Green synthesis method of alpha-ketovaline calcium and intermediate thereof

Abstract

The invention discloses a green synthesis method of alpha-ketovaline calcium and an intermediate thereof, and relates to the technical field of medicines. The green synthesis method comprises the following steps: (1) mixing 5-isopropylidene hydantoin, alkali and water for hydrolysis reaction to obtain an alkaline solution of alpha-ketovaline salt; (2) mixing the alkaline solution of the alpha-ketovaline salt with acid to adjust the pH value, and then distilling to obtain an alpha-ketovaline aqueous solution; and (3) reacting the alpha-ketovaline aqueous solution with calcium salt to obtain the alpha-ketovaline calcium. According to the green synthesis method, no organic solvent is used, and impurities in an alkaline solution of alpha-ketovaline salt are removed by adopting a mode of distilling after acid adjustment, so that the purity of alpha-ketovaline calcium can be effectively improved.

Description

Technical Field

[0001] The invention relates to the field of medical technology, in particular to a green synthesis method of alpha-ketovaline 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-Ketovaline calcium is one of the main ingredients of compound α-keto acid tablets, and its structural formula is as follows:

[0004]

[0005] Document 1 (Igarashi M, Midorikawa H. Syntheses of α-KetoAmides 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-ketovaline: ethyl cyanoacetate and acetone are used as starting materials, 2-isopropyl ethyl cyanoacetate is prepared by Knoevenagel-Cope reaction, and then α-ketovaline 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 (Lu Xiao, Li Yingying, Li Fei. Synthesis of α-ketovalinate calcium [J]. Pharmaceutical Progress, 2007, 31(1):3. DOI:10.3969 / j.issn.1001-5094.2007.01.007.) discloses a route for preparing α-ketovalinate calcium: using isopropylmagnesium bromide and diethyl oxalate as starting materials, α-ketovalinate ethyl ester is prepared by Grignard reaction, and then reacted with calcium salt to obtain α-ketovalinate calcium. This route requires the Grignard reaction to be carried out under anhydrous, oxygen-free and low temperature conditions, and uses flammable and explosive ether as solvent, which is not suitable for industrial production.

[0007] Chinese patent CN106316828A discloses a route for preparing α-keto valine calcium dihydrate (Hydroxymethoxy) as a raw material, and a slightly negative pressure ring-opening reaction is carried out with an alkali solution containing a buffer to obtain the corresponding α-keto acid salt; the obtained α-keto acid salt is first extracted and removed with a hydrocarbon, halogenated hydrocarbon, ketone or ether solvent, and then acidified to obtain the corresponding α-keto acid crude product, and then extracted and removed with a hydrocarbon, halogenated hydrocarbon, ketone or ether solvent, and then adsorbed and refined with activated carbon, clay or resin to obtain α-keto acid; the obtained α-keto acid is made into a calcium salt, and crystallized to obtain α-keto valine calcium dihydrate. This reaction route includes only 4 steps, the starting material has low toxicity, and does not involve dangerous reactions, but the hydrolysis reaction generates many impurities and the yield is low, which needs further improvement and optimization.

[0008] Chinese patent CN102675087A discloses a route for preparing calcium α-ketovaline: diethyl oxalate is dripped into an alcohol solution of a metal alkoxide, then isobutyraldehyde is dripped, the mixture is stirred at room temperature, an alkali solution is added, the mixture is acidified, extracted, a certain amount of water is added to the extract, an alkali solution is added to adjust the pH, and then a calcium chloride aqueous solution is dripped to form a salt to obtain a crude calcium α-ketovaline, and then the crude calcium α-ketovaline is refined in a mixed solvent of purified water and an organic solvent to obtain a refined calcium α-ketovaline. This route uses sodium alcohol hazardous reagents, has a large amount of post-treatment waste liquid, and is difficult to treat the three wastes, which is not conducive to industrial production.

[0009] Compared with Document 1, Document 2 and Chinese Patent CN102675087A, Chinese Patent CN106316828A 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.

[0010] Chinese patent CN113735775A discloses a method for preparing calcium α-ketovaline intermediate: hydantoin and acetone react under the catalysis of ammonia water to obtain isopropylhydantoin, an intermediate of calcium α-ketovaline. This preparation method uses flammable and explosive alcohol organic reagents and is not suitable for industrial production.

[0011] Chinese patent CN117658798A discloses a method for preparing calcium α-ketovaline: using hydantoin as a starting material, reacting with alkali, acetone and water, etc., through heating reaction, heat preservation reaction, gradually heating up and concentrating alcohol under normal pressure, adjusting pH value, etc., finally separating from the solution in solid form, filtering to obtain sodium α-ketovaline, and reacting sodium α-ketovaline with calcium salt solution to generate calcium α-ketovaline. This preparation method uses flammable and explosive alcohol organic reagents and is not suitable for industrial production.

[0012] In view of this, in order to solve the shortcomings of the prior art culture method, the present invention provides a green synthesis method of α-ketovaline calcium and its intermediates. Summary of the invention

[0013] The invention aims to provide a green synthesis method of α-ketovaline calcium and an intermediate thereof. The green synthesis method uses 5-isopropylidene hydroxyquinoline as a starting material and can prepare α-ketovaline calcium with high purity (up to 99.97%) and high yield (two-step total yield of more than 90%). The whole reaction process is carried out in water without any organic solvent, which is green and environmentally friendly, effectively avoiding the problem of three wastes pollution to the environment, and is suitable for industrial large-scale production.

[0014] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0015] A green synthesis method of calcium α-ketovaline and its intermediates comprises the following steps:

[0016] (1) mixing 5-isopropylidene hydantoin, a base and water for hydrolysis reaction to obtain an alkaline solution of α-ketovaline salt;

[0017] (2) mixing the alkaline solution of α-ketovaline salt with an acid to adjust the pH, and then distilling to obtain an α-ketovaline aqueous solution;

[0018] (3) The α-ketovaline aqueous solution is mixed with a calcium salt to obtain α-ketovaline calcium.

[0019] Preferably, the molar ratio of the 5-isopropylidene hydantoin to the base is 1:1.9-3.

[0020] Preferably, the molar ratio of 5-isopropylidene hydantoin to calcium salt is 1:0.4-0.5.

[0021] Preferably, in step (1), the base is selected from any one of sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide.

[0022] Further preferably, in step (1), the base is sodium hydroxide.

[0023] More preferably, in step (1), the mass concentration of sodium hydroxide is 170-180 g / L.

[0024] Preferably, in step (1), the temperature of the hydrolysis reaction is 90-98°C.

[0025] Preferably, in step (1), the hydrolysis reaction time is 7-10 hours.

[0026] Preferably, step (1) further comprises a cooling step after the hydrolysis reaction.

[0027] Further preferably, the specific process of step (1) is as follows: 5-isopropyl 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-ketovaline salt.

[0028] Preferably, in step (2), the acid is selected from any one of hydrochloric acid, nitric acid and sulfuric acid.

[0029] More preferably, in step (2), the acid is hydrochloric acid.

[0030] Preferably, in step (2), the pH is adjusted to 0.5-2.0.

[0031] Preferably, in step (2), the distillation temperature is 40-50°C; the distillation vacuum degree is -0.08 to -0.1 MPa.

[0032] Preferably, in step (3), the calcium salt is selected from any one of calcium chloride, calcium acetate and calcium hydroxide.

[0033] Preferably, in step (3), the calcium salt is a calcium salt aqueous solution or a calcium salt suspension.

[0034] 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.

[0035] The beneficial effects of the present invention are:

[0036] The invention discloses a green synthesis method of α-ketovaline calcium and an intermediate thereof. The green synthesis method does not use an organic solvent and adopts a distillation method after acid adjustment to remove impurities in an alkaline solution of α-ketovaline salt, thereby effectively improving the purity of α-ketovaline calcium. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is the HPLC spectrum of calcium α-ketovaline prepared in Example 1 of the present invention.

[0038] Figure 2 This is the HPLC spectrum of calcium α-ketovaline prepared in Example 2 of the present invention.

[0039] Figure 3 This is the HPLC spectrum of calcium α-ketovaline prepared in Example 3 of the present invention.

[0040] Figure 4 This is the HPLC spectrum of calcium α-ketovaline prepared in Example 4 of the present invention.

[0041] Figure 5 This is the HPLC spectrum of calcium α-ketovaline prepared in Example 5 of the present invention.

[0042] Figure 6 This is the HPLC spectrum of calcium α-ketovaline prepared in Example 6 of the present invention. DETAILED DESCRIPTION

[0043] 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.

[0044] 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.

[0045] Example 1

[0046] (1) Preparation of α-ketovaline

[0047] Add NaOH (17.12 g, 0.428 mol) to purified water (100 mL), heat to 95°C, add 5-isopropylidene hydantoin (20.04 g, 0.143 mol) at one time, and react at 95°C for 10 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 α-ketovaline aqueous solution.

[0048] (2) Preparation of calcium α-ketovaline

[0049] To the above α-ketovaline aqueous solution, add calcium chloride aqueous solution [calcium chloride (7.91 g, 0.071 mol) dissolved in purified water (50 mL)], stir at 20-30° C. for 1 h after the addition is complete, 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-ketovaline calcium (10.59 g) with a purity of 99.95% and a total yield of 90.2%.

[0050] Example 2

[0051] (1) Preparation of α-ketovaline

[0052] Add NaOH (17.12 g, 0.428 mol) to purified water (100 mL), heat to 90 ° C, add 5-isopropylidene hydantoin (20.04 g, 0.143 mol) at one time, and then react at 100 ° C for 8 hours. After the reaction is completed, cool to 20-30 ° C, add concentrated hydrochloric acid to adjust the pH value 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 α-ketovaline aqueous solution.

[0053] (2) Preparation of calcium α-ketovaline

[0054] To the above α-ketovaline aqueous solution, add calcium chloride aqueous solution [calcium chloride (7.91 g, 0.071 mol) dissolved in purified water (50 mL)], stir at 20-30° C. for 1 h after the addition is complete, 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-ketovaline calcium (10.20 g) with a purity of 99.93% and a total yield of 93.1%.

[0055] Example 3

[0056] (1) Preparation of α-ketovaline

[0057] Add NaOH (17.12 g, 0.428 mol) to purified water (100 mL), heat to 97 ° C, add 5-isopropylidene hydantoin (20.04 g, 0.143 mol) at one time, and then react at 97 ° C for 9 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 α-ketovaline aqueous solution.

[0058] (2) Preparation of calcium α-ketovaline

[0059] To the above α-ketovaline aqueous solution, add calcium acetate aqueous solution [calcium acetate (12.57 g, 0.071 mol) dissolved in purified water (50 mL)], stir at 20-30° C. for 1 h after the addition is complete, 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-ketovaline calcium (10.88 g) with a purity of 99.89% and a total yield of 92.2%.

[0060] Example 4

[0061] (1) Preparation of α-ketovaline

[0062] Add NaOH (17.12 g, 0.428 mol) to purified water (100 mL), heat to 98 ° C, add 5-isopropylidene hydantoin (20.04 g, 0.143 mol) at one time, and then react at 98 ° C for 7 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 α-ketovaline aqueous solution.

[0063] (2) Preparation of calcium α-ketovaline

[0064] To the above α-ketovaline aqueous solution, add calcium acetate aqueous solution [calcium acetate (12.57 g, 0.071 mol) dissolved in purified water (50 mL)], 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, filter and dry to obtain α-ketovaline calcium (10.40 g) with a purity of 99.97% and a total yield of 91.8%.

[0065] Example 5

[0066] (1) Preparation of α-ketovaline

[0067] Add NaOH (17.12 g, 0.428 mol) to purified water (100 mL), heat to 96 ° C, add 5-isopropylidene hydantoin (20.04 g, 0.143 mol) at one time, and then react at 96 ° C for 9.5 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 α-ketovaline aqueous solution.

[0068] (2) Preparation of calcium α-ketovaline

[0069] To the above α-ketovaline aqueous solution, add calcium hydroxide aqueous solution [calcium hydroxide (5.28 g, 0.071 mol) dissolved in purified water (50 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-ketovaline calcium (10.40 g) with a purity of 99.96% and a total yield of 92.5%.

[0070] Example 6

[0071] (1) Preparation of α-ketovaline

[0072] Add NaOH (17.12 g, 0.428 mol) to purified water (100 mL), heat to 98 ° C, add 5-isopropylidene hydantoin (20.04 g, 0.143 mol) at one time, and then react at 98 ° C for 7 hours. After the reaction is completed, cool to 20-30 ° C, add concentrated hydrochloric acid to adjust the pH value 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 α-ketovaline aqueous solution.

[0073] (2) Preparation of calcium α-ketovaline

[0074] To the above α-ketovaline aqueous solution, add calcium hydroxide aqueous solution [calcium hydroxide (5.28 g, 0.071 mol) dissolved in purified water (50 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-ketovaline calcium (10.20 g) with a purity of 99.93% and a total yield of 92.4%.

[0075] 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-ketovaline and its intermediates, characterized in that: The following steps are involved: (1) mixing 5-isopropylidene hydantoin, a base and water for hydrolysis reaction to obtain an alkaline solution of α-ketovaline salt; (2) mixing the alkaline solution of α-ketovaline salt with an acid to adjust the pH, and then distilling to obtain an α-ketovaline aqueous solution; (3) reacting an α-ketovaline aqueous solution with a calcium salt to obtain α-ketovaline calcium.

2. The green synthesis method according to claim 1, characterized in that: The molar ratio of the 5-isopropylidene hydantoin to the base is 1:1.9-3.

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

5.

4. 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.

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

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

7. The green synthesis method according to claim 1, characterized in that: In step (1), the temperature of the hydrolysis reaction is 90-98°C.

8. The green synthesis method according to claim 1, characterized in that: In step (1), the hydrolysis reaction time is 7-10 hours.

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

10. The green synthesis method according to claim 9, characterized in that: The specific process of step (1) is as follows: 5-isopropyl 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-ketovaline salt.

11. 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.

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

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

0.

14. 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.

15. 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.

16. 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.

17. The green synthesis method according to claim 16, 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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