CN112684026B - Method for detecting purity of oxitinib intermediate - Google Patents
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Abstract
The invention belongs to the technical field of substance purity analysis, and discloses a method for detecting the purity of an oxitinib intermediate. The oxitinib intermediate is N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine, and the detection method adopts a high performance liquid chromatograph to detect, wherein the chromatographic conditions are as follows: gradient elution with mobile phase; the mobile phase comprises a mobile phase A and a mobile phase B; mobile phase a was phosphate buffer and mobile phase B was acetonitrile. The detection method adopts acetonitrile and phosphate buffer solution as mobile phases for gradient elution, can improve the separation effect, and can realize effective separation with known impurities and unknown impurities, wherein the separation degree is more than 1.5; the detection method can be used for rapid and accurate determination, and has the advantages of high sensitivity, good repeatability and high precision.
Description
Technical Field
The invention belongs to the technical field of substance purity analysis, and particularly relates to a method for detecting the purity of an oxitinib intermediate.
Background
Oxitinib (AZD9291) is a high-efficiency selective EGFR mutant inhibitor, and AZD-9291 can be applied to research and develop a non-small cell advanced lung cancer drug and a drug for treating patients with advanced non-small cell lung cancer, and the structural formula of the Oxitinib is shown as a formula (1).
N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (CAS number: 1421372-66-8) is an important intermediate of Oxicitinib (AZD9291), and the purity of the Oxicitinib directly influences the purity of the AZD9291 and the size of impurities, so that the drug effect and quality of the AZD9291 are influenced.
The structural formula of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine is shown in the formula (2). At present, no relevant literature and reports on a purity detection method of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzene triamine are found.
To enhance the quality control of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine, it is desirable to provide a method for testing the purity of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a method for detecting the purity of the oxitinib intermediate, which can quickly, accurately and reliably detect the purity of the oxitinib intermediate.
A method for detecting the purity of an oxitinib intermediate, wherein the oxitinib intermediate is N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine, the method comprising the following steps:
dissolving N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the diluent to obtain a control sample solution;
dissolving a sample to be detected in a diluent to obtain a sample solution to be detected;
taking the control sample solution, detecting by liquid chromatography, and recording a chromatogram map A;
taking the sample solution to be detected, detecting by liquid chromatography, and recording a chromatogram map B;
calculating according to the chromatogram A and the chromatogram B;
the conditions of the liquid chromatography include: gradient elution with mobile phase;
the mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is phosphate buffer solution, and the mobile phase B is acetonitrile.
Preferably, the phosphate buffer is KH2PO4Buffer solution or K2HPO4And (4) a buffer solution.
Further preferably, the phosphate buffer is KH2PO4The buffer solution and the potassium dihydrogen phosphate buffer solution can improve the peak types of the main peak and the impurity peak.
Preferably, the concentration of the phosphate buffer solution is 0.01mol/L-0.05mol/L, and the pH of the phosphate buffer solution is 3.0 +/-0.2.
Preferably, the conditions of the gradient elution are as follows:
0-3 minutes, wherein the volume percent of the mobile phase A in the mobile phase is 85-95%, and the volume percent of the mobile phase B in the mobile phase is 5-15%;
the volume percentage of the mobile phase A in the mobile phase is changed from 85-95% to 25-35% in 3-25 minutes, and the volume percentage of the mobile phase B in the mobile phase is changed from 5-15% to 65-75%;
25-40 minutes, wherein the volume percent of the mobile phase A in the mobile phase is 25-35%, and the volume percent of the mobile phase B in the mobile phase is 65-75%;
the volume percent of the mobile phase A in the mobile phase is changed from 25-35% to 85-95% and the volume percent of the mobile phase B in the mobile phase is changed from 65-75% to 5-15% in 40-43 minutes;
and the volume percentage of the mobile phase A in the mobile phase is 85-95% and the volume percentage of the mobile phase B in the mobile phase is 5-15% in 43-50 minutes.
Further preferably, the conditions of the gradient elution are as follows:
from 0 to 3 minutes, the volume percentage of mobile phase A in the mobile phase is 90 percent, and the volume percentage of mobile phase B in the mobile phase is 10 percent;
3-25 minutes, wherein the volume percentage of the mobile phase A in the mobile phase is changed from 90% to 30%, and the volume percentage of the mobile phase B in the mobile phase is changed from 10% to 70%;
25-40 minutes, wherein the volume percentage of the mobile phase A in the mobile phase is 10%, and the volume percentage of the mobile phase B in the mobile phase is 70%;
from 30% to 90% by volume of mobile phase A in the mobile phase and from 70% to 10% by volume of mobile phase B in the mobile phase, for 40-43 minutes;
and the volume percentage of the mobile phase A in the mobile phase is 90 percent and the volume percentage of the mobile phase B in the mobile phase is 10 percent in 43-50 minutes.
Expressed in a table, i.e. as in table 1:
TABLE 1
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 3 | 90 | 10 |
| 25 | 30 | 70 |
| 40 | 30 | 70 |
| 43 | 90 | 10 |
| 50 | 90 | 10 |
Preferably, the flow rate of the mobile phase is 0.7-1.2 mL/min; further preferably, the flow rate of the mobile phase is 0.7-1.0 mL/min; more preferably, the flow rate of the mobile phase is 0.8 mL/min.
Preferably, the concentration of said N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in said control sample solution is 0.15-0.4 mg/mL; the concentration of the to-be-tested N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the to-be-tested sample solution is 0.15-0.4 mg/mL.
Further preferably, the concentration of said N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in said control sample solution is 0.2-0.3 mg/mL; the concentration of the to-be-tested N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the to-be-tested sample solution is 0.2-0.3 mg/mL.
More preferably, the concentration of said N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in said control sample solution is 0.25 mg/mL; the concentration of the to-be-tested N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the to-be-tested sample solution is 0.25 mg/mL.
Preferably, the diluent comprises acetonitrile, further preferably, the diluent consists of acetonitrile and water, and more preferably, the volume ratio of acetonitrile to water in the diluent is (1-2): (1-2); most preferably, the volume ratio of acetonitrile to water in the dilution is 1: 1.
Preferably, the calculating step is: and comparing the chromatogram A with the chromatogram B, and taking peaks with consistent retention time to calculate according to an area normalization method.
Preferably, the conditions of the liquid chromatography further comprise: the chromatographic column is selected from Kromasil 100-C18, chiralcel AD column or Phenomenex Luna 5u C18(2)100A column; detection wavelength: 270nm +/-10 nm; column temperature: 35 +/-5 ℃; temperature of the sample pan: 5 +/-2 ℃; a detector: and an ultraviolet detector.
The application of the detection method in preparing the oxitinib.
Further preferably, the chromatographic column is Kromasil 100-C18, and the specification is as follows: 4.6 x 250mm, 3.5 μm.
Compared with the prior art, the invention has the following beneficial effects:
(1) the detection method provided by the invention adopts acetonitrile and phosphate buffer solution as mobile phases for gradient elution, can improve the separation effect, and can realize effective separation of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzene triamine and known impurities and unknown impurities, and the separation degree is more than 1.5.
(2) The detection method provided by the invention can be used for rapid and accurate determination, and has the advantages of high sensitivity, good repeatability and high precision.
Drawings
FIG. 1 is a high performance liquid chromatography of the adaptive solution of the system of example 1;
FIG. 2 is a HPLC chromatogram obtained by the first test of the sample solution to be tested in example 1;
FIG. 3 is a HPLC chromatogram of a second test of the sample solution to be tested in example 1;
FIG. 4 is a HPLC chromatogram of a third test of the sample solution to be tested in example 1;
FIG. 5 is a HPLC chromatogram of the sample solution to be tested in example 2;
FIG. 6 is a HPLC chromatogram of the sample solution to be tested in example 3;
FIG. 7 is a HPLC chromatogram of a sample solution to be tested in example 4.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.
The starting materials, reagents or apparatuses used in the following examples are conventionally commercially available or can be obtained by conventionally known methods, unless otherwise specified.
Example 1
Taking the first produced N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate) product as a sample 1 to be detected, and detecting according to the following detection method:
1. conditions of liquid chromatography
A chromatographic column: kromasil 100-C18(4.6 x 250mm, 3.5 μm) and equivalent chromatography columns
Sample introduction amount: 15 μ l
Flow rate: 0.8mL/min
Column temperature: 35 deg.C
Detection wavelength: 270nm
Temperature of the sample pan: 5 deg.C
Operating time: 50min
Mobile phase: mobile phase A is KH2PO4 buffer (0.05 mol/L, pH 3.0. + -. 0.05 with phosphoric acid);
mobile phase B of acetonitrile
Diluting liquid: acetonitrile: 1:1 of water
A detector: ultraviolet detector
The quantitative method comprises the following steps: area normalization method
The mobile phase gradients are shown in table 1.
2: blank test: and precisely measuring 15 mu l of the diluent, injecting the diluent into a liquid chromatograph, and recording a chromatogram. The blank must not be disturbed.
3: preparing a control sample solution: an appropriate amount of a working substance of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine was taken and placed in a volumetric flask, and dissolved and diluted with a diluent to prepare a solution containing 0.025mg per 1mL to obtain a control sample solution.
4: taking a proper amount of a sample to be detected, precisely weighing, and adding a diluent to dilute into a solution containing 0.25mg per 1mL, wherein the solution is used as a sample solution to be detected;
5: and (3) testing the applicability of the system: precisely measuring 15 μ l of the control sample solution, injecting into a liquid chromatograph, and recording chromatogram, wherein the liquid chromatogram is shown in figure 1. The number of theoretical plates should not be less than 1500 calculated as N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine.
6: precisely measuring 15 μ l of sample solution to be measured, injecting into a liquid chromatograph, and recording chromatogram, wherein the liquid chromatogram is shown in figure 2. And deducting a blank test chromatographic peak from the chromatogram of the sample solution to be detected, and respectively calculating according to an area normalization method.
The results of the sample 1 are shown in Table 2:
TABLE 2
By adopting the method, the sample 1 to be detected is taken and detected twice, and the detection result is analyzed.
The liquid chromatogram of the second detection is shown in FIG. 3, and the detection results are shown in Table 3:
TABLE 3
The liquid chromatogram of the third detection is shown in FIG. 4, and the detection results are shown in Table 4:
TABLE 4
Three test results showed that the peak areas of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate) were 99.34%, 99.44%, 99.30%, and RSD% was 0.08%, respectively.
Example 2
Taking the second batch of the produced N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate) product as a sample 2 to be detected, detecting by the same detection method as in example 1, wherein a liquid chromatogram is shown in FIG. 5, and the detection results are shown in Table 5:
TABLE 5
Example 3
Taking the third batch of the produced N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate) product as the sample 2 to be detected, detecting by the same detection method as in example 1, wherein a liquid chromatogram is shown in FIG. 6, and the detection results are shown in Table 6:
TABLE 6
Example 4
Taking the fourth batch of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate) product as the sample 4 to be detected, detecting by the same detection method as in example 1, wherein a liquid chromatogram is shown in FIG. 7, and the detection results are shown in Table 6:
TABLE 6
In tables 1-6:
impurity A: n- (2-dimethylamino-ethyl) -2-methoxy-N-methyl-N- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-yl ] -5-nitro-benzene-1, 4-diamine;
impurity B: n- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) -2-pyrimidinamine;
impurity C: n- (2-dimethylamino-ethyl) -2-methoxy-N-methyl-N- [4- (1H-indol-3-yl) -pyrimidin-2-yl ] -5-nitro-benzene-1, 4-diamine;
impurity D: 5-methoxy-N, N-dimethyl-N- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-yl ] -1,2, 4-benzenetriamine;
impurity E: n- (4-fluoro-2-methoxy-5-aminophenyl) -4- (1-methyl-1H-indol-3-yl) -2-pyrimidinamine;
impurity F: 4, 6-dimethoxy-N- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-yl ] -1, 3-phenylenediamine;
AZD 06: n1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate).
From examples 1 to 4, the detection method provided by the present invention can improve the separation effect, so that N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine (oxitinib intermediate) can be effectively separated from known impurities and unknown impurities, and the separation degree is greater than 1.5. The detection method has the advantages of high sensitivity, good repeatability and high precision.
Claims (8)
1. A method for detecting the purity of an oxitinib intermediate, wherein the oxitinib intermediate is N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine, the method comprising the following steps:
dissolving N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the diluent to obtain a control sample solution;
dissolving a sample to be detected in a diluent to obtain a sample solution to be detected;
taking the control sample solution, detecting by liquid chromatography, and recording a chromatogram map A;
taking the sample solution to be detected, detecting by liquid chromatography, and recording a chromatogram map B;
calculating according to the chromatogram A and the chromatogram B;
the conditions of the liquid chromatography include: gradient elution with mobile phase;
the mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is phosphate buffer solution, and the mobile phase B is acetonitrile;
the conditions of the gradient elution are as follows:
from 0 to 3 minutes, the volume percentage of mobile phase A in the mobile phase is 90 percent, and the volume percentage of mobile phase B in the mobile phase is 10 percent;
3-25 minutes, wherein the volume percentage of the mobile phase A in the mobile phase is changed from 90% to 30%, and the volume percentage of the mobile phase B in the mobile phase is changed from 10% to 70%;
from 25 to 40 minutes, the volume percentage of mobile phase A in the mobile phase is 30 percent, and the volume percentage of mobile phase B in the mobile phase is 70 percent;
from 30% to 90% by volume of mobile phase A in the mobile phase and from 70% to 10% by volume of mobile phase B in the mobile phase, for 40-43 minutes;
from 43 to 50 minutes, the volume percentage of mobile phase A in the mobile phase is 90 percent, and the volume percentage of mobile phase B in the mobile phase is 10 percent;
the adopted chromatographic column is Kromasil 100-C18, and the specification is as follows: 4.6 x 250mm, 3.5 μm;
the concentration of the phosphate buffer solution is 0.01mol/L-0.05mol/L, and the pH value of the phosphate buffer solution is 3.0 +/-0.2.
2. The method according to claim 1, wherein the phosphate buffer is KH2PO4Buffer solution or K2HPO4And (4) a buffer solution.
3. The method of claim 1, wherein the flow rate of the mobile phase is 0.7-1.2 mL/min.
4. The assay of claim 1, wherein the concentration of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the control sample solution is 0.15-0.4 mg/mL; the concentration of N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] -1,2, 4-benzenetriamine in the sample solution to be tested is 0.15-0.4 mg/mL.
5. The detection method according to claim 1, wherein the diluent consists of acetonitrile and water.
6. The detection method according to claim 5, wherein the volume ratio of acetonitrile to water in the diluent is (1-2): (1-2).
7. The detection method according to claim 1, wherein the conditions of the liquid chromatography further comprise: detection wavelength: 270nm +/-10 nm; column temperature: 35 +/-5 ℃; temperature of the sample pan: 5 +/-2 ℃; a detector: an ultraviolet detector.
8. Use of the assay of any one of claims 1-7 in the preparation of oxitinib.
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