CN102050774B - Oxiracetam compound and new method thereof - Google Patents
Oxiracetam compound and new method thereof Download PDFInfo
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- CN102050774B CN102050774B CN2010105781095A CN201010578109A CN102050774B CN 102050774 B CN102050774 B CN 102050774B CN 2010105781095 A CN2010105781095 A CN 2010105781095A CN 201010578109 A CN201010578109 A CN 201010578109A CN 102050774 B CN102050774 B CN 102050774B
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Abstract
The invention provides an Oxiracetam compound and a new method thereof. The method comprises the following steps: firstly dissolving Oxiracetam in water, carrying out adsorption and purification with activated carbon, precipitating with an organic solvent, separating and purifying with a chromatographic column, and finally carrying out crystallization with an organic solvent, thus the high purity Oxiracetam compound is obtained. The purity of the final product is greatly improved compared with the existing product, the quality of preparation is improved, the toxic and side effects are reduced, and the safety in the application of preparing a drug used for treating senile dementia is ensured; and meanwhile, compared with the prior art, the process in the invention is simple and feasible, the reaction conditions are mild, the cost is low, the yield is high, and the product purity is high, thus being applicable to industrialized production.
Description
Technical field
The present invention relates to a kind of oxiracetam compound and novel method thereof, belong to medicine technology field.
Background technology
Nootropics (nootropics) claims that again it is one type of novel medicine for central nervous system that can promote ability of learning and memory that brain activates medicine (cereboactive drugs); It can optionally act on pallium and hippocampus; Activate, protect or promote the functional rehabilitation of neurocyte; And medicine itself does not have direct vasoactive, does not have the central excitation effect yet, is a kind of persistent promoter action to the influence of ability of learning and memory; This compounds all is a gamma-aminobutyric acid derivative, like piracetam, oxiracetam and nefiracetam etc.At present, such medicine has caused people's extensive attention and interest, and the demand of such medicine is also grown with each passing day.
Oxiracetam (oxiracetam) is a kind of synthetic carboxyamino butyric acid (GABOB) cyclic derivatives; Chemistry 2-[4-hydroxyl pyrrolidine-2-ketone-1 base] by name-ethanamide; Claim oxiracetam, oxiracetam again, trade(brand)name has neuromet, neupan, strong bright magnitude.Chemical formula is: C
6H
10N
2O
3, structural formula is as follows, is more synthetic first in 1974 than Qie Mu company by Italian SmithKline, listing in 1987.External listing formulation has capsule, powder, oral preparation, injection etc., and China succeeded in developing capsule in 1997.
Oxiracetam be drugs approved by FDA be used to one of medicine of treating senile dementia; Be used to treat various factors such as wound, anoxic, chronic cerebral function of organization and do not reach the learning and memory decline that nerve retrograde affection causes, old mental deterioration syndromes, children's amentia etc. entirely, be mainly used in various dementia-AD, vascular dementia and organic brain syndromes etc. clinically.
The pharmacological mechanism of oxiracetam has following four aspects: (1), to the effect of cholinergic system: oxiracetam has vagusstoff (acetylcholine; Ach) agonism; There is the learning and memory that stops or reverse due to the Scopolamine to reduce; Prevent the reduction of the cerebral tissue Ach that Scopolamine causes, stop Ach synthetase inhibitors hemicholine inductive forgetful.(2) to the effect of PKC: the activation of PKC possibly be a nootropics common mechanism of action.The effect of (3) the maincenter glutamate family being united: excitatory amino acid receptor can be divided into ionic glutamate receptor (ionotropic glutamate receptor; IGluR) and metabotropic glutamate receptor (metabotropic glutamate receptor, mGluR).Oxiracetam is through acting on the effect of L-glutamic acid nervous system performance hypermnesis.(4) effect of external all cortex steroid hormones: find that as far back as Mondadori in 1987 effect of oxiracetam class nootropics performance hypermnesis depends on adrenal existence and integrity, the adjustment and the participation of the central action of prompting nootropics and periphery mechanism.Others, oxiracetam can directly influence the cerebral tissue energy metabolism, promotes the utilization of brain to oxygen and glucose, improves the content of ATP in the astrocytes cultured.
WO2005/115978 discloses the preparation method of (S)-oxiracetam; Wherein (S)-4-chloro-3-butyric ester and G-NH2 react under alkaline condition that to obtain the finished product oxiracetam be to add the alkalescence that alkali is controlled reaction solution through disposable; But, so directly influenced the yield of oxiracetam in strong base solution because oxiracetam is destroyed easily.Among the preparation method of (the S)-oxiracetam among the WO2005/115978; Reaction can be to carry out under 0～100 ℃ of condition in temperature; But in so wide TR, the efficient phase difference of reaction is very big, and it still can not provide a highest range of reaction temperature of product yield.
Among the Japanese Patent JP62026267, propose with 3 hydroxyls-4-halo butanoic acid derivative directly and G-NH2 react and prepare purpose product oxiracetam.But in this method, side reaction is more, and the product component that reacts final is very complicated, and after making with extra care, its purity can not reach the requirement that medicine uses fully.In addition, the time of reaction is very long, need more than 20 hours, and its ultimate yield is very low, can not satisfy the needs of commercial scale prodn.
U.S. Pat 4173569 has been addressed a kind of compound method of (S)-oxiracetam: (S)-and GABOB is a starting raw material; Through sillylation reagent protection hydroxyl; Product after the cyclization and the reaction of halogenated acetic acids ethyl ester; Reaction product is through the deprotection base, and ammonia is separated, and obtains target compound at last.This kind preparation method is not suitable for commercial scale prodn, because it has a lot of shortcomings, can increase reactions step as using the protection base that hydroxyl is protected, and wastes raw material, and is consuming time longer, increases cost, and total recovery is reduced.
Tetrahedron:Asymmetry 1992,3 (11) has reported a kind of method of synthetic this compound; With oxysuccinic acid and glycine methyl ester is starting raw material, and Acetyl Chloride 98Min. protection hydroxyl through selective reduction, removes hydroxyl, the deprotection base, and ammonia is separated, and obtains target compound.In this method, need carry out a selective reduction and cause and produce multiple by product, and each midbody all needs column chromatography purification, just can carry out next step reaction.Such technology can not satisfy the requirement of industrially scalable equally.
The synthetic route of oxiracetam is at present:
CN101367757A, CN101575309A, CN101121688A, CN101693685A, CN1948285A disclose technology in synthetic route, but purity does not still reach the requirement of clinical application, need do further refinement treatment.Especially deposit improper or shelf-time when long at oxiracetam, cause active constituents of medicine content to reduce, color and luster is strengthened, and its related substances raises.Also have, in some cases,, cause pharmaceutical purity undesirable because controlling of production process is improper.Be necessary further to carry out purifying, obtain high-quality highly purified oxiracetam compound.The present invention provides a kind of process for purification of oxiracetam compound to satisfy clinical application to requirement of high purity.
To these impure products; Prior art does not disclose the method for purifying oxiracetam compound; In fact; The technician that this area has a universal experience knows clearly all difficulties that face aspect the high-purity compound obtaining, and the theory of all these existing absolutely not general separation and purification just can be expected solution need overcome many difficult problems.
Summary of the invention
The applicant is on the basis of a large amount of existing documents; Experiment through a large amount of screenings; Find above-mentioned document and general method for purifying and separating for example method such as crystallization be difficult to obtain the compound of high purity high yield, and various separation purification method and multiple conditional parameter exist the possibility and the unpredictability of varied combination.The inventor is surprisingly found out that through long-term conscientious research, after process Combination application specific method and the parameters optimization oxiracetam compound of high purity high yield can be provided, thereby have accomplished the present invention.
The object of the present invention is to provide a kind of process for purification of oxiracetam compound; It reaches the purpose of refining purifying through charcoal absorption, organic solvent deposit and chromatographic column absorption and purification; Final product purity improves a lot than currently available products; Optimize the formulation products quality, reduced toxic side effect, guaranteed safety of clinical administration.
The technical scheme that the present invention solves is following:
A kind of process for purification of oxiracetam of structure as follows,
Earlier that oxiracetam is soluble in water, use the charcoal absorption purifying, use organic solvent deposit then, use the chromatographic column separation and purification again, use the organic solvent crystallization at last, obtain highly purified oxiracetam compound.
In one aspect of the invention, preferably, the charcoal absorption purifying described in the aforesaid method comprises the step of heated and stirred, and wherein heating preferred temperature is 30～90 ℃, and preferred temperature is 40～80 ℃, and preferred especially temperature is 50～60 ℃.
In one aspect of the invention, the separation and the purification process of medicine comprise adsorption method, as using gac.Unfortunately, except removing color and other unwanted material, gac also irreversibly adsorbs interested medicine, and this causes productive rate obviously to reduce.The present invention confirms that gac can be used for the purifying of oxiracetam, and wherein the usage quantity of gac is the 0.02-5% (g/ml) of overall solution volume, is preferably 0.1-1% (g/ml), is preferably 0.2-0.5% (g/ml) especially.
In one aspect of the invention, the diameter of chromatographic column is about 0.1 to about 200cm, is preferably 5cm at least.The length range of chromatographic column is preferably about 10 centimetres to about 100 centimetres in this method, and more preferably length range is about 20 centimetres to about 30 centimetres, and most preferred length is 25 centimetres.
Generally speaking; In the separation and purification process; Chromatographic column filler can be silica gel, aluminum oxide or macroporous resin, sephadex G-10 etc., and the particle diameter of used silica gel is 45-250 μ m, the Kiselgel A of aperture for
; Used aluminum oxide most preferably is neutral alumina, and used neutral alumina can be 100～200 orders or 200～300 orders; Used macroporous resin model can be AB-8, D101, HPD400, HPD100, D1300; The inventor finds that alumina column has original isolating effect to these article purifying; And cost is relatively low, and macroporous resin and silicagel column do not have clear improvement to product gas purity.
The inventor carries out a large amount of optimization experiment on the basis of the above; Screening has obtained suitable moving phase, therefore in one aspect of the invention, and preferably; Chromatographic column separation and purification condition under in the aforesaid method is: with 1: 3 acetonitrile of volume ratio and water mixed solvent is moving phase; Fixed phase stuffing is an aluminum oxide, and flow velocity is 2.5-5.0ml/min, column temperature 25-40 ℃.
In one aspect of the invention, as preferably, the quality of each purifying medicine is 1 with the ratio of the quality of chromatographic column filler: 10-200, the preferred mass ratio is 1: 15-100.The consumption of moving phase (eluent) is as long as satisfy the complete basically wash-out of medicine; Flow point Fractional Collections behind the wash-out; The content of the flow point Chinese traditional medicine of different sections is different; In order to obtain highly purified medicine (purity is greater than 99.5%), need medicament contg is merged greater than 85% flow point, preferably medicament contg is merged greater than 90% flow point.Preferably, content flows out greater than 90% flow point basically continuously.
In one embodiment of the invention, as the present invention's one preferred embodiment, the purification step of oxiracetam compound of the present invention comprises:
(1) the oxiracetam bullion is dissolved in the purified water, adds the gac of overall solution volume 0.2-0.5% (g/ml), 50-60 ℃ is stirred 20-30min, filters decarburization, collects filtrating;
(2) in gained filtrating, slowly add organic solvent, stirring reaction produces deposition, filters and obtains the oxiracetam solid;
(3),, be moving phase with 1: 3 acetonitrile of volume ratio and water mixed solvent through the chromatographic column separation and purification with oxiracetam solid upper prop; Fixed phase stuffing is an aluminum oxide, and flow velocity is 2.5-5.0ml/min, column temperature 25-40 ℃; The Fractional Collections flow point merges content greater than 90% elutriant;
(4) elutriant is evaporated to about 1/2 volume, adds organic solvent, room temperature fully stirs 2-4h, separates out solid gradually, places 10 hours in 2-4 ℃, filters, and uses organic solvent washing, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam.
In one aspect of the invention; Preferably; Organic solvent described in the aforesaid method is selected from one or more in acetonitrile, methyl alcohol, methylene dichloride, trichloromethane, ethanol, isopropyl ether, ether, hexanaphthene, the Virahol, and preferred volume ratio is 2: 1 the acetonitrile and the mixed solvent of isopropyl ether.Preferably, the volume ratio of said organic solvent and filtrating is 1: 1～12: 1, is preferably 3: 1～6: 1.
In one aspect of the invention, provide the oxiracetam compound of process for purification of the present invention to be used for treating the purposes of medicine for senile dementia in preparation.
The process for purification of oxiracetam compound provided by the invention through charcoal absorption, organic solvent deposit and chromatographic column absorption and purification, has improved the purity and the content of oxiracetam greatly, has optimized the quality product of preparation; Reduce toxic side effect, guaranteed safety of clinical administration, and compared with prior art; Present method technology is simple and easy to do, and reaction conditions is gentle, and cost is low; Yield is high, and product purity is high, is suitable for suitability for industrialized production.
Bibliographical information is arranged some macroporous resins be the chromatography column of weighting agent or the purification process of ion exchange resin exchange column, the macroporous resin rigidity is strong, be prone to synthesis material such as fragmentation and pore-creating agent or removal of solvents unclean and residual, be prone to flow into soup to cause secondary pollution; Its pre-treatment, regeneration purifying process are lacked compliance index; Using the ion exchange resin exchange column then is that cost is too high, also needs the regeneration activating of pillar, comparatively complicated; And can introduce a large amount of sodium ions, purity does not have clear improvement.The inventor finds that alumina column method of the present invention significantly is superior to these purification process.
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Making with extra care of embodiment 1 oxiracetam
(1) be that 96.7% oxiracetam bullion is dissolved in the 1000ml purified water with 100g purity, add the 2g gac, 60 ℃ are stirred 20min, filter decarburization, collect filtrating;
(2) in gained filtrating, slowly adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 3000ml of isopropyl ether, stirs, and produces deposition, filters and obtains the oxiracetam solid;
(3),, be moving phase with 1: 3 acetonitrile of volume ratio and water mixed solvent through the chromatographic column separation and purification with oxiracetam solid upper prop; Fixed phase stuffing is an aluminum oxide, and flow velocity is 3.0ml/min, 30 ℃ of column temperatures; The Fractional Collections flow point merges content greater than 90% elutriant;
(4) elutriant is evaporated to about 1/2 volume, adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 1000ml of isopropyl ether, and room temperature fully stirs 2h; Separate out solid gradually, placed filtration 10 hours in 2-4 ℃; Using the 100ml volume ratio is the mixed solvent washing of 2: 1 acetonitrile and isopropyl ether, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam 88.3g; Purity is 99.8%, and yield is 91.1%.
Making with extra care of embodiment 2 oxiracetams
(1) be that 96.7% oxiracetam bullion is dissolved in the 1000ml purified water with 100g purity, add the 5g gac, 50 ℃ are stirred 30min, filter decarburization, collect filtrating;
(2) in gained filtrating, slowly adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 6000ml of isopropyl ether, stirs, and produces deposition, filters and obtains the oxiracetam solid;
(3),, be that 1: 3 acetonitrile and water mixed solvent is moving phase with volume ratio through the chromatographic column separation and purification with oxiracetam solid upper prop; Fixed phase stuffing is an aluminum oxide, and flow velocity is 5.0ml/min, 40 ℃ of column temperatures; The Fractional Collections flow point merges content greater than 90% elutriant;
(4) elutriant is evaporated to about 1/2 volume, adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 1000ml of isopropyl ether, and room temperature fully stirs 4h; Separate out solid gradually, placed filtration 10 hours in 2-4 ℃; Using the 100ml volume ratio is the mixed solvent washing of 2: 1 acetonitrile and isopropyl ether, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam 89.1g; Purity is 99.9%, and yield is 92.0%.
Making with extra care of embodiment 3 oxiracetams
(1) be that 96.7% oxiracetam bullion is dissolved in the 1000ml purified water with 100g purity, add the 3g gac, 60 ℃ are stirred 30min, filter decarburization, collect filtrating;
(2) in gained filtrating, slowly adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 4000ml of isopropyl ether, stirs to produce deposition, filters and obtains the oxiracetam solid;
(3),, be that 1: 3 acetonitrile and water mixed solvent is moving phase with volume ratio through the chromatographic column separation and purification with oxiracetam solid upper prop; Fixed phase stuffing is an aluminum oxide, and flow velocity is 2.5ml/min, 25 ℃ of column temperatures; The Fractional Collections flow point merges content greater than 90% elutriant;
(4) elutriant is evaporated to about 1/2 volume, adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 1000ml of isopropyl ether, and room temperature fully stirs 3h; Separate out solid gradually, placed filtration 10 hours in 2-4 ℃; Using the 100ml volume ratio is the mixed solvent washing of 2: 1 acetonitrile and isopropyl ether, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam 87.5g; Purity is 99.8%, and yield is 90.3%.
Embodiment 4 structural identifications
The ultimate analysis conclusive evidence:
Theoretical value: C:45.57%, H:6.33%, N:17.72%, O:30.38%
Measured value: C:45.52%, H:6.38%, N:17.79%, O:30.25%.
Enumerate the part comparative example of prior art similar approach or screening process of the present invention below, so that technique effect of the present invention to be described.
Refining (without the chromatographic column) of Comparative Examples 1 oxiracetam
(1) be that 96.7% oxiracetam bullion is dissolved in the 1000ml purified water with 100g purity, add the 2g gac, 60 ℃ are stirred 20min, filter decarburization, collect filtrating;
(2) in gained filtrating, slowly adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 3000ml of isopropyl ether, and room temperature fully stirs 2h, separates out solid gradually; In 2-4 ℃ of placement 10 hours, filter, using the 100ml volume ratio is the mixed solvent washing of 2: 1 acetonitrile and isopropyl ether; 60 ℃ of drying under reduced pressure; Obtain highly purified oxiracetam 87.5g, purity is 97.1%, and yield is 87.9%.
Refining (the use silica gel column chromatography) of Comparative Examples 2 oxiracetams
(1) be that 96.7% oxiracetam bullion is dissolved in the 1000ml purified water with 100g purity, add the 5g gac, 50 ℃ are stirred 30min, filter decarburization, collect filtrating;
(2) in gained filtrating, slowly adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 6000ml of isopropyl ether, stirs, and produces deposition, filters and obtains the oxiracetam solid;
(3),, be that 1: 3 acetonitrile and water mixed solvent is moving phase with volume ratio through the chromatographic column separation and purification with oxiracetam solid upper prop; Fixed phase stuffing is a silica gel, and flow velocity is 5.0ml/min, 40 ℃ of column temperatures; The Fractional Collections flow point merges content greater than 90% elutriant;
(4) elutriant is evaporated to about 1/2 volume, adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 1000ml of isopropyl ether, and room temperature fully stirs 4h; Separate out solid gradually, placed filtration 10 hours in 2-4 ℃; Using the 100ml volume ratio is the mixed solvent washing of 2: 1 acetonitrile and isopropyl ether, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam 85.4g; Purity is 97.8%, and yield is 86.4%.
Refining (the using sephadex G-10 chromatography column) of Comparative Examples 3 oxiracetams
(1) be that 96.7% oxiracetam bullion is dissolved in the 1000ml purified water with 100g purity, add the 3g gac, 60 ℃ are stirred 30min, filter decarburization, collect filtrating;
(2) in gained filtrating, slowly adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 4000ml of isopropyl ether, stirs to produce deposition, filters and obtains the oxiracetam solid;
(3) with oxiracetam solid upper prop; Through the separation and purification of sephadex G-10 chromatographic column, be that 1: 3 acetonitrile and water mixed solvent is moving phase with volume ratio, fixed phase stuffing is an aluminum oxide; Flow velocity is 2.5ml/min; 25 ℃ of column temperatures, the Fractional Collections flow point merges content greater than 90% elutriant; (3) elutriant is evaporated to about 1/2 volume, adding volume ratio is 2: 1 the acetonitrile and the mixed solvent 1000ml of isopropyl ether, and room temperature fully stirs 3h; Separate out solid gradually, placed filtration 10 hours in 2-4 ℃; Using the 100ml volume ratio is the mixed solvent washing of 2: 1 acetonitrile and isopropyl ether, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam 86.1g; Purity is 97.3%, and yield is 86.6%.
The foregoing description and Comparative Examples have proved absolutely the meliority of particular combination method of the present invention from different aspects, especially comprise the chromatographic condition and the optimum parameters of alumina column, have brought beyond thought effect, are in theory can't rational expectation.Bound by theory not; What possibly be various purification process to different impurities in the medicine removes the effect difference; Process for purification provided by the invention has the characteristics and the obvious improvement of essence, and the beyond thought technique effect of obtaining has obtained the highly purified product of high yield.
Foregoing description of the present invention is intended to as explanation, rather than restriction.Concerning the art technology people, can carry out multiple variation or modification in the embodiment described herein.Do not depart from the scope of the present invention or spirit in can obtain these variations.Each reference that the application quoted is incorporated herein by reference at this in full.
Claims (1)
1. the novel method of the oxiracetam compound of a structure as follows is characterized in that the purification step of oxiracetam comprises:
(1) the oxiracetam bullion is dissolved in the purified water, adds the gac of overall solution volume 0.2-0.5%g/ml, 50-60 ℃ is stirred 20-30min, filters decarburization, collects filtrating;
(2) in gained filtrating, slowly add organic solvent, stirring reaction produces deposition, filters and obtains the oxiracetam solid;
(3),, be moving phase with 1: 3 acetonitrile of volume ratio and water mixed solvent through the chromatographic column separation and purification with oxiracetam solid upper prop; Fixed phase stuffing is an aluminum oxide, and flow velocity is 2.5-5.0ml/min, column temperature 25-40 ℃; The Fractional Collections flow point merges content greater than 90% elutriant;
(4) elutriant is evaporated to 1/2 volume, adds organic solvent, room temperature fully stirs 2-4h, separates out solid gradually, places 10 hours in 2-4 ℃, filters, and uses organic solvent washing, and 60 ℃ of drying under reduced pressure obtain highly purified oxiracetam;
Wherein said organic solvent is that volume ratio is 2: 1 the acetonitrile and the mixed solvent of isopropyl ether.
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9238622B2 (en) | 2010-05-21 | 2016-01-19 | Chongqing Runze Pharmaceutical Co., Ltd. | Crystal form I of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, preparing method and use thereof |
| CN102321007B (en) * | 2011-07-18 | 2013-05-08 | 石药集团欧意药业有限公司 | Oxiracetam compound and preparation method as well as medicine composition thereof |
| CN102531988A (en) * | 2011-08-11 | 2012-07-04 | 重庆润泽医疗器械有限公司 | Purification method for sinistrogyration oxiracetam |
| CN102531989B (en) | 2011-08-11 | 2014-02-05 | 重庆润泽医药有限公司 | Purification method for (S)-oxiracetam |
| CN102558014B (en) * | 2011-11-09 | 2013-11-06 | 天津市汉康医药生物技术有限公司 | Oxiracetam compound with steady crystal form |
| CN102846600B (en) * | 2012-09-06 | 2015-06-17 | 石药集团欧意药业有限公司 | Oxiracetam drug activity composition and preparation method thereof |
| CN103342673B (en) * | 2013-07-31 | 2015-11-18 | 石药集团欧意药业有限公司 | A kind of Oxiracetam crystal form and preparation method thereof |
| CN103554000B (en) | 2013-11-06 | 2015-03-11 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| CN103588695B (en) * | 2013-11-25 | 2015-08-05 | 石药集团欧意药业有限公司 | Oxiracetam compound of a kind of crystallized form and preparation method thereof |
| CN105348167A (en) * | 2015-11-11 | 2016-02-24 | 北京万全德众医药生物技术有限公司 | Refining method for oxiracetam |
| CN105418475B (en) * | 2015-12-31 | 2018-01-19 | 山西普德药业有限公司 | A kind of process for refining of Oxiracetam |
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