CN107085044A - Method of the gas chromatography separation detection agomelatine intermediate body about material - Google Patents
Method of the gas chromatography separation detection agomelatine intermediate body about material Download PDFInfo
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- CN107085044A CN107085044A CN201710186971.3A CN201710186971A CN107085044A CN 107085044 A CN107085044 A CN 107085044A CN 201710186971 A CN201710186971 A CN 201710186971A CN 107085044 A CN107085044 A CN 107085044A
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- benzylamine
- intermediate body
- agomelatine
- separating
- agomelatine intermediate
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention belongs to analytical chemistry field, the invention discloses a kind of method of use gas chromatography quick separating detection agomelatine intermediate body about material benzylamine, this method uses the low pole capillary chromatographic column that 5% phenyl is bonded in polydimethylsiloxanepolymer polymer, flame ionization ditector, the content of benzylamine in agomelatine intermediate body can be quantitative determined, so as to reach effective control to agomelatine intermediate body purity, and then realize the quality controllable of agomelatine.The inventive method specificity is strong, and the degree of accuracy is high, and test limit is low, and durability is good, and simple and quick.
Description
Technical field
The invention belongs to analytical chemistry field, and in particular to gas chromatography separation determination agomelatine intermediate body is relevant
The method of material.
Background technology
Agomelatine is a kind of new antidepressants, is melatonin receptor activator and serotonin (5-HT) 2C
Receptor antagonist, agomelatine to major depressive disorder (MMD) curative effect substantially, adverse reaction is small, can effectively adjust biological rhythm,
Improve sleep quality.Agomelatine intermediate body chemistry is entitled（The naphthyl of 7- methoxyl groups -1）Acetonitrile, molecular formula is C13H11NO, knot
Structure formula is：
。
The relevant material of separation determination agomelatine intermediate body, it is ensured that reactant during synthesis agomelatine
Purity, reduces the generation of side reaction and the generation of impurity, has in terms of the production and its quality control of agomelatine important
Realistic meaning.The organic impurities introduced in synthesis agomelatine intermediate body technique has benzylamine, and its molecular formula is C7H9N, structure
Formula is：
。
Benzylamine is poisonous, there is potential hazard to human body, selects suitable analysis method, separates and determines algebraic oriented language U.S. exactly and draw
The relevant material benzylamine of spit of fland intermediate, to improving agomelatine quality, ensureing that drug safety has great importance.
The content of the invention
It is organic it is an object of the invention to provide what is introduced in a kind of separation, detection synthesis agomelatine intermediate body technique
The method of impurity benzylamine, so as to reach effective control to agomelatine intermediate body purity and quality, and then ensures that algebraic oriented language is beautiful
Draw the quality and drug safety in spit of fland.
A kind of separation of the present invention, measure agomelatine intermediate body, about the method for material, are to use gas phase color
Spectral analysis technology, is dissolved sample from suitable solvent, poly- from methyl according to the formation and physic-chemical property of impurity to be analyzed
Type siloxane chromatographic column and flame ionization ditector.
Above-mentioned described solvent can be one kind in ethanol, methanol, DMF or dimethyl sulfoxide (DMSO) or
It is several.
Above-mentioned described chromatographic column is selected from the brands such as Agilent, Phenomenex or Restek.
Above-mentioned described chromatographic column is the low pole capillary color that 5% phenyl is bonded in polydimethylsiloxanepolymer polymer
Compose post.
Method of separating and assaying of the present invention, can be realized in accordance with the following methods：
1）Take agomelatine intermediate body appropriate, plus 100mg containing agomelatine intermediate body in every 1ml is made in absolute ethyl alcohol dissolving
Solution, be used as need testing solution；It is another to take benzylamine appropriate, plus the molten of μ g containing benzylamine 100 in every 1ml is made in absolute ethyl alcohol dissolving
Liquid, is used as reference substance solution；
2）It is 200 ~ 250 DEG C to set injector temperature, and flow rate of carrier gas is 2.0 ~ 4.0mL/min, programmed temperature method, and heating schedule is
60 °C of initial temperature, 2 ~ 8 DEG C of constant temperature, with 10 ~ 30 °C per minute of heating rate to 220 °C, 1 ~ 5min of constant temperature, detector temperature
For 250 ~ 320 DEG C, split ratio is 10:1~50:1；
3）Take 1）Middle need testing solution and each 1.0~3.0 μ L of reference substance solution, by 2）Chromatographic condition, inject gas chromatograph,
The content of benzylamine in agomelatine intermediate body is calculated using external standard method.
Wherein：The model of gas chromatograph, has no special requirements, and the gas chromatograph that the present invention is used is Shimadzu（2010
plus）Gas chromatograph.
Detector：Flame ionization ditector；
Chromatographic column：The CB capillary chromatographic columns of CP-Sil 8（30m × 0.32mm, 1.0 μm）；
Injector temperature：200℃；
Detector temperature：300℃；
Carrier gas（Nitrogen）Flow velocity：4.0mL/min；
Split ratio：20:1；
Sampling volume：1μL；
Column temperature rise program：
。
The present invention uses gas chromatography, from the low pole capillary that 5% phenyl is bonded in polydimethylsiloxanepolymer polymer
Pipe chromatographic column（30m × 0.32mm, 1.0 μm）, can fast and effeciently organic impurities benzyl in separation determination agomelatine intermediate body
Amine, solves the problems, such as to synthesize the separation determination of the organic impurities benzylamine introduced in agomelatine intermediate body technique, so as to reach
Effective control to agomelatine purity and quality, is as a result shown in accompanying drawing 1 ~ 6.
Brief description of the drawings
Fig. 1：Solvent during embodiment 1（Absolute ethyl alcohol）Gas chromatogram；
Fig. 2：The gas chromatogram of agomelatine intermediate body during embodiment 1；
Fig. 3：The gas chromatogram of benzylamine during embodiment 1；
Fig. 4：The agomelatine intermediate body sample gas chromatogram of benzylamine is added during embodiment 1；
Fig. 5：The gas chromatogram of benzylamine during embodiment 2；
Fig. 6：The gas chromatogram of benzylamine during embodiment 3.
Embodiment：
Following examples are used to further understand the present invention, but are not limited to the scope of this implementation.Below by way of example forms, to this
Invent benzylamine detection method in the agomelatine intermediate body being related to be described in further detail, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following example, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
Instrument and condition
Chromatograph：The plus gas chromatographs of Shimadzu 2010；
Detector：Flame ionization ditector；
Chromatographic column：The CB capillary chromatographic columns of CP-Sil 8（30m × 0.32mm, 1.0 μm）；
Injector temperature：200℃；
Detector temperature：300℃；
Carrier gas（Nitrogen）Flow velocity：4.0mL/min；
Split ratio：20:1；
Sampling volume：1μL；
Column temperature rise program：
。
Experimental procedure
Take agomelatine intermediate body appropriate, plus the 100mg containing agomelatine intermediate body in every 1ml is made in absolute ethyl alcohol dissolving
Solution, is used as agomelatine intermediate body sample solution；Take benzylamine appropriate, plus absolute ethyl alcohol dissolving is made in every 1ml and contains benzylamine
100 μ g solution, is used as reference substance solution；Separately absolute ethyl alcohol is taken as blank solution.Analyzed, remembered by above-mentioned chromatographic condition
Chromatogram is recorded, by external standard method with the content of benzylamine in calculated by peak area agomelatine intermediate body.As a result accompanying drawing 1 ~ 4 is seen, Fig. 1 is
Blank solution chromatogram；Fig. 2 is agomelatine intermediate body sample solution chromatogram；The min of retention time 10.417 in Fig. 3
Chromatographic peak is benzylamine；Fig. 4 is the agomelatine intermediate body sample gas chromatogram for adding benzylamine.Fig. 1 ~ Fig. 4 shows：The present invention
The method of offer can the fast and effeciently relevant material benzylamine of separation determination agomelatine intermediate body, it is possible to accurately quantified
Detection, so as to reach effective control to agomelatine intermediate body purity and quality.
Embodiment 2
Instrument and condition
Chromatograph：The plus gas chromatographs of Shimadzu 2010；
Detector：Flame ionization ditector；
Chromatographic column：The CB capillary chromatographic columns of CP-Sil 8（30m × 0.32mm, 1.0 μm）；
Injector temperature：205℃；
Detector temperature：300℃；
Carrier gas（Nitrogen）Flow velocity：4.0mL/min；
Split ratio：50:1；
Sampling volume：1μL；
Column temperature rise program：
。
Experimental procedure
Take benzylamine appropriate, plus the solution containing the μ g of benzylamine 100 in every 1ml is made in absolute ethyl alcohol dissolving, is used as reference substance solution；Separately
Absolute ethyl alcohol is taken as blank solution.Analyzed by above-mentioned chromatographic condition, record chromatogram.As a result see in accompanying drawing 5, Fig. 5 and protect
The chromatographic peak for staying time 10.398min is benzylamine.
Embodiment 3
Instrument and condition
Chromatograph：The plus gas chromatographs of Shimadzu 2010；
Detector：Flame ionization ditector；
Chromatographic column：The CB capillary chromatographic columns of CP-Sil 8（30m × 0.32mm, 1.00 μm）；
Injector temperature：200℃；
Detector temperature：300℃；
Carrier gas（Nitrogen）Flow velocity：4.2mL/min；
Split ratio：50:1；
Sampling volume：1μL；
Column temperature rise program：
。
Experimental procedure
Take benzylamine appropriate, plus the solution containing the μ g of benzylamine 100 in every 1ml is made in absolute ethyl alcohol dissolving, is used as reference substance solution；Separately
Absolute ethyl alcohol is taken as blank solution.Analyzed by above-mentioned chromatographic condition, record chromatogram.As a result see in accompanying drawing 6, Fig. 6 and protect
The chromatographic peak for staying the min of time 10.347 is benzylamine.
Following items of the present invention to the agomelatine intermediate body about material benzylamine analysis method are verified：
System suitability is tested
Agomelatine intermediate body and appropriate benzylamine are taken, absolute ethyl alcohol sample dissolution is used respectively, is configured to contain in agomelatine
The need testing solution of mesosome and benzylamine.Gas chromatographic analysis is carried out by the chromatographic condition of embodiment 1, chromatogram is recorded.By Fig. 1 ~
Fig. 4 understands that benzylamine peak shape is good on this condition, and separating degree is good between adjacent peak, solvent and agomelatine intermediate body
Other impurities do not disturb the measure of benzylamine.
Sample introduction replica test
Certain density benzylamine need testing solution is taken, by the chromatographic condition of embodiment 1, sample introduction is repeated 6 times, the repetition of method is investigated
Property.It can be added by result, this method sample introduction repeatability is good.
。
Quantitative limit and test limit
Take benzylamine appropriate, it is accurately weighed, absolute ethyl alcohol sample dissolution is used, the stock solution of certain response, then accurate amount is configured to
Take stock solution appropriate, dilute step by step, investigated by the chromatographic condition sample introduction of embodiment 1.Benzylamine quantitative limit and test limit data are as follows
Shown in table：
。
Linearly
Take the impurity benzylamine of agomelatine intermediate body appropriate, it is accurately weighed, dissolved respectively with absolute ethyl alcohol, be configured to benzylamine storage
Standby liquid；Precision measures benzylamine stock solution, and the benzyl of 0.5 μ g/mL, 50 μ g/mL, 105 μ g/mL and 155 μ g/mL concentration is diluted to respectively
Amine need testing solution, each solution is investigated by the chromatographic condition sample introduction of embodiment 1, as a result be see the table below：
。
The degree of accuracy
Take benzylamine appropriate, it is accurately weighed, dissolved respectively with absolute ethyl alcohol, be configured to benzylamine stock solution；Precision measures benzylamine reserve
Appropriate liquid, is diluted with absolute ethyl alcohol, and the accuracy test solution of 85 μ g/mL, 105 μ g/mL and 125 μ g/mL concentration is made into respectively.
Agomelatine intermediate body about 100mg is taken, is dissolved respectively with the accuracy test solution 1mL of above-mentioned various concentrations, is used as difference
The need testing solution of concentration level, each concentration level need testing solution is parallel to prepare 3 parts；Separately take agomelatine intermediate body about
100mg, adds the dissolving of 1mL absolute ethyl alcohols, is used as blank sample solution.Above-mentioned solution is pressed to the chromatographic condition sample introduction of embodiment 1
Investigate, Fig. 4 is 105 μ g/mL need testing solutions（Benzylamine is added in agomelatine intermediate body）Chromatogram, retention time is
10.417min chromatographic peak is benzylamine, and sample introduction result see the table below：
。
Durability
By finely tuning the chromatographic conditions such as injector temperature, flow rate of carrier gas, detector temperature and chromatographic column brand, we further examine
The durability of method is examined.As a result find, this method changes ± 5 DEG C, carrier gas stream to the chromatographic columns of different brands, injector temperature
Fast change ± 0.1mL/min, detector temperature change good tolerance under the conditions of ± 5 DEG C of grades.In different brands chromatographic column, difference
Under the conditions of injector temperature, flow rate of carrier gas and detector temperature, benzylamine retention time can reach effective point without significant changes
From.
Claims (7)
1. a kind of use gas chromatography separation detection agomelatine intermediate body is about the method for material benzylamine, it is characterised in that：
Sample and benzylamine are dissolved from suitable solvent, according to the formation and physic-chemical property of benzylamine, from methyl polysiloxane class color
Compose post and flame ionization ditector.
2. method of separating and assaying according to claim 1, solvent can for ethanol, methanol or DMF,
One or more in dimethyl sulfoxide (DMSO).
3. method of separating and assaying according to claim 1, chromatographic column be selected from brand be Agilent, Phenomenex or
Restek chromatographic column.
4. method of separating and assaying according to claim 1, chromatographic column is that 5% is bonded in polydimethylsiloxanepolymer polymer
The low pole capillary chromatographic column of phenyl.
5. method of separating and assaying according to claim 1, it is characterised in that including following steps：
1）Take agomelatine intermediate body appropriate, plus 100mg containing agomelatine intermediate body in every 1ml is made in absolute ethyl alcohol dissolving
Solution, be used as need testing solution；It is another to take benzylamine appropriate, plus the molten of μ g containing benzylamine 100 in every 1ml is made in absolute ethyl alcohol dissolving
Liquid, is used as reference substance solution；
2）It is 200 ~ 250 DEG C to set injector temperature, and flow rate of carrier gas is 2.0 ~ 4.0mL/min, programmed temperature method, and heating schedule is
60 °C of initial temperature, 2 ~ 8 DEG C of constant temperature is warming up to 220 °C, 1 ~ 5min of constant temperature, detector temperature with 10 ~ 30 °C per minute of speed
For 250 ~ 320 DEG C, split ratio is 10:1~50:1；
3）Take 1）Middle need testing solution and each 1.0~3.0 μ L of reference substance solution, by 2）Chromatographic condition, inject gas chromatograph,
The content of benzylamine in agomelatine intermediate body is calculated using external standard method.
6. method for separating and analyzing according to claim 5, step 2）Described carrier gas is nitrogen or helium.
7. method for separating and analyzing according to claim 5, step 2）Described programmed temperature method, preferably following heating journey
Sequence：
。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710186971.3A CN107085044A (en) | 2017-03-27 | 2017-03-27 | Method of the gas chromatography separation detection agomelatine intermediate body about material |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108445121A (en) * | 2018-03-20 | 2018-08-24 | 常州市盛辉药业有限公司 | A kind of gas chromatography separation determination 2,4- dichloroacetophenones and 2, the method for 6- dichloroacetophenone isomers |
| CN111323524A (en) * | 2020-04-08 | 2020-06-23 | 重庆华森制药股份有限公司 | Propargylamine and impurity detection method thereof |
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| CN101643433A (en) * | 2008-08-05 | 2010-02-10 | 瑟维尔实验室 | New process for the synthesis of agomelatine |
| WO2015033743A1 (en) * | 2013-09-06 | 2015-03-12 | 住友ベークライト株式会社 | Method for preparing labeled sugar chain sample |
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2017
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| US3623840A (en) * | 1969-01-02 | 1971-11-30 | Monsanto Co | Analytical method and apparatus for analysis of labile hydrogen containing compounds |
| CN101643433A (en) * | 2008-08-05 | 2010-02-10 | 瑟维尔实验室 | New process for the synthesis of agomelatine |
| WO2015033743A1 (en) * | 2013-09-06 | 2015-03-12 | 住友ベークライト株式会社 | Method for preparing labeled sugar chain sample |
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|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108445121A (en) * | 2018-03-20 | 2018-08-24 | 常州市盛辉药业有限公司 | A kind of gas chromatography separation determination 2,4- dichloroacetophenones and 2, the method for 6- dichloroacetophenone isomers |
| CN111323524A (en) * | 2020-04-08 | 2020-06-23 | 重庆华森制药股份有限公司 | Propargylamine and impurity detection method thereof |
| CN111323524B (en) * | 2020-04-08 | 2022-04-15 | 重庆华森制药股份有限公司 | Propargylamine and impurity detection method thereof |
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Application publication date: 20170822 |