CN101885696A - Method for synthesizing high-purity levetiracetam - Google Patents
Method for synthesizing high-purity levetiracetam Download PDFInfo
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- CN101885696A CN101885696A CN2009100511557A CN200910051155A CN101885696A CN 101885696 A CN101885696 A CN 101885696A CN 2009100511557 A CN2009100511557 A CN 2009100511557A CN 200910051155 A CN200910051155 A CN 200910051155A CN 101885696 A CN101885696 A CN 101885696A
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- levetiracetam
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Abstract
The invention relates to a method for synthesizing high-purity levetiracetam, belongs to the field of chemical synthesis and particularly relates to a method for preparing high-purity levetiracetam by substituting diisopropylethylamine for triethylamine in a reaction for preparing (S)-a-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) by ammoniation of (S)-a-ethyl-2-oxo-1-pyrrolidineacetic acid.
Description
Technical field
The present invention relates to a kind of preparation method of Levetiracetam, belong to the synthetic field of chemical industry, particularly relate in the reaction by (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ammonification preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam), replace triethylamine with diisopropylethylamine, and the method for preparing high-purity levetiracetam.
Background technology
Antiepileptic drug is the class medicine that prevention and treatment are lacked of proper care by the paroxysmal of epileptics outbreak initiation, temporary brain function.Levetiracetam (Levetiracetam) is to be used for the treatment of limitation and secondary generalized epilepsy medicine by what Belgian UCB. S.A. (BE) Bruxelles Belgium developed.It is a s-generation vagusstoff agonist, is pyrrolidinone derivatives, has unique pharmacological action of selective protection limitation and former general purplish or white patches on the skin epilepsy, and does not influence the metabolism in vivo of other antiepileptic drug.Compare with similar medicine; this product is optionally protected former general and localized epilepsy and is not interacted with other antiepileptic drug; do not show yet and suppress and the effect of excitor nerve transmission, have characteristics such as therapeutic index height, the slight better tolerance of side effect, safety index height, the every index of pharmacokinetics be good.
The synthetic route of Levetiracetam roughly can be divided into two.Article one, route is through the synthetic method of (S)-2-amino-butanamide intermediate.With positive propionic aldehyde is starting raw material, obtains (S)-2-amino-butanamide through Strake reaction, hydrolysis, fractionation; Or be raw material with the 2-bromo-butyric acid, separate, split and obtain (S)-2-amino-butanamide through ammonification, esterification, ammonia.Intermediate (S)-2-amino-butanamide is converted into the method for Levetiracetam again with 4-chlorobutanoylchloride or the amidation of 4-neoprene acid ethyl ester, cyclization.This route raw material is cheaply easily purchased, but that shortcoming is a step is long, yield is low, technology complexity etc. too.Be unfavorable for suitability for industrialized production.Second is to be raw material with 2-Pyrrolidone and 2-bromo-butyric acid methyl esters etc., obtains the route of Levetiracetam through N-hydrocarbylation, hydrolysis, fractionation, amidation.With the 2-Pyrrolidone is raw material, introduces side chain and splits the route that obtains Levetiracetam again.This route is a route that step is simple, yield is high.
In above-mentioned second synthetic route, final step relates to the ammonification of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.Since (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid is easy to racemization under acidity or alkaline condition, be a problem that must solve so how to avoid the quality of the racemization of product, the yield that improves reaction, lifting product in the aminating reaction of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.The method of the bibliographical information of this step aminating reaction mainly is that employing Vinyl chloroformate or methylsulfonyl chloride are that activator, triethylamine are the method for acid binding agent.WO06053441 has reported with the SULPHURYL CHLORIDE to be that activator, triethylamine are acid binding agent, and the crude product that obtains is through the method for the synthetic Levetiracetam of methyl iso-butyl ketone (MIBK) recrystallization.This method experiment condition gentleness, yield higher (78～80%), but use hypertoxic hazardous substance methylsulfonyl chloride.
US4696943 has reported that adopting Vinyl chloroformate is that activator, triethylamine are the method for the synthetic Levetiracetam of acid binding agent.Carry out under the low temperature reaction (30～-40 ℃), crude product is through acetone recrystallization, and yield is 72.3%.The Levetiracetam that obtains only provides the physical data of fusing point and specific rotation.Do not report in all documents about the chemical purity of Levetiracetam and the data of optical purity yet.This method yield is low, the cost height, and severe reaction conditions needs low temperature (30～-40 ℃).
Summary of the invention
The purpose of this invention is to provide a kind of yield height, cost ammonification low, that be suitable for industrialized (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid prepares the method for highly purified Levetiracetam.
The employing Vinyl chloroformate of document US 4696943 reports is that activator, triethylamine are acid binding agent, ammonification by (S)-alpha-ethyl-2-oxo-1-pyrrolidyl acetate prepares the method for Levetiracetam, under-30～-40 ℃ temperature, react, obtain crude product through twice recrystallization, total recovery only is 65～70%.
It is that activator, diisopropylethylamine are the synthetic method of acid binding agent that the present invention adopts Vinyl chloroformate, obtains the Levetiracetam of high-optical-purity and high chemical purity through ammonification by (S)-alpha-ethyl-2-oxo-1-pyrrolidyl acetate.
The present invention prepares in the reaction of Levetiracetam in (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ammonification, with the Vinyl chloroformate is that activator, diisopropylethylamine are acid binding agent, the temperature of aminating reaction is brought up to-5～25 ℃, and reaction obtains crude levetiracetam.Use the ethyl acetate of adding a small amount of organic amine to be recrystallization solvent, promptly obtain qualified highly purified Levetiracetam through a recrystallization.Wherein the consumption of recrystallization solvent is 1～3 times (v/w) of crude levetiracetam, and organic amine is triethylamine, diisopropylethylamine; The content of organic amine in ethyl acetate is 0.5～2% (v/v).Overall yield of reaction is 84～85%.
The highly purified Levetiracetam that the present invention makes, chemical purity are more than 99.6%, and optical purity is more than 99.5%, and the content of known impurities (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid is less than 0.1%.Unknown impuritie is less than 0.05%.
The preparation method of high-purity levetiracetam provided by the invention, the reaction conditions gentleness can at room temperature be carried out, and operation is simple and feasible, yield is expensive low, is suitable for suitability for industrialized production.
Embodiment
Below by embodiment the present invention is further elaborated, embodiment is for understanding the unrestricted interest field of invention.
Embodiment one:
(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid 51.3g and methylene dichloride 120mL are joined in the there-necked flask.Cool to-10 ℃, add diisopropylethylamine 47.8g, Vinyl chloroformate 35.7g successively, controlled temperature is-5 ℃, continues reaction 30min.Keep about temperature-5 ℃, logical ammonia gas react is complete to feedstock conversion.Reaction finishes after-filtration, filter cake washed with dichloromethane.After filtrate and washings merge, the residue that concentrating under reduced pressure obtains, with ethyl acetate 45mL (containing 0.5% diisopropylethylamine) recrystallization, suction filtration, oven dry obtain (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide 43g yield 85%.Optical purity 99.5%, HPLC purity 99.6%, impurity (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid content 0.06%.
Embodiment two:
(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid 55g and methylene dichloride 130ml are joined in the there-necked flask.Add diisopropylethylamine 51.2g, Vinyl chloroformate 38.3g successively, controlled temperature is 25 ℃, continues reaction 30min.Keep about 25 ℃ of temperature, logical ammonia gas react is to the raw material complete reaction.Reaction finishes after-filtration, filter cake washed with dichloromethane.Filtrate and washings merge, concentrating under reduced pressure.The residue that obtains adds ethyl acetate 50mL (containing 0.5% triethylamine) recrystallization, and suction filtration, oven dry obtain (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide 44.7g.Yield 83%.Optical purity 99.6%, HPLC purity 99.7%, impurity (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid content 0.07%.
Comparative example one:
(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid 51.3g and methylene dichloride 120mL are joined in the there-necked flask.The cooling degree adds triethylamine 36.2g, Vinyl chloroformate 35.7g successively to-40 ℃.Temperature control is not higher than-35 ℃.Insulation reaction 30min.Keep about temperature-35 ℃ logical ammonia gas react 3～4 hours.Reaction finishes after-filtration, filter cake washed with dichloromethane.Filtrate and washings merge, concentrating under reduced pressure.The residue acetone recrystallization that obtains obtains (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide 29.8g yield 59%.Optical purity 98.0%, HPLC purity 98.0%, impurity (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid content 0.5%.
Claims (6)
1. method for preparing high-purity levetiracetam may further comprise the steps:
(A) (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid carries out ammonification and prepares crude levetiracetam under the effect of activator and acid binding agent;
(B) crude levetiracetam recrystallization in containing the ethyl acetate of organic amine makes highly purified Levetiracetam.
2. preparation method according to claim 1 is characterized in that the acid binding agent in the step (A) is a diisopropylethylamine.
3. preparation method according to claim 1 is characterized in that the temperature of reaction of step (A) is-5～25 ℃.
4. preparation method according to claim 1 is characterized in that the organic amine in the step (B) is triethylamine, diisopropylethylamine.
5. preparation method according to claim 1 is characterized in that the content of organic amine in ethyl acetate is 0.5～2% (v/v) in the step (B).
6. preparation method according to claim 1 is characterized in that the consumption of recrystallization solvent in the step (B) is 1～5 times (v/w) of crude levetiracetam.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2009100511557A CN101885696A (en) | 2009-05-14 | 2009-05-14 | Method for synthesizing high-purity levetiracetam |
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| CN2009100511557A CN101885696A (en) | 2009-05-14 | 2009-05-14 | Method for synthesizing high-purity levetiracetam |
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| CN101885696A true CN101885696A (en) | 2010-11-17 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103922988A (en) * | 2014-04-29 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Method for purifying levetiracetam crude product |
| CN104370791A (en) * | 2014-11-28 | 2015-02-25 | 上虞京新药业有限公司 | Purifying method of levetiracetam |
| CN107337628A (en) * | 2017-08-10 | 2017-11-10 | 浙江华海药业股份有限公司 | A kind of method for preparing Levetiracetam |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85105301A (en) * | 1984-05-15 | 1987-01-14 | 尤西比公司 | (S)-preparation method of alpha-ethyl-2-oxo-1-pyrrolidine acetamide |
| WO2006053441A1 (en) * | 2004-11-22 | 2006-05-26 | Apotex Pharmachem Inc. | Improved process for the preparation of (s)-alpha-etyl-2-oxo-1-pyrrolidineacetamide and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
| WO2009057137A2 (en) * | 2007-08-22 | 2009-05-07 | Alembic Limited | A process for the purification of levetiracetam |
-
2009
- 2009-05-14 CN CN2009100511557A patent/CN101885696A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85105301A (en) * | 1984-05-15 | 1987-01-14 | 尤西比公司 | (S)-preparation method of alpha-ethyl-2-oxo-1-pyrrolidine acetamide |
| WO2006053441A1 (en) * | 2004-11-22 | 2006-05-26 | Apotex Pharmachem Inc. | Improved process for the preparation of (s)-alpha-etyl-2-oxo-1-pyrrolidineacetamide and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
| WO2009057137A2 (en) * | 2007-08-22 | 2009-05-07 | Alembic Limited | A process for the purification of levetiracetam |
Non-Patent Citations (1)
| Title |
|---|
| 徐宝财等: "( S )-α-乙基-2-氧代-1-吡咯烷基乙酰胺的合成工艺进展", 《精细与专用化学品》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103922988A (en) * | 2014-04-29 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Method for purifying levetiracetam crude product |
| CN104370791A (en) * | 2014-11-28 | 2015-02-25 | 上虞京新药业有限公司 | Purifying method of levetiracetam |
| CN107337628A (en) * | 2017-08-10 | 2017-11-10 | 浙江华海药业股份有限公司 | A kind of method for preparing Levetiracetam |
| CN107337628B (en) * | 2017-08-10 | 2022-02-08 | 浙江华海药业股份有限公司 | Method for preparing levetiracetam |
| US11498897B2 (en) | 2017-08-10 | 2022-11-15 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Method for preparing levetiracetam |
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Application publication date: 20101117 |