CN115792028A - Detection method for related substances of diethyl malonate - Google Patents
Detection method for related substances of diethyl malonate Download PDFInfo
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- CN115792028A CN115792028A CN202211623590.4A CN202211623590A CN115792028A CN 115792028 A CN115792028 A CN 115792028A CN 202211623590 A CN202211623590 A CN 202211623590A CN 115792028 A CN115792028 A CN 115792028A
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- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 title claims abstract description 42
- 239000000126 substance Substances 0.000 title claims abstract description 10
- 238000001514 detection method Methods 0.000 title claims description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims description 47
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 18
- 239000012085 test solution Substances 0.000 claims description 13
- 238000010828 elution Methods 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 35
- HGINADPHJQTSKN-UHFFFAOYSA-M 3-ethoxy-3-oxopropanoate Chemical compound CCOC(=O)CC([O-])=O HGINADPHJQTSKN-UHFFFAOYSA-M 0.000 abstract description 24
- 238000004458 analytical method Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 31
- 230000014759 maintenance of location Effects 0.000 description 21
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 15
- UVSPVEYCSVXYBB-UHFFFAOYSA-N ethyl 3-amino-3-oxopropanoate Chemical compound CCOC(=O)CC(N)=O UVSPVEYCSVXYBB-UHFFFAOYSA-N 0.000 description 15
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 description 14
- 238000012360 testing method Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000007865 diluting Methods 0.000 description 6
- 239000012088 reference solution Substances 0.000 description 6
- 239000012488 sample solution Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical compound CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
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- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention belongs to the field of drug analysis, and relates to a high performance liquid chromatography analysis method for detecting related substances of diethyl malonate. The method overcomes the defect that the conventional gas phase method cannot accurately measure the impurity monoethyl malonate, can effectively separate and detect a plurality of impurities in the diethyl malonate, and can be widely used for detecting related substances of the diethyl malonate.
Description
Technical Field
The invention belongs to the field of drug analysis, and relates to a high performance liquid chromatography analysis method for detecting related substances of diethyl malonate.
Background
Diethyl malonate is a medicine, spice and dye intermediate, can be used for preparing hypnotic barbital, antiepileptic valproic acid and the like, and has the following structural formula:
the industrial preparation method of diethyl malonate takes chloroacetic acid as a starting material, and a target product diethyl malonate is obtained by a one-pot method of substitution, hydrolysis and esterification, and the reaction equation is as follows:
in the preparation process of diethyl malonate, monoethyl malonate, ethyl cyanoacetate, ethyl 3-amino-3-oxopropionate, diethyl 2-methylmalonate, etc. (related impurity structures are shown below) are easily introduced, which can affect the quality of subsequent products. Diethyl malonate is used as a medical intermediate, and the quality of diethyl malonate directly influences the quality and safety of medicines. Therefore, the method is particularly important for detecting impurities in diethyl malonate.
The detection methods of related substances of diethyl malonate reported in the prior literature are all gas phase methods. However, in actual gas-phase detection, it is found that the impurity monoethyl malonate in diethyl malonate undergoes ester exchange and decarboxylation under the action of high temperature of a gas-phase sample inlet to generate diethyl malonate and ethyl acetate, so that the content detection of monoethyl malonate is inaccurate, and the quality control requirement of diethyl malonate cannot be met.
Disclosure of Invention
1. Solves the technical problem
The related substances of the diethyl malonate are detected by adopting the existing gas phase method, so that the impurity monoethyl malonate in the diethyl malonate generates ester exchange and decarboxylation to generate diethyl malonate and ethyl acetate, and the content of the monoethyl malonate cannot be accurately determined. In addition to monoethyl malonate, diethyl malonate also contains impurities such as ethyl cyanoacetate, ethyl 3-amino-3-oxopropionate, diethyl 2-methylmalonate, and the like. In order to better control the quality of diethyl malonate, a related substance detection method capable of accurately detecting the content of diethyl malonate and detecting other various impurities at one time is urgently needed.
2. Technical scheme
The invention provides a high performance liquid chromatography analysis method for detecting related substances of diethyl malonate, which is characterized by comprising the following steps of:
(1) Taking a sample to be detected, and preparing a test solution;
(2) Taking a test solution, detecting by using a high performance liquid chromatograph, wherein the chromatographic conditions are as follows:
a chromatographic column: a chromatographic column with octadecylsilane chemically bonded silica as a filler and terminated end;
detection wavelength: 200-220 nm;
the mobile phase composition is as follows: a mobile phase A: phosphoric acid solution, mobile phase B: acetonitrile;
gradient elution was used:
preferably, the chromatographic column in the step (2) is a chromatographic column adopting octadecylsilane bonded silica gel with a terminal end cap as a filler.
Preferably, the length of the chromatographic column is 150-250 mm.
Preferably, the concentration of the phosphoric acid solution in the step (2) is 0.05-0.25%.
Preferably, the concentration of the phosphoric acid solution in the step (2) is 0.1-0.2%.
Preferably, the flow rate of the mobile phase in the step (2) is 0.6-1.2 ml/min.
Preferably, the flow rate of the mobile phase in the step (2) is 0.8-1.0 ml/min.
Preferably, the gradient elution procedure described in step (2) is as follows:
preferably, the detection wavelength in step (2) is 205-215 nm.
3. Advantageous effects
The invention has the beneficial effects that: (1) The method can accurately and quantitatively detect the impurity of the monoethyl malonate in the diethyl malonate; (2) The method can detect the impurities such as monoethyl malonate, ethyl cyanoacetate, ethyl 3-amino-3-oxopropionate, diethyl 2-methylmalonate and the like in diethyl malonate at one time; (3) The method has high sensitivity, can detect impurities with the content level of 0.05 percent (g/g) in a test sample, has high separation degree of each spectral peak, does not interfere with each other, has good peak shape, ensures the accuracy of the result, and can completely meet the quality control requirement of diethyl malonate.
Drawings
FIG. 1: high performance liquid chromatogram of the test sample in example 1
FIG. 2 is a drawing: high performance liquid chromatogram of the test sample in example 2
FIG. 3 is a drawing: high performance liquid chromatogram of the test sample in example 3
FIG. 4 is a drawing: high performance liquid chromatogram for quantitation limit in example 4
FIG. 5: high performance liquid chromatogram of control in example 5
FIG. 6: high performance liquid chromatogram of test sample in example 5
FIG. 7: high performance liquid chromatogram for labeling test sample in example 5
FIG. 8: gas chromatogram for locating malonic acid monoethyl ester in comparative example 1
Detailed Description
The invention will now be further illustrated by way of the following examples, which are provided only to illustrate the present application and are not intended to limit the invention thereto.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; as used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The reagents and instruments used in the examples are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Liquid chromatography conditions:
and (3) chromatographic column: asahi XYTIMATE C18 (4.6 mm. Times.250mm, 5 μm);
mobile phase: a mobile phase A:0.2% phosphoric acid solution, mobile phase B: acetonitrile;
adopting a gradient elution mode, and eluting under the following conditions:
flow rate: 1.0ml/min
Detection wavelength: 210nm
Sample introduction amount: 50 μ l
Solution preparation: weighing a proper amount of diethyl malonate, dissolving a small amount of acetonitrile, adding a proper amount of a reference solution of ethyl 3-amino-3-oxopropionate, monoethyl malonate, ethyl cyanoacetate and diethyl 2-methylmalonate, and diluting with a diluent (0.2% phosphoric acid solution) to prepare a solution containing 5-20 mg of diethyl malonate and 0.1-0.5% of impurities (relative to the concentration of the sample) in each 1ml of the solution, wherein the solution is used as a sample solution.
The determination method comprises the following steps: according to the chromatographic condition test, sample introduction is carried out on the test solution, a chromatogram is recorded, the chromatogram of the test solution is shown in figure 1, wherein the retention time of diethyl malonate is 19.473min, the retention time of impurity ethyl 3-amino-3-oxopropionate is 5.263min, the retention time of impurity monoethyl malonate is 10.102min, the retention time of impurity ethyl cyanoacetate is 11.395min, the retention time of impurity diethyl 2-methylmalonate is 22.140min, and the minimum separation degree of a main chromatographic peak is 3.126.
Example 2
Liquid chromatography conditions:
a chromatographic column: xue xu Xitimate C18 (4.6 mm. Times.150mm, 5 μm)
Mobile phase: mobile phase A:0.2% phosphoric acid solution, mobile phase B: acetonitrile;
adopting a gradient elution mode, and eluting under the following conditions:
flow rate: 1.0ml/min
Detection wavelength: 210nm
Sample introduction amount: 20 μ l
Solution preparation: weighing a proper amount of diethyl malonate, dissolving a small amount of acetonitrile, adding a proper amount of a reference solution of ethyl 3-amino-3-oxopropionate, monoethyl malonate, ethyl cyanoacetate and diethyl 2-methylmalonate, and diluting with a diluent (0.2% phosphoric acid solution) to prepare a solution containing 5-20 mg of diethyl malonate and 0.1-0.5% of impurities (relative to the concentration of the sample) in each 1ml of the solution, wherein the solution is used as a sample solution.
The determination method comprises the following steps: according to the chromatographic condition test, sample introduction is carried out on the test solution, a chromatogram is recorded, the chromatogram of the test solution is shown in figure 2, wherein the retention time of diethyl malonate is 18.349min, the retention time of impurity ethyl 3-amino-3-oxopropionate is 3.093min, the retention time of impurity monoethyl malonate is 6.072min, the retention time of impurity ethyl cyanoacetate is 6.893min, the retention time of impurity diethyl 2-methylmalonate is 22.286min, the minimum separation degree of a main chromatographic peak is 3.126, and the retention of impurity ethyl 3-amino-3-oxopropionate is weaker.
Example 3
Chromatographic conditions are as follows:
a chromatographic column: xue xu Xitimate C18 (4.6 mm. Times.150mm, 5 μm)
Mobile phase: mobile phase A:0.2% phosphoric acid solution, mobile phase B: acetonitrile;
adopting a gradient elution mode, and eluting under the following conditions:
flow rate: 1.0ml/min
Detection wavelength: 210nm
Sample introduction amount: 20 μ l
Solution preparation: weighing a proper amount of diethyl malonate, dissolving a small amount of acetonitrile, adding a proper amount of a reference solution of ethyl 3-amino-3-oxopropionate, monoethyl malonate, ethyl cyanoacetate and diethyl 2-methylmalonate, and diluting with a diluent (0.2% phosphoric acid solution) to prepare a solution containing 5-20 mg of diethyl malonate and 0.1-0.5% of impurities (relative to the concentration of the sample) in each 1ml of the solution, wherein the solution is used as a sample solution.
The determination method comprises the following steps: and (3) testing according to the chromatographic conditions, sampling a sample solution, recording a chromatogram, wherein the chromatogram of the sample solution is shown in figure 3, the retention time of diethyl malonate is 19.396min, the retention time of the impurity ethyl 3-amino-3-oxopropionate is 3.713min, the retention time of the impurity monoethyl malonate is 8.145min, the retention time of the impurity ethyl cyanoacetate is 8.145min, the retention time of the impurity diethyl 2-methylmalonate is 22.883min, and the monoethyl malonate and the ethyl cyanoacetate are combined to form peaks and are not separated.
Example 4
Chromatographic conditions are as follows:
a chromatographic column: xue xu Xitimate C18 (4.6 mm. Times.250mm, 5 μm)
Mobile phase: mobile phase A:0.2% phosphoric acid solution, mobile phase B: acetonitrile;
adopting a gradient elution mode, and eluting under the following conditions:
flow rate: 1.0ml/min
Detection wavelength: 210nm
Sample injection amount: 50 μ l
Solution preparation: a limiting solution was prepared by diluting ethyl cyanoacetate with a diluent (0.2% phosphoric acid solution) to 5. Mu.g/ml (0.05% relative to the concentration of the sample), a solution containing ethyl 3-amino-3-oxopropionate (2. Mu.g/ml (0.02% relative to the concentration of the sample), monoethyl malonate (2. Mu.g/ml (0.02% relative to the concentration of the sample), and diethyl 2-methylmalonate (2. Mu.g/ml each (0.02% relative to the concentration of the sample).
The determination method comprises the following steps: according to the chromatographic condition test, the quantitative limiting solution is taken for sample injection, the chromatogram is recorded, and the chromatogram of the test solution is shown in figure 4, wherein the signal-to-noise ratio of the ethyl 3-amino-3-oxopropionate is 92.39, the signal-to-noise ratio of the impurity monoethyl malonate is 18.38, the signal-to-noise ratio of the impurity ethyl cyanoacetate is 25.11, and the signal-to-noise ratio of the impurity diethyl 2-methylmalonate is 42.06, so that the sensitivity of the method is better.
Example 5
Chromatographic conditions are as follows:
a chromatographic column: xue xu Xitimate C18 (4.6 mm. Times.250mm, 5 μm)
Mobile phase: mobile phase A:0.2% phosphoric acid solution, mobile phase B: acetonitrile;
adopting a gradient elution mode, and eluting under the following conditions:
flow rate: 1.0ml/min
Detection wavelength: 210nm
Sample injection amount: 50 μ l
Solution preparation:
control solution: the resulting mixture was diluted with a diluent (0.2% phosphoric acid solution) to prepare solutions containing 0.05mg/ml of ethyl 3-amino-3-oxopropionate, 0.025mg/ml of monoethyl malonate, 0.05mg/ml of ethyl cyanoacetate, and 0.05mg/ml of diethyl 2-methylmalonate, respectively, as control solutions.
Test solution: diluting with diluent (0.2% phosphoric acid solution) to prepare a diethyl malonate solution containing 5 mg/ml-10 mg/ml, and using the solution as a test solution.
Adding a standard solution into a test sample: diluting with a diluent (0.2% phosphoric acid solution) to prepare solutions respectively containing 0.5% (relative to the concentration of the sample) of ethyl 3-amino-3-oxopropionate, ethyl cyanoacetate, diethyl 2-methylmalonate, and 0.25% (relative to the concentration of the sample) of monoethyl malonate as sample-added solutions. 3 parts are prepared in parallel.
The determination method comprises the following steps: according to the chromatographic condition test, a reference solution, a test solution and a sample adding standard solution are sampled, a chromatogram is recorded, the chromatogram of the reference solution is shown in figure 5, the chromatogram of the test solution is shown in figure 6, and a typical chromatogram of the sample adding standard solution is shown in figure 7, wherein the retention time of the impurity ethyl 3-amino-3-oxopropionate in the reference solution is 5.280min, the retention time of the impurity monoethyl malonate is 10.152min, the retention time of the impurity ethyl cyanoacetate is 11.417min, the retention time of diethyl malonate is 19.707min, and the retention time of the impurity diethyl 2-methylmalonate is 22.146min. The recovery of each impurity was calculated according to the external standard method and the results are shown in Table 1.
TABLE 1 recovery rate of sample
Comparative example 1
Gas chromatography conditions:
and (3) chromatographic column: agilent DB-1 (30 m.times.0.53 mm.times.3.0 μm)
Carrier gas: nitrogen gas;
column temperature procedure: maintaining at 100 deg.C for 2min, heating to 180 deg.C at 10 deg.C/min, and maintaining for 10min;
flow rate: 2.0mL/min;
sample inlet temperature: 240 ℃;
detector temperature: 280 ℃;
solution preparation: diluting agent (absolute ethyl alcohol) is used for preparing solution containing 1-2 mg/ml of monoethyl malonate, and the solution is used as positioning solution of monoethyl malonate.
The determination method comprises the following steps: the sample was injected with the positioning solution, and the results are shown in FIG. 8, where the peak of 3.765min was ethyl acetate and 9.564min was diethyl malonate, and the results show that the monoethyl malonate could not be quantitatively determined under the gas chromatography conditions.
Claims (9)
1. A method for detecting related substances of diethyl malonate is characterized by comprising the following steps:
(1) Taking a sample to be detected, and preparing a test solution;
(2) Taking a test solution, detecting by using a high performance liquid chromatograph, wherein the chromatographic conditions are as follows:
a chromatographic column: a chromatographic column with octadecylsilane chemically bonded silica as a filler and terminated end;
detection wavelength: 200-220 nm;
mobile phase composition: mobile phase A: phosphoric acid solution, mobile phase B: acetonitrile;
gradient elution was used, the procedure was as follows:
2. the detection method according to claim 1, wherein the chromatographic column in the step (2) is a chromatographic column using octadecylsilane bonded silica gel which is terminated.
3. The detection method according to claim 1, wherein the concentration of the phosphoric acid solution in the step (2) is 0.05 to 0.25%.
4. The detection method according to claim 1, wherein the flow rate of the mobile phase in the step (2) is 0.6 to 1.2ml/min.
5. The detection method according to claim 1, wherein the gradient elution procedure in step (2) is as follows:
6. the detection method according to claim 1, wherein the detection wavelength in the step (2) is 205 to 215nm.
7. The detection method according to claim 2, wherein the length of the chromatographic column is 150 to 250mm.
8. The detection method according to claim 3, wherein the concentration of the phosphoric acid solution is 0.1 to 0.2%.
9. The detection method according to claim 4, wherein the flow rate of the mobile phase is 0.8 to 1.0ml/min.
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| CN117929615A (en) * | 2024-03-22 | 2024-04-26 | 潍坊德高新材料有限公司 | Qualitative and quantitative analysis method for impurities in cyanoacrylate adhesive |
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