A process for the preparation of folic acid

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a folate preparation process, which comprises pre-coating with ammonia monohydrate solution, and synchronously dropping ammonia di-salt aqueous solution and trichloroacetone aqueous solution. Compared with the single-component dropping process, the folate preparation process avoids the problem of local excess of ammonia di or trichloroacetone; compared with the three-component dropping process, the folate preparation process improves the cyclization reaction rate. The process avoids the wrapping of folate on raw materials, intermediates and by-product impurities, promotes the full cyclization reaction of materials, effectively inhibits the generation of EP impurities C, E and F in the reaction system, further improves the purity and yield of folate crude product, and reduces the pressure of subsequent refining. In addition, the folate preparation process also adopts the means of timely separation of solid-phase folate product, avoids the oxidation and decomposition of folate in the weak acid environment for a long time, simultaneously blocks the possibility of condensation reaction between folate and excess ammonia monohydrate in the system, and reduces the generation of EP impurity H.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology. Specifically, this invention relates to a process for preparing folic acid. Background Technology

[0002] Folic acid, chemically known as pteroyl-L-glutamic acid, is an essential water-soluble B vitamin for the human body. It is widely used in pharmaceutical preparations, food and feed additives, and other fields. Clinically, it is mainly used to prevent neural tube defects in fetuses and to treat megaloblastic anemia and other diseases. The market demand is huge.

[0003] The current mainstream industrial folic acid synthesis process involves using N-para-aminobenzoyl-L-glutamic acid (referred to as "ammonia-1"), 2,4,5-triamino-6-hydroxypyrimidine sulfate (referred to as "ammonia disulfide"), and 1,1,3-trichloroacetone (referred to as "trichloroacetone") as core raw materials, and preparing folic acid through cyclization and condensation reactions in an aqueous phase. The existing industrial processes for synthesizing folic acid using the above-mentioned techniques are mainly divided into three categories: one-pot overall reaction process, single-component dropwise continuous reaction process, and microchannel or tubular continuous flow reaction process. However, the above-mentioned processes generally suffer from technical problems such as low purity of crude folic acid, high levels of related impurities in the final product, cumbersome refining processes, and an inability to balance production efficiency, product purity, and production cost.

[0004] The aforementioned problems are specifically manifested in, for example: Chinese patent CN105440035B discloses a low-energy-consumption method for synthesizing high-purity folic acid. This method is a one-pot process, a traditional industrial process for folic acid synthesis. In the process disclosed in this patent, the reactants coexist simultaneously in the system. The generated folic acid solid tends to continuously coat unreacted reactants and intermediates, resulting in a low conversion rate of reactants. The purity of the crude product is generally lower than about 88% by weight, requiring multiple acid dissolution and water precipitation purifications plus at least one alkali dissolution purification to meet the EP11 pharmacopoeia standard. The overall yield of the finished product is less than about 70%, and there are also problems such as large wastewater volume and high production costs.

[0005] To overcome the drawbacks of coexisting raw materials in one-pot synthesis, existing technologies have developed processes that involve the separate addition of pyrimidine salts. For example, Chinese patent CN108558884B discloses a novel method for folic acid synthesis. This patent's process improves the problem of excessively high instantaneous concentrations of raw materials by slowly adding ammonium dichloride. However, this process still has the following shortcomings: folic acid remains in the reactor after generation, continuously contacting excessive ammonia, failing to inhibit the formation of EP impurity H at its source. Although the purity of the crude folic acid obtained using this patent's synthesis method is improved, the final product often contains EP impurity H content exceeding the EP pharmacopoeia limit (0.15% by weight), requiring additional purification cycles to meet the standard requirements.

[0006] In recent years, to further improve the mixing effect in the synthesis of crude folic acid, researchers have studied preparation processes that incorporate microchannels for folic acid synthesis (e.g., Chinese patent application CN115772172A) and methods using tubular continuous flow reaction processes to prepare folic acid (e.g., Chinese patent application CN120757554A). These processes employ tubular counter-flow and microchannel continuous feeding to enhance raw material mixing and heat transfer efficiency, thus reducing the problem of localized raw material enrichment to some extent. However, these processes suffer from unavoidable industrialization limitations: the folic acid cyclization reaction is a typical liquid-solid heterogeneous reaction, and the solid product easily causes blockage of microchannels and tubular equipment, resulting in extremely high equipment maintenance costs and poor production continuity. Furthermore, the investment cost of such equipment is high, and the parameters for small-scale and industrial production deviate significantly. Summary of the Invention

[0007] Purpose of the invention In view of the problems existing in the prior art described in the background section above, the object of the present invention is to provide a new folic acid preparation process.

[0008] Technical solution To achieve the above objectives, the present invention adopts the following technical solution: Option 1: A folic acid preparation process for controlling the content of EP impurity C, EP impurity E, EP impurity F, and / or EP impurity H in folic acid products, wherein the folic acid preparation process involves a cyclization reaction comprising: cyclizing N-p-aminobenzoyl-L-glutamic acid (ammonia-I), 2,4,5-triamino-6-hydroxypyrimidine sulfate (ammonia-disalt), and 1,1,3-trichloroacetone (trichloroacetone) in an acidic aqueous solution with a pH of about 2.5 to about 3.5 in the presence of an antioxidant to generate folic acid. The preparation process includes the following steps: Step 1: Provide aqueous solutions of ammonia-1, ammonia-2 salt, and trichloroacetone, respectively. The ammonia-aqueous solution contains about 0.04 to about 0.13 mol / L of ammonia and about 0.4 to about 0.5% by weight of an antioxidant. The aqueous solution of the ammonium dichloride comprises about 0.40 to about 0.45 mol / L of ammonium dichloride, about 1.2 to about 1.4 wt% of an antioxidant, and about 8.5 to about 9.5 wt% of an alkaline carbonate; and The aqueous trichloroacetone solution contains about 0.50 to about 0.55 mol / L of 1,1,3-trichloroacetone; and Step 2: At a temperature of about 40 to about 45°C, the aqueous solution of ammonium dichloride and the aqueous solution of trichloroacetone are simultaneously added dropwise to the aqueous solution of ammonia-1, thereby causing the cyclization reaction in the formed reaction system where the ammonia-1 in the aqueous solution of ammonia-1, the ammonium dichloride in the aqueous solution of ammonia-2, and the trichloroacetone in the aqueous solution of trichloroacetone are added dropwise such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is in the range of about 1.6 to about 1.7. The dropping rate of the aqueous solution of ammonia-2 does not exceed about 680 mL / h, the dropping rate of the aqueous solution of trichloroacetone does not exceed about 870 mL / h, and the pH value of the reaction system is maintained in the range of about 2.5 to about 3.5 during the dropping and reaction process, thereby obtaining folic acid as a solid precipitate. After filtering out the solid, crude folic acid and filtrate are obtained.

[0009] Option 2: According to the preparation process described in Option 1 above, in step 2, the dropwise addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed about 1 hour.

[0010] Option 3: The preparation process according to Option 1 or 2 above includes the following steps: Step 1: Provide aqueous solutions of ammonia-1, ammonia-2 salt, and trichloroacetone, respectively. The ammonia-water solution contains about 0.12 to about 0.13 mol / L of ammonia and about 0.4 to about 0.5% by weight of an antioxidant, and the volume of the ammonia-water solution is at least about 6 L. The aqueous solution of the ammonium dichloride comprises about 0.40 to about 0.45 mol / L of ammonium dichloride, about 1.2 to about 1.4 wt% of an antioxidant, and about 8.5 to about 9.5 wt% of an alkaline carbonate; and The aqueous trichloroacetone solution contains about 0.50 to about 0.55 mol / L of 1,1,3-trichloroacetone; and Step 2: At a temperature of approximately 40 to approximately 45°C, simultaneously add the aqueous solution of ammonium dichloride and the aqueous solution of trichloroacetone dropwise to the ammonia-1 aqueous solution, thereby causing the cyclization reaction in the formed reaction system where the ammonia in the ammonia-1 aqueous solution, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution are added. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is in the range of approximately 1.6 to approximately 1.7. The dropping rate of the ammonium dichloride aqueous solution does not exceed approximately 680 mL / h, and the dropping rate of the trichloroacetone aqueous solution does not exceed approximately 870 mL / h. The addition rate is mL / hour, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed about 1 hour, and during the addition and reaction process, the pH of the reaction system is optionally maintained in the range of about 2.5 to about 3.5 using another separate alkaline carbonate aqueous solution, and after the addition is completed, stirring is continued for about 4 to about 6 minutes, and then allowed to stand for about 9 to about 11 minutes to obtain the first batch of folic acid as a solid precipitate. After filtering out the solid, the first batch of crude folic acid and the first batch of filtrate are obtained.

[0011] Option 4: According to the preparation process described in Option 3 above, the preparation process further includes step 3 performed after step 2: simultaneously adding the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the first batch of filtrate obtained from step 2 at a temperature of about 40 to about 45°C, so that in the formed reaction system, the ammonia in the first batch of filtrate, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution undergo the cyclization reaction, wherein the amount of the ammonium dichloride aqueous solution and the amount of the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride added to the reaction system is in the range of about 1.6 to about 1.7, the dropping rate of the ammonium dichloride aqueous solution does not exceed about 680 mL / h, and the dropping rate of the trichloroacetone aqueous solution does not exceed about 870 mL / h. The addition rate is mL / hour, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed about 1 hour, and the pH of the reaction system is maintained in the range of about 2.5 to about 3.5 using a separate alkaline carbonate aqueous solution during the addition and reaction process, and stirring is continued for about 4 to about 6 minutes after the addition is completed, and then allowed to stand for about 9 to about 11 minutes to obtain a second batch of folic acid as a solid precipitate. After filtering out the solid, a second batch of crude folic acid and a second batch of filtrate are obtained.

[0012] Option 5: According to the preparation process described in Option 4 above, the preparation process further includes step 4 performed after step 3: At a temperature of about 40 to about 45°C, the aqueous solution of the ammonium dichloride and the aqueous solution of trichloroacetone are simultaneously added dropwise to the second batch of filtrate obtained from step 3, so that in the formed reaction system, the ammonia in the second batch of filtrate, the ammonium dichloride in the aqueous solution of the ammonium dichloride, and the trichloroacetone in the aqueous solution of trichloroacetone undergo the cyclization reaction, wherein the amount of the aqueous solution of the ammonium dichloride and the amount of the aqueous solution of trichloroacetone added are such that the molar ratio of trichloroacetone to ammonium dichloride added to the reaction system is in the range of about 1.6 to about 1.7, the dropping rate of the aqueous solution of the ammonium dichloride does not exceed about 680 mL / h, and the dropping rate of the aqueous solution of trichloroacetone does not exceed about 870 mL / h. The addition rate is mL / hour, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed about 1 hour, and the pH of the reaction system is maintained in the range of about 2.5 to about 3.5 using a separate alkaline carbonate aqueous solution during the addition and reaction process, and stirring is continued for about 4 to about 20 minutes after the addition is completed, and then allowed to stand for about 9 to about 11 minutes to obtain a third batch of folic acid as a solid precipitate. After filtering out the solid, a third batch of crude folic acid and a third batch of filtrate are obtained.

[0013] Option 6: According to the preparation process described in Option 5 above, the preparation process further includes the following step 5 after step 4: detecting whether there is still a sufficient amount of ammonia-1 remaining in the third batch of filtrate; if there is still a sufficient amount of ammonia-1 remaining in the filtrate, then repeating step 4, except that the second batch of filtrate obtained from step 3 in step 4 is replaced with the third batch of filtrate obtained from step 4, to obtain a fourth or higher batch of crude folic acid and a fourth or higher batch of filtrate; or, if there is no longer a sufficient amount of ammonia-1 remaining in the filtrate, then at least a portion of the third batch of filtrate obtained from step 4 is used to prepare the next batch of aqueous solution or discarded.

[0014] Option 7: The preparation process according to any one of Options 1 to 6 above, wherein the antioxidant comprises one or more of sodium metabisulfite, sodium bisulfite, sodium sulfite, L-ascorbic acid, D-isoascorbic acid and its salts, and L-cysteine ​​and its salts.

[0015] Option 8: The preparation process according to any one of Options 1 to 7 above, wherein the alkaline carbonate includes one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

[0016] Option 9: The preparation process according to any one of Options 3 to 8 above, wherein in step 2, the dropwise addition is such that the amount of ammonia in the ammonia-water solution consumed due to the cyclization reaction does not exceed 1 / n of the total amount of ammonia in the ammonia-water solution, where n ≥ approximately 3.

[0017] Option 10: The preparation process according to any one of Options 3 to 9 above, wherein in step 3, the dropwise addition is such that the amount of ammonia-1 contained in the first batch of filtrate consumed due to the cyclization reaction does not exceed 1 / m of the total amount of ammonia-1 in the aqueous solution, wherein m ≥ about 3.

[0018] Option 11: The preparation process according to any one of Options 3 to 9 above, wherein in step 4, the addition is such that the amount of ammonia-1 contained in the second batch of filtrate consumed due to the cyclization reaction does not exceed 1 / p of the total amount of ammonia-1 in the aqueous solution, wherein p ≥ about 3.

[0019] Option 12: The preparation process according to any one of Options 1 to 11 above, wherein the preparation process further includes sequentially subjecting the crude folic acid product or the first batch of crude folic acid product and / or the second batch of crude folic acid product and / or the third batch of crude folic acid product and / or the fourth batch of crude folic acid product and / or higher batches of crude folic acid product to acid dissolution and water precipitation purification once and alkali dissolution purification once to obtain the finished folic acid product.

[0020] Option 13: Crude folic acid obtained by the preparation process according to any one of Options 1 to 11 above, wherein, The crude folic acid product contains EP impurity C, EP impurity E, EP impurity F, and EP impurity H in amounts of approximately 0.69% by weight, approximately 0.63% by weight, approximately 1.38% by weight, and approximately 0.15% by weight, respectively, preferably approximately 0.66% by weight, approximately 0.61% by weight, approximately 1.32% by weight, and approximately 0.08% by weight, respectively, based on the weight of the crude folic acid product; and / or The crude folic acid has an HPLC purity of approximately 95% or higher, preferably approximately 96% or higher; and / or The total yield of the crude folic acid product based on ammonia is over 85%.

[0021] Option 14: A finished folic acid product obtained from the preparation process described in Option 12 above, wherein, The content of EP impurity C, EP impurity E, EP impurity F, and EP impurity H in the folic acid product is respectively less than about 0.3% by weight, less than about 0.3% by weight, less than about 0.1% by weight, and less than about 0.15% by weight, based on the weight of the folic acid product; preferably less than about 0.13% by weight, less than about 0.03% by weight, less than about 0.04% by weight, and less than about 0.08% by weight; and / or The HPLC purity of the folic acid product is above approximately 99%, preferably above approximately 99.3%; and / or The total yield of the folic acid product based on ammonia is over 80%.

[0022] Technical effect The folic acid preparation process of this invention adopts a method of pre-preparing with an ammonia-1 aqueous solution and simultaneously adding an ammonia-2 aqueous solution and a trichloroacetone aqueous solution. Compared with the single-component dropwise addition process, this avoids the problem of local excess of ammonia-2 or trichloroacetone. Compared with the three-component dropwise addition process, it further improves the cyclization reaction rate.

[0023] The folic acid preparation process proposed in this invention specifically includes: continuously adding ammonia-2 aqueous solution and trichloroacetone aqueous solution to an ammonia-1 aqueous solution, discharging the material in stages, and recycling the filtrate. During the reaction, the solid-phase folic acid product is separated in a timely manner, avoiding the self-oxidation and decomposition of folic acid in a weakly acidic environment for a long time. At the same time, it also blocks the condensation reaction between folic acid and excess ammonia-1 in the system, thereby reducing the generation of EP impurity H. In addition, the folic acid preparation process of this invention also avoids the encapsulation of raw materials, intermediates and by-product impurities by folic acid, and promotes the full cyclization reaction of the remaining materials.

[0024] The folic acid preparation process of this invention not only reduces the formation of EP impurity H during folic acid preparation, but also effectively inhibits the formation of pterin-like impurities (EP impurity E, EP impurity F) and EP impurity C in the reaction system, further improving the purity and yield of crude folic acid, thereby reducing the pressure of subsequent purification. The final product meets the EP11 pharmacopoeia standard. This method is stable, easy to scale up industrially, and has good economic and environmental benefits.

[0025] Specifically, the preparation process of the present invention achieves the following effects: (1) By using ammonia-1 aqueous solution as a pre-treatment and simultaneously adding ammonia-2 aqueous solution and trichloroacetone aqueous solution, compared with the single-component dropwise addition process, the problem of local excess of ammonia-2 or trichloroacetone is avoided; compared with the three-component dropwise addition process, the cyclization reaction rate is further improved. Therefore, the folic acid preparation process of the present invention effectively inhibits the formation of pterin impurities (EP impurity E, EP impurity F) and EP impurity C in the reaction system, and further improves the purity and yield of crude folic acid.

[0026] (2) By adopting the method of segmented discharge and timely separation of solid folic acid, the oxidation and decomposition of folic acid in a weakly acidic environment for a long time is avoided. At the same time, the condensation reaction between folic acid and excess ammonia in the system is blocked, thereby reducing the generation of EP impurity H and significantly improving the purity and yield of crude folic acid.

[0027] (3) By adopting the method of segmented discharge and timely separation of solid folic acid, the folic acid is avoided from encapsulating raw materials, intermediates and by-product impurities, which promotes the full cyclization reaction of the remaining materials and effectively improves the utilization rate of raw materials and the product yield. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the specific embodiments of the present invention, the drawings used in the specific embodiments of the present invention will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0029] Figure 1 This is a schematic diagram of an exemplary process flow for the folic acid preparation process of the present invention.

[0030] Figure labels: 1: Reactor 1; 2: Reactor 2; 3: Reactor 3; 4: Filter press. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Those skilled in the art should understand that the embodiments described are merely for the purpose of aiding understanding of this invention and should not be considered as specific limitations on this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. Process parameters in the following embodiments that are not specifically specified are generally performed under conventional conditions.

[0032] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. The term "about" as used in this invention means that the number it modifies may fluctuate within ±20%, ±15%, ±10%, ±5%, or ±2% of that number. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and the individual point values ​​contained within them, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0033] According to a first aspect of the present invention, the present invention provides a folic acid preparation process for controlling (preferably simultaneously controlling) the content of EP impurity C, EP impurity E, EP impurity F and / or EP impurity H.

[0034] The folic acid preparation process according to the first aspect of the present invention involves a cyclization reaction process comprising: cyclizing N-p-aminobenzoyl-L-glutamic acid (ammonia-1), 2,4,5-triamino-6-hydroxypyrimidine sulfate (ammonia-2), and 1,1,3-trichloroacetone (trichloroacetone) in the presence of an antioxidant in an acidic aqueous solution with a pH of about 2.5 to about 3.5 to generate folic acid. The folic acid preparation process according to the first aspect of the present invention includes steps 1 and 2.

[0035] Step 1: Material Preparation Step 1 includes preparing an aqueous solution of ammonia-1, an aqueous solution of ammonia-2 salt, and an aqueous solution of trichloroacetone, respectively.

[0036] Ammonia solution: The ammonia-aqueous solution contains about 0.04 to about 0.13 mol / L (e.g., about 0.06 mol / L, about 0.08 mol / L, or about 0.10 mol / L) of ammonia and about 0.4 to about 0.5% by weight (e.g., about 0.42% by weight, about 0.45% by weight, or about 0.48% by weight) of an antioxidant.

[0037] Preferably, the ammonia-aqueous solution may contain about 0.12 to about 0.13 mol / L (e.g., about 0.122 mol / L, about 0.125 mol / L or about 0.128 mol / L) of the ammonia-aqueous solution.

[0038] Here, the molar concentration of ammonia in the ammonia-water solution should not be too high, for example, it should not exceed about 0.13 mol / L, otherwise ammonia may not dissolve easily; in addition, the molar concentration of ammonia in the ammonia-water solution should not be too low, for example, it should not be lower than about 0.04 mol / L, otherwise, when a specific output is required, the water consumption will be too large, resulting in water waste and increased costs.

[0039] In addition, the concentration of antioxidants in the ammonia-water solution should not be too high, for example, not exceeding about 0.5% by weight. Otherwise, it may not only lead to unnecessary waste, but also excessive antioxidants may affect the synthesis of folic acid, resulting in a decrease in folic acid yield. In addition, the concentration of antioxidants in the ammonia-water solution should not be too low, for example, not less than about 0.4% by weight. Otherwise, it may lead to the generation of some unknown oxide impurities in the reaction system, resulting in a darker color of the obtained product and subsequent decolorization trouble.

[0040] Ammonia disalide aqueous solution The aqueous solution of the ammonium dichloride contains about 0.40 to about 0.45 mol / L (e.g., about 0.41 mol / L, about 0.42 mol / L, about 0.43 mol / L or about 0.44 mol / L) of the ammonium dichloride, about 1.2 to about 1.4 wt% (e.g., about 1.25 wt%, about 1.3 wt% or about 1.35 wt%) of an antioxidant, and about 8.5 to about 9.5 wt% (e.g., about 8.7 wt%, about 9.0 wt% or about 9.3 wt%) of an alkaline carbonate.

[0041] Here, the molar concentration of the diammonium salt in the aqueous solution should not be too high, for example, it should not exceed about 0.45 mol / L, otherwise the diammonium salt may not dissolve completely. In addition, the molar concentration of the diammonium salt in the aqueous solution should not be too low, for example, it should not be lower than about 0.40 mol / L, otherwise, when a specific yield is required, the amount of alkali in the reaction system may increase, and the pH value of the reaction system may be difficult to control.

[0042] In addition, the concentration of antioxidants in the aqueous solution of the ammonium dichloride should not be too high, for example, not exceeding about 1.4% by weight. Otherwise, it may not only lead to unnecessary waste, but also excessive antioxidants may affect the synthesis of folic acid, resulting in a decrease in folic acid yield. In addition, the concentration of antioxidants in the aqueous solution of the ammonium dichloride should not be too low, for example, not less than about 1.2% by weight. Otherwise, the amino group of the ammonium dichloride may be easily oxidized, thereby forming oxide impurities.

[0043] In addition, the concentration of alkaline carbonate in the aqueous solution of the ammonium dichloride should not be too high, for example, it should not exceed about 9.5% by weight, otherwise the alkalinity of the reaction system may be too high when the ammonium dichloride solution is added dropwise, and the pH value may be difficult to control. In addition, the concentration of alkaline carbonate in the aqueous solution of the ammonium dichloride should not be too low, for example, it should not be less than about 8.5% by weight, otherwise the ammonium dichloride may not dissolve completely, and the aqueous solution may be in a suspended state, which will affect the smooth progress of the cyclization reaction.

[0044] chloroacetone aqueous solution The aqueous trichloroacetone solution contains about 0.50 to about 0.55 mol / L (e.g., about 0.51 mol / L, about 0.52 mol / L, about 0.53 mol / L, or about 0.54 mol / L) of 1,1,3-trichloroacetone. In some exemplary embodiments of the invention, the aqueous trichloroacetone solution used may include an industrially available aqueous extract of trichloroacetone.

[0045] Here, the molar concentration of trichloroacetone in the aqueous trichloroacetone solution should not be too high, for example, it should not exceed about 0.55 mol / L, otherwise unwanted side reactions may be triggered in the reaction system; in addition, the molar concentration of trichloroacetone in the aqueous trichloroacetone solution should not be too low, for example, it should not be lower than about 0.50 mol / L, otherwise, when a specific yield is required, the water consumption may be greatly increased, resulting in water waste and increased costs.

[0046] In some preferred embodiments of step 1 of the preparation process of the first aspect of the present invention, the volume of the ammonia-water solution is typically more than about 6 L, so that the molar amount of ammonia-containing in the ammonia-water solution can reach at least about 0.24 mol, preferably at least about 0.48 mol, more preferably at least about 0.72 mol, most preferably at least about 0.75 mol, for example at least about 0.77 mol, at least about 0.80 mol, or at least about 0.90 mol, thereby making the preparation process of the present invention applicable to the large-scale production of folic acid.

[0047] In some preferred embodiments of step 1 of the preparation process of the first aspect of the present invention, the molar amount of 1,1,3-trichloroacetone contained in the provided trichloroacetone aqueous solution can be about 1.75 to about 1.85 times, for example about 1.77 times, about 1.80 times, or about 1.83 times, of the molar amount of ammonia contained in the ammonia-aqueous solution. Here, the molar ratio of trichloroacetone to ammonia should not be too high, for example, not higher than about 1.85 times, otherwise it may not only lead to an excess of trichloroacetone, wasting raw materials, but the excessive addition of trichloroacetone may also further trigger side reactions, resulting in an increase in the impurity content in the product; in addition, the molar ratio of trichloroacetone to ammonia should not be too low, for example, not lower than about 1.75 times, otherwise the cyclization reaction may ultimately be incomplete, resulting in a reduced yield of folic acid.

[0048] In some preferred embodiments of step 1 of the preparation process of the first aspect of the present invention, the molar amount of ammonium disalt contained in the provided ammonium disalt aqueous solution can be about 1.05 to about 1.15 times, for example about 1.07 times, about 1.10 times, or about 1.13 times, the molar ratio of the ammonium disalt to the ammonia-1 in the ammonia-1 aqueous solution. Here, the molar ratio of the ammonium disalt to the ammonia-1 should not be too high, for example, not higher than about 1.15 times, otherwise it may result in excessive residual ammonium disalt after addition, which is difficult to remove in subsequent purification processes; in addition, the molar ratio of the ammonium disalt to the ammonia-1 should not be too low, for example, not lower than about 1.05 times, otherwise it may result in incomplete reaction of the ammonia-1, further leading to a decrease in the yield of the product folic acid.

[0049] Step 2: Add the two components dropwise At a temperature of about 40 to about 45°C, the aqueous solution of ammonium dichloride and the aqueous solution of trichloroacetone are simultaneously added dropwise to the aqueous solution of ammonia-1 under preferred stirring, so that in the formed reaction system, the ammonia-1 in the aqueous solution of ammonia-1, the ammonium dichloride in the aqueous solution of ammonia-2, and the trichloroacetone in the aqueous solution of trichloroacetone undergo the cyclization reaction, wherein the amount of the aqueous solution of ammonia-2 and the amount of the aqueous solution of trichloroacetone added dropwise are such that the molar ratio of trichloroacetone to ammonia-2 added dropwise to the reaction system is in the range of about 1.6 to about 1.7, the dropwise addition rate of the aqueous solution of ammonia-2 does not exceed about 680 mL / h, the dropwise addition rate of the aqueous solution of trichloroacetone does not exceed about 870 mL / h, and the pH value of the reaction system is maintained in the range of about 2.5 to about 3.5 during the addition and reaction process, thereby obtaining folic acid as a solid precipitate, and after filtering the solid, crude folic acid and filtrate are obtained.

[0050] In some particularly preferred embodiments of the present invention, step 2 may include the following process: Step 2: First drip addition and staged discharge and filtrate circulation At a temperature of about 40 to about 45°C, the aqueous solution of ammonium dichloride and the aqueous solution of trichloroacetone are simultaneously added dropwise to the aqueous solution of ammonia-1 under preferred stirring. In the resulting reaction system, the ammonia-1 in the aqueous solution of ammonia-1, the ammonium dichloride in the aqueous solution of ammonia-1, and the trichloroacetone in the aqueous solution of trichloroacetone undergo the cyclization reaction. The amounts of the aqueous solution of ammonia-1 and the aqueous solution of trichloroacetone added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is in the range of about 1.6 to about 1.7. The dropping rate of the aqueous solution of ammonia-1 does not exceed about 680 mL / h, the dropping rate of the aqueous solution of trichloroacetone does not exceed about 870 mL / h, and the dropping time of the aqueous solutions of ammonia-1 and trichloroacetone does not exceed about 1 hour. Preferably, the amount of ammonia-1 in the aqueous solution of ammonia-1 consumed by the cyclization reaction does not exceed 1 / n of the total amount of ammonia-1 in the aqueous solution of ammonia-1, where n ≥ Approximately 3, and optionally using a separate alkaline carbonate aqueous solution during the addition and reaction process to maintain the pH of the reaction system in the range of approximately 2.5 to approximately 3.5, and after the addition is complete, continue stirring for approximately 4 to approximately 6 minutes, and then let stand for approximately 9 to approximately 11 minutes to obtain the first batch of folic acid precipitated as a solid. After filtering out the solid, obtain the first batch of crude folic acid and the first batch of filtrate.

[0051] In step 2 above, the reaction temperature should be in the range of approximately 40 to approximately 45°C, for example, approximately 41°C, approximately 42°C, approximately 43°C, or approximately 44°C. Here, the reaction temperature should not be too high, for example, it should not exceed approximately 45°C, otherwise it may lead to a significant increase in EP impurities such as C and H, and the reaction system will darken in color with increasing temperature, making subsequent decolorization difficult. In addition, the reaction temperature should not be too low, for example, it should not be below approximately 40°C, otherwise the cyclization reaction may be incomplete, resulting in a reduced folic acid yield.

[0052] In step 2 above, the amount of the ammonium dichloride aqueous solution and the amount of the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride added to the reaction system is in the range of about 1.6 to about 1.7, for example, about 1.62, about 1.65, or about 1.68. Here, the molar ratio of trichloroacetone to ammonium dichloride added should not be too high, for example, it should not exceed about 1.7, otherwise it may lead to an increase in side reactions in the reaction system and an increase in the impurity content in the product folic acid; in addition, the molar ratio of trichloroacetone to ammonium dichloride added should not be too low, for example, it should not be lower than about 1.6, otherwise it may lead to incomplete cyclization reaction and an increase in the impurity content in the product folic acid.

[0053] In some preferred embodiments of step 2 above, the dripping time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution is preferably no more than about 1 hour each, for example, no more than about 55 minutes, or no more than about 50 minutes. Here, if the dripping time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution exceeds about 1 hour, it may cause the EP impurity H content to increase beyond the limits required by the present invention.

[0054] In some preferred embodiments of step 2 above, the dropping rates of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution should not be too fast. For example, in some preferred embodiments of the present invention, the dropping rate of the ammonium dichloride aqueous solution preferably does not exceed 680 mL / hour, and / or the dropping rate of the trichloroacetone aqueous solution preferably does not exceed 870 mL / hour. Here, excessively fast dropping rates exceeding the defined rates may not only lead to an increase in side reactions, but may also prevent the ammonia from reacting quickly enough, resulting in an increase in the impurity content in the folic acid product.

[0055] In step 2 above, the pH of the reaction system should be controlled within the range of approximately 2.5 to approximately 3.5, for example, approximately 2.7, approximately 3.0, or approximately 3.3. Here, since the byproduct of the cyclization reaction occurring in the reaction system is hydrochloric acid, the pH value is generally only likely to decrease. When the pH of the reaction system is detected to be decreasing towards approximately 2.5, the pH value can be increased by adjusting the dropping rate of a separate alkaline carbonate aqueous solution.

[0056] In step 2 above, the amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are preferably such that the amount of ammonia ions consumed by the cyclization reaction in the ammonia ion aqueous solution does not exceed 1 / n of the total amount of ammonia ions in the ammonia ion aqueous solution, where n ≥ approximately 3, for example, n is approximately 3.1, approximately 3.2, approximately 3.3, approximately 3.5, approximately 3.7, approximately 4, approximately 4.5, or approximately 5. Here, the value of n should not be less than approximately 3, otherwise it may lead to a decrease in the purity of the crude folic acid, an increase in impurities such as EP impurity H and EP impurity C in the crude product, and further cause the impurities in the subsequent finished folic acid product to exceed the limit.

[0057] In step 2 above, after the addition of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution, the reaction system is stirred for approximately 4 to 6 minutes (e.g., approximately 4.5 minutes, 5 minutes, or 5.5 minutes), and then allowed to stand for approximately 9 to 11 minutes (e.g., approximately 9.5 minutes, 10 minutes, or 10.5 minutes). Here, the stirring time should not be too long, for example, not exceeding approximately 6 minutes, and the standing time should not exceed approximately 11 minutes; otherwise, it may lead to an increase in side reactions in the reaction system, an increase in EP impurities (H) in the crude folic acid, and within this time range, the cyclization reaction is essentially complete. Excessive stirring and standing time would only increase unnecessary costs. Conversely, the stirring time should not be too short, for example, not less than approximately 4 minutes, and the standing time should not be less than approximately 9 minutes; otherwise, the cyclization reaction may be incomplete, resulting in residual raw materials and increased impurities.

[0058] It should be noted that during the dropwise addition process in step 2 above, ammonia I in the reaction system is in significant excess, which promotes the forward cyclization reaction and accelerates the reaction rate. After the initial dropwise addition of ammonium dichloride and trichloroacetone, the amount of ammonium dichloride and trichloroacetone added is directly proportional to the amount reacted, ensuring a complete reaction and effectively reducing the generation of EP impurities C, E, and F. Furthermore, since EP impurity H is related to the large excess of ammonia I in the system due to the formation of folic acid, it is necessary to promptly filter the crude folic acid and recycle the filtrate to avoid its generation. Here, after the reaction system has stood for approximately 9 to 11 minutes, the crude folic acid settles rapidly; therefore, it is not necessary to filter the entire reaction system from step 2. Preferably, only the lower portion of the settled solids and a portion of the filtrate can be extracted, and the filtrate can then be recycled back into the reaction vessel.

[0059] The folic acid preparation process according to the first aspect of the present invention preferably further includes the following optional steps 3, 4 and 5 performed after step 2.

[0060] Step 3: Second dripping and segmented discharge and filtrate circulation Step 3 includes: simultaneously adding the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the first batch of filtrate obtained from step 2 at a temperature of about 40 to about 45°C, so that in the formed reaction system, the ammonia in the first batch of filtrate, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution undergo the cyclization reaction. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is in the range of about 1.6 to about 1.7. The dropping rate of the ammonium dichloride aqueous solution does not exceed about 680 mL / h, the dropping rate of the trichloroacetone aqueous solution does not exceed about 870 mL / h, and the dropping time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed about 1 hour. Preferably, the amount of ammonia dichloride in the first batch of filtrate consumed by the cyclization reaction does not exceed 1 / m of the total amount of ammonia dichloride in the ammonium dichloride aqueous solution, where m ≥ Approximately 3, and during the addition and reaction process, the pH of the reaction system is maintained in the range of approximately 2.5 to approximately 3.5 using a separate alkaline carbonate aqueous solution, and after the addition is complete, stirring is continued for approximately 4 to approximately 6 minutes, and then allowed to stand for approximately 9 to approximately 11 minutes to obtain a second batch of folic acid precipitated as a solid. The solid is filtered out to obtain a second batch of crude folic acid and a second batch of filtrate.

[0061] In step 3 above, for reasons similar to those in step 2, the set reaction temperature, the dropping rates of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution, the pH value of the reaction system, the dropping amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution, and the stirring time and settling time after adding the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution can all be the same as the corresponding indicators in step 2. It should be noted that the ranges for m and n are the same, but the values ​​of m and n can be the same or different.

[0062] It should be noted that in the reaction system of step 3 above, although the concentration of ammonia-1 in the first batch of filtrate is lower than that in the ammonia-1 aqueous solution of the reaction system in step 2, ammonia-1 is still in excess, which can promote the forward progress of the cyclization reaction and accelerate the reaction rate. After the addition of diammonium salt and trichloroacetone, the amount of diammonium salt and trichloroacetone added is directly proportional to the amount of diammonium salt and trichloroacetone reacted, ensuring a complete reaction and effectively reducing the generation of EP impurities C, E, and F. In addition, since EP impurity H is related to the large amount of excess ammonia-1 in the system due to the generation of folic acid, it is necessary to perform subsequent crude folic acid filtration in a timely manner to avoid the generation of EP impurity H, and to recycle the filtrate. Here, after the reaction system is allowed to stand for about 9 to 11 minutes, the crude folic acid settles quickly, so it is not necessary to filter the entire reaction system of step 3. Preferably, only the lower part of the settled solids and a portion of the filtrate can be extracted, and then the filtrate can be recycled back into the reaction vessel.

[0063] Step 4: Third dripping and segmented discharge and filtrate circulation Step 4 includes: simultaneously adding the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the second batch of filtrate obtained from step 3 at a temperature of about 40 to about 45°C, so that in the formed reaction system, the ammonia in the second batch of filtrate, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution undergo the cyclization reaction. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is in the range of about 1.6 to about 1.7. The dropping rate of the ammonium dichloride aqueous solution does not exceed about 680 mL / h, the dropping rate of the trichloroacetone aqueous solution does not exceed about 870 mL / h, and the dropping time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed about 1 hour. Preferably, the amount of ammonia in the second batch of filtrate consumed by the cyclization reaction does not exceed 1 / p of the total amount of ammonia in the ammonium dichloride aqueous solution, where p ≥ Approximately 3, and during the addition and reaction process, the pH of the reaction system is maintained in the range of approximately 2.5 to approximately 3.5 using a separate alkaline carbonate aqueous solution, and after the addition is complete, stirring is continued for approximately 4 to approximately 20 minutes, and then allowed to stand for approximately 9 to approximately 11 minutes to obtain a third batch of folic acid precipitated as a solid. The solid is filtered out to obtain a third batch of crude folic acid and a third batch of filtrate.

[0064] In step 4 above, for reasons similar to those in steps 2 or 3, the set reaction temperature, the dropping rate of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution, the pH value of the reaction system, the dropping volume of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution, and the standing time after adding the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution can all be the same as the corresponding indicators in steps 2 or 3. It should be noted that the ranges of m, n, and p are the same, but the values ​​of m, n, and p can be independently the same or different.

[0065] In addition, in step 4 above, the stirring time after adding the diammonium salt aqueous solution and the trichloroacetone aqueous solution can be appropriately extended depending on the specific circumstances. Specifically, when the third addition in step 4 is the last addition, that is, when the ammonia I in the second batch of filtrate has almost completely reacted after the third addition, the stirring time can be extended to ensure that the cyclization reaction of ammonia I, diammonium salt, and trichloroacetone is complete. This is because the molar concentration of ammonia I is relatively sufficient at the initial addition, but decreases significantly at the last addition. Extending the time allows the reaction to be more complete, for example, extending it to about 15 to about 20 minutes, or about 16 minutes, 17 minutes, 18 minutes, or 19 minutes.

[0066] It should be noted that in the reaction system of step 4 above, although the concentration of ammonia I in the second batch of filtrate is further reduced compared to the concentration of ammonia I in the first batch of filtrate in the reaction system of step 3, ammonia I is still in excess relative to the ammonia disalt and trichloroacetone added to the reaction system (even when the third addition in step 4 is the last addition), which can promote the forward cyclization reaction and accelerate the reaction rate. After the addition of ammonia disalt and trichloroacetone begins, the amount of ammonia disalt and trichloroacetone added is exactly the amount that reacts, resulting in a complete reaction, which can effectively reduce the generation of EP impurities C, E, and F. Here, after the reaction system is allowed to stand for about 9 to about 11 minutes, the crude folic acid settles quickly, so it is not necessary to filter the entire reaction system of step 4. Preferably, only the lower part of the settled solids and a portion of the filtrate can be extracted, and then the filtrate can be recycled back to the reaction vessel or discarded.

[0067] Optional step 5: Fourth or higher addition and staged discharge and filtrate circulation The process involves checking whether a sufficient amount of ammonia-1 remains in the third batch of filtrate. If a sufficient amount of ammonia-1 remains in the filtrate, the process of step 4 is repeated as step 5, except that the second batch of filtrate obtained from step 3 is replaced with the third batch of filtrate obtained from step 4 to obtain a fourth or higher batch of crude folic acid and a fourth or higher batch of filtrate. Alternatively, if a sufficient amount of ammonia-1 no longer remains in the filtrate, at least a portion of the third batch of filtrate obtained from step 4 is used to prepare the next batch of aqueous solution or discarded. Here, the term "sufficient amount" of ammonia means that the amount of ammonia present in the filtrate is sufficient for further cyclization reactions to obtain folic acid in industrial production. A person skilled in the art may define "sufficient amount" according to actual production needs (e.g., cost considerations), for example, it may be more than about 1.2% of the total ammonia content in the ammonia solution, preferably about 1.6%, more preferably about 2%; or the ammonia concentration in the filtrate may be not less than about 0.0015 mol / L, preferably not less than about 0.0020 mol / L, more preferably not less than about 0.0025 mol / L.

[0068] It should be noted that step 5 above, "detecting whether there is still a sufficient amount of ammonia remaining in the filtrate," can also be performed after steps 2 and 3, and the filtrate may need further titration or further treatment depending on the detection results.

[0069] In the context of this invention, the "dropping" is preferably a substantially uniform dripping, for example, the difference between the minimum and maximum dripping rates does not exceed about 5%.

[0070] In some exemplary embodiments of the folic acid preparation process described in the first aspect of the present invention, the antioxidants used preferably include one or more of sodium metabisulfite, sodium bisulfite, sodium sulfite, L-ascorbic acid, D-isoascorbic acid and its salts, and L-cysteine ​​and its salts.

[0071] In some exemplary embodiments of the folic acid preparation process described in the first aspect of the present invention, the alkaline carbonate used may preferably include one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0072] In some further preferred embodiments of the folic acid preparation process according to the first aspect of the present invention, the preparation process preferably includes sequentially subjecting the crude folic acid product, or the first batch of crude folic acid product, the second batch of crude folic acid product, the third batch of crude folic acid product and / or the fourth batch or higher batches of crude folic acid product to acid dissolution and water precipitation purification once and alkali dissolution and purification once to obtain the finished folic acid product.

[0073] In this invention, the acid dissolution and water precipitation purification and the alkali dissolution purification include the purification process described in Chinese Patent CN107312004B.

[0074] According to a second aspect of the present invention, the present invention provides crude folic acid or finished folic acid product obtained by the preparation process according to the first aspect of the present invention described above.

[0075] The contents of EP impurity C, EP impurity E, EP impurity F and EP impurity H contained in the crude folic acid product are respectively about 0.69% by weight or less, about 0.63% by weight or less, about 1.38% by weight or less and about 0.15% by weight, preferably about 0.66% by weight or less, about 0.61% by weight or less, about 1.32% by weight or less and about 0.08% by weight, based on the weight of the crude folic acid product.

[0076] In addition, the HPLC purity of the crude folic acid is above 95%, preferably above 96%.

[0077] In addition, the overall yield of crude folic acid based on ammonia 1 prepared by the aforementioned preparation process is over 85%.

[0078] The content of each of the EP impurity C, EP impurity E, EP impurity F and EP impurity H contained in the folic acid product is less than about 0.3% by weight, less than about 0.3% by weight, less than about 0.1% by weight and less than about 0.15% by weight, preferably less than about 0.13% by weight, less than about 0.03% by weight, less than about 0.04% by weight and less than about 0.08% by weight, respectively, based on the weight of the folic acid product.

[0079] In addition, the HPLC purity of the folic acid product is above approximately 99%, preferably above approximately 99.3%.

[0080] In addition, the overall yield of folic acid products prepared by the aforementioned preparation process based on ammonia is over 80%.

[0081] The present invention will now be described in further detail with reference to specific embodiments and comparative examples.

[0082] The chemicals used in the following examples and comparative examples are all commercially available analytical grade chemicals.

[0083] Example 1: Process for preparing folic acid (two components added dropwise in three steps) See attached document Figure 1 , (1) Prepare ammonia-1 aqueous solution, ammonia-2 salt aqueous solution, and trichloroacetone aqueous solution respectively: Ammonia-1 aqueous solution: Add about 6000 g of purified water to reaction vessel 3 with a capacity of about 10 L, heat to about 42°C, add about 200 g (about 0.751 mol) of ammonia-1 and about 30 g (about 0.158 mol) of sodium metabisulfite, stir to dissolve, and keep warm for later use; Aqueous solution of ammonium disulfide: Add about 2100 g of sodium carbonate aqueous solution with a concentration of about 10% by weight to reaction vessel 1 with a capacity of about 5 L, heat to about 45°C, slowly add about 200 g (about 0.836 mol) of ammonium disulfide and about 30 g (about 0.158 mol) of sodium metabisulfite, stir to dissolve, and keep warm for later use; Aqueous solution of 1,1,3-trichloroacetone: Add approximately 2600 mL of 1,1,3-trichloroacetone aqueous extract with a concentration of approximately 84 g / L (approximately 0.52 mol / L) as an aqueous solution of 1,1,3-trichloroacetone to reaction vessel 2 with a capacity of approximately 5 L, and set aside at room temperature.

[0084] (2) First staged discharge and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the diammonium salt aqueous solution is added dropwise to reactor 3 at a rate of approximately 680 mL / hour. Simultaneously, the trichloroacetone aqueous solution is added dropwise to reactor 3 at a rate of approximately 866 mL / hour. After approximately 1 hour of simultaneous addition, the addition is stopped, so that approximately 1 / 3 of the total volume of the diammonium salt aqueous solution in reactor 1 and the trichloroacetone aqueous solution in reactor 2 are added dropwise to reactor 1. The amount of ammonia I in the ammonia I aqueous solution consumed due to the cyclization reaction is approximately 1 / 3 of the total amount of ammonia I in the ammonia I aqueous solution. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and approximately 3.5. After the addition is complete, stirring is continued for approximately 5 minutes, followed by standing for approximately 10 minutes. After standing, the bottom solid material is immediately filtered through filter press 4, and the filter cake is collected as the first batch of crude folic acid. The first batch of filtrate is then returned to reactor 3.

[0085] (3) Second stage of discharging and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the diammonium salt aqueous solution is continuously added dropwise to reactor 3 at a rate of approximately 680 mL / hour. Simultaneously, the trichloroacetone aqueous solution is added dropwise to reactor 3 at a rate of approximately 866 mL / hour. After approximately 1 hour of simultaneous addition, the addition is stopped, so that approximately 1 / 3 of the total volume of the diammonium salt aqueous solution in reactor 1 and the trichloroacetone aqueous solution in reactor 2 are added dropwise to reactor 1. The amount of ammonia I in the first batch of filtrate consumed due to the cyclization reaction is approximately 1 / 3 of the total amount of ammonia I in the ammonia I aqueous solution. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and approximately 3.5. After the addition is complete, stirring is continued for approximately 5 minutes, followed by standing for approximately 10 minutes. After standing, the bottom solid material is immediately filtered through filter press 4, and the filter cake is collected as the second batch of crude folic acid. The second batch of filtrate is then returned to reactor 3.

[0086] (4) Third stage of discharging and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the diammonium salt aqueous solution is continuously added dropwise to reactor 3 at a rate of approximately 680 mL / hour. Simultaneously, the trichloroacetone aqueous solution is added dropwise to reactor 3 at a rate of approximately 866 mL / hour. After approximately 1 hour of simultaneous addition, almost all of the diammonium salt aqueous solution in reactor 1 and the trichloroacetone aqueous solution in reactor 2 are added to reactor 1. This results in approximately 1 / 3 of the total amount of ammonia in the ammonia aqueous solution being consumed due to the cyclization reaction in the second batch of filtrate. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and 3.5. After the addition is complete, the mixture is stirred for approximately 15 minutes and then allowed to stand for approximately 10 minutes. After standing, the bottom solid material is immediately filtered through filter press 4. The filter cake is collected as the third batch of crude folic acid. Optionally, at least a portion of the filtrate is returned to reactor 3 to prepare the aqueous solution needed for the next batch of folic acid synthesis process or discarded.

[0087] The purity of three batches of crude folic acid and the contents of EP impurities C, E, F, and H were determined by HPLC according to the method described in the 11th edition of the European Pharmacopoeia. The results are shown in Table 1 below.

[0088] In addition, the combined yield of the three batches of crude folic acid was approximately 85.4% based on the raw material ammonia.

[0089] Subsequent refining processes for crude folic acid: Because the crude folic acid obtained contained relatively few impurities, the three batches of crude folic acid were combined and purified only once by acid dissolution and water precipitation, and once by alkali dissolution to obtain the finished folic acid product. The purity of the finished folic acid product and the contents of EP impurities C, E, F, and H were determined by HPLC. The results are shown in Table 2 below.

[0090] The yield of folic acid product based on raw material ammonia is approximately 80.3%.

[0091] Comparative Example 1: The process for preparing folic acid (one-pot method) (1) Prepare an aqueous solution of ammonia and an aqueous solution of trichloroacetone using a process similar to that in Example 1, and also prepare 200 g of diammonium salt, 210 g of sodium carbonate and 30 g of sodium metabisulfite solid.

[0092] (2) While maintaining the temperature in reactor 3 at 40 to 45°C, add the ammonium disalt, sodium carbonate, and sodium metabisulfite solids to the ammonia-water solution in one go. After stirring for about 10 minutes, add the trichloroacetone-water solution dropwise to reactor 3. Use a separate sodium carbonate-water solution to maintain the pH of the reaction system between about 2.5 and about 3.5. After the addition is complete, stir for about 5 minutes to carry out the cyclization reaction, and then let it stand for about 10 minutes. Immediately after standing, filter the bottom material through filter press 4 and collect the filter cake as crude folic acid.

[0093] The purity of crude folic acid and the contents of EP impurities C, E, F, and H were determined by HPLC according to the method described in the 11th edition of the European Pharmacopoeia. The results are shown in Table 1 below.

[0094] In addition, the total yield of the crude folic acid product based on the raw material ammonia was approximately 61.6%.

[0095] Subsequent refining processes for crude folic acid: Because the crude folic acid product contains a relatively high amount of impurities, it needs to undergo two subsequent acid-soluble and water-elution purification processes, followed by one alkali-soluble purification process, to obtain a qualified finished folic acid product. The purity of the finished folic acid product and the contents of EP impurities C, E, F, and H were determined by HPLC. The results are shown in Table 2 below.

[0096] The yield of folic acid product based on raw material ammonia is approximately 57.7%.

[0097] Comparative Example 2: Process for preparing folic acid (two-component, two-time dropwise addition) (1) Prepare an aqueous solution of ammonia, an aqueous solution of ammonia disalt and an aqueous solution of trichloroacetone using a process similar to that in Example 1.

[0098] (2) First staged discharge and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the diammonium salt aqueous solution is added dropwise to reactor 3 at a rate of approximately 680 mL / hour. Simultaneously, the trichloroacetone aqueous solution is added dropwise to reactor 3 at a rate of approximately 866 mL / hour. After approximately 1.5 hours of simultaneous addition, the addition is stopped, so that approximately half of the total volume of the diammonium salt aqueous solution in reactor 1 and the trichloroacetone aqueous solution in reactor 2 are added dropwise to reactor 1. The amount of ammonia I in the ammonia I aqueous solution consumed due to the cyclization reaction is approximately half of the total amount of ammonia I in the ammonia I aqueous solution. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and approximately 3.5. After the addition is complete, stirring is continued for approximately 5 minutes, followed by standing for approximately 10 minutes. After standing, the bottom material is immediately filtered through filter press 4 to collect the filter cake as the first batch of crude folic acid, and the first batch of filtrate is returned to reactor 3.

[0099] (3) Second stage of discharging and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the diammonium salt aqueous solution is continuously added dropwise to reactor 3 at a rate of approximately 680 mL / hour. Simultaneously, the trichloroacetone aqueous solution is added dropwise to reactor 3 at a rate of approximately 866 mL / hour. After approximately 1.5 hours of simultaneous addition, almost all of the diammonium salt aqueous solution in reactor 1 and the trichloroacetone aqueous solution in reactor 2 are added to reactor 1. This results in approximately half of the total amount of ammonia in the first batch of filtrate being consumed due to the cyclization reaction. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and 3.5. After the addition is complete, the mixture is stirred for approximately 15 minutes and then allowed to stand for approximately 10 minutes. After standing, the bottom solid material is immediately filtered through filter press 4 to collect the filter cake as the second batch of crude folic acid. At least a portion of the second batch of filtrate is returned to reactor 3 to prepare the aqueous solution needed for the next batch of folic acid synthesis process or discarded.

[0100] The purity of two batches of crude folic acid and the contents of EP impurities C, E, F, and H were determined by HPLC according to the method described in the 11th edition of the European Pharmacopoeia. The results are shown in Table 1 below.

[0101] In addition, the combined yield of the two batches of crude folic acid was approximately 82.46% based on the raw material ammonia.

[0102] Subsequent refining processes for crude folic acid: The two batches of crude folic acid obtained were combined and then purified once by acid dissolution and water precipitation, and once by alkali dissolution to obtain the finished folic acid product. The purity of the finished folic acid product and the contents of EP impurities C, E, F, and H were determined by HPLC. The results are shown in Table 2 below.

[0103] The yield of folic acid product based on raw material ammonia is approximately 77.6%.

[0104] Comparative Example 3: Process for preparing folic acid (single-component three-time drop addition) (1) Prepare an aqueous solution of ammonia, an aqueous solution of ammonia disalt and an aqueous solution of trichloroacetone using a process similar to that in Example 1, except that the aqueous solution of trichloroacetone is first injected entirely into the reaction vessel 3.

[0105] (2) First staged discharge and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the ammonium dichloride aqueous solution is added dropwise to reactor 3 at a constant rate of approximately 680 mL / hour. The addition is stopped after approximately 1 hour, allowing approximately 1 / 3 of the total volume of the ammonium dichloride aqueous solution in reactor 1 to be added to reactor 1. The amount of ammonia-1 in the ammonia-1 aqueous solution consumed due to the cyclization reaction is approximately 1 / 3 of the total ammonia-1 in the ammonia-1 aqueous solution. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and 3.5. After the addition is complete, stirring continues for approximately 5 minutes, followed by standing for approximately 10 minutes. Immediately after standing, the bottom solid material is filtered through filter press 4, and the filter cake is collected as the first batch of crude folic acid. The first batch of filtrate is returned to reactor 3.

[0106] (3) Second stage of discharging and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, continue to add the ammonium dichloride aqueous solution to reactor 3 at a uniform rate of approximately 680 mL / hour. Stop adding the solution after about 1 hour, so that about 1 / 3 of the total volume of the ammonium dichloride aqueous solution in reactor 1 is added to reactor 1, and the amount of ammonia I in the first batch of filtrate consumed by the cyclization reaction is about 1 / 3 of the total amount of ammonia I in the ammonia I aqueous solution. During the addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and 3.5. After the addition is complete, continue stirring for about 5 minutes, and then let it stand for about 10 minutes. Immediately after standing, filter the bottom material through filter press 4, collect the filter cake as the second batch of crude folic acid, and return the filtrate to reactor 3.

[0107] (4) Third stage of discharging and filtrate circulation: While maintaining the temperature in reactor 3 at approximately 40 to 45°C, the diammonium salt aqueous solution is continuously added dropwise to reactor 3 at a rate of approximately 680 mL / hour. After about 1 hour of dropwise addition, almost all of the diammonium salt aqueous solution in reactor 1 is added to reactor 1, and the amount of ammonia I in the second batch of filtrate consumed due to the cyclization reaction is approximately 1 / 3 of the total amount of ammonia I in the ammonia I aqueous solution. During the dropwise addition and reaction, a separate sodium carbonate aqueous solution is used to maintain the pH of the reaction system between approximately 2.5 and approximately 3.5. After the dropwise addition is complete, the mixture is stirred for about 15 minutes and then allowed to stand for about 10 minutes. Immediately after standing, the bottom material is filtered through filter press 4, and the filter cake is collected as the third batch of crude folic acid. Optionally, at least a portion of the filtrate is returned to reactor 3 for the preparation of the aqueous solution required for the next batch of folic acid synthesis process or discarded.

[0108] The purity of three batches of crude folic acid and the contents of EP impurities C, E, F, and H were determined by HPLC according to the method described in the 11th edition of the European Pharmacopoeia. The results are shown in Table 1 below.

[0109] In addition, the combined yield of the three batches of crude folic acid was approximately 74.9% based on the raw material ammonia.

[0110] Subsequent refining processes for crude folic acid: The three batches of crude folic acid obtained were combined and then purified once by acid dissolution and water precipitation, and once by alkali dissolution to obtain the finished folic acid product. The purity of the finished folic acid product and the contents of EP impurities C, E, F, and H were determined by HPLC. The results are shown in Table 2 below.

[0111] The yield of folic acid product based on raw material ammonia is approximately 70.2%.

[0112] Table 1: Purity and impurity content of crude folic acid obtained in each example and comparative example Table 2: Purity and impurity content of folic acid products obtained in each example and comparative example Example 1 and Comparative Examples 2 and 3 employed a process of one acid dissolution and water precipitation purification followed by one alkali dissolution purification. Comparative Example 1 used a two-stage acid-dissolution-water-precipitation purification process followed by a one-stage alkali-dissolution purification process.

[0113] As can be seen from the above examples and comparative examples, as well as the results listed in Tables 1 and 2, the crude folic acid and the finished product obtained by the two-component three-drop addition method of Example 1 of the present invention both achieved the yield, purity and impurity content range to be achieved by the present invention. However, the crude folic acid and the finished product obtained by the one-pot method, the two-component two-drop addition method and the single-component three-drop addition method of Comparative Examples 1, 2 and 3 could not fully achieve the yield, purity and impurity content range to be achieved by the present invention.

[0114] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions claimed by the present invention.

Claims

1. A folic acid preparation process for controlling the content of EP impurity C, EP impurity E, EP impurity F and / or EP impurity H in a folic acid product, wherein the folic acid preparation process involves a cyclization reaction process comprising: N-p-aminobenzoyl-L-glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate, and 1,1,3-trichloroacetone were cyclized in an acidic aqueous solution at pH 2.5 to 3.5 in the presence of an antioxidant to generate folic acid. in The ammonia mentioned is an abbreviation for N-p-aminobenzoyl-L-glutamic acid. The ammonium disalt is an abbreviation for 2,4,5-triamino-6-hydroxypyrimidine sulfate, and The trichloroacetone mentioned is an abbreviation for 1,1,3-trichloroacetone. The preparation process is characterized by including the following steps: Step 1: Provide aqueous solutions of ammonia-1, ammonia-2 salt, and trichloroacetone, respectively. The ammonia-aqueous solution contains 0.04 to 0.13 mol / L of ammonia and 0.4 to 0.5% by weight of an antioxidant. The aqueous solution of the ammonium dichloride comprises 0.40 to 0.45 mol / L of ammonium dichloride, 1.2 to 1.4 wt% of an antioxidant, and 8.5 to 9.5 wt% of an alkaline carbonate; and The aqueous solution of trichloroacetone contains 0.50 to 0.55 mol / L of 1,1,3-trichloroacetone; and Step 2: At a temperature of 40 to 45°C, simultaneously add the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the ammonia-1 aqueous solution. In the resulting reaction system, the ammonia in the ammonia-1 aqueous solution, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution undergo the cyclization reaction. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is within the range of 1.6 to 1.

7. The dropping rate of the ammonium dichloride aqueous solution does not exceed 680 mL / h, and the dropping rate of the trichloroacetone aqueous solution does not exceed 870 mL / h. During the dropping and reaction process, the pH value of the reaction system is maintained within the range of 2.5 to 3.5, thereby obtaining folic acid as a solid precipitate. After filtering out the solid, crude folic acid and a filtrate are obtained.

2. The preparation process according to claim 1, characterized in that, In step 2, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution shall not exceed 1 hour.

3. The preparation process according to claim 1, characterized in that, The preparation process includes the following steps: Step 1: Provide aqueous solutions of ammonia-1, ammonia-2 salt, and trichloroacetone, respectively. The ammonia-water solution contains 0.12 to 0.13 mol / L of ammonia and 0.4 to 0.5% by weight of an antioxidant, and the volume of the ammonia-water solution is at least 6 L. The aqueous solution of the ammonium dichloride comprises 0.40 to 0.45 mol / L of ammonium dichloride, 1.2 to 1.4 wt% of an antioxidant, and 8.5 to 9.5 wt% of an alkaline carbonate; and The aqueous solution of trichloroacetone contains 0.50 to 0.55 mol / L of 1,1,3-trichloroacetone; and Step 2: At a temperature of 40 to 45°C, simultaneously add the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the ammonia-1 aqueous solution. In the resulting reaction system, the ammonia in the ammonia-1 aqueous solution, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution undergo the cyclization reaction. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is within the range of 1.6 to 1.

7. The dropping rate of the ammonium dichloride aqueous solution does not exceed 680 mL / hour, and the dropping rate of the trichloroacetone aqueous solution does not exceed 870 mL / hour. The addition rate is mL / hour, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed 1 hour, and during the addition and reaction process, an additional separate alkaline carbonate aqueous solution is optionally used to maintain the pH value of the reaction system in the range of 2.5 to 3.5, and after the addition is completed, stirring is continued for 4 to 6 minutes, and then it is allowed to stand for 9 to 11 minutes to obtain the first batch of folic acid as a solid precipitate. After filtering out the solid, the first batch of crude folic acid and the first batch of filtrate are obtained.

4. The preparation process according to claim 3, characterized in that, The preparation process also includes the following steps performed after step 2: Step 3: At a temperature of 40 to 45°C, simultaneously add the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the first batch of filtrate obtained from Step 2. In the resulting reaction system, the ammonia in the first batch of filtrate, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution undergo the cyclization reaction. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is within the range of 1.6 to 1.

7. The dropping rate of the ammonium dichloride aqueous solution does not exceed 680 mL / h, and the dropping rate of the trichloroacetone aqueous solution does not exceed 870 mL / h. The addition rate is mL / hour, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed 1 hour, and during the addition and reaction process, optionally using a separate alkaline carbonate aqueous solution to maintain the pH of the reaction system in the range of 2.5 to 3.5, and after the addition is complete, stirring is continued for 4 to 6 minutes, and then allowed to stand for 9 to 11 minutes to obtain a second batch of folic acid as a solid precipitate. After filtering out the solid, a second batch of crude folic acid and a second batch of filtrate are obtained; and Step 4, preferably performed after step 3, involves simultaneously adding the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution to the second batch of filtrate obtained from step 3 at a temperature of 40 to 45°C. This allows the cyclization reaction to occur in the resulting reaction system, involving the ammonia in the second batch of filtrate, the ammonium dichloride in the ammonium dichloride aqueous solution, and the trichloroacetone in the trichloroacetone aqueous solution. The amounts of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution added are such that the molar ratio of trichloroacetone to ammonium dichloride in the reaction system is within the range of 1.6 to 1.

7. The dropping rate of the ammonium dichloride aqueous solution does not exceed 680 mL / h, and the dropping rate of the trichloroacetone aqueous solution does not exceed 870 mL / h. The addition rate is mL / hour, the addition time of the ammonium dichloride aqueous solution and the trichloroacetone aqueous solution does not exceed 1 hour, and during the addition and reaction process, optionally using a separate alkaline carbonate aqueous solution to maintain the pH of the reaction system in the range of 2.5 to 3.5, and after the addition is complete, stirring is continued for 4 to 20 minutes, followed by standing for 9 to 11 minutes to obtain a third batch of folic acid as a solid precipitate, the solid is filtered out to obtain a third batch of crude folic acid and a third batch of filtrate; and Step 5, optionally performed after step 4: detect whether there is still a sufficient amount of ammonia-1 remaining in the third batch of filtrate. If there is still a sufficient amount of ammonia-1 remaining in the filtrate, repeat step 4, except that the second batch of filtrate obtained from step 3 in step 4 is replaced with the third batch of filtrate obtained from step 4 to obtain a fourth or higher batch of crude folic acid and a fourth or higher batch of filtrate; or, if there is no longer a sufficient amount of ammonia-1 remaining in the filtrate, at least a portion of the third batch of filtrate obtained from step 4 is used to prepare the next batch of aqueous solution or discarded.

5. The preparation process according to claim 1, characterized in that, The antioxidant comprises one or more of sodium metabisulfite, sodium bisulfite, sodium sulfite, L-ascorbic acid, D-isoascorbic acid and its salts, and L-cysteine ​​and its salts.

6. The preparation process according to claim 1, characterized in that, The alkaline carbonate includes one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

7. The preparation process according to any one of claims 3 to 6, characterized in that, In step 2, the addition is made such that the amount of ammonia in the ammonia-water solution consumed due to the cyclization reaction does not exceed 1 / n of the total amount of ammonia in the ammonia-water solution, where n ≥ 3, and / or In step 3, the addition is made such that the amount of ammonia-1 in the first batch of filtrate consumed due to the cyclization reaction does not exceed 1 / m of the total amount of ammonia-1 in the aqueous solution, where m ≥ 3, and / or In step 4, the addition is made such that the amount of ammonia in the second batch of filtrate consumed due to the cyclization reaction does not exceed 1 / p of the total amount of ammonia in the aqueous solution, where p ≥ 3.

8. The preparation process according to any one of claims 1 to 6, characterized in that, The preparation process further includes sequentially subjecting the crude folic acid product, or the first batch of crude folic acid product and / or the second batch of crude folic acid product and / or the third batch of crude folic acid product and / or the fourth batch of crude folic acid product and / or higher batches of crude folic acid product, to acid dissolution and water precipitation purification once and alkali dissolution purification once to obtain the finished folic acid product.

9. The crude folic acid obtained by the preparation process according to any one of claims 1 to 7, characterized in that, The crude folic acid product contains EP impurity C, EP impurity E, EP impurity F, and EP impurity H, with each content below 0.69 wt%, 0.63 wt%, 1.38 wt%, and 0.15 wt% based on the weight of the crude folic acid product, preferably below 0.66 wt%, 0.61 wt%, 1.32 wt%, and 0.08 wt%; and / or The crude folic acid has an HPLC purity of ≥95%, preferably ≥96%; and / or The total yield of the crude folic acid product based on ammonia is over 85%.

10. The folic acid product obtained by the preparation process according to claim 8, characterized in that, The content of EP impurity C, EP impurity E, EP impurity F, and EP impurity H in the folic acid product is respectively less than 0.3% by weight, less than 0.3% by weight, less than 0.1% by weight, and less than 0.15% by weight, based on the weight of the folic acid product; preferably less than 0.13% by weight, less than 0.03% by weight, less than 0.04% by weight, and less than 0.08% by weight; and / or The HPLC purity of the folic acid product is above 99%, preferably above 99.3%; and / or The total yield of the folic acid product based on ammonia is over 80%.

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