CN114213305A - Production process of brivaracetam - Google Patents
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- CN114213305A CN114213305A CN202111646999.3A CN202111646999A CN114213305A CN 114213305 A CN114213305 A CN 114213305A CN 202111646999 A CN202111646999 A CN 202111646999A CN 114213305 A CN114213305 A CN 114213305A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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Abstract
The application relates to the technical field of drug synthesis, and particularly discloses a production process of brivaracetam. The production process of the brivaracetam comprises a synthesis stage and a purification stage, wherein the synthesis stage comprises the following steps: in an anhydrous environment protected by inert atmosphere, carrying out condensation reaction on a compound I and porous L-2-aminobutanamide in an organic solvent to obtain a reaction solution containing a crude product of the Buvaracetam, wherein the porous L-2-aminobutanamide is a compound of the L-2-aminobutanamide and a porous matrix. The porous L-2-aminobutanamide can adsorb the compound I, so that the generation rate of the brivaracetam is accelerated, the time consumption of a synthesis stage is shortened, and the efficiency of producing the brivaracetam product is improved.
Description
Technical Field
The application relates to the technical field of drug synthesis, in particular to a production process of brivaracetam.
Background
The brivaracetam is a sitcomycin derivative, is an antiepileptic drug with small side effect, and plays a great role in treating epilepsy. The synthesis methods of the brivaracetam are various, but in the traditional brivaracetam synthesis method, the production efficiency and the product purity are difficult to be improved simultaneously.
Chinese patent with publication number CN106588741B discloses a preparation method of brivaracetam, which comprises the following steps: (1) dissolving 4.8mol of compound I in 2.5L of dichloromethane solution, then adding the solution into 12.5L of dichloromethane solution containing 4.2mol of L-2-aminobutanamide hydrochloride, 500g of 4A molecular sieve, 500g of potassium hydroxide, 500g of anhydrous sodium sulfate and 49g of tetrabutylammonium bromide, stirring the reaction solution at 20-30 ℃ for 18 hours, then adding diatomite for filtration, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain a crude product of the Buvalsartan; (2) using ethyl acetate and isopropanol as a 90: 10, pulping and filtering the crude product of the brivaracetam, and recrystallizing to obtain the brivaracetam, wherein the chemical formula of the compound I is as follows:
in view of the above-mentioned related technologies, the inventors believe that, although the purification of the product of the invention is performed by pulping and recrystallization, the product purity is increased, but the production rate of the product of the.
Disclosure of Invention
In the related technology, the generation rate of the brivaracetam is slow, and the efficiency of producing brivaracetam products is influenced. In order to improve the defect, the application provides a production process of the brivaracetam.
The application provides a production process of brivaracetam, which adopts the following technical scheme:
a production process of the brivaracetam, which comprises a synthesis stage and a purification stage, wherein the synthesis stage comprises the following steps: in an anhydrous environment protected by an inert atmosphere, carrying out a condensation reaction on a compound I and porous L-2-aminobutanamide in an organic solvent to obtain a reaction solution containing a crude product of Buvaracetam, wherein the porous L-2-aminobutanamide is a compound of L-2-aminobutanamide and a porous matrix, and the reaction equation of the synthesis stage is shown as formula (1):
formula (1).
By adopting the technical scheme, compared with the related technology, the porous L-2-aminobutanamide generated by combining L-2-aminobutanamide and a porous matrix is used as a reactant to react with the compound I instead of using hydrochloride of the L-2-aminobutanamide to participate in the reaction, and the porous L-2-aminobutanamide can adsorb the compound I, so that the generation rate of the brivaracetam is accelerated, the time consumption in a synthesis stage is shortened, and the efficiency of producing the brivaracetam product is improved.
Preferably, the inert atmosphere in the synthesis stage is a carbon dioxide atmosphere or a nitrogen atmosphere.
By adopting the technical scheme, the inert atmosphere is preferably a carbon dioxide atmosphere or a nitrogen atmosphere, the rare gas atmosphere is removed, the cost of applying nitrogen and carbon dioxide is lower than that of applying rare gas, and carbon dioxide and nitrogen are relatively easy to obtain, so that the popularization of the production process of the Buvalsartan is facilitated.
Preferably, the porous L-2-aminobutanamide is prepared according to the following method:
(1) uniformly stirring L-2-aminobutanamide hydrochloride, an ethanol aqueous solution, a cementing agent and an adsorbent to obtain a mixed solution;
(2) adding a curing agent, a carbonate pore-forming agent and a foam stabilizer into the mixed solution, uniformly stirring, and then carrying out reduced pressure evaporation to obtain a mixed paste body;
(3) and (3) freeze-drying the mixed paste, and crushing to obtain the porous L-2-aminobutanamide.
By adopting the technical scheme, in the step (2) of preparing the porous L-2-aminobutanamide, the adsorbent adsorbs L-2-aminobutanamide hydrochloride, and simultaneously, the cementing agent is subjected to primary curing under the action of the curing agent. The carbonate pore-forming agent reacts with hydrogen chloride released by the L-2-aminobutanamide hydrochloride in the presence of water, carbon dioxide generated by the reaction generates air holes in the mixed paste, the foam stabilizer slows down the disappearance of the air holes, and the possibility that the carbon dioxide in the air holes leaves the mixed paste is reduced. In the step (3) for preparing the porous L-2-aminobutanamide, the water in the mixed paste is removed by freeze drying, the water in the mixed paste is firstly converted into ice crystals in the freeze drying process, then the ice crystals are sublimated and converted into water vapor, and the diffusion of the water vapor increases the density of air holes in the mixed paste. Under the condition of low temperature of freeze drying, the primary solidified product of the cementing agent takes the adsorbent as a core to agglomerate, and the mixed paste is converted into a compound of a porous matrix and L-2-aminobutanamide, so that the porous L-2-aminobutanamide is obtained.
When the inert atmosphere is carbon dioxide, the carbon dioxide leaving the mixed paste in the reaction process is mixed with the carbon dioxide atmosphere, and the purity of the carbon dioxide atmosphere is not influenced, so that the carbon dioxide atmosphere can be repeatedly used, and the cost for preparing the brivaracetam is reduced.
Preferably, the porous L-2-aminobutanamide is prepared from the following raw materials in parts by weight: 40-60 parts of L-2-aminobutanamide hydrochloride, 100-120 parts of ethanol aqueous solution, 8-12 parts of cementing agent, 6-10 parts of adsorbent, 2-3 parts of curing agent, 12-24 parts of carbonate pore-forming agent and 4-8 parts of foam stabilizer, wherein the cementing agent is water-soluble alginate.
By adopting the technical scheme, the porous L-2-aminobutanamide is prepared by taking L-2-aminobutanamide hydrochloride, ethanol water solution, cementing agent, adsorbent, curing agent and carbonate pore-forming agent as raw materials.
Preferably, the curing agent is calcium acetate or calcium chloride.
By adopting the technical scheme, both calcium acetate and calcium chloride can be used as curing agents of water-soluble alginate, wherein the calcium acetate can form gel after being mixed with ethanol. In the step (2) of preparing the porous L-2-aminobutanamide, the gel can increase the viscosity of the mixed paste, so that the diffusion of gas in the mixed paste is hindered, the pore content of the porous L-2-aminobutanamide is increased, and the generation rate of the Buvalsartan is accelerated.
Preferably, the adsorbent is diatomite or acid clay.
By adopting the technical scheme, the diatomite and the acid clay can both be used as the adsorbent, and the acid clay can react with a part of carbonate pore-forming agent besides being used as the adsorbent, so that the probability of communication between pores and the pore structure of the adsorbent is increased, the concentration of pore distribution in the porous L-2-aminobutanamide is increased, and the generation rate of the bravaracetam is accelerated.
Preferably, the carbonate pore-forming agent is sodium carbonate or calcium carbonate.
By adopting the technical scheme, both sodium carbonate and calcium carbonate can be used as carbonate pore-forming agents to react with hydrogen chloride to generate carbon dioxide, and calcium ions generated after the calcium carbonate reacts with the hydrogen chloride can also promote the solidification of water-soluble alginate, so that the viscosity of the mixed paste body in the step (2) of preparing the porous L-2-aminobutanamide is increased, the diffusion of gas in the mixed paste body is hindered, the pore content of the porous L-2-aminobutanamide is increased, and the generation rate of the porous L-2-aminobutanamide is accelerated.
Preferably, the foam stabilizer is gelatin enzymatic hydrolysate or cellulose enzymatic hydrolysate.
By adopting the technical scheme, both the cellulose enzymolysis liquid and the gelatin enzymolysis liquid can play a role in binding in the mixed paste, and free carboxyl in the gelatin enzymolysis liquid can be temporarily combined with amino in the L-2-aminobutanamide, so that the effect of protecting the amino is achieved, the oxidation loss of the amino in the reaction process is reduced, and the yield of the busacetam is improved.
Preferably, the purification stage comprises the steps of:
(1) uniformly mixing the reaction solution containing the crude product of the brivaracetam with water to obtain a mixed solution;
(2) cooling and crystallizing the mixed solution, and then filtering to remove liquid components to obtain mixed crystal grains;
(3) and dissolving the mixed crystal grains in water at room temperature to obtain refined liquid, recrystallizing the refined liquid, and filtering to obtain the brivaracetam.
By adopting the technical scheme, in the step (2) of the purification stage, the temperature is reduced for crystallization, so that the brivaracetam, the water and the salts in the mixed solution are crystallized, and the removed liquid components are mainly organic impurities. In the step (3) of the purification stage, the brivaracetam is separated from the salts in the refined solution by recrystallization, and the brivaracetam is finally obtained.
Preferably, the method comprises the following steps: in the step (2) of the purification stage, the temperature of the temperature reduction crystallization is-10 to-20 ℃.
By adopting the technical scheme, when the temperature of cooling crystallization is-10 to-20 ℃, the crystal form of the brivaracetam is more stable, and the purity of the brivaracetam product is favorably improved.
In summary, the present application has the following beneficial effects:
1. according to the application, a compound I and porous L-2-aminobutanamide are subjected to condensation reaction to prepare a crude product of the brivaracetam, the crude product of the brivaracetam is purified to obtain the brivaracetam, and the porous L-2-aminobutanamide can adsorb the compound I in the condensation reaction process, so that the generation rate of the brivaracetam is increased, the condensation reaction is accelerated, and the production efficiency of the brivaracetam product is improved.
2. In the application, the curing agent of the water-soluble alginate is preferably calcium acetate or calcium chloride, wherein the calcium acetate can form gel after meeting ethanol, so that the viscosity of the mixed paste is increased, the pore content of the porous L-2-aminobutanamide is increased, and the generation rate of the brivaracetam is accelerated.
3. According to the method, organic impurities are removed through a cooling crystallization mode to obtain mixed crystal grains, then the mixed crystal grains are dissolved, and the broomrape is extracted through a recrystallization mode.
Detailed Description
Preparation example of porous L-2-aminobutanamide
The starting materials used in the preparation examples of the present application are all commercially available, and preparation example 1 is described below as an example.
Preparation example 1
In this preparation example, porous L-2-aminobutanamide was prepared as follows:
(1) uniformly stirring 4kg of L-2-aminobutanamide hydrochloride, 10kg of ethanol aqueous solution with the ethanol mass fraction of 10%, 0.8kg of cementing agent and 0.6kg of adsorbent to obtain a mixed solution; in the step, the cementing agent is sodium alginate, and the adsorbent is diatomite;
(2) adding 0.2kg of curing agent, 1.2kg of carbonate pore-forming agent and 0.4kg of foam stabilizer into the mixed solution, uniformly stirring, and then carrying out reduced pressure evaporation to obtain a mixed paste; in the step, the curing agent is calcium chloride, the carbonate pore-forming agent is sodium carbonate, the foam stabilizer is cellulose hydrolysate, and the preparation method of the cellulose hydrolysate refers to Chinese patent with publication number of CN 101580860B;
(3) freeze-drying the mixed paste at-40 deg.C, and crushing to obtain porous L-2-aminobutanamide with average particle size of 860 μm.
As shown in Table 1, preparation examples 1 to 5 were different in the preparation examples of porous L-2-aminobutanamide.
TABLE 1
Preparation example 6
The difference between the preparation example and the preparation example 3 is that calcium acetate is used as the curing agent.
Preparation example 7
The difference between this preparation example and preparation example 6 is that acid clay was used as the adsorbent.
Preparation example 8
The difference between this preparation example and preparation example 7 is that calcium carbonate was used as the pore-forming agent, and calcium carbonate was in the form of powder having an average particle size of 140 μm.
Preparation example 9
The difference between the preparation example and the preparation example 8 is that the foam stabilizer is gelatin enzymolysis liquid, and the preparation method of the gelatin enzymolysis liquid refers to the Chinese patent with publication number CN 104206935B.
Examples
Examples 1 to 5
The starting materials used in the examples of the present application are all commercially available, and example 1 is described below.
Example 1
The production process of the brivaracetam in the embodiment 1 comprises a synthesis stage and a purification stage, and the production process of the brivaracetam comprises the following steps:
and (3) a synthesis stage:
(1) 2180g of compound I was dissolved in 4.5L of a dichloromethane solution under a nitrogen atmosphere to obtain a raw material solution A; (2) adding a raw material liquid B with a total volume of 45L into the raw material liquid A, wherein the raw material liquid B contains 800g of a water absorbing agent, 110g of a catalyst and 714g of porous L-2-aminobutanamide in terms of net L-2-aminobutanamide content, and the rest of the raw material liquid B is made up by dichloromethane;
(3) stirring the mixture of the raw material liquid A and the raw material liquid B at 25 ℃ for 5 hours, filtering, and concentrating the filtrate under reduced pressure to a dry state to obtain a reaction solution containing a crude product of the brivaracetam; in this stage, tetrabutylammonium bromide was used as a catalyst, anhydrous sodium sulfate was used as a water absorbent, and porous L-2-aminobutanamide was prepared according to preparation example 1;
and (3) a purification stage:
(1) uniformly mixing reaction liquid containing a crude product of the brivaracetam with water according to a volume ratio of 1:5 to obtain mixed liquid;
(2) cooling and crystallizing the mixed solution at-5 ℃, and filtering to remove liquid components to obtain mixed crystal grains after no new crystal is observed;
(3) and dissolving the mixed crystal grains in water at room temperature to obtain refined liquid, recrystallizing the refined liquid, and filtering to obtain the brivaracetam.
In the procedure for the production of brivaracetam of example 1, compound I has the following formula:
as shown in Table 2, examples 1 to 5 differ mainly in the time for stirring the mixture of starting material liquid A and starting material liquid B at 25 ℃ in the synthesis stage.
TABLE 2
Example 6
This example differs from example 5 in that the nitrogen atmosphere in the synthesis stage is replaced with a carbon dioxide atmosphere.
Example 7
This example is different from example 6 in that porous L-2-aminobutanamide was prepared from preparation example 2.
As shown in Table 3, examples 6 to 14 are different in the preparation examples of porous L-2-aminobutanamide.
TABLE 3
Example 15
This example is different from example 14 in that the temperature of the mixed solution is lowered to crystallize at-10 ℃ in step (2) of the purification stage.
As shown in Table 4, examples 14 to 18 differ in the temperature of the temperature-decreasing crystallization in step (2) of the purification stage.
TABLE 4
Comparative example
Comparative example 1
Refer to the bwaitam prepared in example 3 of chinese patent publication No. CN106588741B, wherein the reaction solution was stirred at 25 ℃ for 18 hours.
Comparative example 2
This comparative example differs from comparative example 1 in that the reaction solution was stirred at 25 ℃ for 9 h.
Comparative example 3
This comparative example differs from example 3 in that the porous L-2-aminobutanamide in the synthesis stage is replaced with 714g L-2-aminobutanamide.
Performance detection test method
And (3) detecting the yield:
and (3) calculating the theoretical product weight of the Buvalsartan production process according to the formula (1) and the fed amount, recording the theoretical product weight as M0, then weighing the actual product weight of the Buvalsartan production process, recording the actual product weight as M1, calculating the yield of Buvalsartan according to the formula (2), and calculating the yield, wherein the calculation result is shown in Table 5.
Formula (2)
TABLE 5
And (3) purity detection:
the purity of the resulting bravaracetam was measured using an APS-8026PLUS liquid chromatograph manufactured by Denational Ompus, and the results are shown in Table 6.
TABLE 6
| Sample(s) | Purity/% of bravaracetam |
| Example 14 | 99.31 |
| Example 15 | 99.42 |
| Example 16 | 99.46 |
| Example 17 | 99.39 |
| Example 18 | 99.34 |
| Comparative example 1 | 99.24 |
Combining examples 1-5 and comparative example 1 and table 5, it can be seen that the yield of the product of the.
Combining example 3, comparative example 1 and comparative example 2 and combining table 5, it can be seen that the yield of bwaitan decreases after shortening the reaction time in comparative example 1 from 18h to 9h, indicating that the rate of bwaitan formation according to the method of the present application is faster at the same reaction time.
Combining example 3 and comparative example 3 and combining table 5, it can be seen that the reaction rate decreases when the porous L-2-aminobutanamide in the synthesis stage is replaced with pure L-2-aminobutanamide, indicating that the porous L-2-aminobutanamide in example 3 increases the reaction rate by adsorption of compound I, and thus the yield of bwexitan measured in example 3 is higher.
Combining examples 3 and 6 with table 5, it can be seen that there is no significant difference in the yield of bwaitan under nitrogen atmosphere and under carbon dioxide atmosphere.
As can be seen by combining examples 6-10 with Table 5, the yield of the busulfacetam measured in examples 6-10 is close, wherein the yield of the busulfacetam in example 8 is the highest, which indicates that the porous L-2-aminobutanamide prepared in preparation 3 performs better in preparation 1-5.
As can be seen by combining example 8 and example 11 and table 5, the yield of the Buvalacetam measured in example 11 is higher than that in example 8, which indicates that the gel formed by mixing the calcium acetate with the ethanol increases the viscosity of the mixed paste, so that the diffusion of gas in the mixed paste is hindered, the content of pores in the porous L-2-aminobutanamide is increased, and the generation rate of the Buvalacetam is increased.
Combining example 11 and example 12 and combining table 5, it can be seen that the yield of the bravaracetam measured in example 12 is higher than that in example 11, which shows that the acid clay reacts with a part of the carbonate pore-forming agent, so that the probability of communicating pores with the pore structure of the adsorbent is increased, the concentration of the pore distribution in the porous L-2-aminobutanamide is increased, and the generation rate of the bravaracetam is accelerated.
Combining example 13 and example 12 and combining table 5, it can be seen that the yield of bravaracetam measured in example 13 is higher than that in example 12, which indicates that calcium ions generated after the reaction of calcium carbonate and hydrogen chloride promote the solidification of water-soluble alginate, so that the viscosity of the mixed paste is increased in the step (2) of preparing the porous L-2-aminobutanamide, the diffusion of gas in the mixed paste is hindered, the content of pores in the porous L-2-aminobutanamide is increased, and the generation rate of bravaracetam is accelerated.
Combining example 14, example 13 and table 5, it can be seen that the yield of the busulfame measured in example 14 is higher than that in example 13, which indicates that the free carboxyl in the gelatin enzymolysis solution can be temporarily combined with the amino in the L-2-aminobutanamide, so that the effect of protecting the amino is achieved, the oxidation loss of the amino in the reaction process is reduced, and the yield of the busulfame is improved.
As can be seen by combining examples 14-18 with comparative example 1 and combining Table 6, the purities of the bravaracetam measured in examples 14-18 are all higher than those of comparative example 1, which shows that the method adopted in the purification stage of the application is more favorable for improving the purity of the bravaracetam. In examples 14 to 18, the purities measured in examples 15 to 17 were relatively high, which indicates that the purity of the prepared bravaracetam was relatively high when the mixed solution was crystallized at a temperature of-10 ℃ to-20 ℃.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. The production process of the brivaracetam is characterized by comprising a synthesis stage and a purification stage, wherein the synthesis stage comprises the following steps: in an anhydrous environment protected by an inert atmosphere, carrying out a condensation reaction on a compound I and porous L-2-aminobutanamide in an organic solvent to obtain a reaction solution containing a crude product of Buvaracetam, wherein the porous L-2-aminobutanamide is a compound of L-2-aminobutanamide and a porous matrix, and the reaction equation of the synthesis stage is shown as formula (1):
2. The production process of bravaracetam according to claim 1, characterized in that the inert atmosphere of the synthesis stage is a carbon dioxide atmosphere or a nitrogen atmosphere.
3. The production process of bravaracetam according to claim 2, wherein the porous L-2-aminobutanamide is prepared according to the following method:
(1) uniformly stirring L-2-aminobutanamide hydrochloride, an ethanol aqueous solution, a cementing agent and an adsorbent to obtain a mixed solution;
(2) adding a curing agent, a carbonate pore-forming agent and a foam stabilizer into the mixed solution, uniformly stirring, and then carrying out reduced pressure evaporation to obtain a mixed paste body;
(3) and (3) freeze-drying the mixed paste, and crushing to obtain the porous L-2-aminobutanamide.
4. The production process of bravaracetam according to claim 3, wherein the porous L-2-aminobutanamide is prepared from the following raw materials in parts by weight: 40-60 parts of L-2-aminobutanamide hydrochloride, 100-120 parts of ethanol aqueous solution, 8-12 parts of cementing agent, 6-10 parts of adsorbent, 2-3 parts of curing agent, 12-24 parts of carbonate pore-forming agent and 4-8 parts of foam stabilizer, wherein the cementing agent is water-soluble alginate.
5. The production process of bravaracetam according to claim 4, wherein the curing agent is calcium acetate or calcium chloride.
6. The production process of bravaracetam according to claim 4, wherein the adsorbent is diatomite or acid clay.
7. The production process of bravaracetam according to claim 4, wherein the carbonate pore-forming agent is sodium carbonate or calcium carbonate.
8. The production process of bravaracetam according to claim 4, wherein the foam stabilizer is selected from gelatin enzymolysis solution or cellulose enzymolysis solution.
9. The production process of bravaracetam according to claim 1, characterized in that said purification stage comprises the following steps:
(1) uniformly mixing the reaction solution containing the crude product of the brivaracetam with water to obtain a mixed solution;
(2) cooling and crystallizing the mixed solution, and then filtering to remove liquid components to obtain mixed crystal grains;
(3) and dissolving the mixed crystal grains in water at room temperature to obtain refined liquid, recrystallizing the refined liquid, and filtering to obtain the brivaracetam.
10. The production process of bravaracetam according to claim 9, characterized in that in step (2) of the purification stage, the temperature of the temperature-reducing crystallization is between-10 ℃ and-20 ℃.
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