CN112684028B - Method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate - Google Patents
Method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate Download PDFInfo
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Abstract
The invention belongs to the technical field of analysis, and discloses a method for detecting the purity of 2- (2-chloro-1-ethylidene) hydrazide methyl formate. The detection method comprises the following steps: dissolving 2- (2-chloro-1-ethylene) hydrazide methyl formate in a 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 a control sample solution, detecting by liquid chromatography, and recording a chromatogram map A; taking a sample solution to be detected, detecting by liquid chromatography, and recording a chromatogram map B; calculating the purity from the chromatogram A and the chromatogram B; the conditions of liquid chromatography include: mobile phase a and mobile phase B; the mobile phase A is phosphate buffer solution and acetonitrile; the mobile phase B is acetonitrile; the volume ratio of the phosphate buffer solution to the acetonitrile in the mobile phase A is (950 +/-8): (50 +/-0.8). The detection method can accurately detect the purity of the 2- (2-chloro-1-ethylidene) hydrazide methyl formate in a sample to be detected.
Description
Technical Field
The invention belongs to the technical field of analysis, and particularly relates to a method for detecting the purity of 2- (2-chloro-1-ethylidene) hydrazide methyl formate.
Background
Aprepitant, also known as acenidazole, is a solid chemical which is gray-white to yellowish crystal-like, and is mainly used for clinically preventing acute and delayed nausea and vomiting in the primary and repeated treatment processes of high-emetic anti-tumor chemotherapy. The CAS number of the methyl 2- (2-chloro-1-ethylene) hydrazide formate is 155742-64-6, the methyl 2- (2-chloro-1-ethylene) hydrazide formate is an important intermediate for producing aprepitant, and the purity and impurity content of the methyl 2- (2-chloro-1-ethylene) hydrazide formate directly influence the purity and impurity content of aprepitant, so that the pharmaceutical efficacy of the aprepitant is directly influenced.
In the process of preparing aprepitant, the purity and impurity content of methyl 2- (2-chloro-1-ethylene) hydrazide formate are particularly important to detect, but related documents and reports of a method for detecting the purity and impurity content of methyl 2- (2-chloro-1-ethylene) hydrazide formate are not found in the prior art. In order to enhance the quality control of the 2- (2-chloro-1-ethylene) hydrazide methyl formate and further control the quality of aprepitant, the method for detecting the purity and impurity content of the 2- (2-chloro-1-ethylene) hydrazide methyl formate is particularly important.
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 2- (2-chloro-1-ethylene) hydrazide methyl formate, which can accurately detect the purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate in a sample to be detected and the content of impurities, and is favorable for preparing high-quality aprepitant. The detection method is simple, convenient, accurate, rapid and reliable, and is beneficial to industrial production of the 2- (2-chloro-1-ethylidene) hydrazide methyl formate. In addition, the detection method can also effectively separate impurities in the sample to be detected. The detection method is qualitative in retention time and quantitative in peak area.
A method for detecting the purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate comprises the following steps:
dissolving 2- (2-chloro-1-ethylene) hydrazide methyl formate in a diluent to obtain a control sample solution;
dissolving a sample to be detected containing 2- (2-chloro-1-ethylidene) hydrazide methyl formate 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 the purity of the 2- (2-chloro-1-ethylene) hydrazide methyl formate in the sample to be detected according to the chromatogram A and the chromatogram B;
the conditions of the liquid chromatography include: the adopted mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is phosphate buffer solution and acetonitrile; the mobile phase B is acetonitrile; the volume ratio of the phosphate buffer solution to the acetonitrile in the mobile phase A is (950 +/-8) to (50 +/-0.8).
Preferably, the phosphate buffer is KH2PO4And (4) a buffer solution.
Preferably, the concentration of the phosphate buffer solution is 0.01-0.1 mol/L; further preferably, the concentration of the phosphate buffer solution is 0.01-0.05 mol/L; a more preferred concentration is 0.02 mol/L.
Preferably, the pH of the phosphate buffer is 3.0 ± 0.1; further preferably, the pH of the phosphate buffer is 3.0 ± 0.05; more preferably, the phosphate buffer has a pH of 3.0. The pH of the phosphate buffer was chosen to help improve the peak profile, which is optimal especially when the pH was 3.0.
Preferably, the diluent is KH2PO4A mixture of buffer and acetonitrile; further preferably, KH in the dilution2PO4The volume ratio of the buffer solution to the acetonitrile is (78-82) to (18-22); a further preferred volume ratio is 80: 20.
Preferably, the concentration of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the control sample solution is 0.1-0.9 mg/mL; further preferably, the concentration of the methyl 2- (2-chloro-1-ethylene) hydrazide formate is 0.4-0.6 mg/mL; more preferably, the concentration of the methyl 2- (2-chloro-1-ethylene) hydrazide formate is 0.5 mg/mL.
Preferably, in the solution of the sample to be detected, the concentration of the sample to be detected is 0.1-0.9 mg/mL; further preferably, the concentration of the sample to be detected is 0.4-0.6 mg/mL; more preferably, the concentration of the sample to be detected is 0.5 mg/mL. The sample to be detected is 2- (2-chloro-1-ethylene) hydrazide methyl formate to be detected in purity. The concentration of the sample to be detected refers to the concentration of the 2- (2-chloro-1-ethylene) hydrazide methyl formate to be detected in the solution.
Preferably, the mobile phase is eluted according to the following concentration gradient during the use process:
0.01 minutes, and the volume of the mobile phase A in the mobile phase accounts for 100 percent;
for 10 minutes, the volume of the mobile phase A in the mobile phase accounts for 85-95%, and the volume of the mobile phase B accounts for 5-15%;
20 minutes, wherein the volume of the mobile phase A in the mobile phase accounts for 75-85%, and the volume of the mobile phase B accounts for 15-25%;
30 minutes, the volume of the mobile phase A in the mobile phase accounts for 65-75%, and the volume of the mobile phase B accounts for 25-35%;
after 40 minutes, the volume of mobile phase a in the mobile phase was 100%.
Preferably, the flow rate of the mobile phase in the detection process by liquid chromatography is 0.8-1.2 mL/min; further preferably 1 mL/min.
Preferably, the chromatographic column in the liquid chromatography detection process is Inertsil ODS-3V (4.6 x 250mm,5 μm) and its equivalent chromatographic column.
Preferably, the chromatographic column temperature of the liquid chromatograph in the detection process by the liquid chromatograph is 28-32 ℃; further preferably 30 ℃.
Preferably, the detection wavelength of the liquid chromatograph in the detection process by the liquid chromatogram is 205-215 nm; further preferably 210 nm.
Preferably, the detection by liquid chromatography is performed by using an ultraviolet detector.
Preferably, the detection method further comprises the following steps of: and detecting the diluent by liquid chromatography, recording a chromatogram C, deducting a chromatogram peak in the chromatogram C from the chromatogram B, and calculating according to an area normalization method. The blank test aims to eliminate the influence caused by the diluent and can further improve the detection accuracy.
Preferably, the dosage of the diluent, the control sample solution or the sample solution to be detected entering the liquid chromatograph is 8-15 μ L; further preferably 8 to 10. mu.L.
Another aspect of the invention provides the use of the above detection method.
The detection method of the methyl 2- (2-chloro-1-ethylene) hydrazide formate is applied to preparation of aprepitant.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the detection method, due to the selection of a proper mobile phase, the purity of the 2- (2-chloro-1-ethylidene) hydrazide methyl formate in the sample to be detected and the content of impurities can be accurately detected, and the preparation of high-quality aprepitant is facilitated.
(2) The detection method disclosed by the invention is beneficial to improving the accuracy of the detection method and improving the detection speed by selecting the elution gradient of the mobile phase. In addition, the detection method is also helpful for separating impurities in the sample to be detected.
(3) The detection method is simple, convenient, accurate, rapid and reliable, and is beneficial to industrial production of the 2- (2-chloro-1-ethylidene) hydrazide methyl formate.
Drawings
FIG. 1 is a chromatogram A obtained in the detection method of example 1;
FIG. 2 is a chromatogram B obtained in the detection method of example 1;
FIG. 3 is a chromatogram B obtained in the detection method of example 2;
FIG. 4 is a chromatogram B obtained in the detection method of example 3;
FIG. 5 is a chromatogram B obtained in the detection method of example 4;
FIG. 6 is a chromatogram B obtained in the detection method of example 5.
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: method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate
A method for detecting the purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate comprises the following steps:
the blank test is as follows: diluting the solution (KH is the diluted solution)2PO4A mixture of buffer and acetonitrile in a volume ratio of 80:20, KH2PO4pH of the buffer was 3) was detected by liquid chromatography, chromatogram C was recorded,
dissolving methyl 2- (2-chloro-1-ethylidene) hydrazide formate in a diluent (the diluent is KH)2PO4A mixture of buffer and acetonitrile in a volume ratio of 80:20, KH2PO4The pH value of the buffer solution is 3) to obtain a control sample solution, wherein the concentration of the 2- (2-chloro-1-ethylene) hydrazide methyl formate in the control sample solution is 0.5 mg/mL;
dissolving a sample 1 to be tested containing 2- (2-chloro-1-ethylene) hydrazide methyl formate in a diluent (the diluent is KH)2PO4A mixture of buffer and acetonitrile according to a volume ratio of 80:20, KH2PO4The pH value of the buffer solution is 3) to obtain a sample solution to be detected, wherein the concentration of a sample to be detected in the sample solution to be detected is 0.5 mg/mL;
taking a control sample solution, detecting by liquid chromatography, and recording a chromatogram map A;
taking a sample solution to be detected, detecting by liquid chromatography, and recording a chromatogram map B;
calculating the purity of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample to be detected according to the chromatogram A, the chromatogram B and the chromatogram C, and calculating the purity and impurity content of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample to be detected 1 by adopting an area normalization method, wherein the results are shown in Table 1;
the conditions of liquid chromatography include: the adopted mobile phase comprises a mobile phase A and a mobile phase B; mobile phaseA is KH2PO4Buffer solution (KH)2PO4The concentration of the buffer solution is 0.02mol/L) and acetonitrile; the mobile phase B is acetonitrile; KH in mobile phase A2PO4The volume ratio of the buffer solution to the acetonitrile is 950: 50;
during the use of the mobile phase, elution is carried out according to the following concentration gradient:
0.01 minutes, and the volume of the mobile phase A in the mobile phase accounts for 100 percent;
10 minutes, wherein the volume of the mobile phase A is 90% and the volume of the mobile phase B is 10%;
20 minutes, wherein the volume of the mobile phase A accounts for 80% and the volume of the mobile phase B accounts for 20%;
30 minutes, wherein the mobile phase A accounts for 70% of the volume, and the mobile phase B accounts for 30% of the volume;
after 40 minutes, the volume of the mobile phase A in the mobile phase accounts for 100 percent;
the flow rate of the mobile phase in the detection process by liquid chromatography is 1 mL/min;
the column was Inertsil ODS-3V (4.6X 250mm,5 μm);
the temperature of a chromatographic column of the liquid chromatograph is 30 ℃;
detecting by using an ultraviolet detector, wherein the detection wavelength is 210 nm;
the dosage of the diluent, the contrast sample solution or the sample solution to be detected entering the liquid chromatograph is 10 mu L.
FIG. 1 is a chromatogram A obtained in the detection method of example 1; "1" in FIG. 1 represents the peak corresponding to methyl 2- (2-chloro-1-ethylene) hydrazide formate (the ordinate "Absorbance" in mAU and the abscissa "Time" in FIG. 1 represents Time in min, i.e., minutes) in FIG. 1.
FIG. 2 is a chromatogram B obtained in the detection method of example 1. "1" in FIG. 2 represents the peak corresponding to methyl 2- (2-chloro-1-ethylene) hydrazide formate, and "2" in FIG. 2 represents the peak corresponding to "maximum single hetero" (the ordinate "Absorbance" in FIG. 2 represents Absorbance in mAU, and the abscissa "Time" represents Time in min, i.e., minutes).
TABLE 1
As can be seen from table 1, the purity of methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 1 to be tested (the purity referred to in the present invention is the mass purity, and the content is the mass content) reaches 99.94%, the maximum single impurity content reaches 0.06%, and the total impurity content reaches 0.06%. (RRT1.68 impurity means description of larger impurity (content. gtoreq.0.10%).
Example 2: method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate
Example 2 is different from example 1 only in that the test sample 1 was replaced with the test sample 2, and the rest of the procedure was the same. The purity and impurity content of methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 2 to be tested were calculated by an area normalization method, and the results are shown in table 2.
FIG. 3 is a chromatogram B obtained in the detection method of example 2. "1" in FIG. 3 represents a peak corresponding to methyl 2- (2-chloro-1-ethylene) hydrazide formate, "4" in FIG. 3 represents a peak corresponding to "maximum single hetero", and "2" and "3" in FIG. 3 represent peaks corresponding to other impurities (the ordinate "Absorbance" in FIG. 3 represents Absorbance in mAU and the abscissa "Time" represents Time in min, i.e., minutes).
TABLE 2
As can be seen from Table 2, the purity of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 2 to be tested reaches 99.73%, the maximum single impurity content reaches 0.10%, and the total impurity content reaches 0.27%.
Example 3: method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate
Example 3 is different from example 1 only in that the test sample 1 was replaced with the test sample 3, and the rest of the procedure was the same. The purity and impurity content of methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 3 to be tested were calculated by an area normalization method, and the results are shown in table 3.
FIG. 4 is a chromatogram B obtained in the detection method of example 3. "1" in FIG. 4 represents the peak corresponding to methyl 2- (2-chloro-1-ethylene) hydrazide formate, and "2" in FIG. 4 represents the peak corresponding to "maximum single hetero" (the ordinate "Absorbance" in FIG. 4 represents Absorbance in mAU, and the abscissa "Time" represents Time in min, i.e., minutes).
TABLE 3
As can be seen from Table 3, the purity of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 3 to be tested reaches 99.93%, the maximum single impurity content reaches 0.07%, and the total impurity content reaches 0.07%.
Example 4: method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate
Example 4 differs from example 1 only in that the test sample 1 was replaced with the test sample 4, and the rest of the procedure was the same. The purity and impurity content of methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 4 to be tested were calculated by an area normalization method, and the results are shown in table 4.
FIG. 5 is a chromatogram B obtained in the detection method of example 4. "1" in fig. 5 represents a peak corresponding to methyl 2- (2-chloro-1-ethylene) hydrazide formate, "2" in fig. 5 represents a peak corresponding to "maximum single impurity," and "3" in fig. 5 represents a peak corresponding to other impurities (the ordinate "Absorbance" in the unit of mAU and the abscissa "Time" in fig. 5 represents Time in the unit of min, i.e., minutes) in fig. 5.
TABLE 4
As can be seen from Table 4, the purity of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the sample 4 to be tested reaches 99.80%, the maximum single impurity content reaches 0.13%, and the total impurity content reaches 0.20%.
The effect of detecting the purity and impurity content of methyl 2- (2-chloro-1-ethylene) hydrazide formate in a sample to be detected in the technical scheme of the present invention is similar to that of examples 1-4, except that the volume ratio of phosphate buffer solution to acetonitrile in the mobile phase a, the specific type of phosphate buffer solution, or some parameters in the liquid chromatography process are changed according to the technical scheme of the present invention.
Example 5
Example 5 differs from example 1 only in the KH used2PO4The pH of the buffer was 7.0. + -. 0.05, and the other components or processes were the same.
FIG. 6 is a chromatogram B obtained in the detection method of example 5. "1" in fig. 6 indicates a peak (purity 99.91%) corresponding to methyl 2- (2-chloro-1-ethylene) hydrazide formate, "3" in fig. 6 indicates a peak corresponding to "maximum single impurity (content 0.05%)", and "2", "4", "5", "6" and "7" in fig. 6 indicate peaks corresponding to other impurities (ordinate "Absorbance" in fig. 6 indicates Absorbance, and abscissa "Time" indicates Time, i.e., min).
Claims (8)
1. A method for detecting the purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate is characterized by comprising the following steps:
dissolving 2- (2-chloro-1-ethylene) hydrazide methyl formate in a diluent to obtain a control sample solution;
dissolving a sample to be detected containing 2- (2-chloro-1-ethylidene) hydrazide methyl formate 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 the purity of the 2- (2-chloro-1-ethylene) hydrazide methyl formate in the sample to be detected according to the chromatogram A and the chromatogram B;
the conditions of the liquid chromatography include: the adopted mobile phase comprises a mobile phase A and a mobile phase B; the mobile phase A is phosphate buffer solution and acetonitrile; the mobile phase B is acetonitrile; the volume ratio of the phosphate buffer solution to the acetonitrile in the mobile phase A is (950 +/-8) to (50 +/-0.8);
during the use of the mobile phase, elution is carried out according to the following concentration gradient:
0.01 minutes, and the volume of the mobile phase A in the mobile phase accounts for 100 percent;
for 10 minutes, the volume of the mobile phase A accounts for 90% and the volume of the mobile phase B accounts for 10%;
20 minutes, wherein the volume of the mobile phase A accounts for 80% and the volume of the mobile phase B accounts for 20%;
30 minutes, wherein the volume of the mobile phase A in the mobile phase accounts for 70 percent, and the volume of the mobile phase B accounts for 30 percent;
after 40 minutes, the volume of the mobile phase A in the mobile phase accounts for 100 percent;
the chromatographic column in the detection process by the liquid chromatogram is Inertsil ODS-3V;
the flow rate of the mobile phase is 0.8-1.2 mL/min;
the detection wavelength of the liquid chromatograph in the process of detecting by liquid chromatogram is 205-215 nm.
2. The method according to claim 1, wherein the phosphate buffer is KH2PO4And (4) a buffer solution.
3. The detection method according to claim 1, wherein the concentration of the phosphate buffer is 0.01 to 0.1 mol/L; the pH of the phosphate buffer solution is 3.0 +/-0.1.
4. The detection method according to claim 1, wherein the diluent is KH2PO4A mixture of buffer and acetonitrile; KH in the dilution2PO4The volume ratio of the buffer solution to the acetonitrile is (78-82) to (18-22).
5. The detection method according to claim 1, wherein the concentration of the methyl 2- (2-chloro-1-ethylene) hydrazide formate in the control sample solution is 0.1-0.9 mg/mL; in the sample solution to be detected, the concentration of the sample to be detected is 0.1-0.9 mg/mL.
6. The detection method according to claim 1, wherein a column temperature of a liquid chromatograph during the detection by liquid chromatography is 28 to 32 ℃; the dosage of the diluent, the contrast sample solution or the sample solution to be detected entering the liquid chromatograph is 8-15 mu L.
7. The detection method according to claim 1, further comprising the step of performing a blank test, wherein the blank test is: detecting the diluent by liquid chromatography, and recording chromatogram map C.
8. Use of the assay of any one of claims 1-7 in the preparation of aprepitant.
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