Method for catalytic resolution of D-aspartic acid

Abstract

The invention discloses a method for catalytic resolution of D-aspartic acid, and belongs to the technical field of chemical engineering. The salicylaldehyde supramolecular system is prepared by taking salicylaldehyde, copper ions and alpha-cyclodextrin as substrates, on the basis of conventional chemical synthesis of D-aspartic acid, the yield of DL-aspartic acid-beta-methyl ester is increased, and the synthesis yield of D-aspartic acid is further increased.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for catalytic resolution of D-aspartic acid, belonging to the field of chemical technology. BACKGROUND

[0002] D-Aspartic acid (D-Asp) is a D-type amino acid, which is an enantiomeric form of L-Aspartic acid. Unlike L-type amino acids widely existing in organisms, D-type amino acids are less in nature, but are detected in some animal tissues, microorganisms and fermentation products, showing their unique physiological activity.

[0003] Studies have shown that D-Aspartic acid plays an important role in neurotransmitter regulation, endocrine regulation, reproductive function enhancement and neural development process. For example, D-Asp can promote the activity of hypothalamic-pituitary-gonadal axis and increase the level of testosterone; in the central nervous system, it is considered to be one of the ligands of NMDA receptor and participates in the learning and memory process. It can be seen that D-Aspartic acid has high research and application value in the fields of nutritional supplements, health foods and pharmaceutical raw materials.

[0004] The traditional synthesis method of D-Aspartic acid mainly includes chemical resolution method and enzyme method. However, these methods have some limitations, such as the need for complex resolving agent and tedious post-processing steps in chemical resolution method, and low yield and low optical purity in biological fermentation method and enzyme method. The literature "New method for preparing D-Aspartic acid from L-Aspartic acid" discloses the use of salicylaldehyde as a catalyst to catalyze the synthesis of L-Aspartic acid-β-dimethyl ester, and then D-Aspartic acid is prepared. However, this method has problems such as low catalytic efficiency and low yield of D-Aspartic acid.

[0005] Therefore, it has high practical and economic value to develop a salicylaldehyde catalyst with higher catalytic effect and improve the chemical synthesis effect of D-Aspartic acid. SUMMARY

[0006] To solve the above problems, the present application uses salicylaldehyde, copper ions and α-cyclodextrin as substrates to prepare a salicylaldehyde supramolecular system, which improves the yield of DL-Aspartic acid-β-methyl ester and further improves the synthesis yield of D-Aspartic acid on the basis of conventional chemical synthesis of D-Aspartic acid.

[0007] The first object of the present application is to provide a method for catalytic resolution of D-Aspartic acid, which uses a salicylaldehyde supramolecular system as a catalyst, and the method comprises: (1) mixing L-Aspartic acid-β-dimethyl ester with glacial acetic acid, adding a salicylaldehyde supramolecular system, heating, concentrating, washing and drying to obtain DL-Aspartic acid-β-methyl ester; (2) DL-aspartic acid-β-methyl ester was mixed with water and heated to dissolve; L-DBTA methanol solution was added, reacted, cooled, and filtered to obtain D-aspartic acid-β-methyl ester·L-DBTA salt; (3) D-aspartic acid-β-methyl ester·L-DBTA salt was hydrolyzed with sulfuric acid, filtered and dried to obtain D-aspartic acid; The preparation method of the salicylaldehyde supramolecular system is as follows: Under sealed conditions, salicylaldehyde and CuSO4 were mixed and stirred; then α-cyclodextrin was added and stirred; after stirring, the mixture was cooled to room temperature to obtain a salicylaldehyde supramolecular system. The molar ratio of salicylaldehyde, CuSO4 and α-cyclodextrin is 100:15~25:1~5.

[0008] In one embodiment, salicylaldehyde and CuSO4 are mixed and stirred at 200-400 rpm for 1-3 h at room temperature.

[0009] In one embodiment, after adding α-cyclodextrin, the temperature is raised to 40~45℃ and stirred for 1.5~2 h.

[0010] In one embodiment, the molar ratio of salicylaldehyde, CuSO4, and α-cyclodextrin is 100:15~20:2~4.

[0011] In one embodiment, the molar ratio of salicylaldehyde, CuSO4, and α-cyclodextrin is 100:15~18:2~3.

[0012] In one embodiment, the ratio of L-aspartic acid-β-dimethyl ester, glacial acetic acid, and salicylaldehyde supramolecular weight is 20-30 g: 150-200 mL: 0.05-0.2 mL.

[0013] A second object of the present invention is to provide the application of any of the above-described methods in the catalytic resolution of D-aspartic acid.

[0014] A third objective of this invention is to provide a salicylaldehyde supramolecular system, wherein the preparation method of the salicylaldehyde supramolecular system includes: Under sealed conditions, salicylaldehyde and CuSO4 were mixed and stirred; then α-cyclodextrin was added and stirred; after stirring, the mixture was cooled to room temperature to obtain a salicylaldehyde supramolecular system. The molar ratio of salicylaldehyde, CuSO4 and α-cyclodextrin is 100:15~25:1~5.

[0015] In one embodiment, salicylaldehyde and CuSO4 are mixed and stirred at 200-400 rpm for 1-3 h at room temperature; after adding α-cyclodextrin, the temperature is raised to 40-45°C and stirred for 1.5-2 h.

[0016] A fourth object of the present application is to provide the use of the salicylaldehyde supramolecular system described above in the preparation of D-aspartic acid.

[0017] A fifth object of the present application is to provide a method for simultaneously increasing the yield of DL-aspartic acid-β-methyl ester and D-aspartic acid in the chemical synthesis of D-aspartic acid, using the salicylaldehyde supramolecular system described above as a catalyst.

[0018] Advantages of the present application The salicylaldehyde supramolecular system prepared using the present application as a catalyst racemizes L-aspartic acid-β-dimethyl ester, increases the yield of DL-aspartic acid-β-methyl ester, and further increases the yield of D-aspartic acid under the condition of ensuring purity during subsequent chemical resolution and hydrolysis.

[0019] The yield of D-aspartic acid prepared by the method of the present application is 11.4% higher than that of the prior art "New method for preparing D-aspartic acid from L-aspartic acid". DETAILED DESCRIPTION

[0020] The preferred embodiments of the present application are described below, and it should be understood that the embodiments are for better explanation of the present application and are not intended to limit the present application.

[0021] Raw materials used in the examples: L-aspartic acid-β-methyl ester hydrochloride: CAS: 16856-13-6; Salicylaldehyde: CAS: 90-02-8; α-cyclodextrin purchased from Anhui Zesheng Technology Co., Ltd.; Catalog No.: A01E080250; molecular weight 972.85; β-cyclodextrin purchased from Shanghai Macklin Biochemical Technology Co., Ltd.; Catalog No.: C804562; molecular weight 1134.98; Preparation method of L-aspartic acid-β-methyl ester: L-aspartic acid-β-methyl ester hydrochloride is mixed with an aqueous sodium bicarbonate solution, wherein the molar ratio of L-aspartic acid-β-methyl ester hydrochloride to sodium carbonate is 1:1~1.2, and the salt acid is removed by sufficient reaction (2~3 h); L-aspartic acid-β-methyl ester is extracted using ethanol, dried, and L-aspartic acid-β-methyl ester is obtained.

[0022] Example 1: Preparation of salicylaldehyde supramolecular system The salicylaldehyde supramolecular system is prepared, and the steps are as follows: Under the condition of sealing, 100.0 mmol of salicylaldehyde (12.2 g), 20 mmol of CuSO4 (3.19 g), and 300 rpm stirring at room temperature for 2 h; then 3 mmol of α-cyclodextrin (2.916 g) was added, the temperature was raised to 45°C, and 500 rpm stirring was performed for 2 h; after stirring, the temperature was lowered to room temperature to obtain a salicylaldehyde supramolecular system.

[0023] Comparative Example 1: Using α-cyclodextrin instead of β-cyclodextrin On the basis of Example 1, 3 mmol (3.40 g) of β-cyclodextrin was used to replace α-cyclodextrin, and the rest was kept unchanged to obtain a salicylaldehyde supramolecular system.

[0024] Comparative Example 2: Using zinc sulfate instead of copper sulfate On the basis of Example 1, 20 mmol of ZnSO4 (3.23 g) was used to replace CuSO4 (3.19 g), and the rest was kept unchanged to obtain a salicylaldehyde supramolecular system.

[0025] Comparative Example 3: Changing the treatment temperature On the basis of Example 1, the reaction temperature was changed to 50°C, and the rest was kept unchanged to obtain a salicylaldehyde supramolecular system.

[0026] Example 2: Using a salicylaldehyde supramolecular system to catalytically synthesize D-aspartic acid A method for catalytically synthesizing D-aspartic acid, comprising the steps of: (1) racemization 28 g (0.19 mol) of L-aspartic acid-β-dimethyl ester and 180 mL of glacial acetic acid were mixed, 0.1 mL of a salicylaldehyde supramolecular system was added, heated to 100°C, and reacted for 1 hour; after the reaction was completed, the solvent was evaporated and concentrated, washed with acetone, and dried to obtain 27.4 g of DL-aspartic acid-β-methyl ester; (2) resolution 25 g (0.17 mol) of DL-aspartic acid-β-methyl ester prepared in step (1) was placed in a three-necked flask, 100 mL of water was added, and the temperature was raised to dissolve the solid; 31.9 g (0.085 mol) of L-DBTA was dissolved in methanol to obtain an L-DBTA methanol solution, which was added dropwise into the reaction flask within 30 min, reacted for 1 h, and then cooled to room temperature to obtain 42.19 g of D-aspartic acid-β-methyl ester·L-DBTA salt; (3) hydrolysis 37 g (0.0732 mol) of D-aspartic acid-β-methyl ester·L-DBTA salt prepared in step (2) was placed in a beaker, 0.6 mol·L -1Sulfuric acid 240 mL, reaction at room temperature for 2 h, filtration, recovery of L-DBTA; the filtrate was supplemented with 15 mL of concentrated sulfuric acid, refluxed for 2 h, concentrated to 20 mL, pH was adjusted to about 2.7 with ammonia water, stirred at room temperature for 4 hours, filtered and dried to obtain 9.69 g of D-aspartic acid with a purity of 99%.

[0027] Comparative Example 4: D-aspartic acid was prepared using conventional salicylaldehyde On the basis of Example 2, an equivalent amount of salicylaldehyde was used to replace the salicylaldehyde supramolecular system, and the rest was kept the same, to obtain a salicylaldehyde supramolecular system.

[0028] Comparative Example 5: D-aspartic acid was prepared using other salicylaldehyde supramolecular systems The salicylaldehyde supramolecular systems prepared in Comparative Examples 1-4 were used to prepare D-aspartic acid according to the method of Example 2, and the amount used was detected, and the results are shown in Table 1.

[0029] Table 1: D-aspartic acid yield

[0030] Although the present application has been disclosed with reference to the preferred embodiments above, it is not intended to limit the present application, and any person skilled in the art can make various modifications and modifications without departing from the spirit and scope of the present application, therefore the protection scope of the present application should be defined by the claims.

Claims

1. A method for catalytic resolution of D-aspartic acid, characterized in that, The method comprises the following steps: (1) mixing L-aspartic acid-β-dimethyl ester with glacial acetic acid, adding a salicylaldehyde supermolecular system, heating and reacting, concentrating, washing, and drying to obtain DL-aspartic acid-β-methyl ester; (2) mixing the DL-aspartic acid-β-methyl ester with water, heating and dissolving; adding L-DBTA methanol solution, reacting, cooling, and filtering to obtain D-aspartic acid-β-methyl ester·L-DBTA salt; (3) adding the D-aspartic acid-β-methyl ester·L-DBTA salt to sulfuric acid for hydrolysis, filtering, and drying to obtain D-aspartic acid; The preparation method of the salicylaldehyde supermolecular system comprises the following steps: Under a sealed condition, salicylaldehyde and CuSO4 are mixed and stirred; then α-cyclodextrin is added and stirred; after stirring, the temperature is lowered to room temperature to obtain the salicylaldehyde supermolecular system. The molar ratio of salicylaldehyde, CuSO4 and α-cyclodextrin is 100:15-25:1-5.

2. The method of claim 1, wherein, After mixing salicylaldehyde and CuSO4, stirring is performed at 200-400 rpm at room temperature for 1-3 h.

3. The method of claim 1, wherein, After adding α-cyclodextrin, the temperature is raised to 40-45 DEG C, and stirring is performed for 1.5-2 h.

4. The method of claim 1, wherein, The molar ratio of salicylaldehyde, CuSO4 and α-cyclodextrin is 100:15-20:2-4.

5. The method of claim 1, wherein, The molar ratio of salicylaldehyde, CuSO4 and α-cyclodextrin is 100:15-18:2-3.

6. The method according to any one of claims 1-5 is used for catalytic resolution of D-aspartic acid.

7. A salicylaldehyde supramolecular system characterized in that, The preparation method of the salicylaldehyde supermolecular system comprises the following steps: Under a sealed condition, salicylaldehyde and CuSO4 are mixed and stirred; then α-cyclodextrin is added and stirred; after stirring, the temperature is lowered to room temperature to obtain the salicylaldehyde supermolecular system. The molar ratio of salicylaldehyde, CuSO4 and α-cyclodextrin is 100:15-25:1-5.

8. The salicylaldehyde supramolecular system according to claim 7, characterized in that, After mixing salicylaldehyde and CuSO4, stirring is performed at 200-400 rpm at room temperature for 1-3 h; after adding α-cyclodextrin, the temperature is raised to 40-45 DEG C, and stirring is performed for 1.5-2 h.

9. The use of the salicylaldehyde supermolecular system according to claim 7 or 8 in the preparation of D-aspartic acid.

10. A method for simultaneously improving the yield of both DL-aspartic acid-β-methyl ester and D-aspartic acid in the chemical synthesis of D-aspartic acid, characterized by, The salicylaldehyde supermolecular system according to claim 7 is used as a catalyst.

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