CN117741025A - Method for detecting impurities in ethyl 2,3-dibromopropionate - Google Patents
Method for detecting impurities in ethyl 2,3-dibromopropionate Download PDFInfo
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- CN117741025A CN117741025A CN202410075706.8A CN202410075706A CN117741025A CN 117741025 A CN117741025 A CN 117741025A CN 202410075706 A CN202410075706 A CN 202410075706A CN 117741025 A CN117741025 A CN 117741025A
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- OENICUBCLXKLJQ-UHFFFAOYSA-N ethyl 2,3-dibromopropanoate Chemical compound CCOC(=O)C(Br)CBr OENICUBCLXKLJQ-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 239000012535 impurity Substances 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000013558 reference substance Substances 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 239000012488 sample solution Substances 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 25
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000523 sample Substances 0.000 claims description 19
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 18
- UCDOJQCUOURTPS-UHFFFAOYSA-N ethyl 2-bromoprop-2-enoate Chemical compound CCOC(=O)C(Br)=C UCDOJQCUOURTPS-UHFFFAOYSA-N 0.000 claims description 14
- 238000004817 gas chromatography Methods 0.000 claims description 14
- 239000012085 test solution Substances 0.000 claims description 10
- UJTJVQIYRQALIK-ONEGZZNKSA-N ethyl (e)-3-bromoprop-2-enoate Chemical compound CCOC(=O)\C=C\Br UJTJVQIYRQALIK-ONEGZZNKSA-N 0.000 claims description 8
- 239000012088 reference solution Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- CDZAAIHWZYWBSS-UHFFFAOYSA-N 2-bromoethyl prop-2-enoate Chemical compound BrCCOC(=O)C=C CDZAAIHWZYWBSS-UHFFFAOYSA-N 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000012159 carrier gas Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 34
- 238000011084 recovery Methods 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 4
- 229960000220 doxazosin mesylate Drugs 0.000 abstract description 3
- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 abstract description 3
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 20
- 239000007789 gas Substances 0.000 description 13
- 238000000926 separation method Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- ROXQOUUAPQUMLN-UHFFFAOYSA-N methyl 2,3-dibromopropanoate Chemical compound COC(=O)C(Br)CBr ROXQOUUAPQUMLN-UHFFFAOYSA-N 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- CBTTXLCKHFLDPW-UHFFFAOYSA-N methyl 2,3-dibromoprop-2-enoate Chemical compound COC(=O)C(Br)=CBr CBTTXLCKHFLDPW-UHFFFAOYSA-N 0.000 description 5
- UJTJVQIYRQALIK-ARJAWSKDSA-N ethyl (z)-3-bromoprop-2-enoate Chemical compound CCOC(=O)\C=C/Br UJTJVQIYRQALIK-ARJAWSKDSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000012490 blank solution Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- -1 Ethyl 2,3-dibromopropionate (Ethyl 2, 3-dibromopropionate) Chemical compound 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- RCZNRJVVXOOAHG-UHFFFAOYSA-N ethyl 2,3-dibromoprop-2-enoate Chemical compound CCOC(=O)C(Br)=CBr RCZNRJVVXOOAHG-UHFFFAOYSA-N 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention relates to the technical field of medicine detection, and particularly discloses a method for detecting impurities in ethyl 2, 3-dibromopropionate. According to the invention, a HP-5 chromatographic column with the specification of 30m multiplied by 0.53mm multiplied by 5 mu m is adopted to carry out gas chromatographic analysis on a 2, 3-dibromopropionic acid ethyl ester sample, so that four related substances and the content thereof in the 2, 3-dibromopropionic acid ethyl ester are accurately detected. The detection method has the advantages of strong specificity, low detection limit and quantitative limit, good linear relation, high recovery rate, good repeatability, strong stability, good durability, simple and quick operation, low detection cost and accurate and reliable detection result, and provides guarantee for monitoring the quality stability and clinical medication safety of taking the ethyl 2,3-dibromopropionate as the doxazosin mesylate intermediate.
Description
Technical Field
The invention relates to the technical field of medicine detection, in particular to a method for detecting impurities in ethyl 2, 3-dibromopropionate.
Background
Ethyl 2,3-dibromopropionate (Ethyl 2, 3-dibromopropionate) has a molecular formula of C 5 H 8 Br 2 O 2 Is a water-insoluble chemical substance, and can be used as pharmaceutical intermediate and organic solvent. At present, 2, 3-dibromopropionic acid ethyl ester is synthesized by ethyl acrylate and bromine, and related substances such as ethyl acrylate, 2-bromoethyl acrylate, 3-bromoethyl acrylate, 2, 3-dibromomethyl acrylate and the like are inevitably generated in the synthesis process. When ethyl 2,3-dibromopropionate is used as a doxazosin mesylate intermediate, the purity directly influences the quality of a finished product, so that the content of related impurities in the ethyl 2,3-dibromopropionate needs to be strictly controlled.
At present, no detection method for related substances (ethyl acrylate, ethyl 2-bromoacrylate, ethyl 3-bromoacrylate and methyl 2, 3-dibromoacrylate) in ethyl 2,3-dibromopropionate is reported, and in order to realize accurate detection of the related substances, multiple detection is required, so that the operation process is complicated, and time and labor are wasted. Accordingly, there is a need in the art to provide a detection method capable of accurately detecting a substance of interest in ethyl 2, 3-dibromopropionate.
Disclosure of Invention
In view of the above problems, the present invention provides a method for detecting impurities in ethyl 2,3-dibromopropionate, which can accurately detect impurities ethyl acrylate, ethyl 2-bromoacrylate, ethyl 3-bromoacrylate and methyl 2, 3-dibromoacrylate in ethyl 2,3-dibromopropionate simultaneously by using a gas chromatography.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
the method for detecting the impurities in the ethyl 2,3-dibromopropionate comprises the following steps:
preparation of test solution: dissolving a 2, 3-dibromopropionic acid ethyl ester sample in a solvent to obtain a sample solution;
preparation of a control solution: dissolving ethyl acrylate reference substance, 2-ethyl bromoacrylate reference substance, 3-ethyl bromoacrylate reference substance and 2,3-dibromo methyl acrylate reference substance in a solvent to obtain reference substance solution;
detecting the reference substance solution and the sample solution by adopting a gas chromatography, wherein the chromatographic conditions of the gas chromatography comprise:
an HP-5 chromatographic column with the specification of 30m multiplied by 0.53mm and the filler diameter of 5 mu m is adopted;
the temperature-raising program is as follows: the initial temperature is 38-42 ℃, the temperature is maintained for 4-6 min, the temperature is raised to 210-230 ℃ at the speed of 18-22 ℃/min, and the temperature is maintained for 10-20 min;
the temperature of the sample inlet is 190-210 ℃;
the temperature of the detector is 240-260 ℃.
Compared with the prior art, the method for detecting the impurities in the ethyl 2,3-dibromopropionate provided by the invention adopts the HP-5 chromatographic column with the specification of 30m multiplied by 0.53mm multiplied by 5 mu m to carry out gas chromatographic analysis on the ethyl 2,3-dibromopropionate sample, thereby realizing the accurate detection of four related substances and the content thereof in the ethyl acrylate, the ethyl 2-bromoacrylate, the ethyl 3-bromoacrylate and the methyl 2, 3-dibromoacrylate existing in the ethyl 2, 3-dibromopropionate. The invention improves the peak response intensity of the sample solution and the reference solution by limiting the temperature rise program of the gas chromatograph, the temperature of the sample inlet, the temperature of the detector and other conditions, thereby improving the detection precision. The detection method has the advantages of strong specificity, low detection limit and quantitative limit, good linear relation, high recovery rate, good repeatability, strong stability, good durability, simple and quick operation, low detection cost and accurate and reliable detection result, can provide data support for effective control of the quality of the ethyl 2,3-dibromopropionate in the process of producing the ethyl 2,3-dibromopropionate, and provides guarantee for monitoring the quality stability and clinical medication safety of the ethyl 2,3-dibromopropionate serving as a doxazosin mesylate intermediate.
Preferably, the solvent is dichloromethane.
Preferably, the concentration of the sample solution is 9-11 mg/mL.
Preferably, the concentration of ethyl acrylate in the reference solution is 20-60 mug/mL.
Preferably, the concentration of the 2-bromoethyl acrylate in the reference substance solution is 20-60 mug/mL.
Preferably, the concentration of the 3-bromoethyl acrylate in the reference substance solution is 20-60 mug/mL.
Preferably, the concentration of the 2, 3-dibromomethyl acrylate in the reference solution is 20-60 mug/mL.
Preferably, the chromatographic conditions of the gas chromatography further include:
the detector is a hydrogen flame ionization detector;
the carrier gas is nitrogen, and the flow rate is 2.8-3.2 mL/min;
the sample injection volume is 0.8-1.2 mu L;
the split ratio is (5-15): 1.
Illustratively, the fixative solution for the HP-5 column is 5% phenyl-95% dimethylpolysiloxane.
Drawings
FIG. 1 is a gas chromatogram of a hollow white solution of example 1 of the present invention;
FIG. 2 is a gas chromatogram of the control solution of example 1 of the present invention;
FIG. 3 is a gas chromatogram of a sample solution in example 1 of the present invention;
FIG. 4 is a gas chromatogram of the sample solution labeled in example 1 of the present invention;
FIG. 5 is a gas chromatogram of the sample solution of comparative example 1 of the present invention;
wherein, the chromatographic peak 1 is ethyl acrylate, the chromatographic peak 2 is 2-ethyl bromoacrylate, the chromatographic peak 3 is 3-ethyl bromoacrylate, the chromatographic peak 4 is 2, 3-methyl dibromoacrylate, and the chromatographic peak 5 is 2, 3-ethyl dibromopropionate.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The embodiment provides a method for detecting impurities in ethyl 2,3-dibromopropionate, which comprises the following steps:
(1) And (5) preparing a solution.
Blank solution: dichloromethane.
Control stock solution: and respectively taking a proper amount of ethyl acrylate reference substance, 2-bromoethyl acrylate reference substance, 3-bromoethyl acrylate reference substance and 2, 3-dibromomethyl acrylate reference substance, precisely weighing, quantitatively diluting and dissolving with dichloromethane, and preparing a mixed solution containing 1000 mug of each 1mL to obtain a reference substance stock solution. Namely, the concentration of the ethyl acrylate, the ethyl 2-bromoacrylate, the ethyl 3-bromoacrylate and the methyl 2, 3-dibromoacrylate in the reference stock solution is 1000 mug/mL.
Control solution: and precisely transferring a proper amount of reference substance stock solution, quantitatively diluting with dichloromethane, and preparing mixed solutions containing 50 mug of each 1mL of the mixed solution to obtain a reference substance solution. Namely, the concentrations of ethyl acrylate, ethyl 2-bromoacrylate, ethyl 3-bromoacrylate and methyl 2, 3-dibromoacrylate in the reference solution are 50 mug/mL.
Test solution: taking 100mg of ethyl 2,3-dibromopropionate sample, precisely weighing, placing into a 10mL volumetric flask, adding dichloromethane to dissolve and diluting to a scale, and obtaining a sample solution.
Adding a labeled test sample solution: 200mg of ethyl 2,3-dibromopropionate sample is taken, precisely weighed, placed in a 10mL volumetric flask, precisely added with 1mL of the reference substance stock solution, dissolved by methylene dichloride and fixed to volume to scale, and the standard-added sample solution is obtained.
(2) Detecting the blank solution, the reference solution, the test solution and the labeled test solution by adopting a gas chromatography method. The chromatographic conditions for specific gas chromatography include:
HP-5 column (30 m.times.0.53 mm,5 μm);
the temperature program of the gas chromatograph is: the initial temperature is 40 ℃, the temperature is maintained for 5min, the temperature is increased to 220 ℃ at the speed of 20 ℃/min, and the temperature is maintained for 15min;
the detector is a hydrogen Flame Ionization (FID) detector, the temperature of the sample inlet is 200 ℃, and the temperature of the detector is 250 ℃;
the carrier gas is nitrogen, and the flow rate is 3mL/min;
the sample injection volume is 1 mu L;
the split ratio was 10:1.
The results of the gas chromatograms of the blank solution, the reference solution, the test solution and the labeled test solution are shown in fig. 1 to 4, and the degree of separation of each impurity in the labeled test solution is measured, and the measurement results are shown in table 1. As can be seen from fig. 1 to 4 and table 1, the method for detecting impurities in ethyl 2,3-dibromopropionate provided in this example, the blank solvent did not interfere with the detection of each component, and the degree of separation between each component was satisfactory, and the method specificity was good.
TABLE 1 retention time and separation of impurities in a labeled sample solution
| Special marked test article | Retention time min | Degree of separation |
| Acrylic acid ethyl ester | 9.979 | -- |
| Unknown impurity 1 | 10.163 | 1.76 |
| 2-Bromoacrylic acid ethyl ester | 12.986 | 28.09 |
| Cis-3-bromoacrylic acid ethyl ester | 13.551 | 6.40 |
| Unknown impurity 2 | 14.036 | 5.52 |
| 2, 3-Dibromopropionic acid methyl ester | 14.630 | 5.56 |
| Unknown impurity 3 | 15.056 | 3.44 |
| 2, 3-Dibromopropionic acid ethyl ester | 15.347 | 2.37 |
Durability test
Test solutions were prepared in the same manner as in example 1, and only the initial temperature, the temperature rise rate, the sample inlet temperature and the detector temperature were changed, and single-factor variables were controlled, and the test was performed in the same manner as in example 1, with the test results shown in tables 2 to 5. As can be seen from tables 2 to 5, the separation degree of each impurity meets the requirements by changing each condition, so that the detection method of the impurity in the ethyl 2,3-dibromopropionate provided by the invention has good durability.
TABLE 2 degree of separation of impurities in sample solutions at different onset temperatures
TABLE 3 degree of separation of impurities in sample solutions at different heating rates
| Rate of temperature rise | 20℃/min | 18℃/min | 22℃/min |
| Acrylic acid ethyl ester | 20.84 | 21.68 | 21.07 |
| 2-Bromoacrylic acid ethyl ester | 32.28 | 32.87 | 31.82 |
| Cis-3-bromoacrylic acid ethyl ester | 6.42 | 6.55 | 6.28 |
| 2, 3-Dibromopropionic acid methyl ester | 11.24 | 11.30 | 11.02 |
TABLE 4 degree of separation of impurities in sample solutions at different sample inlet temperatures
| Temperature of sample inlet | 200℃ | 190℃ | 210℃ |
| Acrylic acid ethyl ester | 20.84 | 21.37 | 21.62 |
| 2-Bromoacrylic acid ethyl ester | 32.28 | 32.25 | 32.48 |
| Cis-3-bromoacrylic acid ethyl ester | 6.42 | 6.38 | 6.42 |
| 2, 3-Dibromopropionic acid methyl ester | 11.24 | 11.17 | 11.16 |
TABLE 5 degree of separation of impurities in sample solutions at different detector temperatures
| Temperature of detector | 250℃ | 245℃ | 255℃ |
| Acrylic acid ethyl ester | 20.84 | 20.97 | 21.25 |
| 2-Bromoacrylic acid ethyl ester | 32.28 | 32.41 | 32.40 |
| Cis-3-bromoacrylic acid ethyl ester | 6.42 | 6.42 | 6.39 |
| 2, 3-Dibromopropionic acid methyl ester | 11.24 | 11.19 | 11.17 |
Methodological verification
Limit of detection and limit of quantification test
A proper amount of ethyl acrylate reference substance, 2-bromoethyl acrylate reference substance, 3-bromoethyl acrylate reference substance and 2, 3-dibromomethyl acrylate reference substance were precisely weighed, a reference substance solution was prepared in the method of example 1, and detection was carried out in accordance with the chromatographic conditions in example 1, and a gas chromatograph was recorded, with a peak height of 10 times the baseline noise being the quantitative limit and a peak height of 3 times the baseline noise being the detection limit. The test results of the quantitative limit and the detection limit are shown in Table 6, and the test results of the reproducibility of the quantitative limit are shown in Table 7. As can be seen from tables 6 to 7, the detection method provided by the invention has the characteristics of low detection limit and low quantitative limit for detecting the impurities in the ethyl 2,3-dibromopropionate and high sensitivity for detecting the impurities in the ethyl 2, 3-dibromopropionate; the maximum Relative Standard Deviation (RSD) of the peak area of each impurity measured repeatedly for 6 times is 2.21%, which shows that the detection method provided by the invention has good quantitative limit repeatability.
TABLE 6 quantitative limit and detection limit test results
TABLE 7 quantitative limit repeatability test results
Test of Linear relation
Precisely weighing a proper amount of ethyl acrylate reference substance, 2-bromoethyl acrylate reference substance, 3-bromoethyl acrylate reference substance, 2, 3-dibromomethyl acrylate reference substance and 2, 3-dibromoethyl propionate reference substance, respectively preparing 8-9 concentration levels of sample solutions, detecting the sample solutions according to the chromatographic conditions in the embodiment 1, measuring the peak area of a gas chromatograph, drawing a standard working curve and establishing a linear equation by taking the concentration of components in the sample solutions as an abscissa and the peak area as an ordinate, and finally testing the results as shown in tables 8-12. From the data in tables 8 to 12, it is understood that the concentration of ethyl 2,3-dibromopropionate and its impurities in the detection method provided by the present invention have a good linear relationship with the peak area measured by gas chromatography.
TABLE 8 test results of the linear relationship of ethyl acrylate
Table 9 2 Linear relation test results of ethyl bromoacrylate
TABLE 10 test results of linear relationship of ethyl 3-bromoacrylate
TABLE 11 test results of the linear relationship of methyl 2,3-dibromopropionate
TABLE 12 test results of the linear relationship of ethyl 2,3-dibromopropionate
Recovery test
A control stock solution was prepared as in example 1. Taking 100mg of ethyl 2,3-dibromopropionate sample, precisely weighing, placing the sample into a 10mL volumetric flask, adding a proper amount of dichloromethane for dissolution, and preparing 9 parts in parallel; adding reference substance stock solution respectively to make the concentration of each impurity be respectively low, medium and high, and 3 parts in parallel; and (3) using dichloromethane to fix the volume to the scale, shaking uniformly, and taking the dichloromethane as a sample solution with recovery rate. The detection was performed according to the detection method and chromatographic conditions in example 1. The recovery rates of the respective impurities in the ethyl 2,3-dibromopropionate samples finally measured are shown in tables 13 to 16. As can be seen from tables 13-16, the recovery rate of each impurity is 98% -106% under 3 different addition amounts, and the maximum RSD is 1.94%, which shows that the detection method provided by the invention has good accuracy.
TABLE 13 recovery of ethyl acrylate
TABLE 14 recovery of ethyl 2-bromoacrylate
TABLE 15 recovery of ethyl 3-bromoacrylate
TABLE 16 recovery of methyl 2,3-dibromopropionate
Repeatability test
6 groups of ethyl 2,3-dibromopropionate samples in the same batch are taken, a sample solution is prepared according to the method in the example 1, and sample injection is carried out according to the chromatographic conditions in the example 1, so that the content of each impurity in the ethyl 2,3-dibromopropionate samples in different groups is respectively detected, and the detection results are shown in Table 17. As can be seen from Table 17, the detection method provided by the invention repeatedly detects the impurity in the same batch of 2, 3-dibromopropionic acid ethyl ester samples, and has basically consistent detection results and good repeatability.
TABLE 17 repeatability test results of the contents of impurities
Solution stability test
A control solution and a test solution were prepared as in example 1, and after being left at room temperature for 0h, 2h, 4h, 8h, 12h, 26h, 35h and 44h, respectively, gas chromatography was performed under the chromatographic conditions in example 1, and the stability test results of the solutions are shown in tables 18 to 19. As can be seen from tables 18 to 19, the control solution is placed at room temperature for 44 hours and detected by the same method, the obtained results are basically consistent, and the Relative Standard Deviation (RSD) of the peak areas of all impurities is less than 4%, which indicates that the stability of the control solution prepared by the invention is good; the sample solution shows new unknown impurity peaks along with the extension of the standing time, and new preparation is suggested.
TABLE 18 stability of control solutions (peak area)
TABLE 19 stability of sample solutions (peak area)
| Impurity(s) | 0h | 2h | 4h | Average value of | RSD％ |
| Ethyl acrylate% | Not detected | Not detected | Not detected | Not detected | - |
| 2-Bromoacrylic acid ethyl ester% | Not detected | Not detected | Not detected | Not detected | - |
| Cis-3-bromoacrylic acid ethyl ester% | 0.066 | 0.065 | 0.066 | 0.066 | 0.88 |
| 2, 3-Dibromopropionic acid methyl ester% | 0.148 | 0.141 | 0.141 | 0.14 | 2.82 |
| Purity% | 99.734 | 99.740 | 99.739 | 99.74 | 0.0032 |
| Other single impurity% | 0.032 | 0.033 | 0.034 | 0.033 | 3.03 |
| Total amount of impurities% | 0.27 | 0.26 | 0.26 | 0.26 | 1.23 |
Comparative example 1
This comparative example provides a method for detecting impurities in ethyl 2,3-dibromopropionate, which is similar to example 1, except that the chromatographic column is replaced with a DB-624 chromatographic column (30 m×0.53mm,3 μm; the fixing solution is 6% cyanopropylphenyl-94% dimethylpolysiloxane), and the other conditions are the same as example 1, and will not be repeated.
As shown in FIG. 5, the gas chromatogram of the comparative example shows a significant decrease in peak form retardation of ethyl 2, 3-dibromoacrylate, as well as in the main component and the peak response values of the impurities.
Comparative example 2
This comparative example provides a method for detecting impurities in ethyl 2,3-dibromopropionate, similar to example 1, except that: (1) the temperature program of the gas chromatograph is: the initial temperature is 40 ℃, the temperature is maintained for 5min, the temperature is increased to 200 ℃ at the speed of 20 ℃/min, and the temperature is maintained for 15min; (2) the temperature of the sample inlet is 120 ℃; other conditions are the same as those of example 1, and will not be described again.
In this comparative example, the peak response of the sample solution was significantly reduced, and the detection accuracy could not reach the level of example 1.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (10)
1. The method for detecting the impurities in the ethyl 2,3-dibromopropionate is characterized by comprising the following steps of:
preparation of test solution: dissolving a 2, 3-dibromopropionic acid ethyl ester sample in a solvent to obtain a sample solution;
preparation of a control solution: dissolving ethyl acrylate reference substance, 2-ethyl bromoacrylate reference substance, 3-ethyl bromoacrylate reference substance and 2,3-dibromo methyl acrylate reference substance in a solvent to obtain reference substance solution;
detecting the reference substance solution and the sample solution by adopting a gas chromatography, wherein the chromatographic conditions of the gas chromatography comprise:
an HP-5 chromatographic column with the specification of 30m multiplied by 0.53mm and the filler diameter of 5 mu m is adopted;
the temperature-raising program is as follows: the initial temperature is 38-42 ℃, the temperature is maintained for 4-6 min, the temperature is raised to 210-230 ℃ at the speed of 18-22 ℃/min, and the temperature is maintained for 10-20 min;
the temperature of the sample inlet is 190-210 ℃;
the temperature of the detector is 240-260 ℃.
2. The method for detecting an impurity in ethyl 2,3-dibromopropionate according to claim 1, wherein the solvent is methylene chloride.
3. The method for detecting an impurity in ethyl 2,3-dibromopropionate according to claim 1, wherein the concentration of the sample solution is 9 to 11mg/mL.
4. The method for detecting an impurity in ethyl 2,3-dibromopropionate according to claim 1, wherein the concentration of ethyl acrylate in the reference solution is 20 to 60 μg/mL; and/or
The concentration of the 2-bromoethyl acrylate in the reference substance solution is 20-60 mug/mL.
5. The method for detecting an impurity in ethyl 2,3-dibromopropionate according to claim 1, wherein the concentration of ethyl 3-bromoacrylate in the reference solution is 20 to 60 μg/mL; and/or
The concentration of the 2, 3-dibromomethyl acrylate in the reference substance solution is 20-60 mug/mL.
6. The method for detecting impurities in ethyl 2,3-dibromopropionate according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise: the detector is a hydrogen flame ionization detector.
7. The method for detecting impurities in ethyl 2,3-dibromopropionate according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise: the carrier gas is nitrogen.
8. The method for detecting an impurity in ethyl 2,3-dibromopropionate according to claim 3, wherein the flow rate of the nitrogen gas is 2.8 to 3.2mL/min.
9. The method for detecting impurities in ethyl 2,3-dibromopropionate according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise: the sample injection volume is 0.8-1.2 mu L.
10. The method for detecting impurities in ethyl 2,3-dibromopropionate according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise: the split ratio is (5-15): 1.
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