CN101429227A - Refining method for Glycyl-L-tyrosine - Google Patents
Refining method for Glycyl-L-tyrosine Download PDFInfo
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- CN101429227A CN101429227A CNA2008102390355A CN200810239035A CN101429227A CN 101429227 A CN101429227 A CN 101429227A CN A2008102390355 A CNA2008102390355 A CN A2008102390355A CN 200810239035 A CN200810239035 A CN 200810239035A CN 101429227 A CN101429227 A CN 101429227A
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Abstract
The invention discloses a method for purifying glycyl-L-tyrosine. Researchers find through experimental researches that the glycyl-L-tyrosine is purified by WA-30 resin column with time flowing column in 2 hours, so that purity of the obtained glycyl-L-tyrosine is more than 99 percent, and single impurity is not more than 0.5 percent. The purification process not only has the advantages of higher yield and lower cost, but also has easily controlled purification process, and is easy for industrialized production.
Description
Affiliated technical field
The invention belongs to chemical technology field, be specifically related to a kind of process for purification of Glycyl-L-tyrosine.
Background technology
The Glycyl-L-tyrosine Chinese name is a glycyl-L-tyrosine; the method for preparing at present glycyl-L-tyrosine; more employing is that starting raw material is condensed into reactive polypeptide with the glycine of L-tyrosine ester and N-protected, and just the condensing agent that adopts is different with the method for deprotection base.Document according to retrieval; more feasible in the production; roughly can be summarized as following three routes: route one biliographic data Paul; R.et al.; Journal OrganicChemistry Vol27:2094～99 (1962), with N, N '-phosphinylidyne diimidazole is that condensing agent is with carbobenzoxyglycine and tyrosine ethyl ester; be condensed into peptide, hydrolysis is fallen protecting group and is promptly got glycyl-L-tyrosine then.Route two biliographic data S.Rajappa; K et al.; Tetrahedron Vol23:4805～9 (1967); adopt O-(N-carbobenzoxy-(Cbz) glycyl) pivalyl hydroxamic acid to add tyrosine ethyl ester down for active ester low temperature; be condensed into peptide earlier, hydrolysis is fallen protecting group and is promptly got glycyl-L-tyrosine then.Route three referenced patent EP311057 (1988); with the dicyclohexyl carbimide is condensing agent; N-hydroxy-succinamide and carbobenzoxyglycine are made active ester, be condensed into peptide with tyrosine ethyl ester then, hydrolysis is fallen protecting group and is promptly got glycyl-L-tyrosine then.
The Glycyl-L-tyrosine crude product is with reference to above path of preparing among the present invention.
With the more and single impurity of Glycyl-L-tyrosine related impurities of above synthetic method preparation greater than 0.5%, be difficult to be directly used in the preparation of medicine injection liquid, the method of therefore inventing a kind of simple refining Glycyl-L-tyrosine is significant, and can create the economic worth of getting well.
Summary of the invention
Researchist of the present invention finds through lot of experiments, adopt the refining Glycyl-L-tyrosine of WA-30 resin column, spending the post time was controlled at 2 hours, obtain Glycyl-L-tyrosine content greater than 99%, and single impurity is not more than 0.5%, and this process for refining not only yield is higher, and cost is lower, and treating process be easy to control, be easy to suitability for industrialized production.
The object of the present invention is to provide a kind of process for purification of Glycyl-L-tyrosine.
The present invention is achieved by the following technical solutions:
Preparation technology
One, Glycyl-L-tyrosine production technology of crude
Add strong aqua in the reactor of 300L, water, bicarbonate of ammonia in about 35 ℃ stirrings of interior temperature, dissolves fully to bicarbonate of ammonia; Add N-chloracetyl-L-tyrosine and water, reaction solution is warming up to about 40 ℃ then, and stirring reaction is 62 hours under this temperature; Stopped reaction, under 65 ℃, pressure reducing and steaming ammoniacal liquor adds entry to doing, and decompression removes and anhydrates once more, add water dissolution in the remaining solid, stirring at room is slowly separated out a large amount of solids, adds ethanol, stirs, suction filtration, the filter cake washing with alcohol, 65 ℃ of drying under reduced pressure 12 hours, the Glycyl-L-tyrosine crude product.
Two, Glycyl-L-tyrosine crude product refining process
Install the WA-30 resin column in advance, and be washed till neutral stand-by with deionized water; The Glycyl-L-tyrosine crude product is dissolved in 15 times of amount pure water, be heated to 65 ± 5 ℃ of stirring and dissolving, resin column is crossed in cooling then, spending the post time was controlled at 1-3 hour, sampling analysis, main peak area content is greater than 99.0%, with the drip washing of 5 times of amount pure water in the HPLC area normalization method calculating cut, distillate is under 75 ± 5 ℃, pressure reducing and steaming water adds 5 times of water gagings to doing, dissolving, stirring at room is slowly separated out a large amount of solids, add 10 times of amount ethanol and stir suction filtration, filter cake washing with alcohol, 65 ± 5 ℃ of drying under reduced pressure 12 ± 2 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is greater than 99%, and single impurity is not more than 0.5%.
Resin column can also be used the D301 resin column in the process for refining of Glycyl-L-tyrosine crude product of the present invention, D201 resin column, D345 resin column.
Doubly amount in the process for refining of Glycyl-L-tyrosine crude product of the present invention is mass ratio.
Embodiment
Embodiment 1
Install the WA-30 resin column in advance, and be washed till neutral stand-by with deionized water; Glycyl-L-tyrosine crude product 14kg is dissolved in the 210L pure water, be heated to 65 ℃ of stirring and dissolving, resin column is crossed in cooling then, and the post time was controlled at 2 hours excessively, sampling analysis, main peak area content is greater than 99.0% in the HPLC area normalization method calculating cut, and with the drip washing of 70L pure water, distillate is under 75 ℃, pressure reducing and steaming water is to doing, add 70L water, dissolving, stirring at room is slowly separated out a large amount of solids, adding 140L ethanol stirs, suction filtration, filter cake washing with alcohol, 65 ℃ of drying under reduced pressure 12 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is 99.8%.
Embodiment 2
Install the WA-30 resin column in advance, and be washed till neutral stand-by with deionized water; Glycyl-L-tyrosine crude product 10kg is dissolved in the 150L pure water, be heated to 60 ℃ of stirring and dissolving, resin column is crossed in cooling then, and the post time was controlled at 1 hour excessively, sampling analysis, main peak area content is greater than 99.0% in the HPLC area normalization method calculating cut, and with the drip washing of 50L pure water, distillate is under 70 ℃, pressure reducing and steaming water is to doing, add 50L water, dissolving, stirring at room is slowly separated out a large amount of solids, adding 100L ethanol stirs, suction filtration, filter cake washing with alcohol, 60 ℃ of drying under reduced pressure 10 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is 99.1%.
Embodiment 3
Install the D301 resin column in advance, and be washed till neutral stand-by with deionized water; Glycyl-L-tyrosine crude product 6kg is dissolved in the 90L pure water, be heated to 70 ℃ of stirring and dissolving, resin column is crossed in cooling then, and the post time was controlled at 1.5 hours excessively, sampling analysis, main peak area content is greater than 99.0% in the HPLC area normalization method calculating cut, and with the drip washing of 30L pure water, distillate is under 80 ℃, pressure reducing and steaming water is to doing, add 30L water, dissolving, stirring at room is slowly separated out a large amount of solids, adding 60L ethanol stirs, suction filtration, filter cake washing with alcohol, 65 ± 5 ℃ of drying under reduced pressure 12 ± 2 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is 99.3%.
Embodiment 4
Install the D201 resin column in advance, and be washed till neutral stand-by with deionized water; Glycyl-L-tyrosine crude product 3kg is dissolved in the 45L pure water, be heated to 65 ℃ of stirring and dissolving, resin column is crossed in cooling then, and the post time was controlled at 1 hour excessively, sampling analysis, main peak area content is greater than 99.0% in the HPLC area normalization method calculating cut, and with the drip washing of 15L pure water, distillate is under 75 ℃, pressure reducing and steaming water is to doing, add 15L water, dissolving, stirring at room is slowly separated out a large amount of solids, adding 30L ethanol stirs, suction filtration, filter cake washing with alcohol, 65 ℃ of drying under reduced pressure 14 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is 99.2%.
Embodiment 5
Install the D345 resin column in advance, and be washed till neutral stand-by with deionized water; Glycyl-L-tyrosine crude product 1kg is dissolved in the 15L pure water, be heated to 60 ℃ of stirring and dissolving, resin column is crossed in cooling then, and the post time was controlled at 2.5 hours excessively, sampling analysis, main peak area content is greater than 99.0% in the HPLC area normalization method calculating cut, and with the drip washing of 5L pure water, distillate is under 80 ℃, pressure reducing and steaming water is to doing, add 5L water, dissolving, stirring at room is slowly separated out a large amount of solids, adding 10L ethanol stirs, suction filtration, filter cake washing with alcohol, 60 ℃ of drying under reduced pressure 12 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is 99.5%.
Claims (6)
1. the process for purification of a Glycyl-L-tyrosine is characterized in that with this process for purification institute purified Glycyl-L-tyrosine purity greater than 99%, single impurity is not more than 0.5%.
2. the process for purification of a kind of Glycyl-L-tyrosine as claimed in claim 1 is characterized in that process for refining is following steps:
Install the WA-30 resin column in advance, and be washed till neutral stand-by with deionized water; The Glycyl-L-tyrosine crude product is dissolved in 15 times of amount pure water, be heated to 65 ± 5 ℃ of stirring and dissolving, resin column is crossed in cooling then, and the post time was controlled at 1-3 hour excessively, sampling analysis, main peak area content is greater than 99.0% in the HPLC area normalization method calculating cut, and with the drip washing of 5 times of amount pure water, distillate is under 75 ± 5 ℃, pressure reducing and steaming water is to doing, add 5 times of water gagings, dissolving, stirring at room is slowly separated out a large amount of solids, adding 10 times of amount ethanol stirs, suction filtration, filter cake washing with alcohol, 65 ± 5 ℃ of drying under reduced pressure 12 ± 2 hours, get the Glycyl-L-tyrosine highly finished product, Glycyl-L-tyrosine purity is greater than 99%.
3. the process for purification of a kind of Glycyl-L-tyrosine as claimed in claim 2 is characterized in that resin column can also be used the D301 resin column in the process for refining, D201 resin column, D345 resin column.
4. the process for purification of a kind of Glycyl-L-tyrosine as claimed in claim 2 is characterized in that the doubly amount in the process for refining is mass ratio.
5. the process for purification of a kind of Glycyl-L-tyrosine as claimed in claim 2 is characterized in that the post time was controlled at 1-3 hour excessively in the process for refining.
6. the process for purification of a kind of Glycyl-L-tyrosine as claimed in claim 5 is characterized in that the post time was controlled at 2 hours excessively in the process for refining.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008102390355A CN101429227A (en) | 2008-12-05 | 2008-12-05 | Refining method for Glycyl-L-tyrosine |
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| CNA2008102390355A CN101429227A (en) | 2008-12-05 | 2008-12-05 | Refining method for Glycyl-L-tyrosine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447946A (en) * | 2014-11-05 | 2015-03-25 | 济南康和医药科技有限公司 | Novel crystal form of N-glycyl tyrosine monohydrate and preparation method of novel crystal form |
| WO2016011786A1 (en) * | 2014-07-20 | 2016-01-28 | 郭克亚 | Hub of spoke-type wheel and spoke-type wheelset formed by same |
| CN108101958A (en) * | 2017-12-25 | 2018-06-01 | 湖北泓肽生物科技有限公司 | A kind of process for purification of glycyl-L-tyrosine |
| CN113880911A (en) * | 2021-09-15 | 2022-01-04 | 湖北泓肽生物科技有限公司 | Synthesis method of glycyl-L-tyrosine |
-
2008
- 2008-12-05 CN CNA2008102390355A patent/CN101429227A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016011786A1 (en) * | 2014-07-20 | 2016-01-28 | 郭克亚 | Hub of spoke-type wheel and spoke-type wheelset formed by same |
| CN104447946A (en) * | 2014-11-05 | 2015-03-25 | 济南康和医药科技有限公司 | Novel crystal form of N-glycyl tyrosine monohydrate and preparation method of novel crystal form |
| CN108101958A (en) * | 2017-12-25 | 2018-06-01 | 湖北泓肽生物科技有限公司 | A kind of process for purification of glycyl-L-tyrosine |
| CN108101958B (en) * | 2017-12-25 | 2020-06-02 | 湖北泓肽生物科技有限公司 | Refining method of glycyl-L-tyrosine |
| CN113880911A (en) * | 2021-09-15 | 2022-01-04 | 湖北泓肽生物科技有限公司 | Synthesis method of glycyl-L-tyrosine |
| CN113880911B (en) * | 2021-09-15 | 2023-11-14 | 湖北泓肽生物科技有限公司 | Synthesis method of glycyl-L-tyrosine |
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Application publication date: 20090513 |