A method for synthesizing α-ketovaline calcium
By employing a mixed alkaline condensation reaction of diethyl oxalate with potassium carbonate and lithium hydroxide in the synthesis of α-ketovaline calcium, combined with hydrogen peroxide oxidation-reduction of formic acid and ethyl acetate extraction, the problems of isobutyraldehyde condensation and formic acid impurities were solved, achieving high-yield and high-purity production of α-ketovaline calcium, which has environmental and economic advantages.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JINAN LIDE PHARM TECH CO LTD
- Filing Date
- 2026-02-27
- Publication Date
- 2026-06-02
AI Technical Summary
In the existing α-ketovaline calcium synthesis route, isobutyraldehyde undergoes frequent self-condensation side reactions, resulting in low yield; formic acid impurities are difficult to completely remove during basic degradation, affecting product purity and economic efficiency.
The condensation reaction of diethyl oxalate with potassium carbonate and lithium hydroxide under mixed alkaline conditions was used to inhibit the condensation of isobutyraldehyde; hydrogen peroxide was used to oxidize and reduce formic acid, combined with ethyl acetate extraction and activated carbon filtration, to achieve the production of high-purity α-ketovaline calcium.
It improves the yield and purity of α-ketovaline calcium, reduces production costs and energy consumption, and reduces emissions of waste, making it suitable for large-scale commercial production.
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Figure CN122127220A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the fields of chemical material synthesis and biomedicine, and specifically relates to a method for synthesizing α-ketovaline calcium. Background Technology
[0002] α-ketovaline calcium is a key component of the drug chemotherapeutic agent, and its synthesis mainly follows two industrial routes, both of which have technical bottlenecks. This invention effectively solves the core problem of the second route through an innovative process, which is summarized below:
[0003] The first synthetic route (shown below) uses glycine and sodium hydroxide as catalysts to induce a condensation and dehydration reaction between hydantoin and acetone in water, generating calcium ketovaline intermediate I. This intermediate is then hydrolyzed and ring-opened in an aqueous potassium hydroxide solution, acidified with hydrochloric acid to give α-ketovaline, and finally neutralized with calcium hydroxide to form a salt. However, this route requires a large amount of hydantoin as a starting material, resulting in high costs and low economic value for commercial production.
[0004]
[0005] The second synthetic route (reported in CN 102675087 A, as shown below) uses diethyl oxalate and isobutyraldehyde as raw materials, undergoing a condensation reaction under sodium methoxide conditions. Subsequent basic degradation yields α-ketovaline, which is then neutralized with calcium hydroxide to form a salt. Diethyl oxalate is economical, making this route more industrially viable, but two major technical drawbacks remain unresolved:
[0006] 1. Isobutyraldehyde self-condensation problem: Isobutyraldehyde is prone to self-condensation side reaction under alkaline conditions, which reduces the yield of the target product;
[0007] 2. Formic acid impurity issue: A large amount of formic acid byproducts are generated during basic degradation. Direct neutralization with calcium hydroxide results in a high proportion of calcium formate impurities in the final calcium salt product. While traditional distillation methods can attempt to separate these impurities, they suffer from low yields, high losses, and incomplete formic acid removal. Summary of the Invention
[0008] To address the aforementioned technical problems, this invention proposes a method for synthesizing α-ketovaline calcium. This method precisely solves the core issues of traditional routes through chemical means, achieving industrial-scale production of high-purity products while ensuring high yields. It possesses significant economic and technological advantages and is particularly suitable for large-scale commercial production.
[0009] The specific technical solution is as follows:
[0010] Diethyl oxalate and isobutyraldehyde condense under mixed alkaline conditions of potassium carbonate and lithium hydroxide, which greatly inhibits the self-condensation of isobutyraldehyde. Subsequent alkaline degradation produces a large amount of formic acid. Then, 30% hydrogen peroxide is added, utilizing its oxidizing properties to reduce the formic acid produced in the reaction, generating carbon dioxide and water. The reaction solution, after removing the formic acid byproduct, is extracted with ethyl acetate and concentrated to α-ketovaline. α-ketovaline is then neutralized with calcium hydroxide in water to form a salt that precipitates out.
[0011] Includes the following steps:
[0012] A method for synthesizing α-ketovaline calcium includes the following steps:
[0013] (1) Condensation reaction: Add purified water, potassium carbonate and lithium hydroxide to diethyl oxalate, stir, heat to 55-60℃, add isobutyraldehyde dropwise, keep warm and stir for 1h.
[0014] The molar ratio of diethyl oxalate: purified water: potassium carbonate: lithium hydroxide: isobutyraldehyde is (0.8-1.2) mol: 500g: 0.5 mol: 0.5 mol: 1.24 mol.
[0015] (2) Basic degradation and formic acid oxidation: After the reaction is completed, the temperature is lowered to 10-20℃, NaOH solution is added within 15 minutes, the temperature is raised to 25℃, the reaction is stirred for 1.5h, and hydrogen peroxide with a volume concentration of 30% is slowly added dropwise while keeping the temperature. After the reaction is completed, the reaction is stirred for 1h. The molar ratio of NaOH: diethyl oxalate: hydrogen peroxide is 1.2: (0.8-1.2): 1.0.
[0016] Adjust the pH to 1.0-2.0, extract, dry the organic phase with anhydrous Na2SO4, concentrate under reduced pressure to obtain α-ketovaline;
[0017] (3) Neutralization and salt formation: Add Ca(OH)2 and purified water to the α-ketovaline obtained in (2), stir and heat to 95-100℃, reflux for 30 minutes, add activated carbon, continue reflux for 30 minutes, filter while hot, and wait for the filtrate to cool to room temperature, stir and crystallize for 2.0-3.0 hours to obtain calcium α-ketovaline.
[0018] As a further preferred embodiment, in (1), the molar mass ratio of diethyl oxalate: purified water: potassium carbonate: lithium hydroxide: isobutyraldehyde is 1.0 mol: 500 g: 0.5 mol: 0.5 mol: 1.24 mol.
[0019] Preferably, in (2), the molar ratio of NaOH: diethyl oxalate: hydrogen peroxide is 1.2:1.0:1.0.
[0020] Preferably, in (2), the mass fraction of the NaOH solution is 5%.
[0021] Preferably, in (2), the pH is adjusted to 1.0-2.0 using concentrated HCl solution.
[0022] Preferably, in (2), the molar ratio of NaOH to hydrogen peroxide is 1.2:1.0.
[0023] Preferably, in (2), ethyl acetate is used for extraction, and the volume-to-mass ratio of ethyl acetate to purified water is 1 mL: 1 g.
[0024] Preferably, in (3), the molar mass ratio of diethyl oxalate: Ca(OH)2: purified water: activated carbon is 1.0 mol: 0.425 mol: 500 g: 2.0 g.
[0025] The reaction mechanism involved in the above technical solution is as follows:
[0026] 1: First step of condensation:
[0027]
[0028] 2: Alkaline degradation:
[0029]
[0030] 3: Formic acid reduced by hydrogen peroxide:
[0031]
[0032] The present invention has the following advantages and effects compared with the prior art:
[0033] (1) The present invention uses environmentally friendly diethyl oxalate as raw material, which significantly reduces the cost compared to the traditional hydantoin route; by replacing the energy-intensive distillation and purification steps with chemical means, the total process energy consumption and waste emissions are also reduced simultaneously, thus combining the advantages of economy and environmental protection.
[0034] (2) In the first step of the condensation reaction, the present invention utilizes a mixed base system to precisely control the pKa value in the reaction, thereby maximally suppressing the side reaction of isobutyraldehyde self-condensation.
[0035] (3) The present invention utilizes the reducing properties of formic acid, a byproduct generated in the second step of alkaline degradation, and removes the byproduct by chemical reaction by adding an oxidant with strictly controlled equivalent (1.0 equivalent). Compared with the traditional method of physical distillation, this method of removing byproducts has less process loss and removes byproducts more thoroughly. Attached Figure Description
[0036] Figure 1This is the overall reaction route diagram of the synthesis method in Example 1 of the present invention;
[0037] Figure 2 This is a reaction route diagram for step (1) of the synthesis method in Example 1 of the present invention;
[0038] Figure 3 This is a reaction route diagram for step (2) of the synthesis method in Example 1 of the present invention. Detailed Implementation
[0039] To enable those skilled in the art to better understand the present invention, the present invention will now be further described in conjunction with specific embodiments.
[0040] Example 1:
[0041] A method for synthesizing α-ketovaline calcium, the reaction route is as follows: Figures 1-3 As shown, the specific steps include the following:
[0042] (1) Condensation reaction: Diethyl oxalate (146.0 g, 1.0 mol) was added to a 3000 mL reaction flask, along with 500 g of purified water, 69.0 g of potassium carbonate (0.5 mol), and 21.0 g of lithium hydroxide (0.5 mol). The mixture was stirred and heated to 57 °C. The reaction temperature was maintained at 57 °C. Isobutyraldehyde (89.0 g, 1.24 mol) was slowly added dropwise. After the addition was completed, the mixture was stirred for 1 hour.
[0043] (2) Basic degradation and formic acid oxidation: After the reaction was completed, the temperature was lowered to 15°C. 5.0% NaOH solution (960.0g, 1.2mol) was added to the reaction flask within 15 minutes. After the addition was complete, the temperature was raised to 25°C and stirred for 1.5 hours. After the reaction was completed, the temperature was maintained at 22°C, and 30% hydrogen peroxide (125g, 1.1mol) was slowly added dropwise. After the addition was completed, the reaction was stirred for 1.0 hour. After the reaction was completed, the pH was adjusted to 1.0 with concentrated HCl solution, and 500.0mL of ethyl acetate was added for extraction. The organic phase was dried with anhydrous Na2SO4, and the ethyl acetate was concentrated under reduced pressure to obtain 98.7g of α-ketovaline (light red oily substance), with a yield of 85.0%.
[0044] (3) Neutralization and purification: The α-ketovaline (98.7 g, 0.85 mol) obtained in (2) was added to a 1000 mL reaction flask, along with Ca(OH)2 (31.45 g, 0.425 mol) and 500 g of purified water. The mixture was stirred, heated to 98 °C, refluxed for 30 minutes, slightly cooled, and 2.0 g of activated carbon was added. The mixture was then refluxed for another 30 minutes. The mixture was filtered while hot to remove the activated carbon. The filtrate was cooled to room temperature and stirred for 2.5 hours to allow crystallization. A large amount of white solid precipitated out. The solid was filtered, and the filter cake was dried to obtain 89.6 g of α-ketovaline calcium. The yield was 78.1%, and the purity was 99.88%.
[0045] Example 2:
[0046] A method for synthesizing α-ketovaline calcium, the reaction route is as follows: Figures 1-3 As shown, the specific steps include the following:
[0047] (1) Condensation reaction: Diethyl oxalate (146.0 g, 1.0 mol) was added to a 3000 mL reaction flask, along with 500 g of purified water, 69.0 g of potassium carbonate (0.5 mol), and 21.0 g of lithium hydroxide (0.5 mol). The mixture was stirred and heated to 55 °C. The reaction temperature was maintained at 55 °C. Isobutyraldehyde (89.0 g, 1.24 mol) was slowly added dropwise. After the addition was completed, the mixture was stirred for 1 hour.
[0048] (2) Basic degradation and formic acid oxidation: After the reaction is completed, the temperature is lowered to 10°C. 5.0% NaOH solution (960.0g, 1.2mol) is added to the reaction flask within 15 minutes. After the addition is completed, the temperature is raised to 25°C and stirred for 1.5 hours. After the reaction is completed, the temperature is maintained at 20°C, and 30% hydrogen peroxide (125g, 1.1mol) is slowly added dropwise. After the addition is completed, the reaction is stirred for 1.0 hours. After the reaction is completed, the pH is adjusted to 1.0 with concentrated HCl solution, and 500.0mL of ethyl acetate is added for extraction. The organic phase is dried with anhydrous Na2SO4 and the ethyl acetate is concentrated under reduced pressure to obtain α-ketovaline.
[0049] (3) Neutralization and purification: Add the α-ketovaline obtained in (2) to a 1000mL reaction flask, add Ca(OH)2 (31.45g, 0.425mol), 500g of purified water, stir, heat to 95℃, reflux for 30 minutes, cool slightly, add 2.0g of activated carbon, continue to reflux for 30 minutes, filter while hot, remove activated carbon, cool the filtrate to room temperature, stir to crystallize for 2.0 hours, a large amount of white solid precipitates, filter, dry the filter cake to obtain α-ketovaline calcium.
[0050] Example 3:
[0051] A method for synthesizing α-ketovaline calcium, the reaction route is as follows: Figures 1-3 As shown, the specific steps include the following:
[0052] (1) Condensation reaction: Diethyl oxalate (146.0 g, 1.0 mol) was added to a 3000 mL reaction flask, along with 500 g of purified water, 69.0 g of potassium carbonate (0.5 mol), and 21.0 g of lithium hydroxide (0.5 mol). The mixture was stirred and heated to 60 °C. The reaction temperature was maintained at 60 °C. Isobutyraldehyde (89.0 g, 1.24 mol) was slowly added dropwise. After the addition was completed, the mixture was stirred for 1 hour.
[0053] (2) Basic degradation and formic acid oxidation: After the reaction is completed, the temperature is lowered to 20°C. 5.0% NaOH solution (960.0g, 1.2mol) is added to the reaction flask within 15 minutes. After the addition is completed, the temperature is raised to 25°C and stirred for 1.5 hours. After the reaction is completed, the temperature is maintained at 25°C, and 30% hydrogen peroxide (125g, 1.1mol) is slowly added dropwise. After the addition is completed, the reaction is stirred for 1.0 hour. After the reaction is completed, the pH is adjusted to 2.0 with concentrated HCl solution, and 500.0mL of ethyl acetate is added for extraction. The organic phase is dried with anhydrous Na2SO4 and the ethyl acetate is concentrated under reduced pressure to obtain α-ketovaline.
[0054] (3) Neutralization and purification: Add the α-ketovaline obtained in (2) to a 1000mL reaction flask, add Ca(OH)2 (31.45g, 0.425mol), 500g of purified water, stir, heat to 100℃, reflux for 30 minutes, cool slightly, add 2.0g of activated carbon, continue to reflux for 30 minutes, filter while hot, remove activated carbon, cool the filtrate to room temperature, stir to crystallize for 3.0 hours, a large amount of white solid precipitates, filter, dry the filter cake to obtain α-ketovaline calcium.
[0055] Comparative Examples 1-2
[0056] The difference between Comparative Examples 1 and 2 and Example 1 is that the amount of hydrogen peroxide was changed, and the yields of α-ketovaline and α-ketovaline calcium were recorded. The results are shown in Table 1 below.
[0057] Table 1. Effect of hydrogen peroxide dosage on the yield of α-ketovaline and α-ketovaline calcium Hydrogen peroxide dosage (molar ratio) α-Ketovaline yield (%) α-Ketovaline calcium yield (%) α-Ketovaline calcium purity (%) Example 1 Diethyl oxalate: hydrogen peroxide = 1:1 85.0% 78.1% 99.88% Comparative Example 1 Diethyl oxalate: hydrogen peroxide = 1:0.5 89.4% 82.3% 97.58% Comparative Example 2 Diethyl oxalate: hydrogen peroxide = 1:2 78.1% 69.4% 99.78%
[0058] In summary, the synthesis method provided by this invention uses environmentally friendly and low-cost diethyl oxalate as raw material. It precisely controls the pKa of the mixed alkali system to suppress the self-condensation side reaction of isobutyraldehyde, and uses the reducing property of formic acid and the chemical reaction with a 1:1 equivalent oxidant to replace the traditional distillation for impurity removal. This achieves reduced process energy consumption, reduced emissions of waste gas, wastewater, and solid waste, and complete removal of by-products, thus possessing both economic and environmental advantages.
[0059] The above are merely preferred embodiments of the present invention and do not limit the scope of the patent. All equivalent changes and modifications made within the scope of the present invention should still fall within the scope of the present invention.
Claims
1. A method for synthesizing α-ketovaline calcium, comprising the following steps: (1) Condensation reaction: Add purified water, potassium carbonate and lithium hydroxide to diethyl oxalate, stir, heat to 55-60℃, add isobutyraldehyde dropwise, keep warm and stir for 1h. The molar ratio of diethyl oxalate: purified water: potassium carbonate: lithium hydroxide: isobutyraldehyde is (0.8-1.2) mol: 500g: 0.5 mol: 0.5 mol: 1.24 mol. (2) Basic degradation and formic acid oxidation: After the reaction is complete, the temperature is lowered to 10-20℃, and NaOH solution is added within 15 minutes. The temperature is then raised to 25℃, and the reaction is stirred for 1.5 hours. Hydrogen peroxide with a volume concentration of 30% is slowly added dropwise while maintaining the temperature. After the reaction is complete, the reaction is stirred for 1 hour. The molar ratio of NaOH: diethyl oxalate: hydrogen peroxide is 1.2:(0.8-1.2):1.0; Adjust the pH to 1.0-2.0, extract, dry the organic phase with anhydrous Na2SO4, concentrate under reduced pressure to obtain α-ketovaline; (3) Neutralization and salt formation: Add Ca(OH)2 and purified water to the α-ketovaline obtained in (2), stir and heat to 95-100℃, reflux for 30 minutes, add activated carbon, continue reflux for 30 minutes, filter while hot, wait for the filtrate to cool to room temperature, stir to precipitate crystals for 2.0-3.0 hours, filter the solid and dry to obtain calcium α-ketovaline.
2. The method for synthesizing α-ketovaline calcium as described in claim 1, characterized in that, In (1), the molar mass ratio of diethyl oxalate: purified water: potassium carbonate: lithium hydroxide: isobutyraldehyde is 1.0 mol: 500 g: 0.5 mol: 0.5 mol: 1.24 mol.
3. The method for synthesizing α-ketovaline calcium as described in claim 1, characterized in that, In (2), the molar ratio of NaOH: diethyl oxalate: hydrogen peroxide is 1.2:1.0:1.
0.
4. The method for synthesizing α-ketovaline calcium as described in claim 1, characterized in that, In (2), the mass fraction of the NaOH solution is 5%.
5. The method for synthesizing α-ketovaline calcium as described in claim 1, characterized in that, (2) In this step, the pH is adjusted to 1.0-2.0 using concentrated HCl solution.
6. The method for synthesizing α-ketovaline calcium as described in claim 1, characterized in that, In (2), ethyl acetate was used for extraction, and the volume-to-mass ratio of ethyl acetate to purified water was 1 mL: 1 g.
7. The method for synthesizing α-ketovaline calcium as described in claim 1, characterized in that, In (3), the molar mass ratio of diethyl oxalate: Ca(OH)2: purified water: activated carbon is (0.8-1.2) mol: 0.425 mol: 500 g: 2.0 g.