CN114394921A - Preparation method of high-purity brivaracetam - Google Patents
Preparation method of high-purity brivaracetam Download PDFInfo
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- CN114394921A CN114394921A CN202210160190.8A CN202210160190A CN114394921A CN 114394921 A CN114394921 A CN 114394921A CN 202210160190 A CN202210160190 A CN 202210160190A CN 114394921 A CN114394921 A CN 114394921A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention relates to a production method of brivaracetam, in particular to a preparation method of high-purity brivaracetam; belongs to the technical field of raw material medicine synthesis. A preparation method of high-purity brivaracetam comprises the following steps: 1) salifying the compound 3 and chiral amine, and dissociating to obtain an intermediate 3; 2) carrying out activation reaction and ammonolysis reaction on the intermediate 3 to obtain the brivaracetam; the invention combines the chiral induction method and the resolution method, thereby not only ensuring the chiral purity of the product, but also ensuring the resolution yield; the method has the advantages of mild reaction conditions, high yield, low cost and high safety in each step, and is suitable for industrial production.
Description
Technical Field
The invention relates to a production method of brivaracetam, in particular to a preparation method of high-purity brivaracetam; belongs to the technical field of raw material medicine synthesis.
Background
Brivaracetam (Brivaracetam), with the chemical name (2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide, and the structural formula is as follows:
brivaracetam is a third generation antiepileptic drug developed by UCB corporation of belgium, marketed under EMEA and FDA approval at 2016 for the treatment of partial seizures, with or without secondary generalized seizures, in adults and adolescent patients over 16 years of age.
Two chiral centers exist in the molecular structure of the bravaracetam, wherein S chiral center is generally introduced by raw materials, such as (S) -2-aminobutanamide, (S) -2-aminobutyric acid or (S) -2-aminobutyric acid methyl ester and the like. The construction of the chiral center of R is the key to the synthesis of the compound.
At present, the construction methods of R chiral centers are mainly divided into five types.
The first kind of process represented by original UCB requires chiral chromatographic column to separate isomers, and has high equipment requirement, low yield and high production cost, such as patent CN 1882535A.
The second type is chiral source synthesis, and this kind of method takes CN105646319B as an example, and has the disadvantages of harsh reaction conditions, many intermediate impurities, difficult purification, low yield, and the like, and is not favorable for quality control and cost control.
The third type is an enzyme method, which selectively reacts with one configuration of the enzyme to achieve the purpose of isomer separation, refer to patent CN 109266630A. But the method has lower yield, and the other configuration needs racemization recovery and repeated application, so the efficiency is lower.
The fourth type is a resolution method, which is characterized in that chiral acid or chiral amine and a substrate are crystallized after salifying, and one configuration is separated out by utilizing the difference of solubility, so that the purpose of isomer separation is achieved. This method can reduce the isomers to a lower level, but if the substrate is racemic, it can only obtain one of the configurations, and suffers from the same disadvantages as the enzymatic method.
The fifth type is a chiral induction method, in which the generation of R chiral center is induced by S chiral center, such as patent CN 109516943A. The method is simple and efficient, but the S chiral center is far away from the R chiral center, so that the induction effect is not good, partial diastereoisomers are inevitably generated, and the quality requirement of the raw material medicine is difficult to achieve.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of high-purity brivaracetam. The invention combines the chiral induction method and the resolution method, and develops a simple, high-efficiency and low-cost synthesis route.
The technical scheme for solving the problems is as follows:
a preparation method of high-purity brivaracetam comprises the following steps:
1) salifying the compound 3 and chiral amine, and dissociating to obtain an intermediate 3;
2) carrying out activation reaction and ammonolysis reaction on the intermediate 3 to obtain the brivaracetam;
wherein, the molecular structural formula of the compound 3 is the same as that of the intermediate 3, and the SR of the compound 3: SS is designated as S1, SR of intermediate 3: SS is marked as S2, then S2 > S1;
in the technical scheme of the invention, SR represents a product with SR configuration, namely the compound shown in formula 3, and SS represents an isomeric product with SS configuration, namely a diastereoisomer of the compound 3. Since both compound 3 and intermediate 3 are SR-dominant, both are represented by formula 3.
Preferably, S1 is (95-99): 1; s2 is (99.5-99.9): 1.
preferably, the compound 3 is obtained by hydrogenating and reducing the compound 2, and the catalyst used for hydrogenating and reducing is selected from one or more of platinum tetrachloride or platinum dioxide; the adopted reducing agent is hydrogen or ammonium formate, and the adopted solvent is a protic solvent;
in the technical scheme of the invention, the adopted catalyst is a platinum compound, and has the effects of high catalytic efficiency and good chiral induction: the reaction is complete in a few hours and allows S1 to reach 95: more than 1 percent and the yield reaches more than 98 percent. The platinum compounds generate 0-valent platinum atoms in situ under the action of a reducing agent, and further play a catalytic role.
Preferably, the protic solvent is selected from methanol, ethanol, water, or a mixed solvent of any of them.
As a preferred aspect of the above technical solution, the salt formation with chiral amine is: the adopted chiral amine is selected from one or more of (1R,2R) -1-amino-2-indanol, (S) -2-amino-3-methyl-1, 1-diphenyl-1-butanol, (1S,2S) -2-aminocyclohexanol, (R) -3-tert-butoxycarbonylaminopyrrolidine, (1R, 2S) -2-amino-1, 2-diphenylethanol; the adopted solvent is selected from one or more of ether solvent, ester solvent, aromatic hydrocarbon solvent, ketone, alcohol and nitrile; the molar ratio of the compound 3 to the chiral amine is 1: (0.8 to 1.5).
In the above technical solution of the present invention, the chiral amine is selected from the following structures:
compound 4, (1R,2R) -1-amino-2-indanol, CAS No.: 163061-73-2;
compound 5, (S) -2-amino-3-methyl-1, 1-diphenyl-1-butanol, CAS No.: 78603-95-9;
compound 6, (1S,2S) -2-aminocyclohexanol, CAS: 74111-21-0;
compound 7, (R) -3-tert-butoxycarbonylaminopyrrolidine, CAS No.: 122536-77-0.
Compound 8, (1R, 2S) -2-amino-1, 2-diphenylethanol, CAS No.: 23190-16-1.
The molar ratio of compound 3 to chiral amine is further preferably 1: (0.9-1.1).
Preferably, the solvent used for salifying with the chiral amine is one or more selected from ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, isopropyl acetate, toluene, acetone, methanol, ethanol, isopropanol, and acetonitrile.
Preferably, the solvent for dissociation is selected from water, a mixed solvent of water and an organic solvent A; the organic solvent A is selected from ethyl acetate, isopropyl acetate, toluene, methyl tert-ether and isopropyl ether; the free acid is selected from dilute hydrochloric acid, dilute sulfuric acid or trifluoroacetic acid.
In the technical scheme of the invention, when only water is used as a solvent, a reaction product can be directly separated by filtration; and when a mixed solvent of water and an organic solvent A is selected, extracting a reaction product into an organic phase, and concentrating to obtain an intermediate 3.
Preferably, the activation reaction is: the activator used is selected from carbonyldiimidazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), p-toluenesulfonyl chloride, isopropyl chloroformate, isobutyryl chloride, acetic anhydride, di-tert-butyl dicarbonate, propylphosphoric anhydride; the solvent used is selected from toluene, methyl tert-ether, acetone, ethyl acetate, dichloromethane, tetrahydrofuran.
Preferably, the activating agent used in the activation reaction is selected from 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), p-toluenesulfonyl chloride (tosyl chloride) or isobutyryl chloride (isobutyryl chloride).
As a preferred aspect of the above technical solution, the ammonolysis reaction specifically includes: introducing ammonia gas, or dropping ammonia-containing liquid, or adding ammonium salt and alkali.
In the above-mentioned method, preferably, the ammonolysis reaction is followed by crystallization using a solvent selected from isopropyl acetate, acetone, isopropanol or a mixed solvent of any of these solvents.
Preferably, the usage amount of the solvent for crystallization is 0.8-2 mL/g relative to the mass of the crude product of the brivaracetam.
Preferably, the usage amount of the solvent for crystallization is 1-1.5 mL/g relative to the mass of the crude product of the brivaracetam.
The invention has the following beneficial effects:
(1) the invention uses the platinum compound with relatively low price to replace the expensive palladium catalyst, thereby having certain advantage in cost; compared with palladium carbon, Raney nickel and the like which can generate spontaneous combustion in air, the catalyst uses a stable platinum compound, so that the safety risk is greatly reduced;
(2) in the process of salifying with chiral amine, the adopted chiral amine is cheap and easily available chemical raw materials, does not need to be synthesized, can be recycled and reused, and is beneficial to reducing the cost and reducing solid wastes;
(3) the chiral induction method and the resolution method are combined, so that the chiral purity of the product is ensured, and the resolution yield is also ensured;
(4) the method has the advantages of mild reaction conditions, high yield, low cost and high safety in each step, and is suitable for industrial production.
Detailed Description
The present embodiments are to be considered in all respects as illustrative and not restrictive. Any changes that may be made by one skilled in the art after reading the description of the invention are, within the purview of the claims, protected by the patent laws.
Example 1: reduction of Compound 2
21.1g of Compound 2 was dissolved in 420mL of methanol, and 0.34g of platinum tetrachloride was added, and the mixture was replaced with nitrogen and hydrogen three times, and then hydrogen was introduced thereinto to 0.5MPa, followed by reaction at 20 ℃ for 6 hours. Filtration and concentration of the filtrate gave 21.0g of a white solid, i.e. compound 3, in 99% yield, SR: SS =98: 2. (SR represents a product of SR configuration, i.e., a compound represented by formula 3, and SS represents an isomeric product of SS configuration, i.e., a diastereomer of compound 3. the abbreviations in the following examples have the same meanings as in example 1.)
Example 2: reduction of Compound 2
Dissolving 21.1g of compound 2 in 420mL of ethanol, adding 0.23g of platinum dioxide, replacing with nitrogen and hydrogen respectively for three times, introducing hydrogen to 0.5Mpa, and reacting at 20 ℃ for 6 h. Filtration and concentration of the filtrate gave 21.0g of a white solid, i.e. compound 3, in 99% yield, SR: SS =97: 3.
Example 3: reduction of Compound 2
21.1g of Compound 2 was dissolved in a mixed solvent of 210mL of methanol and 210mL of water, 0.23g of platinum dioxide and 18.9g of ammonium formate were added, the mixture was replaced with nitrogen three times, and the mixture was reacted at 0 ℃ for 10 hours. Filtered, concentrated to remove methanol, and extracted with 210mL of isopropyl acetate. The organic phase was concentrated to give 20.9g of a white solid, compound 3, 98% yield, SR: SS =99: 1.
Example 4: chiral resolution of intermediate 3
Dissolving 21.3g of the compound 3 in 64mL of ethylene glycol dimethyl ether, adding 14.9g of the compound 4, heating to 70 ℃, dissolving and clearing, cooling to 20 ℃, preserving heat, crystallizing for 0.5h, and filtering.
The filter cake was dissolved in 128mL of water, and 120mL of 1mol/L diluted hydrochloric acid was added dropwise thereto, followed by stirring for 10min and filtration. Leaching the filter cake with a small amount of clear water, and drying to obtain an intermediate 3 with the yield of 91 percent, SR: SS =99.7: 0.3.
Nuclear magnetic characterization results of the product:1H NMR（400MHz，DMSO-d6），δ 8.06（1H，br），4.65~4.61（1H，m），3.46~3.42（1H，t），3.20~3.16（1H，t），2.63~2.57（1H，dd），2.38~2.31（1H，m），2.20~2.13（1H，dd），2.08~2.00（1H，m），1.76~1.68（1H，m），1.50~1.31（4H，m），0.95~0.91（6H，m）。
and (3) product mass spectrum characterization results: MS (m/z): 214.1[ M + H]+。
Example 5: chiral resolution of intermediate 3
Dissolving 21.3g of the compound 3 in 64mL of isopropanol, adding 25.5g of the compound 5, heating to 70 ℃, dissolving, cooling to 20 ℃, preserving heat, crystallizing for 0.5h, and filtering.
The filter cake was dissolved in 128mL of water, 100mL of 1mol/L dilute sulfuric acid was added dropwise thereto, and the mixture was stirred for 10min and then filtered. Leaching the filter cake with a small amount of clear water, and drying to obtain an intermediate 3 with the yield of 93 percent, SR: SS =99.5: 0.5.
The nuclear magnetic and mass spectrum characterization results of the product are the same as those of example 4.
Example 6: chiral resolution of intermediate 3
Dissolving 21.3g of the compound 3 in 64mL of ethyl acetate, adding 11.5g of the compound 6, heating to 70 ℃, dissolving, cooling to 20 ℃, keeping the temperature, crystallizing for 0.5h, and filtering.
Dissolving the filter cake in 128mL of water, adding 128mL of ethyl acetate, dropwise adding 120mL of 1mol/L diluted hydrochloric acid, stirring for 10min, layering, and concentrating the organic phase to obtain an intermediate 3 with the yield of 89%, SR: SS =99.8: 0.2.
The nuclear magnetic and mass spectrum characterization results of the product are the same as those of example 4.
Example 7: chiral resolution of intermediate 3
Dissolving 21.3g of the compound 3 in 64mL of acetone, adding 18.6g of the compound 7, heating to 70 ℃, dissolving, cooling to 20 ℃, preserving heat, crystallizing for 0.5h, and filtering.
Dissolving the filter cake in 128mL of water, adding 128mL of toluene, dropwise adding 13.7g of trifluoroacetic acid, stirring for 10min, demixing, and concentrating and drying the organic phase to obtain an intermediate 3 with the yield of 94%, SR: SS =99.8: 0.2.
The nuclear magnetic and mass spectrum characterization results of the product are the same as those of example 4.
Example 8: chiral resolution of intermediate 3
Dissolving 21.3g of the compound 3 in 64mL of acetonitrile, adding 21.3g of the compound 8, heating to 70 ℃, dissolving, cooling to 20 ℃, preserving heat, crystallizing for 0.5h, and filtering.
Dissolving the filter cake in 128mL of water, adding 128mL of methyl tert-ether, dropwise adding 120mL of 1mol/L diluted hydrochloric acid, stirring for 10min, layering, and concentrating the organic phase to obtain an intermediate 3 with a yield of 94%, SR: SS =99.7: 0.3.
The nuclear magnetic and mass spectrum characterization results of the product are the same as those of example 4.
Example 9: preparation of brivaracetam
21.3g of intermediate 3 was dissolved in 213mL of dichloromethane, 23.0g of EDCI was added, and after 5 hours of reaction at 0 ℃, 20.4g of concentrated ammonia water was added dropwise and the reaction was continued for 1 hour. Layering, washing the organic phase once with 85mL of clear water, concentrating and drying to obtain a crude product of the brivaracetam.
Adding 17mL of isopropanol into the crude product, heating to above 40 ℃ to dissolve the crude product, cooling to 20 ℃ to crystallize to obtain 18.2g of white solid, namely a finished product of the brivaracetam, wherein the yield is 86%, the purity is 99.9%, and the SR: SS =99.9: 0.1.
Nuclear magnetic characterization results of the product:1H NMR（400MHz，DMSO-d6），δ 7.35（1H，br），7.01（1H，br），4.32~4.29（1H，m），3.40~3.37（1H，t），3.11~3.09（1H，t），2.38~2.32（1H，q），2.29~2.19（1H，m），2.00~1.94（1H，q），1.79~1.71（1H，m），1.59~1.51（1H，m），1.39~1.18（4H，m），0.89~0.86（3H，t），0.79~0.76（3H，t）。
and (3) product mass spectrum characterization results: MS (m/z): 213.1[ M + H]+。
Example 10: preparation of brivaracetam
21.3g of the intermediate 3 is dissolved in 213mL of dichloromethane, 22.8g of p-toluenesulfonyl chloride and 11.1g of triethylamine are sequentially added, after the reaction is carried out for 5h at the temperature of 0 ℃, ammonia gas is continuously introduced for about 0.5h, and the pressure maintaining reaction is carried out for 1 h. Filtering, adding 85mL of clear water into the filtrate, washing once, layering, and concentrating and drying the organic phase to obtain a crude product of the brivaracetam.
Adding 21mL of isopropyl acetate into the crude product, heating to above 40 ℃ for dissolving, cooling to 20 ℃ for crystallization to obtain 19.1 g of white solid, namely a finished product of the brivaracetam, wherein the yield is 90%, the purity is 99.9%, and the SR: SS =99.95: 0.05.
The results of nuclear magnetic and mass spectrum characterization of the product are the same as in example 9.
Example 11: preparation of brivaracetam
21.3g of intermediate 3 is dissolved in 213mL of tetrahydrofuran, 12.8g of isobutyryl chloride and 11.1g of triethylamine are sequentially added, after reaction for 5 hours at 0 ℃, 16.1g of ammonium chloride and 25.3g of triethylamine are sequentially added, and the reaction is continued for 1 hour. Filtering, adding 85mL of clear water into the filtrate, washing once, layering, and concentrating and drying the organic phase to obtain a crude product of the brivaracetam.
Adding 42mL of acetone into the crude product, heating to above 40 ℃, dissolving clearly, cooling to 20 ℃, crystallizing to obtain 19.6 g of white solid, namely a finished product of the brivaracetam, with the yield of 93 percent and the purity of 99.9 percent, and the weight ratio of SR: SS =99.97: 0.03.
The results of nuclear magnetic and mass spectrum characterization of the product are the same as in example 9.
Claims (10)
1. A preparation method of high-purity brivaracetam comprises the following steps:
1) salifying the compound 3 and chiral amine, and dissociating to obtain an intermediate 3;
2) carrying out activation reaction and ammonolysis reaction on the intermediate 3 to obtain the brivaracetam;
wherein, the molecular structural formula of the compound 3 is the same as that of the intermediate 3, and the SR of the compound 3: SS is designated as S1, SR of intermediate 3: SS is marked as S2, then S2 > S1;
and the salt formation with chiral amine is as follows: the adopted chiral amine is selected from one or more of (1R,2R) -1-amino-2-indanol, (S) -2-amino-3-methyl-1, 1-diphenyl-1-butanol, (1S,2S) -2-aminocyclohexanol, (R) -3-tert-butoxycarbonylaminopyrrolidine, (1R, 2S) -2-amino-1, 2-diphenylethanol;
2. the method for preparing high-purity bravaracetam according to claim 1, characterized in that: s1 is (95-99): 1; s2 is (99.5-99.9): 1.
3. the method for preparing high-purity bravaracetam according to claim 1, characterized in that: the compound 3 is obtained by hydrogenating and reducing the compound 2, and the catalyst adopted by hydrogenation and reduction is selected from one or more of platinum tetrachloride or platinum dioxide; the adopted reducing agent is hydrogen or ammonium formate; the adopted solvent is a protic solvent;
4. the method for preparing high-purity bravaracetam according to claim 1, characterized in that: and the salt formation with chiral amine is as follows: the adopted solvent is selected from one or more of ether solvent, ester solvent, aromatic hydrocarbon solvent, ketone, alcohol and nitrile; the molar ratio of the compound 3 to the chiral amine is 1: (0.8 to 1.5).
5. The method for preparing high-purity bravaracetam according to claim 1, characterized in that: the solvent for dissociation is selected from water, a mixed solvent consisting of water and an organic solvent A; the organic solvent A is selected from ethyl acetate, isopropyl acetate, toluene, methyl tert-ether and isopropyl ether; the free acid is selected from dilute hydrochloric acid, dilute sulfuric acid or trifluoroacetic acid.
6. The method for preparing high-purity bravaracetam according to claim 1, characterized in that: the activation reaction: the activator used is selected from carbonyldiimidazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, p-toluenesulfonyl chloride, isopropyl chloroformate, isobutyryl chloride, acetic anhydride, di-tert-butyl dicarbonate, propylphosphoric anhydride; the solvent used is selected from toluene, methyl tert-ether, acetone, ethyl acetate, dichloromethane, tetrahydrofuran.
7. The method for preparing high-purity bravaracetam according to claim 1, characterized in that: the ammonolysis reaction specifically comprises the following steps: introducing ammonia gas, or dropping ammonia-containing liquid, or adding ammonium salt and alkali.
8. The method for preparing high-purity bravaracetam according to claim 1, characterized in that: and (3) carrying out crystallization after the ammonolysis reaction, wherein the solvent used for the crystallization is selected from isopropyl acetate, acetone, isopropanol or a mixed solvent of any one of the isopropyl acetate, the acetone and the isopropanol.
9. The method for preparing high-purity bravaracetam according to claim 1, characterized in that: the usage amount of the crystallized solvent is 0.8-2 mL/g relative to the mass of the crude product of the brivaracetam.
10. The method for preparing high-purity bravaracetam according to claim 1 or 9, characterized in that: the usage amount of the crystallized solvent is 1-1.5 mL/g relative to the mass of the crude product of the brivaracetam.
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| WO2017076738A1 (en) * | 2015-11-03 | 2017-05-11 | Ucb Biopharma Sprl | Process for preparing brivaracetam |
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| CN109942516A (en) * | 2019-03-27 | 2019-06-28 | 成都克莱蒙医药科技有限公司 | Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone |
| CN113651745A (en) * | 2021-09-09 | 2021-11-16 | 上海医药工业研究院 | Buvalracetam intermediate, preparation method and purification method thereof |
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2022
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017076738A1 (en) * | 2015-11-03 | 2017-05-11 | Ucb Biopharma Sprl | Process for preparing brivaracetam |
| CN108658831A (en) * | 2017-03-30 | 2018-10-16 | 江苏豪森药业集团有限公司 | The preparation method of 2- OXo-1-pyrrolidine derivatives or its salt |
| CN108101823A (en) * | 2018-02-13 | 2018-06-01 | 扬州奥锐特药业有限公司 | A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan |
| CN108101824A (en) * | 2018-02-13 | 2018-06-01 | 扬州奥锐特药业有限公司 | A kind of preparation method of high chiral purity lactam intermediate and Bu Waxitan |
| CN109942516A (en) * | 2019-03-27 | 2019-06-28 | 成都克莱蒙医药科技有限公司 | Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone |
| CN113651745A (en) * | 2021-09-09 | 2021-11-16 | 上海医药工业研究院 | Buvalracetam intermediate, preparation method and purification method thereof |
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