Method for preparing amino-acid ester by applying dehydration membrane to strengthen amino acid and alcohol esterification

Abstract

The invention discloses a method for preparing amino-acid ester by strengthening esterification of amino acid and alcohol by using a dehydration membrane, which comprises the following specific operation processes: preparing a dehydration membrane tube, carrying out esterification reaction on amino acid and alcohol under the action of a catalyst to generate amino-acid ester and byproduct water, and removing the water through the screening performance of the dehydration membrane so as to break the thermodynamic equilibrium limit. The conversion rate and the yield of amino acid are improved. Compared with a conventional method, the method has the advantages that the conversion rate of amino acid is greatly increased, azeotropic water-carrying agents such as methylbenzene, petroleum ether and cyclohexane do not need to be used, energy is saved, the amino acid ester production process is more environmentally friendly, pollution to the environment is smaller, and energy consumption is smaller; and the cost of product separation is greatly reduced compared with that of a traditional mode.

Description

Technical Field

[0001] The invention belongs to the technical field of amino acid ester preparation, and particularly relates to a method for preparing amino acid ester by using a dehydration membrane to strengthen the esterification of amino acid and alcohol. Background Art

[0002] Amino acid ester is an important pharmaceutical intermediate, widely used in chemical industry, food, agriculture and other fields. At present, the industry mainly adopts the dichlorothionyl method to produce amino acid ester, which has the advantages of simple operation, rapid reaction, high yield and few by-products. However, this method will produce a large amount of sulfur dioxide and hydrogen chloride gas, and a large amount of waste acid. These waste acids will not only corrode the equipment and reduce the service life of the equipment, but also increase the cost of waste acid treatment, which is not in line with the concept of green chemistry and environmental protection. Therefore, it is of great theoretical and practical significance to study and develop a green amino acid ester synthesis process. Summary of the invention

[0003] In order to solve the problem of excessive waste acid discharge in the traditional amino acid esterification process, the present invention provides a method for preparing amino acid ester by using a dehydration membrane to strengthen the esterification of amino acids and alcohols. The present invention replaces the traditional thionyl chloride with a solid acid to reduce the generation of waste acid and sulfur dioxide, and at the same time removes the byproduct water in situ through the dehydration membrane, breaking the thermodynamic equilibrium limitation, and can improve the conversion rate of amino acids and the yield of amino acid esters without the need to add an additional water-carrying agent.

[0004] The specific technical solutions are as follows: A method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols, comprising the following steps: 1) Prepare a dehydration membrane tube and fix it in a reaction device; 2) Adding a solid acid catalyst into the reaction device, and then adding an alcohol solution of amino acid and HCl; 3) Evacuate the permeate side of the dehydration membrane, or add inert gas to the reaction device to increase pressure, and check the air tightness of the device; 4) The temperature is raised to react, and the by-product water is discharged through the pressure difference on both sides of the dehydration membrane. After the reaction is completed, the temperature is lowered to collect the product and analyze it by liquid chromatography.

[0005] Furthermore, the dehydration membrane tube described in step 1) includes a carrier and a loaded membrane, the carrier is an alumina tube, a polyacrylonitrile tube, a polytetrafluoroethylene tube or a polyvinylidene fluoride tube, and the loaded membrane material is a PVA membrane, a PVA / GO mixed matrix membrane, a PVA / SiO2 mixed matrix membrane, a PVA / Al2O3 mixed matrix membrane, a PVA / molecular sieve mixed matrix membrane, a PVA / COFs mixed matrix membrane, a PVA / MOFs mixed matrix membrane or a PVA / ILs mixed matrix membrane.

[0006] Furthermore, the solid acid catalyst in step 2) is HND-2, LX-50J, HND-260, HND-583W, LXC-101 or LXC-501 strong acid resin.

[0007] Furthermore, in step 2), the mass ratio of the added amino acid to the solid acid catalyst is 1:1-1:5; the molar ratio of the added alcohol to the amino acid is 1:1-50:1, preferably 10:1-20:1; the molar ratio of the added hydrogen chloride to the amino acid is 0.5:1-20:1, preferably 3:1-5:1.

[0008] Furthermore, in step 4), the rate of heating and cooling is 1-10°C / min, the reaction temperature is 20-90°C, preferably 50-70°C, and the reaction time is 1-72h.

[0009] Furthermore, the amino acid in step 2) is serine, valine, glycine, alanine, leucine, isoleucine, methionine, proline, tryptophan, tyrosine, cysteine, phenylalanine, aspartic acid, glutamic acid, aspartic acid, lysine, arginine, histidine, selenocysteine ​​or pyrrolysine.

[0010] Furthermore, the alcohol in step 2) is methanol, ethanol, ethylene glycol, isopropanol, isopentanol, n-butanol, isobutanol or benzyl alcohol.

[0011] The beneficial effects of the present invention are: 1) The process of producing amino acid esters is more environmentally friendly and less polluting to the environment; 2) Through the screening performance of the dehydration membrane, water is removed in situ to achieve reaction and separation coupling. Compared with traditional methods, it has higher conversion rate and yield; 3) The cost of product separation is greatly reduced compared to traditional methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Schematic diagram of a high-pressure reactor membrane reactor for dehydration membrane-enhanced esterification of amino acids and alcohols to produce amino acid esters; Figure 2 A schematic diagram of a normal pressure reaction device for dehydration membrane-enhanced esterification of amino acids and alcohols to produce amino acid esters; Figure 3 The scanning electron micrograph of the surface of the dehydrated PVA film used for strengthening the esterification of amino acids and alcohols to produce amino acid esters; Figure 4 It is a test comparison diagram of Example 2, Comparative Example 1 and Comparative Example 2; Figure 5 The performance diagram of dehydration membrane enhanced esterification of L-norvaline and ethanol to produce L-norvaline ethyl ester at different temperatures; Figure 6 The performance diagram of dehydration membrane enhanced esterification of L-norvaline and ethanol to produce L-norvaline ethyl ester under different hydrogen chloride ratios; Figure 7 The performance diagram of dehydration membrane enhanced esterification of L-norvaline and ethanol to produce L-norvaline ethyl ester at different ethanol ratios; Figure 8 It is a test comparison diagram of Example 3, Comparative Example 3 and Comparative Example 4; Fig. 9 Performance diagram of dehydration membrane enhanced esterification of DL-serine and methanol to produce DL-serine methyl ester at different temperatures; Fig.10 The performance diagram of the dehydration membrane enhanced esterification of DL-serine and methanol to produce DL-serine methyl ester under different hydrogen chloride ratios; Fig.11 This is the performance diagram of dehydration membrane enhanced esterification of DL-serine and methanol to produce DL-serine methyl ester under different ethanol ratios.

[0013] In the figure: 1. reaction device; 2. buffer tank; 3. vacuum pump; 4. condenser; 5. thermometer; 6. dehydration membrane tube. DETAILED DESCRIPTION

[0014] The present invention is further described below in conjunction with the examples and the accompanying drawings, but the protection scope of the present invention is not limited thereto. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be purchased from chemical companies.

[0015] Example 1: Preparation of dehydration membrane 1) Treat the alumina tube carrier by grinding it with sandpaper, rinsing it with deionized water, drying it at 80°C overnight, and calcining it at 500°C for two hours to obtain an alumina tube that can be used as a dehydration membrane carrier; 2) Preparation of casting solution: 5 g of polyvinyl alcohol (PVA) particles are heated and dissolved in 95 g of deionized water. After the solution is completely clarified, the casting solution can be obtained; 3) Preparation of dehydration membrane: plug one end of the treated alumina tube carrier with a rubber stopper and connect the other end to a vacuum pump for suction. Immerse the carrier in the casting liquid for dip coating, then slowly pull it above the casting liquid and let it stand. Place the dip coated carrier in a constant temperature oven to dry.

[0016] The scanning electron microscope image of the surface of the polyvinyl alcohol dehydration membrane prepared in Example 1 is as follows Figure 3 As shown in the figure, it can be seen that there are no obvious defects on the surface of the polyvinyl alcohol dehydration membrane, and after the air tightness test, it meets the experimental test requirements.

[0017] The equipment used in the following embodiments is as follows: Figure 1 and Figure 2 As shown, Figure 1 It is a high-pressure reactor device. During use, the device can be filled with inert gas to increase the pressure on the feed side of the dehydration membrane tube (i.e., inside the reaction device), and can also evacuate the permeation side of the membrane tube (i.e., inside the membrane tube), greatly increasing the driving force of the permeation process, thereby promoting the separation of trace water; Figure 2 It is a normal pressure reaction device. The reaction device 1 adopts a three-necked flask. The three openings of the three-necked flask are respectively provided with a condenser 4, a thermometer 5 and a dehydration membrane tube 6. The outlet end of the dehydration membrane tube 6 is connected to a buffer tank 2 and a vacuum pump 3 in sequence. During use, the device can evacuate the permeation side of the dehydration membrane 6. There is no need to pressurize the reaction device 1. The installation is simple and convenient, and the cost is low.

[0018] Example 2: Enhanced esterification of L-norvaline by solid acid and dehydration membrane in ethanolic HCl solution The dehydration membrane prepared in Example 1 was used, one end of which was sealed, and the other end was connected to a cold trap with a polytetrafluoroethylene tube to collect the permeate, which was then placed in a Figure 1 In the reaction device shown, 20 ml of HCl-ethanol solution (4 mol / L), 5.0 g of strongly acidic solid resin HND-2, and 2.4 g of L-norvaline are added into the reaction device, and 1 MPa of nitrogen is filled into the reaction device, which is sealed and checked for air tightness. While ensuring good air tightness, the temperature is raised to 60°C at a heating rate of 1°C / min and the reaction is carried out for 24 hours. During the reaction, due to the large pressure difference between the inside and outside of the dehydration membrane, the by-product water in the reaction device can be used as a driving force to remove the by-product water in the reaction device from the reaction device in situ, thereby breaking the thermodynamic equilibrium limitation and increasing the conversion rate of amino acids. The performance results of the test are shown in the figure below. Figure 4 shown.

[0019] The reaction conditions of Example 2 were adjusted, and other conditions remained unchanged. The reaction temperatures (20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, and 90°C) were changed respectively, and the performance tests were performed to obtain the following results: Figure 5 As shown in the figure, it can be seen that with the increase of temperature, the conversion rate of L-norvaline and the selectivity of L-norvaline ester continue to increase. This is because the increase in temperature accelerates the reaction rate. However, after the temperature exceeds 70°C, the side reaction of dehydration polymerization between L-norvaline molecules intensifies, resulting in an increase in the conversion rate of L-norvaline, but a decrease in the selectivity of L-norvaline ester. When other conditions remain unchanged, the molar feed ratio of L-norvaline to HCl is changed (1 / 0.5, 1 / 1, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, 1 / 20), and the performance test results are as follows Figure 6As shown in the figure, it can be concluded that with the increase of the proportion of hydrogen chloride, the conversion rate of L-norvaline and the selectivity of L-norvaline ester continue to increase; other conditions remain unchanged, the molar feed ratio of L-norvaline to ethanol is changed (1 / 1, 1 / 2, 1 / 5, 1 / 10, 1 / 15, 1 / 20, 1 / 30, 1 / 50), and the performance test results are as follows Figure 7 As shown in the figure, it can be concluded that with the increase of ethanol feed ratio, the conversion rate and selectivity of L-norvaline continue to increase. However, when the ethanol feed ratio exceeds 1 / 20, the conversion rate of L-norvaline and the selectivity of L-norvaline ester begin to decrease. This is because the excessive amount of solvent (ethanol) used makes the concentration of reactants in the reaction solution too low.

[0020] Example 3: Enhanced DL-serine esterification using solid acid and dehydration membrane catalyst in methanolic HCl solution Use the dehydration membrane tube prepared in Example 1, seal one end of it, and install Figure 2 In the reaction device shown in the figure, use a vacuum pump to evacuate the dehydration membrane tube. All pipelines use polytetrafluoroethylene tubes. Add 50ml HCl-methanol solution (5mol / L), 20.0g HND-2 strong acid solid resin, and 8.5g DL-serine into the reaction device, and check the air tightness. While ensuring good air tightness, increase the temperature to 60°C at a heating rate of 1°C / min and react for 24 hours. During the reaction, due to the large pressure difference between the inside and outside of the dehydration membrane, it can be used as a power to remove the by-product water in the reaction device from the reaction device in situ, thereby breaking the thermodynamic equilibrium limitation and increasing the conversion rate of amino acids. The performance results of the test are as follows Figure 8 shown.

[0021] The reaction conditions of Example 3 were adjusted, and other conditions remained unchanged. The reaction temperatures (20°C, 30°C, 40°C, 50°C, 70°C, 80°C, and 90°C) were changed respectively, and the performance tests were performed to obtain the following results: Fig. 9 As shown in the figure, it can be seen that with the increase of temperature, the conversion rate of DL-serine and the selectivity of DL-serine ester continue to increase. This is because the increase in temperature accelerates the reaction rate. However, after the temperature exceeds 70°C, the side reactions of dehydration polymerization between DL-serine molecules and dehydration polymerization within the molecule intensify, resulting in an increase in the conversion rate of DL-serine, but a decrease in the selectivity of DL-serine ester. When other conditions remain unchanged, the molar feed ratio of DL-serine to HCl is changed (1 / 0.5, 1 / 1, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, 1 / 20), and the performance test results are as follows Fig.10As shown in the figure, it can be concluded that with the increase of hydrogen chloride ratio, the conversion rate of DL-serine and the selectivity of DL-serine ester are continuously improved; other conditions remain unchanged, the molar feed ratio of DL-serine to methanol is changed (1 / 1, 1 / 2, 1 / 5, 1 / 10, 1 / 15, 1 / 20, 1 / 30, 1 / 50), and the performance test results are as follows Fig.11 As shown in the figure, it can be concluded that with the increase of methanol feed ratio, the conversion rate of DL-serine and the selectivity of DL-serine ester continue to increase, but when the methanol feed ratio exceeds 1 / 20, the conversion rate of DL-serine and the selectivity of DL-serine ester decrease slightly. This is because the excessive amount of solvent (methanol) used makes the concentration of reactants in the reaction solution too low.

[0022] Comparative Example 1: Solid Acid Catalyzed Esterification of L-Norvaline in Ethanol Solution of HCl use Figure 1 The reaction device was removed and the dehydration membrane tube was completely sealed. 20 ml of HCl-ethanol solution (4 mol / L), 5.0 g of strong acid solid resin HND-2, and 2.4 g of L-norvaline were added to the reaction device, and 1 MPa of nitrogen was filled in to check the air tightness. When ensuring good air tightness, the temperature was raised to 60 °C at a rate of 1 °C / min and the reaction was continued for 24 hours. The performance results of the test are shown in the figure below. Figure 4 As shown in the figure, when the dehydration membrane is not installed, the amino acid conversion rate and selectivity are both low. This is because the presence of water restricts the esterification reaction, and at the same time, condensation reactions occur between some amino acid molecules.

[0023] Comparative Example 2: Solid acid catalyzes the esterification of L-norvaline in a mixed solution of HCl ethanol solution and petroleum ether (30-60°C) use Figure 1 The reaction device was set up, the dehydration membrane tube was removed, and it was connected to the atmosphere with a polytetrafluoroethylene tube. Then 20 ml of HCl-ethanol solution (4 mol / L), 5.0 g of strong acid solid resin HND-2, 2.4 g of L-norvaline, and 35 ml of petroleum ether (30-60°C) were added to the reaction device. Then the temperature was raised to 60°C at a rate of 1°C / min and the reaction was continued for 24 hours. The performance results of the test are shown in the figure below. Figure 4 As shown in the figure, after adding the azeotropic water-carrying agent petroleum ether, the final conversion rate is slightly lower than that of the experimental group with the addition of the dehydration membrane. This is because the introduction of the azeotropic water-carrying agent petroleum ether (boiling range 30-60°C) leads to a decrease in the concentration of amino acids in the reaction solution, which is caused by the limited equilibrium and is accompanied by the occurrence of side reactions.

[0024] Compared with the performance of Comparative Example 1 and Comparative Example 2, the conversion rate of amino acids in Example 2 is greatly improved, and there is no need to use an azeotropic water-carrying agent. This is because the dehydration membrane removes water in situ during the reaction, which can break the thermodynamic equilibrium and promote the forward reaction.

[0025] Comparative Example 3: Solid Acid Catalyzed Esterification of DL-Serine in Methanol Solution of HCl use Figure 2 The reaction device was removed, the dehydration membrane tube was removed, and it was completely sealed; 50 ml of HCl-methanol solution (5 mol / L), 20.0 g of HND-2 strong acid solid resin, and 8.5 g of DL-serine were added, and the air tightness was checked. When the air tightness was ensured to be good, the temperature was raised to 60°C at a rate of 1°C / min and the reaction was continued for 24 hours. The performance results of the test are shown in the figure below. Figure 8 As shown in the figure, when the dehydration membrane is not installed, the amino acid conversion rate and selectivity are both low. This is because the presence of water restricts the esterification reaction, and at the same time, condensation reactions occur between some amino acid molecules.

[0026] Comparative Example 4: Esterification of DL-serine catalyzed by solid acid in a mixed solution of HCl in methanol and petroleum ether (30-60°C) use Figure 2 The reaction device was placed in a heat exchanger, the dehydration membrane tube was removed, and the device was connected to the atmosphere with a polytetrafluoroethylene tube. 50 ml of HCl-methanol solution (5 mol / L), 20.0 g of HND-2 strong acid solid resin, 8.5 g of DL-serine, and 45 ml of petroleum ether (30-60°C) were added to the device. Then, the temperature was raised to 60°C at a heating rate of 1°C / min and the reaction was continued for 24 hours. The performance results of the test are shown in the figure below. Figure 8 As shown in the figure, after adding petroleum ether, the final conversion rate is slightly lower than that of the experimental group with the addition of pervaporation membrane. This is because the introduction of azeotropic water-carrying agent petroleum ether (boiling range 30-60°C) leads to a decrease in the concentration of amino acids in the reaction solution, which is caused by the limited equilibrium and is accompanied by the occurrence of side reactions.

[0027] Compared with the performance of Comparative Example 3 and Comparative Example 4, the conversion rate of amino acids is greatly improved, and there is no need to use an azeotropic water-carrying agent. This is because the dehydration membrane removes water in situ during the reaction, which can break the thermodynamic equilibrium and promote the forward reaction.

[0028] In summary, the method of using a dehydrating membrane to strengthen the esterification of amino acids and alcohols to prepare amino acid esters has greatly improved the conversion rate and yield of the reaction compared with conventional methods. This is because the dehydrating membrane can remove water in situ during the reaction. By removing water, the thermodynamic equilibrium limit of the reaction is broken, the reaction is promoted to proceed in the forward direction, and the conversion rate of the amino acid is improved. Although adding a dehydrating agent to the reaction can also remove water, the introduction of the dehydrating agent will cause other side reactions to occur, resulting in a decrease in the selectivity of the amino acid ester. The use of a dehydrating membrane for reaction strengthening can achieve in situ water removal without introducing side reactions, improve the conversion rate and yield, and has great application value.

[0029] Obviously, the above embodiments are only examples for clear explanation, and are not intended to limit the implementation methods. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from them are still within the protection scope of the invention.

[0030] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols, characterized in that: The steps include: 1) Prepare a dehydration membrane tube and fix it in a reaction device; 2) Adding a solid acid catalyst into the reaction device, and then adding an alcohol solution of amino acid and HCl; 3) Evacuate the permeate side of the dehydration membrane, or add inert gas to the reaction device to increase pressure, and check the air tightness of the device; 4) The temperature is raised to react, and the by-product water is discharged through the pressure difference on both sides of the dehydration membrane. After the reaction is completed, the temperature is lowered to collect the product and analyze it by liquid chromatography.

2. A method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols as claimed in claim 1, characterized in that: The dehydration membrane tube described in step 1) includes a carrier and a loaded membrane, the carrier is an alumina tube, a polyacrylonitrile tube, a polytetrafluoroethylene tube or a polyvinylidene fluoride tube, and the loaded membrane material is a PVA membrane, a PVA / GO mixed matrix membrane, a PVA / SiO2 mixed matrix membrane, a PVA / Al2O3 mixed matrix membrane, a PVA / molecular sieve mixed matrix membrane, a PVA / COFs mixed matrix membrane, a PVA / MOFs mixed matrix membrane or a PVA / ILs mixed matrix membrane.

3. The method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols as claimed in claim 1, characterized in that: The solid acid catalyst in step 2) is HND-2, LX-50J, HND-260, HND-583W, LXC-101 or LXC-501 strong acid resin.

4. The method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols as claimed in claim 1, characterized in that: In step 2), the mass ratio of the added amino acid to the solid acid catalyst is 1:1-1:5; the molar ratio of the added alcohol to the amino acid is 1:1-50:1, preferably 10:1-20:1; the molar ratio of the added hydrogen chloride to the amino acid is 0.5:1-20:1, preferably 3:1-5:

1.

5. The method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols as claimed in claim 1, characterized in that: In step 4), the rate of heating and cooling is 1-10°C / min, the reaction temperature is 20-90°C, preferably 50-70°C, and the reaction time is 1-72h.

6. A method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols as claimed in claim 1, characterized in that: The amino acid in step 2) is serine, valine, glycine, alanine, leucine, isoleucine, methionine, proline, tryptophan, tyrosine, cysteine, phenylalanine, aspartic acid, glutamic acid, aspartic acid, lysine, arginine, histidine, selenocysteine ​​or pyrrolysine.

7. The method for preparing amino acid esters by using a dehydration membrane to strengthen the esterification of amino acids and alcohols as claimed in claim 1, characterized in that: The alcohol in step 2) is methanol, ethanol, ethylene glycol, isopropanol, isopentanol, n-butanol, isobutanol or benzyl alcohol.

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