Method for preparing catalyst for oxidative synthesis of folic acid using 6-R-tetrahydrofolate

Abstract

The present invention relates generally to a method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate. The preparation of the supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate is achieved by the following method: a certain amount of SBA-15 molecular sieves is suspended in 10 volumes of chloroform / ethanol (2:1) solution, a certain amount of tetraphenylporphyrin is added, dissolved under stirring, refluxed for 2 hours, and then a certain amount of ethanol / water (5:1) solution of nickel acetate and manganese acetate is added, and refluxed for 4 hours. Filter, wash 3 times with distilled water, and vacuum dry to obtain a supported composite catalyst. The catalyst is used in the reaction of synthesizing folic acid by oxidation of 6-R-tetrahydrofolate with hydrogen peroxide, and the catalytic effect is good. Using a catalyst of 2% weight of raw material, the obtained folic acid product can reach more than 98.5% purity after refinement, and the yield is more than 90%.

Description

Technical Field

[0001] The invention relates to a method for preparing a supported composite catalyst for synthesizing folic acid through oxidation of 6-R-tetrahydrofolate, and belongs to the technical field of fine chemical industry. Background Art

[0002] In the process of synthesizing 6-S-5-methyltetrahydrofolate using folic acid as raw material, when folic acid is reduced to 6-R,S-tetrahydrofolate and then split to obtain 6-S-tetrahydrofolate, a large amount of biologically inactive 6-R-tetrahydrofolate is produced as a by-product. Since no other uses have been found for it, it can only be treated as production waste. The treatment process not only increases production costs, but also brings greater environmental problems.

[0003] To solve this problem, an effective method is to obtain folic acid from 6-R-5-tetrahydrofolate through catalytic oxidation, which is returned to the production process of 6-S-5-methyltetrahydrofolate as a raw material. At the same time, the by-product treatment process is omitted, the production cost is reduced, and the environmental risk is eliminated.

[0004] Tetrahydrofolate is a compound that is extremely unstable to oxidants and can be oxidized by air during storage. Common oxidants such as potassium permanganate, potassium dichromate, nitric acid, and hydrogen peroxide can oxidize tetrahydrofolate. However, the selectivity of the oxidation products of tetrahydrofolate is extremely poor. The oxidation products obtained by various oxidants under general conditions are all complex mixtures, including folic acid, dihydrofolate, pterin, p-aminobenzoylglutamate, etc., which have no synthetic significance. Therefore, how to improve the selectivity of the oxidation products of tetrahydrofolate is the key technology to be solved by the present invention. Summary of the invention

[0005] Exploratory research has shown that under neutral conditions and low temperatures, hydrogen peroxide is a mild oxidant, and tetrahydrofolate can be slowly oxidized under these conditions. In the absence of a catalyst, the product of hydrogen peroxide oxidation is also a complex mixture, but the content of folic acid can reach about 50%. Another problem with the oxidation reaction under these conditions is that the reaction rate is too slow. At room temperature and pH 7, the conversion rate of tetrahydrofolate after 1% hydrogen peroxide oxidation reaction for 24 hours is only about 20%, which is far from meeting the requirements of industrial synthesis reactions.

[0006] Considering the need to improve both the selectivity and the activity of the reaction, the catalyst used should have the function of directional adsorption of reactant molecules to ensure the positional specificity of the oxidation reaction, while also having the ability to appropriately catalyze the activity of the hydrogen peroxide oxidation reaction.

[0007] The supported catalyst developed by the present invention is a commercially available macroporous molecular sieve SBA-15 as a carrier, and in-situ synthesized tetraphenylporphyrin nickel and tetraphenylporphyrin manganese as catalyst active components. The catalytic principle is as follows: the tetraphenylporphyrin ring supported on the surface of the molecular sieve relies on weak interactions between molecules to adsorb 6-R-tetrahydrofolate to form a reaction substrate enrichment zone, and synergistically acts with divalent nickel ions and divalent manganese ions complexed with the porphyrin ring to catalyze the oxidation of tetrahydrofolate molecules by hydrogen peroxide. The spatial confinement effect in the local micro-reaction zone improves the efficiency of the hydrogen peroxide oxidation reaction on the one hand, and at the same time improves the selectivity of the oxidation reaction.

[0008] After the oxidation reaction is completed, the supported catalyst can be recovered and reused by simple filtration, which reduces production costs and simplifies the product refining process.

[0009] Since the manganese ions in the catalyst can catalyze the decomposition of hydrogen peroxide, the excess hydrogen peroxide can be quickly decomposed under the action of the supported catalyst without the need to add additional reaction termination reagents. It is a catalyst with multiple functions.

[0010] The beneficial effects of the present invention are as follows:

[0011] 1. The supported composite catalyst has the advantages of improving the oxidation reaction efficiency and product selectivity, making the technology of producing folic acid by oxidizing tetrahydrofolate with hydrogen peroxide reach the level of industrial production. It is a highly efficient and multifunctional catalyst.

[0012] 2. The supported composite catalyst also has the function of catalyzing the decomposition of hydrogen peroxide, which simplifies the treatment process of the remaining hydrogen peroxide in the reaction, does not introduce other impurities during the treatment process, and is conducive to the purification of the product.

[0013] 3. The used supported composite catalyst can be simply recovered and reused, which reduces production costs and eliminates the problem of waste catalyst disposal.

[0014] 4. Since the supported composite catalyst of the present invention is used to oxidize tetrahydrofolate to produce folic acid, the synthesis process is simple, easy to operate, and no by-products are generated, which is an environmentally friendly green synthesis process. Specific embodiments

[0015] The following embodiments describe the specific implementation process of the technical solution of the present invention, but the technical solution of the present invention is not limited to the specific implementation methods listed below, and also includes any combination of the specific implementation methods.

[0016] Example 1. 10g of SBA-15 molecular sieve was suspended in 100ml of chloroform / ethanol (2:1) solution, 1g of tetraphenylporphyrin was added, dissolved under stirring, and refluxed for 2 hours. 0.6g of nickel acetate tetrahydrate and 0.7g of manganese acetate tetrahydrate were dissolved in 30ml of ethanol / water (5:1) solution. The mixed solution was added to the reaction system and the reflux reaction was continued for 4 hours. Filtered, washed with distilled water 3 times, and vacuum dried to obtain a supported composite catalyst.

[0017] The effect test of the supported composite catalyst was carried out according to the following steps: 4.6 g of 6-R-tetrahydrofolate was dissolved in 50 ml of water. The pH value was adjusted to 7, 92 mg of the supported composite catalyst was added, stirred at 25°C, and 40 ml of 5% hydrogen peroxide was slowly added dropwise. After 6 hours of reaction, TLC monitored that all the raw materials were consumed, and continued stirring for 60 min. The composite catalyst was filtered and recovered. The crude folic acid product was separated, and 4.13 g of refined folic acid was obtained after recrystallization from ethanol with a purity of 98.5%. The yield of refined folic acid was 90.6%.

[0018] Example 2. Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the amount of tetraphenylporphyrin was changed to 0.5 g, the amount of nickel acetate tetrahydrate was changed to 0.3 g, the amount of manganese acetate tetrahydrate was changed to 0.36 g, and the ethanol aqueous solution was 20 ml.

[0019] The reaction time of the supported composite catalyst was 12 hours. The product was separated and recrystallized from ethanol to obtain 4.0 g of refined folic acid with a purity of 98.4%. The yield of refined folic acid was 87.7%.

[0020] Example 3 Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the amount of tetraphenylporphyrin was changed to 1.5 g, the amount of nickel acetate tetrahydrate was changed to 0.9 g, the amount of manganese acetate tetrahydrate was changed to 1.1 g, and the ethanol aqueous solution was 50 ml.

[0021] The reaction time of the supported composite catalyst was 6 hours. The product was separated and recrystallized from ethanol to obtain 4.1 g of refined folic acid with a purity of 98.5%. The yield of refined folic acid was 89.9%.

[0022] Example 4 Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the amount of tetraphenylporphyrin was changed to 2 g, the amount of nickel acetate tetrahydrate was changed to 1.2 g, the amount of manganese acetate tetrahydrate was changed to 1.4 g, and the ethanol aqueous solution was 60 ml.

[0023] The reaction time of the supported composite catalyst was 5 hours. The product was separated and recrystallized from ethanol to obtain 4.05 g of refined folic acid with a purity of 98.6%. The yield of refined folic acid was 88.8%.

[0024] Example 5 Synthesis of Supported Composite Catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.91 g, and the amount of manganese acetate tetrahydrate was changed to 0.39 g.

[0025] The reaction time of the supported composite catalyst was 8 hours. The product was separated and recrystallized from ethanol to obtain 3.6 g of refined folic acid with a purity of 98.2%. The yield of refined folic acid was 78.9%.

[0026] Example 6 Synthesis of Supported Composite Catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.68 g, and the amount of manganese acetate tetrahydrate was changed to 0.59 g.

[0027] The reaction time of the supported composite catalyst was 6 hours. The product was separated and recrystallized from ethanol to obtain 3.95 g of refined folic acid with a purity of 98.4%. The yield of refined folic acid was 86.6%.

[0028] Example 7 Synthesis of Supported Composite Catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.45 g, and the amount of manganese acetate tetrahydrate was changed to 0.78 g.

[0029] The reaction time of the supported composite catalyst was 6 hours. The product was separated and recrystallized from ethanol to obtain 4.15 g of refined folic acid with a purity of 98.5%. The yield of refined folic acid was 91.0%.

[0030] Example 8 Synthesis of Supported Composite Catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.34 g, and the amount of manganese acetate tetrahydrate was changed to 0.88 g.

[0031] The reaction time of the supported composite catalyst was 6 hours. The product was separated and recrystallized from ethanol to obtain 4.05 g of refined folic acid with a purity of 98.5%. The yield of refined folic acid was 88.8%.

[0032] Example 9 Synthesis of Supported Composite Catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.18 g, and the amount of manganese acetate tetrahydrate was changed to 0.24 g.

[0033] In the test results of the effect of the supported composite catalyst, the raw materials were not completely reacted after 24 hours of reaction time, so the reaction was stopped.

[0034] Example 10. Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.36 g, and the amount of manganese acetate tetrahydrate was changed to 0.47.

[0035] The reaction time of the supported composite catalyst was 12 hours. The product was separated and recrystallized from ethanol to obtain 3.8 g of refined folic acid with a purity of 98.4%. The yield of refined folic acid was 83.3%.

[0036] Example 11. Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.73 g, the amount of manganese acetate tetrahydrate was changed to 0.94, and the ethanol aqueous solution was changed to 50 ml.

[0037] The reaction time of the supported composite catalyst was 6 hours. The product was separated and recrystallized from ethanol to obtain 4.15 g of refined folic acid with a purity of 98.6%. The yield of refined folic acid was 91.0%.

[0038] Example 12 Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the amount of nickel acetate tetrahydrate was changed to 0.91 g, the amount of manganese acetate tetrahydrate was changed to 1.18 g, and the ethanol solution was changed to 50 ml.

[0039] The reaction time of the supported composite catalyst was 6 hours. The product was separated and recrystallized from ethanol to obtain 4.10 g of refined folic acid with a purity of 98.5%. The yield of refined folic acid was 89.9%.

[0040] Example 13 Synthesis of supported composite catalyst The operation process of Example 1 was followed, except that the reaction time after adding nickel acetate tetrahydrate and manganese acetate tetrahydrate ethanol solution was changed to 2 hours.

[0041] The reaction time of the supported composite catalyst was 8 hours. The product was separated and recrystallized from ethanol to obtain 3.9 g of refined folic acid with a purity of 98.3%. The yield of refined folic acid was 85.5%.

[0042] Example 14 Synthesis of Supported Composite Catalyst The operation process of Example 1 was followed, except that the reaction time after adding nickel acetate tetrahydrate and manganese acetate tetrahydrate ethanol solution was changed to 6 hours.

[0043] The reaction time of the supported composite catalyst was 8 hours. The product was separated and recrystallized from ethanol to obtain 4.15 g of refined folic acid with a purity of 98.5%. The yield of refined folic acid was 91.0%.

Claims

1. A method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate, characterized in that The preparation of the supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate is achieved by the following method: a certain amount of SBA-15 molecular sieve is suspended in a solution with a volume ratio of chloroform / ethanol of 2:1, which is 10 times the volume, a certain amount of tetraphenylporphyrin is added, dissolved under stirring, refluxed for 2 hours, and then a certain amount of nickel acetate and manganese acetate are added in a solution with a volume ratio of ethanol / water of 5:1, the reflux reaction is continued for a period of time, filtered, washed with distilled water for 3 times, and vacuum dried to obtain the supported composite catalyst; The effect test of the supported composite catalyst was carried out according to the following steps: 4.6 g of 6-R-tetrahydrofolate was dissolved in 50 ml of water; the pH value was adjusted to 7, 92 mg of the supported composite catalyst was added, the mixture was stirred at 25° C., 40 ml of 5% hydrogen peroxide was slowly added dropwise, and after reacting for 6 hours, all the raw materials were consumed according to TLC monitoring, stirring was continued for 60 min, and the composite catalyst was recovered by filtration; the crude folic acid product was separated, and the product was separated and recrystallized from ethanol to obtain 4.15 g of refined folic acid with a purity of 98.6%; the yield of refined folic acid was 91.0%.

2. The method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate according to claim 1, characterized in that The SBA-15 molecular sieve is a commercially available product, and its basic structural parameters are: pore size 6-11 nm, BET specific surface area 550-600 m2 / g, relative crystallinity>90%.

3. The method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate according to claim 1, characterized in that The mass ratio of the SBA-15 molecular sieve to tetraphenylporphyrin is 1:0.05-0.

2.

4. The method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate according to claim 1, characterized in that The nickel acetate and manganese acetate are both tetrahydrates, and the molar ratio of the two is 1:0.5-2.

5. The method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate according to claim 1, characterized in that The molar ratio of the tetraphenylporphyrin to the nickel acetate / manganese acetate mixture is 1:1-10.

6. The method for preparing a supported composite catalyst for synthesizing folic acid by oxidation of 6-R-tetrahydrofolate according to claim 1, characterized in that The reflux reaction time after adding the mixed solution of nickel acetate and manganese acetate is 2-6 hours.