CN104557655A - Oxiracetam purifying method - Google Patents
Oxiracetam purifying method Download PDFInfo
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- CN104557655A CN104557655A CN201310469133.9A CN201310469133A CN104557655A CN 104557655 A CN104557655 A CN 104557655A CN 201310469133 A CN201310469133 A CN 201310469133A CN 104557655 A CN104557655 A CN 104557655A
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- oxiracetam
- alcohol
- crude product
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- weight ratio
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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
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
Abstract
The invention discloses an oxiracetam purifying method. The method comprises the following steps: 1, adding crude oxiracetam into an alcohol and water mixed solvent, and heating until the crude oxiracetam is completely dissolved; 2, adding active carbon to decolor, and filtering to obtain a filtrate; 3, adding a hydrogen chloride-containing solution to the filtrate, and crystallizing; and 4, separating to obtain purified oxiracetam. The purity of the obtained purified oxiracetam is not lower than 99.9%.
Description
Technical field
The present invention relates to organic chemistry and medicinal chemistry art, be specifically related to a kind of purification process of oxiracetam.
Background technology
Dementia is one group of syndrome being feature with dysmnesia, dementia, personality change and dystropy.Alzheimer's disease (AD) is modal dementia, secondly be that vascular dementia is (by cerebro-vascular diseases, as caused in cerebral infarction or hematencephalon etc.) or the mixed type of alzheimer's disease and vascular dementia, other cause dull-witted reason also to comprise brain injury, brain tumor (postoperative), intracranial infection and brain degenerative disease etc.Announce according to the World Health Organization, existing 3,500 ten thousand Dementia patients in the whole world.Conservative estimation, the senile dementia patient of China has about 6,000,000.
Oxiracetam, chemistry Esomeprazole by name, structural formula is as follows:
。
Oxiracetam is the novel medicine for central nervous system that a class can promote ability of learning and memory; can optionally act on pallium and hippocampus; activate, protect or promote the functional rehabilitation of neurocyte; and itself is without direct vasoactive; also without central excitation effect, be a kind of lasting promoter action to the improvement of ability of learning and memory.Oxiracetam only acts on central nervous system, can improve brain metabolism, strengthens and promotes juvenile intelligence, improving aging brains functional defect and memory disorder, treatment neurosis and mental act disorder, especially senile dementia.Also can be used for the rehabilitation of the encephalopathy such as cerebral trauma, encephalitis.In addition, extremely low toxicity and fabulous tolerance and there is the effect of the unexistent antithrombin Ⅲ of piracetam.The application prospect of oxiracetam is very wide.According to 22 key cities' database of drugs used in the hospitals, oxiracetam sales volume increases swift and violent, and within 2010, reach 5.62 hundred million yuan, spread to the whole nation, the sales volume of oxiracetam is at about 1,000,000,000 yuan.Along with the development trend that the aging of the current world is on the rise, this product domestic and international market from now on has a high potential.
Taking dosage oxiracetam day is 2 ~ 8g, and for the medicine taking dosage this day and be greater than 2g, the security of its impurity receives much concern.According to ICH(human drugs registration technology specification international coordination meeting) and SFDA(State Food and Drug Administration drug evaluation center) regulation to the limit of impurities of bulk drug in governing principle, maximum per daily dose is greater than the bulk drug of 2g, and the Quality Control limit of its single impurity is 0.05%.
The people such as L.Gagliardi (HPLC Determination of Oxiracetam, Its Impurities, and Piracetam in Pharmaceutical Formulations [J] Analytical letters, 1994,27 (5): 879-885) the principal degradation impurity mentioning oxiracetam is oxiracetam acid, chemistry 4-hydroxyl-2-OXo-1-pyrrolidine acetic acid by name, structural formula is as follows:
。
The Major degradation pathways of this impurity is the hydrolysis of acetamido, and desamidizate becomes carboxyl.This impurity is because very similar to the structures and characteristics of oxiracetam, so very difficult removing.In addition, a large amount of inorganic salt are employed, because oxiracetam is water-soluble cpds, so can not with extracting the method removing inorganic salt washed in aftertreatment in oxiracetam preparation technology, inorganic salt are brought in oxiracetam crude product, are difficult to be removed in the purifying of crude product.Prior art cost-effectively can not remove oxiracetam acid and inorganic salt simultaneously, cannot meet the needs of suitability for industrialized production.
At present, the purification process of oxiracetam has following several:
First method is the method adopting simple organic solvent to carry out recrystallization, such as: CN102134212 adopts acetone recrystallization; CN101885697 adopts recrystallisation from isopropanol, and this type of purification process cannot remove oxiracetam acid and inorganic salt, cannot be met the oxiracetam fine work of medicinal requirements.
Second method is the method adopting chromatographic column to carry out separation and purification, the patents such as CN102050774, CN101898993 and CN102846600 all have employed this kind of method, the method complicated operation of chromatographic column separation and purification, adopt a large amount of organic solvents as elutriant, pollute large, cost is high, and yield is low, is also unsuitable for suitability for industrialized production.
The third method is the method that CN102432516 adopts dehydrated alcohol, phosphoric acid and Glacial acetic acid mixed solvent recrystallization, although this method can remove oxiracetam acid impurity, but can not inorganic salt impurities be removed, and employ two kinds of acid, large usage quantity, can remain in finished product in purifying and not easily remove, and a large amount of acid waste liquid environmental pollutions is comparatively large, is not suitable for suitability for industrialized production.
Therefore, in existing oxiracetam purification process, there is product purity not high, cost-effectively can not remove oxiracetam acid and inorganic salt simultaneously, and pollute large, cost is high, and yield is low, is unsuitable for suitability for industrialized production.For deficiency of the prior art, we are studied the purification process of oxiracetam, invent a kind of cost-effective purification process that simultaneously to remove oxiracetam acid, inorganic salt and other impurity, the oxiracetam fine work HPLC purity obtained is more than 99.9%, maximum single impurity < 0.05%, total impurities < 0.1%, residue on ignition < 0.1%.
Summary of the invention
The object of this invention is to provide a kind of purification process of oxiracetam, the method comprises and being added in the mixed solvent of alcohol and water by oxiracetam crude product, is warming up to solid entirely molten; Add activated carbon decolorizing again; Be separated the crystallization of solution adding containing hydrogen chloride in the filtrate obtained; Be separated to obtain oxiracetam fine work.
Method of the present invention removes oxiracetam acid, inorganic salt and other impurity cost-effectively simultaneously, the oxiracetam fine work HPLC purity obtained is more than 99.9%, total impurities < 0.1%, maximum single impurity < 0.05%, residue on ignition < 0.1%.
In order to realize the invention described above object, adopt following embodiment.
In one embodiment, the purification process of a kind of oxiracetam of the present invention, comprises following steps:
(1) oxiracetam crude product is added in the mixed solvent of alcohol and water, be warming up to solid entirely molten;
(2) add activated carbon decolorizing, filter to get filtrate;
(3) in filtrate, the solution of containing hydrogen chloride is added, crystallization;
(4) oxiracetam fine work is separated to obtain.
In above-mentioned specific embodiments, described in step (1), alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and their mixture, wherein, the envelope-bulk to weight ratio of alcohol and oxiracetam crude product is 1 ~ 50:1ml/g, preferably 2 ~ 20:1ml/g, the alcohol in step (1) and the volume ratio of water are 1:0.01 ~ 1; Gac in step (2) and the weight ratio of oxiracetam crude product are 0.01 ~ 0.5:1; The solution of step (3) described containing hydrogen chloride is the aqueous solution of hydrogenchloride, alcoholic solution or their mixing solutions, and wherein, the weight ratio of hydrogenchloride and oxiracetam crude product is 0.01 ~ 3:100.
In one embodiment, the purification process of a kind of oxiracetam of the present invention, comprises the following steps:
(1) added by oxiracetam crude product in the mixed solvent of alcohol and water, be warming up to solid entirely molten, wherein, the envelope-bulk to weight ratio of alcohol and oxiracetam crude product is 1 ~ 50:1ml/g, preferably 2 ~ 20:1ml/g, and the volume ratio of alcohol and water is 1:0.01 ~ 1;
(2) add activated carbon decolorizing, filter to get filtrate;
(3) in filtrate, add the solution of containing hydrogen chloride, crystallization, wherein, the weight ratio of hydrogenchloride and oxiracetam crude product is 0.01 ~ 3:100;
(4) oxiracetam fine work is separated to obtain.
In above-mentioned specific embodiments, described in step (1), alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and their mixture, and in step (2), the consumption of gac corresponds to every gram of oxiracetam crude product is 0.01 ~ 0.50g.
The HPLC purity of gained oxiracetam fine work of the present invention more than 99.9%, total impurities < 0.1%, maximum single impurity < 0.05%, residue on ignition < 0.1%.
Above-mentioned " purity " measures with high performance liquid chromatography (HPLC) area normalization method, and the detectability of each component is not less than 0.02%, and quantitative limit is not less than 0.05%.The numerical value of content or purity to round up gained through take off data.
The oxiracetam crude product that the present invention uses is what prepare by prior art, as Lu Kaixuan, preparation method that the people such as Liao Quan announces (oxiracetam synthesising process research. Sichuan physiological science magazine, 2010, 32 (3): 108.): with 4-chloro-3-hydroxybutanoic acid ester class for starting raw material, with glycyl amide hydrochloride, in alcoholic solvent, using mineral alkali as catalyzer, back flow reaction, filter after completion of the reaction, evaporated under reduced pressure, add alcoholic solvent making beating, filter, obtain oxiracetam crude product, oxiracetam crude product HPLC purity about 98.0%, total impurities < 2.0%, maximum single impurity 0.1 ~ 1.5%, residue on ignition 0.1 ~ 1.5%.
It should be noted that, above method is only the example preparing oxiracetam crude product by prior art, is not limited thereto, and the oxiracetam crude product obtained by the existing oxiracetam preparation method of this area all can carry out purifying according to method of the present invention.
Compared with the prior art, the present invention has outstanding substantive distinguishing features and significant progress, embodies in the following areas:
The present invention adopts the mixed solvent of alcohol and water to remove most of organic impurity and inorganic salt impurities; Add the solution containing micro-hydrogenchloride again, under the existence having water, the oxiracetam acid impurity that catalysis not easily removes and alcoholic solvent generate oxiracetam ester, oxiracetam ester is soluble in alcohol water mixed solvent, thus removed, one time oxiracetam acid impurity and inorganic salt impurities can be removed by purifying, this effect is difficult to expect, the purity of gained oxiracetam fine work is more than 99.9%, total impurities < 0.1%, maximum single impurity < 0.05%, residue on ignition < 0.1%.
The present invention's hydrogenchloride used is very micro-, pollutes few, and solvent is easy to reclaim, purification process of the present invention, easier, cost is lower, be more suitable for suitability for industrialized production.
Embodiment
The following examples are used for understanding further implementing essence of the present invention, instead of limitation of the scope of the invention.
The HPLC analytical procedure of embodiment 1 oxiracetam
According to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) test, be weighting agent with amino bonded silica gel; With 0.002mol/L ammonium dibasic phosphate solution-acetonitrile (15: 85) (by phosphoric acid adjust ph to 2.5), for moving phase, according to the form below carries out flow velocity linear gradient elution.Determined wavelength is 210nm; Column temperature is 25 DEG C.
Table 1 determination of related substances gradient elution table
| Time (min) | Flow velocity (ml/min) |
| 0 | 1.0 |
| 18 | 1.0 |
| 20 | 2.0 |
| 48 | 2.0 |
| 50 | 1.0 |
| 55 | 1.0 |
It is according to two the annex VIII N method operations of Chinese Pharmacopoeia version in 2005 that the residue on ignition of oxiracetam detects.
The purifying of embodiment 2 oxiracetam crude product
Ethanol 4.0L and water 2.0L is added in 10L reaction flask, oxiracetam crude product 1kg is added under stirring, be heated to interior temperature 60 ~ 65 DEG C, molten clear after add 0.1kg gac, be heated to (the interior temperature 76-80 DEG C) 1-3 hour that refluxes, filtered while hot, filtrate be heated to interior temperature 76-80 DEG C clearly molten, adding hydrochloride ethanol liquid 0.025L(hydrochloride ethanol liquid collocation method is that concentrated hydrochloric acid dehydrated alcohol is diluted to 10 times (volume ratios), hydrogenchloride add-on is 10g), finish, be cooled to 0-5 DEG C, insulated and stirred crystallization 2-5h, filter, 40-50 DEG C of drying under reduced pressure obtains white powder oxiracetam fine work 0.90 kg, yield 90%, HPLC purity: 99.95%, maximum single impurity (for oxiracetam acid): 0.02%, total impurities: 0.05%, residue: 0.04%.
Embodiment 3 ~ 17
By method purifying described in above-described embodiment 2, select different solvents and proportioning purifying oxiracetam crude product, the results detailed in following table:
Comparative example 1: according to purification process purifying disclosed in Chinese patent CN102134212.
In 10L reaction flask, add acetone 5L, under stirring, add oxiracetam crude product 0.5kg, be heated to interior temperature 56 ± 1 DEG C, return stirring 1-3 hour, be cooled to 0-5 DEG C, insulated and stirred crystallization 2-5h, filter, 40-50 DEG C of drying under reduced pressure obtains pale yellow powder oxiracetam fine work 0.46 kg, yield 92%, HPLC purity: 98.7%, maximum single impurity (for oxiracetam acid): 1.0%, total impurities: 1.3%, residue: 0.92%.
Comparative example 2: according to purification process purifying disclosed in Chinese patent CN101885697.
In 10L reaction flask, add Virahol 4L, under stirring, add oxiracetam crude product 0.5kg, be heated to interior temperature 80 ~ 84 DEG C, return stirring 1-2 hour, be cooled to 0-5 DEG C, insulated and stirred crystallization 2-5h, filter, 40-50 DEG C of drying under reduced pressure obtains pale yellow powder oxiracetam fine work 0.455 kg, yield 91%, HPLC purity: 99.0%, maximum single impurity (for oxiracetam acid): 0.7%, total impurities: 1.0%, residue: 0.85%.
Comparative example 3: according to purification process purifying disclosed in Chinese patent CN102452972.
Ethanol and water mixed solvent 4L that volume ratio is 8:1 is added in 10L reaction flask, oxiracetam crude product 400g is added under stirring, heating is all dissolved, add gac 232g, reflux decolour 2h, press filtration while hot, filtrate is slow cooling to room temperature, stirring and crystallizing 17h, suction filtration, filter cake ice ethanol is washed, white powder is obtained after 50 DEG C of vacuum-dryings, repeat above operation and finally obtain 310g oxiracetam fine work afterwards 1 time, yield 77.5%, HPLC purity: 99.86%, maximum single impurity (for oxiracetam acid): 0.12%, total impurities: 0.14%, residue: 0.05%.
Compare with above-mentioned comparative example, method of the present invention, effectively can remove the acid of impurity oxiracetam and inorganic salt, and effectively control the content of single impurity.
Those skilled in the art can understand essence of the present invention, and the amendment in essential scope of the present invention also belongs to the scope of protection of the invention.
Claims (8)
1. a purification process for oxiracetam, comprises following steps:
(1) oxiracetam crude product is added in the mixed solvent of alcohol and water, be warming up to solid entirely molten;
(2) add activated carbon decolorizing, filter to get filtrate;
(3) in filtrate, the solution of containing hydrogen chloride is added, crystallization;
(4) oxiracetam fine work is separated to obtain.
2. the method for claim 1, wherein described in step (1), alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols and their mixture.
3. the alcohol the method for claim 1, wherein in step (1) and the envelope-bulk to weight ratio of oxiracetam crude product are 1 ~ 50:1ml/g.
4. method as claimed in claim 3, wherein, the alcohol in step (1) and the envelope-bulk to weight ratio of oxiracetam crude product are 2 ~ 20:1ml/g.
5. the alcohol the method for claim 1, wherein in step (1) and the volume ratio of water are 1:0.01 ~ 1.
6. the gac the method for claim 1, wherein in step (2) and the weight ratio of oxiracetam crude product are 0.01 ~ 0.5:1.
7. the method for claim 1, the solution of step (3) described containing hydrogen chloride is the aqueous solution of hydrogenchloride, alcoholic solution or their mixing solutions.
8. the method for claim 1, in step (3), the weight ratio of hydrogenchloride and oxiracetam crude product is 0.01 ~ 3:100.
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| CN201310469133.9A CN104557655A (en) | 2013-10-10 | 2013-10-10 | Oxiracetam purifying method |
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| CN201310469133.9A CN104557655A (en) | 2013-10-10 | 2013-10-10 | Oxiracetam purifying method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105418475A (en) * | 2015-12-31 | 2016-03-23 | 山西普德药业股份有限公司 | Refining technology of oxiracetam |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223328A1 (en) * | 1985-07-26 | 1987-05-27 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| CN102432516A (en) * | 2011-12-14 | 2012-05-02 | 山东阿如拉药物研究开发有限公司 | Method for refining oxiracetam |
| CN102452972A (en) * | 2011-12-28 | 2012-05-16 | 南京优科生物医药有限公司 | Method for preparing oxiracetam compound |
| CN102746207A (en) * | 2012-07-23 | 2012-10-24 | 信泰制药（苏州）有限公司 | Synthesis method of oxiracetam |
-
2013
- 2013-10-10 CN CN201310469133.9A patent/CN104557655A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223328A1 (en) * | 1985-07-26 | 1987-05-27 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| CN102432516A (en) * | 2011-12-14 | 2012-05-02 | 山东阿如拉药物研究开发有限公司 | Method for refining oxiracetam |
| CN102452972A (en) * | 2011-12-28 | 2012-05-16 | 南京优科生物医药有限公司 | Method for preparing oxiracetam compound |
| CN102746207A (en) * | 2012-07-23 | 2012-10-24 | 信泰制药（苏州）有限公司 | Synthesis method of oxiracetam |
Non-Patent Citations (1)
| Title |
|---|
| 卢凯旋 等: "奥拉西坦合成工艺研究", 《四川生理科学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105418475A (en) * | 2015-12-31 | 2016-03-23 | 山西普德药业股份有限公司 | Refining technology of oxiracetam |
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Application publication date: 20150429 |