Purification method of brivaracetam

Abstract

The invention relates to the technical field of drug synthesis, and discloses a brivaracetam purification method, which comprises: (1) carrying out chiral resolution separation on a brivaracetam crude product to respectively obtain a compound represented by a formula I and a compound represented by a formula II; (2) adding the compound as shown in the formula II into an isopropanol solution containing potassium tert-butoxide, stirring for reaction, and adjusting the pH value to 6-7 after the reaction is completed; (3) adding tetrahydrofuran after vacuum concentration, adding methyl tert-butyl ether, heating and stirring for reaction, and then cooling, filtering and drying; and (4) adding the dried solid into a mixture of diisopropyl adipate and ethyl acetate, carrying out heating reflux reaction, cooling to 0-5 DEG C, standing, filtering, washing with ethanol, and drying to obtain the compound as shown in the formula I. According to the method, the brivaracetam crude product is subjected to chiral resolution, separation and purification, so that the yield of the brivaracetam product is further improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for purifying brivaracetam. Background Art

[0002] Brivaracetam is a new generation of anti-epileptic drugs that can inhibit neuronal voltage-dependent sodium channels and is used to treat intractable partial epileptic seizures. It has broad market prospects. Currently, there are a variety of synthetic routes, most of which involve chiral resolution, separation and purification of brivaracetam intermediates and brivaracetam crude products. Therefore, the separation and purification process steps will greatly affect the product yield and purity.

[0003] The invention patent with publication number WO2007065634 discloses a preparation route of brivaracetam, which uses n-pentene as the starting material, obtains (R)-2-hydroxypentanol through an asymmetric hydroxylation reaction, reacts with thionyl chloride to obtain (4R)-4-propyl-ethylene sulfite, hydrates with ruthenium trichloride, and oxidizes with sodium periodate to obtain (4R)-4-propyl-ethylene sulfate, which is then reacted with dimethyl malonate to obtain (S)-6,6-dimethyl-1-propyl-5,7-dioxospirone-2.5-octane-4,8-dione, and then reacts with (S)-2-aminobutanamide to obtain a mixture of a pair of positional isomers, which is then methylated and decarboxylated to obtain brivaracetam.

[0004] The invention patent with publication number CN1882535A discloses a method for preparing 2-oxo-1-pyrrolidine derivatives, wherein 5-hydroxy-4-n-propyl-2-furanone and S-2-aminobutyramide are reduced and aminated in the presence of sodium borohydride, and then hydrogenated and reduced to obtain racemic brivaracetam, which is then separated by column chromatography to prepare brivaracetam.

[0005] However, the above-mentioned brivaracetam synthesis routes all use simple chromatographic column chiral separation methods, and do not involve separation and purification after separation and further treatment of brivaracetam isomers, resulting in a low yield of brivaracetam. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a method for purifying brivaracetam, which first separates the crude brivaracetam by chiral resolution, and then further performs processes such as epimerization and recrystallization to control the selection of solvent and reaction conditions, thereby improving the separation and purification efficiency and the yield of brivaracetam.

[0007] The purpose of the present invention is achieved through the following technical solutions: The present invention provides a method for purifying brivaracetam, comprising the following steps: (1) separating the crude product of brivaracetam by chiral resolution to obtain a compound represented by formula I and a compound represented by formula II, respectively; (2) adding the compound represented by formula II to an isopropanol solution containing potassium tert-butoxide, stirring for reaction, and adjusting the pH to 6-7 after the reaction is completed; (3) After concentrating under reduced pressure, tetrahydrofuran is added, and then methyl tert-butyl ether is added while heating and stirring to react, and then the temperature is lowered, filtered, and dried; (4) The solid obtained by drying is added to a mixture of diisopropyl adipate and ethyl acetate, the temperature is raised to reflux for reaction, the temperature is lowered to 0-5°C and allowed to stand, filtered and washed with ethanol, and dried to obtain the compound represented by formula I.

[0008] Preferably, in step (2), the ratio of the added amount of the compound represented by formula II to the isopropanol solution containing potassium tert-butoxide is 0.9-1.2 g:10 mL.

[0009] Preferably, in step (2), the concentration of potassium tert-butoxide in the isopropanol solution containing potassium tert-butoxide is 0.02-0.03 g / mL.

[0010] Preferably, in step (2), the stirring reaction is carried out at room temperature for 15-20 hours.

[0011] Preferably, in step (3), the ratio of the added amount of tetrahydrofuran to the compound represented by formula II is 1-1.5 mL: 0.1 g.

[0012] Preferably, in step (3), the volume ratio of methyl tert-butyl ether to tetrahydrofuran is 1.2-1.4:1.

[0013] Preferably, in step (3), the heating and stirring reaction is heating to 60-70°C and stirring the reaction for 1-2 hours; and the cooling is cooling to 0-5°C and standing for 30-60 minutes.

[0014] Preferably, in step (4), the ratio of the added amount of the compound represented by formula II to the mixture of diisopropyl adipate and ethyl acetate is 0.9-1.2 g:5 mL.

[0015] Preferably, in step (4), the volume ratio of diisopropyl adipate to ethyl acetate is 1:5-8.

[0016] Preferably, in step (4), the temperature of the heating reflux reaction is raised to reflux and reacted for 2-3 hours; the temperature is lowered to 0-5°C and allowed to stand for 1-2 hours.

[0017] The present invention also provides a method for synthesizing brivaracetam, comprising the following steps: Step 1: 3-cyanohexanenitrile is catalyzed by nitrilase to obtain (R)-3-cyanohexanoic acid, which is then catalyzed by hydrogenation to obtain (R)-3-aminomethylhexanoic acid, which is then amidated to obtain the compound of formula III; Step 2: reacting the compound represented by formula III with methyl-2-bromobutyrate in an organic solvent in the presence of a base to obtain a compound represented by formula IV; Step 3: Aminolysis the compound represented by formula IV to obtain a crude product of brivaracetam, wherein the crude product of brivaracetam is a mixture of the compound represented by formula I and the compound represented by formula II; Step 4: Chiral separation and purification of the crude brivaracetam to obtain the brivaracetam product represented by formula I;

[0018] 3-Cyanocyanohexanenitrile is hydrolyzed by nitrilase to synthesize (R)-3-cyanohexanoic acid, and then (R)-3-cyanohexanoic acid is hydrogenated and reduced to synthesize (R)-3-aminomethylhexanoic acid. (R)-3-aminomethylhexanoic acid is amidated and ring-closed to prepare (R)-4-propyl-pyrrolidone, i.e., the compound shown in formula I. (R)-4-propyl-pyrrolidone and methyl-2-bromobutyrate are reacted in an organic solvent in the presence of a base to obtain the compound shown in formula II, which is then subjected to aminolysis, and the chiral isomers of the reaction mixture are separated by chromatography, and then purified to obtain the buvacethamine product. The buvacethamine synthesis process of the present invention is simple, efficient, environmentally friendly, and suitable for industrialization.

[0019] Preferably, in step 1, the reaction conditions of the hydrogenation catalysis are: in the presence of a nickel catalyst and hydrogen, water is used as a solvent, the pressure is controlled at 2 to 3 MPa, and the reaction is carried out at room temperature for 8 to 12 hours.

[0020] Preferably, in step 1, the amidation is as follows: first, (R)-3-aminomethylhexanoic acid and dichlorothionyl are heated to 30-40° C. in dichloromethane to react to obtain a reactant; then, a portion of the reactant, triethylamine and N,N'-dicyclohexylcarbodiimide are stirred and mixed in tetrahydrofuran at room temperature, cooled to -20--10° C. and reacted for 30-40 minutes, and then another portion of the reactant is added dropwise and the reaction is continued for 60-80 minutes.

[0021] The thionyl chloride first reacts with the carboxyl group in (R)-3-aminomethylhexanoic acid to obtain an acyl halide, which then undergoes a ring-closing reaction with the amino group to generate an amide. The ring-closing reaction is promoted by controlling the reaction conditions and adding triethylamine and N,N'-dicyclohexylcarbodiimide to obtain a higher reaction yield.

[0022] Preferably, the molar ratio of the (R)-3-aminomethylhexanoic acid to dichlorothionyl is 1:2-4; the ratio of the added amounts of the (R)-3-aminomethylhexanoic acid to dichloromethane is 0.10-0.15 mol:100 mL; the mass percentage of the one part of the reactants to the other part of the reactants is 30-40%:60-70%, and the total percentage is 100%; the ratio of the added amounts of the reactants, triethylamine, N,N'-dicyclohexylcarbodiimide and tetrahydrofuran is 1 g:3-5 g:8-9 g:200 mL.

[0023] Preferably, in step 1, the nitrilase catalyzed reaction is carried out at 30-35° C. and 600-800 r / min in a water bath for 22-26 hours.

[0024] Preferably, in step 2, the base is potassium hydride, sodium hydride, sodium methoxide, potassium methoxide or sodium isopropoxide; the organic solvent is tetrahydrofuran or toluene; the molar ratio of the compound represented by formula I to methyl-2-bromobutyric acid methyl ester is 1:1.1-1.4; the ratio of the added amount of the compound represented by formula I, the base and tetrahydrofuran is 1mmol:1.4-1.5mmol:4mL; the reaction is carried out at -5-5°C for 30-50min.

[0025] Preferably, in step three, the aminolysis is as follows: adding the compound represented by formula II to ammonia water at 0-5°C and stirring for reaction for 5-7h, the volume concentration of ammonia water is 50-60%, and the ratio of the added amount of the compound represented by formula II and ammonia water is 1-1.5mmol:2mL.

[0026] Compared with the prior art, the present invention has the following beneficial effects: (1) In the synthesis process of brivaracetam, by introducing (R)-4-propyl-pyrrolidone synthesized by an enzymatic method as an intermediate, the process can be simplified, the cost can be reduced, and it is environmentally friendly, green and efficient, and suitable for industrialization; (2) The crude brivaracetam obtained after synthesis is first separated by chiral resolution, and then further subjected to processes such as diastereomerization and recrystallization to control the selection of solvents and reaction conditions, thereby improving the separation and purification efficiency and the yield of brivaracetam. DETAILED DESCRIPTION

[0027] The technical scheme of the present invention is described below with specific examples, but the protection scope of the present invention is not limited thereto. The content of the reaction products is detected by chromatography.

[0028] Synthesis and purification of Brivaracetam: Step 1: Add nitrilase and 3-cyanohexanenitrile to PBS buffer, the ratio of PBS buffer, immobilized nitrilase and 3-cyanohexanenitrile added is 10mL:1g:0.3-0.4g, react at 30-35°C, 600-800r / min water bath conditions for 22-26h to prepare (R)-3-cyanohexanoic acid.

[0029] Step 2: Add (R)-3-cyanohexanoic acid into water to obtain a (R)-3-cyanohexanoic acid aqueous solution with a concentration of 200 g / L, add a nickel catalyst into the (R)-3-cyanohexanoic acid aqueous solution, the mass ratio of the nickel catalyst to the (R)-3-cyanohexanoic acid is 1:1-2, the hydrogen pressure is controlled at 2-3 MPa, and the reaction is carried out at room temperature for 8-12 hours to obtain (R)-3-aminomethylhexanoic acid.

[0030] Step 3: Amidate (R)-3-aminomethylhexanoic acid, with tail gas treatment during the process. First, (R)-3-aminomethylhexanoic acid and dichlorothionyl in a molar ratio of 1:2-4 are heated to 30-40°C in dichloromethane for reaction, and the ratio of the added amount of (R)-3-aminomethylhexanoic acid and dichloromethane is 0.10-0.15 mol:100 mL to obtain a reactant; then, a part of the reactant, triethylamine and N,N'-dicyclohexylcarbodiimide are stirred and mixed in tetrahydrofuran at room temperature, cooled to -20--10°C for reaction for 30-40 minutes, and another part of the reactant is added dropwise to continue the reaction for 60-80 minutes, the mass percentage of the part of the reactant and the other part of the reactant is 30-40%:60-70%, and the total percentage is 100%; the added amount ratio of the reactant, triethylamine, N,N'-dicyclohexylcarbodiimide and tetrahydrofuran is 1 g:3-5 g:8-9 g:200 mL to obtain a compound shown in formula III.

[0031] Step 4: reacting the compound represented by formula III and methyl-2-bromobutyric acid methyl ester in an organic solvent (tetrahydrofuran or toluene) in the presence of a base (potassium hydride, sodium hydride, sodium methoxide, potassium methoxide or sodium isopropoxide), wherein the molar ratio of the compound represented by formula III to methyl-2-bromobutyric acid methyl ester is 1:1.1-1.4, and the ratio of the added amount of the compound represented by formula III, the base and tetrahydrofuran is 1mmol:1.4-1.5mmol:4mL, reacting at -5-5°C for 30-50min to obtain a compound represented by formula IV; Step 5: Add the compound represented by formula IV to 50-60% ammonia water at 0-5°C, stir and react for 5-7h, the ratio of the added amount of the compound represented by formula IV to ammonia water is 1-1.5mmol:2mL, to obtain a crude product of brivaracetam.

[0032] Step 6: The crude product of brivaracetam is a mixture of the compound represented by formula I and the compound represented by formula II. The separation and purification of the crude product of brivaracetam comprises the following steps: (1) separating the crude product of brivaracetam by a chiral chromatographic column to obtain a compound represented by formula I and a compound represented by formula II, respectively; (2) adding the compound of formula II to an isopropanol solution containing 0.02-0.03 g / mL potassium tert-butoxide, wherein the ratio of the compound of formula II to the isopropanol solution containing potassium tert-butoxide is 0.9-1.2 g:10 mL, stirring at room temperature for 15-20 hours, and after the reaction is completed, adding acid to adjust the pH to 6-7; (3) After removing the solvent by concentration under reduced pressure, tetrahydrofuran is added and stirred to mix, wherein the ratio of the amount of tetrahydrofuran added to the compound represented by Formula II is 1-1.5 mL: 0.1 g; then methyl tert-butyl ether is added at a volume ratio of 1.2-1.4:1 to tetrahydrofuran, and the temperature is raised to 60-70° C. and stirred to react for 1-2 hours, then the temperature is lowered to 0-5° C. and allowed to stand for 30-60 minutes, filtered, and the filter cake is dried; (4) Add the dried solid to a mixture of diisopropyl adipate and ethyl acetate in a volume ratio of 1:5-8, wherein the ratio of the compound represented by formula II to the mixture of diisopropyl adipate and ethyl acetate is 0.9-1.2 g:5 mL, raise the temperature to reflux, react for 2-3 hours, cool to 0-5°C and stand for 1-2 hours, filter, wash the filter cake with anhydrous ethanol 3-5 times, and dry to obtain the compound represented by formula I, which together with the compound represented by formula I obtained in step (1) is used as the final brivaracetam product, and the yield is calculated.

[0033] Example 1 (Synthesis of Brivaracetam) Step 1: In 10mL 100mM, pH=7.4 PBS buffer, add 1g immobilized nitrilase (Example 2), add 0.3g 3-cyanohexanenitrile, and react for 24h at 30°C and 700r / min water bath conditions. Take a sample of 200μL, add 30μL 6MHCl to terminate the reaction and extract with ethyl acetate. After the reaction solution is centrifuged at 8000rpm for 10min, take the supernatant and add ethyl acetate to extract according to a volume ratio of 3:1, adjust the pH of the aqueous phase to 1-2 by hydrochloric acid solution, add ethyl acetate to extract according to a volume ratio of 3:1, add a NaOH aqueous solution with a pH of 12 to the organic phase for back extraction, take the aqueous phase to obtain an aqueous solution of (R)-3-cyanohexanoic acid, and add water to adjust the concentration to 200g / L.

[0034] Step 2: Add 25g of nickel catalyst to 100mL of (R)-3-cyanohexanoic acid aqueous solution, control the hydrogen pressure to 3MPa, and react at room temperature for 10h to obtain (R)-3-aminomethylhexanoic acid. The reaction solution is filtered, and the filtrate is centrifuged at 8000rpm for 10min, and the supernatant is extracted by adding ethyl acetate at a volume ratio of 3:1, and the aqueous phase is adjusted to pH 1-2 by hydrochloric acid solution, and then ethyl acetate is added at a volume ratio of 3:1 for extraction, and the organic phase is back-extracted by adding NaOH aqueous solution with a pH of 12, and the aqueous phase is taken to obtain (R)-3-aminomethylhexanoic acid aqueous solution, and the (R)-3-aminomethylhexanoic acid is obtained by reduced pressure distillation.

[0035] Step 3: Amidate (R)-3-aminomethylhexanoic acid, add 0.1 mol of (R)-3-aminomethylhexanoic acid to 100 mL of dichloromethane, then drop 0.25 mol of dichlorothionyl, heat to 35°C and react until the raw material disappears by TLC detection, then stop the reaction. Concentrate under reduced pressure to obtain 20.1 g of reactant. Stir and mix 0.3 g of reactant, 1.4 g of triethylamine and 2.6 g of N,N'-dicyclohexylcarbodiimide in 200 mL of tetrahydrofuran at room temperature, cool to -20°C and react for 30 min, then drop 0.7 g of reactant and continue to react for 80 min. After the reaction is completed, add 3 times the volume of water and mix and stir, take the aqueous phase and extract after reduced pressure distillation to obtain the compound shown in formula III.

[0036] Step 4: In a nitrogen atmosphere, add 14.3 mmol of sodium methoxide to 40 mL of tetrahydrofuran, then add 10 mmol of the compound of formula III and 13.5 mmol of methyl-2-bromobutyrate, stir evenly, and react at -5°C for 45 min. After the reaction solution is warmed to room temperature, add an equal volume of water, distill under reduced pressure, and extract to obtain the compound of formula IV.

[0037] Step 5: Add 12 mmol of the compound represented by formula IV to 20 mL of 55% ammonia water at 0°C, stir and react for 7 hours, filter out the white precipitate that appears during the reaction, wash with water and dry to obtain a crude product of brivaracetam; separate the crude product of brivaracetam by a chiral chromatographic column to obtain a brivaracetam product represented by formula I.

[0038] Example 2 The synthesis of brivaracetam was carried out according to the steps in Example 1, and 2 g of the obtained crude brivaracetam was separated and purified, comprising the following steps: (1) 2 g of crude brivaracetam was separated by chiral chromatography to obtain 1.06 g of the compound represented by formula I and 0.94 g of the compound represented by formula II, respectively.

[0039] (2) 0.94 g of the compound represented by formula II was added to 10 mL of an isopropanol solution containing 0.02 g / mL potassium tert-butoxide, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, hydrochloric acid was added to adjust the pH to 6-7.

[0040] (3) After removing the solvent by concentration under reduced pressure, 12 mL of tetrahydrofuran was added and stirred, and then 15 mL of methyl tert-butyl ether was added. The temperature was raised to 65° C. and stirred for reaction for 1 h. The temperature was then lowered to 0° C. and allowed to stand for 30 min. The mixture was filtered and the filter cake was dried.

[0041] (4) Add 5 mL of a mixture of diisopropyl adipate and ethyl acetate in a volume ratio of 1:6 to the dried solid, raise the temperature to reflux, react for 2 h, cool to 0 ° C. and stand for 1 h, filter, wash the filter cake with anhydrous ethanol 4 times, dry, and separate by HPLC to obtain the compound of formula I, which together with the compound of formula I obtained in step (1) is used as the final brivaracetam product, and the yield is calculated.

[0042] Example 3 The synthesis of brivaracetam was carried out according to the steps in Example 1, and 2 g of the obtained crude brivaracetam was separated and purified, comprising the following steps: (1) 2 g of crude brivaracetam was separated by chiral chromatography to obtain 1.06 g of the compound represented by formula I and 0.94 g of the compound represented by formula II, respectively.

[0043] (2) 0.94 g of the compound represented by formula II was added to 10 mL of an isopropanol solution containing 0.03 g / mL potassium tert-butoxide, and the mixture was stirred at room temperature for 20 h. After the reaction was completed, hydrochloric acid was added to adjust the pH to 6-7.

[0044] (3) After removing the solvent by concentration under reduced pressure, 14 mL of tetrahydrofuran was added and stirred, and then 18 mL of methyl tert-butyl ether was added. The temperature was raised to 70° C. and stirred for reaction for 2 h. The temperature was then lowered to 0° C. and allowed to stand for 30 min. The mixture was filtered and the filter cake was dried. (4) Add 5 mL of a mixture of diisopropyl adipate and ethyl acetate in a volume ratio of 1:8 to the dried solid, raise the temperature to reflux, react for 3 h, cool to 5° C. and stand for 2 h, filter, wash the filter cake with anhydrous ethanol 4 times, dry, and separate by HPLC to obtain the compound of formula I, which together with the compound of formula I obtained in step (1) is used as the final brivaracetam product, and the yield is calculated.

[0045] Comparative Example 1 The difference from Example 1 is that N,N'-dicyclohexylcarbodiimide is not added in step (3).

[0046] (3) (R)-3-aminomethylhexanoic acid is amidated. 0.1 mol of (R)-3-aminomethylhexanoic acid is added to 100 mL of dichloromethane, and then 0.25 mol of dichlorothionyl is added dropwise. The mixture is heated to 35°C and reacted until the raw material disappears as detected by TLC, and the reaction is stopped. The mixture is concentrated under reduced pressure to obtain 20.1 g of the reactant. 0.3 g of the reactant and 1.4 g of triethylamine are stirred and mixed in 200 mL of tetrahydrofuran at room temperature, cooled to -20°C and reacted for 30 min, and then 0.7 g of the reactant is added dropwise and the reaction is continued for 80 min. After the reaction is completed, 3 times the volume of water is added and mixed, and the aqueous phase is extracted after reduced pressure distillation to obtain the compound shown in Formula III.

[0047] Comparative Example 2 The difference from Example 1 is that in step (3), the reactants are not subjected to stepwise reaction.

[0048] (3) (R)-3-aminomethylhexanoic acid is amidated. 0.1 mol of (R)-3-aminomethylhexanoic acid is added to 100 mL of dichloromethane, and then 0.25 mol of dichlorothionyl is added dropwise. The mixture is heated to 35°C and reacted until the raw material disappears as detected by TLC. The reaction is stopped. The mixture is concentrated under reduced pressure to obtain 20.1 g of the reactant. 1 g of the reactant, 1.4 g of triethylamine and 2.6 g of N,N'-dicyclohexylcarbodiimide are stirred and mixed in 200 mL of tetrahydrofuran at room temperature, cooled to -20°C and reacted for 110 min. After the reaction is completed, 3 times the volume of water is added and stirred, and the aqueous phase is extracted by distillation under reduced pressure to obtain the compound shown in Formula III.

[0049] Comparative Example 3 The difference from Example 2 is that step (3) is not performed.

[0050] (1) 2 g of crude brivaracetam was separated by chiral chromatography to obtain 1.06 g of the compound represented by formula I and 0.94 g of the compound represented by formula II, respectively.

[0051] (2) 0.94 g of the compound represented by formula II was added to 10 mL of an isopropanol solution containing 0.02 g / mL potassium tert-butoxide, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, hydrochloric acid was added to adjust the pH to 6-7.

[0052] (3) After removing the solvent by concentration under reduced pressure, 5 mL of a mixture of diisopropyl adipate and ethyl acetate in a volume ratio of 1:6 was added, the temperature was raised to reflux, the reaction was carried out for 2 h, the temperature was lowered to 0° C. and allowed to stand for 1 h, and the filter cake was washed 4 times with anhydrous ethanol. After drying, the filter cake was separated by HPLC to obtain the compound represented by formula I, which was used together with the compound represented by formula I obtained in step (1) as the final brivaracetam product, and the yield was calculated.

[0053] Comparative Example 4 The difference from Example 2 is that step (4) is not performed.

[0054] (1) 2 g of crude brivaracetam was separated by chiral chromatography to obtain 1.06 g of the compound represented by formula I and 0.94 g of the compound represented by formula II, respectively.

[0055] (2) 0.94 g of the compound represented by formula II was added to 10 mL of an isopropanol solution containing 0.02 g / mL potassium tert-butoxide, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, hydrochloric acid was added to adjust the pH to 6-7.

[0056] (3) After removing the solvent by concentration under reduced pressure, 12 mL of tetrahydrofuran was added and stirred, and then 15 mL of methyl tert-butyl ether was added. The temperature was raised to 65° C. and stirred for reaction for 1 h. The temperature was then lowered to 0° C. and allowed to stand for 30 min. The mixture was filtered and the filter cake was dried.

[0057] (4) The filter cake was washed four times with anhydrous ethanol, dried, and separated by HPLC to obtain the compound represented by formula I, which together with the compound represented by formula I obtained in step (1) was used as the final brivaracetam product, and the yield was calculated.

[0058] Comparative Example 5 The difference from Example 2 is that the mixture of diisopropyl adipate and ethyl acetate in step (4) is replaced by isopropyl acetate.

[0059] (1) 2 g of crude brivaracetam was separated by chiral chromatography to obtain 1.06 g of the compound represented by formula I and 0.94 g of the compound represented by formula II, respectively.

[0060] (2) 0.94 g of the compound represented by formula II was added to 10 mL of an isopropanol solution containing 0.02 g / mL potassium tert-butoxide, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, hydrochloric acid was added to adjust the pH to 6-7.

[0061] (3) After removing the solvent by concentration under reduced pressure, 12 mL of tetrahydrofuran was added and stirred, and then 15 mL of methyl tert-butyl ether was added. The temperature was raised to 65° C. and stirred for reaction for 1 h. The temperature was then lowered to 0° C. and allowed to stand for 30 min. The mixture was filtered and the filter cake was dried.

[0062] (4) Add 5 mL of isopropyl acetate to the dried solid, raise the temperature to reflux, react for 2 h, cool to 0 ° C. and stand for 1 h, filter, wash the filter cake with anhydrous ethanol 4 times, dry, and separate by HPLC to obtain the compound of formula I, which together with the compound of formula I obtained in step (1) is used as the final brivaracetam product, and the yield is calculated.

[0063] The yield of the compound represented by formula III = the mass of the compound represented by formula III actually obtained / the mass of the compound represented by formula III theoretically obtained*100%.

[0064] The yield of Brivaracetam = the mass of the Brivaracetam product / the mass of the Brivaracetam crude product*100%.

[0065] Table 2 As shown in Table 1, the comparison between Example 1 and Example 2-3 shows that separation and purification by the method of the present invention can further improve the yield of Bu Waxitan, and by introducing (R)-4-propyl-pyrrolidone synthesized by the enzymatic method as an intermediate, the process can be simplified, the cost can be reduced, and it is environmentally friendly, green and efficient, and suitable for industrialization. The data of Comparative Examples 1-2 show that the control of the condition parameters in the amidation preparation process of the compound shown in Formula III has a greater impact on the yield, and obtaining a higher yield of the compound shown in Formula III is more conducive to improving the efficiency of the entire process and reducing costs. The data of Comparative Examples 3-5 show that the steps in the separation and purification process of the crude Bu Waxitan product have a greater impact on the product yield, and the steps of purification using different reagents in the present invention are conducive to obtaining a higher yield.

[0066] The above are only preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the specification of the present invention, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for purifying brivaracetam, characterized in that: The steps include: (1) separating the crude product of brivaracetam by chiral resolution to obtain a compound represented by formula I and a compound represented by formula II, respectively; (2) adding the compound represented by formula II to an isopropanol solution containing potassium tert-butoxide, stirring for reaction, and adjusting the pH to 6-7 after the reaction is completed; (3) After concentrating under reduced pressure, tetrahydrofuran is added, and then methyl tert-butyl ether is added while heating and stirring to react, and then the temperature is lowered, filtered, and dried; (4) The solid obtained by drying is added to a mixture of diisopropyl adipate and ethyl acetate, the temperature is raised to reflux for reaction, the temperature is lowered to 0-5°C and allowed to stand, filtered and washed with ethanol, and dried to obtain the compound represented by formula I.

2. According to the method for purifying brivaracetam according to claim 1, in step (2), the ratio of the added amount of the compound represented by formula II and the isopropanol solution containing potassium tert-butoxide is 0.9-1.2 g:10 mL.

3. According to the method for purifying brivaracetam according to claim 1 or 2, in step (2), the concentration of potassium tert-butoxide in the isopropanol solution containing potassium tert-butoxide is 0.02-0.03 g / mL.

4. According to the method for purifying brivaracetam according to claim 1 or 2, in step (2), the stirring reaction is a stirring reaction at room temperature for 15-20 hours.

5. According to the method for purifying brivaracetam according to claim 1, in step (3), the ratio of the amount of tetrahydrofuran added to the compound represented by formula II is 1-1.5 mL: 0.1 g.

6. The method for purifying brivaracetam according to claim 1 or 5, wherein in step (3), the volume ratio of methyl tert-butyl ether to tetrahydrofuran is 1.2-1.4:

1.

7. The method for purifying brivaracetam according to claim 1 or 5, wherein in step (3), the heating and stirring reaction is heating to 60-70°C and stirring the reaction for 1-2 hours; and the cooling is cooling to 0-5°C and standing for 30-60 minutes.

8. The method for purifying brivaracetam according to claim 1, wherein in step (4), the ratio of the amount of the compound represented by formula II to the mixture of diisopropyl adipate and ethyl acetate added is 0.9-1.2 g:5 mL.

9. The method for purifying brivaracetam according to claim 1, wherein in step (4), the volume ratio of diisopropyl adipate to ethyl acetate is 1:5-8.

10. The method for purifying brivaracetam according to claim 1, 8 or 9, wherein in step (4), the temperature of the reflux reaction is raised to reflux and reacted for 2-3 hours; the temperature is lowered to 0-5°C and allowed to stand for 1-2 hours.

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