A method for recovering and preparing folic acid from (6R)-tetrahydrofolate p-toluenesulfonate waste liquid

Abstract

The invention belongs to the field of pharmaceutical chemical technology, specifically discloses a method for recovering folic acid from (6R) tetrahydrofolate toluenesulfonate waste liquid. The inventive method includes the steps of: obtaining an aqueous solution containing (6R) tetrahydrofolate toluenesulfonate, adjusting the pH value of the reaction system with sodium carbonate to 10 12, obtaining (6R) tetrahydrofolate sodium and sodium p-toluenesulfonate, then using O2 to selectively activate oxidation of (6R) tetrahydrofolate sodium salt under Mn (salen) catalyst, then adjusting the pH value of the reaction system under the action of an antioxidant to 3 4, filter press, and folic acid can be obtained with high selectivity and high yield. The method can improve the recovery and conversion of by-products, reduce the discharge of pollutants, improve the selectivity of tetrahydrofolate oxidation, and reduce the generation of by-products.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and particularly 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 metabolite of folic acid in the body. It can be directly absorbed and utilized by the body without further 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 benefits such as preventing neural tube defects, treating depression, treating megaloblastic anemia, and preventing and treating Alzheimer's disease. Therefore, it possesses advantages unmatched by other folic acid drugs, has excellent market prospects, and has become a hot topic and a difficult point of research.

[0003] The current industrial method for preparing 5-methyltetrahydrofolate uses folic acid as a raw material and sodium borohydride as a reducing agent to obtain tetrahydrofolate, which is then reacted with formaldehyde and reduced with sodium borohydride to obtain 5-methyltetrahydrofolate. The racemic (6R,S)-5-methyltetrahydrofolate is then resolved using a chiral organic base to obtain (6S)-5-methyltetrahydrofolate (WO2008031284A1, US5457202A, WO2013025203A, etc.). However, this synthetic route places the chiral resolution step too late, resulting in a low overall product yield.

[0004] Another preparation route can also be used, with folic acid as raw material and sodium borohydride as reducing agent to obtain tetrahydrofolic acid, in which case 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 split (6S)-tetrahydrofolic acid p-toluenesulfonate, which is then reacted with formaldehyde and reduced with sodium borohydride to obtain (6S)-5-methyltetrahydrofolic acid (CN201810146297.0). This route has a higher yield, but there are also some problems, such as (6R)-tetrahydrofolic acid p-toluenesulfonate in the filtrate, which is discharged as waste liquid, which not only wastes the chiral substance but also increases the amount of waste liquid.

[0005] Jing Bin's master's thesis, "Synthesis of Optically Pure (6S)-5-Methyltetrahydrofolate and Its Amino Acid Ester Derivatives," published the first report on the recycling of (6R)-tetrahydrofolate. Starting with (6R)-tetrahydrofolate p-toluenesulfonate, this work first obtained pure (6R)-tetrahydrofolate with a loss of nearly 50%. The (6R)-tetrahydrofolate was then selectively oxidized to produce folic acid, thereby achieving material recycling. Under optimal process conditions (reaction system pH 7.0, oxygen flow throughout, and reaction temperature at 0°C for 6 hours), the yield of folic acid from (6R)-tetrahydrofolate was 88.5%. This work clearly indicates that when (6R)-tetrahydrofolate p-toluenesulfonate is used directly, sodium carbonate is added to neutralize the p-toluenesulfonic acid, and then the pH is adjusted to neutral before direct oxidation with O2. The yield is only 46.0%, indicating that the presence of free p-toluenesulfonic acid can induce side reactions, necessitating its removal during the oxidation of (6R)-tetrahydrofolate to folic acid. Specifically, the pH of the reaction system is adjusted four times: the first two times to obtain (6R)-tetrahydrofolate and the second two times to obtain folic acid. The first step is to adjust the pH of the reaction system to about 8.0 using a 10% sodium carbonate solution, converting (6R)-tetrahydrofolic acid p-toluenesulfonate into free (6R)-tetrahydrofolic acid and sodium p-toluenesulfonate. The second step is to adjust the pH of the reaction system to 3.0-4.0 using dilute hydrochloric acid, allowing free (6R)-tetrahydrofolic acid to precipitate, thereby separating (6R)-tetrahydrofolic acid from p-toluenesulfonic acid. The third step is to adjust the pH of the system to neutral using a 10% sodium carbonate solution, oxidizing (6R)-tetrahydrofolic acid. The fourth step is to adjust the pH of the reaction system to 3.0-4.0 using dilute hydrochloric acid, allowing folic acid to precipitate. Removing free p-toluenesulfonic acid in this work is complex and results in a certain amount of raw material loss. The selectivity and yield of oxidizing (6R)-tetrahydrofolic acid to raw material 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 response to the shortcomings of the above-mentioned prior art, the present invention aims to provide a method for recovering and preparing folic acid from (6R)-tetrahydrofolate p-toluenesulfonate wastewater. The present invention proposes in-situ dissociation (first pH adjustment) of the (6R)-tetrahydrofolate p-toluenesulfonate filtrate, a byproduct of tetrahydrofolate separation using p-toluenesulfonic acid, to produce (6R)-tetrahydrofolate sodium salt. The (6R)-tetrahydrofolate sodium salt is selectively activated and oxidized using a weak oxidant, O2, in the presence of a Mn(salen) catalyst. The salt is then acidified (second pH adjustment) in the presence of an antioxidant and filtered to obtain folic acid with high selectivity and high yield. Both the p-toluenesulfonic acid and the Mn(salen) catalyst in the filtrate separated by the filter press can be recovered and reused. This method can improve the recovery and conversion of byproducts, reduce pollutant emissions, increase the selectivity of tetrahydrofolate oxidation, and reduce the generation of byproducts.

[0008] The technical concept of the present invention is as follows: 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 sodium (6R)-tetrahydrofolate and sodium p-toluenesulfonate, then using O2 to selectively activate and oxidize the sodium (6R)-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 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 0.5-2 MPa of oxygen, and then carry out selective oxidation at 0-5°C for 2.5-8 hours. 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 dissolve the reaction solution, controlling the temperature below 25°C, slowly adding sodium borohydride solution dropwise thereto, raising the temperature to 60-70°C, reacting for 2 hours, cooling to 10°C, adding a certain amount of antioxidant, and then adding dilute hydrochloric acid dropwise to adjust the pH value of the mixture to 3-4. The mixture is stirred for 1 hour to precipitate a large amount of solid, which is filtered, and the filter cake is rinsed with a small amount of water until the pH value of the filtrate reaches 7. The mixture is vacuum dried 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 metabisulfite, sodium sulfite, and lipoic acid, preferably ascorbic acid.

[0015] Furthermore, in step S2, a red filtrate containing (6R)-tetrahydrofolate p-toluenesulfonate is obtained by dissolving racemic tetrahydrofolate in deionized water under nitrogen protection, heating the mixture to 50-60° C., adding a p-toluenesulfonic acid aqueous solution dropwise, and incubating the mixture for 4 hours until a large amount of precipitate appears. The mixture 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 p-toluenesulfonate; wherein the filter cake is vacuum dried to obtain (6S)-tetrahydrofolate p-toluenesulfonate as a white solid.

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

[0017] Furthermore, 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 metabisulfite, 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 exceeding 99% and a recovery rate of approximately 95%. This significantly reduces the possibility of other oxidation byproducts from the oxidation of tetrahydrofolate and folic acid, effectively improving the selectivity of the reaction and increasing the yield and purity of folic acid.

[0028] Third, (6R)-tetrahydrofolic acid is unstable under acidic conditions and easily decomposes into other byproducts. However, it is relatively stable under alkaline conditions and difficult to oxidize using weak oxidants. This is why the optimal pH for oxidizing (6R)-tetrahydrofolic acid using O2 (a weak oxidant) without the assistance of other catalysts is 7.0. The present invention, however, uses a Mn(salen) catalyst to selectively activate tetrahydrofolic acid sodium salt under strongly alkaline conditions (pH 10-12), improving oxidation efficiency (shortening reaction time) while also increasing the selectivity of the oxidation product, thereby obtaining folic acid with high selectivity and high yield. Furthermore, the use of Mn(salen) catalyst in the present invention eliminates the need for separation and removal of p-toluenesulfonic acid, making the process simpler than 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] To make the purpose and technical solution of the present invention more clear, 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 embodiment.

[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 under a nitrogen atmosphere, add 44.1g (0.1mol) of folic acid to 320g of deionized water. Add sodium hydroxide solution (12g of sodium hydroxide (0.3mol) dissolved in 80g of deionized water) to the folic acid suspension to make the reaction solution clear. Control the temperature below 25°C and slowly add sodium borohydride solution (22.8g of sodium borohydride (0.6mol) dissolved in 40g of water) dropwise to the mixed solution. After addition, raise the temperature to 75°C and react for 2h to complete the reaction. 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 of the mixture to 4. The mixture was stirred for 1 hour to precipitate a large amount of solid. The solid was filtered and the filter cake was rinsed with a small amount of deionized water until the pH of the filtrate reached 7. The solid was then dried under vacuum to obtain racemic tetrahydrofolic acid, designated as R / S-tetrahydrofolic acid, with a yield of 97%. 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-tetrahydrofolic acid was dissolved in 500 g of deionized water. After heating 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 complete, the mixture was kept warm for 4 h. A large amount of precipitate appeared, which 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)-tetrahydrofolic acid p-toluenesulfonate as a white solid in a yield of 95%. The EE value was 99.5%. Liquid chromatography was used for detection using a chiral column model: CHIRALPAK HAS (150 mm × 4 mm × 5 μm), Agilent. Column temperature: 30°C, UV detector wavelength: 280 nm, mobile phase: sodium dihydrogen phosphate dihydrate solution-acetonitrile (97:3) (pH = 6.8), flow rate: 1.0 mL / min, t(minor) = 6.05, t(major) = 7.96. Its characteristics are 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, in the red filtrate (600mL) that step S2 obtains, add solid sodium carbonate, regulate the pH value of the filtrate to 10, then add 150mL absolute ethanol and 0.52g (0.001mol) Mn (salen) catalyst (R1 group is the tert-butyl group; R2 group is ethyl), after catalyst is dissolved completely, reaction system is changed in autoclave, then autoclave is purged with oxygen to remove air wherein completely, behind the sealed still, keeping oxygen pressure is 1MPa, cool to 0 ℃, carry out selective oxidation, reaction 4h, reaction complete, keep reaction temperature 0 ℃, after adding 0.88g (0.005mol) ascorbic acid, then add the hydrochloric acid of 2mol / L, after regulating the pH value of mixed solution to 3, a large amount of light yellow precipitates are had to generate, press filtration, a small amount of water washing filter cake, vacuum drying, obtain 20.7g folic acid, yield is 94%, purity is 99.5% (liquid chromatography external standard method checks its purity), it is 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] The filtrate separated by pressure filtration in step S4 and step S3 is mainly ethanol, containing p-toluenesulfonic acid and Mn(salen) catalyst. The ethanol in the filtrate is removed by vacuum 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 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 used as a resolving agent in step S2.

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

[0041] First, steps S1 to 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, in the red filtrate (600mL) that step S2 obtains, add solid sodium carbonate, regulate the pH value of the filtrate to 12, then add 150mL absolute ethanol and 1.04g (0.002mol) Mn (salen) catalyst (R1 group is the tert-butyl group; R2 group is ethyl), after catalyst is dissolved completely, reaction system is changed in autoclave, then autoclave is purged with oxygen to remove air wherein completely, after sealing still, maintaining oxygen pressure is 0.5MPa, cool to 0 ℃, carry out selective oxidation, reaction 8h, reaction complete, maintain reaction temperature 0 ℃, after adding 0.88g (0.005mol) ascorbic acid, then add the hydrochloric acid of 2mol / L, after regulating the pH value of mixed solution to 3, a large amount of light yellow precipitates are had to generate, filter press, a small amount of water washes filter cake, vacuum drying, obtains 21.2g folic acid, and yield is 96%, and purity is 99.4%.

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

[0044] First, steps S1 to 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, in the red filtrate (600mL) that step S2 obtains, add solid sodium carbonate, regulate the pH value of the filtrate to 12, then add 150mL absolute ethanol and 1.04g (0.002mol) Mn (salen) catalyst (R1 group is the tert-butyl group; R2 group is ethyl), after catalyst is dissolved completely, reaction system is changed in autoclave, then autoclave is purged with oxygen to remove air wherein completely, behind the sealed still, maintaining oxygen pressure is 2MPa, cool to 0 ℃, carry out selective oxidation, react 2.5h, reaction complete, keep reaction temperature 0 ℃, after adding 0.88g (0.005mol) ascorbic acid, then add the hydrochloric acid of 2mol / L, after regulating the pH value of mixed solution to 3, a large amount of light yellow precipitates are had to generate, press filtration, a small amount of water washing filter cake, vacuum drying, obtain 21.6g folic acid, yield is 98%, purity is 95.6%.

[0046] As can be seen from Examples 1-3, the present invention adjusts the pH of a solution of (6R)-tetrahydrofolate p-toluenesulfonate, a byproduct of tetrahydrofolate splitting using p-toluenesulfonic acid, to 10-12 (strong alkalinity) for in-situ dissociation. The (6R)-tetrahydrofolate sodium salt is then selectively activated and oxidized using O2 in the presence of a Mn(salen) catalyst. The pH of the reaction system is then adjusted to 3 under the action of an antioxidant, followed by filter pressing to obtain folic acid with a purity exceeding 99% and a recovery rate exceeding 90%. In the present invention, the method for recovering folic acid by oxidizing (6R)-tetrahydrofolate p-toluenesulfonate, a byproduct of tetrahydrofolate splitting using p-toluenesulfonic acid, does not require separation and removal of p-toluenesulfonic acid before oxidation using O2, making the operation more convenient than in the prior art. The present invention uses a weak oxidant O2 to perform high-pressure and low-temperature selective oxidation on (6R)-tetrahydrofolic acid in the presence of a Mn(salen) catalyst. The oxygen pressure is 0.5-2 MPa. The higher the pressure, the shorter the reaction time. Preferably, the oxygen pressure is 1-2 MPa. The selective oxidation is then performed at 0-5°C for 2.5-4 hours. The oxidation time is short, the possibility of generating by-products is low, and the selectivity of the oxidation product is improved, thereby obtaining folic acid 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, steps S1 to 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, add solid sodium carbonate in the red filtrate (600mL) that step S2 obtains, regulate the pH value of filtrate to 8, then add successively 150mL absolute ethanol and 1.04g (0.002mol) Mn (salen) catalyst (R1 group is the tert-butyl group; R2 group is ethyl), after catalyst is dissolved completely, reaction system is changed in autoclave, then autoclave is purged with oxygen to remove air wherein fully, behind the sealed still, keeping oxygen pressure is 0.5MPa, cool to 0 ℃, oxidize, after reaction 8h, keep reaction temperature 0 ℃, after adding 0.88g (0.005mol) ascorbic acid, then use the hydrochloric acid of 1mol / L to regulate the pH value of mixed solution to 3, there is faint yellow solid to separate out, press filtration, a small amount of water washing filter cake, vacuum drying, obtain 8.83g product, through nuclear magnetic detection, yield is 40%, and purity is 86%.

[0050] This example illustrates that the pH of a solution of (6R)-tetrahydrofolic acid p-toluenesulfonate, a byproduct of tetrahydrofolic acid salification using p-toluenesulfonic acid, is adjusted to 8. At this point, the solution contains free (6R)-tetrahydrofolic acid and sodium p-toluenesulfonate. O2 is then oxidized in the presence of a Mn(salen) catalyst. The pH of the reaction system is then adjusted to 3 in the presence of an antioxidant, and filter presses are performed. However, high-purity, high-yield folic acid cannot be obtained.

[0051] As can be seen from Examples 1, 2, and 3, in the system of the present invention, the pH value of the (6R)-tetrahydrofolate p-toluenesulfonate solution, a byproduct of the splitting of tetrahydrofolate using p-toluenesulfonic acid, needs to be adjusted to 10-12 for in situ dissociation to obtain sodium (6R)-tetrahydrofolate, which is conducive to the subsequent low-temperature selective oxidation using oxygen as an oxidant over 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, steps S1 to 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. 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 the autoclave was purged with oxygen to completely remove the air therein. After sealing the autoclave, the oxygen pressure was maintained at 0.5 MPa, the temperature was lowered to 0°C, and selective oxidation was carried out. The reaction was carried out 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 tetrahydrofolic acid remained and other impurities appeared. The reaction product was no longer homogeneous. The reaction time was further extended to 9 h. After the reaction was completed, 0.88 g (0.005 mol) of ascorbic acid was added while maintaining the reaction temperature at 0°C. 2 mol / L hydrochloric acid was then added to adjust the pH of the mixture to 3. A large amount of light yellow precipitate was generated. The mixture was filtered, and the filter cake was washed with a small amount of water and dried in vacuo 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, hindering the access of the catalyst center metal to tetrahydrofolic acid and activation, thereby resulting in a decrease in the activation ability of the catalyst. In addition, the tetrahydrofolic acid is exposed to an oxygen atmosphere for too long, resulting in side reactions.

[0056] The above is merely a specific embodiment of the present invention, and its description is relatively specific and detailed. However, it should not be construed as limiting the scope of protection claimed in the claims of the present invention. It should be noted that those skilled in the art may make various modifications and improvements without departing from the spirit of the present invention, and such modifications and improvements are all within the scope of protection of the present invention.

Claims

1. A method for recovering and preparing 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. After the catalyst is completely dissolved, the reaction system is transferred to an autoclave, and then the autoclave is purged with oxygen to completely remove the air therein. After the autoclave is sealed, 0.5-2 MPa of oxygen is filled into it, and then selective oxidation is carried out at 0-5 ° C. for 2.5-8 hours. 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 the filter cake is pressed and washed with a small amount of water. It is vacuum dried 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, wherein 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 metabisulfite, sodium sulfite and lipoic acid.

5. The method according to claim 1, wherein The method for obtaining the red filtrate containing (6R)-tetrahydrofolate p-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 p-toluenesulfonic acid solution is added dropwise, and after the addition is completed, the mixture is kept warm for 4 hours to react. A large amount of precipitate appears, and the mixture is filtered while hot. The filter cake is washed with a small amount of hot water, and the obtained red filtrate is the red filtrate containing (6R)-tetrahydrofolate p-toluenesulfonate.

6. The method according to claim 5, characterized in that In step S2, the molar ratio of the racemic tetrahydrofolic acid to 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 the racemic tetrahydrofolic acid to 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, and 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 hours, the temperature is lowered to 10°C, a certain amount of antioxidant is added, and dilute hydrochloric acid is added dropwise to adjust the pH value of the mixture to 3-4. The mixture is stirred for 1 hour to precipitate a large amount of solid, which is filtered with suction. The filter cake is rinsed with a small amount of water until the pH value of the filtrate reaches 7, and vacuum dried 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 metabisulfite, sodium sulfite and lipoic acid.

Images