Preparation methods of briracetam and its intermediates

Abstract

This invention relates to the preparation methods of briracetam and its intermediates, and pertains to the field of pharmaceutical chemical synthesis. Specifically, it describes a method for synthesizing key intermediates of briracetam, namely chiral pyrrolidone derivatives, via an asymmetric reduction reaction catalyzed by a chiral copper catalyst. The advantages of this invention include high reaction yield, low cost, high optical purity of the prepared chiral compounds, a simple and easy-to-implement process route, and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of synthetic chemistry of pharmaceuticals, and relates to a method for preparing brivaracetam and intermediates thereof. BACKGROUND

[0002] Brivaracetam, chemically named as: (2S)-2-[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butyramide, CAS: 357336-20-0, molecular formula: C 11 H 20 N2O2, molecular weight: 317.38, structural formula:

[0003]

[0004] 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-onset seizures with or without secondary generalized seizures in adolescents and adults aged 16 years and older. In 2021, the U.S. Food and Drug Administration (FDA) further approved the expanded indication of brivaracetam, which can be used as a 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 grown from 18 million euros in 2016 to 355 million euros in 2021, so it has a very huge sales scale prospect in the future.

[0005] The patent WO 01 / 62726 first disclosed a route for synthesizing brivaracetam, and the specific method is as follows:

[0006]

[0007] This method first prepared the dihydropyrrolone intermediate (II) through the condensation / reduction reaction of (S)-2-aminobutyramide and 5-hydroxy-4-n-propyl-2-furanone (II). Then, the hydrogenation reaction of intermediate (II) catalyzed by palladium / carbon prepared a diastereoisomer mixture (V) / epi-(V) in a ratio of 50 / 50. Finally, the mixture (V) / epi-(V) was separated by a chiral chromatographic column to finally obtain brivaracetam (V). It was found by research (patent EP1659191B) that the diastereoisomer epi-(V) had no activity in the treatment of epilepsy. Therefore, in this route, the by-product epi-(V) generated in the synthesis of brivaracetam greatly reduced the overall yield and greatly increased the production cost, which is not conducive to large-scale production.

[0008] Similar to the synthesis route of Brivaracetam 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, the same problem of chiral intermediate or final product needing to be separated by chiral chromatographic column is encountered, which greatly reduces the industrial application value of these synthesis routes.

[0009] The document Org. Process Res. Dev. 2016, 20, 1566 reports that although the chiral lactone intermediate of Brivaracetam can be obtained and synthesized by enzyme-catalyzed chiral separation, the enzyme-catalyzed chiral separation also wastes more than half of the material, resulting in a decrease in total yield. Moreover, the synthesis route is lengthy and is not conducive to large-scale production of Brivaracetam.

[0010]

[0011] Since the method of chiral separation will encounter the problem of serious material waste, the development of an asymmetric reaction to obtain the chiral intermediate of Brivaracetam has become a research hotspot in the development of related synthesis routes in recent years. In the process of realizing the present application, the inventors found that at least the above-mentioned problems exist in the prior art, and therefore, in the field of industrial synthesis of Brivaracetam, a simple and environmentally friendly method is urgently needed to be developed to solve a series of problems or at least one of the technical problems encountered in the preparation of Brivaracetam, such as complex process, lengthy steps, waste of raw materials due to chiral separation of racemates, greatly increased preparation time and cost, and generation of environmentally unfriendly waste materials. SUMMARY

[0012] On the one hand, a method for preparing a chiral pyrrolidine derivative (IV), a key intermediate for synthesizing Brivaracetam, by asymmetric reduction of a dihydropyrrolone (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 pyrrolidine derivative (IV) is provided.

[0013] The present application is implemented by the following technical solutions.

[0014] A method for preparing a brivaracetam intermediate pyrrolidinone (IV) comprising: 1,4-reducing a gamma-lactam intermediate (III) with a hydrogen source in the presence of a chiral copper metal catalyst to produce the pyrrolidinone intermediate (IV);

[0015]

[0016] wherein R is an alkyl group, an aryl group, preferably a C1-C6 alkyl group.

[0017] In some embodiments, the copper metal in the chiral copper catalyst is selected from copper acetate anhydrous or copper acetate hydrate.

[0018] In some embodiments, the chiral ligand in the chiral copper catalyst is selected from one or more of (S)-SEGPHOS, (S)-DM-SEGPHOS, (S)-DTBM-SEGPHOS, (S)-BINAP, (S)-Tol-BINAP, (S)-H8-BINAP, (S)-MeO-BIPHEP, (S)-3,5-Xyl-MeOBIPHEP, (S)-3,5-t-Bu-MeOBIPHEP, (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, (S)-C3-TunePhos, (S)-DTBM-C3*-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, or (S,S)-Ph-BPE, in some embodiments, the chiral ligand in the chiral copper catalyst is (S)-DTBM-SEGPHOS.

[0019] In some embodiments, the molar ratio of copper to 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, 1:0.3, in some embodiments, the molar ratio of copper to chiral ligand in the chiral copper catalyst is 1:1; the molar ratio of compound (III) to chiral copper catalyst is about 1:0.001 to about 1:0.1, in some embodiments, the molar ratio of compound (III) to chiral copper catalyst is about 1:0.001 to about 1:0.01, in some embodiments, 1:0.01 to 1:0.1, in some embodiments, the molar ratio of copper to chiral ligand in the chiral copper catalyst is 1:0.001.

[0020] In some embodiments, the hydrogen source is selected from polymethylhydrosiloxane, 1,1,3,3-tetramethyldisiloxane, phenylsilane, diphenylsilane, triphenylsilane, dimethylphenylsilane, methylphenylsilane, diethylsilane, triethylsilane, triethoxysilane, methyldiethoxysilane, pinacol borane, catechol borane, tributyltin hydride, preferably polymethylhydrosiloxane.

[0021] In some embodiments, the reducing reaction solvent is selected from dichloromethane, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, n-hexane, preferably tetrahydrofuran.

[0022] In some embodiments, the reducing reaction temperature is about -20 °C to about 50 °C, in some embodiments, the reducing reaction temperature is about 10 °C to about 40 °C, in some embodiments, the reducing 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.

[0023] In some embodiments, the method for preparing the gamma-lactam intermediate (III) comprises condensation / reduction of the derivative of L-2-aminobutyrate or salt thereof (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of an organic amine, a reducing agent to form the dihydropyrrolone intermediate (III);

[0024]

[0025] In some embodiments, the molar ratio of the derivative of L-2-aminobutyrate or salt thereof (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is about 1:1 to about 1:1.5, preferably about 1:1.

[0026] In some embodiments, the organic amine is selected from triethylamine, diisopropylethylamine, pyridine, and the reducing agent is borohydride or hydride selected from potassium borohydride, sodium borohydride, sodium cyanoborohydride.

[0027] In some embodiments, the method for preparing the gamma-lactam intermediate (III) comprises condensation / reduction of the derivative of L-2-aminobutyrate or salt thereof (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to form the dihydropyrrolone intermediate (III);

[0028] In some embodiments, the molar ratio of the derivative of L-2-aminobutyrate or salt thereof (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is about 1:1 to about 1:1.5, preferably about 1:1.

[0029] In some embodiments, a method of preparing Brivaracetam comprising converting pyrrolidinone (IV) to amide under ammonolysis conditions and forming Brivaracetam (V), in some embodiments, the ammonolysis reaction conditions are ammonolysis in tetrahydrofuran with aqueous ammonia at room temperature, in some embodiments, the ammonolysis is in a mixture of aqueous ammonia and tetrahydrofuran under heating reflux conditions; in some embodiments, the ammonolysis is in an ammonium methanol solution, the ammonolysis reaction temperature can be at room temperature or under heating reflux conditions; in some embodiments, the ammonolysis is in DMF with gassing of aqueous ammonia at room temperature to about 80°C; in some embodiments, the ammonolysis can also be in a DMF solution of ammonium carbonate at room temperature; in some embodiments, the ammonolysis is in aqueous ammonia and tetrahydrofuran system under heating reflux.

[0030] Compounds of formula (I), (III) and (IV):

[0031]

[0032] wherein R is an alkyl group of 1-6 carbons in length, an aryl group, an aralkyl group.

[0033] In another aspect, a method of preparing Brivaracetam is provided:

[0034]

[0035] comprising the steps of:

[0036] Reaction a: condensation / reduction of L-2-aminobutyrate hydrochloride derivative (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to form dihydropyrrolidinone intermediate (III);

[0037] Reaction b: 1,4-reduction of γ-lactam intermediate (III) in the presence of a chiral copper metal catalyst with a hydrogen source to form pyrrolidinone intermediate (IV);

[0038] Reaction c: conversion of the ester group in pyrrolidinone (IV) to amide under appropriate ammonolysis conditions and formation of Brivaracetam (V).

[0039] Reaction a: condensation / reduction of L-2-aminobutyrate hydrochloride derivative (I) and 5-hydroxy-4-propyl-2(5H)-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to form dihydropyrrolidinone intermediate (III);

[0040]

[0041] According to the process for the preparation of the pyrrolidine intermediate (IV) of the present application, the R group in the general formula is selected from alkyl (1-6 carbons in length), aryl, arylalkyl, preferably methyl.

[0042] According to the process for the preparation of the pyrrolidine intermediate (IV) of the present application, the molar ratio of L-methyl 2-aminobutyrate hydrochloride (I) to 5-hydroxy-4-propyl-2(5H)-furanone (II) is 1:1 to 1:1.5, preferably 1:1.

[0043] Reaction b: The reduction reaction is carried out by in situ preparation of chiral copper catalyst in a solvent, adding the dihydropyrrolone intermediate (III) into the reactor. Stirring in the presence of a hydrogen source, after the reaction is complete, washing with water, dichloromethane extraction, drying with anhydrous sodium sulfate, filtering and concentrating to obtain the pyrrolidine intermediate (IV).

[0044]

[0045] According to the process for the preparation of the pyrrolidine intermediate (IV) of the present application, the R group in the general formula is selected from alkyl (1-6 carbons in length), aryl, arylalkyl, preferably methyl.

[0046] According to the process for the preparation of the pyrrolidine intermediate (IV) of the present application, the copper metal source in the in situ preparation of 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, fluorotris(triphenylphosphine)copper, copper oxide, copper hydroxide, copper carbonate, preferably anhydrous copper acetate.

[0047] According to the process for the preparation of the pyrrolidine intermediate (IV) of the present application, 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)-H8-BINAP, (S)-MeO-BIPHEP, (S)-3,5-Xyl-MeOBIPHEP, (S)-3,5-t-Bu-MeOBIPHEP, (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, (S)-C3-TunePhos, (S)-DTBM-C3 *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.

[0048] According to the preparation method of the pyrrolidinone (IV) of the present application, the molar ratio of copper and chiral ligand in the chiral copper catalyst is 1:1-1:0.1, preferably 1:1.

[0049] According to the preparation method of the pyrrolidinone (IV) of the present application, the molar ratio of the pyrrolidinone (IV) and the copper catalyst is 1:0.001-1:0.1, preferably 1:0.001.

[0050] According to the preparation method of the pyrrolidinone (IV) of the present application, the hydrogen source is selected from hydrogen, polymethylhydrosiloxane, 1,1,3,3-tetramethyldisiloxane, phenylsilane, diphenylsilane, triphenylsilane, dimethylphenylsilane, methylphenylsilane, diethylsilane, triethylsilane, triethoxysilane, methyldiethoxysilane, pinacol borane, catechol borane, tributyltin hydride, preferably polymethylhydrosiloxane.

[0051] According to the preparation method of the pyrrolidinone (IV) of the present application, the solvent is selected from dichloromethane, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, n-hexane, preferably tetrahydrofuran.

[0052] According to the preparation method of the pyrrolidinone (IV) of the present application, the temperature of the reduction reaction is -20°C to 50°C, preferably room temperature.

[0053] Reaction c: the pyrrolidinone intermediate (IV) is ammonolysed under appropriate conditions, after the reaction is completed, washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, and after recrystallization, the pure product of brivaracetam (V) is obtained.

[0054]

[0055] According to the method for preparing Brivaracetam (la) of the present application, in some embodiments, the reaction condition of the amination is that the amination is carried out at room temperature in a tetrahydrofuran added with ammonia water, in some embodiments, the amination is carried out in a mixture of ammonia water and tetrahydrofuran under heating reflux condition; in some embodiments, the amination is carried out in an ammonia methanol solution, the amination reaction temperature can be carried out at room temperature or under heating reflux condition; in some embodiments, the amination is carried out in DMF added with ammonia water at room temperature to about 80℃; in some embodiments, the amination can also be carried out in a DMF solution of ammonium carbonate at room temperature; in some embodiments, the amination is carried out in a system of ammonia water and tetrahydrofuran under heating reflux condition.

[0056] One of the above technical solutions has the following advantages or beneficial effects: by using chiral copper catalyst and screening the optimal chiral ligand, the asymmetric 1,4-reduction is carried out on the dihydropyrrolone intermediate (III), so that the pyrrolidone (IV) can be prepared with high optical purity and high yield, and the reaction condition is mild and suitable for industrial scale production. The preparation of Brivaracetam using high optical purity pyrrolidone (IV) only needs three steps, the synthesis route is short, the total yield is high, the stereoselectivity is good, and it has great industrial application prospect.

[0057] In the present application, "room temperature" refers to ambient temperature, which is from about 10℃ to about 40℃. In some embodiments, "room temperature" refers to a temperature from about 20℃ to about 30℃; in other embodiments, "room temperature" refers to a temperature from about 25℃ to about 30℃; in still other embodiments, "room temperature" refers to 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, etc.

[0058] "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, aryl groups 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, as well as analogs.

[0059] "Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenyl-1-yl, and the like. An arylalkyl group can include 7 to 20 carbon atoms, e.g., the alkyl portion is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms. DETAILED DESCRIPTION

[0060] The following provides a specific method of the present application for preparing brivaracetam (V).

[0061] The reagents and materials used in the present application can be purchased from the market.

[0062] Example 1: Preparation of dihydropyrrolone intermediate (III)

[0063]

[0064] In a 100 mL round bottom flask, L-2-aminobutyric acid methyl ester hydrochloride (Ia) (7.6805 g) was dissolved in methanol (50 mL), NEt3(17.5 mL) was added and the solution was stirred at room temperature. 5-Hydroxy-4-propyl-2(5H)-furanone (II) (7.1077 g) was added and the solution was stirred at room temperature for 2 h. The solution was cooled to 0 °C and NaBH4(1.8915 g) was added in portions. After the addition was completed, the solution was stirred at 0 °C for 30 min. At 0 °C, glacial acetic acid (12 mL) was added. The solution was warmed to 50 °C and stirred overnight. The solution was cooled to room temperature and concentrated to dryness. The crude product was dissolved in dichloromethane (50 mL) and 1 M HCl was added to pH < 3. After the organic phase was separated, the aqueous phase was extracted with dichloromethane three times. The organic phases were combined and washed with saturated brine three times and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated to dryness. The crude product was purified by column (petroleum ether / ethyl acetate 4:1) to give yellow oil (IIIa) (10.5885 g) with a yield of 94%.

[0065] MS (m / z): [M+H] + = 226.14

[0066] 1 H NMR (600 MHz, Chloroform-d) δ 5.70 (s, 1H), 4.60 (dt, J = 10.7, 5.4 Hz, 1H), 4.00 - 3.97 (m, 1H), 3.69 (d, J = 19.0 Hz, 1H), 3.55 (s, 3H), 2.23 (q, J = 8.2, 6.0 Hz, 2H), 1.89 (dq, J = 13.9, 7.0, 6.5 Hz, 1H), 1.60 (ddt, J = 14.7, 7.7, 3.7 Hz, 1H), 1.47 (tt, J = 16.1, 13.2, 5.9 Hz, 2H), 0.83 (dd, J = 10.4, 5.1 Hz, 3H), 0.78 - 0.75 (m, 3H) ppm.

[0067] Example 2: Preparation of pyrrolidone intermediate (IV)

[0068]

[0069] 20 mL round bottom flask, copper acetate anhydrous (3.6 mg) and (S)-DTBM-SEGPHOS (23.6 mg) were dissolved in THF (degassed) (10 mL) and stirred at room temperature for 15 min. Polymethylsiloxane (4.8 mL) was added and stirred at room temperature for 1 h, the solution turned to brown red. The solution of dihydropyrrolone intermediate (IIIa) (4.5058 g) in THF (degassed) (10 mL) was added dropwise slowly. After the addition was completed, the stirring was continued at room temperature overnight. The reaction was quenched by the addition of water (10 mL). Dichloromethane (10 mL) was added, after the separation of the organic phase, the aqueous phase was extracted with dichloromethane three times. The organic phases were combined, washed with saturated brine three times and dried over anhydrous sodium sulfate. Filtration, concentrated to dryness. Column chromatography, the flow phase ethyl acetate / petroleum ether (1 :5), yellow oil (IVa) (4.1824 g) was obtained, the yield was 92%, dr 99.5:0.5. The diastereomeric ratio (dr) was determined by HPLC: Daicel Chiralpak IB N-3 column (0.46 x 25 cm), Hexane / iPrOH = 95:5, flow rate = 1.0 mL / min, λ = 210 nm, t R :8.206 min (major), 9.227 min (minor). The diastereomeric ratio (dr) refers to the ratio of (2S)-2–[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butanamide and (2S)-2–[(4S)-2-oxo-4-n-propyl-1-pyrrolidinyl]butanamide.

[0070] MS (m / z): [M+H] + = 228.16

[0071] 1 H NMR (600 MHz, Chloroform-d) δ 4.67 (dd, J = 10.9, 5.1 Hz, 1H), 3.70 (s, 3H), 3.41 (t, J = 8.6 Hz, 1H), 3.11 (dd, J = 9.4, 6.8 Hz, 1H), 2.55 (dd, J = 16.7, 8.5 Hz, 1H), 2.34 - 2.29 (m, 1H), 2.12 (dd, J = 16.7, 7.8 Hz, 1H), 2.01 - 1.97 (m, 1H), 1.69 - 1.64 (m, 1H), 1.45 (p, J = 10.0, 8.8 Hz, 2H), 1.37 - 1.31 (m, 2H), 0.93 - 0.89 (m, 6H) ppm.

[0072] Substrate screening for asymmetric reduction of dihydropyrrolone (III) catalyzed by chiral copper catalyst:

[0073] Entry Substrate conversion rate 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 ]] /

[0074] a Conversion and diastereomeric ratio (dr) were determined by HPLC. b IIIb was recovered in 92 % yield; c IIIc was recovered in 97 % yield; d IIId was recovered in 96 % yield.

[0075] Conditions optimization of the chiral ligand for the asymmetric reduction of the dihydropyrrolone (III) catalyzed by a chiral copper catalyst:

[0076]

[0077]

[0078]

[0079] a Conversion and diastereomeric ratio (dr) were determined by HPLC.

[0080] Conditions optimization of the copper catalyst loading for the asymmetric reduction of the dihydropyrrolone (III) catalyzed by a chiral copper catalyst:

[0081] No. x Conversion 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

[0082] a Conversion and diastereomeric ratio (dr) were determined by HPLC.

[0083] Conditions optimization of the reducing agent for the asymmetric reduction of the dihydropyrrolone (III) catalyzed by a chiral copper catalyst:

[0084]

[0085]

[0086]

[0087] a Conversion and diastereomeric ratio (dr) were determined by HPLC.

[0088] Conditions optimization of the solvent for the asymmetric reduction of the dihydropyrrolone (III) catalyzed by a chiral copper catalyst:

[0089] No. Solvent Conversion a ]] dr a ]]> 1 Tetrahydrofuran >99％ 99.5:0.5 2 Toluene 36％ 99.4:0.6 3 n-Heptane 22％ 99.4:0.6 4 Methyl tert-butyl ether 80％ 97.3:2.7

[0090] a Conversion and diastereomeric ratio (dr) were determined by HPLC.

[0091] Example 3: Preparation of Brivaracetam (V)

[0092]

[0093] The pyrrolidine intermediate (IV) (2.2715 g) was dissolved in tetrahydrofuran (20 mL), 25% ammonia water (20 mL) was added, and heated to reflux overnight. The temperature was lowered to room temperature, dichloromethane (10 mL) was added, and 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. Filtration and concentration to dryness were performed. The obtained solid crude product was recrystallized from methyl tert-butyl ether / n-hexane (5 mL / 20 mL) to obtain 2.0168 g of a white solid, with a yield of 95% and a dr of 99.9:0.1.

[0094] MS (m / z): [M+H] + = 213.16

[0095] 1 H NMR (600 MHz, Chloroform-d) δ 6.31 (s, 1H), 5.56 (s, 1H), 4.44 (dd, J = 8.8, 6.8 Hz, 1H), 3.48 (dd, J = 9.8, 7.9 Hz, 1H), 3.02 (dd, J = 9.8, 7.1 Hz, 1H), 2.57 (dd, J = 16.8, 8.7 Hz, 1H), 2.33 (dq, J = 15.4, 7.7 Hz, 1H), 2.07 (dd, J = 16.8, 8.0 Hz, 1H), 1.93 (dp, J = 14.4, 7.3 Hz, 1H), 1.71 - 1.64 (m, 1H), 1.40 (q, J = 7.5 Hz, 2H), 1.31 (tdd, J = 12.2, 7.6, 5.4 Hz, 2H), 0.90 (q, J = 7.0 Hz, 6H) ppm.

[0096] The above described embodiments only represent the preferred embodiments of the present application, and it should be noted that any improvements and refinements made by those skilled in the art using the concepts and methods of the present application should also be considered within the scope of protection of the present application.

Claims

1. A process for the preparation of a brivaracetam intermediate pyrrolidine (IV) comprising: a 1,4-reduction of the γ-lactam intermediate (III) with a hydrogen source in the presence of a chiral copper catalyst to form a pyrrolidinone intermediate (IV); ， wherein the copper metal in the chiral copper catalyst is selected from copper acetate anhydrous, copper acetate hydrate; the chiral ligand in the chiral copper catalyst is selected from (S)-DTBM-SEGPHOS, (S)-3,5- t -Bu-4-MeO-MeOBIPHEP, (S)-3,5- t -Bu-4-MeO-C3*-TunePhos; the hydrogen source is selected from one or more of polymethylhydrosiloxane, 1,1,3,3-tetramethyldisiloxane; the R group is a C1-C6 alkyl group, the reducing reaction solvent is selected from tetrahydrofuran, the reducing reaction temperature is 10-40 °C.

2. The production method according to claim 1, wherein the ratio between the molar amount of copper metal in the chiral copper catalyst and the molar amount of reactant compound (III) is 0.001-0.1, and the ratio between the molar amount of chiral ligand in the chiral copper catalyst and the molar amount of reactant compound (III) is 0.0001-0.

01.

3. A process for the preparation of Brivaracetam: ； the R group is a C1-C6 alkyl group; which comprises the following steps: Reaction a: condensation / reduction of a derivative of L-2-aminobutyric acid hydrochloride (I) and 5-hydroxy-4-propyl-2(5 H )-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to give the dihydropyrrolone intermediate (III); reaction b: a 1,4-reduction of the γ-lactam intermediate (III) with a hydrogen source in the presence of a chiral copper metal catalyst to form a pyrrolidinone intermediate (IV), in particular a pyrrolidinone intermediate (IV) prepared according to the process of claim 1; reaction c: conversion of the ester group in the pyrrolidinone (IV) to an amide under aminolysis conditions to form Brivaracetam (V).

4. The preparation method according to claim 3, wherein reaction a specifically includes: L-2-aminobutyrate hydrochloride derivative (I) is condensed / reduced with 5-hydroxy-4-propyl-2(5 H )-furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid. The reaction solution is washed with 1 M HCl, and the aqueous phase is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain dihydropyrrolone intermediate (III).

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