A method for preparing tetrahydrofolic acid by continuous hydrogenation with Pd / Al2O3 as catalyst

Abstract

The present application relates to a kind of Pd / Al2O3 as catalyst continuous hydrogenation preparation tetrahydrofolic acid method, at least comprising the following steps: S1, catalyst Pd / Al2O3 is filled in the reaction column of continuous flow device, nitrogen is imported to empty the air inside continuous flow device;S2, after the air inside continuous flow device is evacuated, hydrogen is imported to continuous flow device, until the pressure of reaction system reaches the required pressure value;S3, preparation contains the reaction solution of folic acid, when the temperature of reaction system reaches the required value, reaction solution is transported to the hydrogenation reaction of reaction column;S4, after the stable state of reaction system, the product obtained in oxygen-free environment, after the product is purified, the tetrahydrofolic acid of the present application is obtained.The preparation method is simple, reaction time is short, reaction pressure is low, reduces the risk coefficient of reaction, is suitable for large-scale production;And the catalytic efficiency of Pd / Al2O3 catalyst is high and can be recycled, overcome the problems of large amount of catalyst in prior art and difficult to recover and reuse.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst. Background Art

[0002] Tetrahydrofolate is a coenzyme of one-carbon group (including CH3, CH2, CHO, etc.) transferase. Tetrahydrofolate has the function of transferring one-carbon groups and participates in many important reactions and the synthesis of nucleic acids and amino acids.

[0003] Currently, the most common method for synthesizing tetrahydrofolic acid involves placing a folic acid solution and a catalyst in a reactor, introducing hydrogen, and then catalytically hydrogenating the product under high pressure to produce tetrahydrofolic acid. This synthesis process requires high pressure, is time-consuming, and the catalyst is difficult to recycle, severely hindering the development of tetrahydrofolic acid. Summary of the Invention

[0004] To address the shortcomings of the prior art, the present invention proposes a method for preparing tetrahydrofolic acid by continuous hydrogenation using a Pd / Al2O3 catalyst. This method is simple, has a short reaction time, and a low reaction pressure, which reduces the risk factor of the reaction and is suitable for large-scale production. In addition, the Pd / Al2O3 catalyst has high catalytic efficiency and can be recycled, overcoming the problems of the prior art in which the catalyst requires large amounts of catalyst and is difficult to recycle.

[0005] To solve the above technical problems, the present invention provides a method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst, which comprises at least the following steps:

[0006] S1. Fill the reaction column of the continuous flow device with the catalyst Pd / Al2O3 and introduce nitrogen gas to clear the air inside the continuous flow device;

[0007] S2. After the air inside the continuous flow device is evacuated, hydrogen is introduced into the continuous flow device until the pressure of the reaction system reaches the desired pressure value;

[0008] S3, preparing a reaction solution containing folic acid, and when the temperature of the reaction system reaches the desired value, transporting the reaction solution to a reaction column to cause a hydrogenation reaction;

[0009] S4. After the reaction system is in a stable state, the obtained product is collected in an oxygen-free environment, and the tetrahydrofolic acid is obtained after the product is purified.

[0010] Furthermore, the concentration of folic acid in the reaction solution is 0.1-0.5 mol / L.

[0011] Furthermore, the reaction solution is prepared from folic acid and phosphate buffer.

[0012] Furthermore, the flow rate of the hydrogen gas is 10-40 sccm.

[0013] Furthermore, the pressure of the reaction system is 1-8 MPa.

[0014] Furthermore, the flow rate of the reaction solution is 0.1-2 mL / min.

[0015] Furthermore, the temperature of the reaction system is 40-100°C.

[0016] Furthermore, the product purification step is to cool the collected product to 0°C, add hydrochloric acid dropwise until solid precipitates, collect the precipitated solid, wash it with water several times and vacuum dry it.

[0017] Furthermore, the conversion rate of folic acid is greater than 99%, and the selectivity of tetrahydrofolic acid can reach 99%.

[0018] In summary, the present invention has the following beneficial effects:

[0019] 1. The continuous flow preparation method of tetrahydrofolic acid provided by the present invention is simple, has a short reaction time, a low reaction pressure, reduces the risk factor of the reaction, and is suitable for large-scale production.

[0020] 2. Folic acid is reduced to tetrahydrofolic acid over a Pd / Al2O3 catalyst, achieving a folic acid conversion rate exceeding 99% and a tetrahydrofolic acid selectivity of 99%. Therefore, the Pd / Al2O3 catalyst offers high catalytic efficiency and is recyclable, overcoming the existing issues of high catalyst usage and difficulty in recycling and reuse. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying any creative work.

[0022] Figure 1 Flow chart for the preparation of tetrahydrofolic acid.

[0023] Figure 2 This is a graph showing the contents of folic acid, dihydrofolic acid, and tetrahydrofolic acid at different reaction system temperatures.

[0024] Figure 3 The graph shows the contents of folic acid, dihydrofolic acid, and tetrahydrofolic acid at different hydrogen flow rates.

[0025] Figure 4The graph shows the contents of folic acid, dihydrofolic acid, and tetrahydrofolic acid under different reaction system pressures.

[0026] Figure 5 The graph shows the contents of folic acid, dihydrofolic acid, and tetrahydrofolic acid at different reaction solution flow rates.

[0027] Figure 6 The graph shows the contents of folic acid, dihydrofolic acid, and tetrahydrofolic acid at different folic acid concentrations.

[0028] Among them, 1. Pump; 2. Gas-liquid mixer; 3. Reaction column; 4. Gas-liquid separator; 5. Hydrogen cylinder; 6. Nitrogen cylinder; 7. Hydrogen safety valve; 8. Nitrogen safety valve; 9. Back pressure regulator; 10. Liquid regulator; 11. Feed port.

[0029] The purpose, features and advantages of the present invention will be further described with reference to the accompanying drawings and in conjunction with the embodiments. DETAILED DESCRIPTION

[0030] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0031] The experimental methods in the following examples, unless otherwise specified, are conventional methods. The experimental materials and reagents used in the following examples, unless otherwise specified, are commercially available. The quantitative experiments in the following examples were performed in triplicate, and the data are presented as the mean or mean ± standard deviation of the three replicates.

[0032] In addition, the "and / or" in the full text includes three solutions. Taking A and / or B as an example, it includes technical solution A, technical solution B, and technical solution that satisfies both A and B. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of ordinary technicians in this field to implement. When the combination of technical solutions is mutually contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0033] Example 1: Determination of the optimal reaction conditions for synthesizing tetrahydrofolic acid

[0034] The ranges selected are: folic acid concentration in the reaction solution is 0.1-0.5 mol / L, hydrogen flow rate is 10-60 sccm, reaction system pressure is 1-5 MPa, reaction solution flow rate is 0.3-1.5 mL / min, and reaction system temperature is 30-90°C.

[0035] The device used in this embodiment is a continuous flow device, such as Figure 1 As shown, the continuous flow device includes a reaction column 3, a gas-liquid mixer 2 and a gas-liquid separator 4 respectively connected to the two ends of the reaction column 3, a feed port 11 for introducing liquid, a pump 1 for transmitting liquid, a hydrogen safety valve 7, a nitrogen safety valve 8, a liquid regulator 10, and a back pressure regulator 9; wherein, the gas-liquid mixer 2 is used to mix the reactant solution and gas used for the reaction, and the gas-liquid separator 4 is used to separate the generated product and gas.

[0036] The specific reaction steps for synthesizing tetrahydrofolic acid are:

[0037] S1. Before the reaction starts, the catalyst Pd / Al2O3 is filled in the reaction column 3, and then water is introduced from the feed port 11 to wet the continuous flow device; then nitrogen is introduced into the gas-liquid mixer 2 through the nitrogen cylinder 6, and the nitrogen passes through the reaction column 3 and the gas-liquid separator 4 in sequence, and then discharged from the continuous flow device until the nitrogen empties the air inside the continuous flow device; a nitrogen safety valve 8 is provided on the pipeline between the nitrogen cylinder 6 and the gas-liquid separator 4. When the internal pressure of the continuous flow device is too high, the nitrogen safety valve 8 automatically releases the pressure;

[0038] S2. After the air inside the continuous flow device is evacuated, hydrogen is introduced into the gas-liquid mixer 2 through the hydrogen cylinder 5. The hydrogen passes through the reaction column 3 and the gas-liquid separator 4 in sequence until the pressure of the reaction system reaches the required pressure value. A hydrogen safety valve 7 is installed on the pipeline between the hydrogen cylinder 5 and the gas-liquid separator 4. When the internal pressure of the continuous flow device is too high, the hydrogen safety valve 7 automatically releases the pressure.

[0039] S3, preparing a reactant solution containing folic acid, and when the temperature of the reaction system reaches the desired value, transporting the reactant solution from the feed port 11 to the reaction column 3 via the pump 1 to cause a hydrogenation reaction;

[0040] The steps of preparing the reactant solution are as follows: adding solid folic acid to a NaH2PO4-Na2HPO4 buffer solution, stirring until uniform, and then adjusting the pH of the solution to 7 with a 20% NaOH solution until the folic acid is completely dissolved to obtain a reactant solution;

[0041] S4. After a residence time of not less than 5 times that of the reactant solution, the reaction system is generally considered to be in a stable state. When the liquid at the gas-liquid separator 4 reaches a certain volume, the liquid regulator 10 is automatically opened, and the obtained product is collected in an oxygen-free environment; the collected product is placed at 0° C., and hydrochloric acid is added dropwise until a solid precipitates. The precipitated solid is collected, washed with water several times, and vacuum-dried to obtain tetrahydrofolic acid;

[0042] S5. After the reaction is completed, the temperature of the reaction system is lowered to room temperature, and the pressure of the back pressure regulator 9 is gradually adjusted until the pressure in the reaction system is reduced to atmospheric pressure; then nitrogen and water are introduced into the gas-liquid mixer 2 at the same time, and the nitrogen and water pass through the continuous flow device to fully remove the residual products in the reaction system; after cleaning, the catalyst Pd / Al2O3 in the reaction column 3 can be recovered and reused.

[0043] The contents of folic acid, dihydrofolic acid and tetrahydrofolic acid in the products were determined respectively. The experimental results are as follows: Figures 2 to 6 shown.

[0044] Depend on Figures 2 to 6 It can be seen that the optimal conditions for continuous hydrogenation synthesis of tetrahydrofolic acid using Pd / Al2O3 as a catalyst are: folic acid concentration in the reaction solution is 0.2 mol / L, hydrogen flow rate is 40 sccm, pressure of the reaction system is 3 MPa, flow rate of the reaction solution is 0.3 mL / min, and temperature of the reaction system is 70°C.

[0045] The specific synthesis steps of Examples 2-5 are the same as those of Example 1, and their specific reaction parameters are shown in Table 1.

[0046] Table 1 Reaction parameters of Examples 2-5

[0047] Example 2 Example 3 Example 4 Example 5 <![CDATA[Folic acid concentration / mol·L -1 > 0.2 0.3 0.2 0.3 Reaction system pressure / MPa 3 3 3 3 Hydrogen flow rate / sccm 40 40 40 40 Reaction system temperature / ℃ 70 70 70 40 <![CDATA[Reaction solution flow rate / mL·min -1 > 0.3 0.3 1.5 1.5 Reaction time / min 40 40 8 8

[0048] Comparative Example 1

[0049] At 25°C, add 1 g of solid folic acid to a 100 mL three-necked flask. After replacing the flask with nitrogen three times, add 10 mL of 0.2 mol / L NaH2PO4-Na2HPO4 buffer solution with a pH of 7 to the flask and stir until uniform to obtain a mixed solution. Adjust the pH of the mixed solution to 7 with 20% NaOH solution to obtain a folic acid solution.

[0050] 0.1 g of Pd / Al2O3 catalyst was added to the reactor. After the reactor was purged with nitrogen three times, a folic acid solution with a pH of 7 was added to the reactor. After the reactor was purged with hydrogen five times, hydrogen was added to the reactor. The pressure of the reactor was adjusted to 5 MPa. Under the conditions of the internal temperature of the reactor being 60°C, a hydrogenation reaction occurred. After reacting for 24 hours, a solution containing tetrahydrofolic acid was obtained.

[0051] The pH of the solution containing tetrahydrofolic acid is adjusted to 3 with 1 mol / L hydrochloric acid solution to precipitate tetrahydrofolic acid. The precipitate is filtered and dried in a vacuum drying oven for 8 hours to obtain tetrahydrofolic acid.

[0052] The difference between Comparative Example 2 and Example 2 is that the catalyst is Pd / C.

[0053] The experimental results of Examples 2-5 and Comparative Examples 1-2 are shown in Table 2.

[0054] Table 2 Results of folic acid conversion and tetrahydrofolate selectivity

[0055] Folate conversion rate Tetrahydrofolate selectivity Example 2 >99％ 98％ Example 3 >99％ 97％ Example 4 >99％ 92％ Example 5 >99％ 67％ Comparative Example 1 >99％ 92％ Comparative Example 2 >99％ 57％

[0056] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0057] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst, characterized in that: At least the following steps are included: S1. Fill the reaction column of the continuous flow device with the catalyst Pd / Al2O3 and introduce nitrogen gas to clear the air inside the continuous flow device; S2. After the air inside the continuous flow device is exhausted, hydrogen is introduced into the continuous flow device until the pressure reaches the required pressure value; S3, preparing a reaction solution containing folic acid, heating it until the temperature reaches a desired value, and then transferring the reaction solution to a reaction column to cause a hydrogenation reaction; S4. After the reaction system is in a stable state, the product is collected in an oxygen-free environment, and the tetrahydrofolic acid is obtained after the product is purified.

2. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 1, wherein: The concentration of folic acid in the reaction solution is 0.1-0.5 mol / L.

3. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 2, wherein: The reaction solution is prepared from folic acid and phosphate buffer.

4. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 1, wherein: The flow rate of the hydrogen gas is 10-40 sccm.

5. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 1, wherein: The pressure is 1-8 MPa.

6. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 1, wherein: The flow rate of the reaction solution is 0.1-2 mL / min.

7. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 1, wherein: The temperature is 40-100°C.

8. The method for preparing tetrahydrofolic acid by continuous hydrogenation using Pd / Al2O3 as a catalyst according to claim 1, wherein: The product purification steps are as follows: the collected product is cooled to 0°C, hydrochloric acid is added dropwise until a solid precipitates, the precipitated solid is collected and washed with water several times and dried in vacuo.

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