CN104860863A - High-purity levetiracetam and pharmaceutical composition comprising high-purity levetiracetam - Google Patents
High-purity levetiracetam and pharmaceutical composition comprising high-purity levetiracetam Download PDFInfo
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- 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
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Abstract
The invention provides high-purity levetiracetam and a pharmaceutical composition comprising high-purity levetiracetam. The high-purity levetiracetam is prepared with a one-pot method. According to the invention, (S)-2-aminobutyryl hydrochloride is adopted as an initial material, and is subjected to condensation and cyclization with 4-chlorobutyryl chloride, such that levetiracetam with a purity higher than 99.5% and with unknown individual impurity lower than 0.05% is obtained. Further, the levetiracetam obtained with the above method is dissolved in an organic solvent; the solution is filtered with a filter of 0.22-0.45mum while still hot, such that a chloride-qualified product with a chloride impurity amount lower than 0.02% can be obtained with high conversion rate. According to the invention, levetiracetam purity can be substantially improved, and a raw material and a pharmaceutical composition with excellent qualities can be further obtained.
Description
Technical field
The invention belongs to chemicals technical field, relate to a kind of highly purified Levetiracetam and the pharmaceutical composition containing it.
Background technology
Levetiracetam (Levetiracetam) is a kind of antiepileptic drug of Belgian UCB drugmaker research and development, its chemical name is (S)-2-(2-OXo-1-pyrrolidine) butyramide, English by name: (S)-2-(2-Oxopyrrolidin-1-yl) butananide, molecular formula is: C
8h
14n
2o
2, molecular weight is 170.21, and its chemical structural formula is:
Levetiracetam through CFDA ratify for being grown up and being greater than the epilepsy of 4 years old children or the assisting therapy of partial seizure.It is go on the market, for the epileptic seizures of adult partial's property in Europe and the U.S. for 1999 at first; Its oral tablet and the injection assisting therapy for 4 years old or more children's partial seizures is ratified again in June, 2005; In March, 2007 goes on the market in China, and commodity are called Levetiracetam.
Because Levetiracetam is more better than other antiepileptic drug in pharmacokinetics, oral easy absorption, bioavailability is high, has therapeutic index high, does not interact with other antiepileptic drug, and side effect is slight, the advantages such as better tolerance.Compared with other antiepileptic drug, the prolection of its anti-hypoxia will exceed about 10 times, and the prolection of anti-cerebral ischemia exceeds about 4 times.Levetiracetam is the antiepileptic drug of the special performance uniquely at present with prevention epileptic seizures.
At present, the preparation method of chiral drug Levetiracetam has been reported, and mainly adopts chemical resolution method, asymmetric hydrogenation catalysis method or is that raw material is to synthesize the method for Levetiracetam with amino acid.But more or less all there are some to production or the disadvantageous factor of quality product in these methods.As a kind of method adopting chemical resolution method to synthesize Levetiracetam that Belgian UCB. S.A. (BE) Bruxelles Belgium develops, with racemize (R, S)-2-(2-OXo-1-pyrrolidine) butyric acid is starting raw material, with R-(+)-Alpha-Methyl benzylamine for resolving agent, split in benzene, use highly basic process again, obtain (S)-2-(2-OXo-1-pyrrolidine) butyric acid dissociated.This acid is first reacted with Vinyl chloroformate, then obtains Levetiracetam with ammonia generation ammonolysis reaction.But owing to adopting benzene as resolution solvent, but according to ICH Q3C guide, benzene is listed in a kind solvent, should avoid using, therefore, the method adopts benzene as resolving agent, and existing larger hazardness, does not meet again the requirement of production of raw medicine.
And for example Chinese patent application (publication number: CN101550100A, publication date: on October 07th, 2009) to disclose a kind of take L-threonine as the synthetic method of starting raw material, the method is by taking L-threonine as raw material, prepares Levetiracetam through processes such as over-churning, halo, catalytic reduction, ammonia solution and cyclizations.Wherein, esterification and halo process all employ halogenation sulfoxide; Catalytic reduction uses Raney's nickel, palladium charcoal, rhodium charcoal fire loading type platinum oxide etc.; Ammonia solution preferentially selects ammonia or ammoniacal liquor.Adopt benzene as the problem existing for resolving agent although the method solves to adopt in chemical resolution method, avoid complicated method for splitting, but because sulfur oxychloride has higher corrodibility and tearing property, larger to the hazardness of operator, be public security department's control chemical reagent, and its chance water is easy to hydrolysis generation sulfurous gas and hydrogenchloride, very large to environmental influence.International standard is also comparatively tight to using the regulation of sulfur oxychloride, and the instantaneous threshold value as the sulfur oxychloride in U.S. ACGIH (ACGIH) regulation workshop can not more than 4.9mg/m
3.
And for example United States Patent (USP) (publication number: US2005/0182262A1, publication date: on 08 18th, 2005) disclose one with (S)-2-amino-butyric acid hydrochloride for starting raw material, be obtained by reacting (S)-2-amino-butyric acid methyl ester hydrochloride with sulfur oxychloride and methyl alcohol, then be obtained by reacting (S)-2-amino-butanamide hydrochloric acid with ammoniacal liquor.Amino-butanamide hydrochloride reacts with 4-chlorobutanoylchloride again, and then cyclization obtains Levetiracetam.The halogenating agent used in patent has three kinds: sulfur oxychloride, phosphorus pentachloride and oxalyl chloride.Phosphorus pentachloride belongs to the 3rd class monitoring chemical product, produces and imports and exports and do (national Ministry of Industry and Information) control by country's taboo chemical weapons; Oxalyl chloride has high toxicity and corrodibility, release poisonous gas carbon monoxide, and total recovery is also lower with water vigorous reaction, and cyclization yield is only between 60% ~ 70%.
In addition, Chinese patent CN85105301 (embodiment 4) and CN03130585.7 (embodiment 16) discloses the synthetic method of following synthetic route, but in building-up process, need intermediate to take out, feed intake toward next step again, technique is more loaded down with trivial details, and synthetic route is as follows:
For another document, Yang Yan etc., the process optimization novel method of antiepileptic drug Levetiracetam, East China University of Science's journal (natural science edition), 2013,39 (3): 307, though disclose a kind of method adopting one kettle way to prepare Levetiracetam, but the massfraction of the method known impurities (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid is less than 0.1%, do not have reach pharmacopeia list mix 0.05% limitation requirement, and use intermediate methylsulfonyl chloride for highly toxic product, transport, use all by strict supervision, should avoid during suitability for industrialized production using as far as possible.
At present, due to the conformation of compound and related impurities more complicated, how to optimize operation and prepare Levetiracetam by the least possible preparation process and also need further research.In addition, chloride impurity is more difficult control and the impurity removed by simple method in prior art, and it is residual not only affects environment, and affect purity and the stability of raw material, industrialization method is badly in need of more effective method and is controlled its limitation simultaneously.
Prior art many employings chemical process removes chloride impurity, but because chloride impurity in reality of the present invention and Levetiracetam solvability in various polarity solvent is superior and solubleness is close, is difficult to effective removal.Meanwhile, due to the poor effect adopting chemical process to control chloride impurity, cause repeating purifying, not only make complex process, and cost obviously increases, also have certain influence to the yield losses of Levetiracetam.
Even if having employed the purification process of prior art, though can obtain highly purified Levetiracetam, chloride impurity is difficult to remove relatively, and its content is still more than 1.0%, the Levetiracetam of limiting the quantity containing this muriate is after preserving, and impurity increasing amount obviously can increase in preservation process.Visible, the retention of chloride impurity in Levetiracetam, also affects obviously the stability of Levetiracetam.
Method of the present invention is preferably obtained by Levetiracetam and muriatic special property according to great many of experiments, is different from routine techniques thinking.Levetiracetam has good water-soluble, can be dissolved in identical solvent with chloride impurity, can be dissolved in identical solvent and filter, but chancing on Levetiracetam and chlorine compound impurity, to retain situation at different pore size filter core different, thus realize ensureing that Levetiracetam fully effectively removes chloride impurity by when special pore size distribution filter core, be that this area routine techniques thinking is difficult to expect.
From the result of above-mentioned preparation method, preparation method of the present invention provides the more superior high-quality Levetiracetam raw material of one, more can ensure validity and the security of medication.
The object of the invention is the Levetiracetam raw material providing a kind of obvious high purity and quality, and it is obtained by aforementioned preparation process.
In addition, provide a kind of pharmaceutical composition containing the Levetiracetam raw material of aforementioned a kind of obvious high purity and quality further, its raw material is obtained by aforementioned preparation process, further containing more than one pharmaceutically acceptable vehicle.
Gained pharmaceutical composition comprises solid preparation, as tablet, and granule, capsule, suspensoid, injection powder pin etc.; Also pharmaceutical solutions is comprised, as injection liquid, injection suspension, injectable emulsion, oral liquid etc.Due to high purity and the high quality of Levetiracetam raw material, be conducive to preparing more excellent pharmaceutical composition.
The present invention compared with prior art has following outstanding advantage and beneficial effect:
(1). the invention provides a kind of highly purified Levetiracetam, purity more than 99.5%, unknown single mixing is less than less than 0.05%, and chloride impurity content is no more than 0.02%, there is in preservation process excellent quality stability, thus improve the quality of prepared pharmaceutical composition, good guarantee is provided for the clinical application validity of product and security.
(2). the highly purified Levetiracetam of the present invention by " one kettle way " with (S)-2-amino-butanamide hydrochloride for starting material, with the condensation of 4-chlorobutanoylchloride again cyclization obtain crude levetiracetam, when ensureing yield, optimize greatly and save preparation technology, agents useful for same and reaction conditions are gentle, can in large-scale industrialized production applications well.
(3). adopt aforementioned industrial method, but the chloride impurity of have a significant effect material purity and stability remains, removing of simple and easy and low cost is difficult to by conventional chemistry techniques thinking, not only ensure that Levetiracetam fully effectively removes chloride impurity by when special pore size distribution filter core by the filter element filtering of preferred special pore size distribution size, this process is without the need to adding particular agent and technique is simple, in gained Levetiracetam raw material, chloride content is no more than 0.02%, significantly provides purity and the quality of Levetiracetam raw material.
Summary of the invention
The present invention is directed to the defect existed in above prior art, a kind of highly purified Levetiracetam and the pharmaceutical composition containing it are provided.
A kind of highly purified Levetiracetam, purity more than 99.5%, unknown single mixing is 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 the preparation method providing a kind of highly purified Levetiracetam new more easily.
Concrete is as follows:
A kind of preparation method of highly purified Levetiracetam: comprise, adopt " one kettle way ", react with S-amino-butanamide and four chlorobutanoylchlorides, through condensation, cyclization, prepares Levetiracetam, and synthetic route is as follows:
Wherein, the technique of step (I) is:
In reaction flask, add starting raw material (S)-2-amino-butanamide hydrochloride 150 grams (1.08 moles), add methylene dichloride 1.2 and rise to 3 liters, anhydrous sodium sulphate 300 grams, stir, be cooled to-25 DEG C ~ 0 DEG C;
Add Tetrabutyl amonium bromide 18g to 24g (0.056 mole ~ 0.074 mole), add 4 moles, alkali, stir 30 minutes, less than 0 DEG C, drip 4-chlorobutanoylchloride 180 grams (1.28 moles), react 2 hours;
The technique of step (II) is:
Add 60 grams, potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 ~ 25 DEG C, stirring reaction 30min, filter, filtrate reduced in volume, to dry, add 45L ethyl acetate, stirs more than 4 hours, filter, ethyl acetate is washed, and vacuum-drying, obtains Levetiracetam.
In reactions steps (I) process, the preferred potassium hydroxide of described alkali, sodium hydroxide, sodium carbonate, salt of wormwood, triethylamine etc. are for reaction.But find through many experiments, potassium hydroxide effect is best, and reaction efficiency is fast.
Described " one kettle way " refers to that the polystep reaction in reaction from raw material relatively simple and easy to get, without the separation of intermediate, directly can obtain baroque molecule.Aborning, the aftertreatment loss of intermediate product can be reduced like this, reduce the use of menstruum, bring safety, produce easily.Such reaction obviously economically with environmental friendliness on obviously advantageously.
But above-mentioned " one kettle way ", though synthesis technique is optimized and decreased processing step, we find in the process of preparation of industrialization, the Levetiracetam preparing gained have 1% inorganic salt residual (containing potassium hydroxide, sodium hydroxide, sodium-chlor, Repone K, sodium sulfate etc.).Though limit the chloride impurity limitation of Levetiracetam raw material at present temporarily without any drug standard, but find in a large amount of industrialization practice, these inorganic salt (particularly containing alkali) can make Levetiracetam degrade in long-term put procedure (hydrolysis), degradation.Because Levetiracetam is very easily water-soluble, the method removing inorganic salt washed with water cannot be made.Levetiracetam is dissolved in organic solvent, then the method for conventional filtration, inorganic salt cannot be disposed completely.
The sodium-chlor that chloride impurity of the present invention refers to, the butter in Repone K bottom product, the wherein most of inorganic salt of oxyhydroxide after acidified, when filtration through filtering.
Another object of the present invention is to provide on a kind of " one kettle way " synthesis technique basis, a kind of industrialized preparation method of high-purity levetiracetam is provided, particularly removes the method for chloride impurity.
Concrete:
Preceding method being obtained Levetiracetam is dissolved in organic solvent, adopts the filter core filtered while hot of 0.22 μm-0.45 μm, can obtain the product that muriate is qualified.The basis for estimation that 0.02% is " qualified " is no more than with chloride content.
Described organic solvent is preferably ethyl acetate, acetone or isopropyl acetate.
The volume mL of described Levetiracetam weight g and organic solvent is than being preferably 6 to 10 times.
Described filter core is preferably polypropylene or tetrafluoroethylene.
Described filtered while hot refers to that acetone is temperature 55 DEG C ~ 60 DEG C, and ethyl acetate or isopropyl acetate carry out at 70 DEG C ~ 85 DEG C.
Above-mentioned solvent selection, volume ratio, filtered while hot temperature belong to preferable range, can improve filtration velocity and yield relative to other solvents, ratio and filtration condition.
Above-mentioned technique is especially special, and by a large amount of experiments, contriver to find that filter core is 1.0 μm, muriate is defective, but when filter core is 0.1 μm, its filtration velocity is too slow, easily cause Levetiracetam to be separated out, cause filter core to block, obviously affect the yield of Levetiracetam.
More particularly, present invention process adopts " one kettle way " and above-mentioned filter method to coordinate, and not only simplifies technique but also effectively eliminate impurity, produces have the meaning more wanted for industrialization.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but working of an invention mode is not limited thereto.
" one kettle way " preparation of embodiment 1 Levetiracetam
With (S)-2-amino-butanamide hydrochloride for starting material, with the condensation of 4-chlorobutanoylchloride again cyclization just can obtain crude levetiracetam.
The technique of step (I) is:
In reaction flask, add starting raw material (S)-2-amino-butanamide hydrochloride 150 grams (1.08 moles), add methylene dichloride 1.2 and rise to 3 liters, anhydrous sodium sulphate 300 grams, stir, be cooled to-25 DEG C ~ 0 DEG C.
Add Tetrabutyl amonium bromide 18g to 24g (0.056 mole ~ 0.074 mole), 160 grams, sodium hydroxide (4 moles), stir 30 minutes, less than 0 DEG C, drip 4-chlorobutanoylchloride 180 grams (1.28 moles), react 2 hours.
The technique of step (II) is:
Add 60 grams, potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 DEG C ~ 25 DEG C, stirring reaction 30min, filters, and filtrate reduced in volume is to dry, add 45L ethyl acetate, stir more than 4 hours, filter, ethyl acetate is washed, vacuum-drying, obtain Levetiracetam about 125 grams, yield is 73.4%, purity 99.7%, unknown single mixing is less than less than 0.05%.
" one kettle way " preparation of embodiment 2 Levetiracetam
With (S)-2-amino-butanamide hydrochloride for starting material, with the condensation of 4-chlorobutanoylchloride again cyclization just can obtain crude levetiracetam.
The technique of step (I) is:
In reaction flask, add starting raw material (S)-2-amino-butanamide hydrochloride 150 grams (1.08 moles), add methylene dichloride 1.2 and rise to 3 liters, anhydrous sodium sulphate 300 grams, stir, be cooled to-25 DEG C ~ 0 DEG C.
Add Tetrabutyl amonium bromide 18g to 24g (0.056 mole ~ 0.074 mole), potassium carbonate powder 553 grams (4 moles), stir 30 minutes, less than 0 DEG C, drip 4-chlorobutanoylchloride 180 grams (1.28 moles), react 2 hours.
The technique of step (II) is:
Add 60 grams, potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 DEG C ~ 25 DEG C, stirring reaction 30min, filters, and filtrate reduced in volume is to dry, add 45L ethyl acetate, stir more than 4 hours, filter, ethyl acetate is washed, vacuum-drying, obtain Levetiracetam about 120 grams, reaction yield is 70.5%, purity 99.7%, unknown single mixing is less than less than 0.05%.
" one kettle way " preparation of embodiment 3 Levetiracetam
With (S)-2-amino-butanamide hydrochloride for starting material, with the condensation of 4-chlorobutanoylchloride again cyclization just can obtain crude levetiracetam.
The technique of step (I) is:
In reaction flask, add starting raw material (S)-2-amino-butanamide hydrochloride 150 grams (1.08 moles), add methylene dichloride 1.2 and rise to 3 liters, anhydrous sodium sulphate 300 grams, stir, be cooled to-25 DEG C ~ 0 DEG C.
Add Tetrabutyl amonium bromide 18g to 24g (0.056 mole ~ 0.074 mole), 225 grams, potassium hydroxide (4 moles), stir 30 minutes, less than 0 DEG C, drip 4-chlorobutanoylchloride 180 grams (1.28 moles), react 2 hours.
The technique of step (II) is:
Add 60 grams, potassium hydroxide (1.07 moles), react 2 hours, be warming up to 20 DEG C ~ 25 DEG C, stirring reaction 30min, filters, and filtrate reduced in volume is to dry, add 45L ethyl acetate, stir more than 4 hours, filter, ethyl acetate is washed, vacuum-drying, obtain Levetiracetam about 130 grams, reaction yield is about 76.4%, purity 99.8%, unknown single mixing is less than less than 0.05%.
To sum up, in reaction process, potassium hydroxide adopts other highly basic for reaction, as sodium hydroxide, sodium carbonate, salt of wormwood, triethylamine, ammonia.But find through many experiments, potassium hydroxide effect is best, and reaction efficiency is obviously faster.
As can be seen here, by " one kettle way " of the present invention technique, not only save operation, decrease purge process, and ensure that yield and the purity of suitable for industrial.
Wherein, purity is measured by HPLC method, with reference to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).Chromatographic apparatus and condition reference literature, Li Dan etc., the isomer in chiral separation Levetiracetam bulk drug, Anhui medicine, 2008,12 (12): 1134-1136.Chloride impurity does not have absorption peak under this detection method.
The detection of embodiment 4 organochlorine impurity
The Levetiracetam of embodiment 1-3 gained measures chloride impurity by the following method, and detection method is Chinese Pharmacopoeia version in 2010 two annex VIII A muriate test procedures, and result is as following table
| Chloride impurity amount | |
| Embodiment 1 | ＞1.0％ |
| Embodiment 2 | ＞1.0％ |
| Embodiment 3 | ＞1.0％ |
The temporary chloride impurity limitation limiting Levetiracetam raw material without any drug standard at present, but find in a large amount of industrialization practice, the stability of limitation on product of chloride impurity has larger impact.
The removal of embodiment 5 Levetiracetam chloride impurity
With the Levetiracetam that embodiment 1 prepares, be dissolved in 75 DEG C ~ 85 DEG C hot organic solvent acetic acid ethyl esters, the volume mL ratio of Levetiracetam weight g and organic solvent is 6, be 1.0 μm of polypropylene (or tetrafluoroethylene) filter element filterings by pore size, yield is 80% ~ 88%.
The removal of embodiment 6 Levetiracetam chloride impurity
With the Levetiracetam that embodiment 2 prepares, be dissolved in 75 DEG C ~ 85 DEG C hot organic solvent acetic acid isopropyl esters, the volume mL ratio of Levetiracetam weight g and organic solvent is 8, be 0.22 μm of polypropylene (or tetrafluoroethylene) filter element filtering by pore size, yield is 80% ~ 88%.
The removal of embodiment 7 Levetiracetam chloride impurity
With the Levetiracetam that embodiment 2 prepares, be dissolved in 55 DEG C ~ 60 DEG C hot organic solvent acetone, the volume mL of Levetiracetam weight g and organic solvent is than 10, be 0.45 μm of polypropylene (or tetrafluoroethylene) filter element filtering by pore size, yield is 80% ~ 90%.
The removal of embodiment 8 Levetiracetam chloride impurity
With the Levetiracetam that embodiment 3 prepares, be dissolved in 75 DEG C ~ 85 DEG C hot organic solvent acetic acid ethyl esters, the volume mL of Levetiracetam weight g and organic solvent is than 6, be 0.1 μm of polypropylene (or tetrafluoroethylene) filter element filtering by pore size, yield is 60% ~ 70%.
After the method preparation of above-mentioned previous embodiment 5-8, carry out chloride impurity detection by the method for embodiment 4, in gained Levetiracetam raw material, chloride content is all no more than 0.02%, and chloride impurity obviously reduces, table specific as follows.
| 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 embodiment 9 Levetiracetam
Under aseptic manufacture conditions, adopt each 10g of compound of embodiment 6,7, be dissolved in 100mL water for injection respectively, use activated carbon filtration respectively, embedding in 1000 ampoules, sealing by fusing, sterilizing, obtains the levetiracetam injection pharmaceutical composition of three batches.
Comparative examples 1 adopts different filter element filtering Levetiracetam
As the method for embodiment 5, adopt aperture be the filter element filtering of 1.0mm, chloride impurity amount is > 0.02%, chloride content be no more than 0.02% be judged to be qualified, this muriate limitation obviously defective.
Comparative examples 2 adopts different filter element filtering Levetiracetam
As the method for embodiment 5, adopt aperture to be 0.1 μm of filter core, because filtration velocity is too slow, easily cause Levetiracetam to be separated out, cause filter core to block, the yield of Levetiracetam is 60% ~ 70%, and yield obviously reduces.
To sum up, adopt aperture to be 0.22 μm of-0.45 μm of filter core, filtration velocity is good, reduces filtration time, effectively can remove chloride impurity, ensures quality product, to isomer, Levetiracetam acid, can well control.The yield of Levetiracetam is 80% ~ 90%, and quality, yield significantly improve, and is preferably the inventive method.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. a highly purified Levetiracetam, is characterized in that: purity more than 99.5%, and unknown single mixing is less than less than 0.05%, and chloride impurity content is no more than 0.02%.
2. the preparation method of a highly purified Levetiracetam according to claim 1: comprise, adopt " one kettle way ", react with S-amino-butanamide and four chlorobutanoylchlorides, through condensation, cyclization, prepares Levetiracetam, and synthetic route is as follows:
3. preparation method according to claim 2, is characterized in that: wherein,
The technique of step (I) is:
In reaction flask, add starting raw material (S)-2-amino-butanamide hydrochloride 150 grams, add methylene dichloride 1.2 and rise to 3 liters, anhydrous sodium sulphate 300 grams, stir, be cooled to-25 DEG C ~ 0 DEG C;
Add Tetrabutyl amonium bromide 18g to 24g, add 4 moles, alkali, stir 30 minutes, less than 0 DEG C, drip 4-chlorobutanoylchloride 180 grams, react 2 hours;
The technique of step (II) is:
Add 60 grams, potassium hydroxide, react 2 hours, be warming up to 20 ~ 25 DEG C, stirring reaction 30min, filter, filtrate reduced in volume, to dry, add 45L ethyl acetate, stirs more than 4 hours, filters, and ethyl acetate is washed, and vacuum-drying, obtains Levetiracetam.
4. preparation method according to claim 2, it is characterized in that: in reactions steps (I) process, described alkali is potassium hydroxide, sodium hydroxide, sodium carbonate, salt of wormwood or triethylamine, preferred potassium hydroxide.
5. preparation method according to the arbitrary claim of claim 2-4, is characterized in that: comprise further and preceding method is obtained Levetiracetam be dissolved in organic solvent, adopt the filter core filtered while hot of 0.22 μm-0.45 μm.
6. preparation method according to claim 5, is characterized in that: organic solvent is preferably ethyl acetate, acetone or isopropyl acetate.
7. preparation method according to the arbitrary claim of claim 5-6, is characterized in that: the volume mL of Levetiracetam weight g and organic solvent is than being preferably 6 to 10 times.
8. preparation method according to the arbitrary claim of claim 5-7, is characterized in that: described filter core is preferably polypropylene or tetrafluoroethylene.
9. preparation method according to the arbitrary claim of claim 5-7, is characterized in that: described filtered while hot refers to that acetone is temperature 55 DEG C ~ 60 DEG C, and ethyl acetate or isopropyl acetate carry out at 70 DEG C ~ 85 DEG C.
10. a pharmaceutical composition for Levetiracetam, is characterized in that: described pharmaceutical composition contains highly purified Levetiracetam described in claim 1 and more than one pharmaceutically acceptable vehicle.
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| 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 |
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| 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 |
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| CN114560800A (en) * | 2022-03-03 | 2022-05-31 | 吉林省博大制药股份有限公司 | Production method of levetiracetam bulk drug |
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