CN104860863B - Levetiracetam and the pharmaceutical composition containing it - Google Patents
Levetiracetam and the pharmaceutical composition containing it Download PDFInfo
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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
Abstract
The invention provides a kind of Levetiracetam of high-purity and the pharmaceutical composition containing it.The preparation method of the Levetiracetam of the high-purity is prepared using " one kettle way ", it is starting material with (S) 2 amino-butanamide hydrochloride, cyclization just can obtain Levetiracetam again with the condensation of 4 chlorobutanoylchlorides, purity more than 99.5%, and unknown list is miscellaneous to be less than less than 0.05%.Further include to be dissolved in preceding method acquisition Levetiracetam in organic solvent, filtered while hot using 0.22 μm 0.45 μm of filter core, the qualified product of chloride can be obtained, chloride impurity amount is less than 0.02%, and conversion yields are high.Levetiracetam purity can be significantly improved by the present invention, the raw material and pharmaceutical composition of good quality is further obtained.
Description
Technical field
The invention belongs to chemicals technical field, it is related to a kind of Levetiracetam of high-purity and the drug regimen containing it
Thing.
Background technology
Levetiracetam (Levetiracetam) is a kind of antiepileptic of Belgian UCB drugmakers research and development, its change
Scientific name is referred to as (S) -2- (2- OXo-1-pyrrolidines) butyramide, and English is entitled：(S)-2-(2-Oxopyrrolidin-1-yl)
Butananide, molecular formula is：C8H14N2O2, molecular weight is 170.21, and its chemical structural formula is：
Epilepsy or the auxiliary of part breaking-out for being grown up and more than 4 years old children that Levetiracetam is ratified by CFDA
Treatment.It is initially to be listed in Europe and the U.S. for 1999, for the epileptic attack of adult partial's property；Criticized again in June, 2005
Accurate its oral tablet and injection are used for 4 years old or more the auxiliary treatment of children's partial seizures；In March, 2007 is in China
Listing, trade name Levetiracetam.
It is oral easily to absorb because Levetiracetam is more more preferable than other antiepileptics in pharmacokinetics, it is biological sharp
Expenditure is high, high with therapeutic index, is not interacted with other antiepileptics, and side effect is slight, and better tolerance etc. is excellent
Point.Compared with other antiepileptics, the protection activity of its anti anoxia will be higher by 10 times or so, the protection activity of anti-cerebral ischemia
It is higher by 4 times or so.Levetiracetam is the antiepileptic of the currently the only special performance with prevention epileptic attack.
At present, the preparation method of chiral drug Levetiracetam is it has been reported that mainly using chemical resolution method, asymmetric
Hydrogenating catalytic method or the method for synthesizing Levetiracetam with amino acid as raw material.But these methods more or less all have one
A bit to production or the unfavorable factor of product quality.As a kind of Belgian the of UCB. S.A.'s exploitation synthesizes left second using chemical resolution method
The method of La Xitan, with racemic (R, S) -2- (2- OXo-1-pyrrolidines) butyric acid for initiation material, with R- (+)-Alpha-Methyl benzyl
Amine is resolving agent, is split in benzene, then is processed with highly basic, obtains free (S) -2- (2- OXo-1-pyrrolidines) butyric acid.The acid
First with ethyl chloroformate reaction, then Levetiracetam is obtained with ammonia generation ammonolysis reaction.But due to using benzene as fractionation
Solvent, however, according to ICH Q3C guides, benzene is listed in a class solvent, it should avoid using, therefore, the method uses benzene conduct
Resolving agent, existing larger harmfulness, does not meet the requirement of production of raw medicine again.
And for example Chinese patent application (publication number：CN101550100A, publication date：On October 07th, 2009) disclose one kind
Synthetic method with L-threonine as initiation material, the method is by with L-threonine as raw material, through over-churning, halo, urging
Change the processes such as reduction, ammonolysis and cyclization and prepare Levetiracetam.Wherein, esterification and halo process all employ halogenation sulfoxide；Urge
Change reduction and use Raney's nickel, palladium charcoal, rhodium charcoal fire support type platinum oxide etc.；Ammonolysis preferentially select ammonia or ammoniacal liquor.Although the method
Solve using in chemical resolution method using benzene as the problems of resolving agent, it is to avoid complicated method for splitting, but
It is that the harmfulness to operating personnel is larger, is public security department's control because thionyl chloride has corrosivity and tearing property higher
Chemical reagent, and it meets water and is easy to hydrolysis generation sulfur dioxide and hydrogen chloride, and effect on environment is very big.International standard pair
Regulation using thionyl chloride is also relatively tight, such as the chlorine in U.S. ACGIH (ACGIH) regulations workshop
Change the instantaneous threshold value of sulfoxide no more than 4.9mg/m3。
And for example United States Patent (USP) (publication number：US2005/0182262A1, publication date：On 08 18th, 2005) disclose one kind
It is initiation material with (S) -2-amino-butyric acid hydrochloride, (S) -2-amino-butyric acid methyl esters salt is obtained with thionyl chloride and methyl alcohol reaction
Hydrochlorate, then obtain (S) -2- amino-butanamide hydrochloric acid with ammoniacal liquor reaction.Amino-butanamide hydrochloride reacts with 4- chlorobutanoylchlorides again,
Then cyclization obtains Levetiracetam.The halogenating agent used in patent has three kinds：Thionyl chloride, phosphorus pentachloride and oxalyl chloride.Five
Phosphorus chloride belongs to the 3rd class monitoring chemicals, and production and import and export are prohibited chemical weapons and do (national Ministry of Industry and Information) control by country；Oxalyl chloride has
There are high toxicity and corrosivity, poisonous gas carbon monoxide is released with water vigorous reaction, and total recovery is relatively low, cyclization yield only exists
Between 60%~70%.
In addition, Chinese patent CN85105301 (embodiment 4) and CN03130585.7 (embodiment 16) disclose following conjunctions
Into the synthetic method of route, but need to take out in intermediate in building-up process, then fed intake toward next step, technique is more numerous
Trivial, synthetic route is as follows：
For another document, Yang Yan etc., the process optimization new method of antiepileptic Levetiracetam, East China University of Science's journal
(natural science edition), 2013,39 (3)：307, though a kind of method that use one kettle way prepares Levetiracetam is disclosed, the party
The mass fraction of method known impurities (S)-alpha-ethyl-2-oxo -1- pyrrolidine acetic acids is less than 0.1%, does not there is that to reach pharmacopeia list miscellaneous
0.05% limitation requirement, and used intermediate mesyl chloride is toxic articles, and transport is industrial using strictly being supervised
Metaplasia should try one's best when producing and avoid using.
At present, because the conformation and related impurities of compound are more complicated, operation how is optimized by preparation as few as possible
Step prepares Levetiracetam and also needs further research.In addition, chloride impurity is more difficult in the prior art control and by letter
The impurity that folk prescription method is removed, its residual not only influences environment, while influenceing the purity and stability of raw material, industrialization method is badly in need of
More effective method controls it to limit the quantity.
The content of the invention
The present invention is for defect present in above prior art, there is provided the Levetiracetam of a kind of high-purity and containing it
Pharmaceutical composition.
A kind of Levetiracetam of high-purity, purity more than 99.5%, unknown list is miscellaneous to be less than less than 0.05%, and chloride
Impurity content is no more than 0.02%.
One of still a further object of the present invention is to provide a kind of preparation of the Levetiracetam of more easy new high-purity
Method.
It is specific as follows：
A kind of preparation method of the Levetiracetam of high-purity：Including using " one kettle way ", with S- amino-butanamides and four
Chlorobutanoylchloride is reacted, and through condensation, Levetiracetam is prepared in cyclization, and synthetic route is as follows：
Wherein, the technique of step (I) is：
In reaction bulb, 150 grams of amino-butanamide hydrochlorides of initiation material (S) -2- (1.08 moles) is added, add dichloro
Methane 1.2 rises to 3 liters, and 300 grams of anhydrous sodium sulfate, stirring is cooled to -25 DEG C~0 DEG C；
TBAB 18g to 24g (0.056 mole~0.074 mole) is added, 4 moles of alkali is added, 30 points are stirred
Clock, is added dropwise 180 grams of chlorobutanoylchlorides of 4- (1.28 moles) by less than 0 DEG C, reacts 2 hours；
The technique of step (II) is：
60 grams of potassium hydroxide (1.07 moles) is added, is reacted 2 hours, be warming up to 20~25 DEG C, stirring reaction 30min, mistake
Filter, filtrate decompression is concentrated to dryness, and adds 45L ethyl acetate, stirs more than 4 hours, filtering, ethyl acetate washing, vacuum drying,
Obtain Levetiracetam.
During reactions steps (I), the preferred potassium hydroxide of alkali, NaOH, sodium carbonate, potassium carbonate, triethylamine etc.
For reacting.But found by many experiments, preferably, reaction efficiency is fast for potassium hydroxide effect.
" one kettle way " refers to that the multistep reaction in reaction can be from raw material relatively simple and easy to get, without centre
The separation of body, directly obtains baroque molecule.Aborning, the post processing loss of intermediate product can be so reduced, is subtracted
The use of few menstruum, brings and safely and conveniently produces.It is such reaction obviously economically with it is environment-friendly on clearly more have
Profit.
However, above-mentioned " one kettle way " though synthesis technique optimization and reduce processing step, we have found that being made in industrialization
In standby process, the inorganic salts residual that the Levetiracetam obtained by preparation has 1% (contains potassium hydroxide, NaOH, chlorination
Sodium, potassium chloride, sodium sulphate etc.).Though the chloride impurity limitation of Levetiracetam raw material is temporarily limited without any drug standards at present,
But found in substantial amounts of industrialization practice, these inorganic salts (particularly containing alkali) can be such that Levetiracetam was placed for a long time
There is degraded (hydrolysis), degradation in journey.Because Levetiracetam is highly soluble in water, it is impossible to removed using the method for washing inorganic
Salt.Levetiracetam is dissolved in organic solvent, then the method for conventional filtration, it is impossible to completely remove inorganic salts.
The sodium chloride that chloride impurity of the present invention refers to, the wherein butter in potassium chloride bottom product, hydrogen-oxygen
Most of inorganic salts of the compound after acidified, have been removed by filtration when filtering.
Another object of the present invention is on the basis of providing a kind of " one kettle way " synthesis technique, there is provided a kind of left second of high-purity
The industrialized preparation method of La Xitan, the method for particularly removing chloride impurity.
Specifically：
Preceding method acquisition Levetiracetam is dissolved in organic solvent, using 0.22 μm -0.45 μm of filter core while hot
Filtering, can obtain the qualified product of chloride.It is the basis for estimation of " qualified " to be no more than 0.02% with chloride content.
The organic solvent is preferably ethyl acetate, acetone or isopropyl acetate.
Preferably 6 to 10 times of the volume mL ratios of the Levetiracetam weight g and organic solvent.
The filter core is preferably polypropylene or polytetrafluoroethylene (PTFE).
The filtering while hot refers to acetone in 55 DEG C~60 DEG C of temperature, and ethyl acetate or isopropyl acetate are at 70 DEG C~85 DEG C
Under carry out.
Above-mentioned solvent selection, volume ratio, while hot filtration temperature belong to preferred scope, relative to other solvents, ratio and mistake
Filter condition can improve the rate of filtration and yield.
Above-mentioned technique is especially special, and inventor has found that filter core is 1.0 μm by substantial amounts of experiment, and chloride is unqualified,
However, when filter core is 0.1 μm, its rate of filtration is too slow, Levetiracetam precipitation is easily caused, causes filter core to block, hence it is evident that
Influence the yield of Levetiracetam.
More it is particularly, present invention process is coordinated using " one kettle way " and above-mentioned filter method, had not only been simplified technique but also had been had
What is imitated eliminates impurity, has the meaning more wanted for industrialization production.
Chloride impurity is removed using chemical method more than prior art, but due to chloride impurity and a left side in practice of the invention
Dissolubility is superior and solubility is close in various polarity solvent for etiracetam, it is difficult to effectively removal.Simultaneously as using chemistry
Method controls the effect on driving birds is not good of chloride impurity, causes to repeat to purify, and complex process, and cost is substantially increased,
Also there is certain influence on the yield losses of Levetiracetam.
Even if employing the purification process of prior art, though the Levetiracetam of high-purity can be obtained, chloride is miscellaneous
Matter be relatively difficult to removal, its content still more than 1.0%, containing the chloride limitation Levetiracetam it is saved after, impurity
Incrementss can substantially increase during preservation.It can be seen that, retention of the chloride impurity in Levetiracetam, to Levetiracetam
Stability also influence substantially.
The method of the present invention is preferably obtained by the special nature of Levetiracetam and chloride according to many experiments, no
It is same as routine techniques thinking.Levetiracetam has good water solubility, can be dissolved in identical solvent with chloride impurity
In, can be dissolved in identical solvent and be filtered, but chance on Levetiracetam and chlorine compound impurity in different holes
Footpath filter core retention situation is different, so as to realize ensureing Levetiracetam fully by effectively being gone in the case of special pore size distribution filter core
It is that this area routine techniques thinking is difficult to expect except chloride impurity.
From the result of above-mentioned preparation method, preparation method of the invention provides an a kind of more superior high-quality left side
Etiracetam raw material, more can guarantee that the validity and security of medication.
Present invention aim at the Levetiracetam raw material for providing a kind of obvious high-purity and quality, it is by foregoing preparation
Method is obtained.
In addition, it is further provided a kind of medicine of the Levetiracetam raw material containing a kind of foregoing obvious high-purity and quality
Composition, its raw material is obtained by aforementioned preparation process, further the pharmaceutically acceptable excipient containing more than one.
Gained pharmaceutical composition includes solid pharmaceutical preparation, such as tablet, granule, capsule, supensoid agent, injection powder pin etc.；
Also pharmaceutical solutions, such as parenteral solution, injection suspension, emulsion for injection, oral administration solution etc. are included.Due to Levetiracetam raw material
High-purity and high-quality, are conducive to preparing more excellent pharmaceutical composition.
The present invention has the advantages that following prominent and beneficial effect compared with prior art：
(1) is the invention provides a kind of Levetiracetam of high-purity, purity more than 99.5%, and unknown list is miscellaneous to be less than
Less than 0.05%, and chloride impurity content is no more than 0.02%, has excellent quality stability during preservation, so as to carry
The quality of prepared pharmaceutical composition high, good guarantee is provided for the clinical practice validity and security of product.
(2) Levetiracetam of high-purities of the present invention by " one kettle way " with (S) -2- amino-butanamide hydrochlorides for
Beginning material, cyclization obtains crude levetiracetam again with the condensation of 4- chlorobutanoylchlorides, in the case where yield is ensured, greatly optimizes
With save preparation technology, agents useful for same and reaction condition are gentle, can in large-scale industrialized production applications well.
(3) uses aforementioned industrial method, but have a significant effect material purity and stability chloride impurity residual,
Removing for simple and low cost is difficult to by conventional chemistry techniques thinking, by the filter element filtering of preferred special pore size distribution size not
Only ensure Levetiracetam fully by effective removal chloride impurity in the case of special pore size distribution filter core, the process need not add
Plus particular agent and process is simple, chloride content is no more than 0.02% in gained Levetiracetam raw material, significantly there is provided a left side
The purity and quality of etiracetam raw material.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but the implementation method not limited to this invented.
It is prepared by " one kettle way " of the Levetiracetam of embodiment 1
It is starting material with (S) -2- amino-butanamide hydrochlorides, cyclization just can obtain left second again with the condensation of 4- chlorobutanoylchlorides
La Xitan crude products.
The technique of step (I) is：
In reaction bulb, 150 grams of amino-butanamide hydrochlorides of initiation material (S) -2- (1.08 moles) is added, add dichloro
Methane 1.2 rises to 3 liters, and 300 grams of anhydrous sodium sulfate, stirring is cooled to -25 DEG C~0 DEG C.
Addition TBAB 18g to 24g (0.056 mole~0.074 mole), 160 grams of NaOH (4 moles),
Stirring 30 minutes, is added dropwise 180 grams of chlorobutanoylchlorides of 4- (1.28 moles) by less than 0 DEG C, reacts 2 hours.
The technique of step (II) is：
Add 60 grams of potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 DEG C~25 DEG C, stirring reaction 30min,
Filtering, filtrate decompression is concentrated to dryness, and adds 45L ethyl acetate, stirs more than 4 hours, filtering, and ethyl acetate washing, vacuum is done
It is dry, about 125 grams of Levetiracetam is obtained, yield is 73.4%, purity 99.7%, and unknown list is miscellaneous to be less than less than 0.05%.
It is prepared by " one kettle way " of the Levetiracetam of embodiment 2
It is starting material with (S) -2- amino-butanamide hydrochlorides, cyclization just can obtain left second again with the condensation of 4- chlorobutanoylchlorides
La Xitan crude products.
The technique of step (I) is：
In reaction bulb, 150 grams of amino-butanamide hydrochlorides of initiation material (S) -2- (1.08 moles) is added, add dichloro
Methane 1.2 rises to 3 liters, and 300 grams of anhydrous sodium sulfate, stirring is cooled to -25 DEG C~0 DEG C.
TBAB 18g to 24g (0.056 mole~0.074 mole) is added, (4 rub 553 grams of potassium carbonate powder
You), stir 30 minutes, less than 0 DEG C, 180 grams of chlorobutanoylchlorides of 4- (1.28 moles) is added dropwise, react 2 hours.
The technique of step (II) is：
Add 60 grams of potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 DEG C~25 DEG C, stirring reaction 30min,
Filtering, filtrate decompression is concentrated to dryness, and adds 45L ethyl acetate, stirs more than 4 hours, filtering, and ethyl acetate washing, vacuum is done
It is dry, about 120 grams of Levetiracetam is obtained, reaction yield is 70.5%, purity 99.7%, and unknown list is miscellaneous to be less than less than 0.05%.
It is prepared by " one kettle way " of the Levetiracetam of embodiment 3
It is starting material with (S) -2- amino-butanamide hydrochlorides, cyclization just can obtain left second again with the condensation of 4- chlorobutanoylchlorides
La Xitan crude products.
The technique of step (I) is：
In reaction bulb, 150 grams of amino-butanamide hydrochlorides of initiation material (S) -2- (1.08 moles) is added, add dichloro
Methane 1.2 rises to 3 liters, and 300 grams of anhydrous sodium sulfate, stirring is cooled to -25 DEG C~0 DEG C.
Addition TBAB 18g to 24g (0.056 mole~0.074 mole), 225 grams of potassium hydroxide (4 moles),
Stirring 30 minutes, is added dropwise 180 grams of chlorobutanoylchlorides of 4- (1.28 moles) by less than 0 DEG C, reacts 2 hours.
The technique of step (II) is：
Add 60 grams of potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 DEG C~25 DEG C, stirring reaction 30min,
Filtering, filtrate decompression is concentrated to dryness, and adds 45L ethyl acetate, stirs more than 4 hours, filtering, and ethyl acetate washing, vacuum is done
It is dry, obtain about 130 grams of Levetiracetam, reaction yield is about 76.4%, purity 99.8%, and unknown list is miscellaneous to be less than less than 0.05%.
To sum up, in course of reaction, potassium hydroxide is used to react using other highly basic, such as NaOH, sodium carbonate, carbonic acid
Potassium, triethylamine, ammonia.But found by many experiments, preferably, reaction efficiency is considerably more rapid for potassium hydroxide effect.
As can be seen here, by " one kettle way " technique of the invention, operation is not only saved, reduces purge process, and protect
The yield and purity of suitable for industrial are demonstrate,proved.
Wherein, purity is determined by HPLC methods, with reference to high performance liquid chromatography (Chinese Pharmacopoeia two annex V of version in 2010
D).Chromatographic apparatus and condition reference literature, Li Dan etc., the isomers in chiral resolution Levetiracetam bulk drug, Anhui medicine,
2008,12 (12)：1134-1136.Chloride impurity does not have absworption peak under the detection method.
The detection of the organochlorine impurity of embodiment 4
The Levetiracetam of the gained of embodiment 1-3 determines chloride impurity by the following method, and detection method is middle traditional Chinese medicines
The A chloride inspection techniques of two annex of allusion quotation version in 2010 VIII, as a result such as following table
| Chloride impurity amount | |
| Embodiment 1 | ＞ 1.0% |
| Embodiment 2 | ＞ 1.0% |
| Embodiment 3 | ＞ 1.0% |
The chloride impurity limitation of Levetiracetam raw material is temporarily limited without any drug standards at present, but in substantial amounts of industry
Change discovery in practice, the limitation of chloride impurity has large effect to the stability of product.
The removal of the Levetiracetam chloride impurity of embodiment 5
With the Levetiracetam that embodiment 1 is prepared, it is dissolved in 75 DEG C~85 DEG C organic solvent acetic acid ethyl esters of heat,
The volume mL ratios of Levetiracetam weight g and organic solvent are 6, are 1.0 μm of polypropylene (or polytetrafluoroethyl-ne by pore size
Alkene) filter element filtering, yield is 80%~88%.
The removal of the Levetiracetam chloride impurity of embodiment 6
With the Levetiracetam that embodiment 2 is prepared, 75 DEG C~85 DEG C organic solvent acetic acid isopropyl esters of heat are dissolved in
In, the volume mL ratios of Levetiracetam weight g and organic solvent are 8, are 0.22 μm of polypropylene (or poly- four by pore size
PVF) filter element filtering, yield is 80%~88%.
The removal of the Levetiracetam chloride impurity of embodiment 7
With the Levetiracetam that embodiment 2 is prepared, it is dissolved in 55 DEG C~60 DEG C organic solvent acetone of heat, Zuo Yi
The volume mL of La Xitan weight g and organic solvent compares 10, is that 0.45 μm of polypropylene (or polytetrafluoroethylene (PTFE)) is filtered by pore size
Core is filtered, and yield is 80%~90%.
The removal of the Levetiracetam chloride impurity of embodiment 8
With the Levetiracetam that embodiment 3 is prepared, it is dissolved in 75 DEG C~85 DEG C organic solvent acetic acid ethyl esters of heat,
The volume mL of Levetiracetam weight g and organic solvent compares 6, is 0.1 μm of polypropylene (or polytetrafluoroethylene (PTFE)) by pore size
Filter element filtering, yield is 60%~70%.
After prepared by the method for above-mentioned previous embodiment 5-8, chloride impurity inspection is carried out by the method for embodiment 4
Survey, chloride content is no more than 0.02% in gained Levetiracetam raw material, and chloride impurity is significantly reduced, specific as follows
Table.
| Chloride impurity amount % | Chloride impurity amount % | ||
| Embodiment 1 | ＞ 1% | Embodiment 5 | ＞ 0.02% |
| Embodiment 2 | ＞ 1% | Embodiment 6 | ＜ 0.02% |
| Embodiment 3 | ＞ 1% | Embodiment 7 | ＜ 0.02% |
| Embodiment 8 | ＜ 0.02% |
The pharmaceutical composition of the Levetiracetam of embodiment 9
Under aseptic manufacture conditions, using each 10g of compound of embodiment 6,7,100mL waters for injection are dissolved separately in
In, to be filtered with activated carbon respectively, in 1000 ampoule bottles, sealing, sterilizing obtains three Levetiracetam notes of batch for embedding
Penetrate liquid pharmaceutical composition.
Comparative examples 1 use different filter element filtering Levetiracetams
Such as the method for embodiment 5, it is the filter element filtering of 1.0mm to use aperture, and chloride impurity amount is ＞ 0.02%, chlorination
It is qualified that thing content is judged to no more than 0.02%, and chloride limitation is substantially unqualified.
Comparative examples 2 use different filter element filtering Levetiracetams
Such as the method for embodiment 5, it is 0.1 μm of filter core to use aperture, because the rate of filtration is too slow, is easily caused Levetiracetam
Separate out, cause filter core to block, the yield of Levetiracetam is 60%~70%, and yield is substantially reduced.
To sum up, it is 0.22 μm of -0.45 μm of filter core to use aperture, and the rate of filtration is good, reduces filtration time, can effectively go
Except chloride impurity, it is ensured that product quality, to isomers, Levetiracetam acid, control is can be very good.The receipts of Levetiracetam
Rate is 80%~90%, and quality, yield are significantly improved, preferably the inventive method.
Above-described embodiment is the present invention preferably implementation method, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from Spirit Essence of the invention and the change, modification, replacement made under principle, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (6)
1. a kind of preparation method of the Levetiracetam of high-purity：The high-purity refers to purity more than 99.5%, and unknown list is miscellaneous
Less than less than 0.05%, and chloride impurity content is no more than 0.02%, including, using " one kettle way ", with S- amino-butanamides
With the reaction of four chlorobutanoylchlorides, through condensation, Levetiracetam is prepared in cyclization, and synthetic route is as follows：
Wherein,
The technique of step (I) is：
In reaction bulb, 150 grams of initiation material (S) -2- amino-butanamide hydrochlorides are added, add dichloromethane 1.2 to rise to 3
Rise, 300 grams of anhydrous sodium sulfate, stirring is cooled to -25 DEG C~0 DEG C；
TBAB 18g to 24g is added, 4 moles of alkali is added, stirred 30 minutes, less than 0 DEG C, 4- chlorobutanoylchlorides 180 are added dropwise
Gram, react 2 hours；
The technique of step (II) is：
60 grams of potassium hydroxide is added, is reacted 2 hours, be warming up to 20~25 DEG C, stirring reaction 30min, filtering, filtrate decompression concentration
To dry, 45L ethyl acetate is added, stirred more than 4 hours, filtering, ethyl acetate washing, vacuum drying obtains Levetiracetam, enters
One step includes being dissolved in preceding method acquisition Levetiracetam in organic solvent, using 0.22 μm -0.45 μm of filter core while hot
Filtering.
2. preparation method according to claim 1, it is characterised in that：During reactions steps (I), the alkali is hydroxide
Potassium, NaOH, sodium carbonate, potassium carbonate or triethylamine.
3. preparation method according to claim 1, it is characterised in that：Organic solvent is ethyl acetate, acetone or isopropyl acetate
Ester.
4. the preparation method according to claim 1-3 any claim, it is characterised in that：Levetiracetam weight g and have
The volume mL ratios of machine solvent are 6 to 10 times.
5. the preparation method according to claim 1-3 any claim, it is characterised in that：The filter core be polypropylene or
Polytetrafluoroethylene (PTFE).
6. the preparation method according to claim 3 any claim, it is characterised in that：The filtering while hot refers to that acetone exists
55 DEG C~60 DEG C of temperature, ethyl acetate or isopropyl acetate are carried out at 70 DEG C~85 DEG C.
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| CN85105301A (en) * | 1984-05-15 | 1987-01-14 | 尤西比公司 | (S)-preparation method of alpha-ethyl-2-oxo-1-pyrrolidine acetamide |
| CN1583721A (en) * | 2003-08-20 | 2005-02-23 | 天津泰普药品科技发展有限公司 | Synthesis of (S)-alpha-ethyl-2-oxi-1-pentazane acetamide |
| EP1566376A1 (en) * | 2004-02-18 | 2005-08-24 | Dr. Reddy's Laboratories Limited | Preparation of amino acid amides |
| WO2008077035A2 (en) * | 2006-12-18 | 2008-06-26 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of levetiracetam |
| CN103159661A (en) * | 2011-12-12 | 2013-06-19 | 北大方正集团有限公司 | Preparation method of levetiracetam |
| CN103304464A (en) * | 2013-05-10 | 2013-09-18 | 成都合迅医药技术有限公司 | Preparation method of levetiracetam |
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| CN85105301A (en) * | 1984-05-15 | 1987-01-14 | 尤西比公司 | (S)-preparation method of alpha-ethyl-2-oxo-1-pyrrolidine acetamide |
| CN1583721A (en) * | 2003-08-20 | 2005-02-23 | 天津泰普药品科技发展有限公司 | Synthesis of (S)-alpha-ethyl-2-oxi-1-pentazane acetamide |
| EP1566376A1 (en) * | 2004-02-18 | 2005-08-24 | Dr. Reddy's Laboratories Limited | Preparation of amino acid amides |
| WO2008077035A2 (en) * | 2006-12-18 | 2008-06-26 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of levetiracetam |
| CN103159661A (en) * | 2011-12-12 | 2013-06-19 | 北大方正集团有限公司 | Preparation method of levetiracetam |
| CN103304464A (en) * | 2013-05-10 | 2013-09-18 | 成都合迅医药技术有限公司 | Preparation method of levetiracetam |
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