CN118225952B - A method for detecting impurities in N-(3-chloropropyl)dibutylamine - Google Patents
A method for detecting impurities in N-(3-chloropropyl)dibutylamine Download PDFInfo
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- ANLMKUQEPXRMGV-UHFFFAOYSA-N n-butyl-n-(3-chloropropyl)butan-1-amine Chemical compound CCCCN(CCCC)CCCCl ANLMKUQEPXRMGV-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 239000012535 impurity Substances 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims description 28
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims abstract description 44
- DMPODMBXLRMZSP-UHFFFAOYSA-N 3-(dibutylamino)propan-1-ol Chemical compound CCCCN(CCCC)CCCO DMPODMBXLRMZSP-UHFFFAOYSA-N 0.000 claims abstract description 21
- HYOAGWAIGJXNQH-UHFFFAOYSA-N 1-bromo-1-chloropropane Chemical compound CCC(Cl)Br HYOAGWAIGJXNQH-UHFFFAOYSA-N 0.000 claims abstract description 20
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000004817 gas chromatography Methods 0.000 claims abstract description 17
- 239000013558 reference substance Substances 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000012488 sample solution Substances 0.000 claims description 21
- 239000000523 sample Substances 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000012088 reference solution Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 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
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 41
- 238000011084 recovery Methods 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract description 2
- 238000004458 analytical method Methods 0.000 abstract 1
- 229940121657 clinical drug Drugs 0.000 abstract 1
- 229960000220 doxazosin mesylate Drugs 0.000 abstract 1
- 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 1
- 238000005516 engineering process Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 17
- 239000007789 gas Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000012085 test solution Substances 0.000 description 7
- 238000005303 weighing Methods 0.000 description 5
- 239000011550 stock solution Substances 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
- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960002919 dronedarone hydrochloride Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- JCERKCRUSDOWLT-UHFFFAOYSA-N 1-bromopropan-1-ol Chemical compound CCC(O)Br JCERKCRUSDOWLT-UHFFFAOYSA-N 0.000 description 1
- -1 N- (3-chloropropyl) dibutylamine (N- (3-Chloropropyl) dibutylamine) Chemical compound 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 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
- 238000011002 quantification Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
本发明涉及药物检测技术领域，具体公开一种N‑(3‑氯丙基)二丁基胺中杂质的检测方法。本发明采用规格为60m×0.53mm×5μm的DB‑624色谱柱对N‑(3‑氯丙基)二丁基胺样品进行气相色谱分析，实现了同时对N‑(3‑氯丙基)二丁基胺中存在的二正丁胺、3‑溴‑1‑丙醇、3‑二丁氨基‑1‑丙醇和溴氯丙烷四种有关物质及其含量的准确检测。该检测方法的专属性强、检测限和定量限低、线性关系良好、回收率高、重复性好、稳定性强、耐用性好，且操作简单快捷，检测成本低，检测结果准确可靠，为监控以N‑(3‑氯丙基)二丁基胺作为甲磺酸多沙唑嗪中间体的质量稳定性和临床用药安全性提供了保证。
The present invention relates to the field of drug detection technology, specifically discloses a detection method for impurities in N-(3-chloropropyl) dibutylamine. The present invention uses a DB-624 chromatographic column with a specification of 60m×0.53mm×5μm to perform gas chromatography analysis on N-(3-chloropropyl) dibutylamine samples, and realizes the accurate detection of four kinds of related substances and their contents of di-n-butylamine, 3-bromo-1-propanol, 3-dibutylamino-1-propanol and bromochloropropane present in N-(3-chloropropyl) dibutylamine at the same time. The detection method has strong specificity, low detection limit and quantitative limit, good linear relationship, high recovery rate, good repeatability, strong stability, good durability, and simple and fast operation, low detection cost, and accurate and reliable detection result, which provides a guarantee for monitoring the quality stability and clinical drug safety of N-(3-chloropropyl) dibutylamine as a doxazosin mesylate intermediate.
Description
Technical Field
The invention relates to the technical field of medicine detection, in particular to a detection method of impurities in N- (3-chloropropyl) dibutylamine.
Background
N- (3-chloropropyl) dibutylamine (N- (3-Chloropropyl) dibutylamine) has a molecular formula of C 11H24 ClN, is colorless to pale yellow liquid, is easy to dissolve in organic solvents, and can be used as a medical intermediate and an organic solvent. During the synthesis of N- (3-chloropropyl) dibutylamine, related substances such as di-N-butylamine, 3-bromo-1-propanol, 3-dibutylamino-1-propanol, and bromochloropropane are inevitably present. When N- (3-chloropropyl) dibutylamine is used as a starting material of dronedarone hydrochloride, the purity directly influences the quality of a finished product, so that the content of related impurities in the N- (3-chloropropyl) dibutylamine needs to be strictly controlled.
At present, no report exists on a detection method of related substances (di-N-butylamine, 3-bromo-1-propanol, 3-dibutylamino-1-propanol and bromochloropropane) in N- (3-chloropropyl) dibutylamine, and in order to accurately detect 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 related substance in N- (3-chloropropyl) dibutylamine.
Disclosure of Invention
In view of the above problems, the present invention provides a method for detecting impurities in N- (3-chloropropyl) dibutylamine, which can simultaneously and accurately detect impurities of di-N-butylamine, 3-bromo-1-propanol, 3-dibutylamino-1-propanol and bromochloropropane in N- (3-chloropropyl) dibutylamine by gas chromatography.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a method for detecting impurities in N- (3-chloropropyl) dibutylamine comprises the following steps:
Preparing a sample solution, namely dissolving an N- (3-chloropropyl) dibutylamine sample in a solvent to obtain the sample solution;
Preparing reference substance solution by dissolving di-n-butylamine reference substance, 3-bromo-1-propanol reference substance, 3-dibutylamino-1-propanol reference substance and bromochloropropane reference substance in 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:
DB-624 chromatographic column with specification of 60m x 0.53mm and packing diameter of 5 μm is adopted;
The temperature-raising program is that the initial temperature is 48-52 ℃, the temperature is maintained for 4-6 min, the temperature is raised to 220-240 ℃ at the speed of 18-22 ℃ per min, and the temperature is maintained for 10-20 min;
the temperature of the sample inlet is 240-260 ℃;
The temperature of the detector is 270-290 ℃.
Compared with the prior art, the method for detecting the impurities in the N- (3-chloropropyl) dibutylamine provided by the invention adopts the DB-624 chromatographic column with the specification of 60m multiplied by 0.53mm multiplied by 5 mu m to carry out gas chromatographic analysis on the N- (3-chloropropyl) dibutylamine sample, thereby realizing the accurate detection of four related substances and the content thereof in the N- (3-chloropropyl) dibutylamine. 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, accurate and reliable detection result, can provide data support for effective control of the quality of N- (3-chloropropyl) dibutylamine in the process of producing the N- (3-chloropropyl) dibutylamine, and provides guarantee for monitoring the quality stability and clinical medication safety of using the N- (3-chloropropyl) dibutylamine as the dronedarone hydrochloride intermediate.
Preferably, the solvent is methanol.
Preferably, the concentration of the sample solution is 18-22 mg/mL.
Preferably, the concentration of the di-n-butylamine in the reference substance solution is 60-120 mug/mL.
Preferably, the concentration of 3-bromo-1-propanol in the reference solution is 60-120 mug/mL.
Preferably, the concentration of 3-dibutylamino-1-propanol in the reference substance solution is 60-120 mug/mL.
Preferably, the concentration of the bromochloropropane in the reference substance solution is 60-120 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 4.5-5.5 mL/min;
The sample injection volume is 0.8-1.2 mu L;
the split ratio is (5-15): 1.
Illustratively, the fixing solution of the DB-624 chromatographic column is 6% cyanopropylphenyl-94% 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 control solution of comparative example 2 of the present invention;
FIG. 6 is a gas chromatogram of the sample solution of comparative example 2;
Wherein, the chromatographic peak 1 is bromochloropropane, the chromatographic peak 2 is di-N-butylamine, the chromatographic peak 3 is 3-bromo-1-propanol, the chromatographic peak 4 is 3-dibutylamino-1-propanol, and the chromatographic peak 5 is N- (3-chloropropyl) dibutylamine.
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 N- (3-chloropropyl) dibutylamine, which comprises the following steps:
(1) And (5) preparing a solution.
Blank solution, methanol.
And (3) respectively taking a proper amount of di-n-butylamine reference substance, 3-bromo-1-propanol reference substance, 3-dibutylamino-1-propanol reference substance and bromochloropropane reference substance, precisely weighing, quantitatively diluting and dissolving with methanol to prepare mixed solutions with 1000 mug in each 1mL to obtain the reference substance storage solution. Namely, the concentration of di-n-butylamine, 3-bromo-1-propanol, 3-dibutylamino-1-propanol and bromochloropropane in the reference stock solution is 1000 mug/mL.
The reference substance solution is prepared by precisely transferring a proper amount of reference substance stock solution, quantitatively diluting with methanol, and preparing mixed solution with each 100 mug of each 1mL of mixed solution to obtain the reference substance solution. Namely, the concentrations of di-n-butylamine, 3-bromo-1-propanol, 3-dibutylamino-1-propanol and bromochloropropane in the reference substance solution are all 100 mug/mL.
The test solution is prepared by taking 200mg of N- (3-chloropropyl) dibutylamine sample, precisely weighing, placing in a 10mL volumetric flask, adding methanol for dissolution, and diluting to scale.
Adding standard sample solution, namely taking 200mg of N- (3-chloropropyl) dibutylamine sample, precisely weighing, placing in a 10mL volumetric flask, precisely adding 1mL of the reference stock solution, dissolving with methanol, and calibrating the volume to a scale to obtain the standard sample solution.
(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:
DB-624 column (60 m×0.53mm,5 μm);
the temperature rise program of the gas chromatography is that the initial temperature is 50 ℃ and is maintained for 5min, and the temperature is raised to 230 ℃ at the speed of 20 ℃ per min and is maintained for 15min;
the detector is a hydrogen Flame Ionization (FID) detector, the temperature of the sample inlet is 250 ℃, and the temperature of the detector is 280 ℃;
The carrier gas is nitrogen, and the flow rate is 5mL/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. 1-4, and the separation degree of each impurity in the reference solution is tested, and the test results are shown in table 1. As can be seen from fig. 1 to 4 and table 1, the method for detecting impurities in N- (3-chloropropyl) dibutylamine provided in this example, the blank solvent does not interfere with the detection of each component, the separation degree between each component meets the requirement, and the method specificity is good.
TABLE 1 retention time and separation of impurities in control solutions
| Composition of the components | Retention time min | Degree of separation |
| Methanol | 4.29 | - |
| Bromochloropropane | 12.303 | 75.802 |
| Di-n-butylamine | 12.768 | 6.579 |
| 3-Bromo-1-propanol | 12.942 | 2.524 |
| 3-Dibutylamino-1-propanol | 17.097 | 42.302 |
Methodological verification
Durability test
Control solutions were prepared according to the method of example 1, and 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 detection was performed according to the detection method of example 1, with the detection results shown in tables 2 to 5. As can be seen from tables 2-5, the conditions are changed, and the separation degree of each impurity meets the requirements, so that the detection method of the impurity in the N- (3-chloropropyl) dibutylamine provided by the invention has good durability.
TABLE 2 degree of separation of impurities in control solutions at different onset temperatures
TABLE 3 degree of separation of impurities in control solutions at different heating rates
| Rate of temperature rise | 20°C/min | 18°C/min | 22°C/min |
| Bromochloropropane | 75.819 | 77.115 | 74.503 |
| Di-n-butylamine | 6.58 | 6.755 | 6.34 |
| 3-Bromo-1-propanol | 2.543 | 2.564 | 2.511 |
| 3-Dibutylamino-1-propanol | 42.099 | 42.816 | 41.4 |
TABLE 4 degree of separation of impurities in control solutions at different sample inlet temperatures
| Temperature of sample inlet | 250°C | 240°C | 260°C |
| Bromochloropropane | 75.819 | 75.67 | 75.551 |
| Di-n-butylamine | 6.58 | 6.57 | 6.578 |
| 3-Bromo-1-propanol | 2.543 | 2.542 | 2.545 |
| 3-Dibutylamino-1-propanol | 42.099 | 41.966 | 42.004 |
TABLE 5 degree of separation of impurities in control solutions at different detector temperatures
| Temperature of detector | 280°C | 270°C | 290°C |
| Bromochloropropane | 75.819 | 75.741 | 75.628 |
| Di-n-butylamine | 6.58 | 6.572 | 6.565 |
| 3-Bromo-1-propanol | 2.543 | 2.542 | 2.545 |
| 3-Dibutylamino-1-propanol | 42.099 | 41.923 | 42.074 |
Limit of detection and limit of quantification test
Accurately weighing a proper amount of di-N-butylamine reference substance, 3-bromo-1-propanol reference substance, 3-dibutylamino-1-propanol reference substance, bromochloropropane reference substance and N- (3-chloropropyl) dibutylamine reference substance, respectively preparing sample solutions with the concentration of 100 mug/mL, detecting according to the chromatographic conditions in the example 1, recording a gas chromatograph, and taking the peak height as the quantitative limit when the peak height is 10 times of the baseline noise and the peak height as the detection limit when the peak height is 3 times of the baseline noise. 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 6-7, the detection method provided by the invention has the characteristics of low detection limit and quantitative limit for detecting the impurities in the N- (3-chloropropyl) dibutylamine, high sensitivity for detecting the impurities in the N- (3-chloropropyl) dibutylamine, and maximum Relative Standard Deviation (RSD) of 6 times of peak area of repeated detection of each impurity, and 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
| Composition of the components | 1 | 2 | 3 | 4 | 5 | 6 | RSD% |
| Bromochloropropane | 3080 | 3107 | 3101 | 3028 | 3100 | 3110 | 1.01 |
| Di-n-butylamine | 3492 | 3477 | 3490 | 3446 | 3500 | 3528 | 0.77 |
| 3-Bromo-1-propanol | 3439 | 3459 | 3425 | 3466 | 3416 | 3447 | 0.56 |
| 3-Dibutylamino-1-propanol | 4142 | 4116 | 4112 | 4029 | 3985 | 4382 | 3.35 |
| N- (3-chloropropyl) dibutylamine | 5554 | 5642 | 5516 | 5460 | 5339 | 5541 | 1.85 |
Test of Linear relation
And precisely weighing a proper amount of di-N-butylamine reference substance, 3-bromo-1-propanol reference substance, 3-dibutylamino-1-propanol reference substance, bromochloropropane reference substance and N- (3-chloropropyl) dibutylamine reference substance, respectively preparing 10 concentration-level 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 by taking the concentration of components in the sample solutions as an abscissa and the peak area as an ordinate, and establishing a linear equation, wherein the final test result is shown in tables 8-12. As can be seen from the data in tables 8 to 12, in the detection method provided by the invention, the concentrations of N- (3-chloropropyl) dibutylamine and impurities thereof have a good linear relationship with the peak area measured by gas chromatography.
TABLE 8 Linear relationship test results of di-n-butylamine
Table 9 3 Linear relation test results of bromo-1-propanol
TABLE 10 test results of the linear relationship of 3-dibutylamino-1-propanol
TABLE 11 test results of the linear relationship of bromochloropropane
TABLE 12 test results of Linear relationship of N- (3-chloropropyl) dibutylamine
Recovery test
A control stock solution was prepared as in example 1. 200mg of N- (3-chloropropyl) dibutylamine sample is taken, precisely weighed, placed in a 10mL volumetric flask, added with a proper amount of methanol for dissolution, prepared in parallel to 9 parts, respectively added with a reference substance storage solution to enable the concentration of each impurity to be respectively in three levels of low, medium and high and 3 parts in parallel, and subjected to constant volume to scale by using methanol, and uniformly shaken to serve 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 impurities in the N- (3-chloropropyl) dibutylamine samples are shown in tables 13-16. From tables 13-16, the recovery rate of each impurity is 89% -106% under 3 different addition amounts, and the maximum RSD is 7.03%, which shows that the detection method provided by the invention has good accuracy.
TABLE 13 recovery of di-n-butylamine
TABLE 14 recovery of 3-bromo-1-propanol
TABLE 15 recovery of 3-Dibutylamino-1-propanol
TABLE 16 recovery of bromochloropropane
Repeatability test
6 Groups of N- (3-chloropropyl) dibutylamine samples in the same batch are taken, a test solution is prepared according to the method in the example 1, and samples are injected according to the chromatographic conditions in the example 1, so that the content of each impurity in the N- (3-chloropropyl) dibutylamine samples in different groups is detected respectively, 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 N- (3-chloropropyl) dibutylamine sample in the same batch, and has basically consistent detection results and good repeatability.
Table 17 results of repeated measurement of the impurity contents (%)
Solution stability test
A control solution and a test solution were prepared according to the method of example 1, and after being left at room temperature for 0h, 2h, 4h, 8h, 15h and 26h, respectively, gas chromatography was performed under the chromatographic conditions of example 1, and the stability test results of the solutions are shown in tables 18 to 19. As can be seen from tables 18-19, the same method is adopted for detection within 26 hours at room temperature, the obtained results are basically consistent, namely, the Relative Standard Deviation (RSD) of the peak areas of all impurities of the reference substance solution is less than 2%, the Relative Standard Deviation (RSD) of the peak areas of all impurities of the test substance solution is less than 8%, no obvious difference exists in the detection results, and the stability of the reference substance solution and the test substance solution prepared by the method is good.
TABLE 18 stability of control solutions (peak area)
TABLE 19 stability of sample solutions (peak area)
Comparative example 1
This comparative example provides a method for detecting impurities in N- (3-chloropropyl) dibutylamine, similar to example 1, except that the chromatographic column is replaced with an HP-5 chromatographic column (30 m×0.53mm,3 μm; 5% phenyl-95% dimethylpolysiloxane as the fixing solution), and the other conditions are the same as example 1, and will not be repeated.
In this comparative example, the peak response of the sample solution was significantly reduced, and the peak response values of the main component and the respective impurities were significantly reduced.
Comparative example 2
The comparative example provides a method for detecting impurities in N- (3-chloropropyl) dibutylamine, which is similar to the embodiment 1, and is different in that a heating program of ① gas chromatography is that the initial temperature is 50 ℃, the temperature is maintained for 5min, the temperature is raised to 150 ℃ at the speed of 20 ℃ per min and is maintained for 15min, the temperature of a ② sample inlet is 140 ℃, the temperature of a detector is 250 ℃, and other conditions are the same as the embodiment 1 and are not repeated.
As shown in the figures 5-6, the gas chromatograms of the comparative example show that the peak shape of di-n-butylamine is trailing, the response is obviously reduced, and the detection accuracy cannot reach the level of the 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 impurity in the N- (3-chloropropyl) dibutylamine is characterized by comprising the following steps of:
Preparing a sample solution, namely dissolving an N- (3-chloropropyl) dibutylamine sample in a solvent to obtain the sample solution;
Preparing reference substance solution by dissolving di-n-butylamine reference substance, 3-bromo-1-propanol reference substance, 3-dibutylamino-1-propanol reference substance and bromochloropropane reference substance in 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:
DB-624 chromatographic column with specification of 60m x 0.53mm and packing diameter of 5 μm is adopted;
The temperature-raising program is that the initial temperature is 48-52 ℃, the temperature is maintained for 4-6 min, the temperature is raised to 220-240 ℃ at the speed of 18-22 ℃ per min, and the temperature is maintained for 10-20 min;
the temperature of the sample inlet is 240-260 ℃;
The temperature of the detector is 270-290 ℃.
2. The method for detecting an impurity in N- (3-chloropropyl) dibutylamine according to claim 1, wherein the solvent is methanol.
3. The method for detecting an impurity in N- (3-chloropropyl) dibutylamine according to claim 1, wherein the concentration of the sample solution is 18-22 mg/mL.
4. The method for detecting impurities in N- (3-chloropropyl) dibutylamine as claimed in claim 1, wherein the concentration of di-N-butylamine in the reference solution is 60-120. Mu.g/mL, and/or
The concentration of the 3-bromo-1-propanol in the reference substance solution is 60-120 mug/mL.
5. The method for detecting an impurity in N- (3-chloropropyl) dibutylamine as claimed in claim 1, wherein the concentration of 3-dibutylamino-1-propanol in the reference solution is 60 to 120. Mu.g/mL, and/or
The concentration of the bromochloropropane in the reference substance solution is 60-120 mug/mL.
6. The method for detecting impurities in N- (3-chloropropyl) dibutylamine according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise that the detector is a hydrogen flame ionization detector.
7. The method for detecting impurities in N- (3-chloropropyl) dibutylamine according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise that the carrier gas is nitrogen.
8. The method for detecting impurities in N- (3-chloropropyl) dibutylamine according to claim 7, wherein the flow rate of the nitrogen is 4.5-5.5 mL/min.
9. The method for detecting impurities in N- (3-chloropropyl) dibutylamine according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise a sample injection volume of 0.8-1.2. Mu.L.
10. The method for detecting an impurity in N- (3-chloropropyl) dibutylamine according to claim 1, wherein the chromatographic conditions of the gas chromatography further include a split ratio of (5 to 15): 1.
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