CN107894471A - A kind of detection method of AVM hereinafter Batan sodium intermediate - Google Patents
A kind of detection method of AVM hereinafter Batan sodium intermediate Download PDFInfo
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- CN107894471A CN107894471A CN201711089397.6A CN201711089397A CN107894471A CN 107894471 A CN107894471 A CN 107894471A CN 201711089397 A CN201711089397 A CN 201711089397A CN 107894471 A CN107894471 A CN 107894471A
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Abstract
The invention discloses a kind of detection method of AVM hereinafter Batan sodium intermediate, the AVM hereinafter Batan sodium intermediate is the formamide of (2S, 5R) 7 oxo 6 (benzyloxy) 1,6 diazabicyclo [3.2.1] octane 2.The detection method is detected using high performance liquid chromatograph, carries out quantitative analysis using area normalization method, its chromatographic condition is as follows:Chromatographic column is chiralcel AD H;Sample size is 15~25 μ l;Flow velocity is 0.8~1.2ml/min;Column temperature is 10~40 DEG C;Detection wavelength is 208~212nm;Mobile phase is n-hexane:Absolute ethyl alcohol, its volume ratio are (480~520):500;Dilution is n-hexane:Absolute ethyl alcohol:Diethylamine, its volume ratio are (40~60):(40~60):0.1;Detector is UV-detector.The detection method of the present invention can realize (2S, 5R) (benzyloxy) 1 of 7 oxo 6, the rapid and accurate determination of the formamide of 6 diazabicyclos [3.2.1] octane 2, with very high sensitivity, it is and easy to operate, it can realize and be kept completely separate, the present invention provides the basis researched and developed with quality testing to study such compound.
Description
Technical field
The present invention relates to the detection method of AVM hereinafter Batan sodium intermediate, belong to Pharmaceutical Analysis technical field, and in particular to
The detection method of (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides.
Background technology
(2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, its No. CAS
It is the important intermediate for producing AVM hereinafter Batan sodium (Avibactam) for 1192651-49-2, its chiral purity, isomer impurities
Chiral purity, the number of isomer impurities of AVM hereinafter Batan sodium are directly affected, so as to directly affect the treatment of AVM hereinafter Batan sodium medicine
Effect.
The chemical name of AVM hereinafter Batan sodium:[(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclos
[3.2.1] octyl- 6- yls] sulfuric acid monoester, belong to diazabicyclo octanone compound, be the novel ss-lactam being most expected at present
Enzyme inhibitor.Compared with the beta-lactamase inhibitor that three kinds have listed, have it is long-acting and with enzyme invertibity covalent bond, and not
Beta-lactamase can be induced to produce.Itself do not have obvious antibacterial activity, but A types (including ESBL and KPC) and C can be suppressed
The beta-lactamase of type.Therefore, when being used in combination with all kinds of cephalos and carbapenem antibiotics, there is broad spectrum antibiotic activity, especially
It is to the Escherichia coli containing extended spectrumβ-lactamase and klebostiella pneumoniae, the Escherichia coli containing excess AmpC enzymes
And the activity of the Escherichia coli simultaneously containing AmpC and extended spectrumβ-lactamase is significantly.It is noted that AVM hereinafter Batan
Activity of the cephalosporin analog antibiotic to most of test strain can be recovered.In addition, testing in vitro shows AVM hereinafter Batan and cephalo
When his Lorraine ester shares, the chance for variation of developing immunity to drugs is smaller.
At present, (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- first is not found also
The pertinent literature and report of the chiral purity detection method of acid amides, in order to strengthen (2S, 5R) -7- oxos -6- (benzyloxy) -1,6-
- 2- formamides the quality control of diazabicyclo [3.2.1] octane, it is necessary to develop (2S, 5R) -7- oxos -6- (benzyloxy) -1,
The detection of the detection method of 6- diazabicyclos [3.2.1] octane -2- formamides, particularly its chiral purity, isomer impurities
Method.
The content of the invention
The problem of existing for prior art, the invention provides one kind (2S, 5R) -7- oxos -6- (benzyloxy) -1,6-
The detection method of diazabicyclo [3.2.1] octane -2- formamides.
The structural formula of (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
For:
The structural formula of (2S, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
For:
The structural formula of (2R, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
For:
The structural formula of (2R, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
For:
The present invention uses following technical scheme:
A kind of inspection of (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
Survey method, is detected using high performance liquid chromatography, and detecting step is as follows:
(1) (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclo [3.2.1] octanes -2- is weighed in right amount respectively
Formamide, (2S, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2R, 5R) -
7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2R, 5S) -7- oxo -6- (benzyloxies
Base) -1,6- diazabicyclos [3.2.1] octane -2- formamides these four corresponding work product, it is placed in same volumetric flask,
Dissolving constant volume is carried out with dilution, is configured to certain density system suitability test solution;Further, the system adapts to
The concentration of property testing liquid is 0.3~0.7mg/ml;It is further preferred that the concentration of the system suitability test solution is
0.5mg/ml。
(2) appropriate test sample is taken, it is accurately weighed, add diluted that solution of every 1ml containing about 0.5mg is made, prepare
Into need testing solution, it can be understood as the concentration of the need testing solution is 0.3~0.7mg/ml;
(3) precision measures system suitability test solution, injects liquid chromatograph, sample size is 15~25 μ l, further
Preferably, the sample size is 20 μ l, records chromatogram.Number of theoretical plate presses (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- two
Azabicyclo [3.2.1] octane -2- formamides calculate should be not less than 5000, and the separating degree between any isomers peak should be not less than
1.5。
According to《Chinese Pharmacopoeia》, separating degree (referred to as R) is also resolution ratio, refer to the retention time at adjacent two peak difference and
The ratio of average peak width, its calculation formula be R=2 (tR2-tR1)/(W1+W2)), tR1 and tR2 for adjacent two peak reservation when
Between, W1 and W2 are its corresponding peak width.
Separating degree represents the separation degree at adjacent two peak, and R is bigger, shows that two adjacent groups point separation is better.Generally as R <
When 1, two peaks overlap;As R=1.0, separating degree is up to 98%;As R=1.5, separating degree is up to 99.7%.Generally
The mark being kept completely separate by the use of R=1.5 as two adjacent groups point.
Precision measures need testing solution, injects liquid chromatograph, sample size is 15~25 μ l, it is further preferred that described
Sample size is 20 μ l, records chromatogram.Retain in the chromatogram of need testing solution if any with isomers in system suitability solution
The chromatographic peak of time consistency, calculated respectively by area normalization method.
The system suitability test solution and need testing solution are injected separately into high performance liquid chromatograph, using area
Normalization method is detected, and its chromatographic condition is as follows:
Chromatographic column:chiralcel AD-H;
Flow velocity:0.8~1.2ml/min;
Column temperature:10~40 DEG C;
Detection wavelength:208~212nm;
Mobile phase:N-hexane:Absolute ethyl alcohol, its volume ratio are (480~520):500;
Dilution:N-hexane:Absolute ethyl alcohol:Diethylamine, its volume ratio are (40~60):(40~60):0.1;
Detector:UV-detector.
Using Daicel chiral chromatographic column, make (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos
[3.2.1] octane -2- formamides and its three isomers are realized and efficiently separated, and are detected through UV-detector, are determined with retention time
Property, peak area quantification.
Further, the specification of the chromatographic column or size are 4.6*250mm, 5 μm.The packing material size of chromatographic column is 5 μm,
Aperture is 4.6mm, column's length 250mm.
It is further preferred that the flow velocity is 1.0ml/min;The column temperature is 20~30 DEG C, can also be by the column temperature
Normal room temperature is interpreted as, it is further preferred that the column temperature is 25 DEG C.
It is further preferred that the Detection wavelength is 210nm.
It is further preferred that n-hexane in the mobile phase:The volume ratio of absolute ethyl alcohol is 500:500, using appropriate ratio
N-hexane, the absolute ethyl alcohol of example, can be effectively improved separating effect, reach baseline separation.
It is further preferred that the n-hexane in the dilution:Absolute ethyl alcohol:The volume ratio of diethylamine is 50:50:0.1,
Test sample can be completely dissolved by increasing a small amount of diethylamine in dilution.
Further, quantitative approach is area normalization method.
In the method for the invention (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -
2- formamides and its three isomers, which can be realized, to be efficiently separated.
Beneficial effects of the present invention:
(1) detection method of the invention can realize (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos
The rapid and accurate determination of [3.2.1] octane -2- formamides, there is very high sensitivity;
(2) detection method of the invention is easy to operate, and separating degree is not less than 1.5, meets the standard being kept completely separate;
(3) detection method of the invention is (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1]
The other compound of octane -2- benzamide types provides the basis of research and development and quality testing.
Brief description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 1.
Embodiment
In order to preferably explain the present invention, it is described further in conjunction with specific examples below, but the present invention is unlimited
In specific embodiment.
Embodiment 1
A kind of inspection of (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
Survey method
First, instrument and testing conditions
Shimadzu LC-15C high performance liquid chromatographs, chromatographic column select chiralcel AD-H, and the specification of chromatographic column is 4.6*
250mm, 5 μm.I.e. the packing material size of chromatographic column is 5 μm, aperture 4.6mm, column's length 250mm.Flow velocity:1.0ml/min;
Column temperature:25℃;Detection wavelength:210nm;Detector:UV-detector, sample size are 20 μ l.
Mobile phase:N-hexane:Absolute ethyl alcohol, its volume ratio are 500:500;
Dilution:N-hexane:Absolute ethyl alcohol:Diethylamine, its volume ratio are 50:50:0.1.
2nd, experimental procedure
Detected using high performance liquid chromatography, detecting step is as follows:
(1) (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclo [3.2.1] octanes -2- is weighed in right amount respectively
Formamide, (2S, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2R, 5R) -
7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2R, 5S) -7- oxo -6- (benzyloxies
Base) -1,6- diazabicyclos [3.2.1] octane -2- formamides these four corresponding work product, it is placed in same volumetric flask,
Dissolving constant volume is carried out with dilution, is configured to the system suitability test solution that concentration is about 0.5mg/ml.
(2) appropriate test sample is taken, it is accurately weighed, add diluted that solution of every 1ml containing about 0.5mg is made, prepare
Into need testing solution;
(3) precision measures the μ l of system suitability test solution 20, injects liquid chromatograph, records chromatogram.Number of theoretical plate
Being calculated by (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides to be not less than
5000, the separating degree between isomers peak should be not less than 1.5.
Precision measures the μ l of need testing solution 20, injects liquid chromatograph, records chromatogram.In the chromatogram of need testing solution
If any the chromatographic peak consistent with isomers retention time in system suitability solution, calculated respectively by area normalization method.
Take (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos of four batches of same production specification instruction production
[3.2.1] octane -2- formyl amine products, are detected according to above-mentioned detection method, and chiral purity is carried out using area normalization method
Degree and three isomers calculate, and testing result is shown in Table 1.
Table 1:Four batches of (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides
The testing result of sample.
(2S, 5S) impurity is (2S, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- first
Acid amides, (2R, 5R) impurity are (2R, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formyls
Amine, (2R, 5S) impurity are (2R, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides.
Fig. 1 is the high-efficient liquid phase chromatogram in embodiment 1, is system suitability solution typical case's collection of illustrative plates, and peak sequence is
(2R, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2S, 5R) -7- oxos -
6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2S, 5S) -7- oxos -6- (benzyloxy) -1,6-
Diazabicyclo [3.2.1] octane -2- formamides, (2R, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos
[3.2.1] octane -2- formamides, it is (2R, 5S) -7- oxos -6- (benzyloxy) -1,6- diazas at 5.8~7.8min peak
Bicyclic [3.2.1] octane -2- formamides, it is (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- bis- at 8.2~10.2min peak
Azabicyclo [3.2.1] octane -2- formamides, it is (2S, 5S) -7- oxos -6- (benzyloxy) -1 at 9.8~11.8min peak,
6- diazabicyclos [3.2.1] octane -2- formamides, it is (2R, 5R) -7- oxo -6- (benzyloxies at 30.1~32.1min peak
Base) -1,6- diazabicyclos [3.2.1] octane -2- formamides, wherein detector A channel 1/210nm.
The detection method of the present invention being capable of easy, accurate, quick, efficient, reliable detection (2S, 5R) -7- oxos -6-
The chiral purity and its isomer impurities of (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, have very high
Sensitivity, it is and easy to operate, it is possible to achieve to be kept completely separate, and then research and development and quality are provided to study such compound
The basis of detection.
The specific embodiment of the present invention is the foregoing is only, is not intended to limit the scope of the invention, every utilization
The equivalent transformation that the present invention makees, or other related technical fields are directly or indirectly used in, similarly it is included in the present invention's
Among scope of patent protection.
Claims (10)
- A kind of 1. detection method of AVM hereinafter Batan sodium intermediate, it is characterised in that the AVM hereinafter Batan sodium intermediate for (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, are entered using high performance liquid chromatography Row detection, detecting step are as follows:(1) weigh respectively (2S, 5R) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2S, 5S) -7- oxos -6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2R, 5R) -7- oxos - 6- (benzyloxy) -1,6- diazabicyclos [3.2.1] octane -2- formamides, (2R, 5S) -7- oxos -6- (benzyloxy) -1,6- Diazabicyclo [3.2.1] octane -2- formamides work product accordingly, are placed in same volumetric flask, are carried out with dilution molten Constant volume is solved, is configured to system suitability test solution;(2) accurately weighed test sample, is dissolved with dilution, is configured to need testing solution;(3) the system suitability test solution and need testing solution are injected separately into high performance liquid chromatograph, using area Normalization method is detected, and its chromatographic condition is as follows:Chromatographic column:chiralcel AD-H;Sample size:15~25 μ l;Flow velocity:0.8~1.2ml/min;Column temperature:10~40 DEG C;Detection wavelength:208~212nm;Mobile phase:N-hexane:Absolute ethyl alcohol, its volume ratio are (480~520):500;Dilution:N-hexane:Absolute ethyl alcohol:Diethylamine, its volume ratio are (40~60):(40~60):0.1;Detector:UV-detector.
- 2. detection method according to claim 1, it is characterised in that the concentration of the system suitability test solution is 0.3~0.7mg/ml;The concentration of the need testing solution is 0.3~0.7mg/ml.
- 3. detection method according to claim 2, it is characterised in that the concentration of the system suitability test solution is 0.5mg/ml。
- 4. detection method according to claim 1, it is characterised in that the specification or size of the chromatographic column are 4.6* 250mm, 5 μm.
- 5. detection method according to claim 1, it is characterised in that the sample size is 20 μ l.
- 6. detection method according to claim 1, it is characterised in that the flow velocity is 1.0ml/min;The column temperature is 20 ~30 DEG C.
- 7. detection method according to claim 1, it is characterised in that the Detection wavelength is 210nm.
- 8. detection method according to claim 1, it is characterised in that n-hexane in the mobile phase:The body of absolute ethyl alcohol Product is than being 500:500.
- 9. detection method according to claim 1, it is characterised in that the n-hexane in the dilution:Absolute ethyl alcohol:Two The volume ratio of ethamine is 50:50:0.1.
- 10. detection method according to claim 1, it is characterised in that number of theoretical plate presses (2S, 5R) -7- oxo -6- (benzyls Epoxide) calculating of -1,6- diazabicyclos [3.2.1] octane -2- formamides is not less than 5000, the separation between any isomers peak Degree is not less than 1.5.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113984929A (en) * | 2021-10-25 | 2022-01-28 | 哈药集团技术中心 | Abamebactam sodium substance analysis method |
CN115420829A (en) * | 2022-09-05 | 2022-12-02 | 海南通用三洋药业有限公司 | Method for detecting content of avibactam sodium |
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2017
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CN103328476A (en) * | 2010-12-22 | 2013-09-25 | 明治制果药业株式会社 | Optically-active diazabicyclooctane derivative and method for manufacturing same |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113984929A (en) * | 2021-10-25 | 2022-01-28 | 哈药集团技术中心 | Abamebactam sodium substance analysis method |
CN113984929B (en) * | 2021-10-25 | 2024-05-03 | 哈药集团技术中心 | Abamectin sodium substance analysis method |
CN115420829A (en) * | 2022-09-05 | 2022-12-02 | 海南通用三洋药业有限公司 | Method for detecting content of avibactam sodium |
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