阅读说明：本技术 氨己烯酸及其制备方法 (Vigabatrin and preparation method thereof ) 是由 朱毅 田俊锋 黄赟 李雷 杨波 于 2019-10-25 设计创作，主要内容包括：本发明提出了氨己烯酸及其制备方法,所述制备方法包括：使3-甲酰胺基-5-乙烯基-2-吡咯烷酮在浓盐酸和乙酸中反应,以便得到含有氨己烯酸的反应液；将含有氨己烯酸的反应液进行纯化处理；其中,纯化处理包括：将含有氨己烯酸的反应液进行浓缩处理,以便得到浓缩液；采用溶剂对浓缩液进行结晶处理,以便使得氨己烯酸析晶,离心,收集结晶固体；对结晶固体进行洗涤；其中,溶剂具有式(1)所示的结构,R-1和R-2分别独立地选自氢或C-(1～4)烷基；溶剂与3-甲酰胺基-5-乙烯基-2-吡咯烷酮的质量比为(4～7)：1。本发明的制备方法操作简便、快捷、收率高、纯度高、废水排放量小,适于规模化生产。(The invention provides vigabatrin and a preparation method thereof, wherein the preparation method comprises the following steps: reacting 3-formamido-5-vinyl-2-pyrrolidone in concentrated hydrochloric acid and acetic acid to obtain a reaction solution containing vigabatrin; purifying the reaction solution containing the vigabatrin; wherein, the purification treatment comprises: concentrating the reaction solution containing the vigabatrin so as to obtain a concentrated solution; crystallizing the concentrated solution by using a solvent so as to crystallize the vigabatrin, centrifuging and collecting a crystallized solid; washing the crystalline solid; wherein the solvent has a structure represented by the formula (1), R 1 And R 2 Each independently selected from hydrogen or C 1～4 An alkyl group; solvent and 3-formamido-5-ethyleneThe mass ratio of the base-2-pyrrolidone is (4-7): 1. the preparation method has the advantages of simple and convenient operation, high yield, high purity and small wastewater discharge amount, and is suitable for large-scale production.)

1. A method for preparing vigabatrin, comprising:

(1) reacting 3-formamido-5-vinyl-2-pyrrolidone in concentrated hydrochloric acid and acetic acid to obtain a reaction solution containing vigabatrin;

(2) purifying the reaction solution containing the vigabatrin;

wherein the purification treatment comprises:

(2-1) concentrating the reaction solution containing vigabatrin to obtain a concentrated solution;

(2-2) crystallizing the concentrated solution by using a solvent so as to crystallize the vigabatrin, centrifuging and collecting a crystallized solid;

(2-3) subjecting the crystallized solid to a washing treatment;

wherein the solvent has a structure represented by formula (1), R₁And R₂Each independently selected from hydrogen or C_1～4An alkyl group;

the mass ratio of the solvent to the 3-formamido-5-vinyl-2-pyrrolidone is (4-7): 1.

2. the process according to claim 1, wherein the solvent is selected from at least one of DMF and formamide, preferably DMF.

3. The method according to claim 1, wherein the mass ratio of the concentrated solution to the 3-formamido-5-vinyl-2-pyrrolidone is (2-3): 1.

4. the method of claim 1, wherein step (2-1) comprises:

carrying out low-pressure concentration treatment on the reaction liquid containing the vigabatrin so as to obtain a concentrated primary liquid;

mixing the concentrated primary solution with water, adding ammonia water into the obtained mixed solution until the pH value of the mixed solution is 6.8-7.2, adding activated carbon into the mixed solution, mixing, performing suction filtration on the obtained mixed solution, and collecting filtrate;

carrying out low-pressure concentration treatment on the filtrate so as to obtain a concentrated solution;

optionally, the low-pressure concentration treatment is carried out at a temperature of 55-95 ℃, preferably 65-75 ℃ and a vacuum degree of not less than 0.08 MPa.

5. The method of claim 1, wherein step (2-2) comprises:

dropwise adding the concentrated solution into a solvent at the temperature of 20-45 ℃ in a stirring state, then cooling to 0-20 ℃, standing for crystallization, centrifuging, and collecting a crystalline solid;

preferably, the concentrated solution is dripped into a solvent with the temperature of 20-30 ℃ in a stirring state, then the temperature is reduced to 0-10 ℃, standing is performed for crystallization, centrifugation is performed, and crystalline solids are collected.

6. The method according to claim 5, wherein the dropping is performed at a rate of 0.5 to 2.5 kg/min.

7. The method of claim 1, wherein step (2-3) comprises:

washing the crystalline solid with a detergent, centrifuging, collecting the precipitate and drying;

wherein the detergent is selected from alcohol, ketone or alkane containing 1-6 carbon atoms, preferably at least one of absolute ethyl alcohol, dichloromethane, acetone, methanol and isopropanol, and more preferably the absolute ethyl alcohol.

8. The method of claim 5, wherein step (2-2) further comprises:

repeating the following operations at least once: dissolving the crystalline solid with water, dropwise adding the obtained dissolved solution into a solvent with a stirring state and a temperature of 20-45 ℃, then cooling to 0-20 ℃, standing for crystallization, centrifuging, and collecting the crystalline solid.

9. The method according to claim 8, wherein the solvent is added in an amount of 2 to 6 times the mass of the crystalline solid.

10. A vigabatrin product, characterized in that it is prepared by the method of any one of claims 1 to 9.

Technical Field

The present invention relates to the field of medicine. In particular, the invention relates to vigabatrin and a method for preparing vigabatrin by using the vigabatrin.

Background

Vigabatrin (Vigabatinn) has chemical name of 4-amino-5-hexenoic acid and molecular formula of C₆H₁₁NO₂Molecular weight 129.157, an analog of gamma-aminobutyric acid (GABA), binds specifically to GABA aminotransferase and is irreversible, resulting in increased brain GABA concentrations and thus, antiepileptic effects. Vigabatrin as an adjunctive therapy may be used to treat patients who are otherwise inefficacious with other antiepileptic drugs, particularly patients with partial seizures (primarily to control complex partial seizures), and also infants with wester (West) syndrome (infantile spasms). As an adjuvant treatment medicine, vigabatrin can obtain better curative effect. When applied alone, are effective in treating newly diagnosed patients.

The following methods are currently used for the production of 4-amino-5-hexenoic acid on an industrial scale: 1, 4-dichloro-2-butene reacts with diethyl malonate under alkaline conditions to generate 2-vinylcyclopropane-1, 1-diethyl dicarboxylate. The 2-vinylcyclopropane-1, 1-diethyldicarboxylate is then reacted with ammonia under pressure to form 3-carboxamido-5-vinyl-2-pyrrolidone, which is further hydrolyzed under acidic conditions to form 4-amino-5-hexenoic acid. However, this method is hindered by several industrial disadvantages, especially the last step of desalting requires passing through an ion column, eluting with 2M ammonia water, and removing water with a nanofiltration membrane, and has the disadvantages of low yield, high cost, and large discharge of wastewater.

Therefore, how to obtain a method for preparing 4-amino-5-hexenoic acid with high yield, high purity and small wastewater discharge is a technical bottleneck to be solved urgently in the field.

Disclosure of Invention

The present invention aims to solve at least to some extent at least one of the technical problems of the prior art. Therefore, the invention provides a method for preparing vigabatrin, which is simple and convenient to operate, high in yield, high in purity, small in wastewater discharge amount and suitable for large-scale production, and is fast and convenient to operate.

The inventor finds that the 3-formamido-5-vinyl-2-pyrrolidone is used as a reactant to synthesize the vigabatrin in one step, so that the preparation time is greatly shortened, and the process flow is simplified. Moreover, the inventor conducts research and analysis on the physicochemical properties of the components in the synthesized product, and finds that the vigabatrin in the synthesized product can be separated out by adopting a crystallization treatment mode, so that the aim of effectively removing impurities is fulfilled. Further, the inventors have conducted an optimized screening of a solvent used for crystallization, and found that the use of a solvent having an amide group can improve the crystallization efficiency of vigabatrin. Meanwhile, the inventors found that the mass ratio of the solvent to the reactant (3-carboxamido-5-vinyl-2-pyrrolidone) also significantly affects the crystallization efficiency. Further, the inventors have conducted extensive studies to obtain an optimum mass ratio, whereby the final product has high yield of vigabatrin, high purity and less impurities. In addition, the preparation process is simple, convenient and quick to operate, has small wastewater discharge amount, and is suitable for large-scale production.

To this end, in one aspect of the invention, the invention proposes a method for preparing vigabatrin. According to an embodiment of the invention, the method comprises: (1) reacting 3-formamido-5-vinyl-2-pyrrolidone in concentrated hydrochloric acid and acetic acid to obtain a reaction solution containing vigabatrin; (2) purifying the reaction solution containing the vigabatrin; wherein the purification treatment comprises: (2-1) concentrating the reaction solution containing vigabatrin to obtain a concentrated solution; (2-2) crystallizing the concentrated solution by using a solvent so as to crystallize the vigabatrin, centrifuging and collecting a crystallized solid; (2-3) subjecting the crystallized solid to a washing treatment; wherein the solvent has a structure represented by formula (1), R₁And R₂Each independently selected from hydrogen or C_1～4An alkyl group; the mass ratio of the solvent to the 3-formamido-5-vinyl-2-pyrrolidone is (4-7): 1.

the invention takes 3-formamido-5-vinyl-2-pyrrolidone as a reactant, can synthesize the vigabatrin in one step, greatly shortens the preparation time and simplifies the process flow. Moreover, the inventor conducts research and analysis on the physicochemical properties of the components in the synthesized product, and finds that the vigabatrin in the synthesized product can be crystallized by adopting a crystallization treatment mode, so that the aim of effectively removing impurities is fulfilled. Further, the compound shown in the formula (1) is finally determined to be the optimal crystallization solvent, and the crystallization efficiency of the vigabatrin in the solvent is higher. Meanwhile, the inventors found that the mass ratio of the solvent to the reactant (3-carboxamido-5-vinyl-2-pyrrolidone) also significantly affects the crystallization efficiency. Further, the inventors have conducted extensive studies to obtain an optimum mass ratio, whereby the final product has high yield of vigabatrin, high purity and less impurities. In addition, the preparation process is simple, convenient and quick to operate, has small wastewater discharge amount, and is suitable for large-scale production.

According to an embodiment of the present invention, the method for preparing vigabatrin may further have the following additional technical features:

according to an embodiment of the invention, the solvent is selected from at least one of DMF and formamide, preferably DMF.

According to the embodiment of the invention, the mass ratio of the concentrated solution to the 3-formamido-5-vinyl-2-pyrrolidone is (2-3): 1.

according to an embodiment of the present invention, the step (2-1) includes: carrying out low-pressure concentration treatment on the reaction liquid containing the vigabatrin so as to obtain a concentrated primary liquid; mixing the concentrated primary solution with water, adding ammonia water into the obtained mixed solution until the pH value of the mixed solution is 6.8-7.2, adding activated carbon into the mixed solution, mixing, performing suction filtration on the obtained mixed solution, and collecting filtrate; and carrying out low-pressure concentration treatment on the filtrate so as to obtain the concentrated solution.

According to the embodiment of the invention, the low-pressure concentration treatment adopts the temperature of 55-95 ℃, preferably 65-75 ℃ and the vacuum degree of not less than 0.08 MPa.

According to an embodiment of the present invention, the step (2-2) includes: and dropwise adding the concentrated solution into a solvent at the temperature of 20-45 ℃ in a stirring state, then cooling to 0-20 ℃, standing for crystallization, centrifuging, and collecting a crystalline solid.

According to an embodiment of the present invention, the step (2-2) includes: and dropwise adding the concentrated solution into a solvent at 20-30 ℃ in a stirring state, then cooling to 0-10 ℃, standing for crystallization, centrifuging, and collecting a crystalline solid.

According to the embodiment of the invention, the dropping speed is 0.5-2.5 kg/min.

According to an embodiment of the present invention, the step (2-3) includes: washing the crystalline solid with a detergent, centrifuging, collecting the precipitate and drying; wherein the detergent is selected from alcohol, ketone or alkane containing 1-6 carbon atoms, preferably at least one of absolute ethyl alcohol, dichloromethane, acetone, methanol and isopropanol, and more preferably the absolute ethyl alcohol.

According to an embodiment of the present invention, the step (2-2) further includes: repeating the following operations at least once: dissolving the crystalline solid with water, dropwise adding the obtained dissolved solution into a solvent with a stirring state and a temperature of 20-45 ℃, then cooling to 0-20 ℃, standing for crystallization, centrifuging, and collecting the crystalline solid.

According to the embodiment of the invention, the addition amount of the solvent is 2-6 times of the mass of the crystalline solid.

In another aspect of the invention, the invention provides a vigabatrin product. According to the embodiment of the invention, the vigabatrin product is prepared by the method for preparing vigabatrin, which is described in the foregoing. As mentioned above, the vigabatrin product according to the embodiment of the invention has high purity and less impurities, and is suitable for wide application.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

fig. 1 shows a schematic flow diagram of a method for preparing vigabatrin according to one embodiment of the present invention;

figure 2 shows a schematic flow diagram of a purification process according to one embodiment of the present invention.

Detailed Description

The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.

It should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Further, in the description of the present invention, "a plurality" means two or more unless otherwise specified.

Method for preparing vigabatrin

Fig. 1 shows a schematic flow diagram of the method for preparing vigabatrin according to the invention, and the preparation method of the invention has the advantages of simple and convenient operation, rapidness, high yield, high purity, small wastewater discharge amount and suitability for large-scale production. Each step will be described in detail below.

According to an embodiment of the present invention, referring to fig. 1, the method for preparing vigabatrin comprises:

s100 reaction step

In this example, 3-carboxamido-5-vinyl-2-pyrrolidone was reacted in concentrated hydrochloric acid and acetic acid to obtain a reaction solution containing vigabatrin. The inventor finds that the 3-formamido-5-vinyl-2-pyrrolidone is used as a reactant, the vigabatrin can be synthesized in one step, the preparation time is greatly shortened, and the process flow is simplified. In addition, the side product and the vigabatrin in the synthesized product can be separated in a crystallization mode without adopting a chromatographic column or a filter membrane for treatment, so that the yield and the purity of the vigabatrin in the final product are improved, the impurity content is reduced, and the generation of waste water is reduced.

S200 purification step

In this step, the reaction solution containing vigabatrin was subjected to purification treatment. Therefore, the purpose of removing impurities is achieved, and the content (purity) of the target object in the product is ensured. According to an embodiment of the present invention, referring to fig. 2, the purification process S200 includes the steps of:

s210 concentration treatment

In this step, the reaction solution containing vigabatrin was subjected to a concentration treatment to obtain a concentrated solution. By concentrating the reaction solution, on one hand, acidic substances in the reaction solution can be effectively removed, on the other hand, the reaction solution can reach a saturated state or a state close to the saturated state, so that the subsequent crystallization is convenient, the vigabatrin is quickly and fully recrystallized from the reaction solution, and the aim of effective separation is fulfilled.

According to an embodiment of the invention, the concentration process comprises: carrying out low-pressure concentration treatment on the reaction liquid containing the vigabatrin so as to obtain concentrated primary liquid; mixing the concentrated primary solution with water, adding ammonia water into the obtained mixed solution until the pH value of the mixed solution is 6.8-7.2, adding activated carbon into the mixed solution, mixing, performing suction filtration on the obtained mixed solution, and collecting filtrate; the filtrate was subjected to low-pressure concentration treatment to obtain a concentrated solution. Firstly, the reaction solution is concentrated under low pressure to achieve the purpose of primary concentration, and acidic substances can be removed. Then, adding ammonia water into the mixed solution until the pH value of the system is close to neutral, neutralizing the unremoved acidic substances to form ammonium salts, facilitating subsequent crystallization, and using the activated carbon for adsorbing colored impurities to achieve the purpose of impurity removal. And finally, carrying out low-pressure concentration treatment to enable the system to reach a saturated state or a state close to the saturated state, so as to facilitate subsequent crystallization.

According to the embodiment of the invention, the low-pressure concentration treatment is carried out at a temperature of 55-95 ℃, preferably 65-75 ℃, such as 65, 68 ℃, 72 ℃, 75 ℃ and a vacuum degree of not less than 0.08 MPa. Therefore, the concentrated solution can be quickly obtained, and the subsequent crystallization is convenient. At the same time, the formation of impurities can be avoided. If the temperature is too low, the concentration time is too long; if the temperature is too high, the impurity content increases.

S220 crystallization treatment

In this step, the concentrated solution is crystallized with a solvent to crystallize vigabatrin, centrifuged, and the crystalline solid is collected. In the chemical industry, although crystallization technology is a mature technology, the difficulty is high, crystallization is difficult to separate out, and the target crystal is obtained, especially for the selection of a crystallization solvent, which is a decisive factor for whether the target substance can separate out and can be separated from byproducts. The organic solvents which are disclosed at present are numerous, the compounding relation is numerous and numerous, and the inventor finds that the crystallization efficiency of the vigabatrin in the solvent with the amide group is higher based on a large amount of theoretical analysis and experimental screening optimization on the disclosed organic solvents, so that the vigabatrin in the final product has high yield, high purity and less impurities.

According to an embodiment of the present invention, the solvent has a structure represented by formula (1), R₁And R₂Each independently selected from hydrogen or C_1～4An alkyl group. According to a preferred embodiment of the present invention, the solvent is selected from at least one of DMF and formamide. Experiments show that compared with other organic solvents, DMF and/or formamide has a good crystallization effect, vigabatrin products with high purity and yield can be effectively obtained, and waste water generation is reduced. Among them, DMF is more effective.

According to the embodiment of the invention, the mass ratio of the solvent to the 3-formamido-5-vinyl-2-pyrrolidone is (4-7): 1, for example, can be 4: 1. 5.5: 1. 6.2: 1. 6.8: 1 and 7: 1. the inventor obtains the better proportion through a large number of experiments, so that the synthesized vigabatrin can be fully separated out, the yield and the purity are improved, the difficulty in removing the solvent subsequently is reduced, and the discharge amount of wastewater is reduced.

According to the embodiment of the invention, the mass ratio of the concentrated solution to the 3-formamido-5-vinyl-2-pyrrolidone is (2-2.5): 1, for example, may be 2: 1. 2.1: 1. 2.2: 1. 2.3: 1. 2.4: 1. 2.5: 1. the inventor obtains the better proportioning through a large amount of experiments, thereby further improving the yield and the purity of the vigabatrin in the final product.

According to an embodiment of the present invention, step S220 includes: and dropwise adding the concentrated solution into a solvent at the temperature of 20-45 ℃ in a stirring state, then cooling to 0-20 ℃, standing for crystallization, centrifuging, and collecting a crystalline solid. According to a preferred embodiment of the present invention, step S220 includes: and dropwise adding the concentrated solution into a solvent at 20-30 ℃ in a stirring state, then cooling to 0-10 ℃, standing for crystallization, centrifuging, and collecting a crystalline solid. The inventor obtains the crystallization temperature through a large number of experiments, and the obtained final product has high content of the hexenoic acid and good crystallization effect at the temperature.

According to an embodiment of the present invention, the dropping rate is 0.5 to 2.5kg/min, for example, 0.5kg/min, 1kg/min, 1.5kg/min, 2kg/min and 2.5 kg/min. Therefore, the vigabatrin product with higher purity can be obtained, and if the dropping speed is too high or too low, the product purity can be affected.

According to an embodiment of the present invention, step S220 further includes: repeating the following operations at least once: dissolving the crystalline solid with water, dropwise adding the obtained dissolved solution into a solvent with a stirring state and a temperature of 20-45 ℃, then cooling to 0-20 ℃, standing for crystallization, centrifuging, and collecting the crystalline solid. By performing the above operations several times, the yield and purity of vigabatrin can be further improved.

According to embodiments of the present invention, the solvent is added in an amount of 2 to 6 times, for example, 3 times, 4 times, 5 times, or 6 times the mass of the crystalline solid. Therefore, the purification efficiency can be improved, and the yield and the purity of the vigabatrin in the final product are improved.

S230 washing treatment

In this step, the crystalline solid is subjected to a washing treatment. Thereby removing impurities and solvent remaining on the surface of the crystalline solid.

According to an embodiment of the present invention, step S230 includes: washing the crystallized solid with a detergent, centrifuging, collecting the precipitate, and drying; wherein the detergent is selected from alcohol, ketone or alkane containing 1-6 carbon atoms, preferably at least one of absolute ethyl alcohol, dichloromethane, acetone, methanol and isopropanol, and more preferably absolute ethyl alcohol. The solvent can be dissolved in the detergent, so that the effect of removing the solvent can be achieved, impurities can be further washed, the product purity is improved, and the effect of the absolute ethyl alcohol is the best.

It should be noted that the "discharge amount of wastewater" described in the present invention mainly refers to the mass of liquid removed by centrifugation during S220 crystallization. The method for preparing the vigabatrin reduces the addition of a crystallization solvent, generates less impurities, and reduces the washing times and the washing amount of a detergent, thereby reducing the discharge amount of wastewater on the whole.

Vigabatrin product

In another aspect of the invention, the invention provides a vigabatrin product. According to the examples of the present invention, the vigabatrin product was prepared by the method for preparing vigabatrin described above. As mentioned above, the vigabatrin product according to the embodiment of the invention has high purity and less impurities, and is suitable for wide application.

It will be understood by those skilled in the art that the features and advantages described above for the method of preparing vigabatrin are equally applicable to the vigabatrin product and will not be described in detail here.

The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

Example 1

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 25 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 5 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 82.1%, the vigabatrin content is 99.13%, and the wastewater discharge amount is as follows: about 11.2kg of wastewater was generated per 1kg of vigabatrin produced.

Example 2

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 70 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated solution; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 65 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 30 Kg;

3) and (3) crystallization treatment: pumping 60kg of DMF into a reaction kettle, starting stirring, and maintaining the temperature at 20 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.6kg/min, continuously stirring for 1.5h after the dropwise adding is finished, cooling to 5 ℃, continuously stirring for 1.5h, stopping stirring, and standing for crystallization for 9 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, and drying to obtain the vigabatrin, wherein the yield is 80.4%, the vigabatrin content is 98.97%, and the wastewater discharge amount is as follows: about 7.91kg of wastewater is generated for every 1kg of vigabatrin produced.

Example 3

1) The reaction steps are as follows: 150L of concentrated hydrochloric acid and 75L of acetic acid are pumped into a hydrolysis reaction kettle, and stirring is started; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 75 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 37.5 Kg;

3) and (3) crystallization treatment: adding 90kg of formamide into a reaction kettle, starting stirring, and maintaining the temperature at 30 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 1kg/min, continuously stirring for 2 hours after the dropwise adding is finished, cooling to 0 ℃, continuously stirring for 2 hours, stopping stirring, and standing for crystallization for 10 hours; centrifuging to obtain solid (wet product).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, and drying to obtain the vigabatrin, wherein the yield is 81.7%, the vigabatrin content is 98.72%, and the wastewater discharge amount is as follows: about 11.4kg of wastewater was generated per 1kg of vigabatrin produced.

Example 4

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 95 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 45 Kg;

3) and (3) crystallization treatment: pumping 105kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 25 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 2.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 10 ℃, continuously stirring for 1.5h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using anhydrous isopropanol; centrifuging, washing with a proper amount of anhydrous isopropanol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 82.0%, the vigabatrin content is 98.62%, and the wastewater discharge amount is as follows: about 13.6kg of wastewater was generated per 1kg of vigabatrin produced.

Example 5

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 80.2%, the vigabatrin content is 96.59%, and the wastewater discharge amount is as follows: about 11.5kg of wastewater was generated per 1kg of vigabatrin produced.

Example 6

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 35 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 81.9%, the vigabatrin content is 97.71%, and the wastewater discharge amount is as follows: about 11.2kg of wastewater was generated per 1kg of vigabatrin produced.

Example 7

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using acetone; centrifuging, washing with an appropriate amount of acetone, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 82.2%, the vigabatrin content is 96.91%, and the wastewater discharge amount is as follows: about 11.2kg of wastewater was generated per 1kg of vigabatrin produced.

Example 8

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kg of acetone into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 46.7%, the vigabatrin content is 88.20%, and the wastewater discharge amount is as follows: the discharge amount of waste water generated by producing 1kg of vigabatrin is about 20.5 kg.

The results show that the purity of the vigabatrin is lowered by changing the solvent for crystallization treatment in step 3) to acetone, which may cause the vigabatrin to be not crystallized and separated out sufficiently in the acetone, the vigabatrin is separated out together with the ammonium salt in the crystallization process, and a small amount of impurities are also crystallized and separated out in the acetone, so that the amount of impurities is increased, and simultaneously, acetone residue exists and the discharge amount of wastewater is increased.

Example 9

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kg of isopropanol into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 50.0%, the vigabatrin content is 85.17%, and the wastewater discharge amount is as follows: the discharge amount of waste water generated by producing 1kg of vigabatrin is about 19.1 kg.

The results show that when the crystallization treatment solvent in the step 3) is changed to isopropanol, the purity of the vigabatrin is lowered, which may be caused by that the vigabatrin cannot be sufficiently crystallized and separated out in the isopropanol, an ammonium salt is separated out together in the crystallization process, and a small amount of impurities are also crystallized and separated out in the isopropanol, so that the amount of impurities is increased, isopropanol residue exists, and the discharge amount of wastewater is increased.

Example 10

Loading 30kg of I.R.120 ionic resin into a column with the diameter of 30cm and the height of 150cm, washing the resin with 60kg of 0.1mol/L dilute hydrochloric acid, washing the resin with 60kg of purified water, taking 6kg of the concentrated solution obtained in the step 2) of the example 1, adding the concentrated solution into an ionic column, washing the resin with 100kg of 0.1mol/L dilute ammonia water, collecting eluent, removing water with a nanofiltration membrane to obtain about 1kg of desalted concentrate, adding 20L of ethanol, stirring, crystallizing, centrifuging and drying to obtain vigabatrin, wherein the yield is 47.8%, the content is 84.68%, and the discharge amount of wastewater: the amount of wastewater generated per 1kg of vigabatrin produced was about 220 kg.

The results show that the purification by resin chromatography causes severe loss of vigabatrin, resulting in low purity vigabatrin in the final product. And the discharge amount of waste water is also obviously higher.

Example 11

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 45kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 76.2%, the vigabatrin content is 92.61%, and the wastewater discharge amount is as follows: about 7.46kg of wastewater is generated for every 1kg of vigabatrin produced.

The results show that the addition amount of DMF is too small, which results in low vigabatrin yield and low purity, and probably because the addition amount of DMF is too small, vigabatrin cannot be completely crystallized and separated out, which results in low vigabatrin yield, incomplete crystallization and much salt residue.

Example 12

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 120kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 83.5%, the vigabatrin content is 91.39%, and the wastewater discharge amount is as follows: about 14.8kg of wastewater was generated per 1kg of vigabatrin produced.

The results showed that excessive addition of DMF resulted in low vigabated vigabate yield and low purity, possibly due to vigabate remaining in excess DMF, and that solvent residue resulted in low purity and increased wastewater discharge.

Example 13

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 27 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 87.3%, the vigabatrin content is 94.14%, and the wastewater discharge amount is as follows: about 9.68kg of wastewater is generated for every 1kg of vigabatrin produced.

The results show that too little concentrate results in a higher impurity content, probably due to too long a concentration time.

Example 14

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 48 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 78.6%, the vigabatrin content is 93.58%, and the wastewater discharge amount is as follows: about 13.0kg of wastewater was generated per 1kg of vigabatrin produced.

The results show that the excessive amount of the concentrated solution causes the lower content of the vigabatrin, probably caused by the precipitation of excessive ammonium salt in the crystallization process.

Example 15

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 0.4kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 82.2%, the vigabatrin content is 94.67%, and the wastewater discharge amount is as follows: about 11.2kg of wastewater was generated per 1kg of vigabatrin produced.

The results show that the dropping speed of the concentrated solution is too slow, which results in lower purity of the vigabatrin.

Example 16

1) The reaction steps are as follows: adding 150L of concentrated hydrochloric acid and 75L of acetic acid into a hydrolysis reaction kettle, and starting stirring; adding 15kg of 3-formamido-5-vinyl-2-pyrrolidone into a hydrolysis reaction kettle; heating to reflux, and carrying out reflux reaction at the temperature of 100 ℃ and 110 ℃ for 8-10h to finish the reaction;

2) concentration treatment: cooling the reaction liquid obtained in the step 1) to 65 ℃, and concentrating under reduced pressure (the vacuum degree is not lower than 0.08MPa) to obtain a concentrated liquid; adding 15Kg of purified water into the concentrated solution, adding ammonia water to adjust the pH value of the reaction solution to 7, adding activated carbon, and decolorizing; performing suction filtration, washing a filter cake with 7.5Kg of purified water, combining filtrates, transferring to a concentration kettle, heating to 70 ℃, keeping the vacuum degree not lower than 0.08MPa, and concentrating under reduced pressure until the weight of a concentrated solution is 36 Kg;

3) and (3) crystallization treatment: pumping 90kgDMF into a reaction kettle, starting stirring, and maintaining the temperature at 45 ℃; dropwise adding the concentrated solution obtained in the step 2) into the reaction kettle, controlling the dropwise adding speed to be 2.8kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 20 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

4) Washing treatment: soaking the solid (wet product) obtained in the step 3) for more than 1h by using absolute ethyl alcohol; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, taking out a filter cake, and drying to obtain the vigabatrin, wherein the yield is 82.7%, the vigabatrin content is 93.51%, and the wastewater discharge amount is as follows: about 11.2kg of wastewater was generated per 1kg of vigabatrin produced.

The results show that the dropping speed of the concentrated solution is too fast, which results in lower purity of the vigabatrin.

Example 17

4) Adding 22.5kg of purified water to the solid (wet product) obtained in the step 3) of the example 1 to dissolve the solid to obtain an aqueous solution for later use; pumping 67.5kg of DMF into a refining kettle, starting stirring, and maintaining the temperature at 25 ℃; dropwise adding the aqueous solution into the refining kettle, controlling the dropwise adding speed at 2kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 5 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

5) Pumping DMF (dimethyl formamide) with the weight of 4 times of the wet product into a refining kettle, starting stirring, maintaining the temperature at 25 ℃, adding purified water with the weight of 1.25 times of the wet product into the solid (wet product) obtained in the step 4) to dissolve the solid (wet product), keeping the temperature of a dissolving solution at 25 ℃, dropwise adding the dissolving solution into the refining kettle, controlling the dropwise adding speed at 2kg/min, continuously stirring for 1 hour after dropwise adding, cooling to 5 ℃, continuously stirring for 1 hour, stopping stirring, standing for crystallization for 8 hours, and centrifuging;

soaking in anhydrous ethanol for more than 1 h; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, and drying to obtain the vigabatrin, wherein the yield is 67.4%, the content is 99.83%, and the wastewater discharge amount is as follows: about 30.5kg of wastewater is generated for every 1kg of vigabatrin produced.

Example 18

4) Adding 22.5kg of purified water to the solid (wet product) obtained in the step 3) of the example 1 to dissolve the solid to obtain an aqueous solution for later use; pumping 60kg of DMF into a refining kettle, starting stirring, and maintaining the temperature at 25 ℃; dropwise adding the aqueous solution into the refining kettle, controlling the dropwise adding speed at 1.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 5 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

5) Pumping DMF (dimethyl formamide) with the weight of 3 times of the wet product into a refining kettle, starting stirring, maintaining the temperature at 25 ℃, adding purified water with the weight of 1.25 times of the wet product into the solid (wet product) obtained in the step 4) to dissolve the solid (wet product), keeping the temperature of a dissolving solution at 25 ℃, dropwise adding the dissolving solution into the refining kettle, controlling the dropwise adding speed at 1.5kg/min, continuously stirring for 1 hour after dropwise adding, cooling to 5 ℃, continuously stirring for 1 hour, stopping stirring, standing for 8 hours for crystallization, and centrifuging;

soaking in anhydrous ethanol for more than 1 h; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, and drying to obtain the vigabatrin, wherein the yield is 66.9%, the vigabatrin content is 99.75%, and the wastewater discharge amount is as follows: about 28.7kg of wastewater was generated per 1kg of vigabatrin produced.

Example 19

4) Adding 22.5kg of purified water to the solid (wet product) obtained in the step 3) of the example 1 to dissolve the solid to obtain an aqueous solution for later use; pumping 75kg of DMF into a refining kettle, starting stirring, and maintaining the temperature at 25 ℃; dropwise adding the aqueous solution into the refining kettle, controlling the dropwise adding speed at 2.5kg/min, continuously stirring for 1h after the dropwise adding is finished, cooling to 5 ℃, continuously stirring for 1h, stopping stirring, and standing for crystallization for 8 h; centrifugation gave a solid (wet).

5) Pumping DMF (dimethyl formamide) with the weight 5 times that of the wet product into a refining kettle, starting stirring, maintaining the temperature at 25 ℃, adding purified water with the weight 1.25 times that of the wet product into the solid (wet product) obtained in the step 4) to dissolve the solid (wet product), keeping the temperature of a dissolving solution at 25 ℃, dropwise adding the dissolving solution into the refining kettle, controlling the dropwise adding speed at 2.5kg/min, continuously stirring for 1 hour after dropwise adding, cooling to 5 ℃, continuously stirring for 1 hour, stopping stirring, standing for crystallization for 8 hours, and centrifuging;

soaking in anhydrous ethanol for more than 1 h; centrifuging, washing with a proper amount of absolute ethyl alcohol, centrifuging until almost no liquid drops drip out, and drying to obtain the vigabatrin, wherein the yield is 66.5%, the vigabatrin content is 99.79%, and the wastewater discharge amount is as follows: about 32.5kg of wastewater is generated for every 1kg of vigabatrin produced.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.