CN110305106A - Related substance of a kind of amber love song Ge Lieting and preparation method thereof, analysis method and application - Google Patents
Related substance of a kind of amber love song Ge Lieting and preparation method thereof, analysis method and application Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to it is a kind of there is no literature reported on the related substance L of amber love song Ge Lieting and its preparation, analyzing detecting method and application.The analyzing detecting method can detecte including in relation to 10 kinds of related substances including substance L, separating degree is good, high sensitivity.
Description
Technical field
The present invention relates to field of medicinal chemistry, in particular to the related substance of a kind of amber love song Ge Lieting and its preparation side
Method, analysis method and application.
Background technique
Amber love song Ge Lieting (Trelagliptin succinate) structural formula:
Amber love song Ge Lieting (trade name Zafatek) is that one is the DPP IV of super long effective (DPP-4) suppressions
Preparation, for treating diabetes B, to be taken weekly.New Drug Application is proposed in March, 2014 by Japanese military field, in
On March 26th, 2015 is approved to list in Japan.
Drug itself generally includes the active constituent and related substance of drug, the presence in relation to substance to the quality of product with
And curative effect has great influence.Therefore need to carry out the related substance in raw material detection and effective control.
Starting material, intermediate, polymer, the side reaction product mainly brought into process of production in relation to substance, with
And catabolite in storage etc..And due to the synthesis technology of product difference, the related substance of generation is also different.When rise
When beginning raw material is compound N and compound O, the main related substance of amber love song Ge Lieting is as follows, wherein related substance
B, C, M, I, K, Q are process products, and related substance D is intermediate, and related substance G, J are catabolite, and L is that one kind has no document
The new related substance of report.
Currently, the very more related substance of bent Ge Lieting and analysis method have been disclosed in the prior art.Such as:
CN104237421B discloses the related substance detecting method of a kind of amber love song Ge Lieting and its preparation, flowing
Phase A is phosphate buffer, and Mobile phase B is acetonitrile, Detection wavelength 278nm, but this method has the following problems: (1) this is specially
Any known impurity is not provided in benefit, can not judge the applicability of this method；(2) wavelength parameter of the analysis method is set as
278nm cannot cover all impurity, and by the spectrum figure analysis to each known impurities, certain impurity do not have at that wavelength
UV absorption.
CN106290596A discloses the separation analysis method of amber love song Ge Lieting and its preparation in relation to substance, flowing
Phase A is phosphate buffer (triethylamine of 0.3 volume % is wherein also added), and Mobile phase B is acetonitrile or methanol, mobile phase
The preparation of A is complex, and only detects 3 kinds of impurity, poor for the detection system applicability of plurality of impurities.
CN106526010A discloses the related substance detecting method of a kind of amber love song Ge Lieting and its preparation, flowing
Phase A be ammonium chloride buffer, Mobile phase B be methanol-acetonitrile (15: 85), sample solvent be formic acid water, method specifically for
" impurity III " exploitation does not have applicability for the detection separation of plurality of impurities, and equally exists mobile phase and prepare complicated ask
Topic.
The analysis method of the related substance of a kind of entitled amber love song Ge Lieting of CN106896166A and its preparation, disclosure
The analysis method of the related substance of 11 koji Ge Lieting, with the phosphate-buffered aqueous solution of pH=3.3~3.7 and the body of acetonitrile
Product is mobile phase A than being 88~92:8~12, and the volume ratio with the phosphate-buffered aqueous solution of pH=3.3~3.7 and acetonitrile is
18~22:78~82 are Mobile phase B, it can be seen that the retention time of impurity 11 is 46.276min from table 2 and Figure 13, and have 4
The retention time of a impurity has been more than 40min.This method there are the drawbacks of be: (1) mobile phase A and B be aqueous solvent and
The binary system of organic solvent prepares complex, organic solvent recycling difficulty；(2) elution time is too long, detection separation effect
Rate is lower, and solvent consumption is excessive.
Entitled method of the measurement song Ge Lieting in relation to substance of CN108680678A, discloses 8 kinds of separation in relation to substance,
Mobile phase A is phosphate aqueous solution, and Mobile phase B is acetonitrile, and practical this method is two-part isocratic elution, be unsuitable for various structures,
The elution and separation of the biggish impurity of polarity difference, and this method does not provide corresponding feelings of each impurity with HPLC eluting peak
Condition correspondingly can not also confirm the retention time of every kind of impurity, therefore the analysis method for studying song Ge Lieting other impurities
Reference significance be not very big.
CN105738517B discloses a kind of method in relation to substance in measurement song Ge Lieting piece, 3 implementations of the patent
Mobile phase A is phosphate aqueous solution in example, and Mobile phase B is acetonitrile, and the ratio of Mobile phase B, which has been up in 70%, Fig. 2, to be seen
Its separation for testing 8 kinds of known impurities Yu song Ge Lieting out, all impurity elute within 23 minutes, and elution speed is non-
It is often fast, but there is the retention time of at least five kinds known impurities to concentrate on 20 minutes front and backs as seen from the figure, and these are known miscellaneous
There are also some small peaks between the peak of matter, it cannot be confirmed whether that the peak for having unknown impuritie is covered or produced by the peak of these known impurities
Raw overlapping.Researcher attempts to separation and detection that its method is used for 10 kinds of impurity of the invention, and discovery can generate peak weight
It is folded, it influences to separate.
Method in relation to substance in a kind of entitled measurement amber love song Ge Lieting raw material of CN105699547A, discloses 7 kinds
Detection in relation to substance, mobile phase A and Mobile phase B are the mixed solution of acidic aqueous solution and organic solvent, acid water-soluble
Liquid is trifluoroacetic acid or high chloro acid solution, and with alkali (triethylamine) adjusting solution ph to 3.0, three in the acidic aqueous solution
The percent by volume of fluoroacetic acid or perchloric acid is 0.1%, and mobile phase A is acidic aqueous solution and organic solvent volume ratio is 90: 10
Mixed solution；The mixed solution that Mobile phase B is acidic aqueous solution and organic solvent volume ratio is 40: 60.This method one bright
Aobvious drawback is: the preparation of mobile phase is extremely complex, and one side mobile phase A and B are the two of aqueous solvent and organic solvent
First system, and it also requires pH value is adjusted with alkali.
When using the above-mentioned analysis method detection reported at present containing above-mentioned 10 kinds these samples in relation to substance, institute as above
State, these methods system suitability, ease for use, economy, in terms of there are different problems.Therefore it is badly in need of
A kind of high sensitivity, specificity meet the requirements, and amber can be effectively detected in the preferable analysis method of each separating degree in relation to substance
The related substance of amber love song Ge Lieting raw material and preparation.
On the other hand, the related substance L of the influence amber love song Ge Lieting purity of discovery there is no document report as follows
Road.Therefore it is also required to a kind of synthesis and analysis method, in order to carry out qualitative, quality research in detail to related substance L, and is carried out
Stringent quality control
Summary of the invention
The first object of the present invention is to provide the related substance L of amber love song Ge Lieting a kind of.
The second object of the present invention is to provide the preparation method in relation to substance L.
The third object of the present invention is to provide related comprising 10 kinds of amber love song Ge Lieting including the L in relation to substance
The analysis method of substance.
The fourth object of the present invention is to provide the related substance L having in amber love song Ge Lieting raw material and its preparation
It closes in substance check item as the purposes in relation to substance reference substance.
Above-mentioned purpose is achieved by the following technical solution:
A kind of related substance L of amber love song Ge Lieting, structural formula of compound are as follows:
A kind of preparation method in relation to substance L includes the following steps: with bent Ge Lieting and 2- cyano -5- fluorine bromobenzyl
For raw material, reacted under alkaline condition.
Reaction carries out in reaction dissolvent, and heating stirring is down to room temperature, adds elutriation crystalline substance up to related substance to fully reacting
L。
Further, the alkaline condition is provided by organic base and/or inorganic base, and wherein organic base is selected from triethylamine, three
One or more of methylamine, N- ethyl diisopropylamine, pyridine, picoline, N-methylmorpholine, DBU, inorganic base are selected from alkali gold
Belong to one of hydroxide, alkali carbonate, alkali metal hydrogencarbonate or a variety of, preferably sodium hydroxide, potassium hydroxide, carbon
One of sour potassium, sodium carbonate, sodium bicarbonate, saleratus are a variety of.
Further, the reaction carries out in reaction dissolvent, and the reaction dissolvent is selected from n,N-Dimethylformamide, N-
One of methyl pyrrolidone, dimethyl sulfoxide, methylene chloride, tetrahydrofuran are a variety of, preferably n,N-Dimethylformamide.
A kind of efficient liquid phase (HPLC) analysis method of amber love song Ge Lieting in relation to substance, chromatographic condition are as follows:
Chromatographic column: octadecylsilane chemically bonded silica is the chromatographic column of filler；
Mobile phase: A is the high chloro acid solution of volume ratio 0.04%~0.06%, and B is acetonitrile；
Flow velocity: 0.8~1.3ml/min, preferably 0.8ml/min or 0.9ml/min or 1.0ml/min or 1.1ml/min or
1.2ml/min or 1.3ml/min, more preferable 0.8ml/min or 1.0ml/min；
Detection wavelength: 200-240nm, preferably 200nm or 210nm or 220nm or 230nm or 240nm；
Column temperature: 25 DEG C~35 DEG C, preferably 25 DEG C or 30 DEG C or 35 DEG C, more preferable 25 DEG C or 30 DEG C.
Further, the analysis method can detect in the related substance of 10 kinds of amber love songs Ge Lieting as follows it is a kind of or
It is a variety of, 5 kinds or more or 6 kinds or more or 7 kinds or more or 8 kinds or more or 9 kinds or more or 10 kinds are preferably detected simultaneously,
Further, the analysis method chromatographic column is Agilent Pursuit 3C18, length 150mm, and diameter is
4.6mm, packing material size are 3 μm.
Further, the linear gradient elution program of the analysis method are as follows: 0min, A are 88%~95%；5min, A are
88%~95%；15min, A are 82%~86%；40min, A are 51%~57%；50min, A are 51%~59%；52min,
A is 88%~95%；57min, A are 88%~95%.
Further, the linear gradient elution program of the analysis method are as follows: 0min, A 93%；5min, A 93%；
15min, A are 84%~86%；40min, A are 51%~55%；50min, A 55%；52min, A 93%；57min, A are
93%.
The amber love song Ge Lieting is in relation to substance L in the Related substances separation item of amber love song Ge Lieting and its preparation
As the purposes in relation to substance reference substance.This is easy to get in relation to substance L, and purity is high (being greater than 99.0%), this can be used
Compound carries out quality control to it as reference substance.
Beneficial effects of the present invention:
(1) present invention finds a kind of related substance L of amber love song Ge Lieting, this there is no document report in relation to substance at present
Road；
(2) preparation method is simple by the related substance L provided by the invention, can largely be prepared；
(3) liquid phase analysis method provided by the invention can be quickly detected has comprising 10 kinds including the L in relation to substance
Substance is closed, the analysis method good separating effect, detection limit is low, linear good within the scope of detection limit~1.0% concentration level；
(4) inspection of the related substance provided by the invention that can be used for amber love song Ge Lieting and its preparation in relation to substance L
It looks into, further increases the quality standard of amber love song Ge Lieting and its preparation, improve its safety and controllability.
Detailed description of the invention
HPLC map of Fig. 1 amber love song Ge Lieting in relation to substance I.
HPLC map of Fig. 2 amber love song Ge Lieting in relation to substance Q.
The HPLC map of Fig. 3 song Ge Lieting.
HPLC map of Fig. 4 amber love song Ge Lieting in relation to substance K.
HPLC map of Fig. 5 amber love song Ge Lieting in relation to substance G.
HPLC map of Fig. 6 amber love song Ge Lieting in relation to substance B.
HPLC map of Fig. 7 amber love song Ge Lieting in relation to substance L.
HPLC map of Fig. 8 amber love song Ge Lieting in relation to substance D.
HPLC map of Fig. 9 amber love song Ge Lieting in relation to substance C.
HPLC map of Figure 10 amber love song Ge Lieting in relation to substance J.
HPLC map of Figure 11 amber love song Ge Lieting in relation to substance M.
Each HPLC map in relation to substance and amber love song Ge Lieting mixed solution of Figure 12.
The HPLC map of Figure 13 blank solvent.
Specific embodiment
Since some have been reported and have studied in the prior art in relation to substance, and related substance L is arranged in amber love song lattice
To separate and identifying for the first time in the research process of spit of fland preparation method, only the synthetic method in relation to substance L is carried out specifically below
It is bright.And it is illustrated by embodiment to synthetic method and analysis method, but the present invention is not limited to the following embodiments.Embodiment
In the person that is not specified actual conditions, according to normal conditions or manufacturer suggests that condition carries out.Production is not specified in agents useful for same or instrument
Manufacturer person is the conventional products that can be obtained by commercially available purchase.
Unless otherwise defined, all professional and scientific terms as used herein and meaning familiar to those skilled in the art
Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong
The preferred implement methods and materials are only done demonstration and are used.
Embodiment 1: preparation of the amber love song Ge Lieting in relation to substance L
By bent Ge Lieting (1.0g, 2.8mmol), 2- cyano -5- fluorine bromobenzyl (0.63g, 2.9mmol), potassium carbonate (0.39g,
It 2.8mmol) is added sequentially in 100mL there-necked flask with DMF (20mL), addition finishes, and system is warming up to 60 DEG C, and in the temperature
Lower stirring 4h, TLC detection display reaction are substantially completely.Water (20mL) is slowly added dropwise into system at room temperature, drips
Finish, continues to stir 1h, filter, filter cake is washed with water and methanol respectively, and is dried in vacuo, and obtains white solid 1.0g, as has
Close substance L, yield 73.0%, purity 99.12%.
Related substance L has carried out structural identification, as a result as follows:
Related substance L:m/z:491.3 [M+H]+。
1H-NMR(DMSO-d6,600MHz),δ:1.27(s,1H,-CH 2-)；1.46(s,1H,-CH 2-)；1.73(s,1H,-
CH 2-)；1.85(s,1H,-CH 2-)；2.39(s,1H,-CH 2-)；2.53(s,1H,-CH-NH)；2.68(s,1H,-CH 2-)；
2.93(s,1H,-CH 2-)；3.10(s,4H,-CH 2-,-CH 3)；3.79-3.66(m,2H,-CH 2-)；5.16(s,2H,-CH 2-)；
5.36 (s, 1H ,=CH-)；7.21-7.19(d,1H,Ar-H)；7.30-7.26(m,2H,Ar-H)；7.37-7.36(d,1H,Ar-H)；7.89-7.86(m,2H,Ar-H)。
Embodiment 2: amber love song Ge Lieting Related substance method-mobile phase influence
The preparation of blank solvent: water: methanol=80%:20% (volume ratio)
The preparation of mixed solution:
Related substance I, Q, K, G, B, L, D, C, J, M are weighed respectively and amber love song Ge Lieting is appropriate, and are separately added into sky
White solvent dissolves and is quantitatively diluted to solution of every 1ml containing about 0.5mg, as positioning solution.Above-mentioned related substance is measured respectively
It positions solution each 20 μ l and amber love song Ge Lieting and positions solution 1ml, be uniformly mixed, as each in relation to substance and amber love song
The mixed solution of Ge Lieting.
Chromatographic condition:
Chromatographic column: Agilent Pursuit 3C18 (4.6 × 150mm, 3 μm)
Detection wavelength: 220nm
Column temperature: 30 DEG C
Flow velocity: 1.0ml/min
Mobile phase: being 0.05% high chloro acid solution as mobile phase A using volume ratio, using acetonitrile as Mobile phase B；Different lines
Property gradient elution is shown in Table 1~4.
1 gradient elution program of table
| Experiment number | 1 | 2 | 3 | 4 |
| Time (min) | A (%) | A (%) | A (%) | A (%) |
| 0 | 88 | 90 | 93 | 95 |
| 5 | 88 | 90 | 93 | 95 |
| 15 | 84 | 84 | 84 | 84 |
| 40 | 55 | 55 | 55 | 55 |
| 50 | 55 | 55 | 55 | 55 |
| 52 | 88 | 90 | 93 | 95 |
| 57 | 88 | 90 | 93 | 95 |
2 gradient elution program of table
| Experiment number | 5 | 6 | 7 |
| Time (min) | A (%) | A (%) | A (%) |
| 0 | 93 | 93 | 93 |
| 5 | 93 | 93 | 93 |
| 15 | 80 | 82 | 86 |
| 40 | 55 | 55 | 55 |
| 50 | 55 | 55 | 55 |
| 52 | 93 | 93 | 93 |
| 57 | 93 | 93 | 93 |
3 gradient elution program of table
4 gradient elution program of table
| Experiment number | 12 | 13 | 14 | 15 |
| Time (min) | A (%) | A (%) | A (%) | A (%) |
| 0 | 93 | 93 | 93 | 93 |
| 5 | 93 | 93 | 93 | 93 |
| 15 | 84 | 84 | 84 | 84 |
| 40 | 55 | 55 | 55 | 55 |
| 50 | 51 | 53 | 57 | 59 |
| 52 | 93 | 93 | 93 | 93 |
| 57 | 93 | 93 | 93 | 93 |
Above-mentioned each positioning solution and each 20 μ l of mixed solution are measured, liquid chromatograph is injected separately into, according to different elutions
Program records corresponding chromatogram, according to the chromatography of positioning solution and mixed solution that the linear gradient elution condition of experiment 3 measures
Figure is shown in Fig. 1~12, and investigating see the table below 5~8 in relation to the separating degree result between substance under each experiment condition.
5 song Ge Lieting of table and known related substance separating degree investigate result
| Experiment number | 1 | 2 | 3 | 4 |
| Sample ID | Separating degree | Separating degree | Separating degree | Separating degree |
| Related substance I | --- | --- | --- | --- |
| Related substance Q | 46.8 | 58.5 | 51.2 | 43.7 |
| Bent Ge Lieting | 3.2 | 2.9 | 2.9 | 2.9 |
| Related substance K | 9.8 | 9.8 | 9.2 | 8.9 |
| Related substance G | 9.2 | 8.9 | 8.6 | 8.6 |
| Related substance B | 8.6 | 9.2 | 10.0 | 10.4 |
| Related substance L | 12.5 | 11.7 | 9.6 | 10.5 |
| Related substance D | 3.6 | 4.2 | 6.5 | 5.5 |
| Related substance C | 12.3 | 11.9 | 11.4 | 11.2 |
| Related substance J | 6.4 | 6.1 | 5.7 | 5.5 |
| Related substance M | 1.2 | 1.3 | 1.5 | 1.3 |
6 song Ge Lieting of table and known related substance separating degree investigate result
7 song Ge Lieting of table and known related substance separating degree investigate result
| Experiment number | 8 | 9 | 10 | 11 |
| Sample ID | Separating degree | Separating degree | Separating degree | Separating degree |
| Related substance I | --- | --- | --- | --- |
| Related substance Q | 52.6 | 52.3 | 51.8 | 51.5 |
| Bent Ge Lieting | 2.8 | 2.8 | 2.9 | 2.9 |
| Related substance K | 8.9 | 9.0 | 9.4 | 9.7 |
| Related substance G | 8.4 | 8.5 | 8.8 | 9.0 |
| Related substance B | 10.2 | 10.1 | 9.9 | 9.8 |
| Related substance L | 8.8 | 10.6 | 11.3 | 11.9 |
| Related substance D | 7.0 | 5.2 | 4.7 | 4.4 |
| Related substance C | 10.8 | 11.1 | 11.8 | 12.2 |
| Related substance J | 4.4 | 5.0 | 6.4 | 6.9 |
| Related substance M | 1.6 | 1.5 | 1.1 | 0.8 |
8 song Ge Lieting of table and known related substance separating degree investigate result
| Experiment number | 12 | 13 | 14 | 15 |
| Sample ID | Separating degree | Separating degree | Separating degree | Separating degree |
| Related substance I | --- | --- | --- | --- |
| Related substance Q | 52.2 | 52.0 | 52.2 | 51.5 |
| Bent Ge Lieting | 2.8 | 2.9 | 2.9 | 2.8 |
| Related substance K | 9.2 | 9.2 | 9.2 | 9.2 |
| Related substance G | 8.7 | 8.7 | 8.7 | 8.6 |
| Related substance B | 10.0 | 10.0 | 10.0 | 10.0 |
| Related substance L | 11.0 | 10.9 | 10.9 | 10.9 |
| Related substance D | 5.0 | 5.0 | 5.0 | 5.0 |
| Related substance C | 11.5 | 11.4 | 11.4 | 11.5 |
| Related substance J | 5.7 | 5.7 | 5.7 | 5.7 |
| Related substance M | 1.3 | 1.3 | 1.3 | 1.3 |
By 5~8 separating degree result of table it is found that working as gradient elution program range are as follows: when 0min, A is 88%~95%；5min
When, A is 88%~95%；When 15min, A is 82%~86%；When 40min, A is 51%~57%；When 50min, A 53%
~59%；When 52min, A is 88%~95%；When 57min, A is 88%~95%；10 kinds of related substances it is separable, most
Low separating degree also reaches 1.0 or more.
As 15min: when A is 51%~55% when A is 84%~86%, 40min, the separating degree in relation to substance J and M can
Up to 1.2 or more.
Under the condition of gradient elution of experiment 3,7,8,9, the separating degree in relation to substance J and M is up to 1.5 or more.
Embodiment 3: amber love song Ge Lieting Related substance method-flow velocity influence experiment
Experiment 3 is consistent in chromatographic condition and embodiment 2, only changes flow velocity, 20 μ l of mixed solution in Example 2, injection
Liquid chromatograph records chromatogram, and investigating each separating degree result in relation between substance see the table below 9.
9 song Ge Lieting of table and known related substance separating degree investigate result
Note: "/" is no separating degree, and " -- " is that can not calculate separating degree.
Embodiment 4: amber love song Ge Lieting Related substance method-column temperature influence experiment
Experiment 3 is consistent in chromatographic condition and embodiment 2, only changes column temperature, 20 μ l of mixed solution in Example 2, injection
Liquid chromatograph records chromatogram, and investigating each separating degree result in relation between substance see the table below 10.
10 song Ge Lieting of table and known related substance separating degree investigate result
Note: "/" is no separating degree, and " -- " is that can not calculate separating degree.
Embodiment 5: amber love song Ge Lieting Related substance method-mobile phase influence experiment
Experiment 3 is consistent in chromatographic condition and embodiment 2, only changes the configuration proportion of the high chloro acid solution of mobile phase A, takes
20 μ l of mixed solution in embodiment 2 injects liquid chromatograph, records chromatogram, investigates each separating degree knot in relation between substance
Fruit see the table below 11.
11 song Ge Lieting of table and known related substance separating degree investigate result
Embodiment 6: amber love song Ge Lieting Related substance method-specificity experiment
20 μ l of blank solvent described in embodiment 2 is measured, liquid chromatograph is injected, by the chromatostrip of experiment 3 in embodiment 2
Part measurement, records chromatogram, sees Figure 13.Each positioning solution chromatogram and mixed solution chromatogram are shown in Fig. 1-12, and investigation respectively has
The separating degree result closed between substance is shown in table 1 in embodiment 2.
The results show that main peak meets with adjacent separating degree in relation to substance and other in relation to separating degree between substance
Regulation.Therefore, this method is able to satisfy related substance-measuring requirement.
Embodiment 7: amber love song Ge Lieting Related substance method-detection limit experiment
It is appropriate that solution is respectively positioned in accurate measurement 2 mixed solution process for preparation of embodiment respectively, dilutes step by step, 20 μ l is taken to infuse
Enter liquid chromatograph, by the measurement of 3 chromatographic conditions is tested in embodiment 2, chromatogram is recorded, until each peak height in relation to substance peak is about
For three times (S/N=3) of baseline noise signal.Amber love song Ge Lieting and each related substance detection limit are calculated, and when with amber
When amber love song Ge Lieting concentration is calculated as 0.5mg/ml, each related substance minimum detection limit the results are shown in Table 12.The result shows that respectively
Related substance detection limit is below minimum control limit 0.1%, and this law detection sensitivity meets related substance-measuring requirement.
Each related substance detection limit result of table 12
Embodiment 8: amber love song Ge Lieting Related substance method-Linear Experiment
Accurate measurement amber love song Ge Lieting and each related substance positioning solution add blank solvent to be diluted to step by step dense respectively
The horizontal solution for being 1.0%, 0.5%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005% of degree, as linear molten
Liquid.Each 20 μ l of solution injection liquid chromatograph is taken, by the measurement of 3 chromatographic conditions is tested in embodiment 2, is chosen including detection limit
Wherein 8 concentration levels, using concentration as abscissa, using peak area as ordinate, draw standard curve.It the results are shown in Table 13, table
Bright amber love song Ge Lieting and each concentration level in relation to substance solution linear relationship between detection limit~1.0% are good.
13 amber love song Ge Lieting of table and each linear equation in relation to substance
| Title | Slope of standard curve | Linear equation |
| Bent Ge Lieting | 727598 | Y=727598x+4626, R=1.0000 |
| Related substance I | 447462 | Y=447462x -11300, R=1.0000 |
| Related substance Q | 752272 | Y=752272x-7221, R=1.0000 |
| Related substance K | 779092 | Y=779092x -7173, R=1.0000 |
| Related substance G | 711676 | Y=711676x-8403, R=1.0000 |
| Related substance B | 787619 | Y=787619x -6522, R=1.0000 |
| Related substance L | 755801 | Y=755801x+10310, R=1.0000 |
| Related substance D | 856982 | Y=856982x+2431, R=1.0000 |
| Related substance C | 724211 | Y=724211x-6513, R=1.0000 |
| Related substance J | 713271 | Y=713271x-2220, R=1.0000 |
| Related substance M | 834800 | Y=834800x-16740, R=0.9996 |
Claims (10)
1. a kind of related substance L of amber love song Ge Lieting, structural formula of compound are as follows:
2. a kind of prepare method of the amber love song Ge Lieting in relation to substance L described in claim 1, which is characterized in that the method
The following steps are included: being reacted under alkaline condition using bent Ge Lieting and 2- cyano -5- fluorine bromobenzyl as raw material.
3. the preparation method according to claim 2 in relation to substance L, which is characterized in that the alkaline condition is by organic base
And/or electrodeless alkali carries supply, wherein organic base is selected from triethylamine, trimethylamine, N- ethyl diisopropylamine, pyridine, picoline, N- first
One or more of base morpholine, DBU, inorganic base are selected from alkali metal hydroxide, alkali carbonate, alkali metal hydrogencarbonate
One of or a variety of, preferably one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus
Or it is a variety of.
4. the preparation method according to claim 2 in relation to substance L, it is characterised in that: the reaction is in reaction dissolvent
It carries out, the reaction dissolvent is selected from n,N-Dimethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide, methylene chloride, tetrahydro furan
It one of mutters or a variety of, preferably n,N-Dimethylformamide.
5. a kind of high efficient liquid phase analysis method of the amber love song Ge Lieting in relation to substance, it is characterised in that:
Chromatographic column: octadecylsilane chemically bonded silica is the chromatographic column of filler；
Mobile phase: A is the high chloro acid solution of volume ratio 0.04%~0.06%, and B is acetonitrile；
Flow velocity: 0.8~1.3ml/min, preferably 0.8ml/min or 0.9ml/min or 1.0ml/min or 1.1ml/min or
1.2ml/min or 1.3ml/min, more preferable 0.8ml/min or 1.0ml/min；
Detection wavelength: 200-240nm, preferably 200nm or 210nm or 220nm or 230nm or 240nm；
Column temperature: 25 DEG C~35 DEG C, preferably 25 DEG C or 30 DEG C or 35 DEG C, more preferable 25 DEG C or 30 DEG C.
6. the analysis method according to claim 5 in relation to substance, which is characterized in that the analysis method is detectable as follows
Shown 10 kinds of amber love song Ge Lieting preferably detect 5 kinds or more or 6 kinds or more or 7 kinds in relation to the one or more of substance simultaneously
Above or 8 kinds or more or 9 kinds or more or 10 kinds,
7. the analysis method according to claim 5 in relation to substance, which is characterized in that the analysis method chromatographic column is
Agilent Pursuit 3 C18, length 150mm, diameter 4.6mm, packing material size are 3 μm.
8. the analysis method according to claim 5 in relation to substance, which is characterized in that the analysis method is used as offline
Property gradient elution program: 0min, A be 88%~95%；5min, A are 88%~95%；15min, A are 82%~86%；
40min, A are 51%~57%；50min, A are 51%~59%；52min, A are 88%~95%；57min, A be 88%~
95%.
9. the analysis method according to claim 8 in relation to substance, which is characterized in that the analysis method is used as offline
Property gradient elution program: 0min, A 93%；5min, A 93%；15min, A are 84%~86%；40min, A be 51%~
55%；50min, A 55%；52min, A 93%；57min, A 93%.
10. the related substance L of amber love song Ge Lieting described in claim 1 has amber love song Ge Lieting raw material and its preparation
It closes in substance inspection as the purposes in relation to substance reference substance.
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