CN102442936A - Purifying method of (S)-4-hydroxyl-2oxo-1-pyrrolidine acetamide - Google Patents
Purifying method of (S)-4-hydroxyl-2oxo-1-pyrrolidine acetamide Download PDFInfo
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- CN102442936A CN102442936A CN2010105011470A CN201010501147A CN102442936A CN 102442936 A CN102442936 A CN 102442936A CN 2010105011470 A CN2010105011470 A CN 2010105011470A CN 201010501147 A CN201010501147 A CN 201010501147A CN 102442936 A CN102442936 A CN 102442936A
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Abstract
The invention discloses a purifying method of (S)-4-hydroxyl-2oxo-1-pyrrolidine acetamide. The method comprises the following steps of: dissolving (S)-4-hydroxyl-2oxo-1-pyrrolidine acetamide into an optimum solvent; preparing into a saturated solution at the room temperature; and diffusing with a poor solvent in the enclosed environment. (S)-oxiracetam prepared with the purifying method of (S)-oxiracetam has a small quantity of impurities and high purity which can be more than or equal to 99.5 percent; the method has the advantages of simple preparation process, mild reaction condition, easiness for controlling and low preparation cost simultaneously; and meanwhile, a stable (S)-oxiracetam crystal can be obtained with the method disclosed by the invention.
Description
Technical field
The present invention relates to a kind of crystallization purifying method, be specifically related to a kind of crystallization purifying method of (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide.
Background technology
Oxiracetam (Olaxiracetam), be by Italian SmithKline than Qie Mu company in 1974 synthetic nootropics first, this medicine went on the market in Italy in 1987.(S)-oxiracetam is a single enantiomer of oxiracetam; Chemistry (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide by name; Abbreviate left-handed oxiracetam (following usefulness (S)-oxiracetam statement) as; Its chemical structure is shown below:
oxiracetam can promote the synthetic of Phosphorylcholine and phosphatidyl ethanolamine, promote the brain metabolism, through hemato encephalic barrier special nervus centralis road is had hormesis; Improve the ratio of ATP/ADP in the brain; Make the synthetic increase of protein and nucleic acid in the brain, can improve disturbance of intelligence patient's memory and learning functionality, and medicine itself does not have direct vasoactive; Also not having the central excitation effect, is a kind of persistent promoter action to the influence of ability of learning and memory.
Patent CN1513836, CN1948285, CN101121688 have reported the compound method of oxiracetam racemic modification respectively; Patent CN101367757, CN101575309 have reported the preparation method of (S)-oxiracetam respectively; Patent CN1424034, CN1555794, CN1562000, CN101152175 have reported the preparation method of oxiracetam injection formulations, dispersible tablet, freeze-dried prepn and a kind of new preparation respectively.Still the report that does not have at present left-handed oxiracetam crystallization purifying technology.
Summary of the invention
The object of the present invention is to provide a kind of purification process of (S)-oxiracetam, this method (S)-oxiracetam purity simple, that make is high.
The present invention seeks to realize like this:
A kind of purification process of (S)-oxiracetam comprises synthetic (S)-oxiracetam is dissolved in its optimum solvent, and at room temperature processes saturated solution, under closed environment, spreads with its poor solvent.
Above-mentioned optimum solvent be meant (S)-oxiracetam within it solubleness greater than 10 the gram/100 the gram solvents; Above-mentioned poor solvent is meant (the S)-oxiracetam solvent of solubleness below 1 gram/100 grams within it, is that those skilled in the art all know for the optimum dissolving (being prone to broad dose) and the definition of poor solvent (slightly soluble or indissoluble solvent).
In order to make (the S)-oxiracetam purity that makes higher, above-mentioned optimum solvent is preferably absolute ethyl alcohol or propyl carbinol; Above-mentioned poor solvent is preferably anhydrous diethyl ether, sherwood oil or normal hexane; Wherein agents useful for same all can be analytical pure or chemical purity rank.
(the S)-oxiracetam purity that makes is higher, crystallisate is more stable in order further to make, and the consumption of above-mentioned poor solvent is 5-10 a times of above-mentioned (S)-oxiracetam saturated solution volume, and preferable amount is 7-8 times.
The temperature of above-mentioned employing poor solvent diffusion is a room temperature, is preferably 20-25 ℃; Be preferably 5-7 days above-mentioned diffusion time; Above-mentioned synthetic (S)-oxiracetam is preferably purity >=99.0%.
Specifically; A kind of purification process of (S)-oxiracetam; (the S)-oxiracetam that is preferably purity >=99.0% is dissolved in absolute ethyl alcohol; Under 20-25 ℃, stir and process saturated solution, the anhydrous diethyl ether of under closed environment, doubly measuring with said saturated solution volume 7-8 spread 5-7 days down at 20-25 ℃, and the crystal of separating out is obtained (S)-oxiracetam crystallisate through filtration, drying; Perhaps (the S)-oxiracetam with purity >=99.0% is dissolved in propyl carbinol; Under 20-25 ℃, stir and process saturated solution; The sherwood oil of under closed environment, doubly measuring with said saturated solution volume 7-8 spread 5-7 days down at 20-25 ℃, and the crystal of separating out is obtained (S)-oxiracetam crystallisate through filtration, drying.
(S)-oxiracetam impurity that the purification process of the present invention (S)-oxiracetam makes is few, purity is high, its purity can >=99.5%, simultaneously preparation technology is simple, reaction conditions is gentle, easy control, preparation cost is cheap; (S)-oxiracetam crystallisate proterties that the inventive method obtains is stable.
Embodiment
Through embodiment the present invention is further specifically described below.Be necessary to be pointed out that at this following examples only are used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present invention, the technician in this field can make some nonessential improvement and adjustment to the present invention according to the invention described above content.
Embodiment 1
A kind of purification process of (S)-oxiracetam:
It is saturated that 100 mg purity are that (S)-oxiracetam of 99.3% places triangular flask to add to be dissolved under 25 ℃ of the absolute ethyl alcohols; This saturated solution is placed in the anhydrous diethyl ether air-tight bottle that contains 8 times of volumes of this saturated solution; Leave standstill diffusion 5 days under 23-25 ℃, will separate out crystal filtration, drying, obtain granular (the S)-oxiracetam of water white transparency crystallisate 80 mg; Productive rate 80%, purity 99.7%.
Embodiment 2
A kind of purification process of (S)-oxiracetam:
It is saturated that 100 mg purity are that (S)-oxiracetam of 99.0% places triangular flask to add to be dissolved under 20-25 ℃ of the propyl carbinol; This solution is placed in the air-tight bottle of the normal hexane that contains 10 times of volumes of this saturated solution; 22-27 ℃ leaves standstill diffusion 7 days, will separate out crystal filtration, drying, obtains granular (the S)-oxiracetam of water white transparency crystallisate 85 mg; Productive rate 85%, purity 99.6%.
Embodiment 3
A kind of purification process of (S)-oxiracetam:
With purity is that (S)-oxiracetam of 99.2% is dissolved in anhydrous methanol; At room temperature stir and process saturated solution; Anhydrous diethyl ether with 5 times of volumes of this saturated solution under closed environment at room temperature spread 6 days; The crystal of separating out is obtained (S)-oxiracetam crystallisate, purity 99.5% through filtration, drying.
Embodiment 4
A kind of purification process of (S)-oxiracetam:
With purity is that (S)-oxiracetam of 99.1% is dissolved in propyl carbinol; At room temperature stir and process saturated solution; Sherwood oil with 7 times of volumes of this saturated solution under closed environment at room temperature spread 5 days; The crystal of separating out is obtained (S)-oxiracetam crystallisate through filtration, drying, and purity is 99.7%.
Claims (10)
1. the purification process of (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide; Comprise synthetic (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide is dissolved in its optimum solvent; And at room temperature process saturated solution, under closed environment, spread with its poor solvent.
2. purification process as claimed in claim 1 is characterized in that: said optimum solvent is absolute ethyl alcohol or propyl carbinol.
3. according to claim 1 or claim 2 purification process, it is characterized in that: said poor solvent is anhydrous diethyl ether, sherwood oil or normal hexane.
4. according to claim 1 or claim 2 purification process is characterized in that: the consumption of said poor solvent be said (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide saturated solution volume 5-10 doubly.
5. purification process as claimed in claim 3 is characterized in that: the consumption of said poor solvent is 5-10 a times of said (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide saturated solution volume.
6. according to claim 1 or claim 2 purification process is characterized in that: said employing poor solvent diffusion time is 5-7 days; Said synthetic (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide purity >=99.0%.
7. purification process as claimed in claim 3 is characterized in that: said employing poor solvent diffusion time is 5-7 days; Said synthetic (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide purity >=99.0%.
8. purification process as claimed in claim 4 is characterized in that: said employing poor solvent diffusion time is 5-7 days; Said synthetic (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide purity >=99.0%.
9. purification process as claimed in claim 5 is characterized in that: said employing poor solvent diffusion time is 5-7 days; Said synthetic (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide purity >=99.0%.
10. purification process as claimed in claim 1; (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide of purity >=99.0% is dissolved in absolute ethyl alcohol; Under 20-25 ℃, stir and process saturated solution; The anhydrous diethyl ether of under closed environment, doubly measuring with said saturated solution volume 7-8 spread 5-7 days down at 20-25 ℃, and the crystal of separating out is obtained (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide crystallisate through filtration, drying; Perhaps (the S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide with purity >=99.0% is dissolved in propyl carbinol; Under 20-25 ℃, stir and process saturated solution; The sherwood oil of under closed environment, doubly measuring with said saturated solution volume 7-8 spread 5-7 days down at 20-25 ℃, and the crystal of separating out is obtained (S)-4-hydroxyl-2 OXo-1-pyrrolidine ethanamide crystallisate through filtration, drying.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973739A (en) * | 2016-10-24 | 2018-05-01 | 重庆润泽医药有限公司 | Dextrorotation Oxiracetam crystal form II and its preparation method and application |
| CN109251157A (en) * | 2017-07-13 | 2019-01-22 | 重庆润泽医药有限公司 | (R)-Esomeprazole preparation method |
| US10556863B1 (en) | 2016-10-24 | 2020-02-11 | Chongqing Ruzer Pharmaceutical Company Limited | Crystalline form of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, preparation method therefor and use thereof |
| US10696629B2 (en) | 2016-10-24 | 2020-06-30 | Chongqing Runze Pharmaceutical Company Limited | Crystalline form of dextral oxiracetam, preparation method therefor and use thereof |
| US10961192B2 (en) | 2017-01-12 | 2021-03-30 | Chongqing Ruzer Pharmaceutical Company Limited | (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, preparation method therefor, and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
-
2010
- 2010-10-09 CN CN2010105011470A patent/CN102442936A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973739A (en) * | 2016-10-24 | 2018-05-01 | 重庆润泽医药有限公司 | Dextrorotation Oxiracetam crystal form II and its preparation method and application |
| WO2018076783A1 (en) * | 2016-10-24 | 2018-05-03 | 重庆润泽医药有限公司 | Crystalline form ii of dextral oxiracetam, preparation method therefor and use thereof |
| US10556863B1 (en) | 2016-10-24 | 2020-02-11 | Chongqing Ruzer Pharmaceutical Company Limited | Crystalline form of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, preparation method therefor and use thereof |
| CN107973739B (en) * | 2016-10-24 | 2020-03-20 | 重庆润泽医药有限公司 | Dextro-oxiracetam crystal form II and preparation method and application thereof |
| US10696629B2 (en) | 2016-10-24 | 2020-06-30 | Chongqing Runze Pharmaceutical Company Limited | Crystalline form of dextral oxiracetam, preparation method therefor and use thereof |
| US10793521B2 (en) | 2016-10-24 | 2020-10-06 | Chongqing Ruzer Pharmaceutical Company Limited | Crystalline form II of dextral oxiracetam, preparation method therefor and use thereof |
| US10961192B2 (en) | 2017-01-12 | 2021-03-30 | Chongqing Ruzer Pharmaceutical Company Limited | (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, preparation method therefor, and application thereof |
| CN109251157A (en) * | 2017-07-13 | 2019-01-22 | 重庆润泽医药有限公司 | (R)-Esomeprazole preparation method |
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Application publication date: 20120509 |