CN107941944B - Detection method of (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate - Google Patents
Detection method of (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate Download PDFInfo
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- CN107941944B CN107941944B CN201711179904.5A CN201711179904A CN107941944B CN 107941944 B CN107941944 B CN 107941944B CN 201711179904 A CN201711179904 A CN 201711179904A CN 107941944 B CN107941944 B CN 107941944B
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- 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
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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
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- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
A detection method of (2S,5R) -benzyloxypiperidine-2-carboxylic acid ethyl ester oxalate is a liquid phase detection method and specifically comprises the following steps: (1) preparing a diluent; (2) preparing a system adaptive solution; (3) preparing a test solution; (4) blank test: precisely measuring a diluent, injecting the diluent into a liquid chromatograph, and recording a chromatogram; (5) and (3) system adaptability test: precisely measuring a system adaptability test solution, injecting the system adaptability test solution into a liquid chromatograph, and recording a chromatogram; (6) testing the test sample: precisely measuring a test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram; (7) high performance liquid chromatography conditions: a chromatographic column: phenomenex Luna 5u C18(2)100A (4.6 x 250mm,5 μm); mobile phase: mobile phase A is aqueous TFA; the mobile phase B is acetonitrile; a detector: an ultraviolet detector; the quantitative method comprises the following steps: area normalization method.
Description
Technical Field
The invention relates to the technical field of analysis, and particularly relates to detection of purity, known impurities and unknown impurities of (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate.
Background
The (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate has CAS number of 1416134-48-9, and the product is an important intermediate for producing the avibactam sodium, and the purity and the impurity of the product directly influence the purity and the size of the impurity of the avibactam sodium, so that the curative effect of the medicine is directly influenced.
At present, no related documents and reports on a method for detecting the purity of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate are found, and the company develops the detection method in order to enhance the quality control of the (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate.
Disclosure of Invention
The invention provides a detection method of (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate, and provides a simple, convenient, accurate, rapid and reliable detection method for industrial production of (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate.
The technical scheme of the invention is as follows:
a detection method of (2S,5R) -benzyloxypiperidine-2-carboxylic acid ethyl ester oxalate is a liquid phase detection method and specifically comprises the following steps:
(1) preparing a diluent: water;
(2) preparing a system adaptive solution: taking a proper amount of (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate, a proper amount of hydrolysis impurity A and a proper amount of non-corresponding isomer, placing the materials in the same volumetric flask, and dissolving the materials with a diluent to a constant volume to obtain a system adaptability test solution;
(3) preparing a test solution: taking a proper amount of a test sample, precisely weighing, and diluting with a diluent to prepare a solution containing 0.5mg-1mg per 1ml as a test sample solution;
(4) blank test: precisely measuring a diluent, injecting the diluent into a liquid chromatograph, and recording a chromatogram;
(5) and (3) system adaptability test: precisely measuring a system adaptability test solution, injecting the system adaptability test solution into a liquid chromatograph, and recording a chromatogram;
(6) testing the test sample: precisely measuring a test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram;
(7) high performance liquid chromatography conditions:
a chromatographic column: phenomenex Luna 5u C18(2)100A (4.6X 250mm,5 μm)
Mobile phase: mobile phase A is aqueous TFA; mobile phase B of acetonitrile
A detector: ultraviolet detector
The quantitative method comprises the following steps: area normalization method.
The mobile phase A: the concentration of aqueous TFA was 0.05%.
The flow rate of the mobile phase is 1mL/min, and the sample injection amount is 20 mu L.
The mobile phase is eluted according to a gradient, and the method comprises the following specific steps:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 5 | 80 | 20 |
| 25 | 20 | 80 |
| 30 | 80 | 20 |
| 50 | 80 | 20 |
The detection wavelength of the ultraviolet detector is 210 nm.
The temperature of the chromatographic column is normal temperature.
In the system adaptability test, the number of theoretical plates is not less than 5000 calculated according to (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate, and the separation degree between a main peak and any impurity peak is not less than 1.5.
And (3) deducting the chromatographic peak of the blank test from the chromatographic peak in the result chromatogram of the test sample test, and calculating according to an area normalization method.
Compared with the prior art, the invention has the following beneficial effects:
the method adopts a Phenomenex Luna 5u C18(2)100A (4.6 x 250mm,5 mu m) chromatographic column, the mobile phase is 0.05 percent TFA water solution and acetonitrile, the mobile phase is eluted according to gradient, the separation effect is improved by using proper amount, so that the (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate is effectively separated from known impurities and unknown impurities, and the quality control of the (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate is effectively enhanced.
Drawings
FIG. 1 shows the results of an adaptability test chromatogram and a systematic analysis;
FIG. 2 shows the chromatogram of the test solution 1 and the system analysis results;
FIG. 3 shows the chromatogram of sample solution 2 and the system analysis results;
FIG. 4 shows the chromatogram of the test solution 3 and the system analysis results;
Detailed Description
The following describes in detail specific embodiments of the present invention.
Taking three batches of (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate products produced according to the same production specification instruction, detecting according to the detection method provided by the invention, and calculating the purity and impurities thereof by adopting an area normalization method, wherein the specific operations are as follows:
example 1
Determination of liquid chromatography conditions:
a chromatographic column: phenomenex Luna 5u C18(2)100A (4.6X 250mm,5 μm)
Sample introduction amount: 20 μ l
Flow rate: 1ml/min
Column temperature: at normal temperature
Detection wavelength: 210nm
Mobile phase: mobile phase A0.05% TFA water solution; mobile phase B of acetonitrile
Diluting liquid: water (W)
A detector: ultraviolet detector
The mobile phase is eluted according to a gradient, which comprises the following specific steps:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 5 | 80 | 20 |
| 25 | 20 | 80 |
| 30 | 80 | 20 |
| 50 | 80 | 20 |
Example 2
Preparing a solution:
(1) preparing a diluent: water (W)
(2) Preparing a system adaptive solution: taking a proper amount of (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate, a proper amount of hydrolysis impurity A and a proper amount of non-corresponding isomer, placing the materials in the same volumetric flask, and dissolving the materials with a diluent to a constant volume to obtain a system adaptability test solution;
(3) preparing three test sample solutions: taking appropriate amount of three test samples, accurately weighing, adding diluent, diluting to obtain solutions containing 0.5-1 mg per 1ml, respectively, as test sample solution 1, test sample solution 2, and test sample solution 3;
example 3
The tests were as follows:
(1) blank test:
precisely measuring 20 mul of diluent, injecting into a liquid chromatograph, and recording a chromatogram;
(2) and (3) system adaptability test:
precisely measuring 20 mul of system adaptability test solution, injecting into a liquid chromatograph, and recording a chromatogram;
(3) testing the test sample:
precisely measuring 120 mu l of test solution, injecting into a liquid chromatograph, and recording a chromatogram;
precisely measuring 220 mu l of test solution, injecting into a liquid chromatograph, and recording a chromatogram;
precisely measuring 320 mu l of test solution, injecting into a liquid chromatograph, and recording a chromatogram;
in the system adaptability test, the number of theoretical plates is not less than 5000 calculated according to (2S,5R) -benzyloxyaminopiperidine-2-formamide, and the separation degree between a main peak and any impurity peak is not less than 1.5.
And (3) deducting the chromatographic peak of the blank test from the chromatographic peak in the result chromatogram of the test sample test, and calculating according to an area normalization method.
Results of the experiment
Test solution 1:
| substance(s) | Time to peak (min) | Peak area | Peak area ratio (%) | Degree of separation of main peak | Number of theoretical plate in main peak |
| Hydrolyzed impurities A | 6.4 | 212 | 0.10 | / | / |
| Non-corresponding isomers | 12.4 | 620 | 0.30 | / | / |
| AVB05 | 11.2 | 204372 | 99.23 | 3.81 | 10726 |
| Maximum single hetero | 16.2 | 763 | 0.37 | / | / |
| Total miscellaneous | / | 1596 | 0.77 | / | / |
Sample solution 2:
| substance(s) | Time to peak (min) | Peak area | Peak area ratio (%) | Degree of separation of main peak | Number of theoretical plate in main peak |
| Hydrolyzed impurities A | 6.1 | 124 | 0.08 | / | / |
| Non-corresponding isomers | 12.2 | 265 | 0.17 | / | / |
| AVB05 | 10.9 | 160056 | 99.67 | 4.63 | 12545 |
| Maximum single hetero | 15.2 | 82 | 0.05 | / | / |
| Total miscellaneous | / | 535 | 0.33 | / | / |
Test solution 3:
| substance(s) | Time to peak (min) | Peak area | Peak area ratio (%) | Degree of separation of main peak | Number of theoretical plate in main peak |
| Hydrolyzed impurities A | / | 0 | 0 | / | / |
| Non-corresponding isomers | 12.3 | 313 | 0.12 | / | / |
| AVB05 | 10.9 | 259431 | 99.20 | 4.23 | 8509 |
| Maximum single hetero | 15.3 | 630 | 0.24 | / | / |
| Total miscellaneous | / | 2100 | 0.80 | / | / |
The materials in the above table are as follows:
AVB05 ethyl (2S,5R) -benzyloxyaminopiperidine-2-carboxylate oxalate;
non-corresponding isomers: (2S,5S) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate, (2R,5R) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate;
hydrolyzing the impurity A, namely (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid acetic acid.
The detection result of the technical scheme can obtain that the (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate is effectively separated from known impurities and unknown impurities, and the quality control of the (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate is effectively enhanced.
The above examples are given for the purpose of illustrating the invention clearly and not for the purpose of limiting the same, and it will be apparent to those skilled in the art that, in light of the foregoing description, numerous modifications and variations can be made in the form and details of the embodiments of the invention described herein, and it is not intended to be exhaustive or to limit the invention to the precise forms disclosed.
Claims (7)
1. A detection method of (2S,5R) -benzyloxypiperidine-2-carboxylic acid ethyl ester oxalate is characterized by comprising the following steps: the detection method is a liquid phase detection method, and specifically comprises the following steps:
(1) preparing a diluent: water;
(2) preparing a system adaptive solution: taking a proper amount of (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate, a proper amount of hydrolysis impurity A and a proper amount of non-corresponding isomer, placing the materials in the same volumetric flask, and dissolving the materials with a diluent to a constant volume to obtain a system adaptability test solution; wherein the hydrolysis impurity A is (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid;
(3) preparing a test solution: taking a proper amount of a test sample, precisely weighing, and diluting with a diluent to prepare a solution containing 0.5mg-1mg per 1ml as a test sample solution;
(4) blank test: precisely measuring a diluent, injecting the diluent into a liquid chromatograph, and recording a chromatogram;
(5) and (3) system adaptability test: precisely measuring a system adaptability test solution, injecting the system adaptability test solution into a liquid chromatograph, and recording a chromatogram;
(6) testing the test sample: precisely measuring a test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram;
(7) high performance liquid chromatography conditions:
a chromatographic column: phenomenex Luna 5u C18(2)100A, 4.6 x 250mm,5 μm
Mobile phase: mobile phase A is aqueous TFA; mobile phase B of acetonitrile
A detector: ultraviolet detector
The quantitative method comprises the following steps: area normalization;
the mobile phase is eluted according to a gradient, and the method comprises the following specific steps:
for 0 minute, the mobile phase A is 80%, and the mobile phase B is 20%;
5 minutes, the mobile phase A is 80 percent, and the mobile phase B is 20 percent;
for 25 minutes, the content of mobile phase A is 20 percent, and the content of mobile phase B is 80 percent;
30 minutes, the mobile phase A is 80 percent, and the mobile phase B is 20 percent;
for 40 minutes, mobile phase a was 80% and mobile phase B was 20%.
2. The method for detecting oxalate salt of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid ethyl ester according to claim 1, wherein: the mobile phase A: the concentration of aqueous TFA was 0.05%.
3. The method for detecting the oxalate salt of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid according to claim 1, wherein: the flow rate of the mobile phase is 1mL/min, and the sample injection amount is 20 mu L.
4. The method for detecting the oxalate salt of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid according to claim 1, wherein: the detection wavelength of the ultraviolet detector is 210 nm.
5. The method for detecting the oxalate salt of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid according to claim 1, wherein: the temperature of the chromatographic column is normal temperature.
6. The method for detecting the oxalate salt of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid according to claim 1, wherein: in the system adaptability test, the number of theoretical plates is not less than 5000 calculated according to (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate, and the separation degree between a main peak and any impurity peak is not less than 1.5.
7. The method for detecting the oxalate salt of (2S,5R) -benzyloxyaminopiperidine-2-carboxylic acid according to claim 1, wherein: and (3) deducting the chromatographic peak of the blank test from the chromatographic peak in the result chromatogram of the test sample test, and calculating according to an area normalization method.
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