Method for recovering and preparing folic acid from (6R)-tetrahydrofolic acid p-toluenesulfonate waste liquid

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly discloses a method for recovering and preparing folic acid from (6R)-tetrahydrofolic acid p-toluenesulfonate waste liquid. The method comprises the following steps: obtaining an aqueous solution containing (6R)-tetrahydrofolic acid p-toluenesulfonate, adjusting the pH value of the reaction system to 10-12 by using sodium carbonate to obtain (6R)-sodium tetrahydrofolate and sodium p-toluenesulfonate, then carrying out selective activation and oxidation on the (6R)-sodium tetrahydrofolate by using O2 in the presence of a Mn (salen) catalyst, and finally carrying out purification and purification on the (6R)-sodium tetrahydrofolate to obtain the (6R)-tetrahydrofolate. Then adjusting the pH value of the reaction system to 3-4 under the action of an antioxidant, and carrying out filter pressing to obtain the folic acid with high selectivity and high yield. The method can improve the recovery, conversion and utilization of by-products, reduce the emission of pollutants, improve the oxidation selectivity of tetrahydrofolic acid and reduce the generation of by-products.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a method for recovering and preparing folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid. Background Art

[0002] Active folic acid, also known as (6S)-5-methyltetrahydrofolate (5-MTHF), is the main component of natural folic acid and the active product of folic acid metabolism in the body. It can be directly absorbed and utilized by the human body without undergoing metabolic conversion. Compared with other forms of folic acid, it has no upper tolerance limit and will not mask vitamin B12 deficiency. As a vitamin preparation, it has the effects of preventing neural tube defects, treating depression, treating megaloblastic anemia, and preventing and treating Alzheimer's disease. Therefore, it has unparalleled advantages over other folic acid drugs, has a good market prospect, and has become a hot spot and difficulty in research.

[0003] At present, the industrial preparation method of 5-methyltetrahydrofolate is to use folic acid as raw material and sodium borohydride as reducing agent to obtain tetrahydrofolate, which is then reacted with formaldehyde and reduced with sodium borohydride to obtain 5-methyltetrahydrofolate, and then the racemic (6R,S)-5-methyltetrahydrofolate is split by a chiral organic base to obtain (6S)-5-methyltetrahydrofolate (WO2008031284A1, US5457202A, WO2013025203A, etc.). However, in this synthetic route, the chiral splitting step is too late, resulting in a low overall yield of the product.

[0004] Another preparation route can also be used, with folic acid as a raw material and sodium borohydride as a reducing agent to obtain tetrahydrofolate, in which p-toluenesulfonic acid is used to form a salt, and the difference in solubility in water after the R / S configuration and p-toluenesulfonic acid salt is used to separate (6S)-tetrahydrofolate p-toluenesulfonate, which is then reacted with formaldehyde and reduced with sodium borohydride to obtain (6S)-5-methyltetrahydrofolate (CN201810146297.0). This route has a high yield, but there are also some problems, such as (6R)-tetrahydrofolate p-toluenesulfonate in the filtrate, which is discharged as waste liquid, which wastes chiral substances and increases the amount of waste liquid.

[0005] Jing Bin's master's thesis (Study on the Synthesis of Optically Pure (6S)-5-Methyltetrahydrofolate and Its Amino Acid Ester Derivatives) first disclosed the recycling of (6R)-tetrahydrofolate. This work uses (6R)-tetrahydrofolate p-toluenesulfonate as the starting material to first obtain pure (6R)-tetrahydrofolate with a loss of nearly 50%. Then, (6R)-tetrahydrofolate is selectively oxidized to obtain folic acid, thereby realizing the recycling of materials. Under the optimal process conditions (reaction system pH value of 7.0, O2 throughout the process, 0℃ reaction for 6h), the yield of (6R)-tetrahydrofolate oxidized to folic acid is 88.5%. This work clearly points out that when (6R)-tetrahydrofolate p-toluenesulfonate is used directly, sodium carbonate is added to neutralize p-toluenesulfonic acid, and then the pH value is adjusted to neutral before directly passing O2 for oxidation. The yield is only 46.0%, indicating that in the presence of free p-toluenesulfonic acid, free p-toluenesulfonic acid will induce side reactions. Therefore, in the process of oxidizing (6R)-tetrahydrofolate to folic acid, free p-toluenesulfonic acid needs to be removed. Specifically, the pH value of the reaction system is adjusted four times, the first two times to obtain (6R)-tetrahydrofolate and the last two times to obtain folic acid. The first time the pH value of the reaction system is adjusted, a 10% sodium carbonate solution is used to adjust the pH value of the reaction system to about 8.0, and (6R)-tetrahydrofolate toluenesulfonate is converted into free (6R)-tetrahydrofolate and sodium p-toluenesulfonate; the second time the pH value is adjusted, the pH value of the reaction system is adjusted to 3.0-4.0 with dilute hydrochloric acid, so that free (6R)-tetrahydrofolate is precipitated, and the purpose of separating (6R)-tetrahydrofolate from p-toluenesulfonic acid is achieved; the third time the pH value is adjusted, a 10% sodium carbonate solution is used to adjust the pH value of the system to neutral, and (6R)-tetrahydrofolate is oxidized; the fourth time the pH value is adjusted, the pH value of the reaction system is adjusted to 3.0-4.0 with dilute hydrochloric acid, so that folic acid is precipitated. The removal of free p-toluenesulfonic acid in this work is complicated, and a certain amount of raw material is lost. The selectivity and yield of oxidizing (6R)-tetrahydrofolate to raw folic acid using O2 as an oxidant need to be further improved.

[0006] How to solve the above problems has become a difficult problem in the development of an industrial preparation method for (6S)-5-methyltetrahydrofolate. Summary of the invention

[0007] In view of the deficiencies in the above-mentioned prior art, the present invention aims to provide a method for recovering and preparing folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid. The present invention proposes to dissociate the byproduct (6R)-tetrahydrofolate p-toluenesulfonate filtrate after the splitting of tetrahydrofolate by p-toluenesulfonic acid salification in situ (the first pH adjustment) to (6R)-tetrahydrofolate sodium salt, use a weak oxidant O2 to selectively activate and oxidize (6R)-tetrahydrofolate sodium salt under the catalyst of Mn (salen), and then adjust the acid (the second pH adjustment) and filter press under the action of an antioxidant, so as to obtain folic acid with high selectivity and high yield. The p-toluenesulfonic acid and Mn (salen) catalyst in the filtrate separated by filter press can be recycled and reused. This method can improve the recovery and conversion of by-products, reduce the emission of pollutants, improve the selectivity of tetrahydrofolate oxidation, and reduce the generation of by-products.

[0008] The technical concept of the present invention is: obtaining an aqueous solution containing (6R)-tetrahydrofolate p-toluenesulfonate, adjusting the pH value of the reaction system to 10-12 with sodium carbonate to obtain (6R)-sodium tetrahydrofolate and sodium p-toluenesulfonate, then using O2 to selectively activate and oxidize the (6R)-sodium tetrahydrofolate in the presence of a Mn(salen) catalyst, and then adjusting the pH value of the reaction system to 3-4 under the action of an antioxidant, and filtering by pressure to obtain folic acid with high selectivity and high yield.

[0009] In order to achieve the above object, the present invention specifically adopts the following technical solutions:

[0010] A method for recovering and preparing folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid comprises the following steps:

[0011] S1. Using folic acid as a raw material, reducing it with sodium borohydride and purifying it to obtain racemic tetrahydrofolic acid;

[0012] S2, using p-toluenesulfonic acid as a salt-forming resolving agent to obtain a red filtrate containing (6R)-tetrahydrofolate p-toluenesulfonate;

[0013] S3. Add solid sodium carbonate to the red filtrate obtained in step S2, adjust the pH value of the filtrate to 10-12, and then add anhydrous ethanol and Mn (salen) catalyst in sequence. After the catalyst is completely dissolved, transfer the reaction system to an autoclave, then purge the autoclave with oxygen to completely remove the air therein, seal the autoclave, fill it with 0.5-2MPa oxygen, and then carry out selective oxidation at 0-5°C for 2.5-8h. After the reaction is completed, maintain the reaction temperature at 0-5°C, add a certain amount of antioxidant, and then add hydrochloric acid to adjust the pH value of the mixed solution to 3-4. A large amount of light yellow precipitate is generated, filter press, wash the filter cake with a small amount of water, and vacuum dry to obtain folic acid.

[0014] Furthermore, the method for obtaining racemic tetrahydrofolic acid in step S1 is as follows: under a nitrogen atmosphere, adding sodium hydroxide solution to a suspension of folic acid to make the reaction solution clear, controlling the temperature below 25°C, slowly dripping sodium borohydride solution therein, raising the temperature to 60-70°C after dripping, reacting for 2h, cooling to 10°C, adding a certain amount of antioxidant, dripping dilute hydrochloric acid to adjust the pH value of the mixed solution to 3-4, stirring for 1h, precipitating a large amount of solid, filtering, rinsing the filter cake with a small amount of water until the pH value of the filtrate is 7, and vacuum drying to obtain racemic tetrahydrofolic acid; wherein the molar ratio of folic acid: sodium hydroxide: sodium borohydride: antioxidant is 1:(3-5):(6-8):(0.05-0.1); the antioxidant is selected from any one of ascorbic acid, sodium pyrosulfite, sodium sulfite, and lipoic acid, preferably ascorbic acid.

[0015] Further, in step S2, a red filtrate containing (6R)-tetrahydrofolate toluenesulfonate is obtained by: dissolving racemic tetrahydrofolate in deionized water under nitrogen protection, heating to 50-60° C., adding an aqueous solution of toluenesulfonic acid dropwise, and reacting for 4 hours after the addition is completed. A large amount of precipitate is generated, and the precipitate is filtered while hot, and the filter cake is washed with a small amount of hot water. The obtained red filtrate is the red filtrate containing (6R)-tetrahydrofolate toluenesulfonate; wherein the filter cake is vacuum dried to obtain a white solid (6S)-tetrahydrofolate toluenesulfonate;

[0016] Furthermore, in step S2, the molar ratio of racemic tetrahydrofolate:p-toluenesulfonic acid is 1:(1-1.5), preferably 1:(1-1.2).

[0017] Further, in step S3, the structural formula of the Mn(salen) catalyst is as shown below:

[0018]

[0019] In the formula, the R1 group is tert-butyl and the R2 group is ethyl.

[0020] Furthermore, in step S3, the autoclave is sealed and filled with 1-2 MPa oxygen, and then selective oxidation is carried out at 0-5° C. for 2.5-4 hours.

[0021] Furthermore, in step S3, the molar ratio of (6R)-tetrahydrofolate toluenesulfonate to the Mn(salen) catalyst in the red filtrate is 1:(0.01-0.05).

[0022] Furthermore, in step S3, the volume ratio of the red filtrate to anhydrous ethanol is (4-6):1.

[0023] Furthermore, in step S3, the molar ratio of (6R)-tetrahydrofolate toluenesulfonate to the antioxidant in the red filtrate is 1:(0.05-0.1).

[0024] Furthermore, in step S3, the antioxidant is selected from any one of ascorbic acid, sodium pyrosulfite, sodium sulfite, and lipoic acid, preferably ascorbic acid.

[0025] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0026] First, by oxidizing the byproduct (6R)-sodium tetrahydrofolate, raw material folic acid is obtained, which greatly reduces the emission of pollutants, converts waste into raw materials, and reduces production costs;

[0027] Second, (6R)-sodium tetrahydrofolate is selectively oxidized at high pressure and low temperature using a weak oxidant O2 in the presence of a Mn(salen) catalyst to obtain folic acid with a purity of more than 99% and a recovery rate of about 95%, which greatly reduces the possibility of obtaining other oxidation by-products due to oxidation of tetrahydrofolate and folic acid, effectively improves the selectivity of the reaction, and increases the yield and purity of folic acid.

[0028] Third, (6R)-tetrahydrofolic acid is unstable under acidic conditions and is easily decomposed into other byproducts. It is relatively stable under alkaline conditions and is difficult to oxidize using weak oxidants. This is also the reason why the optimal pH for oxidizing (6R)-tetrahydrofolic acid using O2 (O2 is a weak oxidant) as an oxidant without assisting other catalysts is 7.0 in the prior art. The present invention uses Mn (salen) catalyst to selectively activate tetrahydrofolic acid sodium salt under strong alkaline conditions (pH is 10-12), improves oxidation efficiency (shortening reaction time), and improves the selectivity of oxidation products, thereby obtaining folic acid with high selectivity and high yield. At the same time, the present invention uses Mn (salen) catalyst, and there is no need to separate and remove p-toluenesulfonic acid, which is simpler to operate relative to the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The present invention is a flow chart of the method for recovering and preparing folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid. DETAILED DESCRIPTION

[0030] In order to make the purpose and technical solution of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] In the following examples, the Mn (salen) catalyst used was purchased from Alfa Aesar (China) Chemical Co., Ltd., and its structural formula is shown below:

[0032]

[0033] Wherein, R1 and R2 groups are indicated in each example.

[0034] Example 1: A method for recovering folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid, comprising the following steps:

[0035] S1. At 25°C and nitrogen atmosphere, add 44.1g (0.1mol) folic acid to 320g deionized water, add sodium hydroxide solution (12g sodium hydroxide (0.3mol) dissolved in 80g deionized water) to the suspension of folic acid to make the reaction solution clear. Control the temperature below 25°C, slowly add sodium borohydride solution (22.8g sodium borohydride (0.6mol) dissolved in 40g water) to the above mixed solution, after the dripping, heat to 75°C for 2h, and the reaction is complete. The mixture was cooled to 10°C, 0.88 g of ascorbic acid (0.005 mol) was added, and 2 mol / L hydrochloric acid was added dropwise to adjust the pH value of the mixture to 4. The mixture was stirred for 1 h, and a large amount of solid was precipitated. The solid was filtered and the filter cake was rinsed with a small amount of deionized water until the pH value of the filtrate reached 7. The solid was dried in vacuo to obtain racemic tetrahydrofolic acid, which was recorded as R / S-tetrahydrofolic acid. The yield was 97%, and the solid was characterized as follows: 1 H NMR (300MHz, CDCl3): δ = 12.58 (s, 1H), 12.03 (s, 1H), 11.31 (s, 1H), 8.85 (s, 1H), 7.60 (d, J = 7.4Hz, 2H), 7.29 (s, 1H), 6.82 (d, J = 7.4H) z,2H),6.61(s,2H),4.54-4.56(m,1H),3.11-3.45(m,4H),2.52-2.54(m,1H),2.32-2.35(m,2H),2.08-2.10(m,2H),1.51(s,2H)ppm; 13 CNMR (75MHz, CDCl3): δ=178.2,174.5,167.3,156.2,153.1,150.9,148.1,130.1,122.3,112.0,86.1,60.4,56.5,48.2,41.5,30.2,26.3ppm.

[0036] S2. Under nitrogen protection, 44.5 g (0.1 mol) of R / S-tetrahydrofolate was dissolved in 500 g of deionized water. After the temperature was raised to 50° C., an aqueous solution of p-toluenesulfonic acid {17.2 g (0.1 mol) of p-toluenesulfonic acid was dissolved in 100 g of water} was added dropwise. After the addition was completed, the mixture was kept warm for 4 h. A large amount of precipitate appeared. The mixture was filtered while hot. The filter cake was washed with a small amount of hot water (50° C.) and dried in vacuo to obtain (6S)-tetrahydrofolate p-toluenesulfonate as a white solid. The yield was 95%. EE value is 99.5%, detected by liquid chromatography, chiral column model: CHIRALPAK HAS (150mm×4mm×5μm), Agilent, column temperature: 30°C, UV detector wavelength: 280nm, mobile phase: sodium dihydrogen phosphate dihydrate solution-acetonitrile (97:3) (pH=6.8), flow rate: 1.0mL / min, t(minor)=6.05, t(major)=7.96. Its characterization is as follows: 1 H NMR (300MHz, CDCl3): δ = 12.58 (s, 1H), 12.03 (s, 1H), 11.31 (s, 1H), 8.85 (s, 1H), 8.4 8(s,1H),7.77(d,J=6.8Hz,2H), 7.60(d,J=7.4Hz,2H), 7.46(d,J=6.8Hz,2H), 7.29( s,1H),6.82(d,J=7.4Hz,2H),6.61(s,2H),4.54-4.56(m,1H),3.11-3.45(m,4H),2. 52-2.54(m,1H),2.44(s,3H),2.32-2.35(m,2H),2.08-2.10(m,2H),1.51(s,2H)ppm; 13 C NMR (75MHz, CDCl3): δ=178.2,174.5,167.3,156.2,153.1,150.9,148.1,142.2,138.1, 130.4,130.1,126.6,122.3,112.0,86.1,60.4,56.5,48.2,41.5,30.2,26.3,21.3ppm.

[0037] The red filtrate obtained is an aqueous solution containing (6R)-tetrahydrofolate p-toluenesulfonate;

[0038] S3, solid sodium carbonate was added to the red filtrate (600mL) obtained in step S2, the pH value of the filtrate was adjusted to 10, and then 150mL of anhydrous ethanol and 0.52g (0.001mol) of Mn (salen) catalyst (R1 group is tert-butyl; R2 group is ethyl) were added in sequence, until the catalyst was completely dissolved, the reaction system was transferred to an autoclave, and then the autoclave was purged with oxygen to completely remove the air therein, and after the autoclave was sealed, the oxygen pressure was maintained at 1MPa, and the temperature was lowered to 0°C, and selective oxidation was carried out for 4h. The reaction was complete, and the reaction temperature was maintained at 0°C. After adding 0.88g (0.005mol) of ascorbic acid, 2mol / L of hydrochloric acid was added, and after the pH value of the mixed solution was adjusted to 3, a large amount of light yellow precipitates were generated, and filter pressing was performed, and the filter cake was washed with a small amount of water and dried in vacuo to obtain 20.7g of folic acid, with a yield of 94% and a purity of 99.5% (the purity was tested by liquid chromatography external standard method), which was characterized as follows: 1 H NMR (300MHz, CDCl3): δ = 12.60 (s, 1H), 12.01 (s, 1H), 10.30 (s, 1H), 9.05 (s, 1H), 8.88 (s, 1H), 7.60 (d, J = 7.2Hz, 2H), 6.8 5(d,J=7.2Hz,2H),6.62(s,2H),6.26(s,1H),4.54-4.56(m,1H),4.38(s,2H),2.32-2.35(m,2H),2.08-2.10(m,2H),ppm; 13 C NMR (75MHz, CDCl3): δ=178.3,174.4,167.5,157.2,153.7,152.6,150.1,147.2,130.2,129.3,122.5,112.2,56.6,47.5,30.3,26.1ppm.

[0039] S4, the filtrate separated by pressure filtration in step S3 is mainly ethanol, containing p-toluenesulfonic acid and Mn (salen) catalyst, and the ethanol in the filtrate is removed by reduced pressure distillation. As the ethanol content in the filtrate decreases, the Mn (salen) catalyst is continuously precipitated. After filtration, the filter cake is vacuum dried at 50° C. for 12 hours to obtain 0.50 g of the recovered catalyst, with a recovery rate of 96%. The remaining filtrate (about 560 mL) is a concentrated solution containing p-toluenesulfonic acid, which can be repeatedly applied to step S2 as a resolving agent.

[0040] Example 2: A method for recovering folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid, comprising the following steps:

[0041] First, step S1-step S2 are performed according to the method of Example 1 to obtain a red filtrate, which is an aqueous solution containing (6R)-tetrahydrofolate p-toluenesulfonate;

[0042] S3, solid sodium carbonate was added to the red filtrate (600mL) obtained in step S2, the pH value of the filtrate was adjusted to 12, and then 150mL of anhydrous ethanol and 1.04g (0.002mol) of Mn (salen) catalyst (R1 group is tert-butyl; R2 group is ethyl) were added in sequence, until the catalyst was completely dissolved, the reaction system was transferred to an autoclave, and then the autoclave was purged with oxygen to completely remove the air therein, and after the autoclave was sealed, the oxygen pressure was maintained at 0.5MPa, and the temperature was lowered to 0°C for selective oxidation, and the reaction was carried out for 8h. The reaction was complete, and the reaction temperature was maintained at 0°C. After adding 0.88g (0.005mol) of ascorbic acid, 2mol / L of hydrochloric acid was added, and after the pH value of the mixed solution was adjusted to 3, a large amount of light yellow precipitates were generated, and filter press was performed, and the filter cake was washed with a small amount of water and dried in vacuo to obtain 21.2g of folic acid, with a yield of 96% and a purity of 99.4%.

[0043] Example 3: A method for recovering folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid, comprising the following steps:

[0044] First, step S1-step S2 are performed according to the method of Example 1 to obtain a red filtrate, which is an aqueous solution containing (6R)-tetrahydrofolate p-toluenesulfonate;

[0045] S3, solid sodium carbonate was added to the red filtrate (600 mL) obtained in step S2, the pH value of the filtrate was adjusted to 12, and then 150 mL of anhydrous ethanol and 1.04 g (0.002 mol) of Mn (salen) catalyst (R1 group is tert-butyl; R2 group is ethyl) were added in sequence, until the catalyst was completely dissolved, the reaction system was transferred to an autoclave, and then the autoclave was purged with oxygen to completely remove the air therein, and after the autoclave was sealed, the oxygen pressure was maintained at 2 MPa, and the temperature was lowered to 0 ° C, and selective oxidation was carried out for 2.5 h. The reaction was complete, and the reaction temperature was maintained at 0 ° C. After adding 0.88 g (0.005 mol) of ascorbic acid, 2 mol / L of hydrochloric acid was added, and after the pH value of the mixed solution was adjusted to 3, a large amount of light yellow precipitates were generated, and filter press was performed, and the filter cake was washed with a small amount of water and vacuum dried to obtain 21.6 g of folic acid, with a yield of 98% and a purity of 95.6%.

[0046] As can be seen from Examples 1-3, the present invention adjusts the pH value of the byproduct (6R)-tetrahydrofolate p-toluenesulfonate solution after the splitting of tetrahydrofolate by p-toluenesulfonic acid to 10-12 (strong alkalinity) for in-situ dissociation, and then directly uses O2 to selectively activate and oxidize the (6R)-tetrahydrofolate sodium salt under the catalyst of Mn (salen), and then adjusts the pH value of the reaction system to 3 under the action of an antioxidant, and filter presses to obtain folic acid with a purity of more than 99% and a recovery rate of more than 90%. In the method for recovering folic acid by oxidizing the byproduct (6R)-tetrahydrofolate p-toluenesulfonate after the splitting of tetrahydrofolate by p-toluenesulfonic acid, it is not necessary to separate and remove p-toluenesulfonic acid before using O2 for oxidation, that is, the operation is simpler than the prior art. The invention uses a weak oxidant O2 to carry out high-pressure and low-temperature selective oxidation on (6R)-tetrahydrofolic acid in the presence of a Mn(salen) catalyst, wherein the oxygen pressure is 0.5-2MPa, the higher the pressure, the shorter the reaction time, and the oxygen pressure is preferably 1-2MPa, and then the selective oxidation is carried out at 0-5°C for 2.5-4h, the oxidation time is short, the possibility of generating by-products is low, the selectivity of the oxidation product is improved, and folic acid is obtained with high selectivity and high yield.

[0047] Example 4: A method for recovering folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid, comprising the following steps:

[0048] First, step S1-step S2 are performed according to the method of Example 1 to obtain a red filtrate, which is an aqueous solution containing (6R)-tetrahydrofolate p-toluenesulfonate;

[0049] S3, solid sodium carbonate was added to the red filtrate (600mL) obtained in step S2, the pH value of the filtrate was adjusted to 8, and then 150mL of anhydrous ethanol and 1.04g (0.002mol) of Mn (salen) catalyst (R1 group is tert-butyl; R2 group is ethyl) were added successively, until the catalyst was completely dissolved, the reaction system was transferred to an autoclave, and then the autoclave was purged with oxygen to completely remove the air therein, and after the autoclave was sealed, the oxygen pressure was maintained at 0.5MPa, cooled to 0°C, and oxidation was carried out. After the reaction was carried out for 8h, the reaction temperature was maintained at 0°C, and after 0.88g (0.005mol) of ascorbic acid was added, the pH value of the mixed solution was adjusted to 3 with 1mol / L hydrochloric acid, and a light yellow solid was separated out, and filter press was performed, and the filter cake was washed with a small amount of water and dried in vacuo to obtain 8.83g of product. The yield was 40% and the purity was 86% by nuclear magnetic resonance detection.

[0050] This example illustrates that the pH value of the byproduct (6R)-tetrahydrofolate toluenesulfonate solution after the splitting of tetrahydrofolate by p-toluenesulfonic acid is adjusted to 8. At this time, the solution contains free (6R)-tetrahydrofolate and sodium p-toluenesulfonate. Then, it is oxidized using O2 in the presence of a Mn(salen) catalyst, and then the pH value of the reaction system is adjusted to 3 under the action of an antioxidant. Then, it is filtered and filtered, but high-purity and high-yield folic acid cannot be obtained.

[0051] It can be seen from Examples 1, 2 and 3 that in the system of the present invention, the pH value of the byproduct (6R)-tetrahydrofolate p-toluenesulfonate solution after the splitting of tetrahydrofolate by p-toluenesulfonic acid needs to be adjusted to 10-12 for in-situ dissociation to obtain (6R)-sodium tetrahydrofolate, which is conducive to the subsequent low-temperature selective oxidation using oxygen as an oxidant under a Mn(salen) catalyst.

[0052] Example 5: A method for recovering folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid, comprising the following steps:

[0053] First, step S1-step S2 are performed according to the method of Example 1 to obtain a red filtrate, which is an aqueous solution containing (6R)-tetrahydrofolate p-toluenesulfonate;

[0054] S3. Solid sodium carbonate was added to the red filtrate (600 mL) obtained in step S2, and the pH value of the filtrate was adjusted to 10. Then 150 mL of anhydrous ethanol and 1.16 g (0.002 mol) of Mn (salen) catalyst (R1 group is tert-butyl; R2 group is tert-butyl) were added in sequence. After the catalyst was completely dissolved, the reaction system was transferred to an autoclave, and then the autoclave was purged with oxygen to completely remove the air therein. After the autoclave was sealed, the oxygen pressure was maintained at 0.5 MPa, and the temperature was lowered to 0° C. for selective oxidation. The reaction was continued for 4 h. Liquid chromatography detection revealed that a large amount of tetrahydrofolate was present, and the conversion rate was low. The reaction time was further extended to 8 h. Liquid chromatography revealed that a small amount of tetrahydrofolate remained and other impurities appeared. The reaction product was no longer single. The reaction time was further extended to 9 h. After the reaction was completed, the reaction temperature was maintained at 0°C. 0.88 g (0.005 mol) of ascorbic acid was added, and then 2 mol / L hydrochloric acid was added. After adjusting the pH value of the mixed solution to 3, a large amount of light yellow precipitate was generated. The mixture was filtered, the filter cake was washed with a small amount of water, and vacuum dried to obtain 20.3 g of folic acid with a yield of 92% and a purity of 89.2%.

[0055] It can be seen from Examples 2 and 5 that when the R1 and R2 groups in the Mn(salen) catalyst are both tert-butyl, the steric hindrance of the catalyst is greatly increased, which hinders the central metal of the catalyst from approaching and activating tetrahydrofolate, thereby resulting in a decrease in the activation ability of the catalyst, and the tetrahydrofolate is exposed to an oxygen atmosphere for too long, resulting in side reactions.

[0056] The above is only a specific embodiment of the present invention, and its description is relatively specific and detailed, but it cannot be understood as limiting the scope of protection requested by the claims of the present invention. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for recovering folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid, characterized in that: The steps include: S1. Using folic acid as a raw material, reducing it with sodium borohydride and purifying it to obtain racemic tetrahydrofolic acid; S2, using p-toluenesulfonic acid as a salt-forming resolving agent to obtain a red filtrate containing (6R)-tetrahydrofolate p-toluenesulfonate; S3, adding solid sodium carbonate to the red filtrate obtained in step S2, adjusting the pH value of the filtrate to 10-12, and then adding anhydrous ethanol and Mn (salen) catalyst in sequence, until the catalyst is completely dissolved, transferring the reaction system to an autoclave, then purging the autoclave with oxygen to completely remove the air therein, sealing the autoclave and filling it with 0.5-2MPa oxygen, and then performing selective oxidation at 0-5°C for 2.5-8h. After the reaction is completed, the reaction temperature is maintained at 0-5°C, a certain amount of antioxidant is added, and hydrochloric acid is added to adjust the pH value of the mixed solution to 3-4, a large amount of light yellow precipitate is generated, and filter pressing is performed, the filter cake is washed with a small amount of water, and vacuum drying is performed to obtain folic acid; The structural formula of the Mn(salen) catalyst is shown below: In the formula, the R1 group is tert-butyl and the R2 group is ethyl.

2. The method according to claim 1, characterized in that In step S3, the autoclave is sealed and filled with 1-2 MPa oxygen, and then selective oxidation is carried out at 0-5° C. for 2.5-4 hours.

3. The method according to claim 1, characterized in that In step S3, the molar ratio of (6R)-tetrahydrofolate toluenesulfonate to the Mn(salen) catalyst in the red filtrate is 1:(0.01-0.05); and / or The volume ratio of the red filtrate to anhydrous ethanol is (4-6):

1.

4. The method according to claim 1, characterized in that: In step S3, the molar ratio of (6R)-tetrahydrofolate toluenesulfonate to the antioxidant in the red filtrate is 1:(0.05-0.1); and / or The antioxidant is selected from any one of ascorbic acid, sodium pyrosulfite, sodium sulfite and lipoic acid.

5. The method according to claim 1, characterized in that The method for obtaining the red filtrate containing (6R)-tetrahydrofolate toluenesulfonate in step S2 is as follows: under nitrogen protection, racemic tetrahydrofolate is dissolved in deionized water, the temperature is raised to 50-60° C., an aqueous solution of toluenesulfonic acid is added dropwise, and after the addition is completed, the reaction is kept warm for 4 hours, a large amount of precipitate appears, and the precipitate is filtered while hot, and the filter cake is washed with a small amount of hot water. The obtained red filtrate is the red filtrate containing (6R)-tetrahydrofolate toluenesulfonate.

6. The method according to claim 5, characterized in that In step S2, the molar ratio of racemic tetrahydrofolate:p-toluenesulfonic acid is 1:(1-1.5).

7. The method according to claim 6, characterized in that In step S2, the molar ratio of racemic tetrahydrofolate:p-toluenesulfonic acid is 1:(1-1.2).

8. The method according to claim 1, characterized in that The method for obtaining racemic tetrahydrofolic acid in step S1 is as follows: under a nitrogen atmosphere, sodium hydroxide solution is added to a suspension of folic acid to make the reaction liquid clear, the temperature is controlled below 25° C., sodium borohydride solution is slowly added dropwise thereto, after the addition is completed, the temperature is raised to 60-70° C., the reaction is carried out for 2 h, the temperature is lowered to 10° C., a certain amount of antioxidant is added, dilute hydrochloric acid is added dropwise to adjust the pH value of the mixed solution to 3-4, the mixture is stirred for 1 h, a large amount of solid is precipitated, the mixture is filtered, the filter cake is rinsed with a small amount of water until the pH value of the filtrate is 7, and the mixture is dried in vacuo to obtain racemic tetrahydrofolic acid.

9. The method according to claim 8, characterized in that In step S1, the molar ratio of folic acid: sodium hydroxide: sodium borohydride: antioxidant is 1: (3-5): (6-8): (0.05-0.1); and / or The antioxidant is selected from any one of ascorbic acid, sodium pyrosulfite, sodium sulfite and lipoic acid.

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