CN103641887A - Method for separating and purifying glutamine dipeptide by employing D301 macroporous resin - Google Patents
Method for separating and purifying glutamine dipeptide by employing D301 macroporous resin Download PDFInfo
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- CN103641887A CN103641887A CN201310689791.9A CN201310689791A CN103641887A CN 103641887 A CN103641887 A CN 103641887A CN 201310689791 A CN201310689791 A CN 201310689791A CN 103641887 A CN103641887 A CN 103641887A
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Abstract
The invention belongs to the medicinal chemistry field, and specifically relates to a method for separating and purifying glutamine dipeptide by employing D301 macroporous resin. The method comprises the following steps: preparing the crude glutamine dipeptide into an aqueous solution having the mass fraction ranging from 5% to 10%; continuously carrying out adsorption separation through a D301 macroporous resin column, and collecting the effluent until the glutamine dipeptide is detected in the effluent; next, leaching the D301 macroporous resin column with water and collecting the effluent; blending the effluents and concentrating the mixed effluent; dropwise adding ethanol to the concentrated solution and separating out crystals; filtering, and drying the obtained solid in vacuum to obtain the crude product of pure glutamine dipeptide. According to the invention, the physical method is adopted and is environment-friendly; impurities are all adsorbed in the resin, so that the usage amount of ethanol to separate out crystals is reduced, and simultaneously, the purity of the product is also improved; the purity of the glutamine dipeptide obtained after separation and purification is above 99.6% and no obvious impurity can be found in high performance liquid chromatography detection; moreover, the loss rate of the glutamine dipeptide product is low, the yield is improved and the production cost is reduced.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of method of the D301 of employing macroporous resin separation and purification glutamine dipeptide.
Background technology
N (2)-Ala-Gln (abbreviation glutamine dipeptide) belongs to amino acid whose derivative, is at present domestic and international important amino acid dipeptide product, is mainly used in body-care industry; The desirable substitute products of the abundantest amino acid glutamine of body burden.
Chinese invention patent CN1392156 discloses a kind of glutamine dipeptide synthetic method; the amino acid of N end protection reacts and forms active ester with triphenyl phosphorus, hexachloroethane in organic solvent; active ester and glutamine carry out in the mixing solutions of organic solvent and inorganic base aqueous solution; use mineral acid catalysis, then slough N end blocking group.Chinese invention patent 1786019 discloses a kind of manufacture method of glutamine dipeptide, and the Pfansteihl of esterification, under catalyzer condition, is hydrolyzed after reacting, then carries out obtaining glutamine dipeptide product after series reaction with sulfur oxychloride.In glutamine dipeptide production technique, the purification of product is important step, and common purification process can not get the glutamine dipeptide product that purity is higher, the development of restriction glutamine dipeptide technique.
Summary of the invention
A kind of method that the object of this invention is to provide the D301 of employing macroporous resin separation and purification glutamine dipeptide, purification procedures adopts physical method, and environmental protection, has reduced environmental pollution; Reduced the consumption of alcohol in purification process; The yield that has improved glutamine dipeptide technique, has reduced production cost.
The method of employing D301 macroporous resin separation and purification glutamine dipeptide of the present invention, comprises the following steps:
(1) glutamine dipeptide crude product is mixed with to the aqueous solution of massfraction 5%～10%; By D301 macroporous resin column, carry out fractionation by adsorption continuously, while glutamine dipeptide being detected in effluent liquid, collect effluent liquid;
(2) then use water wash D301 macroporous resin column, collect effluent liquid;
(3) merge the effluent liquid in described step (1) and step (2), and concentrated;
(4) in the concentrated solution obtaining in step (3), drip ethanol, crystallize out;
(5) filter, the solid vacuum-drying obtaining, obtains pure glutamine dipeptide crude product.
Wherein:
Glutamine dipeptide crude product is not for limiting the glutamine dipeptide crude product that any synthetic method obtains.In glutamine dipeptide crude product, the major impurity of more difficult separation is L-Ala-L-Glu, and D301 macroporous resin is weakly base resin, can adsorb preferably this impurity.
D301 macroporous resin is H type D301 macroporous adsorbent resin.The solvent of D301 macroporous resin column is 40-80mL.
In step (2), the flow velocity of water is 1-3mL/min, preferably 2mL/min.If flow velocity is too fast, adsorption effect is bad, and impurity is large, and flow velocity is too little, affects production capacity.
The feed ratio of glutamine dipeptide crude product and water is 5:80-160, and wherein glutamine dipeptide crude product is in g, and water is in mL.
In step (4), in the concentrated solution obtaining in step (3), drip ethanol, crystallize out; Drip the product that ethanol can obtain better crystal formation.It is more that ethanol obtains product more, but purity is lower, and the ratio of concentrated solution and ethanol is preferably 2-2.5:5, and concentrated solution is in g, and ethanol is in mL.
Step (4) is preferably to dripping ethanol in the concentrated solution obtaining in step (3) muddy to producing, and after standing 0.8-1.2h, continues to drip ethanol, crystallize out.Add in two steps ethanol and make the product crystal formation that obtains better, can not produce the too fast problem of crystallization, the product that crystal formation is good is easy to filtering separation, and purity is high.
Purity by the glutamine dipeptide product that obtains after above-mentioned steps separating-purifying is more than 99.6%, uses high performance liquid chromatography to detect to find without obvious impurity.
In sum, the present invention has the following advantages:
(1) purification procedures adopts physical method, and environmental protection, has reduced environmental pollution;
(2) impurity is all adsorbed in resin, can improve the concentration of the front crude product of crystallization, thereby reduce the usage quantity of ethanol crystallization, reduced the consumption of alcohol in purification process, reached the maximum protection to operator, also improved the purity of product, the purity of the glutamine dipeptide product obtaining after separating-purifying, more than 99.6%, is used high performance liquid chromatography to detect and is found obviously impurity of nothing simultaneously;
(3) this separating-purifying step is low to the rate of loss of glutamine dipeptide product, has improved the yield of glutamine dipeptide technique, has reduced production cost.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1:
Adopt D301 macroporous resin separation and purification glutamine dipeptide from the thick product of glutamine dipeptide, glutamine dipeptide crude product 5g is mixed with to the aqueous solution of massfraction 5%; Solution is passed through to 40cm continuously
3d301 macroporous resin column carry out fractionation by adsorption, while glutamine dipeptide being detected in effluent liquid, collect effluent liquid; By 80mL water wash D301 macroporous resin column; The flow velocity of water is 1mL/min, merges effluent liquid concentrated; The solution receiving is concentrated into 20g, drips ethanol 10mL, after crystallization 1h, continue to drip ethanol 40mL, suction filtration, vacuum-drying obtains product 4.4g, purity 99.6%.
Embodiment 2:
Adopt D301 macroporous resin separation and purification glutamine dipeptide from the thick product of glutamine dipeptide, glutamine dipeptide crude product 5g is mixed with to the aqueous solution of massfraction 7%; Solution is passed through to 60cm continuously
3d301 macroporous resin column carry out fractionation by adsorption, while glutamine dipeptide being detected in effluent liquid, collect effluent liquid; By 120mL water wash D301 macroporous resin column; The flow velocity of water is 2mL/min, merges effluent liquid concentrated; The solution receiving is concentrated into 25g, drips ethanol 10mL, after crystallization 0.8h, continue to drip ethanol 40mL, suction filtration, vacuum-drying obtains product 4.5g, purity 99.8%.
Embodiment 3:
Adopt D301 macroporous resin separation and purification glutamine dipeptide from the thick product of glutamine dipeptide, glutamine dipeptide crude product 5g is mixed with to the aqueous solution of massfraction 10%; Solution is passed through to 80cm continuously
3d301 macroporous resin column carry out fractionation by adsorption, while glutamine dipeptide being detected in effluent liquid, collect effluent liquid; By 160mL water wash D301 macroporous resin column; The flow velocity of water is 3mL/min, merges effluent liquid concentrated; The solution receiving is concentrated into 25g, drips ethanol 10mL, after crystallization 1.2h, continue to drip ethanol 40mL, suction filtration, vacuum-drying obtains product 4.2g, purity 99.7%.
Claims (7)
1. a method that adopts D301 macroporous resin separation and purification glutamine dipeptide, is characterized in that: comprise the following steps:
(1) glutamine dipeptide crude product is mixed with to the aqueous solution of massfraction 5%～10%; By D301 macroporous resin column, carry out fractionation by adsorption continuously, while glutamine dipeptide being detected in effluent liquid, collect effluent liquid;
(2) then use water wash D301 macroporous resin column, collect effluent liquid;
(3) merge the effluent liquid in described step (1) and step (2), and concentrated;
(4) in the concentrated solution obtaining in step (3), drip ethanol, crystallize out;
(5) filter, the solid vacuum-drying obtaining, obtains pure glutamine dipeptide crude product.
2. the method for employing D301 macroporous resin separation and purification glutamine dipeptide according to claim 1, is characterized in that: D301 macroporous resin is H type D301 macroporous adsorbent resin.
3. the method for employing D301 macroporous resin separation and purification glutamine dipeptide according to claim 1 and 2, is characterized in that: the solvent of D301 macroporous resin column is 40-80mL.
4. the method for employing D301 macroporous resin separation and purification glutamine dipeptide according to claim 1, is characterized in that: in step (2), the flow velocity of water is 1-3mL/min.
5. the method for employing D301 macroporous resin separation and purification glutamine dipeptide according to claim 1, is characterized in that: the feed ratio of glutamine dipeptide crude product and water is 5:80-160, and wherein glutamine dipeptide crude product is in g, and water is in mL.
6. the method that adopts according to claim 1 or 5 D301 macroporous resin separation and purification glutamine dipeptide, is characterized in that: in step (4), the ratio of concentrated solution and ethanol is 2-2.5:5, and concentrated solution is in g, and ethanol is in mL.
7. the method for employing according to claim 1 D301 macroporous resin separation and purification glutamine dipeptide, it is characterized in that: step (4) is muddy to producing for drip ethanol in the concentrated solution obtaining in step (3), after standing 0.8-1.2h, continue to drip ethanol, crystallize out.
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| CN201310689791.9A CN103641887B (en) | 2013-12-16 | 2013-12-16 | Adopt the method for D301 macroporous resin separation and purification glutamine dipeptide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432412A (en) * | 2016-09-23 | 2017-02-22 | 精晶药业股份有限公司 | Method using resin to extract alanyl-glutamine |
| CN110407914A (en) * | 2018-06-11 | 2019-11-05 | 合肥川迪医药技术有限公司 | A kind of process for separation and purification of glutamine dipeptide |
Citations (4)
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| CN1680428A (en) * | 2005-02-01 | 2005-10-12 | 上海依福瑞实业有限公司 | Preparation of alanyl glutamine dipeptide compound |
| CN101062938A (en) * | 2006-04-25 | 2007-10-31 | 福建三爱药业有限公司 | Process for producing N (2) -L-alanyl-L-glutamine |
| CN101659691A (en) * | 2009-09-28 | 2010-03-03 | 绍兴民生医药有限公司 | Industrial process for producing glutamine dipeptide |
| CN102823715A (en) * | 2012-09-19 | 2012-12-19 | 昆明理工大学 | Method for preparing bioactive peptide through full-bionic digestion model method |
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2013
- 2013-12-16 CN CN201310689791.9A patent/CN103641887B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680428A (en) * | 2005-02-01 | 2005-10-12 | 上海依福瑞实业有限公司 | Preparation of alanyl glutamine dipeptide compound |
| CN101062938A (en) * | 2006-04-25 | 2007-10-31 | 福建三爱药业有限公司 | Process for producing N (2) -L-alanyl-L-glutamine |
| CN101659691A (en) * | 2009-09-28 | 2010-03-03 | 绍兴民生医药有限公司 | Industrial process for producing glutamine dipeptide |
| CN102823715A (en) * | 2012-09-19 | 2012-12-19 | 昆明理工大学 | Method for preparing bioactive peptide through full-bionic digestion model method |
Non-Patent Citations (2)
| Title |
|---|
| 廖春燕等: "D301大孔阴离子树脂固定化β-淀粉酶的研究", 《安徽农业科学》, vol. 37, no. 33, 31 December 2009 (2009-12-31), pages 16218 - 16220 * |
| 许汉林等: "D301大孔树脂分离纯化大黄总蒽醌的研究", 《中国中药杂志》, vol. 31, no. 14, 31 July 2006 (2006-07-31), pages 1163 - 1165 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432412A (en) * | 2016-09-23 | 2017-02-22 | 精晶药业股份有限公司 | Method using resin to extract alanyl-glutamine |
| CN110407914A (en) * | 2018-06-11 | 2019-11-05 | 合肥川迪医药技术有限公司 | A kind of process for separation and purification of glutamine dipeptide |
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| CN103641887B (en) | 2016-03-16 |
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Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL GROUP CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL & CHEMICAL Co.,Ltd. |