Method for preparing folic acid through continuous hedging of tubular reactor

Abstract

The invention relates to the technical field of organic synthesis, and discloses a method for preparing folic acid through continuous hedging of a tubular reactor. Sodium pyrosulfite is homogeneously dispersed with N-(4-aminobenzoyl)-L-glutamic acid and 2, 4, 5-triamino-6-hydroxypyrimidine sulfate through high pressure of a tubular reactor, raw materials are fully dispersed under the condition of a small amount of water solvent, and N-(4-aminobenzoyl)-L-glutamic acid, 2, 4, 5-triamino-6-hydroxypyrimidine sulfate and N-(4-aminobenzoyl)-L-glutamic acid are fully dispersed through high-speed flow generated by high pressure. 2, 5-triamino-6-hydroxypyrimidine sulfate and trichloroacetone are subjected to hedging to generate cyclization reaction, so that the problem of insufficient material reaction caused by folic acid deposition and wrapping is avoided; the sodium carbonate solution is sprayed to the continuous flushing liquid flow, so that raw material loss caused by hydrolysis of trichloroacetone by local alkali liquor is avoided, the purity and the yield of the crude folic acid product are remarkably improved, and the wastewater amount is reduced. The whole preparation process adopts a closed pipeline and a closed container, avoids influence of peculiar smell volatilization on operation space, and is easy to automatically control and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing folic acid by continuous hedging in a tubular reactor. Background Art

[0002] Folic acid, also known as vitamin B9, has the chemical name of styloylglutamic acid. It appears as a light yellow flaky crystalline powder, is slightly soluble in water, and is easily soluble in potassium carbonate solution and sodium hydroxide solution. As an important active growth factor for the synthesis of DNA and RNA in cells, folic acid participates in cell growth and tissue repair, and is an essential nutrient for the growth and reproduction of human cells. Folic acid deficiency can lead to incomplete fetal growth and development, and the risk of cleft lip and palate, heart defects, and miscarriage. Folic acid plays a key role in the normal closure of the neural tube. Adequate folic acid intake can significantly reduce the risk of neural tube defects such as anencephaly and spina bifida in the fetus. In addition, folic acid can promote the maturation of young cells in the bone marrow to form normal-looking red blood cells, thereby avoiding anemia, and is often used as a preventive and therapeutic agent for anemia.

[0003] Since folic acid cannot be synthesized in the body, it can only be obtained through medication or food. Folic acid in food is mainly found in green leafy vegetables, citrus fruits, soy products, animal liver, lean meat, and eggs. Natural folic acid from food is less stable and has low bioavailability. When it is difficult to obtain sufficient folic acid through food, synthetic pharmaceutical folic acid becomes the first choice for folic acid supplementation. Synthetic folic acid is highly stable and has a high absorption rate in the human intestine. Currently, folic acid is used as a primary nutritional supplement in medicine, food, and feed.

[0004] The original synthetic route for folic acid involved reacting α,β-dibromopropionaldehyde, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and N-(4-aminobenzoyl)-L-glutamic acid in an acetic acid-sodium acetate buffer to produce crude folic acid. However, this method was discontinued due to the high cost of the α,β-dibromopropionaldehyde used, yields below 40%, and significant bromine pollution, resulting in high costs for industrial production. Instead, tetramethoxypropanol and p-aminobenzoylglutamic acid were used as the main raw materials, reacting them with triaminopyrimidine sulfate to produce folic acid. This route, however, was expensive, produced numerous side reaction impurities that were difficult to remove, consumed a large amount of water, and the ammonia nitrogen and inorganic salts in the wastewater severely polluted the environment, limiting its viability.

[0005] Currently, most industrial folic acid production methods use 1,1,3-trichloroacetone as an intermediate, which is then cyclized with 2,4,5-triamino-6-hydroxypyrimidine sulfate and N-(4-aminobenzoyl)-L-glutamic acid in a one-pot aqueous environment to produce crude folic acid in a 60% yield. This method uses low-cost raw materials and is easily available in large quantities, making it the mainstream technical route for folic acid synthesis.

[0006] However, when using this technical route for production, the large amount of wastewater has always plagued the development of the industry, and the reaction by-products contain many impurities, resulting in large raw material losses and low yields. The main reasons are: (1) The synthesis process of this technology adopts a one-pot reaction. The solubility of 2,4,5-triamino-6-hydroxypyrimidine sulfate in water is limited, so a large amount of water is required as a solvent. Usually, more than 50 times the amount of water solvent is required to disperse the reactants, which will result in a huge amount of wastewater output, which is not conducive to environmental protection; (2) The folic acid produced by the one-pot method is insoluble in the acidic environment of the reaction solution. As folic acid is continuously produced, it is deposited and wrapped on the interface of 2,4,5-triamino-6-hydroxypyrimidine sulfate, resulting in low raw material reaction efficiency. Usually, an excessive amount of 2,4,5-triamino-6-hydroxypyrimidine sulfate needs to be used, resulting in increased raw material loss and reduced yield; (3) During the cyclization reaction of folic acid, hydrochloric acid is continuously released, and alkali solution needs to be added to neutralize the hydrochloric acid to maintain the reaction. However, the added alkali solution is difficult to disperse quickly in the one-pot method. Local alkali solution will hydrolyze 1,1,3-trichloroacetone, resulting in raw material loss, and an excessive amount of 1,1,3-trichloroacetone needs to be used.

[0007] Patent publication number CN107312004B discloses a method for producing folic acid. To reduce the amount of aqueous solvent used, the cyclization reaction is performed by adding raw materials in batches to a fixed aqueous solvent. The concentration of the materials in the reaction solution is maintained within a reasonable range, thereby reducing the amount of water required for the synthesis of crude folic acid. However, this method is still a one-pot reaction. As the folic acid product is generated in the reaction solution, there is a risk of precipitation and encapsulation of 2,4,5-triamino-6-hydroxypyrimidine sulfate. The addition of sodium carbonate lye causes hydrolysis loss of 1,1,3-trichloroacetone, typically requiring the use of excess 2,4,5-triamino-6-hydroxypyrimidine sulfate and 1,1,3-trichloroacetone, resulting in significant raw material loss and low yield. Summary of the Invention

[0008] At present, the one-pot process for preparing folic acid has low reaction efficiency, many impurities, and low yield, resulting in large raw material losses and large amounts of wastewater during industrial production. In view of this, the present invention proposes a method for preparing folic acid by continuous hedging in a tubular reactor, wherein sodium metabisulfite is homogeneously dispersed with N-(4-aminobenzoyl)-L-glutamic acid and 2,4,5-triamino-6-hydroxypyrimidine sulfate in a tubular reactor, and the raw materials are fully dispersed under conditions of less water solvent; the high-speed flow generated by high pressure is used to hedge the reaction, so that N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate and trichloroacetone are fully cyclized, thereby avoiding the generation of multiple by-product impurities and raw material losses caused by the one-pot process, and improving the purity and yield of the crude folic acid. The trichloroacetone mentioned below refers to 1,1,3-trichloroacetone.

[0009] In order to solve the above technical problems, this application adopts the following technical solutions:

[0010] A method for preparing folic acid by continuous hedging in a tubular reactor mainly comprises the following steps:

[0011] S1. Add water to a stirring tank I, control the temperature at 40-50 ° C, add N-(4-aminobenzoyl)-L-glutamic acid to the stirring tank I and stir, then add sodium metabisulfite and stir until uniformly dispersed, to prepare liquid A; the amount of water is 8-10 times the weight of N-(4-aminobenzoyl)-L-glutamic acid; the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid to sodium metabisulfite is 1:(0.2-0.3);

[0012] S2. Add water to the stirring tank II, control the temperature at 30-40°C, add 2,4,5-triamino-6-hydroxypyrimidine sulfate to the stirring tank II and stir, then add sodium metabisulfite and stir until uniformly dispersed, which is used as liquid B; the amount of water is 8-12 times the weight of 2,4,5-triamino-6-hydroxypyrimidine sulfate; the molar ratio of the 2,4,5-triamino-6-hydroxypyrimidine sulfate to the sodium metabisulfite is 1:(0.2-0.3);

[0013] S3. Trichloroacetone having a purity greater than 85% was placed in a stirred tank Ⅲ as liquid C;

[0014] S4. According to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and trichloroacetone of 1:1:1.2, liquid A, liquid B, and liquid C are respectively input into pressure vessel I, pressure vessel II, and pressure vessel III for pressurization, and then respectively passed through tubular reactor I, tubular reactor II, and tubular reactor III for homogenization to form high-speed flow counterflow at the discharge port. At the same time, 10 wt% sodium carbonate solution is continuously sprayed onto the counterflow liquid flow through an alkali liquid pump to maintain the pH range of 3.0-4.0. The reactants are precipitated into a sedimentation tank; the material is then collected into a closed magnetic stirrer and stirred for 3-6 hours, and filtered through a centrifuge to obtain crude folic acid; the filtrate is aged for 3-5 days to remove impurities, neutralized with alkali, and then recycled to replace water for steps S1 and S2;

[0015] S5. The crude folic acid is sequentially refined by acid and alkali to obtain high-purity folic acid.

[0016] Preferably, the inner diameters of the tubular reactor I, tubular reactor II, and tubular reactor III are 30-40 mm, the length of the pipeline is 5-8 m, and the diameter of the discharge port is narrowed to 10-20 mm.

[0017] Preferably, the fluid pressure of liquid A in the tubular reactor I is 4.0-6.0 MPa; the fluid pressure of liquid B in the tubular reactor II is 4.0-6.0 MPa; and the fluid pressure of liquid C in the tubular reactor III is 2.5-3.0 MPa.

[0018] Specifically, the fluids within the tubular reactor are propelled by pressure, creating a turbulent flow that homogenizes the flow and fully disperses the raw materials with minimal aqueous solvent. The high pressure allows Liquids A, B, and C to be completely atomized and countered at high speed. This high-speed counteraction improves mass transfer efficiency, allowing trichloroacetone to rapidly attack the amino groups of 2,4,5-triamino-6-hydroxypyrimidine sulfate to form a pteridine ring, which is then dehydrogenated to form folic acid, improving reaction efficiency. This avoids the generation of byproduct impurities in a one-pot process and prevents incomplete reaction of materials due to folic acid inclusion.

[0019] Preferably, the temperature of the tubular reactor I and the tubular reactor II is controlled at 40-45°C.

[0020] Preferably, the temperature of the tubular reactor III is controlled at 30-35°C.

[0021] Preferably, the 10 wt % sodium carbonate solution is continuously sprayed into the counter flow to maintain the pH at 3.5.

[0022] Specifically, in step S4, 10 wt % sodium carbonate solution is sprayed onto the counter-flushing liquid flow. By spraying the sodium carbonate solution onto the continuous counter-flushing liquid flow, the raw material loss caused by the local alkaline solution hydrolysis of trichloroacetone in the one-pot process is avoided.

[0023] Specifically, in step S4, the mixture is stirred in a closed magnetic stirrer to fully dehydrochlorinate and link a small portion of unreacted reactants to form folic acid, thereby increasing the yield of folic acid.

[0024] Preferably, the acid purification is to dissolve the crude folic acid in 3-5 times the mass of 30wt% H2SO4, stir until completely dissolved, then add 8-10 times the mass of water of the crude folic acid, precipitate a yellow solid, let it stand for 2 hours and then filter to obtain the acid purified product.

[0025] Preferably, the alkali refining is to add 10-12 times the mass of water to the acid refined product, add sodium hydroxide at 80°C to adjust the pH to 9.5-10, stir until completely dissolved, then add an appropriate amount of activated carbon for adsorption and decolorization, filter while hot to obtain a yellow filtrate, adjust the pH of the filtrate to 3-3.5 with hydrochloric acid, cool to room temperature, filter, and take the filter cake and dry it to obtain high-purity folic acid.

[0026] Specifically, acid refining and alkali refining are performed based on the characteristics that folic acid dissolves in strong acid and strong alkali environments and is easily precipitated in an environment with a pH value of 1-5.

[0027] The present invention utilizes continuous dynamic homogenization in a tubular reactor to homogenously disperse sodium metabisulfite with N-(4-aminobenzoyl)-L-glutamic acid and 2,4,5-triamino-6-hydroxypyrimidine sulfate, ensuring full dispersion of the raw materials with minimal aqueous solvent. Sodium metabisulfite acts as an antioxidant and catalyst, improving catalytic efficiency. High-pressure, high-speed flow counteracts the reaction, enhancing reaction efficiency. N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and trichloroacetone undergo full contact and cyclization, avoiding the generation of multiple byproduct impurities and raw material loss associated with a one-pot process, thereby improving the purity and yield of crude folic acid. The high-speed, continuous flow counteracts the reactants, increasing the efficiency of folic acid formation by dehydrogenation and linking. Furthermore, the continuous flow counteracts the reaction, preventing localized accumulation of folic acid and encapsulation of 2,4,5-triamino-6-hydroxypyrimidine sulfate and localized hydrolysis of trichloroacetone by alkali solution. This promotes full reaction of the raw materials, reduces raw material loss, and improves folic acid yield. According to metering control, the molar ratio of the raw materials N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, trichloroacetone, and sodium metabisulfite is 1:1:1.2:(0.4-0.6), and there is no need for excessive use of 2,4,5-triamino-6-hydroxypyrimidine sulfate, thereby reducing the use of trichloroacetone.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. The present invention utilizes high pressure in a tubular reactor to homogeneously disperse sodium metabisulfite, N-(4-aminobenzoyl)-L-glutamic acid, and 2,4,5-triamino-6-hydroxypyrimidine sulfate, respectively, thereby ensuring that the raw materials are fully dispersed under conditions of less water solvent and improving catalytic efficiency.

[0030] 2. The present invention enhances the reaction efficiency by counteracting the high-speed flow generated by high pressure. N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and trichloroacetone counteract each other to produce a cyclization reaction, so that the reaction materials are fully in contact without accumulation, which is conducive to the linking and formation of folic acid. At the same time, it effectively avoids the problem of insufficient material reaction caused by folic acid deposition and encapsulation, and significantly improves the purity and yield of crude folic acid.

[0031] 3. The present invention forms a continuous flow high-speed impact reaction by high pressure in a tubular reactor, and by spraying a sodium carbonate solution into the continuous counterflow, the raw material loss caused by local alkali hydrolysis of trichloroacetone is avoided, thereby reducing the amount of 1,1,3-trichloroacetone.

[0032] 4. The preparation method of the present invention uses closed pipelines and closed containers throughout the process, which prevents the volatilization of odor from affecting the working space, is easy to automatically control, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The following is a simplified process flow diagram of the continuous hedging process for preparing folic acid using a tubular reactor according to the present invention.

[0034] 1- Agitation tank I; 2- Agitation tank II; 3- Agitation tank III; 4- Pressurized vessel I; 5- Pressurized vessel II; 6- Pressurized vessel III; 7- Tubular reactor I; 8- Tubular reactor II; 9- Tubular reactor III; 10- Alkali liquid pump; 11- Sedimentation tank; 12- Closed magnetic stirrer; 13- Centrifuge; 14- Acid refining; 15- Alkali refining. DETAILED DESCRIPTION

[0035] The following is a clear and complete description of the technical solutions of the present invention in conjunction with the accompanying drawings and embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of protection of the present invention.

[0036] The raw materials involved in the following examples are:

[0037] N-(4-aminobenzoyl)-L-glutamic acid: purity greater than 99%;

[0038] 2,4,5-Triamino-6-hydroxypyrimidine sulfate: purity greater than 99%;

[0039] Trichloroacetone: Self-made 65% pure trichloroacetone was extracted with water and purified to a purity of 86.2%;

[0040] Sodium metabisulfite: purity greater than 99%.

[0041] Tubular reactor I and tubular reactor II: inner diameter 30 mm, pipe length 6 m, discharge port diameter 10 mm.

[0042] Tubular reactor III: inner diameter 30 mm, pipe length 5 m, discharge port diameter 12 mm.

[0043] The process flow of the tubular reactor for continuous hedging of folic acid of the present invention is as shown in the attached figure. Figure 1 , the process is as follows:

[0044] S1. Add water to a stirring tank Ⅰ (1), control the temperature to 40-50 ° C, add N-(4-aminobenzoyl)-L-glutamic acid and stir, then add sodium metabisulfite and stir until uniformly dispersed, which is used as liquid A;

[0045] S2. Add water to the stirring tank II (2), control the temperature to 30-40°C, add 2,4,5-triamino-6-hydroxypyrimidine sulfate and stir, then add sodium metabisulfite and stir until uniformly dispersed, which is used as liquid B;

[0046] S3. Trichloroacetone having a purity greater than 85% was placed in a stirred tank Ⅲ as liquid C;

[0047] S4. According to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate and trichloroacetone of 1:1:1.2, liquid A, liquid B and liquid C are respectively fed into pressure vessel I (4), pressure vessel II (5) and pressure vessel III (6) for pressurization, and are respectively homogenized through tubular reactor I (7), tubular reactor II (8) and tubular reactor III (9), forming a high-speed flow counterflow at the discharge port, and simultaneously continuously spraying 10 wt% sodium carbonate solution to the counterflow through an alkali liquid pump (10), maintaining the pH range of 3.0-4.0, and the reactants are sunk into a sedimentation tank (11); the materials are collected into a closed magnetic stirrer (12) and stirred for 3-6 hours, and filtered through a centrifuge (13) to obtain a crude folic acid product;

[0048] S5. The crude folic acid is sequentially subjected to acid refining (14) and alkali refining (15) to obtain high-purity folic acid.

[0049] Example 1

[0050] S1. Add 22 kg of water to a stirred tank I, control the temperature to 50°C, weigh 10 mol of N-(4-aminobenzoyl)-L-glutamic acid (2.66 kg) and add it to the stirred tank I, stirring. Then, add 2 mol of sodium metabisulfite (0.38 kg) and stir until evenly dispersed. This is Solution A.

[0051] S2. Add 20 kg of water to the stirring tank II, control the temperature at 40 ° C, add 10 mol of 2,4,5-triamino-6-hydroxypyrimidine sulfate 2.39 kg to the stirring tank II and stir, then add 3 mol of sodium metabisulfite 0.57 kg and stir until uniformly dispersed, as liquid B;

[0052] S3. In a stirred tank Ⅲ containing 86.2% purity of trichloroacetone as liquid C;

[0053] S4. According to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate and trichloroacetone of 1:1:1.2, liquid A, liquid B and liquid C are respectively input into pressure vessel I, pressure vessel II and pressure vessel III for pressurization; the fluid pressure of liquid A is 4.0 MPa; the fluid pressure of liquid B is 4.4 MPa; the fluid pressure of liquid C is 2.8 MPa; after pressurization, they are respectively homogenized through tubular reactor I, tubular reactor II and tubular reactor III to form high-speed flow collision at the discharge port, and the temperature of tubular reactor I and tubular reactor II is controlled at 45°C, and the temperature of tubular reactor III is controlled at 45°C. The temperature was controlled at 35° C.; simultaneously, a 10 wt % sodium carbonate solution was continuously sprayed onto the countercurrent flow via an alkali pump to maintain a pH of 3.5. 10 mol of raw material, calculated as N-(4-aminobenzoyl)-L-glutamic acid, was input, and the reactants were allowed to settle in a sedimentation tank. The material was collected into a closed magnetic stirrer and stirred for 3 hours. The mixture was filtered through a centrifuge to obtain 9.27 kg of a crude wet folic acid product. The filtrate was aged for 3 days to remove impurities, neutralized with alkali, and then recycled to replace water in steps S1 and S2. The solid content of the crude wet folic acid product was 45.72%, and the folic acid content of the dry crude folic acid product was determined to be 88.13% by high performance liquid chromatography (HPLC). The folic acid yield was 84.62%.

[0054] S5. The wet crude folic acid was dissolved in 30 kg of 30 wt% H2SO4 solution and stirred until completely dissolved. Then, 75 kg of water was added to the crude folic acid to precipitate a yellow solid. The solid was allowed to stand for 2 hours and then filtered to obtain an acid-refined product. The acid-refined product was added with 10 times the weight of water, and sodium hydroxide was added at 80°C to adjust the pH to 10 and stirred until completely dissolved. Then, 0.2 kg of activated carbon was added for decolorization by adsorption. The product was filtered while hot to obtain a yellow filtrate. The pH of the filtrate was adjusted to 3.5 with hydrochloric acid, cooled to room temperature, filtered, and the filter cake was dried to obtain 3.47 kg of high-purity folic acid. The purity of the high-purity folic acid was determined by high-performance liquid chromatography (HPLC) to be 98.72%, and the total yield of folic acid was 77.61%.

[0055] Example 2

[0056] S1. Add 26 kg of water to a stirred tank I, control the temperature to 50°C, weigh 10 mol of N-(4-aminobenzoyl)-L-glutamic acid (2.66 kg) and add it to the stirred tank I, stirring. Then, add 3 mol of sodium metabisulfite (0.57 kg) and stir until evenly dispersed. This is Solution A.

[0057] S2. Add 26 kg of water to the stirring tank II, control the temperature to 40 ° C, add 10 mol of 2,4,5-triamino-6-hydroxypyrimidine sulfate 2.39 kg to the stirring tank II and stir, then add 3 mol of sodium metabisulfite 0.57 kg and stir until uniformly dispersed, as liquid B;

[0058] S3. In a stirred tank Ⅲ containing 86.2% purity of trichloroacetone as liquid C;

[0059] S4. According to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate and trichloroacetone of 1:1:1.2, liquid A, liquid B and liquid C are respectively input into pressure vessel I, pressure vessel II and pressure vessel III for pressurization; the fluid pressure of liquid A is 4.2MPa; the fluid pressure of liquid B is 4.8MPa; the fluid pressure of liquid C is 3.0MPa; after pressurization, they are respectively homogenized through tubular reactor I, tubular reactor II and tubular reactor III to form high-speed flow counter-flow at the discharge port, and the temperature of tubular reactor I and tubular reactor II is controlled at 45°C, and the temperature of tubular reactor III is controlled at 45°C. The temperature was controlled at 35° C. At the same time, a 10 wt % sodium carbonate solution was continuously sprayed into the countercurrent flow through an alkali pump to maintain a pH of 3.0. 10 mol of raw material was input based on N-(4-aminobenzoyl)-L-glutamic acid, and the reactants were allowed to settle in a sedimentation tank. The material was collected into a closed magnetic stirrer and stirred for 6 hours. The material was filtered through a centrifuge to obtain 9.35 kg of crude wet folic acid. The filtrate was aged for 3 days to remove impurities, neutralized with alkali, and then recycled to replace water in steps S1 and S2. The solid content of the crude wet folic acid was 44.95%, and the folic acid content of the dry crude folic acid was 89.75% as determined by high performance liquid chromatography (HPLC). The folic acid yield was 85.46%.

[0060] S5. The wet crude folic acid was dissolved in 35 kg of 30 wt% H2SO4 solution and stirred until completely dissolved. Then, 85 kg of water was added to the crude folic acid to precipitate a yellow solid. The solid was allowed to stand for 2 hours and then filtered to obtain an acid-refined product. The acid-refined product was added with 12 times the weight of water, and sodium hydroxide was added at 80°C to adjust the pH to 10 and stirred until completely dissolved. Then, 0.2 kg of activated carbon was added for decolorization by adsorption. The product was filtered while hot to obtain a yellow filtrate. The pH of the filtrate was adjusted to 3.5 with hydrochloric acid, cooled to room temperature, filtered, and the filter cake was dried to obtain 3.52 kg of high-purity folic acid. The purity of the high-purity folic acid was determined by high-performance liquid chromatography (HPLC) to be 98.65%, and the total yield of folic acid was 78.67%.

[0061] Comparative Example 1

[0062] S1. According to Example 1, liquid A, liquid B, and liquid C were prepared. According to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and trichloroacetone of 1:1:1.2, liquid A, liquid B, and liquid C were added to a reactor. 10 mol of N-(4-aminobenzoyl)-L-glutamic acid was added, and the mixture was stirred at 40° C. While a 10 wt % sodium carbonate solution was pumped into the reactor via an alkali pump to maintain the pH at 3.5. The mixture was reacted for 3 h and filtered through a centrifuge to obtain 9.87 kg of a crude wet folic acid product. The solid content of the crude wet folic acid product was 43.19%, and the folic acid content of the crude dry folic acid product was 79.45% as determined by high performance liquid chromatography (HPLC). The folic acid yield was 76.73%.

[0063] S2. The wet crude folic acid was dissolved in 30 kg of 30 wt% H2SO4 solution and stirred until completely dissolved. Then, 75 kg of water was added to the crude folic acid to precipitate a yellow solid. The solid was allowed to stand for 2 hours and then filtered to obtain an acid-refined product. The acid-refined product was added with 10 times the weight of water, and sodium hydroxide was added at 80°C to adjust the pH to 10 and stirred until completely dissolved. Then, 0.2 kg of activated carbon was added for decolorization by adsorption. The product was filtered while hot to obtain a yellow filtrate. The pH of the filtrate was adjusted to 3.5 with hydrochloric acid, cooled to room temperature, filtered, and the filter cake was dried to obtain 2.98 kg of high-purity folic acid. The purity of the high-purity folic acid was determined by high-performance liquid chromatography (HPLC) to be 97.19%, and the total yield of folic acid was 65.62%.

[0064] This comparative example adopts a one-pot reaction in a relatively low aqueous solvent to prepare folic acid. Due to the limited solubility of 2,4,5-triamino-6-hydroxypyrimidine sulfate and the hydrolysis of trichloroacetone, the purity of folic acid is reduced, and the yield is reduced, making it difficult to meet the folic acid pharmacopoeia standard requirement of greater than 98% purity.

[0065] Comparative Example 2

[0066] Liquid A, Liquid B, and Liquid C were prepared according to the scheme of Example 1, except that the pressure of the tubular reactor was reduced for the reaction, and the liquids A, B, and C were respectively fed into the pressure vessel I, the pressure vessel II, and the pressure vessel III for pressurization according to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and trichloroacetone of 1:1:1.2; the fluid pressure of the liquid A was 1.0 MPa; the fluid pressure of the liquid B was 1.3 MPa; the fluid pressure of the liquid C was 0.75 MPa; and at the same time, 10 wt% of carbonate was added via the alkali liquid pump. The sodium solution was continuously sprayed onto the countercurrent flow to maintain a pH of 3.5. 10 mol of the raw material was input based on N-(4-aminobenzoyl)-L-glutamic acid, and the reactant was allowed to settle in a sedimentation tank. The material was collected into a closed magnetic stirrer and stirred for 3 hours. The mixture was filtered through a centrifuge to obtain 9.73 kg of a crude wet folic acid product. The filtrate was aged for 3 days to remove impurities, neutralized with alkali, and then recycled to replace water in steps S1 and S2. The solid content of the crude wet folic acid product was 42.81%, and the folic acid content of the dry crude folic acid product was determined to be 82.57% by high performance liquid chromatography (HPLC). The folic acid yield was 77.92%.

[0067] The wet crude folic acid product was dissolved in 30 kg of 30 wt% H2SO4 solution and stirred until completely dissolved. Then, 75 kg of water containing the crude folic acid was added to precipitate a yellow solid. The solid was allowed to stand for 2 hours and then filtered to obtain an acid-refined product. The acid-refined product was added with 10 times the weight of water, and sodium hydroxide was added at 80°C to adjust the pH to 10 and stirred until completely dissolved. Then, 0.2 kg of activated carbon was added for decolorization by adsorption. The product was filtered while hot to obtain a yellow filtrate. The pH of the filtrate was adjusted to 3.5 with hydrochloric acid, cooled to room temperature, filtered, and the filter cake was dried to obtain 3.16 kg of high-purity folic acid. The purity of the high-purity folic acid was determined by high-performance liquid chromatography (HPLC) to be 98.33%, and the total yield of folic acid was 70.40%.

[0068] After reducing the pressure of the tubular reactor, liquid A and liquid B were not well homogenized, the catalyst efficiency was reduced, the homogeneous dispersion of 2,4,5-triamino-6-hydroxypyrimidine sulfate was weakened, the reaction efficiency was reduced during hedging, fewer cyclization reactions occurred, resulting in raw material loss and reduced yield.

[0069] The purity and yield of the crude folic acid of Example 1-2 and Comparative Example 1-2 were measured; the purity and total yield of the refined folic acid were also measured, as shown in Table 1.

[0070] Purity of crude folic acid: A certain amount of wet crude folic acid was taken, dried, and the folic acid content of the dry crude folic acid was determined by high performance liquid chromatography (HPLC), which is the purity of the crude folic acid.

[0071] The yield of folic acid in the crude folic acid product is: wet crude folic acid product × solid content × folic acid content of dry crude folic acid product = output folic acid. The yield of folic acid in the crude folic acid product = (output folic acid amount / theoretical folic acid output) × 100%.

[0072] Purity of refined folic acid: Take a quantitative amount of purified high-purity folic acid and use high performance liquid chromatography (HPLC) to determine the folic acid content of the high-purity folic acid, which is the purity of the refined folic acid.

[0073] Total yield of refined folic acid: amount of refined folic acid × purity of refined folic acid = total amount of refined folic acid, total yield of refined folic acid = (total amount of refined folic acid / theoretical folic acid output) × 100%.

[0074] Table 1:

[0075]

[0076] According to the above test analysis, the present invention produces folic acid through high-pressure homogenization and high-speed flow dilution, achieving full reaction of the materials while using less water solvent. This not only reduces wastewater generation but also significantly improves folic acid yield. The purity of the refined folic acid is above 98%, meeting pharmacopoeial quality requirements.

Claims

1. A method for preparing folic acid by continuous hedging in a tubular reactor, characterized in that: The method comprises the following preparation steps: S1. Add water to a stirring tank I, control the temperature at 40-50 ° C, add N-(4-aminobenzoyl)-L-glutamic acid to the stirring tank I and stir, then add sodium metabisulfite and stir until uniformly dispersed, to prepare liquid A; the amount of water is 8-10 times the weight of N-(4-aminobenzoyl)-L-glutamic acid; the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid to sodium metabisulfite is 1:(0.2-0.3); S2. Add water to the stirring tank II, control the temperature at 30-40°C, add 2,4,5-triamino-6-hydroxypyrimidine sulfate to the stirring tank II and stir, then add sodium metabisulfite and stir until uniformly dispersed, which is used as liquid B; the amount of water is 8-12 times the weight of 2,4,5-triamino-6-hydroxypyrimidine sulfate; the molar ratio of the 2,4,5-triamino-6-hydroxypyrimidine sulfate to the sodium metabisulfite is 1:(0.2-0.3); S3. Trichloroacetone having a purity greater than 85% was placed in a stirred tank Ⅲ as liquid C; S4. According to the molar ratio of N-(4-aminobenzoyl)-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and trichloroacetone of 1:1:1.2, liquid A, liquid B, and liquid C are respectively input into pressure vessel I, pressure vessel II, and pressure vessel III for pressurization, and then respectively passed through tubular reactor I, tubular reactor II, and tubular reactor III for homogenization to form high-speed flow counterflow at the discharge port. At the same time, 10 wt% sodium carbonate solution is continuously sprayed onto the counterflow liquid flow through an alkali liquid pump to maintain the pH range of 3.0-4.

0. The reactants are precipitated into a sedimentation tank; the material is then collected into a closed magnetic stirrer and stirred for 3-6 hours, and filtered through a centrifuge to obtain crude folic acid; the filtrate is aged for 3-5 days to remove impurities, neutralized with alkali, and then recycled to replace water for steps S1 and S2; S5. The crude folic acid is sequentially refined by acid and alkali to obtain high-purity folic acid.

2. The method for preparing folic acid by continuous hedging in a tubular reactor according to claim 1, characterized in that: The inner diameters of the tubular reactor I, tubular reactor II and tubular reactor III are 30-40 mm, the length of the pipeline is 5-8 m, and the diameter of the discharge port is narrowed to 10-20 mm.

3. The method for preparing folic acid by continuous hedging in a tubular reactor according to claim 1, characterized in that: The fluid pressure of liquid A in the tubular reactor I is 4.0-6.0 MPa; the fluid pressure of liquid B in the tubular reactor II is 4.0-6.0 MPa; and the fluid pressure of liquid C in the tubular reactor III is 2.5-3.0 MPa.

4. The method for preparing folic acid by continuous hedging in a tubular reactor according to claim 1, characterized in that: The temperature of the tubular reactor I and the tubular reactor II is controlled at 40-45°C; the temperature of the tubular reactor III is controlled at 30-35°C.

5. The method for preparing folic acid by continuous hedging in a tubular reactor according to claim 1, characterized in that: The 10 wt% sodium carbonate solution was sprayed to maintain the pH at 3.

5.

6. The method for preparing folic acid by continuous hedging in a tubular reactor according to claim 1, characterized in that: The acid purification is to dissolve the crude folic acid in 3-5 times the mass of 30wt% H2SO4, stir until completely dissolved, then add 8-10 times the mass of water of the crude folic acid, precipitate a yellow solid, let it stand for 2 hours and then filter to obtain the acid purified product.

7. The method for preparing folic acid by continuous hedging in a tubular reactor according to claim 1, characterized in that: The alkali refining comprises adding 10-12 times the mass of water to the acid refined product, adding sodium hydroxide at 80° C. to adjust the pH to 9.5-10, stirring until completely dissolved, then adding an appropriate amount of activated carbon for adsorption and decolorization, filtering while hot to obtain a yellow filtrate, adjusting the pH of the filtrate to 3-3.5 with hydrochloric acid, cooling to room temperature, filtering, and taking the filter cake and drying it to obtain high-purity folic acid.

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