A catalyst for claisen ester condensation and its preparation method and application

Abstract

The application belongs to the field of fine chemicals and medicinal chemistry, and particularly relates to a catalyst for Claisen ester condensation and a preparation method and application thereof. The application improves the preparation method of alpha-ketoglutarate calcium, adopts cheaper and more easily obtained raw materials, and innovatively invents a guanidino-amino co-functional KIT-6 mesoporous silica (Gua-NH2@KIT-6) to catalyze the Claisen ester condensation reaction. The catalyst carrier obtained by the application has a large pore size (4-12 nm), a high specific surface area (>600 m 2 / g), a surface rich in silicon hydroxyl groups (-SiOH), is convenient for grafting organic bases, has good thermal / chemical stability, is simple to handle, is safe to operate, reduces water consumption, is completely free of metal residues, is not dissolved, can be separated by filtration, can be reused after simple washing, has a wide substrate application range, and is suitable for industrialization.

Description

Technical Field

[0001] This invention belongs to the fields of fine chemicals and medicinal chemistry, specifically relating to a catalyst for the condensation of Claisen esters, its preparation method, and its application. Background Technology

[0002] Calcium alpha-ketoglutarate (Ca-AKG) is the calcium salt form of the endogenous substance alpha-ketoglutarate (AKG). AKG is a key intermediate in the tricarboxylic acid cycle (TCA cycle) and plays an important role in energy metabolism, amino acid synthesis, nitrogen transport, and antioxidation. Calcium is an essential mineral for the human body, playing a vital role in the formation of bones and teeth, regulating cell signaling, maintaining muscle function, and regulating nerve excitability.

[0003] Calcium α-ketoglutarate (Ca-AKG), as a stable salt form of AKG, has better water solubility, stability, and bioavailability. Ca-AKG possesses antioxidant and anti-aging properties, nitrogen transport and ammonia detoxification, collagen synthesis and tissue repair, immune regulation, improved athletic performance and muscle protection, and acts as a NAD+ agonist. + An indirect supporter of metabolism. It has broad prospects in the fields of medicine, nutrition and health products, and cosmetic raw materials.

[0004] Most of the reported processes use α-ketoglutaric acid as a raw material, which first reacts with an alkali to produce a sodium salt, and then reacts with calcium chloride to produce calcium α-ketoglutarate.

[0005] Patent publication CN112955139A discloses a method for preparing calcium α-ketoglutarate. This method uses α-ketoglutaric acid as a raw material, first dissolving it in water, then adding sodium carbonate or sodium hydroxide and reacting for a period of time, followed by the addition of calcium chloride and heating. Finally, filtration yields calcium α-ketoglutarate. Furthermore, patent publication CN102976927A discloses another method for preparing calcium α-ketoglutarate. This method uses methyl dichloroacetate and methyl acrylate as raw materials, reacting them in the presence of sodium methoxide to generate the intermediate dimethyl 2,2-dichloroglutarate. Subsequently, sodium hydroxide solution is added to the intermediate and heated for hydrolysis to generate sodium α-ketoglutarate. Calcium chloride is then added and reacted for a period of time to obtain calcium α-ketoglutarate. Patent document CN117865790A discloses a method for preparing α-ketoglutaric acid. This patent first prepares potassium ethoxide using potassium hydroxide and anhydrous ethanol, then uses potassium ethoxide to catalyze the Claisen ester condensation of diethyl succinate and diethyl oxalate, followed by acidification and hydrolysis to obtain α-ketoglutaric acid. Patent document CN112941116A discloses an enzymatic method for preparing calcium α-ketoglutarate. This patent uses L-glutamic acid as a raw material, oxidizing it in the presence of L-glutamic acid oxidase and catalase to obtain α-ketoglutarate, which is then reacted with calcium chloride to prepare calcium α-ketoglutarate.

[0006] Most of the methods reported above use α-ketoglutaric acid as a raw material, but α-ketoglutaric acid is expensive, making these methods unsuitable for large-scale production. While methods using methyl dichloroacetate and methyl acrylate as raw materials exist, methyl dichloroacetate remains expensive, and its market supply is limited, making large-scale procurement difficult. Furthermore, most of these methods use calcium chloride as a calcium source, which introduces chloride ions, potentially leading to excessive chloride ion content in subsequent products. Existing methods for synthesizing α-ketoglutaric acid mainly rely on the Claisen ester condensation of diethyl succinate and diethyl oxalate catalyzed by sodium ethoxide or potassium ethoxide. While traditional catalysts like sodium ethoxide and potassium ethoxide can catalyze the reaction, they suffer from drawbacks such as high activity, susceptibility to side reactions, poor selectivity, susceptibility to autocondensation, high solvent requirements (must use anhydrous solvents), complex post-processing (requiring acid neutralization), non-recoverable catalysts, metal residues, violent reactions with water, flammability, and a narrow substrate range. Although enzymatic methods for preparing α-ketoglutaric acid do not have these problems, enzymes are expensive, have poor stability, are highly sensitive to temperature and pH, have a low upper limit on product concentration, and high concentrations of α-ketoglutaric acid can inhibit enzyme activity. Furthermore, the process is complex, requires multiple enzymes working together, downstream separation is difficult, and large-scale scale-up is challenging. Therefore, a novel catalyst is urgently needed to address these issues. Summary of the Invention

[0007] To overcome the technical shortcomings of existing processes for preparing calcium α-ketoglutarate, we provide a catalyst for the condensation of Claisen esters, its preparation method, and its application. This invention improves the preparation method of calcium α-ketoglutarate by using cheaper and more readily available raw materials. It innovatively develops a guanidinyl-amino cofunctionalized KIT-6 mesoporous silica (Gua-NH2@KIT-6) to catalyze the condensation reaction of Claisen esters. This catalyst uses KIT-6 mesoporous silica as a support, which has a large pore size (4-12 nm) and a high specific surface area (>600 m²). 2 / g), with a surface rich in silanol groups (-SiOH), facilitating the grafting of organic bases, exhibiting good thermal / chemical stability (resistant to ≤400℃, pH 1-9); the basic sites utilize bifunctional synergistic bases, with the primary amine (-NH2) derived from (3-aminopropyl)triethoxysilane (APTES), providing moderate alkalinity (pK). a ≈10.6), promotes enolization, hydrophilic diffusion aid; guanidino (-NHC(NH2)2 + Derived from guanidinopropyltriethoxysilane, it is extremely basic (conjugate acid pK). a (≈13.6), rapid and complete deprotonation of α-H. In the selection of calcium source, the use of chlorine-containing reagents was avoided, effectively reducing the chloride ion content.

[0008] The technical solution of the present invention is as follows:

[0009] A method for preparing a catalyst for Claisen ester condensation comprises the following steps: (1) Vacuum activation of mesoporous silica KIT-6, followed by dispersion in anhydrous toluene, yields solution A; (2) APTES and guanidinopropyltriethoxysilane were added to solution A, and the mixture was refluxed for 24 h under nitrogen protection. After filtration, the mixture was washed with toluene and ethanol and dried under vacuum at 80 °C for 5 h to obtain the catalyst for Claisen ester condensation, namely guanidino-amino cofunctional KIT-6 mesoporous silica (Gua-NH2@KIT-6).

[0010] Preferably, in step (1), the vacuum activation temperature of KIT-6 is 150℃ and the vacuum activation time is 6h.

[0011] Preferably, the ratio of KIT-6 to anhydrous toluene in step (1) is 1:20, g / mL.

[0012] Preferably, in step (2), 0.6-0.8 mmol of APTES and 0.3-0.4 mmol of guanidopropyltriethoxysilane are added to every 1g of KIT-6.

[0013] Preferably, the reflux temperature in step (2) is 80°C.

[0014] The present invention also provides the application of the above-mentioned guanidino-amino cofunctional KIT-6 mesoporous silica (Gua-NH2@KIT-6) catalyst in the preparation of calcium α-ketoglutarate.

[0015] A method for preparing calcium α-ketoglutarate includes the following steps: (1) The Gua-NH2@KIT-6 catalyst and methyl tert-butyl ether were mixed, and diethyl succinate and diethyl oxalate were added successively under stirring. The reaction was carried out at room temperature. After the reaction was completed, the catalyst was recovered by filtration, and the methyl tert-butyl ether was rotary evaporated to obtain the intermediate triethyl oxaloyl succinate.

[0016] (2) Add hydrochloric acid and water to the intermediate triethyl oxaloyl succinate and perform high-temperature hydrolysis and reflux. After hydrolysis, an aqueous solution of α-ketoglutaric acid can be obtained. Remove excess water by rotary evaporation and vacuum concentration to obtain high-purity α-ketoglutaric acid solid.

[0017] (3) Dissolve the solid α-ketoglutaric acid obtained in (2) in water, add activated carbon to decolorize, filter to remove the waste activated carbon, add anhydrous calcium acetate or calcium bicarbonate to the aqueous solution of α-ketoglutaric acid in batches, stir at room temperature for 2-3 hours; then heat at 65-75℃ for 3-4 hours; after the reaction is completed, crystallize at 0-5℃ for 4-5 hours; filter and wash, dry at 60-65℃ for 6-8 hours to obtain calcium α-ketoglutaric acid.

[0018] Preferably, in step (1), the mass-to-volume ratio of Gua-NH2@KIT-6 catalyst to methyl tert-butyl ether is 1:12, g / mL.

[0019] Preferably, in step (1), the molar ratio of diethyl succinate and diethyl oxalate used for the condensation of Claisen ester is 1:1.1, and the mass molar ratio of Gua-NH2@KIT-6 catalyst to diethyl succinate is 50:1, mg / mmol.

[0020] Preferably, in step (2), the amount of hydrochloric acid added during hydrolysis is 3.3 equiv, the amount of water added is twice the volume of hydrochloric acid, the reflux temperature during hydrolysis is 70℃-100℃, and the reflux time is 2-4h; more preferably, reflux at 100℃ for 3h.

[0021] Preferably, in step (3), the molar volume ratio of α-ketoglutaric acid solid to water is 1:120-150, mol / mL; when adding activated carbon for decolorization, the mass ratio of activated carbon to α-ketoglutaric acid is 1:5, and the molar ratio of α-ketoglutaric acid to anhydrous calcium acetate or calcium bicarbonate is 1:0.8-1.2, more preferably 1:0.9.

[0022] The reaction process is shown in Equation I:

[0023] Catalytic mechanism of Gua-NH2@KIT-6: The methylene group of diethyl succinate is weakly acidic and can be deprotonated by a strong base. However, in a homogeneous system, the deprotonation rate is slow and self-condensation easily occurs. Gua-NH2@KIT-6 can effectively solve the self-condensation problem through surface-confined deprotonation. The primary amino group (-NH2) interacts with one of the ester carbonyl groups through hydrogen bonds, "anchoring" diethyl succinate to the surface of the KIT-6 pores. The adjacent guanidino group (pK) a (≈13.6) As a superbase, it abstracts α-H to form surface-adsorbed enol anions; diethyl oxalate diffuses from the solution into the three-dimensional interpenetrating mesopores of KIT-6, where the adsorbed enol anions nucleophilically add to a highly electron-deficient carbonyl carbon of diethyl oxalate to form a tetrahedral intermediate. The tetrahedral intermediate rearranges, eliminating EtO- to form the final product triethyl oxaloylsuccinate. EtO- combines with the protonated guanidinium group on the surface, releasing EtOH, restoring the basicity of the guanidinium group, and the primary amino group also releases the product, regenerating the active site; the product desorbs from the KT-6 surface and rapidly diffuses into the bulk solution through the 3D interconnected channels, freeing up the catalyst surface to welcome the next round of substrates.

[0024] The beneficial effects of this invention are as follows: (1) High reaction selectivity, avoiding the occurrence of side reactions; (2) It has low requirements for solvents, is stable to air and moisture, and does not require inert atmosphere protection; (3) The post-treatment is simple, no acidification is required, the operation is safe, the water consumption is reduced, and there is no metal residue. The catalyst is insoluble and can be separated by filtration. It can be reused after simple washing. The substrate has a wide range of applications and is suitable for industrialization. Detailed Implementation

[0025] The present invention will be further illustrated below with reference to specific embodiments. These examples are merely illustrative and not intended to limit the scope of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0026] Example 1: A method for preparing a catalyst for Claisen ester condensation 1 g of KIT-6 was activated under vacuum at 150 °C for 6 h, dispersed in 20 mL of anhydrous toluene, and 0.7 mmol of APTES and 0.35 mmol of guanidinopropyltriethoxysilane were added. The mixture was refluxed at 80 °C for 24 h under nitrogen protection. After the reaction was complete, the mixture was filtered, washed successively with toluene and ethanol, and dried under vacuum at 80 °C for 5 h to obtain guanidino-amino cofunctionalized KIT-6 mesoporous silica (Gua-NH2@KIT-6). Recovery of the Gua-NH2@KIT-6 catalyst: After the reaction was complete, the catalyst was filtered out, washed with ethanol, and dried at 100 °C for 6 h. After 9 cycles, the activity remained >90%.

[0027] Example 2: A method for preparing calcium α-ketoglutarate Take a dry 2L round-bottom flask, add 50g of Gua-NH2@KIT-6 obtained in Example 1, then add 600mL of methyl tert-butyl ether. Under stirring at room temperature, add 174.22g of diethyl succinate and 160.78g of diethyl oxalate successively. React at room temperature for 2h. After the reaction is complete, filter to recover the catalyst, and evaporate the methyl tert-butyl ether by rotary evaporation to obtain the intermediate triethyl oxaloyl succinate. Add 330mL of hydrochloric acid and 660mL of water to the intermediate, and reflux at 100℃ for 3h to hydrolyze it. After hydrolysis, remove excess water by rotary evaporation under reduced pressure, and concentrate under vacuum to obtain 132.91g of AKG solid with HPLC purity of 99.2% and yield of 93.1%. 1 mol of AKG solid was dissolved in 150 mL of water. Activated carbon (20% by weight of AKG solid) was added for decolorization. The waste activated carbon was removed by filtration. 128.2 g of anhydrous calcium acetate was added in portions to the AKG aqueous solution. The reaction was carried out at room temperature for 3 h, followed by a reaction at 75 °C for 4 h. After the reaction was complete, the mixture was placed in an environment of 0-5 °C for 4 h to crystallize. The crystals were then filtered, washed, and dried in an oven at 60-65 °C for 6 h to obtain 149.93 g of Ca-AKG with an HPLC purity of 99.8% and a yield of 97.2%.

[0028] Example 3: A method for preparing calcium α-ketoglutarate Take a dry 2L round-bottom flask, add 50g of Gua-NH2@KIT-6 obtained in Example 1 and 600mL of methyl tert-butyl ether, and add 174.22g of diethyl succinate and 160.78g of diethyl oxalate successively under stirring at room temperature. React at room temperature for 2h. After the reaction is complete, filter to recover the catalyst, and rotary evaporate methyl tert-butyl ether to obtain the intermediate triethyl oxaloyl succinate. Add 330mL of hydrochloric acid and 660mL of water to the intermediate, reflux at 100℃ for 3h for hydrolysis. After hydrolysis, remove excess water by rotary evaporation under reduced pressure, and concentrate under vacuum to obtain 130g of AKG solid with HPLC purity of 99.4% and yield of 92.2%. 1 mol of AKG solid was dissolved in 150 mL of water. Activated carbon (20% by weight of AKG solid) was added for decolorization. The waste activated carbon was filtered off. 128.5 g of calcium bicarbonate was added in batches. The mixture was reacted at room temperature for 3 h, then at 75 °C for 4 h. After the reaction was complete, the mixture was placed in an environment of 0-5 °C for 4 h to crystallize. The crystals were then filtered, washed, and dried in an oven at 60-65 °C for 6 h to obtain 146.47 g of Ca-AKG with an HPLC purity of 99.9% and a yield of 96.8%.

[0029] Comparative Example 1: A method for preparing calcium α-ketoglutarate Take a dry 2L round-bottom flask, add 68.05g sodium ethoxide and 600mL anhydrous methyl tert-butyl ether, and add 146.16g diethyl oxalate and 174.22g diethyl succinate successively under stirring at room temperature. React at room temperature for 2h. After the reaction is complete, quench with water and extract the organic phase with water, and separate the aqueous phase. Add 330mL hydrochloric acid to the aqueous phase and acidify for 1h. Extract the aqueous phase with ethyl acetate and rotary evaporate the ethyl acetate to obtain the intermediate triethyl oxaloyl succinate. Add 330mL hydrochloric acid and 660mL water to the intermediate and reflux at 100℃ for 3h to hydrolyze. After hydrolysis, remove excess water by rotary evaporation under reduced pressure and concentrate under vacuum to obtain 124.33g of AKG solid, with a yield of 85.1% and an HPLC purity of 96.3%. 1 mol of AKG solid was dissolved in 150 mL of water. Activated carbon (20% by weight of AKG solid) was added for decolorization. The waste activated carbon was filtered off. 73.51 g of calcium carbonate was added in batches. The reaction was carried out at room temperature for 3 h, then at 75 °C for 4 h. After the reaction was complete, the mixture was placed in an environment of 0-5 °C for 4 h to crystallize. The crystals were filtered, washed, and dried in an oven at 60-65 °C for 6 h to obtain 88.91 g of Ca-AKG with an HPLC purity of 98.2% and a yield of 58.9%.

[0030] Comparative Example 2: A method for preparing calcium α-ketoglutarate Take a dry 2L round-bottom flask, add 68.05g sodium ethoxide and 600mL anhydrous methyl tert-butyl ether, and add 146.16g diethyl oxalate and 174.22g diethyl succinate successively under stirring at room temperature. React at room temperature for 2h. After the reaction is complete, quench with water and extract the organic phase with water, and separate the aqueous phase. Add 330mL hydrochloric acid to the aqueous phase and acidify for 1h. Extract the aqueous phase with ethyl acetate and rotary evaporate the ethyl acetate to obtain the intermediate triethyl oxaloyl succinate. Add 330mL hydrochloric acid and 660mL water to the intermediate and reflux at 100℃ for 3h to hydrolyze. After hydrolysis, remove excess water by rotary evaporation under reduced pressure and concentrate under vacuum to obtain 126.67g AKG solid, with a yield of 86.7% and an HPLC purity of 97.1%. 1 mol of AKG solid was dissolved in 150 mL of water. Activated carbon (20% by weight of AKG solid) was added for decolorization. The waste activated carbon was filtered off. 89.24 g of anhydrous sodium carbonate was added in batches, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, 93.45 g of anhydrous calcium chloride was added, and the mixture was reacted at 65 °C for 4 h. After the reaction was complete, the mixture was placed in an environment of 0-5 °C for 4 h to crystallize. The crystals were filtered, washed, and dried in an oven at 60-65 °C for 6 h to obtain 125.6 g of Ca-AKG with an HPLC purity of 98.1% and a yield of 81%.

[0031] The purity and yield of AKG and the purity and yield of Ca-AKG in each embodiment and comparative example are shown in Table 1: Table 1. Yields and Purities of Examples and Comparative Examples

[0032] Experimental results show that using the catalyst Gua-NH2@KIT-6 invented in this paper to catalyze the condensation of Claisen esters significantly improves both the purity and yield of AKG, with the purity exceeding 99% and the yield exceeding 90% (Examples 2 and 3). Regarding the choice of calcium source, the calcium acetate and calcium bicarbonate used in this invention both resulted in a Ca-AKG purity exceeding 99.5% (Examples 2 and 3), and compared to using calcium carbonate as the calcium source (Comparative Example 1), the yield was significantly improved.

Claims

1. A method for preparing a catalyst for Claisen ester condensation, characterized in that, The specific steps of the preparation method are as follows: (1) Vacuum activation of mesoporous silica KIT-6, followed by dispersion in anhydrous toluene, yields solution A; (2) APTES and guanidinopropyltriethoxysilane were added to solution A, refluxed for 24 h under nitrogen protection, filtered, washed with toluene and ethanol, and dried under vacuum at 80 °C for 5 h to obtain the catalyst Gua-NH2@KIT-6 for Claysen ester condensation.

2. The preparation method according to claim 1, characterized in that, In step (1), the vacuum activation temperature of KIT-6 is 150℃; the vacuum activation time is 6h; and the mass-to-volume ratio of KIT-6 to anhydrous toluene is 1:20, g / mL.

3. The preparation method according to claim 1, characterized in that, In step (2), 0.6-0.8 mmol of APTES and 0.3-0.4 mmol of guanidopropyltriethoxysilane are added to every 1g of KIT-6; the reflux temperature is 80℃ under nitrogen protection.

4. The catalyst Gua-NH2@KIT-6 for Claisen ester condensation obtained by the preparation method according to any one of claims 1-3.

5. The application of the Gua-NH2@KIT-6 catalyst as described in claim 4 in the preparation of calcium α-ketoglutarate.

6. A method for preparing calcium α-ketoglutarate, characterized in that, The preparation method includes the following steps: ① The Gua-NH2@KIT-6 catalyst as described in claim 5 and methyl tert-butyl ether are mixed, and diethyl succinate and diethyl oxalate are added successively under stirring. The reaction is carried out at room temperature. After the reaction is completed, the catalyst is recovered by filtration, and the methyl tert-butyl ether is rotary evaporated to obtain the intermediate triethyl oxaloyl succinate. ② Add hydrochloric acid and water to the intermediate triethyl oxaloyl succinate obtained in step ① and perform high-temperature hydrolysis and reflux. After hydrolysis, an aqueous solution of α-ketoglutaric acid is obtained. Remove excess water by rotary evaporation and concentrate under vacuum to obtain high-purity α-ketoglutaric acid solid. ③ Dissolve the α-ketoglutaric acid solid obtained in step ② in water, add activated carbon for decolorization, filter, add anhydrous calcium acetate or calcium bicarbonate in batches to the α-ketoglutaric acid aqueous solution, stir the reaction at room temperature, then heat the reaction, crystallize at low temperature after the reaction is complete, filter, wash and dry; thus, calcium α-ketoglutaric acid is obtained.

7. The preparation method according to claim 6, characterized in that, In step ①, the mass-to-volume ratio of Gua-NH2@KIT-6 catalyst to methyl tert-butyl ether is 1:12, g / mL; the molar ratio of diethyl succinate to diethyl oxalate used for Claisen ester condensation is 1:1.1; and the mass-to-molar ratio of Gua-NH2@KIT-6 catalyst to diethyl succinate is 50:1, mg / mmol.

8. The preparation method according to claim 6, characterized in that, In step ②, the amount of hydrochloric acid added during hydrolysis is 3.3 equiv, and the volume ratio of water to hydrochloric acid is 2:1; the reflux temperature during hydrolysis is 70℃-100℃, and the reflux time is 2-4h; preferably, reflux at 100℃ for 3h.

9. The preparation method according to claim 6, characterized in that, In step ③, the molar volume ratio of α-ketoglutaric acid solid to water is 1:120-150, mol / mL; the mass ratio of activated carbon to α-ketoglutaric acid is 1:5; and the molar ratio of α-ketoglutaric acid to anhydrous calcium acetate or calcium bicarbonate is 1:0.8-1.2, preferably 1:0.

9.

10. The preparation method according to claim 6, characterized in that, In step ③, the reaction time at room temperature is 2-3 hours; the heating reaction temperature is 65-75℃ and the reaction time is 3-4 hours; the low-temperature crystallization temperature is 0-5℃ and the crystallization time is 4-5 hours; the drying temperature is 60-65℃ and the drying time is 6-8 hours.

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