methods in the process of preparing racemic ketoisoleucine calcium, and still needs to use organic solvents, which makes it difficult to treat the three wastes and the post-treatment steps are cumbersome.

[0022] Improvement method 3 of route 2:

[0023] Ketoisoleucine is first prepared, and then calcium salt is added to obtain calcium ketoisoleucine.

[0024] The prior art (invention patent with publication number CN106316828A and application date August 16, 2016) discloses a method for preparing high-purity α-ketoisoleucine calcium dihydrate, which comprises the following steps: using sec-butylene glycol or isopropylene glycol as a raw material, and subjecting the raw material to a slightly negative pressure ring-opening reaction with an alkali solution containing a buffer solution to obtain a corresponding α-ketoisoleucine salt; extracting the obtained α-ketoisoleucine salt with a hydrocarbon, halogenated hydrocarbon, ketone or ether solvent to remove impurities, and then acidifying the obtained α-ketoisoleucine crude product, and then extracting the obtained α-ketoisoleucine with a hydrocarbon, halogenated hydrocarbon, ketone or ether solvent to remove impurities, and then adsorbing and refining the obtained α-ketoisoleucine with activated carbon, clay or resin; preparing the obtained α-keto acid into a calcium salt, and crystallizing the obtained α-keto acid calcium dihydrate.

[0025] It can be seen that the above technology uses multiple organic solvent extractions and adsorption to remove impurities in the process of preparing ketoisoleucine, the post-treatment steps are cumbersome, and the treatment of the three wastes is difficult.

[0026] In summary, the currently disclosed methods for preparing calcium α-ketoisoleucine have too many product impurities and are difficult to purify, and the problems of cumbersome post-processing and difficulty in treating the three wastes still exist. In industrial production, there is still a need for further improvement and optimization. Summary of the invention

[0027] Aiming at the problem that the alkaline reaction liquid of α-ketoisoleucine salt after hydrolysis of 2-butylene hydantoin has many impurities and high concentration, the improved method of route 2 in the prior art mostly adopts the method of "preparing sodium ketoisoleucine & preparing calcium ketoisoleucine", "preparing crude calcium ketoisoleucine & refining" or "extracting and preparing ketoisoleucine & forming calcium salt" after acid adjustment to prepare calcium ketoisoleucine product with qualified purity. The problems of cumbersome post-treatment and difficulty in treating three wastes still exist. In view of the problems existing in the prior art, the present invention provides a method for synthesizing calcium α-ketoisoleucine intermediate and its application in preparing calcium α-ketoisoleucine. After optimizing the hydrolysis reaction process parameters and creatively preparing an aqueous solution of α-ketoisoleucine by distillation, the impurity level of α-ketoisoleucine is effectively reduced, and then stirring and reacting with calcium salt can directly prepare a high-purity calcium α-ketoisoleucine product. The entire reaction process uses pollution-free water as the reaction solvent. The reaction route is green and environmentally friendly, effectively avoiding the three wastes pollution problem caused to the environment. It is suitable for industrial large-scale production and has high industrial value.

[0028] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0029] In a first aspect, the present invention provides a method for synthesizing an α-ketoisoleucine calcium intermediate, comprising:

[0030] 1) hydrolyzing 2-butylene hydantoin with alkali to prepare an alkaline solution of α-ketoisoleucine salt;

[0031] 2) The alkaline solution of α-ketoisoleucine salt obtained in step 1) is adjusted to an acidic pH and distilled to prepare an aqueous solution of α-ketoisoleucine, i.e., an α-ketoisoleucine calcium intermediate.

[0032] In the step 1), the hydrolysis temperature is 95-100°C; the hydrolysis time is 7-10 hours. The base is selected from any one of sodium hydroxide, lithium hydroxide, calcium hydroxide, and potassium hydroxide, preferably NaOH. The molar ratio of the base to 2-butylene glycol is 3.1-3.5:1, preferably 3.3:1. In one embodiment, the base is sodium hydroxide, and the molar ratio of sodium hydroxide to 2-butylene glycol is 3.1-3.5:1, preferably 3.3:1.

[0033] In one embodiment, the step 1) is specifically as follows: adding 2-butylene hydantoin to an aqueous solution of NaOH at 95-100° C. to carry out a hydrolysis reaction to prepare an alkaline solution of sodium α-ketoisoleucine. Preferably, the concentration of the aqueous solution of NaOH is 285 mg / mL.

[0034] In the step 2), the pH range is 0.5 to 2.0. The pH is adjusted to acidic by using any one of hydrochloric acid, nitric acid and sulfuric acid. During the distillation, the temperature of the distillation head is 40-50°C; the vacuum degree of the distillation is -0.08 to -0.1 MPa.

[0035] In one embodiment, the synthesis method of α-ketoisoleucine calcium intermediate comprises:

[0036] 1) adding 2-butylene hydantoin to an aqueous solution of NaOH at 95-100° C. to carry out a hydrolysis reaction for 7-10 hours to prepare an alkaline solution of sodium α-ketoisoleucine; the molar ratio of NaOH to 2-butylene hydantoin is 3.1-3.5:1, preferably 3.3:1;

[0037] 2) at 20-30° C., using concentrated hydrochloric acid to adjust the pH of the alkaline solution of sodium α-ketoisoleucine obtained in step 1) to an acidic state, wherein the pH range is 0.5 to 2.0; and then distilling the solution. During the distillation, the temperature of the distillation head is 40-50° C., and the vacuum degree of the distillation is -0.08 to -0.1 MPa; and an aqueous solution of α-ketoisoleucine is prepared, i.e., an α-ketoisoleucine calcium intermediate.

[0038] In a second aspect, the present invention also provides a use of the calcium α-ketoisoleucine intermediate described in the above technical solution in the preparation of calcium α-ketoisoleucine.

[0039] In a third aspect, the present invention further provides a method for synthesizing calcium α-ketoisoleucine, comprising: reacting the calcium α-ketoisoleucine intermediate described in the above technical solution with a calcium salt to obtain calcium α-ketoisoleucine.

[0040] The calcium salt is calcium chloride, calcium acetate or calcium hydroxide.

[0041] The molar ratio of the calcium salt to 2-butylene hydantoin is 1:1.5-2.5, preferably 1:2.

[0042] Specifically, the calcium salt aqueous solution or suspension is added dropwise to the aqueous solution of α-ketoisoleucine for reaction, preferably in a manner of adding dropwise while stirring, the reaction temperature is 20-30° C., the reaction time is 1-2 hours, and then concentrated under reduced pressure to obtain a concentrated solution, the temperature of the reduced pressure concentration is 30-65° C.; the concentrated solution is cooled to 20-30° C., allowed to stand, filtered, and dried to obtain α-ketoisoleucine calcium.

[0043] Compared with the prior art, the present invention has the following beneficial effects: the present invention uses 2-butylene glycol as a starting material, hydrolyzes 2-butylene glycol to prepare an alkaline solution of α-ketoisoleucine salt, adjusts the pH to acidic and then distills to prepare an α-ketoisoleucine calcium intermediate, and then reacts with a calcium salt to prepare α-ketoisoleucine calcium. The prepared α-ketoisoleucine calcium has high purity (up to 99.9% or more) and high yield (two-step total yield is about 60% or more), and meets the pharmaceutical standards. The entire reaction process is carried out in water without any organic solvent, the reaction route is green and environmentally friendly, effectively avoids the three wastes pollution problem to the environment, is suitable for industrial large-scale production, and has high industrial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the HPLC spectrum of calcium α-ketoisoleucine obtained in Example 1;

[0045] Figure 2 This is the HPLC spectrum of calcium α-ketoisoleucine obtained in Example 2;

[0046] Figure 3 This is the HPLC spectrum of calcium α-ketoisoleucine obtained in Example 3;

[0047] Figure 4 This is the HPLC spectrum of calcium α-ketoisoleucine obtained in Example 4;

[0048] Figure 5 This is the HPLC spectrum of calcium α-ketoisoleucine obtained in Example 5;

[0049] Figure 6This is the HPLC spectrum of calcium α-ketoisoleucine obtained in Example 6. DETAILED DESCRIPTION

[0050] It is worth noting that, unless otherwise specified, the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0051] Example 1

[0052] (1) Preparation of an aqueous solution of α-ketoisoleucine calcium intermediate α-ketoisoleucine

[0053] NaOH (17.1 g, 0.428 mol) was added to purified water (60 mL), the temperature was raised to 95° C., 2-butylene hydantoin (20.00 g, 0.13 mol) was added at once, and the mixture was reacted at 95° C. for 10 hours to prepare an alkaline solution of sodium α-ketoisoleucine.

[0054] At 20-30° C., concentrated hydrochloric acid is added to the prepared alkaline solution of sodium α-ketoisoleucine to adjust the pH value to 0.5, and then distillation is performed, and the temperature of the distillation head is controlled at 40-50° C. and the vacuum degree is -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoisoleucine.

[0055] (2) Preparation of α-ketoisoleucine calcium

[0056] Calcium chloride (7.19 g, 0.0645 mol) was dissolved in purified water (40 mL) to prepare a calcium chloride aqueous solution. The calcium chloride aqueous solution was added dropwise to the aqueous solution of α-ketoisoleucine obtained in step (1), stirred at 20-30° C. for 1 h after the addition was completed, then the mixture was concentrated under reduced pressure (to 70.0-80.0 g) with the internal temperature controlled not to exceed 65° C., cooled to 20-30° C. and kept warm for 0.5 h, then filtered to obtain a solid, and dried to obtain α-ketoisoleucine calcium (11.98 g) with a purity of 99.92% and a two-step total yield of 62%.

[0057] The HPLC spectrum of the obtained α-ketoisoleucine calcium is as follows: Figure 1 shown.

[0058] Example 2

[0059] (1) Preparation of an aqueous solution of α-ketoisoleucine calcium intermediate α-ketoisoleucine

[0060] NaOH (17.1 g, 0.428 mol) was added to purified water (60 mL), the temperature was raised to 100° C., 2-butylene hydantoin (20.00 g, 0.13 mol) was added at once, and the mixture was reacted at 100° C. for 7 hours to prepare an alkaline solution of sodium α-ketoisoleucine.

[0061] At 20-30° C., concentrated hydrochloric acid is added to the prepared alkaline solution of sodium α-ketoisoleucine to adjust the pH value to 2.0, and then distillation is performed, and the distillation head temperature is controlled at 40-50° C. and the vacuum degree is -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoisoleucine.

[0062] (2) Preparation of α-ketoisoleucine calcium

[0063] Calcium chloride (7.19 g, 0.0645 mol) was dissolved in purified water (40 mL) to prepare a calcium chloride aqueous solution. The calcium chloride aqueous solution was added dropwise to the aqueous solution of α-ketoisoleucine obtained in step (1), stirred at 20-30° C. for 1 h after the addition was completed, then the mixture was concentrated under reduced pressure (to 70.0-80.0 g) with the internal temperature controlled not to exceed 65° C., cooled to 20-30° C. and kept warm for 0.5 h, then filtered to obtain a solid, dried, and α-ketoisoleucine calcium (12.27 g) was obtained, with a purity of 99.86% and a total yield of 63.5%.

[0064] The HPLC spectrum of the obtained α-ketoisoleucine calcium is as follows: Figure 2 shown.

[0065] Example 3

[0066] (1) Preparation of an aqueous solution of α-ketoisoleucine calcium intermediate α-ketoisoleucine

[0067] NaOH (17.1 g, 0.428 mol) was added to purified water (60 mL), the temperature was raised to 97° C., 2-butylene hydantoin (20.00 g, 0.13 mol) was added at once, and the mixture was reacted at 97° C. for 9 hours to prepare an alkaline solution of sodium α-ketoisoleucine.

[0068] At 20-30° C., concentrated hydrochloric acid is added to the prepared alkaline solution of sodium α-ketoisoleucine to adjust the pH value to 1.0, and then distillation is performed, the distillation head temperature is controlled at 40-50° C., and the vacuum degree is -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoisoleucine.

[0069] (2) Preparation of α-ketoisoleucine calcium

[0070] Calcium acetate (11.36 g, 0.0645 mol) was dissolved in purified water (40 mL) to obtain an aqueous solution of calcium acetate. The aqueous solution of calcium acetate was added dropwise to the aqueous solution of α-ketoisoleucine obtained in step (1), stirred at 20-30° C. for 1 h after the addition was completed, then the mixture was concentrated under reduced pressure (to 70.0-80.0 g) with the internal temperature controlled not to exceed 65° C., cooled to 20-30° C. and kept warm for 0.5 h, then filtered to obtain a solid, and dried to obtain α-ketoisoleucine calcium (11.98 g) with a purity of 99.91% and a total yield of 62%.

[0071] The HPLC spectrum of the obtained α-ketoisoleucine calcium is as follows: Figure 3 shown.

[0072] Example 4

[0073] (1) Preparation of an aqueous solution of α-ketoisoleucine calcium intermediate α-ketoisoleucine

[0074] NaOH (17.1 g, 0.428 mol) was added to purified water (60 mL), the temperature was raised to 98° C., 2-butylene hydantoin (20.00 g, 0.13 mol) was added at once, and the mixture was reacted at 98° C. for 8.5 hours to prepare an alkaline solution of sodium α-ketoisoleucine.

[0075] At 20-30° C., concentrated hydrochloric acid is added to the prepared alkaline solution of sodium α-ketoisoleucine to adjust the pH value to 1.0, and then distillation is performed, the distillation head temperature is controlled at 40-50° C., and the vacuum degree is -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoisoleucine.

[0076] (2) Preparation of α-ketoisoleucine calcium

[0077] Calcium acetate (11.36 g, 0.0645 mol) was dissolved in purified water (40 mL) to obtain an aqueous solution of calcium acetate. The aqueous solution of calcium acetate was added dropwise to the aqueous solution of α-ketoisoleucine obtained in step (1), stirred at 20-30° C. for 1 h after the addition was completed, then the mixture was concentrated under reduced pressure (to 70.0-80.0 g) with the internal temperature controlled not to exceed 65° C., cooled to 20-30° C. and kept warm for 0.5 h, then filtered to obtain a solid, and dried to obtain α-ketoisoleucine calcium (11.6 g) with a purity of 99.91% and a total yield of 60%.

[0078] The HPLC spectrum of the obtained α-ketoisoleucine calcium is as follows: Figure 4 shown.

[0079] Example 5

[0080] (1) Preparation of an aqueous solution of α-ketoisoleucine calcium intermediate α-ketoisoleucine

[0081] NaOH (17.1 g, 0.428 mol) was added to purified water (60 mL), the temperature was raised to 96° C., 2-butylene hydantoin (20.00 g, 0.13 mol) was added at once, and the mixture was reacted at 96° C. for 9 hours to prepare an alkaline solution of sodium α-ketoisoleucine.

[0082] At 20-30° C., concentrated hydrochloric acid is added to the prepared alkaline solution of sodium α-ketoisoleucine to adjust the pH value to 1.5, and distillation is performed. The temperature of the distillation head is controlled at 40-50° C. and the vacuum degree is -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoisoleucine.

[0083] (2) Preparation of α-ketoisoleucine calcium

[0084] Calcium hydroxide (4.8 g, 0.0645 mol) was added to purified water (40 mL) to obtain a calcium hydroxide suspension. The calcium hydroxide suspension was added dropwise to the aqueous solution of α-ketoisoleucine obtained in step (1), stirred at 20-30° C. for 1 h after the addition was completed, and then the internal temperature was controlled not to exceed 65° C. and concentrated under reduced pressure (to 70.0-80.0 g), and then the temperature was lowered to 20-30° C. and kept warm for 0.5 hours, and then the solid was filtered and dried to obtain α-ketoisoleucine calcium (12.37 g) with a purity of 99.89% and a total yield of 64%.

[0085] The HPLC spectrum of the obtained α-ketoisoleucine calcium is as follows: Figure 5 shown.

[0086] Example 6

[0087] (1) Preparation of an aqueous solution of α-ketoisoleucine calcium intermediate α-ketoisoleucine

[0088] NaOH (17.1 g, 0.428 mol) was added to purified water (60 mL), the temperature was raised to 98° C., 2-butylene hydantoin (20.00 g, 0.13 mol) was added at once, and the mixture was reacted at 98° C. for 8.5 hours to prepare an alkaline solution of sodium α-ketoisoleucine.

[0089] At 20-30° C., concentrated hydrochloric acid is added to the prepared alkaline solution of sodium α-ketoisoleucine to adjust the pH value to 1.5, the temperature of the distillation head is controlled at 40-50° C., and the vacuum degree is -0.08 to -0.1 MPa to obtain an α-ketoisoleucine aqueous solution.

[0090] (2) Preparation of calcium α-ketoisoleucine

[0091] Calcium hydroxide (4.8 g, 0.0645 mol) was added to purified water (40 mL) to obtain a calcium hydroxide suspension. The calcium hydroxide suspension was added dropwise to the aqueous solution of α-ketoisoleucine obtained in step (1), stirred at 20-30° C. for 1 h after the addition was completed, and then the internal temperature was controlled not to exceed 65° C. and concentrated under reduced pressure (to 70.0-80.0 g), and then the temperature was lowered to 20-30° C. and kept warm for 0.5 hours, and then the solid was filtered and dried to obtain α-ketoisoleucine calcium (12.56 g) with a purity of 99.90% and a total yield of 65%.

[0092] The HPLC spectrum of the obtained α-ketoisoleucine calcium is as follows: Figure 6 shown.

[0093] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing an α-ketoisoleucine calcium intermediate, characterized in that: include: 1) hydrolyzing 2-butylene hydantoin with alkali to prepare an alkaline solution of α-ketoisoleucine salt; 2) The alkaline solution of α-ketoisoleucine salt obtained in step 1) is adjusted to an acidic pH and distilled to prepare an aqueous solution of α-ketoisoleucine, i.e., an α-ketoisoleucine calcium intermediate.

2. The synthesis method according to claim 1, characterized in that: During the distillation process, the temperature of the distillation head is 40-50°C; the vacuum degree of the distillation is -0.08 to -0.1 MPa.

3. The synthesis method according to claim 1, characterized in that: In the step 2), the pH value is in the range of 0.5 to 2.0; and the step of adjusting the pH value to acidic is specifically: adjusting the pH value to acidic by using any one of hydrochloric acid, nitric acid and sulfuric acid.

4. The synthesis method according to claim 1, characterized in that: In the step 1), the hydrolysis temperature is 95-100° C. and the hydrolysis time is 7-10 hours.

5. The synthesis method according to claim 1, characterized in that: In the step 1), the base is selected from any one of sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide; and the molar ratio of the base to 2-butylene hydantoin is 3.1 to 3.5:

1.

6. The synthesis method according to claim 5, characterized in that: The step 1) specifically comprises: adding 2-butylene hydantoin to an aqueous solution of NaOH at 95-100° C. to carry out a hydrolysis reaction to prepare an alkaline solution of sodium α-ketoisoleucine.

7. Use of the calcium α-ketoisoleucine intermediate according to any one of claims 1 to 6 in the preparation of calcium α-ketoisoleucine.

8. A method for synthesizing calcium α-ketoisoleucine, characterized in that: include: The calcium α-ketoisoleucine intermediate according to any one of claims 1 to 6 is reacted with a calcium salt to obtain calcium α-ketoisoleucine.

9. The synthesis method according to claim 8, characterized in that: The calcium salt is calcium chloride, calcium acetate or calcium hydroxide; the molar ratio of the calcium salt to 2-butylene hydantoin is 1:1.5-2.

5.

10. The synthesis method according to claim 8, characterized in that: Specifically: The calcium salt aqueous solution or suspension is added dropwise to the aqueous solution of α-ketoisoleucine for reaction at a temperature of 20 to 30° C. for a reaction time of 1 to 2 hours, and then concentrated under reduced pressure to obtain a concentrated solution at a temperature of 30 to 65° C.; the concentrated solution is cooled to 20 to 30° C., allowed to stand, filtered, and dried to obtain α-ketoisoleucine calcium.

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