A film crystallization process for glycine methyl ester hydrochloride

Abstract

The application relates to the fine chemical technology field, and particularly discloses a membrane crystallization process of glycine methyl ester hydrochloride, which comprises the following steps: S1, stirring and mixing an industrial-grade glycine methyl ester hydrochloride sample with an organic solvent to obtain a colorless transparent solution; S2, flowing the transparent solution through a membrane assembly, and making the transparent solution pass through a shell channel of the membrane assembly; S3, flowing pure water through the membrane assembly, and making the pure water pass through a tube channel of the membrane assembly; S4, collecting the solution flowing out of the shell channel of the membrane assembly to obtain a mixed solution containing glycine methyl ester hydrochloride solid particles; and S5, centrifuging the mixed solution, collecting a solid product, and drying the solid product to obtain purified glycine methyl ester hydrochloride. The membrane crystallization process of the glycine methyl ester hydrochloride provided by the application is a continuous production process, the production efficiency is obviously improved, the glycine monomer and the glycine multimer impurities in the crude glycine methyl ester hydrochloride can be effectively removed, and the obtained product is high in purity and high in yield.

Description

Technical Field

[0001] This invention relates to the field of fine chemical technology, and more specifically, to a membrane crystallization process for glycine methyl ester hydrochloride. Background Technology

[0002] Glycine methyl ester hydrochloride is an important organic synthesis intermediate widely used in the synthesis of pharmaceuticals (such as antibiotics), pesticides, and food additives. With the increasing demands for product quality from downstream industries, stringent requirements have been placed on the purity and impurity content of glycine methyl ester hydrochloride. Currently, industrial-grade glycine methyl ester hydrochloride is typically produced by esterification of glycine and methanol in the presence of hydrogen chloride gas. This product often contains unreacted glycine monomers, polyglycine byproducts, other amino acid impurities, and trace amounts of ester impurities generated during the reaction, making it difficult to meet the high purity and low impurity content requirements of practical applications.

[0003] Currently, the industrial purification of glycine methyl ester hydrochloride generally adopts the recrystallization method. This involves heating and dissolving the crude industrial-grade glycine methyl ester hydrochloride, filtering it, and then crystallizing it through natural cooling or by adding a poor solvent. Finally, the product is obtained by filtration, washing, and drying. However, existing recrystallization processes have certain drawbacks, such as: ① Limited purification effect: Glycine and its polymers (such as diglycine) have small differences in solubility with the target product, and are prone to crystallization or co-precipitation during recrystallization. Therefore, existing recrystallization processes are not ideal in removing glycine monomer and polymer impurities, often failing to effectively remove impurities and resulting in limited purification effect; ② Low production efficiency: Recrystallization processes are mostly intermittent operations with long production cycles and high heat consumption, increasing production costs; ③ Low yield: The overall yield of glycine methyl ester hydrochloride purified by current recrystallization processes is usually low (generally between 70% and 80%), which leads to significantly low utilization of raw materials and directly increases production costs; ④ High solvent consumption: To further ensure the purification effect of the product, multiple recrystallization processes are often required, leading to the large-scale use of organic solvents. This not only increases the risk of VOC emissions but also places a heavy burden on recycling and significant environmental pressure.

[0004] In summary, existing methods for purifying industrial-grade glycine methyl ester hydrochloride using recrystallization not only have limited purification effects but also suffer from numerous problems such as low production efficiency, low yield, high cost, and significant environmental impact. Therefore, developing a new purification process for glycine methyl ester hydrochloride is of great practical significance. Summary of the Invention

[0005] The purpose of this invention is to address the problems existing in the traditional recrystallization process for purifying industrial-grade glycine methyl ester hydrochloride, and to propose a membrane crystallization process for glycine methyl ester hydrochloride, which solves the problems faced by the recrystallization purification process, such as limited purification effect, low production efficiency, low yield, high cost and great environmental pressure.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention provides a membrane crystallization process for glycine methyl ester hydrochloride, the process comprising the following steps: S1. Mix the industrial-grade glycine methyl ester hydrochloride sample with an organic solvent to obtain a colorless and transparent solution; S2. The transparent solution flows through the membrane module, and the transparent solution flows through the shell side of the membrane module; S3. Pure water flows through the membrane module, and the pure water flows through the tubing of the membrane module; S4. Collect the solution flowing out of the shell side of the membrane module to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. Centrifuge the mixture, collect the solid product, dry it, and obtain purified glycine methyl ester hydrochloride.

[0007] The membrane crystallization process for glycine methyl ester hydrochloride provided by this invention is a continuous production process with significantly improved production efficiency. It can also effectively remove glycine monomers and polymers from crude glycine methyl ester hydrochloride, resulting in a product with high purity and high yield.

[0008] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: the concentration of industrial-grade glycine methyl ester hydrochloride sample in the transparent solution of step S1 is 0.1–1.0 g / ml.

[0009] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: the organic solvent in step S1 is anhydrous methanol.

[0010] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: in step S1, the stirring temperature is 70-75°C, the stirring time is 30-60 minutes, and the stirring speed is 100-200 rpm.

[0011] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: in step S2, the transparent solution is maintained at a temperature of 60-65°C and flows through the shell side of the membrane module, with a flow rate of 1-50 ml / min.

[0012] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride is described, in step S2, where the flow rate of the transparent solution is set to 3–15 ml / min.

[0013] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: In step S3, pure water is maintained at a temperature of 55-60°C and flows through the tube side of the membrane module, with a flow rate of 1-50 ml / min.

[0014] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: in step S3, the flow rate of pure water is set to 6-20 ml / min.

[0015] Furthermore, a membrane crystallization process for glycine methyl ester hydrochloride: in step S5, the drying temperature is 70-80℃ and the drying time is 4-6 hours.

[0016] The beneficial effects of this invention are: The membrane crystallization purification process for glycine methyl ester hydrochloride provided by this invention constructs a membrane module crystallization system with a transparent solution phase flowing through the shell side and a pure aqueous phase flowing through the tube side. In situ anti-solvent crystallization of glycine methyl ester hydrochloride is induced in the shell side. Compared with the traditional recrystallization process, this invention achieves effective removal of impurities and continuous production process, showing significant advantages in product yield, purity and production efficiency. It is particularly suitable for the large-scale continuous production of pharmaceutical-grade glycine methyl ester hydrochloride.

[0017] The membrane crystallization purification process for glycine methyl ester hydrochloride provided by this invention employs membrane-assisted crystallization, resulting in high product purity (over 96.5%) and high yield (over 85%), significantly superior to existing recrystallization processes. Furthermore, the process of this invention enables continuous production and has excellent prospects for industrial application. Detailed Implementation

[0018] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0019] Example 1

[0020] Example 1 provides a membrane crystallization process for glycine methyl ester hydrochloride, which includes the following specific steps: S1. Weigh 90.84g of industrial-grade glycine methyl ester hydrochloride sample and add it to a three-necked flask. Then add 232.0ml of anhydrous methanol to the three-necked flask. Transfer the three-necked flask to an oil bath, turn on the stirrer, set the speed to 150rpm, set the temperature of the oil bath to 75℃, and stir for 45 minutes. The methanol in the three-necked flask will show stable reflux. When all the solid in the three-necked flask disappears and the solution becomes colorless and transparent, continue stirring for another 30 minutes to obtain a colorless and transparent solution. S2. When the temperature of the transparent solution in the three-necked flask is 62°C, it is flowed through the shell side of the membrane module at a flow rate of 3.0 ml per minute. The membrane module is a 1-cell membrane module. A single-stage membrane module of 1; S3. Pure water at 55℃ is flowed through the tube side of the membrane module at a flow rate of 6.0 ml per minute, and the pure water is discharged directly. S4. Collect the solution flowing out of the shell side of the membrane module in a glass container to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. The mixture is centrifuged to collect the white solid product, and then dried at 80°C for 5 hours to obtain approximately 79.68 g of purified glycine methyl ester hydrochloride sample, with a calculated yield of approximately 87.7%.

[0021] After HPLC and infrared spectroscopy analysis, the purified sample obtained in Example 1 contained approximately 96.5% glycine methyl ester hydrochloride, less than 1.0% glycine monomer and polymer, and no other ester impurities were detected.

[0022] Example 2

[0023] Example 2 provides a membrane crystallization process for glycine methyl ester hydrochloride, which includes the following specific steps: S1. Weigh 44.35g of industrial-grade glycine methyl ester hydrochloride sample and add it to a three-necked flask. Then add 339.0ml of anhydrous methanol to the three-necked flask. Transfer the three-necked flask to an oil bath, turn on the stirrer, set the speed to 120rpm, set the temperature of the oil bath to 73℃, and stir for 50 minutes. The methanol in the three-necked flask will show stable reflux. When all the solid in the three-necked flask disappears and the solution becomes colorless and transparent, continue stirring for another 25 minutes to obtain a colorless and transparent solution. S2. When the temperature of the transparent solution in the three-necked flask is 60°C, it is flowed through the shell side of the membrane module at a flow rate of 3.0 ml per minute. The membrane module is a 1-cell membrane module. A single-stage membrane module of 1; S3. Pure water at a temperature of 56℃ is flowed through the tube side of the membrane module at a flow rate of 6.0 ml per minute, and the pure water is discharged directly. S4. Collect the solution flowing out of the shell side of the membrane module in a glass container to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. The mixture is centrifuged to collect the white solid product, and then dried at 72°C for 6 hours to obtain approximately 38.5 g of purified glycine methyl ester hydrochloride sample, with a calculated yield of approximately 86.8%.

[0024] After HPLC and infrared spectroscopy analysis, the purified sample obtained in Example 2 contained approximately 96.2% glycine methyl ester hydrochloride, less than 1.0% glycine monomer, and no glycine polymer was detected.

[0025] Example 3

[0026] Example 3 provides a membrane crystallization process for glycine methyl ester hydrochloride, which includes the following specific steps: S1. Weigh 90.84g of industrial-grade glycine methyl ester hydrochloride sample and add it to a three-necked flask. Then add 255.0ml of anhydrous methanol to the three-necked flask. Transfer the three-necked flask to an oil bath, turn on the stirrer, set the speed to 100rpm, set the temperature of the oil bath to 70℃, and stir for 60 minutes. The methanol in the three-necked flask will show stable reflux. When all the solid in the three-necked flask disappears and the solution becomes colorless and transparent, continue stirring for another 35 minutes to obtain a colorless and transparent solution. S2. When the temperature of the transparent solution in the three-necked flask is 65°C, it is flowed through the shell side of the membrane module at a flow rate of 5.0 ml per minute. The membrane module is a 2-cell membrane module. 2-stage single-stage membrane module; S3. Pure water at 60℃ is flowed through the tube side of the membrane module at a flow rate of 10.0 ml per minute, and the pure water is discharged directly. S4. Collect the solution flowing out of the shell side of the membrane module in a glass container to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. The mixture is centrifuged to collect the white solid product, and then dried at 72°C for 6 hours to obtain approximately 79.2 g of purified glycine methyl ester hydrochloride sample, with a calculated yield of approximately 87.2%.

[0027] After HPLC and infrared spectroscopy analysis, the purified sample obtained in Example 3 contained approximately 97.5% glycine methyl ester hydrochloride, less than 0.3% glycine monomer, and no glycine polymer was detected.

[0028] Example 4

[0029] Example 4 provides a membrane crystallization process for glycine methyl ester hydrochloride, which includes the following specific steps: S1. Weigh 44.35g of industrial-grade glycine methyl ester hydrochloride sample and add it to a three-necked flask. Then add 400.0ml of anhydrous methanol to the three-necked flask. Transfer the three-necked flask to an oil bath, turn on the stirrer, set the speed to 180rpm, set the temperature of the oil bath to 74℃, and stir for 35 minutes. The methanol in the three-necked flask will show stable reflux. When all the solid in the three-necked flask disappears and the solution becomes colorless and transparent, continue stirring for another 15 minutes to obtain a colorless and transparent solution. S2. When the temperature of the transparent solution in the three-necked flask is 62°C, it is flowed through the shell side of the membrane module at a flow rate of 5.0 ml per minute. The membrane module is a 2-cell membrane module. 2-stage single-stage membrane module; S3. Pure water at a temperature of 57℃ is flowed through the tube side of the membrane module at a flow rate of 10.0 ml per minute, and the pure water is discharged directly. S4. Collect the solution flowing out of the shell side of the membrane module in a glass container to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. The mixture is centrifuged to collect the white solid product, and then dried at 75°C for 4 hours to obtain approximately 37.8 g of purified glycine methyl ester hydrochloride sample, with a calculated yield of approximately 85.2%.

[0030] After HPLC and infrared spectroscopy analysis, the purified sample obtained in Example 4 contained approximately 96.7% glycine methyl ester hydrochloride, less than 1.0% glycine monomer, and no glycine polymer was detected.

[0031] Example 5

[0032] Example 5 provides a membrane crystallization process for glycine methyl ester hydrochloride, which includes the following specific steps: S1. Weigh 180.0g of industrial-grade glycine methyl ester hydrochloride sample and add it to a three-necked flask. Then add 232.0ml of anhydrous methanol to the three-necked flask. Transfer the three-necked flask to an oil bath, turn on the stirrer, set the speed to 200rpm, set the temperature of the oil bath to 75℃, and stir for 40 minutes. The methanol in the three-necked flask will show stable reflux. When all the solid in the three-necked flask disappears and the solution becomes colorless and transparent, continue stirring for another 20 minutes to obtain a colorless and transparent solution. S2. When the temperature of the transparent solution in the three-necked flask is 64°C, it is flowed through the shell side of the membrane module at a flow rate of 15.0 ml per minute. The membrane module is a 3-necked flask. 3-stage single-stage membrane module; S3. Pure water at a temperature of 58℃ is flowed through the tube side of the membrane module at a flow rate of 20.0 ml per minute, and the pure water is discharged directly. S4. Collect the solution flowing out of the shell side of the membrane module in a glass container to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. The mixture is centrifuged to collect the white solid product, and then dried at 80°C for 4 hours to obtain approximately 155.8 g of purified glycine methyl ester hydrochloride sample, with a calculated yield of approximately 86.5%.

[0033] After HPLC and infrared spectroscopy analysis, the purified sample obtained in Example 5 contained approximately 99.5% glycine methyl ester hydrochloride, less than 0.1% glycine monomer, and no glycine polymer was detected.

[0034] The membrane crystallization process for glycine methyl ester hydrochloride of this invention achieves the following excellent results: ① High product purity: The HPLC purity of the product is >96%, significantly better than that of traditional recrystallization processes (usually <94%), and no other ester impurities were detected, indicating that the membrane crystallization process of this invention has good selectivity; the total content of glycine monomers and polymers after purification by this invention is <1.0%, solving the problem that such impurities are difficult to completely remove by recrystallization in traditional processes; ② High product yield: The product yield of this invention can reach over 85%, improving purity without causing significant product loss, achieving a balance between high purity and high yield; ③ Continuous production: The process of this invention can achieve continuous production with high efficiency and stable continuous operation, ensuring small fluctuations in product quality and good product stability, and has significant prospects for industrial application.

[0035] The above-described preferred embodiments of the present invention are for illustrative purposes only and are not intended to limit the scope of the invention. Any obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A membrane crystallization process for glycine methyl ester hydrochloride, characterized in that, The process includes the following steps: S1. Mix the industrial-grade glycine methyl ester hydrochloride sample with an organic solvent to obtain a colorless and transparent solution; S2. The transparent solution flows through the membrane module, and the transparent solution flows through the shell side of the membrane module; S3. Pure water flows through the membrane module, and the pure water flows through the tubing of the membrane module; S4. Collect the solution flowing out of the shell side of the membrane module to obtain a mixture containing glycine methyl ester hydrochloride solid particles. S5. Centrifuge the mixture, collect the solid product, dry it, and obtain purified glycine methyl ester hydrochloride.

2. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 1, characterized in that, The concentration of industrial-grade glycine methyl ester hydrochloride sample in the transparent solution of step S1 is 0.1–1.0 g / ml.

3. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 1 or 2, characterized in that, The organic solvent in step S1 is anhydrous methanol.

4. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 1, characterized in that, The stirring temperature in step S1 is 70-75℃, the stirring time is 30-60 minutes, and the stirring speed is 100-200 rpm.

5. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 1, characterized in that, In step S2, the transparent solution is maintained at a temperature of 60-65°C and flows through the shell side of the membrane module, with a flow rate of 1-50 ml / min.

6. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 5, characterized in that, In step S2, the flow rate of the transparent solution is set to 3-15 ml / min.

7. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 1, characterized in that, In step S3, the pure water is maintained at a temperature of 55-60°C and flows through the tube side of the membrane module, with a flow rate of 1-50 ml / min.

8. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 7, characterized in that, In step S3, the flow rate of pure water is set to 6-20 ml / min.

9. The membrane crystallization process for glycine methyl ester hydrochloride according to claim 1, characterized in that, In step S5, the drying temperature is 70-80℃ and the drying time is 4-6 hours.