Preparation method of brivaracetam and its intermediates

Abstract

The present invention discloses a method for preparing a bu Waxitan intermediate shown in formula B-R, comprising reacting a compound shown in formula B-P with a resolving agent to prepare a compound shown in formula B-Q; and converting the compound shown in formula B-Q into a bu Waxitan intermediate shown in formula B-R, wherein the resolving agent is a (1S, 2S)-(+)-1,2-cyclohexanediamine compound. The present invention also provides a method for preparing bu Waxitan. The method of the present invention can conveniently and effectively split a mixture of two diastereoisomers of (2S)-2-(2-oxo-4-propylpyrrolidine-1-yl)butyric acid, avoids the use of a chiral chromatographic column, greatly shortens the process time, simplifies the operation and reduces the process cost, and is conducive to industrial production and environmental protection.

Description

Technical Field

[0001] The invention relates to a preparation method of brivaracetam and an intermediate thereof, and belongs to the technical field of medicines. Background Art

[0002] Brivaracetam, with the chemical name (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide, was developed by UCB Pharma of Belgium. It is an analog of the antiepileptic drug levetiracetam, in which a propyl group is attached to the 4-carbon atom of the pyrrolidine. Brivaracetam is also a selective and high-affinity ligand for the brain synaptic vesicle protein 2a (SV2A), which is an important site for inhibiting partial epileptic seizures. The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) approved Brivaracetam on January 14, 2016 and February 18, 2016, respectively, for the adjunctive treatment of patients aged 16 years and older with partial epilepsy with or without secondary generalized seizures. The trade name is This drug is a derivative of levetiracetam and belongs to the third generation of anti-epileptic drugs.

[0003] At present, including the original drug, the existing preparation process of buvacetham almost inevitably uses a chiral chromatographic column to separate its non-corresponding isomer (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]butanamide. For example, the original drug patent WO 2005028435 mentioned that at a temperature of 25±2°C, a chiral solid phase and n-hexane / ethanol (45 / 55, V / V) were used as eluents to separate the two diastereomers by chromatography. WO 2007065634 uses another synthetic route, using an expensive metal catalyst RuCl3. This preparation method also inevitably obtains buvacetham (26%, ee=94%) and its diastereomers by column chromatography. The structures of buvacetham and its diastereomers are as follows:

[0004]

[0005] Patent document CN106748950A reports a method for preparing a brivaracetam intermediate, and the reaction route is as follows:

[0006]

[0007] It uses an R-phenylethylamine / isopropanol system to split the compound mixture shown in B-IV to obtain the buvacethamine intermediate shown in B-VI. The intermediate is used to prepare buvacethamine without the need for a chiral chromatographic column for splitting, thereby reducing production costs. However, after repeating the examples in the document, the inventors of the present application found that the buvacethamine intermediate shown in B-VI could only be obtained at a very low yield, and the content of the SS isomer was not significantly reduced. Therefore, this method has no obvious splitting and purification effect and is not industrially practical.

[0008] In view of the high production cost and poor industrial feasibility of the existing preparation methods, there is an urgent need to provide a simpler and repeatable industrial production method for preparing high-purity brivaracetam. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing a brivaracetam intermediate represented by formula BR, and a method for preparing high-purity brivaracetam from the intermediate.

[0010] In one aspect, the present invention provides a method for preparing a brivaracetam intermediate represented by the following formula BR, comprising:

[0011] (1) reacting the compound represented by formula BP with a resolving agent to prepare a compound represented by formula BQ; and

[0012] (2) converting the compound represented by formula BQ into the brivaracetam intermediate represented by formula BR;

[0013]

[0014] The resolving agent is a (1S, 2S)-(+)-1,2-cyclohexanediamine compound having the following formula (I):

[0015]

[0016] In formula (I), R1, R2 and R3 are independently H, CH3 or Ts, and R1, R2 and R3 are not Ts at the same time.

[0017] In the present invention, the compound represented by formula BP is a mixture of two diastereoisomers of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanoic acid. Ts is p-toluenesulfonyl.

[0018] The inventors of the present application have conducted in-depth research on the prior art and found that some splitting reagents reported in the prior art, such as R-phenylethylamine, cannot achieve the splitting of the compound represented by BP; however, during further exploration, the inventors unexpectedly discovered that the specific splitting reagents described above can effectively split the brivaracetam intermediate represented by formula BR from the compound represented by formula BP.

[0019] In some embodiments, the resolving agent can be selected from 1S,2S-cyclohexanediamine, 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine, (1S,2S)-N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine and N-((1S,2S)-2-(dimethylamino)cyclohexyl)-4-toluenesulfonamide or any combination thereof.

[0020] The inventors further found that as the molar ratio of the resolving agent and the compound represented by formula BP increases, the yield of the compound represented by BQ first increases and then decreases; after the chiral purity increases to a certain extent, it basically does not change. Taking into account the yield, chiral purity and cost factors, the molar ratio of the compound represented by formula BP and the resolving agent should be controlled. In some embodiments, the molar ratio of the compound represented by formula BP to the resolving agent is 1: (0.8-1.5), preferably 1: 1.

[0021] In the above method, step (1) may further include:

[0022] a. dissolving the compound represented by formula BP and the resolving agent in a resolving solvent, dissolving the solid at the resolving temperature to obtain a clear solution, cooling the solution to crystallize, and separating the crystals to obtain a crude solid product of the compound represented by formula BQ;

[0023] b. The above crude solid product is recrystallized in a recrystallization solvent, and the crystals are separated to obtain the compound represented by formula BQ.

[0024] In some embodiments, the resolution solvent can be selected from methyl tert-butyl ether (MTBE), isopropyl ether, tetrahydrofuran (THF), acetonitrile, ethyl acetate (EA), isopropyl acetate (IPAC), isopropanol and dimethyl ether (DME) or any combination thereof, preferably selected from isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether or any combination thereof.

[0025] The inventors of the present application further discovered that as the volume mass ratio of the resolution solvent to the compound represented by BP increases, the yield of the compound represented by the product BQ gradually decreases, but the chiral purity increases. Taking into account the yield and chiral purity of the compound represented by BQ, in some embodiments, the ratio of the volume of the resolution solvent to the mass of the mixture of diastereomers can be (1-30) mL: 1 g, preferably (1-10) mL: 1 g, and more preferably (3-6) mL: 1 g. Within the above ratio range, a compound represented by formula BQ with a higher yield and chiral purity can be obtained.

[0026] In some embodiments, the resolution temperature is 1-100°C, preferably 50-75°C.

[0027] In step b, the recrystallization solvent can be selected from MTBE, acetonitrile, ethyl acetate, IPAC and DME or any combination thereof, preferably selected from isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether or any combination thereof. The compound BQ obtained using the above recrystallization solvent has good chiral purity, especially when at least one of isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether is used as the recrystallization solvent, the chiral purity of the compound BQ can reach more than 99%.

[0028] In step b, the ratio of the volume of the recrystallization solvent to the mass of the solid crude product of the compound represented by formula BQ is (1-30) mL:1 g, preferably (1-10) mL:1 g, and more preferably 3 mL:1 g.

[0029] In some embodiments, the separation in the method of the present invention can be achieved by filtration.

[0030] In the above method, step (2) may include: converting the compound represented by formula BQ into a brivaracetam intermediate represented by formula BR in a reaction solvent in the presence of an acid.

[0031] The reaction solvent described in step (2) can be selected from isopropanol, ethyl acetate, isopropyl acetate and water. In particular, the reaction solvent described in step (2) can be water, or a combination of water and an organic solvent selected from isopropanol, ethyl acetate and isopropyl acetate. The above organic solvents can be used alone or in combination in any proportion.

[0032] The inventors have discovered that by reacting the compound represented by BQ with an acid, the compound represented by BQ can be decomposed into the compound represented by BR and a salt of a resolving agent; the compound represented by BR is insoluble in water but soluble in an organic solvent, but the salt of the resolving agent is soluble in water. Based on this difference in solubility, the compound represented by BR can be separated using the above-mentioned reaction solvent.

[0033] Regarding the reaction solvent of step (2), only water can be used as the reaction solvent; when the compound represented by BQ reacts with an acid in water, the generated salt of the resolving agent will dissolve in the water, while the generated compound represented by BR will precipitate from the water.

[0034] When the reaction solvent contains both water and an organic solvent, the compound represented by BQ reacts with an acid in the reaction solvent, and the generated salt of the splitting agent enters the aqueous phase; while the generated compound represented by BR enters the organic phase. After the organic phase and the aqueous phase are separated, the organic phase can be extracted, concentrated, and dried to obtain the brivaracetam intermediate represented by BR.

[0035] In some embodiments, step (2) is performed in the presence of dilute hydrochloric acid, trifluoroacetic acid, or a combination thereof.

[0036] In some embodiments, step (2) is performed at a pH of 1 to 2. Acid can be used to adjust the pH of the reaction mixture to the above range, which can ensure that the compound represented by BQ is fully reacted, thereby increasing the yield of the compound represented by BR.

[0037] On the other hand, the present invention also provides a method for preparing brivaracetam, comprising:

[0038] According to the above method, a brivaracetam intermediate represented by formula BR is prepared; and the brivaracetam intermediate represented by formula BR is aminated to brivaracetam.

[0039] This preparation method can avoid the use of a chiral chromatographic column, shorten the preparation time, simplify the operation, and reduce the preparation cost.

[0040] There is no particular limitation on the amination process of the brivaracetam intermediate shown in BR, and brivaracetam can be prepared by a known amination reaction. For example, brivaracetam can be obtained by reacting the brivaracetam intermediate shown in BR, HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), ammonium chloride and diisopropylethylamine in tetrahydrofuran; wherein the molar ratio of the brivaracetam intermediate shown in BR, HATU, ammonium chloride and diisopropylethylamine is 1:(1.5-2.5):(2-3):(2.5-3.5), preferably 1:2:2.5:3; the volume mass ratio of tetrahydrofuran to the brivaracetam intermediate shown in BR is (10-50) mL:1 g.

[0041] Buvaracetam can also be obtained by mixing the brivaracetam intermediate shown in BR with dichloromethane, adding an activator, and introducing ammonia gas for reaction. The activator can be selected from at least one of thionyl chloride, oxalyl chloride, phosphorus oxychloride, methanesulfonyl chloride, pivaloyl chloride and isobutyl chloroformate; and the reaction temperature can be -20°C to 30°C.

[0042] The above embodiments and preferred conditions can be combined arbitrarily without violating the common sense in the art. The reagents and raw materials used in the present invention can be commercially available products or obtained by conventional methods in the art.

[0043] Compared with the prior art, the advantages of the method of the present invention are:

[0044] (1) It can avoid the use of chiral chromatographic columns to separate diastereomers during the synthesis process, greatly shorten the process time, simplify the operation and reduce the process cost, which is conducive to industrial production;

[0045] (2) Compared with the existing R-phenylethylamine separation method, it has significantly better separation and purification effects;

[0046] (3) The splitting reagents used are cheap, have a high recovery rate, and can be reused. DETAILED DESCRIPTION

[0047] The present invention is further described below by way of examples, which are only for illustrative purposes and are not intended to limit the scope of the present invention in any aspect.

[0048] The raw materials used in the examples can be commercially available products or obtained by conventional methods in the art. For example, the preparation of (S)-2(4-propyl-1,5-dihydropyrrole-2-one)butyric acid can refer to patent CN1 07513031; (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butyric acid shown in formula BP can be prepared by palladium carbon hydrogenation method, and can also refer to patent CN106748950A for preparation; the preparation method of buvacetam (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyramide can refer to patent CN106748950A for preparation; the preparation method of 1S,2S-cyclohexanediamine can refer to patent US200 9 / 30235; the preparation method of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine can refer to patent US4215114; the preparation method of (1S,2S)-N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine can refer to the literature Kizirian, Jean-Claude; Caille, Jean-Claude; Alexakis, Alexandre [Tetrahedron Letters, 2003, vol.44, #49, p.8893-8895]; the preparation method of N-((1S,2S)-2-(dimethylamino)cyclohexyl)-4-toluenesulfonamide can refer to the literature Chai, Zhuo; Yang, Pei-Jun [Angew.Chem., 2017, vol.129, #2, p.665-669,5].

[0049] Example 1: Preparation of the compound represented by formula BP

[0050] 150 g of (S)-2(4-propyl-1,5-dihydropyrrole-2-one)butyric acid (0.71 mol, 1 eq) was added into a 2 L hydrogen autoclave, 1.5 L methanol was added, 1.5 g of Pd(OH)2 / C (1%) was added, and the reaction was carried out at 20 MPa for 20 h. The reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 140 g of a solid compound represented by the formula BP.

[0051] The ratio of the two isomers in the compound represented by formula BP is calculated to be RS configuration: SS configuration = 85:15, and the chiral purity is 85%. RS represents the isomeric product of RS configuration, i.e., the compound represented by formula BR; SS represents the isomeric product of SS configuration, i.e., the diastereomer of the compound represented by formula BR. The abbreviations in the following examples have the same meanings as in Example 1.

[0052] Example 2: Preparation of the compound represented by formula BP

[0053] 150 g of (S)-2(4-propyl-1,5-dihydropyrrole-2-one)butyric acid (0.71 mol, 1 eq) was added into a 2 L hydrogen autoclave, 1.5 L of isopropanol and 45 g of Pd(OH)2 / C (30%) were added, and the mixture was reacted at 20 MPa for 20 h. The reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 145 g of a solid compound represented by the formula BP.

[0054] The calculated ratio of the two isomers in the compound represented by formula BP is RS configuration:SS configuration=54:45, and the chiral purity is 54%.

[0055] Example 3: Preparation of the compound represented by formula BQ

[0056] In a 500ml three-necked flask, 180ml of ethyl acetate, 6g of the compound represented by the formula BP prepared in Example 1 (0.028mol, 1eq, containing SS15%) and 3.2g of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine (0.8eq, 0.0224mol) were added, and the mixture was stirred at about 1°C for 1h and filtered to obtain 10g of a solid crude product of the compound represented by the formula BQ (hereinafter referred to as the "wet product"). The wet product was directly added to 10ml of ethyl acetate, the temperature was raised to dissolve the solid to obtain a clear solution, and the temperature was slowly lowered to 20°C for 1.5h for crystallization. The solution was filtered to obtain 8.0g of the compound represented by the formula BQ, with a yield of 94.6%, a purity of 99.8%, and 0.2% of diastereomers.

[0057] Example 4: Preparation of the compound represented by formula BQ

[0058] Into a 500ml three-necked flask, 360ml of acetonitrile, 60g of the compound represented by the formula BP prepared in Example 1 (0.28mol, 1eq, containing SS15%) and 47.7g of (1S, 2S)-N1, N1, N2, N2-tetramethylcyclohexane-1,2-diamine (1eq, 0.28mol) were added, and the mixture was stirred at about 50°C for 1h and filtered to obtain 108g of a wet product. The wet product was directly added to 300ml of isopropanol, heated to dissolve, and slowly cooled to 20°C over 1.5h. The mixture was filtered to obtain 89.6g of a compound represented by the formula BQ, with a yield of 98.1% and a purity of 99.8%, containing SS0.2%.

[0059] Example 5: Preparation of the compound represented by formula BQ

[0060] In a 500ml three-necked flask, 60ml of isopropyl acetate, 60g of the compound of formula BP prepared in Example 1 (0.28mol, 1eq, containing SS15%) and 47.88g of 1S,2S-cyclohexanediamine (1.5eq, 0.42mol) were added, the temperature was raised to about 100°C, the solution was dissolved, the temperature was naturally lowered to 20°C±5°C, and the mixture was stirred for 1h and filtered to obtain 100g of a wet product. The wet product was directly added to 180ml of acetonitrile, the temperature was raised to 72°C and dissolved, the temperature was slowly lowered to 20°C over 1.5h, and the solution was filtered to obtain 73.3g of a compound of formula BQ, with a yield of 94%, a purity of 99.8%, and containing 0.2% SS.

[0061] Example 6: Preparation of the compound represented by formula BQ

[0062] In a 500ml three-necked flask, 180ml of ethylene glycol dimethyl ether, 60g of the compound represented by the formula BP prepared in Example 1 (0.28mol, 1eq, containing SS15%) and 83g of N-((1S,2S)-2-(dimethylamino)cyclohexyl)-4-toluenesulfonamide (1eq, 0.28mol) were added, the temperature was raised to about 75°C, the solution was clear, the temperature was naturally lowered, and the mixture was stirred for 1h and filtered to obtain 145g of a wet product. The wet product was directly added to 700ml of IPAC, the temperature was raised to dissolve, the temperature was slowly lowered for 1.5h, and the mixture was filtered to obtain 118g of the compound represented by the formula BQ, with a yield of 97.3%, a purity of 99.8%, and containing 0.2% SS.

[0063] Example 7: Preparation of the compound represented by formula BQ

[0064] In a 500ml three-necked flask, 300ml of methyl tert-ether, 60g of the compound represented by the formula BP prepared in Example 2 (0.28mol, 1eq, containing SS 45%) and 39.8g of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine (1eq, 0.28mol) were added, and the mixture was stirred at about 50°C for 1h and filtered to obtain 65g of a wet product. The wet product was directly added to 60ml of ethyl acetate, heated to dissolve, and slowly cooled to 20°C over 1.5h. Filtered to obtain 52g of the compound represented by the formula BQ, with a yield of 95%, a purity of 99.5%, and containing SS 0.5%.

[0065] Example 8: Preparation of the compound represented by formula BQ

[0066] In a 100ml three-necked flask, 60ml of isopropyl ether, 6g of the compound of formula BP prepared in Example 2 (0.028mol, 1eq, containing SS 45%) and 3.98g of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine (1eq, 0.028mol) were added, and the mixture was stirred at about 40°C for 1h and filtered to obtain 6.5g of wet product. The wet product was directly added to 60ml of tertiary methyl ether, heated to dissolve, cooled and filtered to obtain 4.9g of compound of formula BQ, with a yield of 90%, a purity of 99.5%, and containing SS 0.5%.

[0067] Example 9: Preparation of the compound represented by formula BQ

[0068] In a 100ml three-necked flask, 18ml of tetrahydrofuran, 6g of the compound of formula BP prepared in Example 2 (0.028mol, 1eq, containing SS 45%) and 3.98g of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine (1eq, 0.028mol) were added, and the mixture was stirred at about 75°C for 1h and filtered to obtain 5g of wet product. The wet product was directly added to 120ml of tertiary methyl ether, heated to dissolve, cooled and filtered to obtain 4.5g of compound of formula BQ, with a yield of 82%, a purity of 99.5%, and containing SS 0.5%.

[0069] Example 10: Preparation of the compound represented by formula BQ

[0070] In a 50ml three-necked flask, 180ml of isopropyl acetate (3v), 6g of the compound of formula BP prepared in Example 2 (0.028mol, 1eq, containing SS 45%), and 3.18g of 1S,2S-cyclohexanediamine (1eq, 0.028mol) were added, and the temperature was raised to about 72°C to dissolve, and the temperature was naturally lowered to 20°C±5°C. After stirring for 1h, filtration was performed to obtain 7g of wet product, and the wet product was directly added to 18ml of isopropyl acetate, and the temperature was raised to dissolve, and the temperature was slowly lowered and filtration was performed to obtain 4.8g of the compound of formula BQ, with a yield of 95%, a purity of 99.8%, and containing SS0.2%.

[0071] Example 11: Preparation of the compound represented by formula BQ

[0072] In a 50ml three-necked flask, 240ml of isopropyl acetate, 6g of the compound of formula BP prepared in Example 2 (0.028mol, 1eq, containing SS 45%), and 3.98g of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine (1eq, 0.028mol) were added, the temperature was raised to about 72°C, the solution was dissolved, the temperature was naturally lowered to 20°C±5°C, and the solution was stirred for 1h and filtered to obtain 7.5g of a wet product. The wet product was directly added to 18ml of ethyl acetate, the temperature was raised to dissolve, the temperature was lowered, and the solution was filtered to obtain 5.25g of a compound of formula BQ, with a yield of 96%, a purity of 99.8%, and containing SS 0.2%.

[0073] Example 12: Preparation of the compound represented by formula BR

[0074] In a 500 ml three-necked flask, 30 g of the compound represented by formula BQ prepared in any of the above examples was added, 120 ml of water and 240 ml of ethyl acetate were added, the pH was adjusted to 1-2 with 6N hydrochloric acid, and the layers were separated after stirring for 0.5 h. The aqueous phase was extracted with 30 ml of EA, and the organic phases were combined and concentrated under reduced pressure to obtain 19.5 g of a white solid compound represented by formula BR with a yield of 100% and a purity of 99.8%.

[0075] Example 13: Preparation of the compound represented by formula BR

[0076] In a 500 ml three-necked flask, add 30 g of the compound represented by formula BQ prepared in any of the above examples, add 120 ml of water, adjust the pH to 1-2 with 6N trifluoroacetic acid, stir for 0.5 h and filter to obtain 19.5 g of a white solid represented by formula BR, with a yield of 100% and a purity of 99.8%.

[0077] Example 14: Preparation of Brivaracetam

[0078] Referring to Example 1-(7) of patent CN10106748950A, 80 ml of tetrahydrofuran, the compound represented by formula BR (6.4 g, 0.03 mol), HATU (28.5 g, 0.075 mol), ammonium chloride (4.9 g, 0.09 mol), and diisopropylethylamine (11.7 g, 0.09 mol) were added to a 250 ml four-necked bottle and stirred at room temperature for 2 h. 80 ml of water and 160 ml of ethyl acetate were added to the reaction solution and stirred. The layers were separated and the organic phase was washed once with 40 ml of saturated sodium bicarbonate, 40 ml of saturated ammonium chloride solution, and 40 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 7 g of buvacetam as a white solid with a purity of 99.5% determined by HPLC and a chiral purity of 99.85%.

[0079] Example 15: Using 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine as a resolution agent to resolve the compound represented by formula BP

[0080] In a 50ml three-necked flask, 18ml of isopropanol and 9g of the compound of formula BP prepared in Example 2 (0.042mol, 1eq, containing 45% isomers) were added, and the temperature was raised to about 55°C, which was numbered as a. In another 50ml three-necked flask, 18ml of isopropanol and 5g (0.83eq, 0.035mol) of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine were added, and the mixture was stirred to dissolve, which was numbered as b. The solution obtained in a was then added dropwise to b, and the mixture was stirred and heated to 70°C, then cooled for crystallization, filtered, and 7g of solid was precipitated, with a yield of 86%, a purity of 99.5%, and a diastereoisomer of 0.5%.

[0081] Comparative Example: Using R-(+)-a-phenylethylamine as a resolution agent to resolve the compound represented by formula BP

[0082] In a 50ml three-necked flask, 18ml of isopropanol and 9g of the compound represented by the formula BP (0.042mol, 1eq, containing 45% isomers) were added, and the temperature was raised to about 55°C, which was numbered as a. In another 50ml three-necked flask, 18ml of isopropanol and 4.2g of R-(+)-a-phenylethylamine (0.83eq, 0.035mol) were added, and the mixture was stirred to dissolve, which was numbered as b. The solution obtained in a was then added dropwise to b, and the mixture was cooled and crystallized after stirring, and no solid was precipitated. Part of the isopropanol was concentrated to precipitate 1g of solid, with a yield of 13%. The ratio of RS:SS isomers was 55:45, and there was no obvious separation and purification effect.

Claims

1. A method for preparing a brivaracetam intermediate represented by the following formula BR, comprising: (1) reacting the compound represented by formula BP with a resolving agent to prepare a compound represented by formula BQ; and (2) converting the compound represented by formula BQ into the brivaracetam intermediate represented by formula BR; Wherein step (1) comprises: a. dissolving the compound represented by formula BP and the resolving agent in a resolving solvent, dissolving the solid at the resolving temperature to obtain a clear solution, cooling the solution to crystallize, and separating the crystals to obtain a crude solid product of the compound represented by formula BQ; b. Recrystallizing the crude solid product in a recrystallization solvent, separating the crystals to obtain a compound of formula BQ, The resolving agent is a (1S, 2S)-(+)-1,2-cyclohexanediamine compound having the following formula (I): In formula (I), R1, R2 and R3 are independently H, CH3 or Ts, and R1, R2 and R3 are not Ts at the same time, The molar ratio of the compound represented by the formula BP to the resolution agent is 1:(0.8-1.5), wherein the resolution solvent is selected from methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, isopropanol and dimethyl ether or any combination thereof, The ratio of the volume of the resolution solvent to the mass of the compound represented by Formula BP is (1-30) mL:1 g. The splitting temperature is 1°C-100°C, wherein the recrystallization solvent is selected from methyl tert-butyl ether, acetonitrile, ethyl acetate, isopropyl acetate and dimethyl ether or any combination thereof, The step (2) comprises: in a reaction solvent, in the presence of an acid, converting the compound represented by formula BQ into a brivaracetam intermediate represented by formula BR, and the step (2) is carried out at a pH of 1-2.

2. The preparation method according to claim 1, wherein the resolving agent is selected from 1S,2S-cyclohexanediamine, 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine, (1S,2S)-N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine and N-((1S,2S)-2-(dimethylamino)cyclohexyl)-4-toluenesulfonamide or any combination thereof.

3. The preparation method according to claim 1, wherein the molar ratio of the compound represented by formula BP to the resolution agent is 1:

1.

4. The preparation method according to claim 1, wherein the ratio of the volume of the resolution solvent to the mass of the compound represented by formula BP is (1-10) mL:1 g.

5. The preparation method according to claim 1, wherein the ratio of the volume of the resolution solvent to the mass of the compound represented by formula BP is (3-6) mL:1 g. The preparation method according to claim 1 , wherein the resolution temperature is 50° C.-75° C.

7. The preparation method according to claim 1, wherein the recrystallization solvent is selected from isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether or any combination thereof.

8. The preparation method according to claim 1, wherein the ratio of the volume of the recrystallization solvent to the mass of the compound represented by formula BQ is (1-30) mL:1 g.

9. The preparation method according to claim 1, wherein the ratio of the volume of the recrystallization solvent to the mass of the compound represented by formula BQ is (1-10) mL:1 g.

10. The preparation method according to claim 1, wherein the ratio of the volume of the recrystallization solvent to the mass of the compound represented by formula BQ is 3 mL: 1 g.

11. The preparation method according to claim 1, wherein the acid in step (2) is dilute hydrochloric acid, trifluoroacetic acid or a combination thereof.

12. The preparation method according to claim 1, characterized in that: The reaction solvent described in step (2) is selected from isopropanol, ethyl acetate, isopropyl acetate and water.

13. The preparation method according to claim 1, characterized in that: The reaction solvent in step (2) is water.

14. A method for preparing brivaracetam, comprising: The method according to claim 1, preparing a brivaracetam intermediate represented by formula BR; and amminating the brivaracetam intermediate represented by formula BR to brivaracetam.

15. The preparation method according to claim 14, characterized in that: The amination is to react the brivaracetam intermediate shown by BR, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, ammonium chloride and diisopropylethylamine in tetrahydrofuran to obtain brivaracetam.

16. The preparation method according to claim 15, characterized in that: The molar ratio of the brivaracetam intermediate shown in BR, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, ammonium chloride and diisopropylethylamine is 1:(1.5-2.5):(2-3):(2.5-3.5), and the volume mass ratio of tetrahydrofuran to the brivaracetam intermediate shown in BR is (10-50) mL:1 g.

17. The preparation method according to claim 14, characterized in that: The amination is to mix the brivaracetam intermediate shown by BR with dichloromethane, add an activator, and introduce ammonia gas to react to obtain brivaracetam.

18. The preparation method according to claim 17, characterized in that: in, The activator is selected from at least one of thionyl chloride, oxalyl chloride, phosphorus oxychloride, methanesulfonyl chloride, pivaloyl chloride and isobutyl chloroformate.

Images