A preparation method of pentetic acid and its application

Abstract

The invention provides a preparation method of pentetic acid. The pentetic acid is obtained by taking chloroacetic acid and diethylenetriamine as raw materials through an optimized process method. The purity of the product is as high as 99.8% or more, the uniformity is good and there is no agglomeration. The content of aminotriacetic acid, which is a difficult-to-remove impurity, is less than 0.1%. The requirements for the use of precise chemical products and medicinal use are met, and the method is more economical and suitable for the industrial production of pentetic acid.

Description

Technical Field

[0001] The invention relates to the technical field of chelating agent products, and in particular to a preparation method of pentetic acid and application thereof. Background Art

[0002] Pentetic acid, referred to as DTPA, CAS No. 67-43-6, is a chelating agent with a particularly strong complexing ability for metal ions. It is a white crystalline powder with the following structural formula:

[0003]

[0004] Pentetic acid is widely used in the papermaking, textile, cosmetic and pharmaceutical industries. For example, in the papermaking process, pentetic acid can be used as a stabilizer in H2O2 bleaching to prevent the decomposition of H2O2 by various metal ions; in textile processing, pentetic acid can be used as a water softener to remove metal ions such as calcium and magnesium in water and reduce the formation of scale. At the same time, pentetic acid can also be used as an excipient in radiopharmaceutical preparations, such as lutetium 177 injection

[0005] At present, there are two main methods for synthesizing pentetic acid in domestic enterprises: the first is the chloroacetic acid method, which uses chloroacetic acid, diethylenetriamine and sodium hydroxide as raw materials for synthesis; the second is the synthesis using formaldehyde, sodium cyanide and diethylenetriamine as raw materials. Due to the simple process and low equipment requirements, the chloroacetic acid method is generally used for preparation. However, when pentetic acid is prepared by the chloroacetic acid method in the prior art, chloroacetic acid is prone to side reactions under sodium hydroxide conditions to generate impurities such as hydroxyacetic acid, and the reaction will produce mixed salts such as sodium chloride. Therefore, it is necessary to repeatedly desalt and purify the crude pentetic acid product, resulting in a low final yield. In particular, although most impurities can be removed by purification using commonly used crystallization means, for some impurities that are difficult to remove (such as aminotriacetic acid), the yield needs to be sacrificed and at least 2 refinings can be controlled below 0.1%, which is not conducive to industrial production.

[0006] In order to solve the problem that industrial production of pentetic acid requires multiple purification, desalination and impurity control, Chinese patent CN101607921A discloses a method for synthesizing pentetic acid, which uses chloroacetic acid and diethylenetriamine as raw materials and is prepared through salt formation, condensation, acidification and purification steps. In this route, sodium hydroxide is used to adjust the alkalinity of the condensation reaction, and the operation steps of each step are cumbersome, which is not conducive to industrialization.

[0007] Chinese patent CN115650870A discloses a method for preparing high-purity pentetic acid, which uses sodium chloroacetate and ethylenetriamine as raw materials, and obtains pentetic acid with a purity of 99.9% by adding an antioxidant, controlling the dropwise addition temperature during the reaction, and controlling related substances during the refining process. However, the post-processing of this process still requires two recrystallization refinings.

[0008] In recent years, solid-supported alkaline catalysts can be used in reactions such as deacidification, desulfurization and cracking. For example, Chinese patent CN116120168A discloses the use of Na2O / SiO2 as a solid alkaline catalyst to promote the synthesis of 2,4-dichlorophenol and chloroacetic acid into 2,4-dichlorophenoxyacetic acid.

[0009] Pentetic acid, as an intermediate, often requires precise weighing when preparing fine chemical products or APIs or pharmaceutical preparations, and its quality is particularly important. For example, when preparing the developer gadopentetate dimeglumine API, the first step in preparing gadopentetate requires strict control of the molar ratio of pentetic acid to gadolinium oxide at 2:1, and even requires accuracy to one thousandth (see Chinese patent CN103664672A). When pentetic acid of poor quality is used as a raw material in subsequent applications, it needs to be crushed or ground before processing to ensure the reliability and accuracy of subsequent experiments, which is difficult to meet production needs.

[0010] In summary, it is necessary to seek a preparation method for pentetic acid that meets mild process conditions, simple operation, and can effectively control the content of impurities in large-scale production of pentetic acid, while taking into account higher quality properties, and easily achieving accurate measurement to meet the requirements of precise chemical product use and medicinal use. Summary of the invention

[0011] In view of the above needs, the purpose of the present invention is to provide a method for preparing pentetic acid, using chloroacetic acid and diethylenetriamine as raw materials, and obtaining pentetic acid by optimizing the process method. The product has high yield and purity, good uniformity and no agglomeration, and the content of difficult-to-remove impurities is less than 0.1%, which meets the requirements of precision chemical product use and medicinal use. It is a more economical and suitable method for industrial production of pentetic acid.

[0012] The above-mentioned purpose of the present invention is achieved through the following solutions:

[0013] A method for preparing pentetic acid, comprising the following steps:

[0014] S1, dissolving chloroacetic acid with an appropriate amount of water, controlling the temperature at 10-25°C, adding sodium hydroxide aqueous solution, reacting for 0.3-0.8h, preparing a sodium chloroacetate solution;

[0015] S2, dissolving diethylenetriamine in an appropriate amount of water to obtain a diethylenetriamine aqueous solution; adding a solid carrier base catalyst, adding a sodium chloroacetate solution, controlling the temperature at 55-85°C, and reacting for 1-6 hours;

[0016] S3. After the reaction is completed, filter, control the acidification temperature to 20-35°C, add concentrated hydrochloric acid, adjust the pH to 1.2-2.5, cool to the crystallization temperature of 0-20°C, stir for 8-18h, precipitate crystals; filter, wash with cold water, and dry to obtain pentetic acid.

[0017] Specifically, in order to ensure complete reaction, in the preparation method of pentetic acid, the molar ratio of chloroacetic acid to diethylenetriamine is 1:0.16-0.22; preferably 1:0.18-0.20.

[0018] The reaction formula of the condensation reaction is as follows:

[0019]

[0020] In the aforementioned S1 step, the reaction of chloroacetic acid with sodium hydroxide to generate sodium chloroacetate is a neutralization exothermic reaction. In the prior art, a condensing device is conventionally required to maintain the reaction system ≤10°C. In the present application, by optimizing the feed ratio and the feed sequence, the hydrolysis of chloroacetic acid caused by excessive temperature can be avoided, so that the reaction can be carried out under mild conditions, and the reaction conversion rate can be guaranteed to be optimal. Specifically, chloroacetic acid and sodium hydroxide are first fully dissolved in an appropriate amount of water, and after releasing part of the dilution heat, sodium hydroxide aqueous solution is added and mixed for reaction. Considering factors such as process equipment and efficiency, the concentration of sodium hydroxide aqueous solution is 25-40%, preferably 30-35%. In the subsequent condensation reaction, when the alkalinity in the system is strong, chloroacetic acid is hydrolyzed to generate glycolic acid, and then glycolate is formed subsequently. To ensure the complete reaction, in step S1, the molar ratio of chloroacetic acid to sodium hydroxide is 1:1.0-1.8; the preferred molar ratio of chloroacetic acid to sodium hydroxide is 1:1.2-1.6; more preferably 1:1.3-1.5.

[0021] In step S1, if the temperature is too high, the decomposition of chloroacetic acid will be promoted, and if the temperature is too low, the reaction conversion rate will be low. Therefore, the temperature is preferably controlled at 15 to 20°C.

[0022] In step S1, in order to ensure a better reaction effect, the reaction time is preferably 0.4 to 0.6 h.

[0023] In the aforementioned S2 step, adding a solid support base catalyst in the preparation of the diethylenetriamine aqueous solution is one of the keys to achieve the technical effect. Chloroacetic acid and diethylenetriamine need to be catalyzed in an alkaline system, and in the prior art, a homogeneous base, such as sodium hydroxide, is generally added. However, the technician found that sodium hydroxide is used in this step to catalyze the reaction, and sodium hydroxide is added later to neutralize the hydrochloric acid produced, that is, sodium hydroxide is added as a reaction catalyst and as a reaction acid binding agent, so that the by-product sodium salt in the product is more, and the subsequent acidification degree of pentetic acid sodium salt will be affected, resulting in the low purity of the pentetic acid product obtained, and the properties are not good, there is a sticky / jelly phenomenon, and it is necessary to repeatedly purify and process. The technician occasionally found that adding a solid support base catalyst can promote the condensation reaction of chloroacetic acid and diethylenetriamine, and the reaction conversion rate is better. The reason for the speculation is that a solid support base catalyst is added to diethylenetriamine, and the nitrogen atom in diethylenetriamine can be activated, which is more conducive to the nucleophilic substitution of the carbon atom adjacent to the chlorine atom in chloroacetic acid / sodium chloroacetate, and then the condensation is completed.

[0024] Specifically, in the aforementioned step S2, the volume mass ratio of the amount of water added (volume) to the amount of diethylenetriamine (mass) is 1:18-22 ml / g, preferably 1:19-21 ml / g.

[0025] Specifically, in the aforementioned step S2, the amount (mass) of the solid supported alkali catalyst added is 3 to 10% of the mass of the diethylenetriamine aqueous solution, preferably 5 to 8%.

[0026] Further, in the aforementioned S2 step, the solid support base catalyst is Na2O / SiO2 or MgO / SiO2 type catalyst, preferably Na2O / SiO2 catalyst. In the present application, the technician finds that the solid support base catalyst can also be used as an important catalyst carrier in addition to being used as a catalyst. For example, chloroacetic acid and diethylenetriamine condense under the catalytic action of Na2O to generate small molecule hydrogen chloride (hydrochloric acid) by-products, which can be adsorbed on the surface of Na2O. It is speculated that the reason is that hydrogen chloride can react with the surface Na2O sodium chloride, which is deposited on the catalyst surface, thereby facilitating the separation of secondary salts and products.

[0027] Furthermore, in the aforementioned step S2, the reaction temperature is preferably 65 to 75°C.

[0028] Furthermore, in the aforementioned step S2, the reaction time is preferably 2 to 5 hours, more preferably 3 to 4 hours.

[0029] In the aforementioned S3 step, the acidification temperature and the acid-base environment are one of the keys to achieving the technical effects of the present invention. In the actual production of pentetic acid, the reaction liquid before acidification contains pentetic acid sodium salt, which is a liquid that is easily soluble in water. If the acidification effect is not good, the crude pentetic acid will be viscous, yellowish in color, and the product will be severely agglomerated after drying. At the same time, in the crystallization process, unsuitable reaction conditions will also lead to poor properties of pentetic acid, such as the precipitated product is thin, which is not conducive to filtration, and the product obtained by easily embedding impurities is in the form of a white powder with poor fluidity, and is often accompanied by agglomeration after drying. Appropriate temperature can effectively control the generation of impurities, and a suitable acid-base environment can effectively increase the amount of product precipitation. If the temperature is too high, some of the products dissolved in the reaction cannot be fully precipitated. If the temperature is too low, while the pentetic acid is precipitated, related impurities (such as aminotriacetic acid and edetic acid, etc.) and sodium salts will also precipitate together; at the same time, too high or too low pH will affect the precipitation of the product. Only when the pH value is in a suitable range can the pentetic acid be fully precipitated.

[0030] Specifically, in the aforementioned step S3, the acidification temperature is preferably controlled to be 25-30°C.

[0031] Specifically, in the aforementioned step S3, concentrated hydrochloric acid is preferably added to adjust the pH to 1.5-2.0.

[0032] Specifically, in the aforementioned step S3, the preferred crystallization temperature is 5 to 15°C.

[0033] Specifically, in the aforementioned step S3, the preferred stirring time is 10 to 16 hours, and more preferably 13 to 15 hours.

[0034] In the aforementioned step S3, the crude product after acidification and crystallization is simple to post-process, and only needs to be washed with cold water to obtain pentetic acid with good quality and properties. The washing number is 1-2 times, preferably 1 time.

[0035] A preferred technical solution of the present invention is a method for preparing pentetic acid, which comprises the following steps:

[0036] S1, after dissolving chloroacetic acid with an appropriate amount of water, the temperature is controlled at 15-20°C, and an aqueous sodium hydroxide solution is added, and the reaction time is 0.4-0.6h to prepare a sodium chloroacetate solution;

[0037] S2, dissolving diethylenetriamine in water to obtain a diethylenetriamine aqueous solution; adding 3-10% of Na2O / SiO2 type catalyst relative to the mass of the diethylenetriamine aqueous solution, adding sodium chloroacetate solution, controlling the temperature at 65-75°C, and the reaction time at 2-5h;

[0038] S3, after the reaction is completed, filter, control the acidification temperature to 25-30°C, add concentrated hydrochloric acid, adjust the pH to 1.5-2.0, cool to the crystallization temperature of 5-15°C, stir for 10-16h, precipitate crystals; filter, wash with cold water, and dry to obtain pentetic acid;

[0039] Among them, the molar ratio of the chloroacetic acid to diethylenetriamine is 1:0.18-0.20; in step S1, the molar ratio of the chloroacetic acid to sodium hydroxide is 1:1.2-1.6; in step S2, the volume mass ratio of the added water (volume) to the diethylenetriamine (mass) is 1:18-22 ml / g.

[0040] A preferred technical solution of the present invention is a method for preparing pentetic acid, which comprises the following steps:

[0041] S1. After dissolving chloroacetic acid with an appropriate amount of water, the temperature was controlled at 18°C, and a 30-35% sodium hydroxide aqueous solution was added. The reaction time was 0.5 h to prepare a sodium chloroacetate solution, wherein the molar ratio of chloroacetic acid to sodium hydroxide was 1:1.4;

[0042] S2, dissolving diethylenetriamine in water to obtain a diethylenetriamine aqueous solution; adding 5-8% of Na2O / SiO2 type catalyst relative to the mass of the diethylenetriamine aqueous solution, adding sodium chloroacetate solution, controlling the temperature at 70°C, and reacting for 3.5h; wherein the volume mass ratio of the amount of water added (volume) to the amount of diethylenetriamine (mass) is 1:19-21ml / g;

[0043] S3, after the reaction is completed, filter, control the acidification temperature to 28°C, add concentrated hydrochloric acid, adjust the pH to 1.8, cool to the crystallization temperature of 10°C, stir for 14 hours, precipitate crystals; filter, wash once with cold water, and dry to obtain pentetic acid;

[0044] The molar ratio of chloroacetic acid to diethylenetriamine is 1:0.19.

[0045] The second object of the present invention is to provide an application of pentetic acid for use in purifying water quality, preparing cosmetics or medicines. The preparation method of pentetic acid is as defined in the present invention. The pentetic acid has high purity, good uniformity, good properties, and is easy to achieve the requirement of accurate weighing.

[0046] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0047] 1. In the present invention, a solid carrier base catalyst is added to prepare pentetic acid through a condensation reaction, the reaction system has good stability, high conversion rate, reduces the steps of repeated desalting and crystallization purification, and is conducive to the optimization of product properties.

[0048] 2. The present invention optimizes the acidification and crystallization conditions to control the content of aminotriacetic acid, a difficult-to-remove impurity, to below 0.1%, while having high yield and purity. The purity detected by HPLC is greater than 99.8%, meeting the requirements for the use of precision chemical products and medicinal use.

[0049] 3. The product obtained by the present invention has good uniformity, no agglomeration, good properties, qualified color, and is easy to realize industrialization.

[0050] 4. The overall process design is reasonable, the operation is simple, no high pressure and high temperature conditions are required, the raw materials are easy to obtain and the cost is low, and it has high economic efficiency.

[0051] Instruction Manual

[0052] Figure 1 This is the HPLC analysis spectrum of the pentetic acid product prepared in Example 1. DETAILED DESCRIPTION

[0053] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If the specific conditions are not specified in the examples, they are carried out under normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially. The chloroacetic acid and diethylenetriamine used in the examples are all commercially available raw materials with a purity of ≥99.0%.

[0054] Example 1 Preparation of Pentetic Acid

[0055] S1, after dissolving 500 mol of chloroacetic acid with an appropriate amount of water, the temperature was controlled at 18°C, 30-35% aqueous sodium hydroxide solution (700 mol) was added, and the reaction time was 0.5 h to prepare a sodium chloroacetate solution;

[0056] S2, dissolving 95 mol of diethylenetriamine in 200 L of water to obtain a diethylenetriamine aqueous solution; adding 12.6 kg of Na2O / SiO2 type catalyst, adding sodium chloroacetate solution, controlling the temperature at 70°C, and the reaction time for 3.5 h;

[0057] S3. After the reaction is completed, filter, control the acidification temperature to 28°C, add concentrated hydrochloric acid, adjust the pH to 1.8, cool to the crystallization temperature of 10°C, stir for 14 hours, precipitate crystals; filter, wash with cold water (once), and dry to obtain pentetic acid.

[0058] Example 2 Preparation of Pentetic Acid

[0059] S1, after dissolving 0.05 mol of chloroacetic acid with an appropriate amount of water, the temperature was controlled at 20°C, 30-35% aqueous sodium hydroxide solution (0.07 mol) was added, and the reaction time was 0.5 h to prepare a sodium chloroacetate solution;

[0060] S2, dissolve 0.0095 mol of diethylenetriamine in 20 ml of water to obtain a diethylenetriamine aqueous solution; add 1.26 g of Na2O / SiO2 type catalyst, add sodium chloroacetate solution, control the temperature at 70°C, and react for 3.5 h;

[0061] S3. After the reaction is completed, filter, control the acidification temperature to 28°C, add concentrated hydrochloric acid, adjust the pH to 1.8, cool to the crystallization temperature of 10°C, stir for 14 hours, precipitate crystals; filter, wash with cold water (once), and dry to obtain pentetic acid.

[0062] Example 3 Preparation of Pentetic Acid

[0063] S1, after dissolving 0.05 mol of chloroacetic acid with an appropriate amount of water, the temperature was controlled at 20°C, 30-35% aqueous sodium hydroxide solution (0.07 mol) was added, and the reaction time was 0.5 h to prepare a sodium chloroacetate solution;

[0064] S2, dissolving 0.0095 mol of diethylenetriamine in 20 ml of water to obtain a diethylenetriamine aqueous solution; adding 1.36 g of MgO / SiO2 type catalyst, adding sodium chloroacetate solution, controlling the temperature at 70°C, and the reaction time for 3 hours;

[0065] S3. After the reaction is completed, filter, control the acidification temperature to 30°C, add concentrated hydrochloric acid, adjust the pH to 1.8, cool to the crystallization temperature of 10°C, stir for 14 hours, precipitate crystals; filter, wash with cold water (once), and dry to obtain pentetic acid.

[0066] Comparative Example 1 Preparation of Pentetic Acid (without Addition of Solid Base Catalyst)

[0067] S1, after dissolving 0.05 mol of chloroacetic acid with an appropriate amount of water, the temperature was controlled at 20°C, 30-35% aqueous sodium hydroxide solution (0.07 mol) was added, and the reaction time was 0.5 h to prepare a sodium chloroacetate solution;

[0068] S2, dissolving 0.0095 mol of diethylenetriamine in 20 ml of water to obtain a diethylenetriamine aqueous solution; adjusting the pH to 10-11 with 30-35% sodium hydroxide solution, then adding sodium chloroacetate solution, controlling the temperature to 70°C, the reaction time to 6 hours, and using pH test paper to monitor the reaction solution to see if it is close to neutral;

[0069] S3. After the reaction is completed, filter, control the acidification temperature to 28°C, add concentrated hydrochloric acid, adjust the pH to 1.8, cool to the crystallization temperature of 10°C, stir for 14 hours, precipitate crystals; filter, wash with cold water (once), and dry to obtain pentetic acid.

[0070] Comparative Example 2 Preparation of Pentetic Acid (Solid Base Catalyst Not of the Present Invention)

[0071] Pentetic acid was prepared according to the method of Example 1, except that 1.26 g of ZnO / SiO2 catalyst was added in step S2.

[0072] Comparative Example 3 Preparation of Pentetic Acid (Reference Patent CN101607921 Example 1)

[0073] After dissolving 0.01 mol chloroacetic acid and 0.022 mol sodium hydroxide respectively with appropriate amount of water, the temperature is controlled at 20-25°C, and the sodium hydroxide aqueous solution is added dropwise to the chloroacetic acid solution for 2.5 hours, and the mixture is kept warm and stirred for 1 hour; 0.0095 mol diethylenetriamine is added for 3 hours, and the mixture is stirred for 0.5 hours and then heated to 40°C, and kept warm and stirred for 12 hours. The reaction solution is close to neutral when monitored by pH test paper; after the reaction is completed, the mixture is filtered, the temperature is controlled at 5°C, concentrated hydrochloric acid is added, the pH is adjusted to 2, the mixture is kept warm and stirred for crystallization for 12 hours, filtered, recrystallized with water (twice), and dried to obtain pentetic acid.

[0074] Preparation of Example 4-10 and Comparative Example 4-13 Pentetic Acid

[0075] The feed ratio of chloroacetic acid (4.73 g) and diethylenetriamine (0.98 g) is calculated as 0.05 mol: 0.0095 mol = 1: 0.19. Referring to the method of Example 2, the pentetic acid product is prepared according to the reaction conditions and parameters in Table 1. Unless otherwise specified, other parameters are the same as those in Example 2:

[0076] Table 1: Example / Comparative Example Reaction Conditions Table

[0077]

[0078]

[0079] Test 1 Pentetic Acid Quality Analysis Results

[0080] Table 2 Quality analysis results of pentetic acid obtained in Examples and Comparative Examples

[0081]

[0082]

[0083] Note: a: The limit of aminotriacetic acid content refers to the quality standard of pentetic acid products in the United States Pharmacopoeia USP43-NF38: aminotriacetic acid content <0.1%. b: Chloride detection limit requirement: Compared with the control solution made of 3.0ml standard sodium chloride solution, it must not be more concentrated (0.01%). c: The limit of total impurity content is set to <0.3%.

[0084] Analysis of the data in Table 2 shows that each reaction condition in each step of the reaction has an impact on the product quality and yield. Specifically, in Examples 1-10, the molar ratio of chloroacetic acid to sodium hydroxide in step S1 is 1:1.4 (0.05 mol:0.07 mol), and a solid carrier base catalyst is added in step S2; in step S3, the acidification temperature is controlled to be 70 or 75°C, the acidification pH is 1.8-2.0, the crystallization temperature is 10°C, and the stirring time is 14h, which can effectively control the content of aminotriacetic acid, a difficult-to-remove impurity, and the total impurity content is lower than the limit, and the product yield is ideal and uniform, and there is no caking phenomenon.

[0085] In particular, Example 1 is a scheme for the scale-up pilot test of the present invention. The results show that the scheme can also achieve the technical effect in industrial scale-up reactions. The HPLC analysis spectrum of the product obtained in Example 1 is as follows: Figure 1 As shown, the purity is as high as 99.8 or more, and the impurities aminotriacetic acid and edetic acid can be controlled in an extremely low range of only 0.01% and 0.02%.

[0086] Further analysis of the product quality results of Comparative Examples 1-11 shows that there is a condition in the reaction process and post-treatment that is not within the scope of protection of the present invention, and the quality or yield of the obtained product is inferior to that of the product obtained by the method of the present invention. Specifically:

[0087] In the preparation method described in Comparative Example 1, the condensation reaction does not use a solid base catalyst, but uses sodium hydroxide to maintain the alkaline conditions of the system. The chloride detection does not meet the standard. At the same time, too much by-product sodium chloride is added to the product. After acidification and crystallization, only cold water washing is used, and the impurity removal effect cannot be achieved. The aminotriacetic acid and total impurity content do not meet the quality control standards. The product after drying has poor properties, is hard and agglomerated, and has a yellowish color.

[0088] In the preparation method described in Comparative Example 2, a ZnO / SiO2 solid base catalyst is used in the condensation reaction, and the product yield is low. It can be inferred that ZnO / SiO2 has a poor catalytic effect on this reaction, a low degree of reaction, and no improvement in the properties of the obtained product. The impurity aminotriacetic acid and total impurity content do not meet the quality control standards.

[0089] Comparative Example 3 is a preparation method of Example 1 of reference patent CN101607921. Through process control of each step and recrystallization purification, although the quality of the obtained product can meet the requirements, the yield is slightly worse than that of the present invention. In addition, the impurity content of aminotriacetic acid is 0.09%, which is close to the limit of 0.1%. There is a possibility of impurity amplification in large-scale production, and it is necessary to increase the number of purification times to reduce impurities.

[0090] In the preparation method described in Comparative Example 4, too much sodium hydroxide is added in step S1, and the content of chloride (secondary salt) is too high.

[0091] In the preparation method described in Comparative Example 5, the reaction temperature in step S1 is too low, and the chloroacetic acid salt formation is incomplete, resulting in a low conversion rate in the subsequent reaction and a significantly reduced yield.

[0092] From the results of Comparative Examples 6-8, it can be seen that compared with Comparative Example 1 without adding a catalyst, the product obtained by adding a catalyst can control the chloride to drop significantly, but the parameters of water addition / catalyst amount, reaction temperature and reaction time in step S2 also have an important influence on product quality and yield. In Comparative Example 6, too much water was added, and the degree of reaction decreased slightly, resulting in a decrease in yield. In Comparative Example 7, the reaction temperature was too low, the reaction was incomplete, and the unreacted raw materials were doped in the product, resulting in a yellowish appearance with agglomeration and impurity content that did not meet quality control requirements. In Comparative Example 8, the reaction time was too long, and although the product quality met the requirements, the yield did not increase.

[0093] From the results of Comparative Examples 9-13, it can be seen that the acidification temperature, pH, and crystallization temperature and time in step S3 also have a significant effect on the product quality and yield. In Comparative Example 9, the acidification temperature is low, the acidification is incomplete, and too much pentetic acid or other secondary salts remain. In Comparative Example 10, the acidification temperature is high, and the product or impurities decompose, which all lead to a high impurity content in the obtained product, a yellowish appearance, and severe agglomeration after drying. In Comparative Example 11, the crystallization temperature is low, and the impurity content increases. In Comparative Example 12, the crystallization stirring time is short, the crystallization is insufficient, the color of the obtained product is yellowish, and the product has agglomerations after drying. In Comparative Example 13, the pH of the acidification process is low, and the pentetic acid dissolves, resulting in a poor yield.

[0094] In summary, the present invention synthesizes and prepares pentetic acid by optimizing the process route, and can effectively control the impurity content by regulating the reaction conditions such as the content of the reaction substrate and the solvent in each step, with a purity of more than 99.8%, and can be applied to a variety of fine chemical products and the preparation of pharmaceutical raw materials or preparations.

[0095] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for preparing pentetic acid, characterized in that: The method comprises the following steps: S1, after dissolving chloroacetic acid with an appropriate amount of water, the temperature is controlled at 10-25°C, and an aqueous sodium hydroxide solution is added, and the reaction time is 0.3-0.8h to prepare a sodium chloroacetate solution; S2, dissolving diethylenetriamine in water to obtain a diethylenetriamine aqueous solution; adding a solid carrier base catalyst, adding a sodium chloroacetate solution, controlling the temperature at 55-85° C., and reacting for 1-6 hours; S3, after the reaction is completed, filter, control the acidification temperature to 20-35°C, add concentrated hydrochloric acid, adjust the pH to 1.2-2.5, cool to the crystallization temperature of 0-20°C, stir for 8-18h, precipitate crystals; filter, wash with cold water, and dry to obtain pentetic acid; Wherein, the molar ratio of chloroacetic acid to diethylenetriamine is 1:0.16-0.22; The solid carrier base catalyst is selected from Na2O / SiO2 or MgO / SiO2 type catalyst; The solid carrier alkali catalyst is added in an amount of 3 to 10% of the mass of the diethylenetriamine aqueous solution; The acidification temperature is 25-30°C.

2. The preparation method according to claim 1, characterized in that: In step S2, the volume mass ratio of the added water to the diethylenetriamine is 1:18-22 ml / g.

3. The preparation method according to claim 1, characterized in that: The solid carrier alkali catalyst is a Na2O / SiO2 catalyst.

4. The preparation method according to claim 1, characterized in that: In step S1, the molar ratio of chloroacetic acid to sodium hydroxide is 1:1.0-1.

8.

5. The preparation method according to claim 1, characterized in that: In step S3, the crystallization temperature is 5-15°C.

6. The method for preparing pentetic acid according to any one of claims 1 to 5, comprising: S1, after dissolving chloroacetic acid with an appropriate amount of water, the temperature is controlled at 15-20°C, and an aqueous sodium hydroxide solution is added, and the reaction time is 0.4-0.6h to prepare a sodium chloroacetate solution; S2, dissolving diethylenetriamine in water to obtain a diethylenetriamine aqueous solution; adding 3-10% of Na2O / SiO2 type catalyst relative to the mass of the diethylenetriamine aqueous solution, adding sodium chloroacetate solution, controlling the temperature at 65-75°C, and the reaction time at 2-5h; S3, after the reaction is completed, filter, control the acidification temperature to 25-30°C, add concentrated hydrochloric acid, adjust the pH to 1.5-2.0, cool to the crystallization temperature of 5-15°C, stir for 10-16h, precipitate crystals; filter, wash with cold water, and dry to obtain pentetic acid; The molar ratio of chloroacetic acid to diethylenetriamine is 1:0.18-0.20; in step S1, the molar ratio of chloroacetic acid to sodium hydroxide is 1:1.2-1.6; in step S2, the volume mass ratio of added water to diethylenetriamine is 1:18-22 ml / g.

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