A method for the preparation of brivaracetam

Abstract

The application belongs to the field of chemical medicine preparation and relates to a preparation method of brivaracetam. The brivaracetam is prepared from 3-alkenyl pyrrolidone through an asymmetric Michael addition reaction, a substitution reaction, an aminolysis reaction and the like. The method has high stereoselectivity, does not need to purchase chiral raw materials, and can obtain the brivaracetam with high yield and high purity by using common raw materials.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug preparation and relates to a method for preparing briracetam, (S)-2-((R)-3-propylpyrrolidone-1-yl)butyramide. Background Technology

[0002]

[0003] Brivaceratam, developed by UCB (Universal Biomedical Engineering Co., Ltd.) of Belgium, is a third-generation antiepileptic drug used to treat partial seizures in adults and adolescents aged 16 years and older, with or without secondary generalized seizures, as adjunctive therapy. It has entered phase III clinical trials in China. Compared to other antiepileptic drugs, brivaceratam requires a lower dosage and is well-tolerated. Brivaceratam selectively binds to synaptic vesicle protein 2A (SV2A) located on the presynaptic membrane, thereby reducing the release of excitatory neurotransmitters and controlling seizures by regulating the balance of excitatory and inhibitory neurotransmitters in the brain. Brivaceratam is a derivative of levetiracetam. However, its affinity is 15-30 times that of levetiracetam, allowing for a clinical dosage reduction of approximately 10 times.

[0004] The previously reported synthetic routes for briracetam have two significant drawbacks. First, the synthetic routes are long and complex, resulting in low overall yields. For example, CN108503610A and CN108503609A mention using (R)-4-propyl-dihydrofuran-2-one as a key intermediate, followed by several reaction steps to obtain briracetam. The preparation of this type of method is extremely complex, especially the intermediate preparation itself, and requires the purchase of high-purity chiral raw materials to obtain a qualified product. Second, it involves the issue of chiral resolution, requiring the use of chiral resolving agents for separation, as reported in CN113582902 and CN111333563. Such separation methods result in low yields, high costs, and are not conducive to industrial production. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing briracetam. This method exhibits high stereoselectivity, eliminates the need for chiral raw materials, and utilizes common raw materials to perform two asymmetric synthesis processes to achieve high yields and high purity of briracetam.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a method for preparing bricetan, comprising the following steps:

[0007]

[0008] S1. Using 3-enpyrrolidone (Formula I) as a starting material, it undergoes an asymmetric Michael addition reaction with dipropylzinc in a solvent under the catalysis of a chiral ligand and a Cu catalyst to obtain R-4-propylpyrrolidone (Formula II).

[0009] This step involves an asymmetric reaction to obtain the highly selective intermediate of Formula II, wherein dipropylzinc provides the propyl side chain, and the propyl group is transferred from Zn to Cu via an organocopper catalyst, yielding a more active organocopper reagent. The alkylzinc fragment complexes with the ketene carbonyl group, and the alkylcopper forms a π-complex with the ketene, resulting in a bimetallic complex with a fixed conformation, thus achieving high stereoselectivity. The ability of organozinc reagents to undergo metal transformation converts them into more active organometallic reagents, as demonstrated by Ni, Cu, Pd, and Ti.

[0010]

[0011] Monodentate phosphoramide ligands exhibit extremely high catalytic activity in asymmetric Michael addition reactions. Different functional groups show different stereoselectivities, with stronger electron-donating abilities resulting in higher catalytic activity. Of the three phosphoramide ligands screened in this patent, compound A exhibits the highest stereoselectivity, producing a product with a high ee value. Excessive addition of chiral ligands should be avoided, as it can negatively impact the reaction rate and chiral selectivity.

[0012]

[0013] S2, R-4-propylpyrrolidone (Formula II) undergoes a substitution reaction with tert-butyl bromoacetate (Formula III) in a solvent in the presence of a base and iodide salt to give α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate (Formula IV);

[0014] Nucleophilic substitution reactions occur when a base removes hydrogen from nitrogen. The base cannot be too strong, otherwise tert-butyl ester will hydrolyze. Weak bases such as Na₂CO₃ or K₂CO₃ are used. Iodized salts increase the reactivity of brominated derivatives through halogen substitution.

[0015] S3, α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate (Formula IV) reacts with bromoethane in the presence of a base, solvent and ligand to give (S)-2-((R)-3-propylpyrrolidone-1-yl)tert-butyl butyrate (Formula V);

[0016] The chiral ligand is the compound (R,R)-bis(2-naphthyl)-NAS bromide, which forms a negative complex with oxygen, thus affecting chiral selectivity. The amount of ligand added should not be excessive, otherwise it will affect the reaction rate and the chiral selectivity of the ligand. The structure is shown below:

[0017]

[0018] (R,R)-bis(2-naphthyl)-NASbromide

[0019] The reaction mechanism is as follows:

[0020]

[0021] S4, (S)-2-((R)-3-propylpyrrolidone-1-yl)butyrate tert-butyl ester (Formula V) undergoes ammonolysis with ammonia to give (S)-2-((R)-3-propylpyrrolidone-1-yl)butyramide, namely bricetan (Formula VI).

[0022] Specifically, the reaction process is as follows:

[0023]

[0024] Preferably, in S1, the chiral ligand is one of compounds A, B, and C, and preferably compound A;

[0025] Preferably, in S1, the molar ratio of compound I to the chiral ligand is 1:0.34 to 0.45, more preferably 1:0.4;

[0026] Preferably, in S1, the Cu catalyst is Cu(OTf)2, CuI, CuTC, or copper acetate, with CuTC being the most preferred.

[0027] Preferably, in S1, the molar ratio of the chiral ligand to the Cu catalyst is 2:1;

[0028] Preferably, in S1, the molar ratio of compound I to dipropyl zinc is 1:1.0-3.0, more preferably 1:2.0;

[0029] Preferably, in S1, the solvent is toluene, ethylbenzene, DMF, THF, DCM, or acetone, with toluene being the most preferred.

[0030] Preferably, in S2, the reaction temperature is 60-100℃, more preferably 85-90℃;

[0031] Preferably, in S2, the alkali is one or a mixture of Na2CO3, K2CO3, LDA, tBuOK, tBuONa, KOH, triethylamine, cesium carbonate, and sodium hydride;

[0032] Preferably, in S2, the solvent is selected from one or more of isopropyl acetate, isopropyl ether, dioxane, DMF, THF, DCM, chloroform, methanol, ethanol, and acetonitrile.

[0033] Preferably, in S2, the molar ratio of compound II to compound III is 1:1.02 to 1.05;

[0034] Preferably, in S3, the molar ratio of compound IV to bromoethane is 1:1.0 to 1.3, more preferably 1:1.1; the molar ratio of compound IV to the ligand is 45-55:1, more preferably 50:1.

[0035] Preferably, in S3, the alkali may be one or a mixture of potassium carbonate, sodium carbonate, cesium carbonate, KOH, NaOH, cesium carbonate, tBuOK, and tBuONa;

[0036] Preferably, in step S3, the solvent is selected from one or more of DMF, DMSO, DMA, THF, DCM, toluene, and tert-butanol;

[0037] Preferably, in S3, the ligand is R,R-bis(2-naphthyl)-NASbromide;

[0038] Preferably, in S4, the reaction temperature is 0-80℃, more preferably 50-60℃.

[0039] The advantages of this invention are: the method of this invention has high stereoselectivity, does not require the purchase of chiral raw materials, and can obtain high yield and high purity bricillan using ordinary raw materials. Detailed Implementation

[0040] The following specific embodiments are provided to further illustrate the present invention and should not be construed as limiting the present invention.

[0041] The yields in the following examples are calculated based on the number of moles of substrate added in each specific step.

[0042]

[0043] Example 1

[0044] 1) Preparation of R-4-propylpyrrolidone (Formula II):

[0045] Dry toluene was added to a reaction flask, followed by compound I (4.15 g, 50 mmol), CuTC (1.9 g, 10 mmol), and compound A (10.79 g, 20 mmol). The mixture was stirred at room temperature for 40 min. A 2M toluene solution of (Pr)₂Zn (50 mL, 100 mmol) was added while stirring, and the reaction was continued for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous NH₄Cl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄), concentrated, and chromatographically analyzed (n-hexane-EA) to give 5.41 g of compound II, with a yield of 85%, purity of 99.2%, and ee of 98.0%.

[0046] 2) Preparation of α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate (Formula IV):

[0047] In a reaction flask, a mixture of R-4-propylpyrrolidone (Formula II) (5.1 g, 40 mmol), compound III (8.04 g, 41.2 mmol), sodium iodide (0.6 g, 4 mmol), and sodium carbonate (0.06 g, 80 mmol) was refluxed at 88 °C for 10 h in 60 mL of isopropyl acetate. After cooling, the mixture was washed with 8% sodium bicarbonate solution to separate the organic layer, which was then washed three times with saturated brine. The organic layer was dried on anhydrous MgSO4 and evaporated to dryness. 30 mL of isopropyl ether was added, the mixture was concentrated, heated, and crystallized to give 7.72 g of compound IV, with a yield of 80%, purity of 99.0%, and optical purity ee of 98.5%.

[0048] 3. Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidone-1-yl)butyrate (Formula V)

[0049] To a reaction flask, compound IV (7.24 g, 30 mmol), bromoethane (3.6 g, 33 mmol), and (R,R)-bis(2-naphthyl)-NAS bromide (0.5 g, 0.6 mmol) in toluene (30 mL) were added, followed by 30 mL of 50 wt% potassium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 6:1 as eluent) to give 7.50 g of compound V, yield 93%, purity 99.2%, ee 99.0%.

[0050] 4) Preparation of briracetam (Formula VI)

[0051] Compound V (7.5 g, 27.9 mmol) and methanol (50 ml) were added to a pressurized reactor. After stirring until dissolved, the reactor was evacuated, and then ammonia gas was introduced until the pressure inside the reactor reached 0.6 MPa. The pressure was maintained during the process, and the temperature was raised to 55 °C and stirred for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry methanol. Isopropyl ether (80 ml) was added to the residue, and the temperature was raised to 48 °C and stirred until completely dissolved. The temperature was lowered to 0 °C and stirred to precipitate crystals. After filtration and drying, 5.32 g of bricetan was obtained, with a yield of 90% and a purity of 99.4%.

[0052] Example 2

[0053] 1) Preparation of R-4-propylpyrrolidone (Formula II):

[0054] Dry toluene was added to a reaction flask, followed by compound I (4.15 g, 50 mmol), CuTC (1.9 g, 10 mmol), and compound A (10.79 g, 20 mmol). The mixture was stirred at room temperature for 40 min. A 2M toluene solution of (Pr)₂Zn (50 mL, 100 mmol) was added while stirring, and the reaction was continued for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous NH₄Cl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄), concentrated, and chromatographically analyzed (n-hexane-EA) to give 5.15 g of compound II, yield 81%, purity 99.1%, ee 98.2%.

[0055] 2) Preparation of α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate (Formula IV):

[0056] A mixture of R-4-propylpyrrolidone (Formula II) (5.1 g, 40 mmol), compound III (8.04 g, 41.2 mmol), sodium iodide (0.6 g, 4 mmol), and sodium carbonate (0.06 g, 80 mmol) was refluxed in 60 mL of isopropyl acetate at 85 °C for 10 h. After cooling, the mixture was washed with 8% sodium bicarbonate solution to separate the organic layer, which was then washed three times with saturated brine. The organic layer was dried on anhydrous MgSO4 and evaporated to dryness. 30 mL of isopropyl ether was added, the mixture was concentrated, heated, and crystallized to give 7.55 g of compound IV. The yield was 78%, the purity was 99.0%, and the optical purity was ee 98.6%.

[0057] 3. Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidone-1-yl)butyrate (Formula V)

[0058] To a reaction flask, compound IV (7.24 g, 30 mmol), bromoethane (3.6 g, 33 mmol), and (R,R)-bis(2-naphthyl)-NAS bromide (0.5 g, 0.6 mmol) in toluene (30 mL) were added, followed by 30 mL of 50 wt% potassium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 5:1 as eluent) to give 7.65 g of compound V. The yield was 95%, the purity was 99.3%, and the ee was 99.1%.

[0059] 4) Preparation of briracetam (Formula VI)

[0060] Compound V (7.5 g, 27.9 mmol) and methanol (50 ml) were added to a pressurized reactor. After stirring until dissolved, the reactor was evacuated, and then ammonia gas was introduced until the pressure inside the reactor reached 0.6 MPa. The pressure was maintained during the process, and the mixture was heated to 50 °C and stirred for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry methanol. Isopropyl ether (80 ml) was added to the residue, and the mixture was heated to 45 °C and stirred until completely dissolved. The mixture was then cooled to 5 °C and stirred to induce crystallization. After filtration and drying, 5.36 g of bricetan was obtained, with a yield of 91% and a purity of 99.3%.

[0061] Example 3

[0062] 1) Preparation of R-4-propylpyrrolidone (Formula II):

[0063] Dry toluene was added to a reaction flask, followed by compound I (4.15 g, 50 mmol), CuTC (1.9 g, 10 mmol), and compound A (10.79 g, 20 mmol). The mixture was stirred at room temperature for 40 min. A 2M toluene solution of (Pr)₂Zn (50 mL, 100 mmol) was added while stirring, and the reaction was continued for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous NH₄Cl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄), concentrated, and chromatographically analyzed (n-hexane-EA) to give 5.16 g of compound II, yield 81%, purity 99.0%, ee 98.3%.

[0064] 2) Preparation of α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate (Formula IV):

[0065] In a reaction flask, a mixture of R-4-propylpyrrolidone (Formula II) (5.1 g, 40 mmol), compound III (8.04 g, 41.2 mmol), sodium iodide (0.6 g, 4 mmol), and sodium carbonate (0.06 g, 80 mmol) was refluxed at 90 °C for 10 h in 60 mL of isopropyl acetate. After cooling, the mixture was washed with 8% sodium bicarbonate solution to separate the organic layer, which was then washed three times with saturated brine. The organic layer was dried on anhydrous MgSO4 and evaporated to dryness. 30 mL of isopropyl ether was added, the mixture was concentrated, heated, and crystallized to give 7.90 g of compound IV, with a yield of 82%, a purity of 99.2%, and an optical purity of ee of 98.5%.

[0066] 3. Preparation of tert-butyl (S)-2-((R)-3-propylpyrrolidone-1-yl)butyrate (Formula V)

[0067] To a reaction flask, compound IV (7.24 g, 30 mmol), bromoethane (3.6 g, 33 mmol), and (R,R)-bis(2-naphthyl)-NAS bromide (0.5 g, 0.6 mmol) in toluene (30 mL) were added, followed by 30 mL of 50 wt% potassium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 7:1 as eluent) to give 7.53 g of compound V, yield 93%, purity 99.1%, ee 99.2%.

[0068] 4) Preparation of briracetam (Formula VI)

[0069] Compound V (7.5 g, 27.9 mmol) and methanol (50 ml) were added to a pressurized reactor. After stirring until dissolved, the reactor was evacuated, and then ammonia gas was introduced until the pressure inside the reactor reached 0.6 MPa. The pressure was maintained during the process, and the mixture was heated to 60 °C and stirred for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dry methanol. Isopropyl ether (80 ml) was added to the residue, and the mixture was heated to 50 °C and stirred until completely dissolved. The mixture was then cooled to 0 °C and stirred to induce crystallization. After filtration and drying, 5.47 g of bricetan was obtained, with a yield of 93% and a purity of 99.1%.

[0070] Example 4

[0071] Preparation of R-4-propylpyrrolidone (Formula II):

[0072] Dry toluene was added to a reaction flask, followed by compound I (4.15 g, 50 mmol), CuTC (1.9 g, 10 mmol), and compound B (8.31 g, 20 mmol). The mixture was stirred at room temperature for 40 min. A 2M toluene solution of (Pr)₂Zn (50 mL, 100 mmol) was added while stirring, and the reaction was continued for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous NH₄Cl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄), concentrated, and chromatographically analyzed (n-hexane-EA) to give 5.02 g of compound II, yield 79%, purity 99.2%, ee 95.0%.

[0073] Example 5

[0074] Preparation of R-4-propylpyrrolidone (Formula II):

[0075] Dry toluene was added to a reaction flask, followed by compound I (4.15 g, 50 mmol), CuTC (1.9 g, 10 mmol), and compound C (7.19 g, 20 mmol). The mixture was stirred at room temperature for 40 min. A 2M toluene solution of (Pr)₂Zn (50 mL, 100 mmol) was added while stirring, and the reaction was continued for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous NH₄Cl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄), concentrated, and chromatographically analyzed (n-hexane-EA) to give 5.21 g of compound II, yield 82%, purity 99.0%, optical purity ee 94.0%.

[0076] As can be seen from Examples 1, 4 and 5, the R-4-propylpyrrolidone prepared by chiral ligand compound A has higher optical purity than compounds B and C.

[0077] Comparative Example 1

[0078] Preparation of R-4-propylpyrrolidone (Formula II):

[0079] Dry toluene was added to a reaction flask, followed by compound I (4.15 g, 50 mmol), CuTC (1.9 g, 10 mmol), and compound A (16.19 g, 30 mmol). The mixture was stirred at room temperature for 40 min. A 2M toluene solution of (Pr)₂Zn (50 mL, 100 mmol) was added while stirring, and the reaction was continued for 2 h. After the reaction was complete, the mixture was quenched with saturated aqueous NH₄Cl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄), concentrated, and chromatographically analyzed (n-hexane-EA) to give 4.64 g of compound II, yield 73%, purity 99.0%, optical purity ee 90.5%.

[0080] Compared to Example 1, Comparative Example 1 increased the proportion of compound A, resulting in a significant decrease in yield and optical purity.

[0081] Comparative Example 2

[0082] Preparation of (S)-2-((R)-3-propylpyrrolidone-1-yl)tert-butyl butyrate (Formula V)

[0083] To a reaction flask, compound IV (7.24 g, 30 mmol), bromoethane (3.6 g, 33 mmol), and (R,R)-bis(2-naphthyl)-NAS bromide (0.83 g, 1.0 mmol) in toluene (30 mL) were added, followed by 30 mL of 50 wt% potassium hydroxide aqueous solution. The mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 6:1 as eluent) to give 6.47 g of compound V, yield 80%, purity 99.0%, ee 86.0%.

[0084] Compared to Example 1, Comparative Example 2 increased the proportion of (R,R)-bis(2-naphthyl)-NAS bromide, resulting in a significant decrease in yield and optical purity.

[0085] As can be seen from Comparative Examples 1 and 2, the proportion of chiral ligands is crucial to the reaction yield and optical purity.

[0086] The above embodiments are only used to illustrate the technical solutions of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any way. All technical solutions obtained by equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A method for preparing briracetam, characterized in that, Includes the following steps: S1. Using 3-enpyrrolidone as shown in Formula I as a starting material, it undergoes an asymmetric Michael addition reaction with (Pr)2Zn in a solvent under the catalysis of chiral ligands and CuTC to obtain R-4-propylpyrrolidone as shown in Formula II. S2. R-4-propylpyrrolidone of Formula II undergoes a substitution reaction with tert-butyl bromoacetate of Formula III in a solvent in the presence of a base and an iodide salt to give α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate of Formula IV. S3 and IV, α-((R)-3-propylpyrrolidone-1-yl)tert-butyl acetate, react with bromoethane in the presence of a base, solvent, and chiral ligand to give (S)-2-((R)-3-propylpyrrolidone-1-yl)tert-butyl butyrate, as shown in Formula V. S4 and V, tert-butyl (S)-2-((R)-3-propylpyrrolidone-1-yl)butyrate, undergo ammonolysis with ammonia to give (S)-2-((R)-3-propylpyrrolidone-1-yl)butyramide, i.e., bricetan, as shown in Formula VI. The structures of Formula I, Formula II, Formula III, Formula IV, and Formula V are as follows: In S1, the chiral ligand is at least one of compounds A, B, and C; In S3, the ligand is R,R-bis(2-naphthyl)-NAS bromide; 2. The method for preparing briracetam according to claim 1, characterized in that, In S1, the molar ratio of compound I to the chiral ligand is 1:0.35 to 0.45; the molar ratio of the chiral ligand to CuTC is 2:

1.

3. The method for preparing briracetam according to claim 2, characterized in that, In S1, the molar ratio of compound I to the chiral ligand is 1:0.

4.

4. The method for preparing briracetam according to claim 1, characterized in that, In S1, the molar ratio of compound I to (Pr)2Zn is 1:2.0-3.0; the solvent is at least one of toluene, ethylbenzene, DMF, THF, DCM, and acetone.

5. The method for preparing briracetam according to claim 4, characterized in that, In S1, the molar ratio of compound I to (Pr)2Zn is 1:2.

0.

6. The method for preparing briracetam according to claim 1, characterized in that, In S2, the reaction temperature is 85–90°C; the alkali is one or a mixture of Na2CO3, K2CO3, LDA, tBuOK, tBuONa, KOH, triethylamine, cesium carbonate, and sodium hydride.

7. The method for preparing briracetam according to claim 1, characterized in that, In S2, the solvent is selected from one or more of isopropyl acetate, isopropyl ether, dioxane, DMF, THF, DCM, chloroform, methanol, ethanol, and acetonitrile; the molar ratio of compound II to compound III is 1:1.02 to 1.

05.

8. The method for preparing briracetam according to claim 1, characterized in that, In S3, the molar ratio of compound IV to bromoethane is 1:1.0 to 1.3; the molar ratio of compound IV to the ligand is 45-55:

1.

9. A method for preparing briracetam according to claim 8, characterized in that, In S3, the molar ratio of compound IV to bromoethane is 1:1.1; the molar ratio of compound IV to the ligand is 50:

1.

10. A method for preparing briracetam according to claim 1, characterized in that, In S3, the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, KOH, NaOH, cesium carbonate, tBuOK, and tBuONa; the solvent is selected from one or more of DMF, DMSO, DMA, THF, DCM, toluene, and tert-butanol.

11. A method for preparing briracetam according to claim 1, characterized in that, In S4, the reaction temperature is 50-60℃.

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