A process for the preparation of levetiracetam

Abstract

The application discloses a preparation method of levetiracetam, which comprises the following steps: after (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetate is ammoniated in water, excessive ammonia gas in a reaction system is removed, part of water is removed through distillation, and inorganic salt is added before extraction, so that the yield and quality of levetiracetam are improved.

Description

Technical Field

[0001] This invention relates to a method for preparing levetiracetam, belonging to the field of pharmaceutical chemicals. Background Technology

[0002] Levetiracetam (trade name Keppra) is a novel antiepileptic drug developed by the Belgian company UCB. It is an acetylpyrrolidine compound with the chemical name (S)-α-ethyl-2-oxo-1-acetamide-pyrrolidine, and its structure is shown below:

[0003]

[0004] UCB Corporation reported in patent US7122682 a method for obtaining levetiracetam via ammonolysis of (S)-α-ethyl-2-oxo-1-pyrrolidine acetate (II) under ammonia conditions. The synthetic route is shown below:

[0005]

[0006] After the reaction was completed, the ammonia was removed by direct distillation under vacuum conditions, and then the solid to be purified was obtained by toluene drag. The yield was only 92%, which was low. In addition, since levetiracetam is not stable under ammonia conditions, the process requires distillation to remove a large amount of solvent water. The material temperature will rise in the later stage of distillation, which may cause hydrolysis and racemization of levetiracetam, generating isomer (III) and hydrolysate (IV), thus affecting the quality of the final product. For specific data, see Comparative Example 1. Therefore, this post-processing method is not conducive to large-scale industrial production.

[0007]

[0008] Another patent, US7214803, reports a method for obtaining levetiracetam by ammonolysis with ammonia. The post-processing method reported in this patent involves extracting the product from the reaction solution with 15 times the volume of dichloromethane after the reaction is completed, and concentrating the dichloromethane, resulting in only 73% of the solid to be purified. Therefore, this post-processing method is not conducive to large-scale industrial production due to its low yield. Summary of the Invention

[0009] The purpose of this invention is to provide a method for obtaining high-quality, high-yield levetiracetam from ammonia hydrolysis, comprising the following steps:

[0010] (a) At -5 to 5°C, (S)-α-ethyl-2-oxo-1-pyrrolidine methyl acetate or (S)-α-ethyl-2-oxo-1-pyrrolidine ethyl acetate reacts with ammonia in water until complete;

[0011] (b) Remove some of the ammonia from the system until the pH of the system is less than 12;

[0012] (c) Distillation is carried out at a temperature below 45°C to remove some of the water;

[0013] (d) Add inorganic salts to the feed solution;

[0014] (e) The feed solution is extracted with an organic solvent, and the organic solvent extract layer is distilled to dryness to obtain levetiracetam.

[0015] The amount of water used in step (a) is 0.6 to 4 times the mass of (S)-α-ethyl-2-oxo-1-pyrrolidine acetate;

[0016] Whether the reaction in step (a) is complete can be confirmed by monitoring the presence of (S)-α-ethyl-2-oxo-1-pyrrolidine acetate residue using TLC.

[0017] Step (b) Method for removing ammonia: Preferably, ammonia is removed at a controlled temperature of 20-30°C and a vacuum of ≥0.09 MPa. Alternatively, ammonia in the system can be replaced by methods such as introducing nitrogen. Preferably, ammonia is removed until the pH of the system is 10-12.

[0018] In step (c), the amount of water removed by distillation is 0.2 to 0.7 times the initial water mass, preferably 0.5 times; the distillation temperature is preferably controlled at 40-45℃.

[0019] The inorganic salt mentioned in step (d) is selected from sodium chloride, sodium sulfate, calcium chloride, magnesium sulfate, and ammonium sulfate, preferably sodium chloride, and the amount used is 0.1 to 1 times the mass of (S)-α-ethyl-2-oxo-1-pyrrolidine acetate;

[0020] The extraction solvent in step (e) is preferably dichloromethane, and the amount of dichloromethane used is 1 to 5 times the mass of (S)-α-ethyl-2-oxo-1-pyrrolidine acetate. It is preferred to extract with dichloromethane three times.

[0021] The innovation of this invention lies in: removing excess ammonia from the reaction system in step (b) reduces hydrolysis and racemization of the product during solvent distillation; removing part of the solvent through distillation in step (c) improves subsequent extraction efficiency; and adding inorganic salts in step (d) reduces the solubility of levetiracetam in the aqueous system, further improving extraction efficiency. These operations improve yield without compromising product quality, demonstrating high practical value. Detailed Implementation

[0022] Example 1:

[0023] 100g of water and 50g of (S)-α-ethyl-2-oxo-1-pyrrolidine acetate methyl ester (isomer: 0.2%) were added to a reaction vessel. The mixture was stirred and cooled to -5℃, and ammonia gas was introduced until saturation. The ammonia gas was then stopped, and the mixture was kept at -5℃ under sealed conditions with stirring for 9 hours. TLC showed no (S)-α-ethyl-2-oxo-1-pyrrolidine acetate residue, and the reaction was stopped. The reaction solution was then subjected to ammonia evacuation at 30℃ and a vacuum of 0.095MPa for 2 hours. The pH of the solution was measured to be 11.5. 50g of solvent was removed under vacuum at 45℃, and 15g of sodium chloride was added. The mixture was stirred and dissolved, and then extracted three times with 200g of dichloromethane. The dichloromethane layers were combined and concentrated to dryness at a temperature below 45℃ to obtain 44.5g of levetiracetam (yield: 97%, purity: 99.95%, isomer: 0.3%).

[0024] Example 2:

[0025] 150 g of water and 50 g of ethyl (S)-α-ethyl-2-oxo-1-pyrrolidine (isomer: 0.2%) were added to a reaction vessel. The mixture was stirred and cooled to 5 °C. Ammonia gas was introduced until saturation, then the ammonia gas was stopped. The reaction was then kept at 5 °C under a sealed environment for 12 hours. TLC showed no residue of ethyl (S)-α-ethyl-2-oxo-1-pyrrolidine, and the reaction was stopped. The reaction solution was then subjected to ammonia evacuation at 20 °C and a vacuum of 0.095 MPa for 2 hours. The pH of the solution was measured to be 11.6. 50 g of solvent was removed under vacuum at 40 °C. 25 g of sodium sulfate was added and stirred to dissolve the solvent. The solution was extracted three times with 100 g of dichloromethane. The dichloromethane layers were combined and concentrated to dryness at a temperature below 45 °C to obtain 41.8 g of levetiracetam (yield: 96%, purity: 99.93%, isomer: 0.4%).

[0026] Comparative Example 1:

[0027] 50g of levetiracetam (purity: 100.0%; isomer: ND) was dissolved in 100g of concentrated ammonia solution. The mixture was stirred at 40℃, 50℃, and 60℃ for 1 hour, 3 hours, 7 hours, 12 hours, and 24 hours, respectively. Samples were taken to test the purity and isomers. The data are as follows:

[0028]

[0029]

[0030] The above data indicate that levetiracetam has poor stability in an ammonia-water system at 40°C.

[0031] Comparative Example 2:

[0032] In Comparative Example 2, all operations were the same as in Example 1, except that sodium chloride was not added, and 34.4 g of levetiracetam was finally obtained (yield: 75%, purity: 99.96%, isomers: 0.3%).

[0033] This example illustrates that the absence of sodium chloride can severely impact the subsequent extraction yield.

[0034] Comparative Example 3:

[0035] In Comparative Example 2, all operations were the same as in Example 1, except that the ammonia gas extraction operation was not performed. The final yield was 36.7g of levetiracetam (yield: 80%, purity: 98.11%, isomers: 0.4%).

[0036] This example illustrates that the absence of ammonia extraction can severely impact subsequent extraction yield and the quality of the final product.

[0037] Comparative Example 4:

[0038] In Comparative Example 2, all operations were the same as in Example 1, except that there was no distillation of the solvent after the ammonia extraction operation. The final yield was 38.1g of levetiracetam (yield: 83%, purity: 99.31%, isomers: 0.4%).

[0039] This example illustrates that the lack of solvent distillation after ammonia extraction can severely impact subsequent extraction yield.

Claims

1. A method for preparing levetiracetam, comprising the following steps: (a) At -5~5℃, (S)-α-ethyl-2-oxo-1-pyrrolidine methyl acetate or (S)-α-ethyl-2-oxo-1-pyrrolidine ethyl acetate reacts with ammonia in water until complete; (b) Remove some of the ammonia from the system until the pH of the system is less than 12; (c) Distillation to remove some water while controlling the temperature below 45°C; (d) Add inorganic salts to the feed solution; (e) The feed solution was extracted with an organic solvent, and the organic solvent extract was distilled to dryness to obtain levetiracetam. In step (c), the amount of water removed by distillation is 0.2 to 0.7 times the initial water mass.

2. The method according to claim 1, wherein the amount of water used in step (a) is 0.6 to 4 times the mass of methyl (S)-α-ethyl-2-oxo-1-pyrrolidine acetate or ethyl (S)-α-ethyl-2-oxo-1-pyrrolidine.

3. According to the method of claim 1, the method for removing ammonia in step (b) is selected from: removing ammonia at a controlled temperature of 20~30℃ and a vacuum degree ≥0.09MPa.

4. The method according to claim 1, wherein step (b) removes ammonia to a system pH of 10-12.

5. The method according to claim 1, wherein the amount of water removed by distillation in step (c) is 0.5 times the initial water mass.

6. The method according to claim 1, wherein the distillation temperature in step (c) is 40-45°C.

7. The method according to claim 1, wherein the inorganic salt in step (d) is selected from sodium chloride, sodium sulfate, calcium chloride, magnesium sulfate, and ammonium sulfate.

8. The method according to claim 1, wherein the inorganic salt in step (d) is selected from sodium chloride.

9. The method according to claim 1, wherein the amount of inorganic salt used in step (d) is 0.1 to 1 times the mass of methyl (S)-α-ethyl-2-oxo-1-pyrrolidine acetate or ethyl (S)-α-ethyl-2-oxo-1-pyrrolidine.

10. The method according to claim 1, wherein the extraction solvent in step (e) is dichloromethane.

11. The method according to claim 10, wherein the amount of dichloromethane used is 1 to 5 times the mass of methyl (S)-α-ethyl-2-oxo-1-pyrrolidine acetate or ethyl (S)-α-ethyl-2-oxo-1-pyrrolidine.

12. The method according to claim 11, characterized in that... Extract three times with dichloromethane.

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