A kind of preparation method of high-purity 3-morpholinepropanesulfonic acid

Abstract

The present invention provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which comprises the following steps: (a) methanol is added to a reaction vessel, followed by sequentially dropping morpholine and 1,3-propane sultone, and the temperature is raised after the dropwise addition to carry out a condensation reaction; (b) the first mixture is centrifuged, and a white solid is taken to obtain a crude 3-morpholinepropanesulfonic acid product; (c) the crude 3-morpholinepropanesulfonic acid product is added to purified water for stirring and dissolving, and a coarse filtration is performed to obtain a 3-morpholinepropanesulfonic acid solution; (d) the 3-morpholinepropanesulfonic acid solution is introduced into an ultrasonic crystallization system for continuous and cyclic treatment to obtain a 3-morpholinepropanesulfonic acid clear liquid; (e) the 3-morpholinepropanesulfonic acid clear liquid is finely filtered, and then decolorized to obtain a refined 3-morpholinepropanesulfonic acid solution; (f) methanol is added to the refined 3-morpholinepropanesulfonic acid solution, and crystals are separated and dried to obtain 3-morpholinepropanesulfonic acid. It is not necessary to increase the purity by multiple recrystallizations to make its absorbance qualified.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for preparing 3-morpholinepropanesulfonic acid, in particular to a method for preparing high-purity 3-morpholinepropanesulfonic acid. Background Art

[0002] 3-Morpholinepropanesulfonic acid (MOPS) is a white crystalline powder and a sulfonic acid substance. It is a biological buffer and is often used to prepare RNA electrophoresis buffer. It can not only be used as a buffer system for cell culture media, but also is a common electrophoresis buffer and protein purification chromatography buffer. In the existing MOPS production, ethanol and water are usually used as solvents. The quality of the final product is poor, resulting in poor solution absorbance and the need for multiple recrystallizations, which will lead to material loss and high costs.

[0003] The Chinese invention patent with application number 201911105474.1 discloses a method for producing 3-morpholinepropanesulfonic acid, which comprises the following steps: dissolving 100g of propane sultone in 1L of pyridine according to the weight ratio; then adding 71.3g of morpholine at a preset speed, and controlling the reaction temperature at 30°C by the preset speed of adding materials; after adding materials, continue to keep warm for N hours, and then filter and dry to obtain 162g of 3-morpholinepropanesulfonic acid finished product. Pyridine is used as a solvent in this production method. Pyridine has a pungent odor, and long-term contact has an impact on health.

[0004] The Chinese invention patent with application number 201911233354.X discloses a method for preparing 3-morpholinepropanesulfonic acid, comprising dissolving 1,3-propane sultone with an organic solvent A to obtain an organic solution containing 1,3-propane sultone, and dissolving morpholine with an organic solvent B to obtain an organic solution containing morpholine; the molar ratio of 1,3-propane sultone to morpholine is 1:1; the organic solution containing 1,3-propane sultone and the organic solution containing morpholine are respectively pumped into a microchannel reactor at the same time to react to obtain a reaction solution; the pumping rate of the organic solution containing 1,3-propane sultone is 20 to 35 kg / h, and the pumping rate of the organic solution containing morpholine is 10 to 25 kg / h; the obtained reaction solution is subjected to freeze crystallization to precipitate a crude 3-morpholinepropanesulfonic acid product, and then nitrogen is passed through the reaction solution for pressure filtration to obtain a finished 3-morpholinepropanesulfonic acid product. This method requires the use of a high-cost microchannel reactor as the reaction equipment, and requires precise control of the type and concentration of the reactants, otherwise the yield will vary greatly: some are as high as 99%, while others are only 81%. Summary of the invention

[0005] In order to solve the above technical problems, the object of the present invention is to provide a method for preparing high-purity 3-morpholinepropanesulfonic acid.

[0006] In order to achieve the above technical problem, the present invention provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which comprises the following steps:

[0007] (a) adding methanol to a reaction container, and then dropping morpholine and 1,3-propane sultone in sequence, raising the temperature after the dropping is completed to carry out a condensation reaction, and lowering the temperature after the reaction is completed to obtain a first mixture;

[0008] (b) centrifuging the first mixture and taking the filter residue to obtain a crude product of 3-morpholinepropanesulfonic acid;

[0009] (c) adding the crude 3-morpholinepropanesulfonic acid product to purified water for stirring and dissolving, and performing coarse filtration to obtain a 3-morpholinepropanesulfonic acid solution;

[0010] (d) introducing the 3-morpholinepropanesulfonic acid solution into an ultrasonic crystallization system for continuous and cyclic treatment to obtain a 3-morpholinepropanesulfonic acid clear solution, and inducing the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 10° C. to 60° C., hydraulic residence time 0.5 h to 1.5 h, and ultrasonic power frequency 10 to 40 KHz;

[0011] (e) finely filtering the 3-morpholinepropanesulfonic acid clear solution, and then decolorizing to obtain a refined 3-morpholinepropanesulfonic acid solution;

[0012] (f) adding methanol to the refined 3-morpholinepropanesulfonic acid solution, and then adding a crystallizer to perform crystallization purification, separating crystals, and drying to obtain 3-morpholinepropanesulfonic acid.

[0013] Optimally, in step (a), the molar ratio of the morpholine to the 1,3-propane sultone is 0.9-1.1:1, the temperature of the condensation reaction is 40-60°C, and the cooling is to reduce the temperature to 5-15°C.

[0014] Furthermore, in step (a), a large amount of crystals will precipitate during the cooling process accompanied by obvious heat release, and the temperature should be well controlled; in step (b), the filtrate after centrifugation is added to step (a) for recycling.

[0015] Optimally, in step (c), the mass ratio of the crude 3-morpholinepropanesulfonic acid to purified water is 1:1-2; and coarse filtration is performed in a coarse filter to remove impurities.

[0016] Furthermore, in step (d), the control parameters of the ultrasonic crystallization system are: temperature 20°C to 30°C, hydraulic residence time 1h to 1.2h and frequency of ultrasonic power supply 20 to 28KHz.

[0017] Optimally, in step (e), the 3-morpholinepropanesulfonic acid clear solution is introduced into a filter for precision filtration to remove fine impurity crystals; and then passed through a decolorizer to remove trace impurities dissolved in the 3-morpholinepropanesulfonic acid clear solution to obtain a refined 3-morpholinepropanesulfonic acid solution.

[0018] Furthermore, in step (f), the mass ratio of the added amount of the methanol to the crude 3-morpholinepropanesulfonic acid is 5 to 6:1.

[0019] The method for preparing high-purity 3-morpholinepropanesulfonic acid comprises the following steps: after a crude 3-morpholinepropanesulfonic acid product is obtained by reaction, ultrasonic crystallization, precision filtration, decolorization and crystallization are carried out in combination with specific process steps to obtain the high-purity 3-morpholinepropanesulfonic acid. In this way, the purity can be improved (purity can reach 99.8%) without multiple recrystallizations, the absorbance is qualified, material loss is avoided, production efficiency is improved and production cycle is reduced, the absorbance can reach the qualified standard (260nm 0.005, 280nm 0.002) through one refining, and the product is white; while the product produced by the existing traditional process is light yellow, and the absorbance can only reach (260nm 0.092, 280nm 0.057). BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The chemical reaction formula for preparing high-purity 3-morpholinepropanesulfonic acid of the present invention is:

[0021] Figure 2 The present invention is a flow chart for preparing high-purity 3-morpholinepropanesulfonic acid;

[0022] Figure 3 This is a flow chart of post-treatment during the preparation of high-purity 3-morpholinepropanesulfonic acid of the present invention;

[0023] Figure 4 is the liquid chromatogram of 3-morpholinepropanesulfonic acid prepared in Example 1;

[0024] Figure 5 This is the absorbance test graph of 3-morpholinepropanesulfonic acid prepared in Example 1;

[0025] Figure 6 This is the absorbance test graph of 3-morpholinepropanesulfonic acid prepared in Example 2;

[0026] Figure 7 This is the absorbance test chart of 3-morpholinepropanesulfonic acid prepared in Comparative Example 1. DETAILED DESCRIPTION

[0027] The preparation method of high-purity 3-morpholinepropanesulfonic acid of the present invention is as follows: Figure 1As shown, it is prepared by reacting morpholine and 1,3-propane sultone; it comprises the following steps: (a) adding methanol to a reaction container, then dropping morpholine and 1,3-propane sultone in sequence, heating after the dropping is completed to carry out condensation reaction, and cooling after the reaction is completed to obtain a first mixture; (b) centrifuging the first mixture to obtain a white solid to obtain a crude 3-morpholinepropanesulfonic acid product; (c) adding the crude 3-morpholinepropanesulfonic acid product to purified water for stirring and dissolving, and coarsely filtering to obtain a 3-morpholinepropanesulfonic acid solution; (d) introducing the 3-morpholinepropanesulfonic acid solution into a supernatant. The ultrasonic crystallization system performs continuous and cyclic treatment to obtain a 3-morpholinepropanesulfonic acid clear solution and induces the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 10°C to 60°C, hydraulic retention time 0.5h to 1.5h and frequency of the ultrasonic power supply 10 to 40KHz; (e) the 3-morpholinepropanesulfonic acid clear solution is finely filtered and then decolorized to obtain a refined 3-morpholinepropanesulfonic acid solution; (f) methanol is added to the refined 3-morpholinepropanesulfonic acid solution, and then a crystallizer is added to perform crystallization purification, and the crystals are separated and dried to obtain 3-morpholinepropanesulfonic acid. After the crude 3-morpholinepropanesulfonic acid is obtained by reaction, ultrasonic crystallization, precision filtration, decolorization and crystallization in specific process steps can be used to obtain high-purity 3-morpholinepropanesulfonic acid. In this way, there is no need to increase the purity through multiple recrystallizations (the purity reaches 99.8%), the absorbance is qualified, material loss is avoided, production efficiency is improved and production cycle is reduced. The absorbance can reach the qualified standard (260nm 0.005, 280nm 0.002) through one refining, and the product is white; while the product produced by the existing traditional process is light yellow, and the absorbance can only reach (260nm 0.092, 280nm 0.057).

[0028] In step (a), the molar ratio of the morpholine to the 1,3-propane sultone is 0.9-1.1:1, the temperature of the condensation reaction is 40-60°C, and the cooling is to reduce the temperature to 5-15°C; in step (a), a large amount of crystals are precipitated during the cooling process with obvious heat release, and the temperature is well controlled; in step (b), the filtrate after centrifugation is added to step (a) for recycling; in step (c), the mass ratio of the crude 3-morpholinepropanesulfonic acid to purified water is 1:1-2; coarse filtration is performed in a coarse filter to remove impurities; in step (d), the ultrasonic wave is The control parameters of the crystallization system are: temperature 20°C to 30°C, hydraulic retention time 1h to 1.2h and frequency of ultrasonic power supply 20 to 28KHz; in step (e), the 3-morpholinepropanesulfonic acid clear solution is introduced into a filter for precision filtration to remove fine impurity crystals; then the 3-morpholinepropanesulfonic acid clear solution is passed through a decolorizer to remove trace impurities dissolved in the 3-morpholinepropanesulfonic acid clear solution to obtain a refined 3-morpholinepropanesulfonic acid solution; in step (f), the mass ratio of the amount of methanol added to the crude 3-morpholinepropanesulfonic acid product is 5 to 6:1; each of the above steps can improve the yield or purity of 3-morpholinepropanesulfonic acid.

[0029] The present invention will be further described below in conjunction with the embodiments shown in the accompanying drawings.

[0030] Example 1

[0031] This embodiment provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, and its process flow is as follows: Figure 2 and Figure 3 As shown, the following steps are included:

[0032] (a) adding 600 g of methanol to a reaction container, and then dropping 87.2 g of morpholine and 122 g of 1,3-propane sultone in sequence (the total dropping time of morpholine and 1,3-propane sultone is controlled within 1 hour), heating to 50° C. for condensation reaction after the dropping is completed, and cooling (to 10° C.) after the reaction is completed to obtain a first mixture;

[0033] (b) adding the first mixture into a centrifuge for centrifugation, taking out a white solid to obtain a crude 3-morpholinepropanesulfonic acid, and adding the filtrate into step (a) for recycling;

[0034] (c) adding 250 g of 3-morpholinepropanesulfonic acid crude product (wet product) to 300 g of purified water for stirring and dissolving, and then introducing it into a coarse filter for coarse filtration to remove impurities to obtain a 3-morpholinepropanesulfonic acid solution;

[0035] (d) introducing the 3-morpholinepropanesulfonic acid solution into an ultrasonic crystallization system for continuous and cyclic treatment to obtain a 3-morpholinepropanesulfonic acid clear solution, and inducing the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 30° C., pressure normal pressure, hydraulic residence time 1 h, and ultrasonic power supply frequency 25 KHz (the ultrasonic crystallization system is developed by the same company Hunan Wu Gan, see the Chinese invention patent application number 202010192916.7, but the control parameters need to be adjusted);

[0036] (e) introducing the 3-morpholinepropanesulfonic acid clear solution into a filter for precision filtration to remove fine impurity crystals; and then introducing the 3-morpholinepropanesulfonic acid clear solution into a decolorizer to remove trace impurities dissolved in the 3-morpholinepropanesulfonic acid clear solution to obtain a refined 3-morpholinepropanesulfonic acid solution;

[0037] (f) adding 800 g of methanol into a crystallization kettle, and then adding the refined 3-morpholinepropanesulfonic acid solution into a crystallizer to carry out crystallization purification, separating crystals, and drying and packaging to obtain 3-morpholinepropanesulfonic acid.

[0038] The dried 3-morpholinepropanesulfonic acid was tested and the purity was up to 99.8% (the liquid chromatogram is shown in FIG. Figure 4 The absorbance can reach the qualified standard (260nm 0.005, 280nm 0.002) after one purification, and the product is white (for specific absorbance spectrum, see Figure 5 ), the absorbance test results are shown in Table 1.

[0039] Example 2

[0040] This embodiment provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which is basically the same as that in Example 1, except that: in step (d), the frequency of the ultrasonic power supply is 28KHz;

[0041] The dried 3-morpholinepropanesulfonic acid was tested and the purity was up to 99.6%. The absorbance test results are shown in Figure 6 and Table 1.

[0042] Example 3

[0043] This embodiment provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which is basically the same as that in Example 1, except that: in step (d), the frequency of the ultrasonic power supply is 20 KHz;

[0044] The dried 3-morpholinepropanesulfonic acid was tested and the purity was found to be 99.0%. The absorbance test results are shown in Table 1.

[0045] Comparative Example 1

[0046] This example provides a method for preparing 3-morpholinepropanesulfonic acid, which is basically the same as that in Example 1, except that: in step (d), a traditional impurity removal method is used, specifically: This example provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which is basically the same as that in Example 1, except that: in step (d), an ultrasonic impurity removal system is not used, and only a filtering device is used to directly filter and remove impurities;

[0047] The dried 3-morpholinepropanesulfonic acid was tested and the purity was up to 93%. The absorbance test results are shown in Figure 7 and Table 1.

[0048] Table 1 Purity and absorbance values ​​of 3-morpholinepropanesulfonic acid in Examples 1-3 and Comparative Example 1

[0049] Serial number Way purity Absorbance (260nm) Absorbance (280nm) Comparative Example 1 Traditional impurity removal 93％ 0.092 0.057 Example 1 Ultrasonic cleaning 99.8％ 0.005 0.002 Example 2 Ultrasonic cleaning 99.6％ 0.007 0.001 Example 3 Ultrasonic cleaning 99.0％ 0.007 0.002

[0050] Example 4

[0051] This embodiment provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which is basically the same as that in Example 1, except that: in step (a), 78.4 g of morpholine and 122 g of 1,3-propane sultone are subsequently added dropwise;

[0052] The dried 3-morpholinepropanesulfonic acid was tested and found to have a purity of 95.5% and an absorbance of (260nm 0.042, 280nm 0.025).

[0053] Example 5

[0054] This embodiment provides a method for preparing high-purity 3-morpholinepropanesulfonic acid, which is basically the same as that in Example 1, except that: in step (a), 95.8 g of morpholine and 122 g of 1,3-propane sultone are subsequently added dropwise;

[0055] The dried 3-morpholinepropanesulfonic acid was tested and found to have a purity of 97.8% and an absorbance of (260nm 0.036, 280nm 0.010).

[0056] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing high-purity 3-morpholinepropanesulfonic acid, characterized in that: It includes the following steps: (a) adding 600 g of methanol to a reaction container, and then dropping 87.2 g of morpholine and 122 g of 1,3-propane sultone in sequence, heating the mixture to 50° C. for condensation reaction after the dropping, and cooling the mixture to 10° C. after the reaction to obtain a first mixture; the total dropping time of the morpholine and 1,3-propane sultone is controlled within 1 hour; (b) adding the first mixture into a centrifuge for centrifugation, taking out a white solid to obtain a crude 3-morpholinepropanesulfonic acid, and adding the filtrate into step (a) for recycling; (c) adding 250 g of crude 3-morpholinepropanesulfonic acid to 300 g of purified water for stirring and dissolving, and then introducing the mixture into a coarse filter for coarse filtration to remove impurities to obtain a 3-morpholinepropanesulfonic acid solution; (d) introducing the 3-morpholinepropanesulfonic acid solution into an ultrasonic crystallization system for continuous and cyclic treatment to obtain a 3-morpholinepropanesulfonic acid clear solution, and inducing the precipitation of fine impurities; the control parameters of the ultrasonic crystallization system are: temperature 30° C., pressure normal pressure, hydraulic residence time 1 hour, and ultrasonic power frequency 25 kHz or 28 kHz; (e) introducing the 3-morpholinepropanesulfonic acid clear solution into a filter for precision filtration to remove fine impurity crystals; and then introducing the 3-morpholinepropanesulfonic acid clear solution into a decolorizer to remove trace impurities dissolved in the 3-morpholinepropanesulfonic acid clear solution to obtain a refined 3-morpholinepropanesulfonic acid solution; (f) adding 800 g of methanol to the crystallization kettle, and then adding the refined 3-morpholinepropanesulfonic acid solution to a crystallizer for crystallization purification, separating the crystals, drying and packaging to obtain 3-morpholinepropanesulfonic acid.

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