CN111848483A - Asymmetric catalytic preparation method of brivaracetam - Google Patents

Abstract

The invention discloses a preparation method of brivaracetam, which adopts hydrogen with low price and easy availability as a hydrogen source, can realize asymmetric preparation of brivaracetam under a catalytic system with rhodium (I) as a metal center, and has the advantages of mild reaction conditions, simplicity, controllability, high yield and enantioselectivity, environmental protection, good atom economy, low cost and the like. In addition, the invention also provides the brivaracetam compound prepared by the method.

Description

Asymmetric catalytic preparation method of brivaracetam

technical field

The invention belongs to the technical field of chemical synthesis, and in particular relates to an asymmetric catalytic preparation method of brivaracetam.

Background technique

Brivaracetam is the latest third-generation anti-epileptic drug developed by Belgian UCB Company. It was approved by the EMA and FDA in January and February 2016 respectively. structural derivatives. As a novel antiepileptic drug, brivaracetam can be used for the treatment of partial seizures in epilepsy patients aged 16 years and older, as well as for the adjuvant treatment of generalized epilepsy with or without secondary seizures.

The structures of brivaracetam and levetiracetan are very similar, and both belong to pyrrolidone derivatives. Compared with the chemical structure of levetiracetam, brivaracetam only has an n-propyl group attached to the 4-position of pyrrolidine, but the binding force of brivaracetam is 10 times that of levetiracetam. It has better pharmacological activity, clinical efficacy and safety, such as high bioavailability and short time to peak. Because of its good medicinal value and market prospects, it is expected to become another blockbuster antiepileptic drug after levetiracetam.

The synthesis involving brivaracetam mainly includes the following:

(1) Preparation of diastereomers by chiral chromatography or chiral reagent resolution

The typical preparation route comes from the preparation method (route a) of the original UCB company's Buiracetam disclosed in CN 1882535. First, the unsaturated lactam intermediate (I) is prepared, and then the Pd/C hydrogenation reduction is carried out to obtain Buisy. The mixture of tan-diastereoisomers is finally separated by chiral column chromatography to obtain brivaracetam with higher purity. On this basis, more improved methods have emerged. For example, in WO 2007065634A1, the Pd/C catalyst is replaced by a precious metal catalyst RuCl ₃ and in CN106748950A, brivaracetam is prepared by using equivalent chiral phenethylamine as a resolution reagent, but , these methods are all diastereoisomeric separation processes, which not only consume a large amount of separation reagents and solvents, which are time-consuming and labor-intensive, but also have poor atom economy and high production costs.

2) Preparation from chiral starting materials

Patent CN 106279074A discloses a new preparation method (route b) of brivaracetam, which starts from chiral raw material (R)-4-n-propyl-dihydrofuran-2-one, goes through bromination, Amine alkylation, lactam condensation, 3-step reaction to obtain the target product. However, the reaction steps of this route are relatively long, the total reaction yield is low, a large amount of expensive condensing agent needs to be used during the amide condensation, the production cost is high, and it is difficult to be used in industrial production.

3) Preparation by asymmetric catalytic hydrogenation

Patent CN104892483 provides a kind of preparation of cloth by asymmetric catalytic hydrogenation of unsaturated lactam intermediate (I) in the presence of cuprous chloride, (R)-DTBM-SegPhos, sodium tert-butoxide and polymethyl hydrogen siloxane Methods of Varacetam and Its Analogs. However, this method must use a silicon hydride compound with high atom economy and cost as the hydrogen source. Due to the high boiling point of its unreacted products and by-products, separation and purification treatment is required, although it is mentioned in the description that this method can be used instead. Hydrogen can be used as a hydrogen source, but the Cu catalytic hydrogenation reaction using hydrogen as a hydrogen source has not yet had any successful reports, and the application also does not have any embodiment records, so it cannot be realized at all, in addition, the method also needs to use preparation difficulty and Only the bulky sterically hindered ligand DTBM-SegPhos with higher price can achieve ideal results, which further increases the cost in process application.

Therefore, it is of great significance to develop a simpler, efficient, green and low-cost method for preparing brivaracetam.

SUMMARY OF THE INVENTION

definition

To facilitate the understanding of the present invention, unless otherwise specified, some terms, abbreviations or other abbreviations used herein are defined as follows.

"Alkyl", when used alone or in combination with other groups, represents a saturated straight or branched chain group containing 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- Butyl, sec-butyl, tert-butyl, pentyl, n-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and n-decyl, etc.

"Aryl", when used alone or in combination with other groups, refers to an optionally substituted aromatic carbocyclic group containing 1, 2 or 3 rings connected by linkage or fusion, such as : phenyl, biphenyl, naphthyl, tetralin, indane, which may be further substituted by other aryl or aryl-containing substituents.

"Heteroaryl", when used alone or in combination with other groups, refers to an optionally substituted aromatic heterocyclic group containing 1 or 2 rings, and the heteroatoms on the heterocyclic ring are 1 to 3, the same or different, selected from O, N, S, such as: phenyl, biphenyl, naphthyl, tetralin, indane, which may be further substituted by other aryl or aryl-containing substituents.

COD represents 1,5-cyclooctadiene.

COT stands for cyclooctatetraene.

NBD stands for norbornadiene.

Detailed description of the invention

In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a method for preparing brivaracetam, which uses chiral rhodium (I)-ligand complex as a catalyst, and uses hydrogen as a hydrogen source, which can The chiral preparation of brivaracetam under mild conditions has the advantages of cheap and easily available ligands, simple reaction, high yield, good enantioselectivity, low cost, and environmental protection.

The preparation method of brivaracetam provided by the present invention comprises: in the presence of a rhodium (I) catalyst, the compound of formula (I) undergoes an asymmetric catalytic hydrogenation reaction in a hydrogen atmosphere and an organic solvent to generate a compound represented by formula (II) ,

Wherein, the rhodium (I) catalyst is generated by mixing the rhodium metal precursor and the ligand;

The ligand has the structure shown in the following formula (III),

in,

R is H, D, CF ₃ or C ₁ -C ₃ alkyl;

Ar is an aryl group or a heteroaryl group, wherein each aryl group and heteroaryl group is optionally independently selected from one or more of D, F, Cl, Br, I, CN, NO ₂ , CF ₃ , C ₁ . -C ₄ alkyl, C ₁ -C ₄ alkoxy group substituted.

In some embodiments, R is H, D, _CF3 , methyl, ethyl, or isopropyl;

In some embodiments, Ar is aryl or heteroaryl, wherein each aryl and heteroaryl are optionally independently selected from D, F, Cl, Br, I, CN by 1-3 or 5 , NO ₂ , CF ₃ , methyl, ethyl, methoxy groups are substituted.

In some instances, the ligand is selected from _IIIa - _IIIj , wherein _IIIa - _IIIj , in turn, are compounds of formula (III) having the following combinations of R and Ar groups:

III _a : R=H, Ar=Ph;

_IIIb : R=Me, Ar=Ph;

_IIIc : R=H, Ar=p-Me-Ph;

III _d : R=H, Ar=p-MeO-Ph;

III _e : R=H, Ar=3,5-di-Me-Ph;

III _f : R=H, Ar=3,5-di-Me-4-MeO-Ph;

_IIIg : R=H, Ar=3,5-di-MeO-Ph;

III _h : R=H, Ar=3,5-di-MeO-4-Me-Ph;

III _i : R=H, Ar=3,4,5-tri-MeO-Ph;

III _j : R=Me, Ar=3,4,5-tri-Me-Ph.

Preferably, the ligand is selected from III _e to III _j .

In some embodiments, the rhodium (I) catalyst is generated by pre-complexing rhodium metal precursors and ligands in an organic solvent, and then mixed with other reaction system components for reaction; or, the rhodium (I) catalyst is composed of The rhodium metal precursor and the ligand are mixed in the reaction system and then complexed in-situ, thereby directly participating in the reaction with other components in the reaction system.

The preparation and transfer of the rhodium(I) catalyst is carried out under an inert atmosphere.

In some embodiments, the rhodium metal precursor is a rhodium(I) complex having the general formula RhY ¹ Y ² X or RhY ¹ Z ¹ Z ² X or a rhodium (I) complex having the general formula [RhY ¹ X] ₂ or [RhZ ¹ Z ² X] the dimerized rhodium (I) complex of ₂ , wherein Y ¹ , Y ² are independently selected from norbornadiene (NBD) or 1,5-cyclooctadiene (COD), Z ¹ , Z 1 ² is independently selected from ethylene or _PPh3 , and X is selected from F, Cl, Br, I, OH, BF4, _SbF6 , _OTf , _PF6 or _PPh2 .

In some embodiments, the rhodium metal precursor is selected from Rh(NBD) _2BF4 , Rh(COD _{) 2BF4} , Rh(COD) _2Cl , Rh(COD _{) 2SbF6} , Rh(COD _{) 2} OTf, [Rh(COD)(PPh ₃ ) ₂ ]BF ₄ , [Rh(NBD)Cl] ₂ , [Rh(COD)BF ₄ ] ₂ , [Rh(COD)Cl] ₂ , [Rh(ethylene) ₂ A mixture of one or more of Cl] ₂ , [Rh(COD)PF ₆ ] ₂ , [Rh(COD)PPh ₂ ] ₂ and [Rh(COD)OH] ₂ .

In some embodiments, the molar percentage of the rhodium (I) catalyst relative to the compound of formula (I) is 0.1% to 5%; preferably 0.5% to 3%, more preferably 1%.

In some embodiments, the feeding ratio of rhodium metal precursor to ligand is 1:1 to 1:1.2, preferably 1:1.1.

The system for asymmetric catalytic hydrogenation provided by the present invention is a homogeneous system.

In some embodiments, the organic solvent is selected from chloroform, dichloromethane, 1,2-dichloroethane, isopropanol, ethanol, methanol, trifluoroethanol, 1,4-dioxane, tetrahydrofuran, Mixing of one or more of acetonitrile, preferably a mixed solvent of dichloromethane and tetrahydrofuran, more preferably, in the mixed solvent, the volume ratio of dichloromethane to tetrahydrofuran is 1: 1 to 1: 5, particularly preferably Typically, the volume ratio of dichloromethane to tetrahydrofuran is 1:2 to 1:3.

In some embodiments, the molar volume ratio (mol/L) of the compound of formula (I) to the organic solvent is 1:1 to 1:100, preferably, the molar volume ratio of the compound of formula (I) to the organic solvent is 1:1 ~1:10.

In some embodiments, the temperature of the reaction is 15-60°C; preferably, the temperature of the reaction is 25-45°C; more preferably, the temperature of the reaction is 35°C.

In some embodiments, the pressure of the hydrogen atmosphere is 1-10 Mpa, preferably 3-8 Mpa, more preferably 5.5-6.5 MPa, such as 60 atm or 6 Mpa.

In some embodiments, the average reaction time is 48-72 hours.

In addition, one aspect of the present invention also provides a brivaracetam compound prepared by applying the aforementioned method for preparing brivaracetam, which has the structure shown in the following formula (II):

Beneficial effects:

The invention provides a preparation method of brivaracetam. The method adopts hydrogen as the hydrogen source, and can realize the asymmetric preparation of brivaracetam under the catalytic system in which rhodium (I) is the metal center, and has mild reaction conditions. , high yield and enantioselectivity, green environmental protection, low cost and other advantages.

Specifically, the reaction system adopted by the brivaracetam preparation method provided by the invention has the following advantages:

(1) For the first time, cheap and readily available hydrogen is used instead of expensive silicon hydrogen as the hydrogen source to realize asymmetric catalytic hydrogenation to prepare brivaracetam, which is not only one-step, no need to split diastereomers; and no reagent by-products are generated, Atomic economy, green environmental protection, simple post-processing.

(2) Hydrogen is cheap and easy to obtain and is widely used. The ligand used in the present invention is simple to prepare, mature in method, less catalyst dosage, mild and easy to control reaction conditions, simple post-processing, and low in raw materials, operation steps and post-processing costs.

(3) Through the optimization and screening of reaction conditions, it is found that under the condition of a certain proportion of DCM and THF mixed solvent, the hydrogenation reduction of brivaracetam can obtain ideal yield and ee value

(4) Near-equivalent product conversion with an ee value as high as 99%, with excellent yield and stereoselectivity control.

Detailed ways

In order to make the present invention easy to understand, the present invention will be further described with reference to specific embodiments.

The experimental methods for which specific conditions are not specified in the examples are usually in accordance with the conventional conditions and the conditions described in the manual, or in accordance with the conditions suggested by the manufacturer; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial channels. .

Example 1

To the reaction vessel were added n-heptane (394 mL) and morpholine (128 mL). The mixture was cooled to 0°C and glyoxylic acid 1 (195 g, 150 mL, 50 w% in water) was added. The mixture was heated at 20°C for 1 hour, then n-valeraldehyde 2 (149 mL) was added. The reaction mixture was heated at 45°C for 20 hours, and after cooling to 20°C, 37% aqueous hydrochloric acid (197 mL) was slowly added to the reaction mixture, and stirring was continued for 2 hours. After the reaction, the n-heptane was removed by liquid separation, and the aqueous phase was washed three times with n-heptane. Diisopropyl ether was added to extract the organic phase, the organic phases were combined, washed with saturated brine, and then dried by azeotropic distillation. After filtering and concentrating the solvent, 165 g of 5-hydroxy-4-n-propylfuran-2-one, namely compound 3, was obtained, and the reaction yield was 88%.

Example 2

Add (S)-2-aminobutanamide 4 (250g) and 500mL isopropanol in the there-necked flask of 1000mL with mechanical stirring function, add 5-hydroxyl-4-n-propyl furan- 2-keto 3 (290 g), and the mixture was heated to 30 °C. The reaction was maintained at this temperature for 3 hours, and the mother liquor was concentrated to obtain a crude product, which was purified by silica gel column to obtain 336 g of the product, namely compound 5, with a reaction yield of 80%.

Embodiment 3 (catalyst type investigation and condition screening)

In the glove box, weigh bisphosphine ligand (0.011 mmol), Rh(NBD) ₂ BF ₄ (3.7 mg, 0.01 mmol), add 1 mL of ultra-dry solvent, stir at room temperature for 40 minutes, and prepare a concentration of 0.01 mol/L Catalyst metal complex solution, the catalyst solution can be directly used for homogeneous catalytic hydrogenation.

Under argon atmosphere, the prepared catalyst solution (100uL, 0.001mmol) was added to compound 5 (0.1mmol, 21mg), and then 0.9mL of solvent was added, the reaction tube was placed in an autoclave, and the autoclave was replaced with hydrogen The gas in the medium is three times, and finally 60 atm of hydrogen is charged, and the reaction is carried out in a constant temperature oil bath at a certain temperature (T ° C) for 48 hours. After the reaction is finished, the gas in the autoclave is slowly released, the reaction mixture is purified with a silica gel short column, and the concentrated filtrate is vacuum-dried to obtain a white solid, namely brivaracetam 6, and HPLC records the conversion rate and the ee value, and the results are shown in Table 1 below. Show.

Table 1.

a: Hydrogen pressure is 30atm

Embodiment 4 (similar catalyst derivative investigation)

In the glove box, weigh bisphosphine ligand III (0.011 mmol), Rh(NBD) ₂ BF ₄ (3.7 mg, 0.01 mmol), add 1 mL of ultra-dry DCM and THF in a mixed solvent prepared at a volume ratio of 1:2 , and stirred at room temperature for 40 minutes to prepare a solution with a concentration of 0.01 mol/L of the catalyst metal complex.

Under an argon atmosphere, compound 5 (0.1 mmol, 21 mg) was added with the prepared catalyst solution (100 uL, 0.001 mmol), and then 0.9 MI DCM and THF were added in a mixed solvent prepared at a volume ratio of 1:2. The reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 60 atm of hydrogen was charged, and the reaction was carried out in a constant temperature oil bath at 35°C for 48 hours. After the reaction is finished, the gas in the autoclave is slowly released, the reaction mixture is purified with a silica gel short column, and the concentrated filtrate is vacuum-dried to obtain a white solid, namely brivaracetam 6, and HPLC records the conversion rate and the ee value, and the results are as follows in Table 2 shown.

Table 2

Example 5

In a glove box, weigh bisphosphine ligand III _f (DMBM-Zhaophos, 12.5 mg, 0.011 mmol), Rh(COD) ₂ BF ₄ (4.1 mg, 0.01 mmol), add 1 mL of ultra-dry DCM and THF according to the volume ratio A mixed solvent prepared in a ratio of 1:2 was stirred at room temperature for 40 minutes to prepare a catalyst metal complex with a concentration of 0.01 mol/L, and the catalyst solution could be directly used for homogeneous catalytic hydrogenation.

Under an argon atmosphere, compound 5 (0.1 mmol, 21 mg) was added with the prepared catalyst solution (100 uL, 0.001 mmol), and then 0.9 mL of a mixed solvent prepared with DCM and THF in a volume ratio of 1:2 was added. The reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 60 atm of hydrogen was charged, and the reaction was carried out in a constant temperature oil bath at 35°C for 48 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified with a silica gel short column, and the concentrated filtrate was vacuum-dried to obtain a white solid, namely brivaracetam 6, the reaction yield was 96%, and the HPLC measured 99% ee.

Example 6

In a glove box, weigh out Bisphosphine Ligand III _f (DMBM-Zhaophos, 12.5 mg, 0.011 mmol), [Rh(COD)Cl] ₂ (2.5 mg, 0.005 mmol), add 1 mL of ultra-dry DCM and THF by volume The mixed solvent prepared with a ratio of 1:2 was stirred at room temperature for 40 minutes to prepare a catalyst metal complex with a concentration of 0.01 mol/L, and the catalyst solution could be directly used in the homogeneous catalytic hydrogenation reaction.

Under an argon atmosphere, compound 5 (0.1 mmol, 21 mg) was added with the prepared catalyst solution (100 uL, 0.001 mmol), and then 0.9 mL of a mixed solvent prepared with DCM and THF in a volume ratio of 1:2 was added. The reaction tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 60 atm of hydrogen was charged, and the reaction was carried out in a constant temperature oil bath at 35°C for 48 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified with a silica gel short column, and the concentrated filtrate was vacuum-dried to obtain a white solid, namely brivaracetam 6, with a reaction yield of 94% and 97% ee measured by HPLC.

Example 7 (enlarged)

In the glove box, weigh bisphosphine ligand III _f (DMBM-Zhaophos, 50.1 mg, 0.044 mmol), Rh(NBD) ₂ BF ₄ (15 mg, 0.04 mmol), add 10 mL of DCM and THF according to the volume ratio of 1: 2. The prepared mixed solvent is stirred at room temperature for 40 minutes to prepare a catalyst metal complex with a concentration of 0.004 mol/L, and the catalyst solution can be directly used in the homogeneous catalytic hydrogenation reaction.

Under an argon atmosphere, the prepared catalyst solution (10 mL, 0.04 mmol) was added to compound 5 (40 mmol, 8.4 g), and then 280 mL of a mixed solvent prepared with DCM and THF in a volume ratio of 1:2 was added. The tube was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 60 atm of hydrogen was charged, and the reaction was carried out in a constant temperature oil bath at 35°C for 60 hours. After the reaction, the gas in the autoclave was slowly released, the reaction mixture was purified with a silica gel short column, and the concentrated filtrate was vacuum-dried to obtain a white solid, namely brivaracetam 6, the reaction yield was 97%, and the HPLC measured 99% ee.

Claims (10)

1. the preparation method of brivaracetam, is characterized in that: comprise formula (I) compound in the presence of rhodium (I) catalyst, react in hydrogen atmosphere and organic solvent, generate compound shown in formula (II),

Wherein, the rhodium (I) catalyst is generated by mixing the rhodium metal precursor and the ligand; The ligand has the structure shown in the following formula (III),

in, R is H, D, CF ₃ or C ₁ -C ₃ alkyl; Ar is an aryl group or a heteroaryl group, wherein each aryl group and heteroaryl group is optionally independently selected from one or more of D, F, Cl, Br, I, CN, NO ₂ , CF ₃ , C ₁ . -C ₄ alkyl, C ₁ -C ₄ alkoxy group substituted. 2. the preparation method of brivaracetam according to claim 1, is characterized in that: R is H, D, _CF3 , methyl, ethyl or isopropyl; And/or, Ar is an aryl group or a heteroaryl group, wherein each aryl group and heteroaryl group are optionally independently selected from D, F, Cl, Br, I, CN, NO ₂ , CF ₃ , methyl, ethyl, methoxy groups are substituted; And/or, the substituents on the aryl group and the heteroaryl group are 1, 2, 3 or 5. 3. the preparation method of brivaracetam according to claim 1, is characterized in that, described ligand is selected from compound _IIIa ～ _IIIj with following R and Ar group combination, III _a : R=H, Ar=Ph; _IIIb : R=Me, Ar=Ph; _IIIc : R=H, Ar=p-Me-Ph; III _d : R=H, Ar=p-MeO-Ph; III _e : R=H, Ar=3,5-di-Me-Ph; III _f : R=H, Ar=3,5-di-Me-4-MeO-Ph; _IIIg : R=H, Ar=3,5-di-MeO-Ph; III _h : R=H, Ar=3,5-di-MeO-4-Me-Ph; III _i : R=H, Ar=3,4,5-tri-MeO-Ph; III _j : R=Me, Ar=3,4,5-tri-Me-Ph. 4. the preparation method of brivaracetam according to claim 1, is characterized in that, described rhodium metal precursor is the rhodium (I) complex with general formula RhY ¹ Y ² X or RhY ¹ Z ¹ Z ² X compound or a dimerized rhodium (I) complex with the general formula [RhY ¹ X] ₂ or [RhZ ¹ Z ² X] ₂ , wherein Y ¹ and Y ² are independently norbornadiene NBD, 1, 5-cyclooctadiene COD, cyclooctatetraene COT, Z ¹ , Z ² are independently ethylene or PPh ₃ , X is F, Cl, Br, I, OH, BF ₄ , SbF ₆ , OTf, PF ₆ or _PPh2 ; And/or, the molar percentage of the rhodium (I) catalyst relative to the compound of formula (I) is 0.1% to 5%. 5. The preparation method of brivaracetam according to claim 4, wherein the rhodium metal precursor is selected from Rh(NBD) ₂ BF ₄ , Rh(COD) ₂ BF ₄ , Rh(COD) ₂ Cl, Rh(COD) ₂ SbF ₆ , Rh(COD) ₂ OTf, [Rh(COD)(PPh ₃ ) ₂ ]BF ₄ , [Rh(NBD)Cl] ₂ , [Rh(COD)BF ₄ ] ₂ , One of [Rh(COD)Cl] ₂ , [Rh(ethylene) ₂ Cl] ₂ , [Rh(COD)PF ₆ ] ₂ , [Rh(COD)PPh ₂ ] ₂ and [Rh(COD)OH] ₂ or a mixture of various. 6. the preparation method of brivaracetam according to any one of claim 1 to 5, is characterized in that, The rhodium (I) catalyst is generated by pre-complexing a rhodium metal precursor and a ligand in an organic solvent, or the rhodium (I) catalyst is in-situ complexed by mixing the rhodium metal precursor and the ligand in the reaction system. synthesized; And/or, the ligand is selected from III _e to III _j ; And/or, the molar percentage of the rhodium (I) catalyst relative to the compound of formula (I) is 0.1% to 1%; And/or, the feeding ratio of the rhodium metal precursor to the ligand is 1:1 to 1:1.2. 7. the preparation method of brivaracetam according to any one of claim 1 to 5, is characterized in that, The organic solvent is selected from one of chloroform, dichloromethane, 1,2-dichloroethane, isopropanol, ethanol, methanol, trifluoroethanol, 1,4-dioxane, tetrahydrofuran, acetonitrile or Various mixes. 8. the preparation method of brivaracetam according to any one of claim 1 to 5, is characterized in that, The organic solvent is a mixed solvent of dichloromethane and tetrahydrofuran; And/or, the molar volume ratio (mol/L) of the compound of formula (I) to the organic solvent is 1:1 to 1:100; And/or, the temperature of the reaction is 15-60°C; And/or, the pressure of the hydrogen atmosphere is 1-10 Mpa. 9. the preparation method of brivaracetam according to any one of claim 1 to 5, is characterized in that, The organic solvent is a mixed solvent in which the volume ratio of dichloromethane and tetrahydrofuran is 1:1 to 1:5; The molar volume ratio mol/L of the compound of formula (I) to the organic solvent is 1:1 to 1:10; And/or, the temperature of the reaction is 25～45℃; And/or, the pressure of the hydrogen atmosphere is 3-8 Mpa. 10. The brivaracetam compound prepared by the preparation method of any one of claims 1 to 9.