CN111141849A - Liquid phase detection and separation method for positional isomer of dexmedetomidine starting material - Google Patents
Liquid phase detection and separation method for positional isomer of dexmedetomidine starting material Download PDFInfo
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- 238000001514 detection method Methods 0.000 title claims abstract description 27
- 238000000926 separation method Methods 0.000 title claims abstract description 18
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 title claims abstract description 16
- 229960004253 dexmedetomidine Drugs 0.000 title claims abstract description 16
- 239000007858 starting material Substances 0.000 title claims abstract description 16
- 239000007791 liquid phase Substances 0.000 title claims abstract description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012085 test solution Substances 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 17
- 239000012071 phase Substances 0.000 claims abstract description 16
- 238000010828 elution Methods 0.000 claims abstract description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000945 filler Substances 0.000 claims abstract description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 9
- WJDKWRSEFKVTIE-UHFFFAOYSA-N 1-(2,3-dimethylphenyl)ethanol Chemical compound CC(O)C1=CC=CC(C)=C1C WJDKWRSEFKVTIE-UHFFFAOYSA-N 0.000 claims description 7
- BFLGMBBJIHKTAY-UHFFFAOYSA-N 1-(2,6-dimethylphenyl)ethanol Chemical compound CC(O)C1=C(C)C=CC=C1C BFLGMBBJIHKTAY-UHFFFAOYSA-N 0.000 claims description 4
- WTTSQZZOTXFJJG-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)ethanol Chemical compound CC(O)C1=CC=C(C)C(C)=C1 WTTSQZZOTXFJJG-UHFFFAOYSA-N 0.000 claims description 4
- RHBAJFPGUNNLFA-UHFFFAOYSA-N 1-(3,5-dimethylphenyl)ethanol Chemical compound CC(O)C1=CC(C)=CC(C)=C1 RHBAJFPGUNNLFA-UHFFFAOYSA-N 0.000 claims description 4
- DNHQUGRUHBFDFT-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)ethanol Chemical compound CC(O)C1=CC=C(C)C=C1C DNHQUGRUHBFDFT-UHFFFAOYSA-N 0.000 claims description 3
- VHLZFCOCNJEXTQ-UHFFFAOYSA-N 1-(2,5-dimethylphenyl)ethanol Chemical compound CC(O)C1=CC(C)=CC=C1C VHLZFCOCNJEXTQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 238000005191 phase separation Methods 0.000 claims 2
- -1 1- (2, 3-dimethylphenyl) ethanol compound Chemical class 0.000 claims 1
- 239000012535 impurity Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 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
-
- 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
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- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/36—Control of physical parameters of the fluid carrier in high pressure liquid systems
-
- 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
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
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Abstract
The invention discloses a liquid phase detection separation method of a positional isomer of dexmedetomidine starting material, which comprises the following steps: preparing a test solution from a 1- (2, 3-dimethylbenzene) ethanol compound, injecting the test solution into a high performance liquid chromatograph, and detecting and recording a chromatogram under the following chromatographic conditions: octadecylsilane chemically bonded silica is used as a filling agent; taking 0.1% phosphoric acid water solution as a mobile phase A; taking acetonitrile solution as a mobile phase B; the elution mode is gradient elution; the flow rate is 0.9-1.1 ml/min; the detection wavelength is 215-222 nm; the column temperature is 30-40 ℃. According to the technical scheme, the position isomer in the 1- (2, 3-dimethylbenzene) ethanol compound can be effectively separated by adopting the chromatographic conditions.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to a liquid phase detection separation method for a positional isomer of dexmedetomidine starting material.
Background
1- (2, 3-dimethylphenyl) ethanol is one of the starting materials in the preparation of dexmedetomidine and is a colorless to pale yellow liquid.
The 1- (2, 3-dimethyl benzene) ethanol compound has 5 position isomer impurities according to the prior synthesis process, and the impurities are shown in the following table:
wherein, the position isomer impurity structures in the 1- (2, 3-dimethyl benzene) ethanol compound are similar. At present, the pharmacopoeia of various countries does not contain a detection method for the position isomer impurities of the compound, so that a separation method is needed to obtain the 1- (2, 3-dimethyl benzene) ethanol compound with high purity.
Disclosure of Invention
The invention mainly aims to provide a liquid phase detection separation method for positional isomers of dexmedetomidine starting material, and aims to solve the problem that no separation method is used for separating 1- (2, 3-dimethyl benzene) ethanol compounds and isomers thereof in the prior art.
In order to achieve the above object, the present invention provides a liquid phase detection separation method for positional isomers of dexmedetomidine starting material, comprising the following steps:
preparing a test solution from a 1- (2, 3-dimethylbenzene) ethanol compound, injecting the test solution into a high performance liquid chromatograph, and detecting and recording a chromatogram under the following chromatographic conditions:
octadecylsilane chemically bonded silica is used as a filling agent;
taking 0.1% phosphoric acid water solution as a mobile phase A;
taking acetonitrile solution as a mobile phase B;
the elution mode is gradient elution;
the flow rate is 0.9-1.1 ml/min;
the detection wavelength is 215-222 nm;
the column temperature is 30-40 ℃.
Preferably, the flow rate is 1.0ml/min, the detection wavelength is 220nm, and the column temperature is 30 ℃.
Preferably, the gradient elution is in particular:
preferably, the test solution is a solution containing 0.3mg of the 1- (2, 3-dimethylbenzene) ethanol compound per 1 ml.
Preferably, before the detection of the test solution, the method further comprises the following steps:
preparing a mixed solution containing 0.0015mg of each of 1ml of 1- (2, 4-dimethylphenyl) ethanol, 1- (2, 5-dimethylphenyl) ethanol, 1- (2, 6-dimethylphenyl) ethanol, 1- (3, 4-dimethylphenyl) ethanol and 1- (3, 5-dimethylphenyl) ethanol as main components, 0.3mg of 1- (2, 3-dimethylphenyl) ethanol as a system suitability solution;
and (3) injecting the system applicability solution into a high performance liquid chromatograph, and detecting and recording a chromatogram under the chromatographic condition.
The technical scheme of the invention is that octadecylsilane chemically bonded silica is used as a filling agent; the 1- (2, 3-dimethyl benzene) ethanol compound can be effectively separated from various position isomers by gradient elution with 0.1% phosphoric acid water solution as a mobile phase A and acetonitrile solution as a mobile phase B.
Drawings
FIG. 1 is a liquid phase detection chromatogram of a positional isomer of dexmedetomidine starting material in example 1;
FIG. 2 is a liquid phase detection chromatogram of a positional isomer of dexmedetomidine starting material in example 2;
FIG. 3 is a liquid phase detection chromatogram of the positional isomer of dexmedetomidine starting material in example 3.
Detailed Description
The present invention will be described in further detail below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. Such changes and modifications as would normally occur to one skilled in the art to which the invention relates are deemed to be within the scope and ambit of the invention as defined by the appended claims.
The invention provides a liquid phase detection separation method of a positional isomer of dexmedetomidine starting material, which comprises the following steps:
preparing a mixed solution containing 0.0015mg of each of 1ml of 1- (2, 4-dimethylphenyl) ethanol A-1, 1- (2, 5-dimethylphenyl) ethanol A-2, 1- (2, 6-dimethylphenyl) ethanol A-3, 1- (3, 4-dimethylphenyl) ethanol A-4 and 1- (3, 5-dimethylphenyl) ethanol A-5 as main components, 0.3mg of each of 1- (2, 3-dimethylphenyl) ethanol positional isomers, 1- (2, 3-dimethylphenyl) ethanol and 1- (2, 3-dimethylphenyl) ethanol, and accurately measuring 10ul of the system suitability solution to inject into a liquid chromatograph to record a chromatogram, wherein the system suitability is characterized in that the positional isomers of 1- (3, 4-dimethylphenyl) ethanol, 1- (2, 3-dimethylphenyl) ethanol and 1- (2), the 5-dimethylphenyl) ethanol, the 1- (2, 6-dimethylphenyl) ethanol and the 1- (3, 5-dimethylphenyl) ethanol sequentially peak, and the system has the following suitability requirement: the separation degree of the main peak and the adjacent impurity peak is not less than 1.5.
Preparing a solution containing 0.3mg of the 1- (2, 3-dimethylbenzene) ethanol compound in each 1ml as a test solution, and precisely measuring 10ul of the test solution to be injected into a liquid chromatograph. Wherein the mobile phase A is 0.1% phosphoric acid aqueous solution, and is prepared by adding 1.0ml phosphoric acid into 1000ml water and mixing; the mobile phase B is acetonitrile solution, an ultraviolet detector is adopted, the detection wavelength can be 215-222 nm, and the flow rate can be 0.9-1.1 ml/min; the column temperature can be 30-40 ℃ and elution is carried out according to the elution gradient shown in table 1:
TABLE 1 gradiometer
Example 1
High performance liquid chromatograph: agilent1260 (Agilent);
a chromatographic column: YMC-Pack ODS-AQ (250X 4.6mm, 5 μm)
Mobile phase A: adding 1.0ml phosphoric acid into 1000ml water and mixing uniformly to obtain the product
Mobile phase B: acetonitrile
Gradient elution procedure:
the flow rate is 1.0 ml/min;
the detection wavelength is 220 nm;
the column temperature was 40 ℃.
The implementation steps are as follows: preparing a solution containing 0.3mg of 1- (2, 3-dimethylbenzene) ethanol compound per 1ml as a test solution, precisely measuring 10ul of the test solution, injecting into a liquid chromatograph, recording chromatogram, and obtaining the results shown in Table 2 (the corresponding liquid chromatogram is shown in figure 1)
Table 2 example 1 liquid chromatography test results
| Impurities | Retention time | Degree of separation | Symmetry factor |
| A-1/A-2 | 20.663 | 1.09 | N.A |
| A-3 | 21.000 | 1.52 | N.A |
| A-4 | 20.320 | 1.11 | N.A |
| A-5 | 21.463 | 16.91 | 0.99 |
| 1- (2, 3-Dimethylbenzene) ethanol | 19.633 | 2.23 | 1.01 |
Therefore, adjacent isomer peaks and isomer peaks of the 1- (2, 3-dimethylbenzene) ethanol peak can be effectively separated, and the separation degree is larger than 1.0.
Example 2
High performance liquid chromatograph: agilent1260 (Agilent);
a chromatographic column: YMC-Pack ODS-AQ (250X 4.6mm, 5 μm)
Mobile phase A: adding 1.0ml phosphoric acid into 1000ml water and mixing uniformly to obtain the product
Mobile phase B: acetonitrile
Gradient elution procedure:
the flow rate is 0.9 ml/min;
the detection wavelength is 215 nm;
the column temperature was 35 ℃.
The implementation steps are as follows: preparing a solution containing 0.3mg of 1- (2, 3-dimethylbenzene) ethanol compound per 1ml as a test solution, precisely measuring 10ul of the test solution, injecting into a liquid chromatograph, recording chromatogram, and obtaining the results shown in Table 3 (the corresponding liquid chromatogram is shown in figure 2)
Table 3 example 2 liquid chromatography test results
Therefore, adjacent isomer peaks and isomer peaks of the 1- (2, 3-dimethylbenzene) ethanol peak can be effectively separated, and the separation degree is larger than 1.0.
Example 3
High performance liquid chromatograph: agilent1260 (Agilent);
a chromatographic column: YMC-Pack ODS-AQ (250X 4.6mm, 5 μm)
Mobile phase A: adding 1.0ml phosphoric acid into 1000ml water and mixing uniformly to obtain the product
Mobile phase B: acetonitrile
Gradient elution procedure:
the flow rate is 1.1 ml/min;
the detection wavelength is 215 nm;
the column temperature was 35 ℃.
The implementation steps are as follows: preparing a solution containing 0.3mg of 1- (2, 3-dimethylbenzene) ethanol compound per 1ml as a test solution, precisely measuring 10ul of the test solution, injecting into a liquid chromatograph, recording chromatogram, and obtaining the results shown in Table 4 (the corresponding liquid chromatogram is shown in figure 3)
Table 4 example 3 liquid chromatography test results
| Impurities | Retention time | Degree of separation | Symmetry factor |
| A-1/A-2 | 20.928 | 1.15 | N.A |
| A-3 | 21.282 | 1.50 | N.A |
| A-4 | 20.585 | 1.12 | N.A |
| A-5 | 21.738 | 54.07 | 1.00 |
| 1- (2, 3-Dimethylbenzene) ethanol | 19.898 | 2.23 | 1.01 |
Therefore, adjacent isomer peaks and isomer peaks of the 1- (2, 3-dimethylbenzene) ethanol peak can be effectively separated, and the separation degree is larger than 1.0.
The above description is only a part of or preferred embodiments of the present invention, and neither the text nor the drawings should be construed as limiting the scope of the present invention, and all equivalent structural changes, which are made by using the contents of the present specification and the drawings, or any other related technical fields, are included in the scope of the present invention.
Claims (5)
1. A liquid phase detection separation method for positional isomers of dexmedetomidine starting material is characterized by comprising the following steps:
preparing a test solution from a 1- (2, 3-dimethylbenzene) ethanol compound, injecting the test solution into a high performance liquid chromatograph, and detecting and recording a chromatogram under the following chromatographic conditions:
octadecylsilane chemically bonded silica is used as a filling agent;
taking 0.1% phosphoric acid water solution as a mobile phase A;
taking acetonitrile solution as a mobile phase B;
the elution mode is gradient elution;
the flow rate is 0.9-1.1 ml/min;
the detection wavelength is 215-222 nm;
the column temperature is 30-40 ℃.
2. The method for the liquid-phase detection and separation of a positional isomer of dexmedetomidine starting material as set forth in claim 1, characterized in that the flow rate is 1.0ml/min, the detection wavelength is 220nm, and the column temperature is 30 ℃.
3. The method for the liquid-phase detection and separation of a positional isomer of dexmedetomidine starting material as claimed in claim 1, characterized in that the gradient elution is specifically:
4. the method for the liquid-phase separation and detection of a positional isomer of dexmedetomidine starting material as set forth in claim 1, characterized in that the test solution contains 0.3mg of 1- (2, 3-dimethylphenyl) ethanol compound per 1 ml.
5. The method for the liquid-phase separation and detection of a positional isomer of dexmedetomidine starting material as set forth in claim 1, further comprising the steps of, before the detection of the test solution:
preparing a mixed solution containing 0.0015mg of each of 1ml of 1- (2, 4-dimethylphenyl) ethanol, 1- (2, 5-dimethylphenyl) ethanol, 1- (2, 6-dimethylphenyl) ethanol, 1- (3, 4-dimethylphenyl) ethanol and 1- (3, 5-dimethylphenyl) ethanol as main components, 0.3mg of 1- (2, 3-dimethylphenyl) ethanol as a system suitability solution;
and (3) injecting the system applicability solution into a high performance liquid chromatograph, and detecting and recording a chromatogram under the chromatographic condition.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113325096A (en) * | 2021-05-08 | 2021-08-31 | 石家庄四药有限公司 | Detection method of 1- (2, 3-dimethylphenyl) ethanol related substances |
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Denomination of invention: Liquid phase detection and separation method for positional isomers of starting materials of dexmedetomidine Effective date of registration: 20231208 Granted publication date: 20231103 Pledgee: Bank of Nanjing Co.,Ltd. Nanjing Chengnan sub branch Pledgor: SKYRUN PHARMA Co.,Ltd. Registration number: Y2023980070258 |
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