Green synthesis method of alpha-ketoleucine calcium and intermediate thereof

Abstract

The invention discloses a green synthesis method of alpha-ketoleucine calcium and an intermediate thereof, and relates to the technical field of medicines. The green synthesis method comprises the following steps: (1) mixing 5-isobutylidene hydantoin, alkali and water for hydrolysis reaction to obtain an alkaline solution of alpha-ketoleucine salt; (2) mixing the alkaline solution of the alpha-ketoleucine salt with acid to adjust the pH value, and then distilling to obtain an alpha-ketoleucine aqueous solution; and (3) reacting the alpha-ketoleucine aqueous solution with calcium salt to obtain the alpha-ketoleucine calcium. Compared with a treatment mode of twice acid adjustment or extraction, the method provided by the invention adopts a mode of distillation after acid adjustment to remove impurities, and can effectively improve the purity of alpha-ketoleucine calcium.

Description

Technical Field

[0001] The invention relates to the field of medical technology, and in particular to a green synthesis method of alpha-ketoleucine calcium and an intermediate thereof. Background Art

[0002] Compound a-keto acid tablets are a compound preparation 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.

[0003] α-Ketoleucine calcium is one of the main ingredients of compound α-ketoacid tablets, and its structural formula is as follows:

[0004]

[0005] Document 1 (Igarashi M, Midorikawa H. Syntheses of α-Keto Amides and Acids from Ethyl Alkylidenecyanoacetates 1 [J]. Journal of Organic Chemistry, 1963, 28: 3088-3092. DOI: 10.1021 / JO01046A038.) discloses a route for preparing α-keto leucine: ethyl cyanoacetate and isobutylaldehyde are used as starting materials, 2-isobutylidene ethyl cyanoacetate is prepared by Knoevenagel-Cope reaction, and then α-keto leucine is prepared by oxidation and hydrolysis. This reaction route includes 6 steps, and the operation is complicated. The starting material ethyl cyanoacetate is highly toxic. The use of hydrogen peroxide in the oxidation reaction is not conducive to safe production and industrial production.

[0006] Reference 2 (Hua Jinxiu, Zou Jianzhong, Zhang Zhenglin. Synthesis of several α-keto acids by the hydantoin method [J]. Chemical Industry Journal, 2007, 21(12): 4. DOI: 10.3969 / j.issn.1002-154X.2007.12.002.) discloses a route for preparing calcium α-ketoleucine (hydantoin method): hydantoin and isobutylaldehyde are used as starting materials, 5-isobutylene hydantoin is obtained through condensation reaction, and then α-ketoleucine is obtained through hydrolysis and acidification reaction, and further α-ketoleucine calcium is obtained. This reaction route includes only 4 steps, and the operation is simple. The starting materials are easy to obtain and have low toxicity, and no dangerous reactions are involved. However, the hydrolysis reaction generates many impurities and the yield is low, and further improvement and optimization are still needed.

[0007] Chinese patent CN102030631A discloses a route for preparing calcium α-ketoleucine: using glycine and isobutylaldehyde as starting materials, 4-isobutylidene-2-methyldihydrooxazolone is obtained through cyclization reaction, and then α-ketoleucine calcium is obtained through high temperature hydrolysis (120-180°C) in a pipeline reactor and methanol / water recrystallization. This reaction route includes only 4 steps, the starting materials are easy and have low toxicity, but the reaction conditions of high temperature and long residence time make industrial implementation difficult.

[0008] Compared with document 1 and Chinese patent CN102030631A, document 2 avoids the use of highly toxic materials and the implementation of high-risk and high-difficulty reactions, and has a large room for improvement. Other existing technologies mainly focus on the improvement of the Hein method in document 2.

[0009] Chinese patent CN104058954A discloses a green process for preparing calcium ketoleucine in an aqueous phase: using isobutylene hydantoin and calcium chloride aqueous solution as raw materials, and water as solvent, the steps are: heating isobutylene hydantoin in water and industrial liquid alkali for reflux hydrolysis, dropping calcium chloride aqueous solution, filtering and collecting the filtrate, cooling the filtrate, acidifying with hydrochloric acid, replacing with vacuum nitrogen, adding liquid alkali for alkalization, cooling, dropping calcium chloride aqueous solution to form calcium salt, cooling, filtering to obtain a crude product, and then refining the crude product in purified water to obtain a refined calcium ketoleucine product. The preparation process adjusts the pH of the reaction system twice, and the steps are cumbersome.

[0010] Chinese patent CN102079714A discloses a method for integrating continuous multi-stage countercurrent liquid-liquid extraction and vacuum distillation to separate α-ketoleucine and water: first, a 10% α-ketoleucine aqueous solution is subjected to multi-stage countercurrent liquid-liquid extraction with an extractant, and after extraction and separation, the water phase at the bottom of the liquid-liquid extraction tower is sent to a water treatment tower, and the solvent at the top of the water treatment tower is recycled, and the water at the bottom of the water treatment tower is sent to a wastewater pool, and the extraction phase at the top of the liquid-liquid extraction tower is a mixed solution of the extractant and α-ketoleucine, which is sent to a continuous vacuum distillation tower for treatment, and α-ketoleucine with a mass content of 82.7% is obtained at the bottom of the continuous vacuum distillation tower, and the yield of α-ketoleucine reaches 93%, and the solvent at the top of the vacuum distillation tower is recycled. The extraction step in this method still uses organic solvents, and the three wastes are difficult to treat.

[0011] In view of this, in order to solve the shortcomings of the prior art culture methods, the present invention provides a green synthesis method of α-ketoleucine calcium and its intermediates. Summary of the invention

[0012] The invention aims to provide a green synthesis method of α-ketoleucine calcium and its intermediates. The green synthesis method uses 5-isobutylene hydroxylamine as a starting material and can prepare α-ketoleucine calcium with high purity (HPLC purity>99.9%) and high yield (two-step total yield>68%). The whole reaction process is carried out in water without any organic solvent, which is green and environmentally friendly, effectively avoiding the three wastes pollution problem to the environment. The method is simple to implement, can be operated continuously, and is suitable for industrial large-scale production.

[0013] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0014] A green synthesis method of α-ketoleucine calcium and its intermediates comprises the following steps:

[0015] (1) mixing 5-isobutylene hydantoin, a base and water for hydrolysis reaction to obtain an alkaline solution of α-ketoleucine salt;

[0016] (2) mixing the alkaline solution of α-ketoleucine salt with an acid to adjust the pH, and then distilling to obtain an α-ketoleucine aqueous solution;

[0017] (3) The α-ketoleucine aqueous solution is reacted with a calcium salt to obtain α-ketoleucine calcium.

[0018] Preferably, the molar ratio of the 5-isobutylene hydantoin, the base and the calcium salt is 1:1.9-3:0.4-0.5.

[0019] Preferably, in step (1), the base is selected from any one of sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide.

[0020] Further preferably, in step (1), the base is sodium hydroxide.

[0021] More preferably, in step (1), the mass concentration of sodium hydroxide is 170-180 g / L.

[0022] Preferably, in step (1), the temperature of the hydrolysis reaction is 90-95°C.

[0023] Preferably, in step (1), the hydrolysis reaction time is 1-3 hours.

[0024] Preferably, step (1) further comprises a cooling step after the hydrolysis reaction.

[0025] Further preferably, the specific process of step (1) is as follows: 5-isobutylene hydantoin, alkali and water are mixed for hydrolysis reaction, and after the hydrolysis reaction is completed, the temperature is lowered to 20-30° C. to obtain an alkaline solution of α-ketoleucine salt.

[0026] Preferably, in step (2), the acid is selected from any one of hydrochloric acid, nitric acid and sulfuric acid.

[0027] More preferably, in step (2), the acid is hydrochloric acid.

[0028] Preferably, in step (2), the pH is adjusted to 0.5-2.0.

[0029] Preferably, in step (2), the distillation temperature is 40-50°C; the distillation vacuum degree is -0.08 to -0.1 MPa.

[0030] Preferably, in step (3), the calcium salt is selected from any one of calcium chloride, calcium acetate and calcium hydroxide.

[0031] Preferably, in step (3), the calcium salt is a calcium salt aqueous solution or a calcium salt suspension.

[0032] Further preferably, in step (3), the molar concentration of the calcium salt aqueous solution or calcium salt suspension is 1.1-1.5 mol / L.

[0033] The beneficial effects of the present invention are:

[0034] Since the alkaline solution of α-ketoleucine salt has many impurities and high alkalinity, α-ketoleucine calcium with qualified purity cannot be obtained without treatment. Compared with the treatment method of twice acid adjustment or extraction, the present invention adopts the method of acid adjustment followed by distillation to remove impurities, which can effectively improve the purity of α-ketoleucine calcium. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the HPLC spectrum of calcium α-ketoleucine prepared in Example 1 of the present invention.

[0036] Figure 2 This is the HPLC spectrum of calcium α-ketoleucine prepared in Example 2 of the present invention.

[0037] Figure 3 This is the HPLC spectrum of calcium α-ketoleucine prepared in Example 3 of the present invention.

[0038] Figure 4 This is the HPLC spectrum of calcium α-ketoleucine prepared in Example 4 of the present invention.

[0039] Figure 5 This is the HPLC spectrum of calcium α-ketoleucine prepared in Example 5 of the present invention.

[0040] Figure 6 This is the HPLC spectrum of calcium α-ketoleucine prepared in Example 6 of the present invention. DETAILED DESCRIPTION

[0041] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present invention.

[0042] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0043] Example 1

[0044] (1) Preparation of α-ketoleucine

[0045] Add NaOH (10.37 g, 0.259 mol) to purified water (60 mL), heat to 90°C, add 5-isobutylene hydantoin (20.04 g, 0.13 mol) at one time, and react at 90°C for 3 hours. After the reaction is completed, cool to 20-30°C, add concentrated hydrochloric acid to adjust the pH to 0.5, control the temperature of the distillation head at 40-50°C, and distill at a vacuum degree of -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoleucine.

[0046] (2) Preparation of calcium α-ketoleucine

[0047] To the above α-ketoleucine aqueous solution, add calcium chloride aqueous solution [calcium chloride (6.19 g, 0.056 mol) dissolved in purified water (40 mL)] dropwise, stir at 20-30°C for 1 h, then control the internal temperature not to exceed 65°C and concentrate under reduced pressure (70.0-80.0 g), cool to 20-30°C and keep warm for 0.5 hour, then filter and dry to obtain α-ketoleucine calcium (13.52 g) with HPLC purity of 99.909% and total yield of 69.87%.

[0048] Example 2

[0049] (1) Preparation of α-ketoleucine

[0050] Add NaOH (15.57 g, 0.389 mol) to purified water (90 mL), heat to 95°C, add 5-isobutylene hydantoin (20.04 g, 0.13 mol) at one time, and react at 95°C for 1 hour. After the reaction is completed, cool to 20-30°C, add concentrated hydrochloric acid to adjust the pH to 2.0, control the temperature of the distillation head at 40-50°C, and distill at a vacuum degree of -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoleucine.

[0051] (2) Preparation of calcium α-ketoleucine

[0052] To the above α-ketoleucine aqueous solution, add calcium chloride aqueous solution [calcium chloride (6.47 g, 0.058 mol) dissolved in purified water (50 mL)] dropwise, stir at 20-30°C for 0.5 h, then control the internal temperature not to exceed 65°C and concentrate under reduced pressure to (70.0-80.0 g), cool to 20-30°C and keep warm for 0.5 hour, then filter and dry to obtain α-ketoleucine calcium (13.56 g) with HPLC purity of 99.909% and total yield of 70.12%.

[0053] Example 3

[0054] (1) Preparation of α-ketoleucine

[0055] Add NaOH (12.97 g, 0.324 mol) to purified water (75 mL), heat to 92 ° C, add 5-isobutylene hydantoin (20.04 g, 0.13 mol) at one time, and then react at 92 ° C for 2 hours. After the reaction is completed, cool to 20-30 ° C, add concentrated hydrochloric acid to adjust the pH value to 1.0, control the temperature of the distillation head at 40-50 ° C, and distill at a vacuum degree of -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoleucine.

[0056] (2) Preparation of calcium α-ketoleucine

[0057] To the above α-ketoleucine aqueous solution, add calcium acetate aqueous solution [calcium acetate monohydrate (9.87 g, 0.056 mol) dissolved in purified water (40 mL)], stir at 20-30°C for 0.5 h after the addition is complete, then control the internal temperature not to exceed 65°C and concentrate under reduced pressure to (65.0-75.0 g), cool to 20-30°C and keep warm for 0.5 hour, then filter and dry to obtain α-ketoleucine calcium (13.30 g), HPLC purity 99.908%, total yield 68.75%.

[0058] Example 4

[0059] (1) Preparation of α-ketoleucine

[0060] Add NaOH (12.45 g, 0.311 mol) to purified water (70 mL), heat to 94 ° C, add 5-isobutylene hydantoin (20.04 g, 0.13 mol) at one time, and then react at 94 ° C for 1.5 hours. After the reaction is completed, cool to 20-30 ° C, add concentrated hydrochloric acid to adjust the pH to 1.0, control the temperature of the distillation head at 40-50 ° C, and distill at a vacuum degree of -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoleucine.

[0061] (2) Preparation of calcium α-ketoleucine

[0062] To the above α-ketoleucine aqueous solution, add calcium acetate aqueous solution [calcium acetate (10.57 g, 0.060 mol) dissolved in purified water (40 mL)], stir at 20-30°C for 0.5 h after the addition is complete, then control the internal temperature not to exceed 65°C and concentrate under reduced pressure to (70.0-80.0 g), cool to 20-30°C and keep warm for 0.5 hour, filter and dry to obtain α-ketoleucine calcium (13.78 g), HPLC purity 99.902%, total yield 71.23%.

[0063] Example 5

[0064] (1) Preparation of α-ketoleucine

[0065] Add NaOH (12.97 g, 0.324 mol) to purified water (75 mL), heat to 92 ° C, add 5-isobutylene hydantoin (20.04 g, 0.13 mol) at one time, and then react at 92 ° C for 2 hours. After the reaction is completed, cool to 20-30 ° C, add concentrated hydrochloric acid to adjust the pH to 1.5, control the temperature of the distillation head at 40-50 ° C, and distill at a vacuum degree of -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoleucine.

[0066] (2) Preparation of calcium α-ketoleucine

[0067] Calcium hydroxide suspension [calcium hydroxide (4.33 g, 0.058 mol) and purified water (40 mL) were mixed] was added dropwise to the above α-ketoleucine aqueous solution. After the addition was completed, it was stirred at 20-30°C for 0.5 h, and then the internal temperature was controlled not to exceed 65°C and concentrated under reduced pressure to (70.0-80.0 g). After cooling to 20-30°C and keeping warm for 0.5 hour, it was filtered and dried to obtain α-ketoleucine calcium (13.43 g) with HPLC purity of 99.910% and total yield of 69.42%.

[0068] Example 6

[0069] (1) Preparation of α-ketoleucine

[0070] Add NaOH (11.93 g, 0.298 mol) to purified water (70 mL), heat to 93 ° C, add 5-isobutylene hydantoin (20.04 g, 0.13 mol) at one time, and then react at 93 ° C for 1.5 hours. After the reaction is completed, cool to 20-30 ° C, add concentrated hydrochloric acid to adjust the pH to 1.5, control the temperature of the distillation head at 40-50 ° C, and distill at a vacuum degree of -0.08 to -0.1 MPa to obtain an aqueous solution of α-ketoleucine.

[0071] (2) Preparation of calcium α-ketoleucine

[0072] Calcium hydroxide suspension [calcium hydroxide (4.46 g, 0.060 mol) and purified water (40 mL) were mixed] was added dropwise to the above α-ketoleucine aqueous solution. After the addition was completed, it was stirred at 20-30°C for 0.5 h, and then the internal temperature was controlled not to exceed 65°C and concentrated under reduced pressure to (70.0-80.0 g). After cooling to 20-30°C and keeping warm for 0.5 hour, it was filtered and dried to obtain α-ketoleucine calcium (13.31 g) with HPLC purity of 99.909% and total yield of 68.79%.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A green synthesis method of calcium α-ketoleucine and its intermediates, characterized in that: The following steps are involved: (1) mixing 5-isobutylene hydantoin, a base and water for hydrolysis reaction to obtain an alkaline solution of α-ketoleucine salt; (2) mixing the alkaline solution of α-ketoleucine salt with an acid to adjust the pH, and then distilling to obtain an α-ketoleucine aqueous solution; (3) The α-ketoleucine aqueous solution is reacted with a calcium salt to obtain α-ketoleucine calcium.

2. The green synthesis method according to claim 1, characterized in that: The molar ratio of the 5-isobutylene hydantoin, the base and the calcium salt is 1:1.9-3:0.4-0.

5.

3. The green synthesis method according to claim 1, characterized in that: In step (1), the base is selected from any one of sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide.

4. The green synthesis method according to claim 3, characterized in that: In step (1), the base is sodium hydroxide.

5. The green synthesis method according to claim 4, characterized in that: In step (1), the mass concentration of the sodium hydroxide is 170-180 g / L.

6. The green synthesis method according to claim 1, characterized in that: In step (1), the temperature of the hydrolysis reaction is 90-95°C.

7. The green synthesis method according to claim 1, characterized in that: In step (1), the hydrolysis reaction time is 1-3h.

8. The green synthesis method according to claim 1, characterized in that: Step (1) also includes a cooling step after the hydrolysis reaction.

9. The green synthesis method according to claim 8, characterized in that: The specific process of step (1) is as follows: 5-isobutylene hydantoin, alkali and water are mixed for hydrolysis reaction, and after the hydrolysis reaction is completed, the temperature is lowered to 20-30° C. to obtain an alkaline solution of α-ketoleucine salt.

10. The green synthesis method according to claim 1, characterized in that: In step (2), the acid is selected from any one of hydrochloric acid, nitric acid and sulfuric acid.

11. The green synthesis method according to claim 10, characterized in that: In step (2), in step (2), the acid is hydrochloric acid.

12. The green synthesis method according to claim 1, characterized in that: In step (2), the pH is adjusted to 0.5-2.

0.

13. The green synthesis method according to claim 1, characterized in that: In step (2), the distillation temperature is 40-50°C; the distillation vacuum degree is -0.08 to -0.1 MPa.

14. The green synthesis method according to claim 1, characterized in that: In step (3), the calcium salt is selected from any one of calcium chloride, calcium acetate and calcium hydroxide.

15. The green synthesis method according to claim 1, characterized in that: In step (3), the calcium salt is a calcium salt aqueous solution or a calcium salt suspension.

16. The green synthesis method according to claim 15, characterized in that: In step (3), the molar concentration of the calcium salt aqueous solution or calcium salt suspension is 1.1-1.5 mol / L.

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