A method for the synthesis of levetiracetam

Abstract

The application provides a synthesis method of levetiracetam, wherein starting material I is reacted with SOCl2 under the action of a solvent A to generate an intermediate I; the intermediate I is reacted with starting material II under the action of a solvent B to generate an intermediate II; and the intermediate II is reacted with 4-chlorobutyryl chloride under the action of a solvent C to generate levetiracetam. The method is simple in operation, mild in reaction condition, high in yield, low in cost, friendly to the environment and suitable for industrialized mass production of levetiracetam.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing levetiracetam. Background Technology

[0002] Levetiracetam is a novel antiepileptic drug developed by UCB Pharmaceuticals in Belgium. Its chemical name is (S)-2-(2-oxo-1-pyrrolidine)butyramide, with the molecular formula C8H14N2O2 and a molecular weight of 170.21. Its chemical structural formula is as follows: Levetiracetam is approved by the State Food and Drug Administration of China for adjunctive treatment of epilepsy or partial seizures in adults and children over 4 years of age. It was initially marketed in Europe and the United States in 1999 for the treatment of partial seizures in adults; in June 2005, its oral tablets and injections were approved for adjunctive treatment of partial seizures in children aged 4 years and older; and it was launched in my country in March 2007 under the brand name Keppra.

[0003] Levetiracetam exhibits superior pharmacokinetics compared to other antiepileptic drugs, boasting advantages such as easy oral absorption, high bioavailability, a high therapeutic index, no interactions with other antiepileptic drugs, mild side effects, and good tolerability. Compared to other antiepileptic drugs, its protective activity against hypoxia is approximately 10 times higher, and its protective activity against cerebral ischemia is approximately 4 times higher. Levetiracetam is currently the only antiepileptic drug with the unique property of preventing epileptic seizures, and it has broad market prospects.

[0004] Currently, levetiracetam is mainly synthesized using chemical resolution, asymmetric hydrogenation catalysis, or amino acids as raw materials. However, these methods all have some drawbacks that are detrimental to production or product quality. For example, a method developed by UCB in Belgium for synthesizing levetiracetam using chemical resolution involves using racemic (R,S)-2-(2-oxo-1-pyrrolidine)butyric acid as the starting material and R-(+)-α-methylbenzylamine as the resolving agent. The solution is resolved in benzene and then treated with a strong base to obtain free (S)-2-(2-oxo-1-pyrrolidine)butyric acid. This acid reacts with ethyl chloroformate, and then undergoes ammonolysis with ammonia to obtain levetiracetam. However, because benzene is used as the resolving solvent, and benzene is classified as a Class I solvent and should be avoided, this method using benzene as the resolving solvent is both hazardous and does not meet the requirements for active pharmaceutical ingredient (API) production.

[0005] US Patent (US4696943) discloses a synthetic route using α-pyrrolidone as a starting material. First, levetiracetam acid is synthesized, then resolved using R-α-phenylethylamine to obtain S-type levetiracetam acid. Following esterification and ammonolysis, levetiracetam is finally obtained. This synthetic route represents an early process for obtaining levetiracetam, but it involves lengthy reaction steps, low overall yield, and significant difficulties in recovering and reusing the resolving agent, resulting in high resolving agent costs, making it unsuitable for large-scale industrial production.

[0006] US Patent (Publication No.: US2005 / 0182262A1) discloses a process using (S)-2-aminobutyrate as a starting material, reacting with thionyl chloride and methanol to obtain (S)-2-aminobutyrate methyl hydrochloride, reacting with ammonia to obtain (S)-2-aminobutyramide hydrochloride, then reacting with 4-chlorobutyryl chloride, and finally cyclizing to obtain levetiracetam. The patent uses phosphorus pentachloride and oxalyl chloride. Phosphorus pentachloride is a Class III controlled chemical, and its production and import / export are regulated by the National Chemical Weapons Control Office (Ministry of Industry and Information Technology); oxalyl chloride is highly toxic and corrosive, reacts violently with water to release the toxic gas carbon monoxide, and has a low overall yield, with a cyclization yield of only 60-70%.

[0007] Chinese patent (publication number: CN101550100A) discloses a process for preparing levetiracetam from L-threonine as a starting material via esterification, chlorination, catalytic reduction, ammonolysis, and cyclization. This process has a long synthetic route, and the metal catalysts such as palladium on carbon and rhodium on carbon used in the reduction reaction are very expensive, significantly increasing the overall cost.

[0008] The literature “Synthetic Study of Levetiracetam, an Antiepileptic Drug” [J] Fine Chemical Intermediates, 2005, 35(2):27-28) synthesizes levetiracetam from L-methionine as the starting material. The synthesis of levetiracetam is carried out through desulfurization methylation, esterification, ammonolysis, amidation and intramolecular cyclocondensation reaction. The starting material L-methionine is readily available and inexpensive. However, the removal of the methylthio group requires a large amount of nickel catalyst, and sulfur-containing compounds can easily lead to catalyst poisoning. The catalyst is not easy to recover and the production cost is high. Moreover, the demethylthio group byproduct is odorous and is not conducive to environmental protection.

[0009] The above-mentioned existing synthetic methods for preparing levetiracetam have disadvantages such as inconvenient raw material sources, complex reaction steps, high catalyst prices, and environmental disadvantages. Summary of the Invention

[0010] In order to overcome the problems of inconvenient raw material sources, complex reaction steps, high catalyst prices, and environmental disadvantages in the existing technology, this invention aims to provide a simple, mild reaction condition, high yield, low cost, and environmentally friendly method for synthesizing levetiracetam.

[0011] To achieve the above-mentioned objectives, this invention provides a method for synthesizing levetiracetam, the specific implementation of which is as follows: The present invention discloses a method for synthesizing levetiracetam, wherein the synthetic route for levetiracetam is as follows:

[0012] The present invention discloses a method for synthesizing levetiracetam, which includes the following steps: 1) Starting material I: Starting material I reacts with thionyl chloride in solvent A to generate intermediate I: S-2-aminobutyrate hydrochloride; 2) Intermediate I reacts with reagent A in solvent B to generate intermediate II: S-2-aminobutyramide; 3) Intermediate II reacts with 4-chlorobutyryl chloride: S-2-aminobutyramide in solvent C and reagent B to generate levetiracetam.

[0013] The present invention discloses a method for synthesizing levetiracetam, wherein the solvent A used in step 1) is one or more of methanol, ethanol, and isopropanol; the molar ratio of the starting material I to SOCl2 is 1:1.05 to 1:2; the system is heated to 10 to 60°C under stirring; and the reaction time is 0.5 to 5 hours.

[0014] The present invention describes a method for synthesizing levetiracetam, wherein in step 2), solvent B is one or more of acetonitrile, ethanol, methanol, 2-methyltetrahydrofuran, ethyl acetate, and N-methylpyrrolidone; the molar ratio of intermediate I to reagent A is 1:1 to 1:5; the system is heated to 10 to 30°C under stirring; and the reaction time is 0.5 to 5 hours.

[0015] The method for synthesizing levetiracetam according to the present invention includes the following steps: In step 3), the solvent C used is one or more of dichloromethane, 2-methyltetrahydrofuran, toluene, and DMF; the molar ratio of intermediate II to 4-chlorobutyryl chloride is 1:0.1 to 1:1.0; the molar ratio of intermediate II to reagent B is 1:3 to 1:7; the reaction temperature of the system under stirring is -10 to 35°C; the crystallization temperature of the system is 0 to 35°C; the dissolution temperature under stirring during the purification process is 65 to 95°C; the purification crystallization temperature is -15 to 10°C; and the purification crystallization time is 0.5 to 5 hours.

[0016] The present invention discloses a method for synthesizing levetiracetam, wherein the solvent A used in step 1) is dichloromethane; the molar ratio of the starting material I to m-CPBA is 1:1.35; the system is heated to -5~5℃ under stirring; the reaction time is 1~2 hours, wherein the mass-volume ratio of dichloromethane is 4V / W~10V / W.

[0017] The synthesis process of this invention overcomes the shortcomings of existing levetiracetam preparation methods and technologies. Following the atom-economic synthesis concept of green chemistry, it provides an improved method for preparing levetiracetam. This method uses starting material I as raw material and can synthesize levetiracetam that meets clinical needs at a lower cost. Furthermore, it is simple to operate, has mild reaction conditions, high yield, low cost, and is environmentally friendly, thus being more environmentally friendly and saving reagents, avoiding solid waste pollution, achieving the goal of green synthesis, and is suitable for large-scale industrial production of levetiracetam.

[0018] Intermediate II is prepared using organic ammonia, which is simpler to operate than the usual ammonia-amined method. The yield of the prepared product is higher than that of the previous process route (the overall yield reaches 93%). Due to the use of mild reagents, it has less environmental pollution. Detailed Implementation

[0019] The following examples are only for further illustration of the present invention and do not limit the scope of the present invention in any way. Example 1

[0020] 1. Synthesis of Intermediate I Take 56.68 g of (S)-2-aminobutyric acid in a 500 mL reaction flask and suspend it in 12 equivalents of ethanol. Under the condition of controlling the temperature not exceeding 30°C, add 78.28 g of thionyl chloride dropwise. After the addition is complete, slowly raise the temperature to 50°C and keep it at this temperature for 4 h with stirring. Take a sample for testing. After the (S)-2-aminobutyric acid content is less than 2%, concentrate the solvent under reduced pressure while controlling the internal temperature below 50~70°C. As the solvent evaporates, a large amount of product precipitates out. Add 2 equivalents of ethanol solvent, stir and cool to -5~0°C to form an ethanol suspension.

[0021] 2. Synthesis of Intermediate II: In a reaction flask containing a suspension of intermediate I, four equivalent volumes of methanol-ammonia solution cooled to 0-10°C were slowly added. After the addition was complete, stirring was started, and the reaction time was started once intermediate I was completely dissolved. After approximately 6 hours of reaction, a sample was taken to check if intermediate I was less than 10%. The temperature was then raised to 10-30°C, and the reaction was stirred for approximately 1-4 hours. A sample was taken again, and if intermediate I was ≤2%, the reaction was considered complete. 10.00 g of ethanol was added to the reaction solution, and ammonia was distilled off under reduced pressure at 85°C. When only a small amount of solvent remained, a white solid product precipitated. Distillation was continued until a large amount of product precipitated. 144.00 g of ethyl acetate was added, and the mixture was kept at 50°C and stirred for 2 hours. The mixture was filtered, and the product was washed twice with 20.00 g of ethyl acetate. The filter cake was dried under reduced pressure at 20-40°C to obtain the purified salt-forming intermediate II. A sample of the purified product was sent for testing. The yield of this step was approximately 95%.

[0022] 3. Synthesis of Levetiracetam as a finished product Add 65.52 g of intermediate II, 0.05 equivalents of TBAB, and 800.00 g of DCM sequentially to a clean, dry 2000 mL reaction flask. Under N2 protection (the same applies below), cool the flask with circulating cooling solution to an internal temperature of -10℃. With rapid stirring, slowly add 63.56 g of KOH. After the temperature stabilizes, allow it to naturally rise to an internal temperature of 10-30℃ (the addition rate of KOH needs to be controlled, as the system temperature rise is somewhat delayed). Stir the reaction for 30-60 min. Cool and control the internal temperature to below -5℃, then slowly add 88.67 g of 4-chlorobutyryl chloride and 150 g of a mixed solution of DCM. After the addition is complete, continue to maintain the temperature at 0±5℃ for 2 h. Continue cooling to -15~0℃, then slowly add 31.78 g of 90% KOH. After the addition is complete, maintain the temperature at 0±5℃ for 2 h. Take a sample and control the reaction by HPLC (when the residue of intermediate II is ≤ 2.0%, and the chloride residue is ≤ 0.0%). (5.0% is acceptable); after the reaction is complete, the reaction solution is quickly filtered using a filter. After processing, the filter cake is thoroughly washed with DCM, and the washing filtrates are combined.

[0023] Hydrolysis: Add the filtrate to a 1000 mL reaction flask, add 15.63 g of purified water to the washing filtrate, stir and hydrolyze for 30-60 min, adjust the pH to 7-9 with dilute hydrochloric acid, allow to stand and separate the layers, and separate the organic layer; add 20.00 g of DCM to the upper aqueous layer for extraction, and store the extracted aqueous layer in a container (nearly neutral, containing organic and inorganic salts) for further processing; combine the DCM extract with the separated DCM, transfer the combined solution to a 1000 mL reaction flask, add 30.00 g of anhydrous sodium sulfate, stir, dry, filter, wash the filter cake thoroughly with 10.00 g of DCM, combine the DCM filtrates, and transfer the filtrate in portions to a 500 mL reaction flask, concentrate under reduced pressure to dryness at an internal temperature of 30-60℃, a large amount of product precipitates, distill to dryness, then add 72.62 g of acetone, stir at 50℃ for 1 h to crystallize, cool to -10℃ and stir to crystallize for 3 hours. h, filter, and wash the product with cooled ethyl acetate to obtain the crude product; Purification: Add the crude product to a 1000 mL reaction flask, add 500.00 g of a mixture of ethyl acetate and ethanol (9:1), heat to reflux until clear, add 2.50-4.50 g of pharmaceutical charcoal, reflux and stir to decolorize for 0.5-1 h, filter while hot, wash the reaction flask with 30.00 g of ethyl acetate, control the internal temperature of the filtrate at 30-60℃ and concentrate under reduced pressure until a large amount of white solid precipitates, then cool to -10℃ and stir to crystallize for 0.5-3.5 h, filter the product, and dry at 50℃ to obtain the purified product with a yield of 86% and an overall yield of 81%. Example 2

[0024] 1. Synthesis of Intermediate I Take 56.68 g of (S)-2-aminobutyric acid and suspend it in 12 equivalents of methanol in a 500 mL reaction flask. Under the condition of controlling the temperature not exceeding 30℃, add 78.28 g of thionyl chloride dropwise. After the addition is complete, slowly raise the temperature to 20 ~ 50℃ and keep it at this temperature for 4 h with stirring. Take a sample for testing. After the (S)-2-aminobutyric acid content is less than 2%, concentrate the solvent under reduced pressure while controlling the internal temperature below 50℃. As the solvent evaporates, a large amount of product precipitates. When the product becomes viscous, take a sample. HPLC test shows that the purity is >98% to be qualified. Add 1.89 equivalents of reaction solvent, stir and cool to -5~15℃ to form a methanol suspension.

[0025] 2. Synthesis of Intermediate II Slowly add 6 equivalents of ammonia water cooled to 0°C to a reaction flask containing a methanol suspension of intermediate I. After the addition is complete, start stirring and begin timing once intermediate I is completely dissolved. After approximately 6 hours of reaction, when intermediate I was found to be less than 10%, the temperature was raised to 10–30°C, and the reaction was stirred for approximately 1–4 hours. Sampling was then performed; if intermediate I was ≤2%, the reaction was considered complete. 10.00 g of methanol was added to the reaction solution, and ammonia was distilled off under reduced pressure at 85°C. When only a small amount of solvent remained, a white solid product precipitated. Distillation continued until a large amount of product precipitated. Then, 200.00 g of methanol was added, and the mixture was stirred and heated to reflux. 14.00 g of hydrochloric acid was added to adjust the pH to weakly acidic, and the mixture was heated to dissolve completely. The mixture was kept at this temperature and stirred for 0.5–3 hours to form a salt. After salt formation, methanol was removed by reduced pressure distillation until a large amount of white product precipitated. 20.00 g of ethanol was added to remove excess water, followed by 144.00 g of ethyl acetate. The mixture was kept at 50°C and stirred for 2 hours. It was then centrifuged while hot, and the product was collected using 20.00 g of ethyl acetate. The product was washed twice with ethyl acetate, and the filter cake was dried under reduced pressure at 50-80°C to obtain the refined salt-forming intermediate II. The yield of this step was about 90%.

[0026] 3. Preparation and purification of levetiracetam Add 65.52 g of intermediate II and 800.00 g of tetrabutylammonium hydrogen sulfate (0.05 times the raw material equivalent) sequentially to a clean, dry 2000 mL reaction flask. Under N2 protection (the same applies below), cool the flask with a circulating cooling solution to an internal temperature of -10℃. With rapid stirring, slowly add 63.56 g of 90% KOH. After the temperature stabilizes, allow it to naturally rise to an internal temperature of 10-30℃ (the addition rate of KOH needs to be controlled, as the system temperature rise is slightly delayed). Stir the reaction for 30-60 min. Cool and control the internal temperature to below -5℃, then slowly add 93.32 g of 4-CBC and 150 g of a DCM mixed solution. Continue cooling to -15~0℃, then slowly add 31.78 g of 90% KOH. After the addition is complete, maintain the temperature at 0±5℃ for 2-5 h. Take a sample and control the reaction by HPLC (when the ABAH residue is ≤...). 2.0%, chloride residue ≤5.0% is acceptable); after the reaction is complete, the reaction solution is quickly filtered using a filter, and after treatment, the filter residue is thoroughly washed twice with 20 g of DCM, and the washing filtrate is combined.

[0027] Hydrolysis: Transfer the filtrate to a 1000 mL reaction flask, add 15.63 g of purified water to the washing filtrate, stir and hydrolyze for 30-60 min, adjust the pH to 7-9 with dilute hydrochloric acid, allow to stand and separate the layers, and separate the liquid to obtain the organic layer; transfer the combined liquid to a 1000 mL reaction flask, add 30.00 g of anhydrous sodium sulfate, stir and dry for 4 h, filter, concentrate the solution under reduced pressure at 30-60℃ until no liquid flows out, continue distillation with 12.32 g of acetone to dryness, then add 72.62 g of acetone, stir at 50℃ to crystallize for 1 h, cool to -10℃ and stir to crystallize for 0.5-3 h, filter, wash the product with cooled ethyl acetate to obtain crude levetiracetam; Purification: Add crude levetiracetam to a 1000 mL reaction flask, add 500.00 g of ethyl acetate, heat to reflux until clear, add 2.50 g of pharmaceutical charcoal, reflux and stir for decolorization for 0.5-1 h, filter while hot, wash the reaction flask with 30.00 g of ethyl acetate, concentrate the filtrate under reduced pressure at 30-60℃ until a large amount of white solid precipitates, then cool to -10℃ and stir for crystallization for 0.5-3.5 h, centrifuge the product, wash the reaction flask wall and product with 30.00 g of ethyl acetate, remove the solvent and discharge, dry at 50℃ to obtain the purified product (the washing filtrate contains a large amount of product, which is combined and the ethyl acetate and product are recovered). The yield of this step is 87%, and the overall yield is 78.3%. Example 3

[0028] 1. Synthesis of Intermediate I In a 300 L reactor, 23.62 kg of starting material I was suspended in 88.07 kg of methanol. The temperature was controlled to not exceed 30°C. 32.62 kg of thionyl chloride was added dropwise (of which 22.26 mol reacted with water). After the addition was complete, the temperature was slowly raised to 40-45°C and the reaction was maintained for 4 h. Samples were taken for testing. After the content of starting material I was less than 2%, the solvent was concentrated under reduced pressure while controlling the internal temperature below 50°C to obtain a light yellow viscous intermediate I. 54.12 kg of ethyl acetate was added, the temperature was lowered to 0-10°C and stirred for 1 h. After centrifugation and drying, intermediate I was obtained. 33.5 kg of product was obtained. HPLC analysis showed that the purity was >98%.

[0029] 2. Synthesis of Intermediate II In a 300 L reactor, 78.65 kg of methanol-ammonia solution was slowly added, followed by 6.97 kg of methanol. The mixture was cooled to below 10°C, and then the solid intermediate I synthesized in the previous step was slowly added. After the addition was complete, stirring was started, and the reaction time was started once intermediate I was completely dissolved. After about 6 hours of reaction, a sample was taken to check if intermediate I was between 10% and 15%. The temperature was controlled to rise no more than 20 to 25°C, and the reaction was stirred for about 2 hours. A sample was taken to check if intermediate I was ≤2%, which was considered a complete reaction. 2.50 kg of ethanol was added to the reaction solution, and ammonia water was distilled off under reduced pressure at 85°C. When only a small amount of solvent remained, 10.00 kg of ethanol was added to remove excess water, and the mixture was distilled to obtain a white solid product. The mixture was cooled to room temperature, and 60.00 kg of ethyl acetate was added. The mixture was stirred at room temperature for 1 hour and centrifuged to obtain intermediate II, with a yield of 94%.

[0030] 3. Preparation and purification of levetiracetam In a clean, dry 1000 L reactor, 27.14 kg of intermediate II, 3.16 kg of TBAB, and 364.38 kg of DCM were added sequentially. Under N2 protection (the same applies below), the reactor was cooled to below -5°C with stirring in an ice-water bath. With rapid stirring, 26.33 kg of powdered KOH was slowly added. After the temperature stabilized, the reactor was allowed to naturally heat to 20-25°C (the rate of KOH addition needs to be controlled, as the system heating is slightly delayed). The reaction was stirred for 30-60 min. The reactor was then cooled and the internal temperature controlled to below 0°C. A mixed solution of 32 kg of 4-chlorobutyryl chloride and 93.87 kg of DCM was slowly added dropwise (the addition speed can be slightly accelerated as long as the temperature can be controlled within the range, without any impact). After the addition was complete, the reactor was kept at 0±5°C for another 60 min. Then, the reactor was cooled to -10 to -5°C, and 13.16 kg of 90% KOH was slowly added. kg (the system is significantly exothermic, so control the feeding rate of KOH and strictly control the internal temperature below 0℃). After the addition is complete, maintain the temperature at 0±5℃ for 3 h. Take intermediate samples for HPLC control (intermediate II residue ≤ 2.0%, chloride residue ≤ 5.0% is acceptable). After the reaction is complete, rapidly centrifuge the reaction solution (potassium hydroxide particles are easily ejected, it is best to use two layers of filter bags). After treatment, thoroughly wash the filter residue with 20.00 kg of DCM, and combine the washing filtrate. The centrifuged filter residue is recycled.

[0031] Hydrolysis: Transfer the filtrate to a 500 L reactor, add 6.79 kg of purified water to the washing filtrate, stir and hydrolyze for 30-60 min, adjust to a slightly weak pH of 8-9 with hydrochloric acid (approximately 1.8 kg), allow to stand and separate into layers, obtain the organic layer; add 20.00 kg of DCM to the upper aqueous layer for one extraction, and store the extracted aqueous layer in a container (nearly neutral, containing organic and inorganic salts) for further processing; combine the dichloromethane extracts, add 6.00 kg of anhydrous sodium sulfate, stir and dry for 2 h, centrifuge, wash the filter residue thoroughly with 20.00 kg of DCM, combine the solutions, concentrate to dryness under reduced pressure in a water bath at 40-45℃ (the recovered DCM can be reused after dehydration); distill to dryness with 4.28 kg of acetone, solids precipitate, add 21.39 kg of acetone, stir thoroughly at 50℃ for 30 min, then cool to - The mixture was stirred and crystallized at 5°C for 2 hours; the product was centrifuged and washed with 10.00 kg of ethyl acetate at 0-10°C (the color turned white) to obtain crude levetiracetam. Refining: All crude product was placed in a 500 L glass reactor, and 225.5 kg of a mixed solution of ethyl acetate and ethanol (volume ratio: 9:1) was added. The mixture was heated under reflux to dissolve. If it was not completely dissolved, ethyl acetate was added again until it was completely dissolved. 1.25 kg of pharmaceutical charcoal was added, and the mixture was stirred for decolorization for 1 h. The mixture was filtered while hot, and the reactor was washed with 10.00 kg of ethyl acetate. The filtrate was concentrated under reduced pressure to 5 L in a 50 °C water bath, then cooled to room temperature for crystallization, and then cooled to -5 °C for stirring and crystallization for 2 h. The product was centrifuged, washed with 10.00 kg of ethyl acetate, dried under vacuum, and dried at 50 °C to obtain the refined product (the ethyl acetate washing filtrate was combined and the ethyl acetate was recovered; the residue was combined from multiple batches and re-refined to recover the finished product). The total yield was 84.6%. Comparative Example 1: Preparation method of levetiracetam (US4696943).

[0032] Comparative Example 2: Patent CN101550100A: A method for preparing levetiracetam.

[0033] Comparative Example 3: Synthesis of the antiepileptic drug levetiracetam.

[0034] Comparison of the embodiments of the present invention with comparative examples: .

Claims

1. A method for synthesizing levetiracetam, characterized in that, The synthetic route for levetiracetam is as follows: 。 2. The method for synthesizing levetiracetam according to claim 1, characterized in that, The synthesis method includes the following steps: 1) Starting material I: Starting material I reacts with thionyl chloride in solvent A to generate intermediate I: S-2-aminobutyrate hydrochloride; 2) Intermediate I reacts with reagent A in solvent B to generate intermediate II: S-2-aminobutyramide; 3) Intermediate II reacts with 4-chlorobutyryl chloride: S-2-aminobutyramide in solvent C and reagent B to generate levetiracetam.

3. The method for synthesizing levetiracetam according to claim 2, characterized in that, The solvent A used in step 1) is one or more of methanol, ethanol, and isopropanol; the molar ratio of the starting material I to SOCl2 is 1:1.05 to 1:2; the system is heated to 10 to 60°C under stirring; and the reaction time is 0.5 to 5 hours.

4. The method for synthesizing levetiracetam according to claim 2, characterized in that, Step 2) The solvent B used is one or more of acetonitrile, ethanol, methanol, 2-methyltetrahydrofuran, ethyl acetate, and N-methylpyrrolidone; the molar ratio of intermediate I to reagent A is 1:1 to 1:5; the system is heated to 10 to 30°C with stirring; the reaction time is 0.5 to 5 hours.

5. The method for synthesizing levetiracetam according to claim 2, characterized in that, Step 3) The solvent C used is one or more of dichloromethane, 2-methyltetrahydrofuran, toluene, and DMF; the molar ratio of intermediate II to 4-chlorobutyryl chloride is 1:0.1~1:1.0; the molar ratio of intermediate II to reagent B is 1:3~1:7; the reaction temperature of the system under stirring is -10~35℃; the crystallization temperature of the system is 0~35℃; the dissolution temperature under stirring during the purification process is 65~95℃; the purification crystallization temperature is -15~10℃; and the purification crystallization time is 0.5~5h.

6. The method for synthesizing levetiracetam according to claim 3, characterized in that, Step 1) The solvent A used is dichloromethane; the molar ratio of the starting material I to SOCl2 is 1:1.35; the system is heated to -5~5℃ under stirring; the reaction time is 1~2 hours, wherein the mass-volume ratio of dichloromethane is 6V / W~15V / W.

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