A method for preparing tetrahydrofolic acid by continuously adding folic acid to hydrogen in the presence of a Co / CeO2-Al2O3 catalyst

Abstract

The application discloses a method for preparing tetrahydrofolic acid by continuously flowing folic acid hydrogenation with Co / CeO2-Al2O3 catalyst, and aims to provide a method for preparing tetrahydrofolic acid by continuously flowing folic acid hydrogenation, which is low in catalyst cost, high in catalytic efficiency, high in folic acid conversion rate and selectivity, low in reaction temperature and pressure in the continuous hydrogenation process, and low in energy consumption; and the technical scheme is as follows: the method comprises the following steps in sequence: filling the catalyst Co / CeO2-Al2O3 in a reaction column of a continuous flow hydrogenation device, setting reaction parameters of the continuous flow hydrogenation device, flowing a reaction solution into the reaction column through a high-pressure constant-flow infusion pump after the reaction system reaches the set temperature and pressure, and opening a gas valve to perform hydrogenation reaction; collecting liquid products in a glove box in a nitrogen atmosphere after the reaction system temperature, pressure, gas flow rate and liquid flow rate are stable; acidifying the collected liquid products in the glove box to precipitate solids, washing, drying and obtaining tetrahydrofolic acid; and the application relates to the technical field of chemical synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing tetrahydrofolic acid by catalytic continuous flow hydrogenation using a cobalt-based catalyst supported by a Co / CeO2-Al2O3 composite oxide. Background Art

[0002] Tetrahydrofolic acid (THFA) is an important intermediate in the pharmaceutical, nutritional, and chemical industries, often produced through the hydrogenation of folic acid. Existing technologies for the synthesis and stability of THFA primarily rely on traditional autoclave reaction systems, which present significant drawbacks in catalyst recovery, reaction efficiency, and product stability.

[0003] Compared with traditional high-pressure reactor synthesis technology, continuous flow hydrogenation technology has many advantages: 1) Reaction conditions are more precisely controllable: the continuous flow reactor is small in size, has high heat transfer efficiency, and the temperature and pressure control accuracy far exceeds that of traditional kettle reactions; 2) High reaction safety: the amount of hydrogen used is small, the system is closed, and the safety risks brought by high-pressure hydrogen are reduced; improve yield and selectivity: 3) Continuous flow can finely control the reaction residence time, avoid excessive hydrogenation or side reactions, and help improve the selectivity of tetrahydrofolate; 4) Easy to scale up production: increase production through parallel amplification without doubling the equipment volume; facilitate automation and online monitoring: 5) Continuous flow equipment can be combined with online analytical technologies (such as HPLC, FTIR) to monitor the reaction progress in real time and ensure product quality. Summary of the Invention

[0004] The present invention aims to provide a method for preparing tetrahydrofolic acid by continuous hydrogenation using Co / CeO2-Al2O3 as a catalyst. The catalyst has low cost, high catalytic efficiency, high folic acid conversion rate and selectivity, low reaction temperature and pressure during the continuous hydrogenation process, and energy saving.

[0005] To this end, the technical solution provided by the present invention is as follows:

[0006] A method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by a Co / CeO2-Al2O3 catalyst comprises the following steps in sequence:

[0007] 1) Fill the reaction column of a continuous flow hydrogenation apparatus with the catalyst Co / CeO2-Al2O3 and set the reaction parameters of the continuous flow hydrogenation apparatus as follows: hydrogen flow rate 30-100 mL / min, solution flow rate 1-5 mL / min, reaction temperature 80-120°C, and reaction pressure 1-5 MPa;

[0008] 2) When the reaction system reaches the temperature and pressure set in step 1), the reaction solution is flowed into the reaction column through a high-pressure constant-flow infusion pump, and the gas valve is opened to carry out the hydrogenation reaction;

[0009] 3) After the temperature, pressure, gas flow rate, and liquid flow rate of the reaction system stabilize, collect the liquid product in a nitrogen atmosphere glove box;

[0010] 4) Acidifying the liquid product collected in step 3) in a glove box to precipitate a solid, washing, and drying the solid to obtain tetrahydrofolic acid; the reaction solution in step 2) is a folic acid solution and a NaOH solution.

[0011] Furthermore, the above-mentioned method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the Co / CeO2-Al2O3 catalyst is prepared by the following steps:

[0012] 1) Dissolving Co salt, Ce salt and Al salt in water to form a mixed solution;

[0013] 2) Add the citric acid solution while stirring. After the addition is complete, continue stirring for 0.5 to 1.5 hours to obtain a mixed reaction solution;

[0014] 3) evaporating the mixed reaction solution prepared in step 2) until a viscous gel is formed, and then drying to obtain a solid;

[0015] 4) calcining the solid prepared in step 3) in air at 500-700° C. for 3-5 hours to obtain an oxidized catalyst precursor;

[0016] 5) The catalyst precursor prepared in step 4) is reduced at 500-600° C. for 1.5-2.5 hours under a hydrogen atmosphere to obtain Co / CeO 2 -Al 2 O 3 .

[0017] The molar ratio of the Co salt, Ce salt and Al salt is 0.02-0.6: 0.1-1: 2.

[0018] Furthermore, in the method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the above-mentioned Co / CeO2-Al2O3 catalyst, the cobalt loading amount in the Co / CeO2-Al2O3 is 1wt% to 15wt%.

[0019] Furthermore, in the method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the above-mentioned Co / CeO2-Al2O3 catalyst, the molar ratio of CeO2 to Al2O3 in the Co / CeO2-Al2O3 is 0.1~1:1.

[0020] Furthermore, in the method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the above-mentioned Co / CeO2-Al2O3 catalyst, the Co salt is Co(NO3)2·6H2O; the Ce salt is Ce(NO3)3·6H2O; and the Al salt is Al((NO3)3·9H2O.

[0021] Furthermore, in the method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the above-mentioned Co / CeO2-Al2O3 catalyst, the reaction solution is prepared by simultaneously dissolving folic acid and NaOH in deionized water to prepare a solution with a folic acid and NaOH concentration of 0.01-0.2 mol / L.

[0022] Furthermore, in the above-mentioned method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst, the acidification to precipitate solids is to drop strong acid into the collected liquid product until the pH of the solution reaches 7 to precipitate solids.

[0023] Furthermore, in the method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the above-mentioned Co / CeO2-Al2O3 catalyst, the strong acid is one of hydrochloric acid, nitric acid, and sulfuric acid.

[0024] Furthermore, in the above-mentioned method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by the Co / CeO2-Al2O3 catalyst, the washing in step 4) is performed by washing with deionized water; and the drying is performed by vacuum drying at 60-100°C.

[0025] Compared with the prior art, the technical solution provided by the present invention has the following technical advantages:

[0026] 1. The technical solution provided by the present invention has high activity when using Co / CeO2-Al2O3 as a catalyst to catalyze continuous hydrogenation to prepare tetrahydrofolic acid, with a folic acid conversion rate of up to 99%; and high selectivity, with a tetrahydrofolic acid selectivity of up to 99%.

[0027] 2. The technical solution provided by the present invention adopts the catalyst Co / CeO2-Al2O3 as the catalyst for continuous hydrogenation to prepare tetrahydrofolic acid. The catalyst has low cost and a simple preparation method.

[0028] 3. The technical solution provided by the present invention requires low temperature and pressure for the continuous hydrogenation process, and the reaction device is simple, which can be used for large-scale production. DETAILED DESCRIPTION

[0029] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these specific embodiments. Any person skilled in the art who is familiar with the present invention can make equivalent substitutions or changes based on the technical solutions and inventive concepts of the present invention within the technical scope disclosed in the present invention, and these changes should be included in the scope of protection of the present invention. Example 1

[0030] The present invention provides a method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by a 10Co / 1CeO2-Al2O3 catalyst. The method comprises the following steps in sequence:

[0031] 1) A 10Co / 1CeO2-Al2O3 catalyst was placed in a reaction column of a continuous flow hydrogenation apparatus with an inner diameter of 0.6 cm and a catalyst loading height of 10 cm. The reaction parameters of the continuous flow hydrogenation apparatus were set as follows: a hydrogen flow rate of 30 mL / min, a solution flow rate of 1 mL / min, a reaction temperature of 90°C, and a reaction pressure of 1 MPa.

[0032] 2) Prepare the reaction solution: Weigh 26.48 g of folic acid and 4.8 g of NaOH and dissolve them in 300 mL of deionized water. Stir thoroughly to obtain a 0.2 mol / L folic acid solution and a 0.2 mol / L NaOH solution.

[0033] 3) After the reaction system temperature reaches the temperature set in step 1) of 90°C and the pressure reaches 1 MPa, the reaction solution prepared in step 2) is flowed into the reaction column in step 1) at a rate of 1 mL / min using a double-plunger high-pressure constant-flow infusion pump. Simultaneously, the gas valve is opened to carry out the hydrogenation reaction, and the liquid product is then collected in a glove box under a nitrogen atmosphere.

[0034] 4) Acidification of the liquid product: 1 mol / L hydrochloric acid is added dropwise to the product to adjust the pH of the solution to 7. The precipitated solid is then washed 2-3 times with deionized water and dried under vacuum at 80°C to obtain tetrahydrofolate. The folate conversion rate is >99%, and the tetrahydrofolate selectivity is 99%.

[0035] The 10Co / 1CeO2-Al2O3 catalyst used in this embodiment was prepared by the following method:

[0036] 1) Weigh 4.94 g Co(NO₃)₂·6H₂O, 10.50 g Ceo(NO₃)₃·6H₂O, and 18.14 g Al((NO₃)₃·9H₂O) and dissolve them in 100 mL deionized water to obtain a mixed salt solution.

[0037] 2) Weigh 37.62 g of citric acid and dissolve it in 100 mL of deionized water. Then, add the solution dropwise to the mixed salt solution from step 1) while stirring. Continue stirring for 1 hour, then heat to 80°C and evaporate the solution until it forms a viscous colloid. Then, dry it at 120°C for 12 hours. Finally, calcine the resulting solid in air at 600°C for 4 hours to obtain a catalyst precursor.

[0038] 3) The catalyst precursor prepared in step 2) was reduced at 550°C for 2 hours under a hydrogen atmosphere to obtain a CeO2-Al2O3-supported metal cobalt catalyst 10Co / 1CeO2-Al2O3, wherein the Co loading was 10 wt% and the molar ratio of CeO2 to Al2O3 was 1:1.

[0039] Examples 2-5

[0040] The specific operation steps, reaction substrates, and catalysts of Examples 2-5 are the same as those of Example 1. The difference lies in the specific reaction parameters, which are shown in Table 1.

[0041] Table 1 Reaction parameters, folic acid conversion rate, and tetrahydrofolate selectivity data of Examples 2-5

[0042] Hydrogen flow rate mL / min Solution flow rate mL / min Temperature Pressure MPa Folic acid concentration mol / L Folate conversion rate% Tetrahydrofolate selectivity% Example 2 30 3 80 1 0.1 99 99 Example 3 60 3 100 3 0.2 99 99 Example 4 30 5 80 3 0.01 99 99 Example 5 100 5 120 5 0.2 99 99

[0043] Examples 6-11

[0044] The bulk operation steps and reaction substrates of Examples 6-11 are the same as those of Example 1. The differences are the specific reaction parameters and the catalysts used, as shown in Table 2.

[0045] Table 2 Reaction parameters and folic acid conversion rate, tetrahydrofolate selectivity data of Examples 6-11

[0046] Catalyst composition Hydrogen flow rate mL / min Solution flow rate mL / min Temperature Pressure MPa Folic acid concentration mol / L Folate conversion rate% Tetrahydrofolate selectivity% Example 6 <![CDATA[1Co / 1CeO2-Al2O3]]> 30 3 80 1 0.01 99 99 Example 7 <![CDATA[5Co / 1CeO2-Al2O3]]> 50 2 120 3 0.1 99 99 Example 8 <![CDATA[15Co / 1CeO2-Al2O3]]> 30 1 100 3 0.1 99 99 Example 9 <![CDATA[2Co / 0.1CeO2-Al2O3]]> 30 1 120 5 0.01 99 99 Example 10 <![CDATA[5Co / 0.4CeO2-Al2O3]]> 30 1 120 5 0.02 99 99 Example 11 <![CDATA[7Co / 0.8CeO2-Al2O3]]> 30 1 120 5 0.04 99 99

[0047] The preparation steps and process parameters of the catalysts used in Examples 6-11 are basically the same as those of the catalyst 10Co / 1CeO2-Al2O3 in Example 1. The difference lies in the different masses of Co(NO3)2·6H2O, Ceo(NO3)3·6H2O, Al((NO3)3·9H2O, and citric acid used. See Table 3 for details.

[0048] Table 3 Amounts of raw materials used in the catalyst preparation process described in Examples 6-11

[0049] catalyst <![CDATA[Co(NO3)2·6H2O(g)]]> Ce(NO3)3-6H2O(g) <![CDATA[Al(NO3)3·9H2O(g)]]> Citric acid (g) Example 6 1 Co / 1 CeO2-Al2O3 0.49 11.44 19.77 33.93 Example 7 <![CDATA[5Co / 1CeO2-Al2O3]]> 2.47 10.98 18.97 35.45 Example 8 <![CDATA[15Co / 1CeO2-Al2O3]]> 7.41 9.83 16.98 39.24 Example 9 <![CDATA[2Co / 0.1CeO2-Al2O3]]> 0.99 3.57 61.68 73.99 Example 10 <![CDATA[5Co / 0.4CeO2-Al2O3]]> 2.47 9.66 41.73 59.67 Example 11 <![CDATA[7Co / 0.8CeO2-Al2O3]]> 3.45 13.49 29.14 50.68

[0050] Comparative Example 1

[0051] This comparative example provides a method for preparing tetrahydrofolic acid by continuous hydrogenation using 10Co / CeO2 as a catalyst, wherein the Co loading is 10wt%, and the catalyst preparation and reaction conditions include the following:

[0052] 1) Preparation of 10Co / CeO2 precursor by citric acid method: 4.94g Co(NO3)2·6H2O and 22.72g Ceo(NO3)3·6H2O were weighed and dissolved in 100mL deionized water to obtain a mixed salt solution, and then 26.3g citric acid was weighed and dissolved in 100mL deionized water. The mixture was then added dropwise to the mixed salt solution under stirring. After stirring for 1 hour, the mixture was heated to 80°C and evaporated to form a viscous colloid. The mixture was then dried at 120°C for 12 hours. Finally, the obtained solid was calcined in air at 600°C for 4 hours to obtain a catalyst precursor. The reduction step was the same as in Example 1.

[0053] 2) Continuous hydrogenation was performed under the following conditions: a hydrogen flow rate of 30 mL / min, a solution concentration of 0.2 mol / L, a solution flow rate of 1 mL / min, a reaction temperature of 90°C, and a reaction pressure of 1 MPa. The folic acid conversion rate was 95%, and the tetrahydrofolate selectivity was 61%.

[0054] Comparative Example 2

[0055] This comparative example provides a method for preparing tetrahydrofolic acid by continuous hydrogenation using 10Co / Al2O3 as a catalyst, wherein the Co loading is 10wt%, and the catalyst preparation and reaction conditions include the following:

[0056] 1) Preparation of 10Co / Al2O3 precursor by citric acid method: 4.94g Co(NO3)2·6H2O and 66.17g Al((NO3)3·9H2O were weighed and dissolved in 100mL deionized water to obtain a mixed salt solution, 81.27g citric acid was weighed and dissolved in 150mL deionized water, and then added dropwise to the mixed salt solution under stirring. After stirring for 1 hour, the mixture was heated to 80°C and evaporated to form a viscous colloid, which was then dried at 120°C for 12 hours. Finally, the obtained solid was calcined in air at 600°C for 4 hours to obtain a catalyst precursor. The reduction step was the same as in Example 1.

[0057] 2) Continuous hydrogenation was performed under the following conditions: a hydrogen flow rate of 30 mL / min, a solution concentration of 0.2 mol / L, a solution flow rate of 1 mL / min, a reaction temperature of 90°C, and a reaction pressure of 1 MPa. The folic acid conversion rate was 15%, and the tetrahydrofolate selectivity was 46%.

[0058] It can be seen that the folic acid conversion rate and tetrahydrofolate selectivity of the continuous flow hydrogenation of folic acid to produce tetrahydrofolate catalyzed by the catalyst provided in the examples of the present application are significantly higher than the folic acid conversion rate and tetrahydrofolate selectivity of the continuous flow hydrogenation of folic acid to produce tetrahydrofolate catalyzed by the catalyst used in the comparative example.

[0059] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be considered as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid using a Co / CeO2-Al2O3 catalyst, characterized in that: The method includes the following steps in sequence: 1) Fill the reaction column of a continuous flow hydrogenation apparatus with the catalyst Co / CeO2-Al2O3 and set the reaction parameters of the continuous flow hydrogenation apparatus as follows: hydrogen flow rate 30-100 mL / min, solution flow rate 1-5 mL / min, reaction temperature 80-120°C, and reaction pressure 1-5 MPa; 2) When the reaction system reaches the temperature and pressure set in step 1), the reaction solution is flowed into the reaction column through a high-pressure constant-flow infusion pump, and the gas valve is opened to carry out the hydrogenation reaction; 3) After the temperature, pressure, gas flow rate, and liquid flow rate of the reaction system stabilize, collect the liquid product in a glove box under a nitrogen atmosphere; 4) Acidifying the liquid product collected in step 3) in a glove box to precipitate a solid, washing, and drying to obtain tetrahydrofolic acid; The reaction solution in step 2) is folic acid solution and NaOH solution.

2. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid using a Co / CeO2-Al2O3 catalyst according to claim 1, characterized in that: The Co / CeO2-Al2O3 is prepared by the following steps: 1) Dissolving Co salt, Ce salt and Al salt in water to form a mixed solution; 2) Add the citric acid solution while stirring. After the addition is complete, continue stirring for 0.5 to 1.5 hours to obtain a mixed reaction solution; 3) evaporating the mixed reaction solution prepared in step 2) until a viscous gel is formed, and then drying to obtain a solid; 4) calcining the solid prepared in step 3) in air at 500-700° C. for 3-5 hours to obtain an oxidized catalyst precursor; 5) reducing the catalyst precursor prepared in step 4) at 500-600° C. for 1.5-2.5 hours under a hydrogen atmosphere to obtain Co / CeO2-Al2O3; The molar ratio of the Co salt, Ce salt and Al salt in step 1) is 0.02-0.6: 0.1-1:

2.

3. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 2, characterized in that: The cobalt loading in the Co / CeO2-Al2O3 is 1wt% to 15wt%.

4. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 2, characterized in that: The molar ratio of CeO2 to Al2O3 in the Co / CeO2-Al2O3 is 0.1-1:

1.

5. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 2, characterized in that: The Co salt is Co(NO3)2·6H2O; the Ce salt is Ce(NO3)3·6H2O; and the Al salt is Al((NO3)3·9H2O.

6. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 1, characterized in that: The reaction solution is prepared by dissolving folic acid and NaOH in deionized water at the same time to prepare a solution with the concentrations of both folic acid and NaOH being 0.01-0.2 mol / L.

7. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 1, characterized in that: The acidification to precipitate solids is to drop strong acid into the collected liquid product until the pH of the solution reaches 7, thereby precipitating solids.

8. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 7, characterized in that: The strong acid is one of hydrochloric acid, nitric acid and sulfuric acid.

9. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 7, characterized in that: The washing is performed with deionized water.

10. The method for preparing tetrahydrofolic acid by continuous flow hydrogenation of folic acid catalyzed by Co / CeO2-Al2O3 catalyst according to claim 1, characterized in that: The drying is vacuum drying at 60-100°C.