CN113105399A - Alanyl glutamine high-temperature degradation impurity and preparation method and application thereof - Google Patents
Alanyl glutamine high-temperature degradation impurity and preparation method and application thereof Download PDFInfo
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- CN113105399A CN113105399A CN202110352155.1A CN202110352155A CN113105399A CN 113105399 A CN113105399 A CN 113105399A CN 202110352155 A CN202110352155 A CN 202110352155A CN 113105399 A CN113105399 A CN 113105399A
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- alanyl
- glutamine
- temperature degradation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
Abstract
The invention provides alanyl glutamine high-temperature degradation impurities and a preparation method and application thereof, the alanyl glutamine is dissolved in purified water, the reaction is carried out by heating in water bath at 90-100 ℃, and the reaction liquid is separated and purified by preparative liquid chromatography to obtain the product. The invention provides another novel high-temperature degradation impurity of L-alanyl-L-glutamine, which has high purity and can be used as a reference substance for detecting related substances and used for quality control and toxicological evaluation of L-alanyl-L-glutamine and compound preparation thereof.
Description
Technical Field
The invention relates to alanyl glutamine high-temperature degradation impurities and a preparation method and application thereof, belonging to the field of impurity compounds.
Background
L-alanyl-L-glutamine (Ala-Gln) is an important parenteral nutrition product that is metabolized in vivo to L-alanine and L-glutamine. The product is taken as an injection and a freeze-dried powder product, is put into Chinese pharmacopoeia, is clinically used for nitrogen balance and protein synthesis, maintains the integrity of intestinal mucosa and the like.
L-alanyl-L-glutamine is dipeptide, and is easily degraded at high temperature, and the degradation product is complex. The literature (Journal of Chromatography A,1259(2012) 111-120; European Journal of Pharmaceutical Sciences,7(1998) 107-112) reports the degradation pathway of Ala-Gln, and the structures cyclo (AlaGlu), cyclo (AlaGln), PyroGlu, pyroGlu, Glu (Ala), Glu Ala, AlaGlu, AlaGlu (AlaGln) of 7 related impurities were proposed.
Disclosure of Invention
The first purpose of the invention is to provide another alanyl-glutamine high-temperature degradation impurity, the second purpose of the invention is to provide the application of the impurity, and the third purpose is to provide the preparation method of the impurity.
In order to achieve the first object of the present invention, the present invention provides an alanyl-glutamine high-temperature degradation impurity, which has the structural formula:
the alanyl-glutamine high-temperature degradation impurity is applied to the quality control of alanyl-glutamine.
The third object of the present invention is achieved by: the preparation method of the alanyl-glutamine high-temperature degradation impurity is characterized by comprising the following steps: dissolving alanyl glutamine in purified water, heating in 90-100 deg.c water bath for reaction, and separating and purifying the reaction liquid with preparative liquid chromatographic process to obtain the product.
In the scheme, the separation and purification conditions of the preparative liquid chromatography are as follows: the preparative column was isocratically eluted with COSMOSIL5C18-MS-II, 5C18-PAQ, 2.0X 25cm, mobile phase 0.05% aqueous TFA (trifluoroacetic acid) at a flow rate of 10 ml/min.
Through long-term research, the invention provides another novel high-temperature degradation impurity of the L-alanyl-L-glutamine, has high purity, can be used as a reference substance for detecting related substances, and is used for quality control and toxicological evaluation of the L-alanyl-L-glutamine and compound preparation thereof.
Description of the drawings:
FIG. 1 is an ESIMS + diagram of impurity 1
FIG. 2 is an ESIMS diagram of impurity 1.
FIG. 3 is a MSMS map of impurity 1.
FIG. 4 is a 1H-NMR chart of impurity 1.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to examples.
EXAMPLE 1 high temperature degradation of L-alanyl-L-Glutamine
Dissolving 1g of L-alanyl-L-glutamine in 10ml of purified water, placing the solution in water with the temperature of 90-100 ℃ for reaction for 1 hour, and directly separating and purifying the reaction solution by using a preparative liquid chromatography.
Example 2 separation and purification of degraded impurities
Subjecting the high temperature degradation solution to preparative liquid chromatography, eluting with 0.05% TFA water solution with flow rate of 10ml/min by using preparative chromatographic column (COSMOSIL 5C18-MS-II, 5C18-PAQ, 2.0 × 25cm), and separating to obtain Fr4 solution.
Fr4 solution was subjected to preparative chromatography (column: COSMOSIL5C18-MS-II, 5C18-PAQ, 2.0X 25cm, mobile phase: 0.05% TFA, flow rate: 10ml/min isocratic elution) to give impurity 1 solution, which was lyophilized to give impurity 1 as white powder, with HPLC normalized content of 96.0% respectively.
Impurity 1: ms (esi) [ M + H ] + ═ 201, [ M-H ] - (199). 1H NMR (D2O,600MHz) nuclear magnetic data: δ H ═ 1.34d (7.3),2.08m,2.42m,2.81dd (6.7,15.8),4.16q (7.3),4.43dd (5.7, 9.0). Mass spectrometry fragmentation was: m/z 183 (5%), 155 (80%), and 109 (29%). According to the nuclear magnetic data and the HPLC-MSMS data, the structure of impurity 1 is determined as follows:
the above description is for the purpose of describing the invention in more detail with reference to specific preferred embodiments, and it should not be construed that the embodiments of the invention are limited to those described herein, and it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (4)
1. An alanyl glutamine high temperature degradation impurity, the structural formula of which is:
2. use of the alanyl glutamine high temperature degradation impurity of claim 1 for alanyl glutamine quality control.
3. A method for preparing alanyl glutamine high temperature degradation impurity according to claim 1, comprising the steps of: dissolving alanyl glutamine in purified water, heating in 90-100 deg.c water bath for reaction, and separating and purifying the reaction liquid with preparative liquid chromatographic process to obtain the product.
4. The method for preparing alanyl-glutamine high-temperature degradation impurities according to claim 3, wherein the conditions for separation and purification by preparative liquid chromatography are as follows: the preparative column was isocratically eluted with COSMOSIL5C18-MS-II, 5C18-PAQ, 2.0X 25cm, mobile phase 0.05% aqueous TFA at a flow rate of 10 ml/min.
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| CN202110352155.1A CN113105399A (en) | 2021-03-31 | 2021-03-31 | Alanyl glutamine high-temperature degradation impurity and preparation method and application thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2198878A1 (en) * | 2008-12-18 | 2010-06-23 | University Of Miami | Polypeptide bombesin antagonists |
| CN103360462A (en) * | 2013-07-09 | 2013-10-23 | 山东齐都药业有限公司 | Refining method of alanyl-glutamine crude drug |
| US20150038740A1 (en) * | 2011-11-28 | 2015-02-05 | Hainan Lingkang Pharmaceutical Co., Ltd. | Alanyl glutamine compound and preparation method thereof |
| CN111170953A (en) * | 2019-12-27 | 2020-05-19 | 郑州手性药物研究院有限公司 | Process for preparing diazacyclooctane intermediates and diazacyclooctanes |
| CN111812259A (en) * | 2020-07-24 | 2020-10-23 | 费森尤斯卡比华瑞制药有限公司 | Method for detecting alanyl glutamine impurity in compound amino acid injection |
-
2021
- 2021-03-31 CN CN202110352155.1A patent/CN113105399A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2198878A1 (en) * | 2008-12-18 | 2010-06-23 | University Of Miami | Polypeptide bombesin antagonists |
| US20150038740A1 (en) * | 2011-11-28 | 2015-02-05 | Hainan Lingkang Pharmaceutical Co., Ltd. | Alanyl glutamine compound and preparation method thereof |
| CN103360462A (en) * | 2013-07-09 | 2013-10-23 | 山东齐都药业有限公司 | Refining method of alanyl-glutamine crude drug |
| CN111170953A (en) * | 2019-12-27 | 2020-05-19 | 郑州手性药物研究院有限公司 | Process for preparing diazacyclooctane intermediates and diazacyclooctanes |
| CN111812259A (en) * | 2020-07-24 | 2020-10-23 | 费森尤斯卡比华瑞制药有限公司 | Method for detecting alanyl glutamine impurity in compound amino acid injection |
Non-Patent Citations (1)
| Title |
|---|
| 徐志文等: "丙氨酰谷氨酰胺注射液处方筛选及稳定性研究", 《亚太传统医药》 * |
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Application publication date: 20210713 |