CN110590635A - Preparation method of levetiracetam and intermediate thereof - Google Patents

Preparation method of levetiracetam and intermediate thereof Download PDF

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Publication number
CN110590635A
CN110590635A CN201910963935.2A CN201910963935A CN110590635A CN 110590635 A CN110590635 A CN 110590635A CN 201910963935 A CN201910963935 A CN 201910963935A CN 110590635 A CN110590635 A CN 110590635A
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China
Prior art keywords
formula
compound
toluene
dropwise
levetiracetam
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杨桂芝
陈雨
周国华
朱典成
傅丽
陈丽姣
王路
杨永宁
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Shandong Polytechnic College
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Shandong Polytechnic College
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/18Heterocyclic 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
    • C07D207/22Heterocyclic 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
    • C07D207/24Oxygen or sulfur atoms
    • C07D207/262-Pyrrolidones
    • C07D207/2632-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/272-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

Abstract

The invention provides a preparation method of levetiracetam and an intermediate thereof, which comprises the following steps: adding pyrrolidone dropwise into a toluene solution of sodium methoxide or sodium hydrogen, concentrating to be dry after the reaction is finished, adding toluene again, adding ethyl 2-bromobutyrate dropwise, and heating to react to obtain a compound shown in the formula 3; adding NaOH aqueous solution into the compound in the formula 3, heating to react completely, and dropwise adding concentrated hydrochloric acid to precipitate a compound in a formula 4; reacting the compound of the formula 4, R- (+) -phenethylamine and triethylamine to obtain a compound of a formula 6; hydrolyzing with NaOH solution, acidifying with concentrated salt, and purifying to obtain compound of formula 7; the compound shown in the formula 8 is prepared by TsOH/EtOH esterification, and levetiracetam is obtained by aminolysis.

Description

Preparation method of levetiracetam and intermediate thereof
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of levetiracetam and an intermediate thereof.
Background
Levetiracetam is a broad-spectrum antiepileptic drug developed by UCB company of Belgium with high efficiency and small toxic and side effects, is mainly used for treating local and secondary generalized epilepsy and has the chemical name of (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide.
At present, a plurality of reports exist on the preparation method of levetiracetam at home and abroad, and a chemical resolution method is mainly adopted. The main method comprises the following steps: 1) the initial raw material is methionine, and is prepared by multi-step reaction and final reduction desulfurization. 2) (S) -2-aminobutanamide having a chiral center, which is free from resolution, is reacted with 4-chlorobutyryl chloride in a two-step ring-closure reaction, as disclosed in EP1566376A 1. 3) The method is a cyclization method, and takes 2-pyrrolidone as a raw material to obtain a final product levetiracetam through nucleophilic substitution reaction, hydrolysis, resolution dissociation and final amidation. The synthesis method commonly used in industry adopts the traditional chemical resolution method to construct the chiral center, and has long process route and low atom utilization rate.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of levetiracetam and an intermediate thereof, which does not need to use high-toxicity reagents such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, ethyl chloroformate, alkyl chloroformate and the like, and has small potential safety hazard and low safe input cost in industrial mass production.
In order to solve the technical problems, the invention provides the following technical scheme:
on one hand, the invention provides a preparation method of levetiracetam, which comprises the following specific steps:
the compound in the formula 7 is esterified by TsOH/EtOH to prepare a compound in a formula 8, and then the levetiracetam is obtained by aminolysis;
further, in the method, the molar ratio of the compound of formula 7 to TsOH is 10:1, and the amount of EtOH used is 10mL/g of the compound of formula 7.
Further, in the method, the reagent used for ammonolysis is concentrated ammonia water, and the dosage of the concentrated ammonia water is 10mL/g of the compound shown in the formula 7.
Further, in the method, after the ammonolysis is finished, nitrogen is introduced to remove ammonia gas, the mixture is concentrated to be dry in vacuum, and acetone and ethyl acetate (the volume ratio of the acetone to the ethyl acetate is 1:3) are added to be stirred at the temperature of 0-10 ℃ to separate out a product.
Further, the preparation process of the compound of formula 7 is as follows:
reacting the compound of the formula 4, R- (+) -phenethylamine and triethylamine to obtain a compound of a formula 6;
and hydrolyzing the compound shown in the formula 6 by using NaOH solution, acidifying by using concentrated salt, and purifying to obtain the compound shown in the formula 7.
Further, adding the compound of the formula 4 into toluene, dropwise adding a mixed solution of R- (+) -phenethylamine and triethylamine, dissolving the solid, raising the temperature to 80-90 ℃ after adding the solid, reacting for 1-2h, slowly cooling to 0-10 ℃ for crystallization, preserving the temperature for 1-2h, and performing suction filtration to obtain a compound of the formula 6;
adding the compound of formula 6 into water, dripping 30% NaOH solution to pH 4-5, stirring, adding toluene for extraction, cooling water phase to 0-10 deg.C, dripping concentrated hydrochloric acid to pH 4-5, separating out solid, adding CH2Cl2Extracting, and vacuum concentrating the organic phase to obtain a crude product; the dosage of the toluene is 3mL/g of the compound shown in the formula 6;
adding EtOH or ethyl acetate into the crude product, heating to 70 ℃, stirring to dissolve, cooling to 0-10 ℃, keeping the temperature for 2 hours, performing suction filtration, and performing vacuum drying to obtain the compound shown in the formula 7.
Further, in the preparation process of the compound shown in the formula 6, the dosage of the toluene is 2-3mL/g of the compound shown in the formula 4; the molar ratio of the compound of formula 4, R- (+) -phenethylamine and triethylamine is 10:6: 5.
Further, the crude compound of formula 6 needs to be recrystallized 2 times from toluene; the amount of toluene used was 4-5mL/g of crude compound of formula 6.
Further, the specific recrystallization process is as follows: stirring at 110 deg.C for dissolving, cooling to 0-10 deg.C, maintaining the temperature for 1-2 hr, and vacuum filtering to obtain wet product; the wet product is dried in vacuum at 40 ℃ for 4-8h and then used for the next step; the amount of water used is 2mL/g of the compound of formula 6.
Further, the preparation process of the compound of formula 4 is as follows:
adding pyrrolidone dropwise into a toluene solution of sodium methoxide or sodium hydrogen, concentrating to be dry after the reaction is finished, adding toluene again, adding ethyl 2-bromobutyrate dropwise, and heating to react to obtain a compound shown in the formula 3;
and adding an aqueous NaOH solution into the compound of the formula 3, heating to react completely, dropwise adding concentrated hydrochloric acid until the pH value is 4-5, and precipitating the compound of the formula 4.
Further, the compound of formula 4 is purified as follows: addition of CH to the Compound of formula 42Cl2Dissolving the solid with water, separating liquid, vacuum concentrating the organic phase to dry to obtain crude product, adding EtOH, heating to 70 deg.C to dissolve the solid, cooling to 0-10 deg.C, stirring for 1-2 hr, vacuum filtering, and vacuum drying to obtain the final product. Further, the CH2Cl2And water volume ratio of 50: 3.
Further, before the pyrrolidone is dripped into the sodium methoxide or sodium hydrogen toluene solution, the temperature of the mixed solution needs to be reduced to 0-10 ℃. Further, before dropwise adding ethyl 2-bromobutyrate, the reaction system needs to be cooled to 0-10 ℃. Further, in the process of preparing the compound of the formula 3 by heating reaction, the temperature is 80-90 ℃, and the reaction time is 8-10 h.
Further, NaOH aqueous solution is added into the compound shown in the formula 3, the compound is heated to 60 ℃ for reaction, after the reaction is finished, the temperature is reduced to 0-10 ℃, and then concentrated hydrochloric acid is dropwise added.
On the other hand, the invention provides a preparation method of levetiracetam, which comprises the following specific steps:
adding pyrrolidone dropwise into a toluene solution of sodium methoxide or sodium hydrogen, concentrating to be dry after the reaction is finished, adding toluene again, adding ethyl 2-bromobutyrate dropwise, and heating to react to obtain a compound shown in the formula 3;
adding NaOH aqueous solution into the compound shown in the formula 3, heating to react completely, dropwise adding concentrated hydrochloric acid until the pH value is 4-5, and precipitating the compound shown in the formula 4;
reacting the compound of the formula 4, R- (+) -phenethylamine and triethylamine to obtain a compound of a formula 6;
hydrolyzing the compound shown in the formula 6 by using NaOH solution, acidifying by using concentrated salt, and purifying to obtain a compound shown in a formula 7;
the compound in the formula 7 is esterified by TsOH/EtOH to prepare a compound in a formula 8, and then the levetiracetam is obtained by aminolysis;
advantageous effects
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of levetiracetam and an intermediate thereof, which has the following advantages: 1) benzene is not needed to be used as a solvent; expensive catalysts in the process of synthesizing the chiral compounds are avoided, and meanwhile, the obtained product has high purity and high quality of finished products; 2) in the reaction process, high-toxicity reagents such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, ethyl chloroformate, alkyl chloroformate and the like are not needed, so that the potential safety hazard is small, and the safe input cost is low; 3) by applying the method, the total yield is over 22 percent, and the purity is high; 4) the preparation process of the compound shown in the formula 4 has the advantages of high atom utilization rate, easily obtained raw materials, simple and efficient reaction steps; sodium methoxide and sodium hydrogen are used as alkali, so that the yield is high, and the sodium methoxide is preferred, so that the cost is lower and the safety is higher; the compound in the formula 6 is separated out by adopting toluene recrystallization, which is more beneficial to industrialization, and the toluene is used as an industrial common reagent and is more beneficial to subsequent industrialization; the compound shown in the formula 8 is obtained by combining p-toluenesulfonic acid and ethanol, and levetiracetam can be obtained by aminolysis with concentrated ammonia water, so that the overall process is simple and efficient, the yield reaches 59%, and the purity reaches 99.98%.
Drawings
The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification.
FIG. 1 shows an HPLC chromatogram of the obtained levetiracetam product.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but it should not be construed that the scope of the subject matter of the present invention is limited to the examples.
The process equipment or devices not specifically noted in the following examples are conventional in the art; all reagents are commercially available.
Example 1
1) Step one and step two: synthesis of lacitamic acid
Step 1: adding sodium methoxide (67.7g,1.1eq) into toluene (3mL/g), reducing the temperature to 0-10 ℃, dropwise adding pyrrolidone (100g), reacting at room temperature for 2h after the addition is finished, concentrating at 50 ℃ to dryness, adding toluene (5mL/g) again, reducing the temperature to 0-10 ℃, dropwise adding ethyl 2-bromobutyrate (252g,1.1eq), increasing the temperature to 80-90 ℃ after the addition is finished, reacting for 8-10h, reducing the temperature to room temperature, adding water (2mL/g), separating, and concentrating the organic phase at 40-50 ℃ in vacuum to dryness, wherein the oily matter is directly used in the next step.
Step 2: adding NaOH (2.2eq) and water (2mL/g) solution into the oily substance in the last step, raising the temperature to 60 ℃, reacting for 3h, completely reacting, reducing the temperature to 0-10 ℃, dropwise adding concentrated hydrochloric acid (about 180mL) until the pH value is 4-5, and separating out a solid. Adding CH2Cl2(1L) and water (60mL) dissolve the solid, the liquid separation is carried out, the organic phase is concentrated in vacuum at 40 ℃ until the organic phase is dried to obtain a crude product, EtOH (150mL) is added, the temperature is increased to 70 ℃ to dissolve the solid, the temperature is reduced to 0-10 ℃, the temperature is kept and the stirring is carried out for 1-2h, the suction filtration is carried out, and the vacuum drying at 40 ℃ is carried out for 4h to obtain the product (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, and a white solid (176.6g,88.0 percent).
2) Step three:
adding 74.0g of (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid into toluene (2-3mL/g), dropwise adding a mixed solution of R- (+) -phenethylamine (0.6eq) and triethylamine (0.5eq) at room temperature, dissolving the solid, raising the temperature to 80-90 ℃ for reaction for 1-2h after the solid is added, possibly precipitating the solid, slowly cooling to 0-10 ℃ for crystallization (seed crystal can be added), preserving the temperature for 1-2h, performing suction filtration, and washing a small amount of toluene to obtain a white solid crude product.
Adding toluene (4-5mL/g) into the crude product, raising the temperature to 110 ℃, stirring and dissolving, reducing the temperature to 0-10 ℃, preserving the temperature for 1-2h, filtering to obtain a wet product, crystallizing once by using toluene again, and drying in vacuum at 40 ℃ for 4-8h to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (R) -alpha-methylbenzylamine salt as a white solid (62.1g, 98.2% of monomer yield).
3) Step four
Adding 70.3g of the white solid prepared in the step 3 into water (2mL/g), dropwise adding a 30% NaOH solution at 0-10 ℃ until the pH value is 4-5, stirring for 0.5h, adding toluene (3mL/g) for extraction, cooling the water phase to 0-10 ℃, dropwise adding concentrated hydrochloric acid until the pH value is 4-5, precipitating the solid, adding CH (methyl chloride), and stirring2Cl2(3 mL/g.times.2) and the organic phase concentrated to dryness in vacuo at 40 ℃ to give 36g of crude product.
Adding EtOH (1.5mL/g crude product) into the crude product, raising the temperature to 70 ℃, stirring and dissolving, reducing the temperature to 0-10 ℃, preserving the temperature for 2h, filtering, and drying in vacuum at 40 ℃ for 4h to obtain the product (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, namely a white solid (35.79g, 87.1%).
4) Step five and step six
And 5: 21.1g of (S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid, anhydrous ethanol (10mL/g) and p-toluenesulfonic acid (0.1eq) were added, the reaction was allowed to warm to 60 ℃ for 7h, the reaction was concentrated to dryness at 50 ℃ in vacuo, ethyl acetate (10mL/g) was added, the mixture was stirred and washed twice with water (2.5mL/g), and the organic phase was concentrated to dryness at 50 ℃ in vacuo to give an oil of ethyl (S) -alpha-ethyl-2-oxo-1-pyrrolidineacetate.
Step 6: adding concentrated ammonia water (10mL/g) into the oily matter in the last step, reducing the temperature to 0-10 ℃ for reaction for 24h, completing TLC reaction, introducing nitrogen to remove ammonia gas, concentrating at 50 ℃ in vacuum to dryness, adding acetone (6mL) and ethyl acetate (18mL), stirring at 0-10 ℃ to separate out a solid, performing suction filtration, washing with a small amount of EA, and performing vacuum drying at 40 ℃ for 8h to obtain the product levetiracetam, wherein the white solid (12.4g and 59%) has the total yield of 22.2% and the ee of 99.98%.
It will be understood that the above embodiments are merely exemplary embodiments taken to illustrate the principles of the present invention, which is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention, and these changes and modifications are also considered to be included in the scope of the invention.

Claims (10)

1. A preparation method of levetiracetam is characterized by comprising the following specific steps:
the compound in the formula 7 is esterified by TsOH/EtOH to prepare a compound in a formula 8, and then the levetiracetam is obtained by aminolysis;
2. the process for preparing levetiracetam according to claim 1, wherein the molar ratio of the compound of formula 7 to TsOH is 10:1, and EtOH is used in an amount of 10mL/g of the compound of formula 7;
in the method, the reagent used for ammonolysis is concentrated ammonia water, and the dosage of the concentrated ammonia water is 10mL/g of the compound shown as the formula 7.
3. The method for preparing levetiracetam according to claim 2, wherein after the ammonolysis is completed, nitrogen is introduced to remove ammonia gas, the mixture is concentrated to dryness in vacuum, and acetone and ethyl acetate (the volume ratio of the acetone to the ethyl acetate is 1:3) are added and stirred at 0-10 ℃ to separate out the product.
4. The process for preparing levetiracetam according to claim 1, wherein the compound of formula 7 is prepared by the following steps:
reacting the compound of the formula 4, R- (+) -phenethylamine and triethylamine to obtain a compound of a formula 6;
and hydrolyzing the compound shown in the formula 6 by using NaOH solution, acidifying by using concentrated salt, and purifying to obtain the compound shown in the formula 7.
5. The preparation method of levetiracetam according to claim 4, characterized in that the compound of formula 4 is added into toluene, a mixed solution of R- (+) -phenethylamine and triethylamine is added dropwise, the solid is dissolved, after the addition is finished, the temperature is raised to 80-90 ℃ for reaction for 1-2h, the temperature is slowly reduced to 0-10 ℃ for crystallization, the temperature is kept for 1-2h, and the compound of formula 6 is obtained by suction filtration;
adding the compound of formula 6 into water, dripping 30% NaOH solution to pH 4-5, stirring, adding toluene for extraction, cooling water phase to 0-10 deg.C, dripping concentrated hydrochloric acid to pH 4-5, separating out solid, adding CH2Cl2Extracting, and vacuum concentrating the organic phase to obtain a crude product; the dosage of the toluene is 3mL/g of the compound shown in the formula 6;
adding EtOH or ethyl acetate into the crude product, heating to 70 ℃, stirring to dissolve, cooling to 0-10 ℃, keeping the temperature for 2 hours, performing suction filtration, and performing vacuum drying to obtain the compound shown in the formula 7.
6. The method for preparing levetiracetam according to claim 5, wherein the amount of toluene used in the preparation of the compound of formula 6 is 2-3mL/g of the compound of formula 4; the molar ratio of the compound of formula 4, R- (+) -phenethylamine and triethylamine is 10:6: 5.
7. The process for preparing levetiracetam according to claim 6, wherein the crude compound of formula 6 is recrystallized 2 times from toluene; the dosage of the toluene is 4-5mL/g of the crude product of the compound shown in the formula 6;
further, the specific recrystallization process is as follows: stirring at 110 deg.C for dissolving, cooling to 0-10 deg.C, maintaining the temperature for 1-2 hr, and vacuum filtering to obtain wet product; the wet product is dried in vacuum at 40 ℃ for 4-8h and then used for the next step; the amount of water used is 2mL/g of the compound of formula 6.
8. The process for preparing levetiracetam according to claim 4, wherein the compound of formula 4 is prepared by the following steps:
adding pyrrolidone dropwise into a toluene solution of sodium methoxide or sodium hydrogen, concentrating to be dry after the reaction is finished, adding toluene again, adding ethyl 2-bromobutyrate dropwise, and heating to react to obtain a compound shown in the formula 3;
and adding an aqueous NaOH solution into the compound of the formula 3, heating to react completely, dropwise adding concentrated hydrochloric acid until the pH value is 4-5, and precipitating the compound of the formula 4.
9. The process for preparing levetiracetam according to claim 8, wherein the compound of formula 4 is purified by the following steps: addition of CH to the Compound of formula 42Cl2Dissolving the solid with water, separating liquid, vacuum concentrating the organic phase to dry to obtain crude product, adding EtOH, heating to 70 deg.C to dissolve the solid, cooling to 0-10 deg.C, stirring for 1-2 hr, vacuum filtering, and vacuum drying to obtain product;
before pyrrolidone is dripped into the sodium methoxide or sodium hydrogen toluene solution, the temperature of the mixed solution is required to be reduced to 0-10 ℃; before dropwise adding ethyl 2-bromobutyrate, the reaction system needs to be cooled to 0-10 ℃;
adding NaOH aqueous solution into the compound shown in the formula 3, heating to 60 ℃ for reaction, cooling to 0-10 ℃ after the reaction is finished, and then dropwise adding concentrated hydrochloric acid.
10. A preparation method of levetiracetam is characterized by comprising the following specific steps:
adding pyrrolidone dropwise into a toluene solution of sodium methoxide or sodium hydrogen, concentrating to be dry after the reaction is finished, adding toluene again, adding ethyl 2-bromobutyrate dropwise, and heating to react to obtain a compound shown in the formula 3;
adding NaOH aqueous solution into the compound shown in the formula 3, heating to react completely, dropwise adding concentrated hydrochloric acid until the pH value is 4-5, and precipitating the compound shown in the formula 4;
reacting the compound of the formula 4, R- (+) -phenethylamine and triethylamine to obtain a compound of a formula 6;
hydrolyzing the compound shown in the formula 6 by using NaOH solution, acidifying by using concentrated salt, and purifying to obtain a compound shown in a formula 7;
the compound in the formula 7 is esterified by TsOH/EtOH to prepare a compound in a formula 8, and then the levetiracetam is obtained by aminolysis;
CN201910963935.2A 2019-10-11 2019-10-11 Preparation method of levetiracetam and intermediate thereof Pending CN110590635A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321476A (en) * 2020-11-10 2021-02-05 江苏八巨药业有限公司 Preparation method of levetiracetam
WO2022001649A1 (en) * 2020-06-30 2022-01-06 浙江华海药业股份有限公司 Preparation method for levetiracetam intermediate
US11384050B1 (en) 2021-02-03 2022-07-12 Vitaworks Ip, Llc Method for preparing levetiracetam and intermediates thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019028671A1 (en) * 2017-08-08 2019-02-14 浙江华海药业股份有限公司 Method for preparing levetiracetam

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019028671A1 (en) * 2017-08-08 2019-02-14 浙江华海药业股份有限公司 Method for preparing levetiracetam

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BENOIT M. KENDA等: "Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity", 《J. MED. CHEM.》 *
刘跃金等: "左乙拉西坦及其衍生物的合成", 《中国新药杂志》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022001649A1 (en) * 2020-06-30 2022-01-06 浙江华海药业股份有限公司 Preparation method for levetiracetam intermediate
CN112321476A (en) * 2020-11-10 2021-02-05 江苏八巨药业有限公司 Preparation method of levetiracetam
US11384050B1 (en) 2021-02-03 2022-07-12 Vitaworks Ip, Llc Method for preparing levetiracetam and intermediates thereof
WO2022169747A1 (en) * 2021-02-03 2022-08-11 Vitaworks Ip, Llc Method for preparing levetiracetam and intermediates thereof

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