CN115872913A - Preparation method of Brivaracetam and its intermediate - Google Patents

Abstract

本发明具有的优点在于反应收率高，成本低，制备的手性化合物光学纯度高，工艺路线简单易行,易于工业化生产等。The preparation method of brivaracetam and its intermediate relates to the field of pharmaceutical chemical synthesis, including the method of preparing the key intermediate of brivaracetam, that is, chiral pyrrolidone derivatives, through an asymmetric reduction reaction catalyzed by a chiral copper catalyst.

The invention has the advantages of high reaction yield, low cost, high optical purity of the prepared chiral compound, simple and easy process route, easy industrial production and the like.

Description

Preparation method of brivaracetam and its intermediates

Technical Field

The invention belongs to the field of pharmaceutical chemical synthesis and relates to a preparation method of brivaracetam and its intermediates.

Background Art

Brivaracetam, chemical name: (2S)-2-[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butanamide, CAS: 357336-20-0, molecular formula: C ₁₁ H ₂₀ N ₂ O ₂ , molecular weight: 317.38, structural formula:

In 2016, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved brivaracetam, a third-generation anti-epileptic drug developed by UCB, for the adjunctive treatment of partial seizures with or without secondary generalized seizures in adolescents and adults with epilepsy aged 16 years and above. In 2021, the U.S. Food and Drug Administration (FDA) further approved the expanded indications of brivaracetam, which can be used as monotherapy or adjunctive therapy for epilepsy patients as young as 1 month old. With good pharmacological activity, clinical efficacy and safety, the global sales of brivaracetam have increased significantly from 18 million euros in 2016 to 355 million euros in 2021, so it has a huge sales prospect in the future.

Patent WO 01/62726 first disclosed a route for synthesizing brivaracetam, and the specific method is as follows:

The method first prepares a dihydropyrrolidone intermediate (II) by a condensation/reduction reaction of (S)-2-aminobutyramide and 5-hydroxy-4-n-propyl-2-furanone (II). Then, a diastereoisomer mixture (V)/epi-(V) with a ratio of 50/50 is prepared by a palladium/carbon-catalyzed hydrogenation reaction of the intermediate (II). Finally, the mixture (V)/epi-(V) is separated by a chiral chromatographic column to finally obtain brivaracetam (V). It has been found through research (patent EP1659191B) that the diastereoisomer epi-(V) has no activity in the treatment of epilepsy. Therefore, in this route, the byproduct epi-(V) produced by the synthesis of brivaracetam greatly reduces the total yield, greatly increases the production cost, and is not conducive to scale-up production.

The brivaracetam synthesis routes similar to those disclosed in patent WO 01/62726, including patents WO2007065634A1, WO2018042393, US8338621B2, US20080009638A1, WO 01/62726 A2, WO2005028435 and WO2017076738 and documents Tetrahedron Letters, 2019, 60, 46, 151249 and Journal of Medicinal Chemistry, 2004, 47, 53, all encounter the same problem that chiral intermediates or final products need to be separated by chiral chromatographic columns, which greatly reduces the industrial application value of these synthesis routes.

Document Org. Process Res. Dev. 2016, 20, 1566 reported that although the chiral lactone intermediate of brivaracetam can be obtained and synthesized by enzyme-catalyzed chiral resolution, the enzyme-catalyzed chiral resolution will also waste more than half of the materials, resulting in a decrease in the total yield. Moreover, the synthetic route is lengthy, which is not conducive to the large-scale production of brivaracetam.

Since the chiral separation method will encounter the problem of serious material waste, the development of asymmetric reactions to obtain chiral intermediates of brivaracetam has become a research hotspot for developing related synthetic routes in recent years. In the process of realizing the present invention, the inventors found that at least the above problems exist in the prior art. Therefore, in the field of industrial synthesis of brivaracetam, a method that is simple to operate, environmentally friendly and efficient needs to be developed to solve the complex process and lengthy steps encountered in the current preparation of brivaracetam, the waste of raw materials caused by the chiral separation of racemates, the greatly increased preparation time and cost, the generation of environmentally unfriendly waste materials, and a series of problems or at least one of the technical problems.

Summary of the invention

On the one hand, a method for preparing a chiral pyrrolidone derivative (IV), a key intermediate for synthesizing brivaracetam, by an asymmetric reduction reaction of dihydropyrrolidone (III) catalyzed by a chiral copper catalyst is provided; on the other hand, a method for preparing brivaracetam (V) by using the key intermediate chiral pyrrolidone derivative (IV) is provided.

The present invention is implemented through the following technical solutions.

A method for preparing a brivaracetam intermediate pyrrolidone (IV), comprising: subjecting a γ-lactam intermediate (III) to a 1,4-reduction reaction with a hydrogen source under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone intermediate (IV);

Among them, the R group is an alkyl group or an aryl group, preferably a C1-C6 alkyl group.

In some embodiments, the copper metal in the chiral copper catalyst is selected from anhydrous copper acetate or copper acetate hydrate.

In some embodiments, the chiral ligand in the chiral copper catalyst is selected from (S)-SEGPHOS, (S)-DM-SEGPHOS, (S)-DTBM-SEGPHOS, (S)-BINAP, (S)-Tol-BINAP, (S)-H ₈ -BINAP, (S)-MeO-BIPHEP, (S)-3,5-Xyl-MeOBIPHEP, (S)-3,5-t-Bu-MeOBIPHEP, (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, (S)-C ₃ -TunePhos, (S)-DTBM-C ₃ *-TunePhos, (S,S)-Me-DUPHOS, (S)-ZhaoPhos, (S)-(R)-Josiphos, Josiphos SL-J007-2, (S,S)-Me-DUPHOS, One or more of (S,S)-Et-DUPHOS, (S,S)-i-Pr-DUPHOS, (S,S)-Et-Ferrocelane or (S,S)-Ph-BPE. In some embodiments, the chiral ligand in the chiral copper catalyst is (S)-DTBM-SEGPHOS.

In some embodiments, the molar ratio of copper to the chiral ligand in the chiral copper catalyst is 1:1 to 1:0.1, or 1:0.9, 1:0.8, 1:0.6, 1:0.5, or 1:0.3. In some embodiments, the molar ratio of copper to the chiral ligand in the chiral copper catalyst is 1:1; the molar ratio of compound (III) to the chiral copper catalyst is about 1:0.001 to about 1:0.1. In some embodiments, the molar ratio of compound (III) to the chiral copper catalyst is about 1:0.001 to about 1:0.01. In some embodiments, it is 1:0.01 to 1:0.1. In some embodiments, the molar ratio of copper to the chiral ligand in the chiral copper catalyst is 1:0.001.

In some embodiments, the hydrogen source is selected from polymethylhydrogensiloxane, 1,1,3,3-tetramethyldisiloxane, phenylsilane, diphenylsilane, triphenylsilane, dimethylphenylsilane, methylphenylsilane, diethylsilane, triethylsilane, triethoxysilane, methyldiethoxysilane, pinacol borane, catechol borane, tributyltin hydride, preferably polymethylhydrogensiloxane.

In some embodiments, the reduction reaction solvent is selected from dichloromethane, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentanehexyl methyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, and n-hexane, preferably tetrahydrofuran.

In some embodiments, the reduction reaction temperature is about -20°C to about 50°C, in some embodiments, the reduction reaction temperature is about 10°C to about 40°C, in some embodiments, the reduction reaction temperature is about -10°C, or about 0°C, or about 10°C, or about 20°C, or about 25°C, or about 30°C, or about 40°C.

In some embodiments, the preparation method of the γ-lactam intermediate (III) comprises condensing/reducing a derivative of L-2-aminobutyric acid ester or its salt (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of an organic amine and a reducing agent to generate a dihydropyrrolone intermediate (III);

In some embodiments, the molar ratio of the derivative of L-2-aminobutyric acid ester or its salt (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is 1:1 to 1:1.5.

In some embodiments, the organic amine is selected from triethylamine, diisopropylethylamine, and pyridine, and the reducing agent is a borohydride or a hydride selected from potassium borohydride, sodium borohydride, and sodium cyanoborohydride.

In some embodiments, a method for preparing a γ-lactam intermediate (III) comprises condensing/reducing a derivative of L-2-aminobutyric acid ester or a salt thereof (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to generate a dihydropyrrolone intermediate (III);

In some embodiments, the molar ratio of the derivative of L-2-aminobutyrate or its salt (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is about 1:1 to about 1:1.5, preferably about 1:1.

In some embodiments, a method for preparing brivaracetam comprises converting pyrrolidone (IV) into an amide under aminolysis conditions to generate brivaracetam (V). In some embodiments, the reaction conditions of the aminolysis are to add aqueous ammonia to tetrahydrofuran and carry out the aminolysis reaction at room temperature. In some embodiments, the aminolysis is carried out in a mixture of aqueous ammonia and tetrahydrofuran under heating reflux conditions; in some embodiments, the aminolysis is carried out in an ammonia methanol solution, and the aminolysis reaction temperature can be carried out at room temperature or under heating reflux conditions; in some embodiments, the aminolysis is to pass aqueous ammonia into DMF and react at room temperature to about 80°C; in some embodiments, the aminolysis can also be carried out in a DMF solution of ammonium carbonate at room temperature; in some embodiments, the aminolysis is heated to reflux in an aqueous ammonia and tetrahydrofuran system.

Compounds represented by formula (I), (III) and (IV):

Among them, the R group is an alkyl group, aryl group, or aralkyl group with a length of 1 to 6 carbons.

On the other hand, a method for preparing brivaracetam is provided:

It comprises the following steps:

Reaction a: L-2-aminobutyric acid ester hydrochloride derivative (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) are condensed/reduced in the presence of triethylamine, sodium borohydride and glacial acetic acid to generate dihydropyrrolone intermediate (III);

Reaction b: The γ-lactam intermediate (III) undergoes a 1,4-reduction reaction with a hydrogen source under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone intermediate (IV);

Reaction c: The ester group in pyrrolidone (IV) is converted into an amide under appropriate aminolysis conditions to produce brivaracetam (V).

Reaction a: L-2-aminobutyric acid ester hydrochloride derivative (I) is subjected to condensation/reduction reaction with 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid. After the reaction solution is washed with 1M HCl, the aqueous phase is extracted with dichloromethane, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain a dihydropyrrolone intermediate (III).

According to the preparation method of the dihydropyrrolone intermediate (III) of the present invention, in the general formula, the R group is selected from an alkyl group (with a length of 1 to 6 carbons) and an aryl group, and is preferably a methyl group.

According to the method for preparing the dihydropyrrolone intermediate (III) of the present invention, the molar ratio of L-2-aminobutyric acid methyl ester hydrochloride (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is 1:1 to 1:1.5, preferably 1:1.

Reaction b: A chiral copper catalyst is prepared in situ in a solvent, and a dihydropyrrolidone intermediate (III) is added to the reactor for reduction reaction. The mixture is stirred in the presence of a hydrogen source, and after the reaction is complete, the mixture is washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a pyrrolidone intermediate (IV).

According to the preparation method of pyrrolidone (IV) of the present invention, in the general formula, the R group is selected from alkyl (with a length of 1-6 carbons), aryl, arylalkyl, and is preferably methyl.

According to the preparation method of pyrrolidone (IV) of the present invention, the copper metal source in the in-situ preparation of the chiral copper catalyst is selected from anhydrous copper acetate, copper acetate hydrate, copper sulfate, cuprous chloride/potassium tert-butoxide, cuprous chloride/sodium tert-butoxide, copper chloride, copper fluoride, copper bromide, fluorotri(triphenylphosphine) cuprous, copper oxide, copper hydroxide, and copper carbonate, and is preferably anhydrous copper acetate.

According to the preparation method of pyrrolidone (IV) of the present invention, the chiral ligand in the in-situ preparation of chiral copper catalyst is selected from (S)-SEGPHOS, (S)-DM-SEGPHOS, (S)-DTBM-SEGPHOS, (S)-BINAP, (S)-Tol-BINAP, (S)-H ₈ -BINAP, (S)-MeO-BIPHEP, (S)-3,5-Xyl-MeOBIPHEP, (S)-3,5-t-Bu-MeOBIPHEP, (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, (S)-C ₃ -TunePhos, (S)-DTBM-C ₃ ^* -TunePhos, (S,S)-Me-DUPHOS, (S)-ZhaoPhos, (S)-(R)-Josiphos, Josiphos SL-J007-2, (S,S)-Me-DUPHOS, (S,S)-Et-DUPHOS, (S,S)-i-Pr-DUPHOS, (S,S)-Et-Ferrocelane, (S,S)-Ph-BPE, preferably (S)-DTBM-SEGPHOS.

According to the method for preparing pyrrolidone (IV) of the present invention, the molar ratio of copper to chiral ligand in the chiral copper catalyst is 1:1 to 1:0.1, preferably 1:1.

According to the method for preparing pyrrolidone (IV) of the present invention, the molar ratio of pyrrolidone (IV) to the copper catalyst is 1:0.001 to 1:0.1, preferably 1:0.001.

According to the preparation method of pyrrolidone (IV) of the present invention, the hydrogen source is selected from hydrogen, polymethyl hydrogen siloxane, 1,1,3,3-tetramethyldisiloxane, phenylsilane, diphenylsilane, triphenylsilane, dimethylphenylsilane, methylphenylsilane, diethylsilane, triethylsilane, triethoxysilane, methyldiethoxysilane, pinacol borane, catechol borane, tributyltin hydride, preferably polymethyl hydrogen siloxane.

According to the preparation method of pyrrolidone (IV) of the present invention, the solvent is selected from dichloromethane, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentanehexyl methyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, and n-hexane, and is preferably tetrahydrofuran.

According to the method for preparing pyrrolidone (IV) of the present invention, the reduction reaction temperature is -20°C to 50°C, preferably room temperature.

Reaction c: The pyrrolidone intermediate (IV) is subjected to aminolysis under appropriate conditions. After the reaction is completed, the product is washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which is then recrystallized to obtain pure brivaracetam (V).

According to the preparation method of brivaracetam (Ia) of the present invention, in some embodiments, the reaction conditions of the aminolysis are to add ammonia water to tetrahydrofuran and carry out the aminolysis reaction at room temperature. In some embodiments, the aminolysis is carried out in a mixture of ammonia water and tetrahydrofuran under heating reflux conditions; in some embodiments, the aminolysis is carried out in an ammonia methanol solution, and the aminolysis reaction temperature can be carried out at room temperature or under heating reflux conditions; in some embodiments, the aminolysis is to pass ammonia water into DMF and react at room temperature to about 80°C; in some embodiments, the aminolysis can also be carried out in a DMF solution of ammonium carbonate at room temperature; in some embodiments, the aminolysis is heated to reflux in an ammonia water and tetrahydrofuran system.

One of the above technical solutions has the following advantages or beneficial effects: by using a chiral copper catalyst and screening the optimal chiral ligand, the dihydropyrrolidone intermediate (III) is subjected to asymmetric 1,4-reduction, that is, pyrrolidone (IV) can be prepared with high optical purity and high yield, and the reaction conditions are mild, which is suitable for industrial scale-up production. It only takes three steps to prepare brivaracetam using high optical purity pyrrolidone (IV), the synthetic route is short, the total yield is high, the stereoselectivity is good, and it has great industrial application prospects.

In the present invention, "room temperature" refers to ambient temperature, which is from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C; in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

"Aryl" means an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, and the like, and the like.

"Arylalkyl" refers to an acyclic alkyl group that is bonded to a carbon atom (usually a terminal or sp3 carbon atom) in a hydrogen atom that is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl and the like.Arylalkyl groups can include 7 to 20 carbon atoms, for example, the alkyl moiety is 1 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms.

DETAILED DESCRIPTION

The following provides a specific implementation method of the present invention for preparing brivaracetam (V).

The reagents and raw materials used in the present invention can all be purchased from the market.

Example 1: Preparation of dihydropyrrolidone intermediate (III)

In a 100mL round-bottom flask, L-2-aminobutyric acid methyl ester hydrochloride (Ia) (7.6805g) was dissolved in methanol (50mL), NEt ₃ (17.5mL) was added, and the mixture was stirred at room temperature to dissolve. 5-Hydroxy-4-propyl-2(5H)-furanone (II) (7.1077g) was added and stirred at room temperature for 2h. The reaction solution was cooled to 0℃, and NaBH ₄ (1.8915g) was added in batches. After the addition was completed, stirring was continued at 0℃ for 30min. Glacial acetic acid (12mL) was added at 0℃. The reaction solution was heated to 50℃ and stirred overnight. Cooled to room temperature and concentrated to dryness. The crude product was dissolved in dichloromethane (50mL), and 1M HCl was added until pH <3. After separation of the organic phase, the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Filtered and concentrated to dryness. The crude product was passed through a column (petroleum ether/ethyl acetate 4:1) to obtain a yellow oil (IIIa) (10.5885 g) with a yield of 94%.

MS (m/z): [M+H] ⁺ = 226.14

¹ H NMR (600MHz, Chloroform-d) δ5.70 (s, 1H), 4.60 (dt, J = 10.7, 5.4Hz, 1H), 4.00-3.97 (m, 1H), 3.69 (d, J = 19.0Hz ,1H),3.55(s,3H),2.23(q,J＝8.2,6.0Hz,2H),1.89(dq,J＝13.9,7.0,6.5Hz,1H),1.60(ddt,J＝14.7,7.7 ,3.7Hz,1H),1.47(tt,J＝16.1,13.2,5.9Hz, 2H),0.83(dd,J＝10.4,5.1Hz,3H),0.78-0.75(m,3H)ppm.

Example 2: Preparation of pyrrolidone intermediate (IV)

In a 20mL round-bottom flask, anhydrous copper acetate (3.6mg) and (S)-DTBM-SEGPHOS (23.6mg) were dissolved in THF (degassed) (10mL) and stirred at room temperature for 15min. Polymethylsiloxane (4.8mL) was added and stirred at room temperature for 1 h. The reaction solution turned brown-red. A THF (degassed) solution (10mL) of dihydropyrrolone intermediate (IIIa) (4.5058g) was slowly added dropwise. After the addition was completed, stirring was continued at room temperature overnight. Water (10mL) was added to quench the reaction. Dichloromethane (10mL) was added, and after the organic phase was separated, the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Filtered and concentrated to dryness. The column was passed through with the mobile phase of ethyl acetate/petroleum ether (1:5) to obtain a yellow oil (IVa) (4.1824 g) with a yield of 92% and dr of 99.5:0.5. The diastereomeric ratio dr was determined by HPLC: Daicel Chiralpak IB N-3 column (0.46x25cm), Hexane/iPrOH=95:5, flow rate=1.0 mL/min, λ=210nm, t _R :8.206min(major),9.227min(minor). The diastereomeric ratio (dr) refers to the ratio of (2S)-2-[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butanamide to (2S)-2-[(4S)-2-oxo-4-n-propyl-1-pyrrolidinyl]butanamide.

MS (m/z): [M+H] ⁺ = 228.16

¹ H NMR (600MHz, Chloroform-d) δ4.67(dd,J＝10.9,5.1Hz,1H),3.70(s,3H),3.41(t,J＝8.6Hz,1H),3.11(dd,J ＝9.4,6.8Hz,1H),2.55(dd,J＝16.7,8.5Hz,1H),2.34-2.29(m, 1H),2.12(dd,J＝16.7,7.8Hz,1H),2.01-1.97( m,1H),1.69-1.64(m,1H),1.45(p,J＝10.0, 8.8Hz,2H),1.37-1.31(m,2H),0.93-0.89(m,6H)ppm.

Substrate screening for the asymmetric reduction of dihydropyrrolidine (III) catalyzed by chiral copper catalysts:

Entry 底物 转换率^a dr^a 1 IIIa >99％ 99.5:0.5 2 IIIb <5％^b 95.6:4.4 3 IIIc <5％^c 98.0:2.0 4 IIId <5％^d /

Entry Substrate Conversion ^rate dr ^a 1 IIIa >99% 99.5:0.5 2 IIIb <5% ^b 95.6:4.4 3 IIIc <5% ^c 98.0:2.0 4 IIId <5% ^d /

^a Conversion and diastereomeric ratio (dr) were determined by HPLC; ^b IIIb recovery was 92%; ^c IIIc recovery was 97%; ^d IIId recovery was 96%.

Optimization of chiral ligand conditions for the asymmetric reduction of dihydropyrrolidine (III) catalyzed by chiral copper catalysts:

^aThe conversion and diastereomeric ratio (dr) were determined by HPLC.

Optimization of copper catalyst loading conditions for the asymmetric reduction of dihydropyrrolone (III) catalyzed by chiral copper catalysts:

序号 x 转化率^a dr^a 1 1 >99％ 99.5:0.5 2 0.5 >99％ 99.5:0.5 3 0.25 >99％ 99.5:0.5 4 0.1 >99％ 99.5:0.5

Serial number x Conversion ^rate dr ^a 1 1 >99% 99.5:0.5 2 0.5 >99% 99.5:0.5 3 0.25 >99% 99.5:0.5 4 0.1 >99% 99.5:0.5

^aThe conversion and diastereomeric ratio (dr) were determined by HPLC.

Optimization of reducing agent conditions for asymmetric reduction of dihydropyrrolone (III) catalyzed by chiral copper catalysts:

^aThe conversion and diastereomeric ratio (dr) were determined by HPLC.

Optimization of solvent conditions for the asymmetric reduction of dihydropyrrolone (III) catalyzed by chiral copper catalysts:

序号 溶剂 转化率^a dr^a 1 四氢呋喃 >99％ 99.5:0.5 2 甲苯 36％ 99.4:0.6 3 正庚烷 22％ 99.4:0.6 4 甲基叔丁基醚 80％ 97.3:2.7

Serial number Solvents Conversion ^rate dr ^a 1 Tetrahydrofuran >99% 99.5:0.5 2 Toluene 36% 99.4:0.6 3 n-Heptane twenty two% 99.4:0.6 4 Methyl tert-butyl ether 80% 97.3:2.7

^aThe conversion and diastereomeric ratio (dr) were determined by HPLC.

Example 3: Preparation of Brivaracetam (V)

Dissolve the pyrrolidone intermediate (IV) (2.2715 g) in tetrahydrofuran (20 mL), add 25% ammonia water (20 mL), and heat under reflux overnight. Cool to room temperature, add dichloromethane (10 mL), separate the organic phase, and extract the aqueous phase three times with dichloromethane. Combine the organic phases, wash three times with saturated brine, and dry over anhydrous sodium sulfate. Filter and concentrate to dryness. The obtained solid crude product is recrystallized with methyl tert-butyl ether/n-hexane (5 mL/20 mL) to obtain 2.0168 g of white solid, with a yield of 95% and dr99.9:0.1.

MS (m/z): [M+H] ⁺ = 213.16

¹ H NMR (600MHz, Chloroform-d) δ6.31 (s, 1H), 5.56 (s, 1H), 4.44 (dd, J = 8.8, 6.8Hz, 1H), 3.48 (dd, J = 9.8, 7.9Hz ,1H),3.02(dd,J＝9.8,7.1Hz,1H),2.57(dd,J＝16.8,8.7Hz, 1H),2.33(dq,J＝15.4,7.7Hz,1H),2.07(dd, J＝16.8,8.0Hz,1H),1.93(dp,J＝14.4,7.3Hz, 1H),1.71-1.64(m,1H),1.40(q,J＝7.5Hz,2H),1.31(tdd,J＝12.2,7.6,5.4Hz,2H),0.90(q,J＝7.0Hz,6H )ppm.

The above-described embodiments only represent preferred implementations of the present invention. It should be pointed out that improvements and modifications made by technicians in the field of this technical process using the concepts and methods of the present invention should also be regarded as within the scope of protection of the present invention.

Claims (10)

1. A method for preparing a brivaracetam intermediate pyrrolidone (IV), comprising: subjecting a γ-lactam intermediate (III) to a 1,4-reduction reaction with a hydrogen source under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone intermediate (IV);

Wherein, the R group is an alkyl group or an aryl group, preferably a C1-C6 alkyl group; the copper metal in the chiral copper catalyst is selected from anhydrous copper acetate and copper acetate hydrate; the chiral ligand in the chiral copper catalyst is selected from (S)-SEGPHOS, (S)-DM-SEGPHOS, (S)-DTBM-SEGPHOS, (S)-MeO-BIPHEP, (S)-3,5-Xyl-MeOBIPHEP, (S)-3,5-t-Bu-MeOBIPHEP, (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, (S)-3,5-t-Bu-4-MeO-C ₃ *-TunePhos, and the structure is shown as follows:

Wherein, Ar represents an aromatic group selected from phenyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl; the hydrogen source is selected from one or more of polymethylhydrogensiloxane, 1,1,3,3-tetramethyldisiloxane, triethoxysilane, and methyldiethoxysilane. 2. The preparation method according to claim 1, characterized in that the ratio between the molar amount of copper metal in the copper catalyst and the molar amount of the reactant compound (III) is 0.001-0.1, and the ratio between the molar amount of the chiral ligand in the copper catalyst and the molar amount of the reactant compound (III) is 0.0001-0.01. 3. The preparation method according to claim 1, characterized in that the reduction reaction solvent is selected from one of dichloromethane, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentanehexyl methyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, and n-hexane, or a mixture in any proportion. 4. The preparation method according to claim 1, characterized in that the reduction reaction temperature is -20°C to 50°C. 5. A method for preparing a γ-lactam intermediate (III), which comprises condensing/reducing a derivative of L-2-aminobutyric acid ester or its salt (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of an organic amine and a reducing agent to generate a dihydropyrrolone intermediate (III);

6. The preparation method according to claim 1, wherein the molar ratio of the derivative of L-2-aminobutyric acid ester or its salt (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is 1:1 to 1:1.5. 7. The preparation method according to claim 1, wherein the organic amine is selected from triethylamine, diisopropylethylamine, and pyridine, and the reducing agent is a borohydride or a hydride selected from potassium borohydride, sodium borohydride, and sodium cyanoborohydride. 8. A method for preparing brivaracetam, comprising converting pyrrolidone (IV) into amide under aminolysis conditions to produce brivaracetam (V),

The aminolysis conditions are selected from ammonia water/tetrahydrofuran/room temperature reaction, ammonia water/tetrahydrofuran/heating reflux, ammonia methanol solution/room temperature reaction, ammonia methanol solution/heating reflux, ammonia water/DMF/room temperature reaction, ammonia water/DMF/80°C reaction, and ammonium carbonate/DMF/room temperature reaction. 9. A method for preparing Brivaracetam:

It comprises the following steps: Reaction a: L-2-aminobutyric acid ester hydrochloride derivative (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) are condensed/reduced in the presence of triethylamine, sodium borohydride and glacial acetic acid to generate dihydropyrrolone intermediate (III); Reaction b: The γ-lactam intermediate (III) undergoes a 1,4-reduction reaction with a hydrogen source under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone intermediate (IV); Reaction c: The ester group in pyrrolidone (IV) is converted into an amide under appropriate aminolysis conditions to produce brivaracetam (V). 10. The preparation method according to claim 9, wherein the reaction a specifically comprises: L-2-aminobutyric acid ester hydrochloride derivative (I) is subjected to condensation/reduction reaction with 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid, the reaction solution is acid-washed with 1M HCl, the aqueous phase is extracted with dichloromethane, the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain a dihydropyrrolone intermediate (III).