CN105467027A - A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography - Google Patents
A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography Download PDFInfo
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- CN105467027A CN105467027A CN201510794424.4A CN201510794424A CN105467027A CN 105467027 A CN105467027 A CN 105467027A CN 201510794424 A CN201510794424 A CN 201510794424A CN 105467027 A CN105467027 A CN 105467027A
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- G—PHYSICS
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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
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
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- G01N30/6073—Construction of the column body in open tubular form
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- G—PHYSICS
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- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas chromatography
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Abstract
The invention belongs to the field of analytical chemistry, and discloses a method of separating and measuring purity of compounds related to a minodronic acid intermediate that is ethyl trans-4-oxo-2-butenoate through gas chromatography. The method adopts a polysiloxane nonpolar capillary column and a flame ionization detector, and can quantitatively measure contents of the minodronic acid intermediate the related compounds, thus effectively controlling purity of a reactant in a minodronic acid synthesizing process, reducing side reactions and impurities and increasing a product yield. The method is high in specificity, high in accuracy and simple and convenient to operate.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related to the method for vapor-phase chromatography separation determination Minodronate intermediate and related substance thereof.
Background technology
Minodronic acid is a kind of azepine aryl biphosphonate derivative, the bone dissolving being used for the treatment of osteoporosis clinically and being caused by osteoporosis and malignant tumour.Minodronic acid, by suppressing the farnesylpyrophosphate synzyme in osteoclast, suppresses the bone information function of osteoclast, and then Bone m etabolism circulation is gone down.Minodronic acid chemistry [1-hydroxy-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] bisphosphonicacidmonohydrate by name, molecular formula is C
9h
12n
2o
7p
2h
2o.Minodronate intermediate chemistry Ethyltrans-4-oxo-2-butenoate by name, molecular formula is C
6h
8o
3, structural formula is:
In the process of synthesis minodronic acid, need the purity controlling some important intermediate, with the generation of the generation and impurity that reduce subsidiary reaction, thus improve product yield and purity.For Minodronate intermediate Ethyltrans-4-oxo-2-butenoate, need the related substance controlled to have 2, i.e. Glyoxal1,1-dimethylacetalsolution (related substance A), structural formula is:
With Ethy2-(diethoxyphosphoryl) acetate) (related substance B), structural formula is:
Impurity removal in Minodronate intermediate is incomplete, will affect pharmaceutical purity and quality.Therefore, realize separation determination Minodronate intermediate and related substance thereof, the purity of synthesizing reactant in minodronic acid process can be ensured, reduce the generation of subsidiary reaction and the generation of impurity, improve product yield and purity, have important practical significance in the production and quality control thereof of minodronic acid.
Summary of the invention
The object of the present invention is to provide and a kind ofly analyze the purity of Minodronate intermediate Ethyltrans-4-oxo-2-butenoate and be separated the method for its related substance, thus realize the separated island form of Minodronate intermediate and its related substance, to ensure the purity of Minodronate intermediate, reduce the generation of subsidiary reaction, improve product yield.
A kind of method measuring Minodronate intermediate related substance of the present invention, is select suitable solvent by sample dissolution, adopts polysiloxane-based capillary chromatographic column;
Above-mentioned said solvent can be one or more in dimethyl sulfoxide (DMSO), DMF, methyl alcohol, ethanol, isopropyl ether.
Above-mentioned said chromatographic column is selected from the chromatographic column that brand is Agilent, OHIOVALLEY or SGE.
Above-mentioned said chromatographic column is nonpolar or the polysiloxane-based capillary chromatographic column of low pole.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get Minodronate intermediate and related substance thereof appropriate, dissolved with solvent respectively, be mixed with the sample solution of every 1mL containing Minodronate intermediate and related substance 0.1 ~ 10mg thereof;
2) arranging injector temperature is 180 ~ 300 DEG C, flow rate of carrier gas is 2.0 ~ 5.0mL/min, programmed temperature method, heating schedule is initial temperature 40 DEG C, constant temperature 1 ~ 10min, with the heating rate to 150 DEG C of 5 ~ 15 DEG C per minute, constant temperature 8 ~ 20min, detector temperature is 220 ~ 320 DEG C, and split ratio is 1:1 ~ 50:1;
3) get 1) sample solution 1 ~ 5 μ L, inject gas chromatograph, completes the separation determination of Minodronate intermediate and related substance thereof.
Wherein:
The model of gas chromatograph, has no special requirements, and the chromatograph that the present invention adopts is Agilent6890N gas chromatograph
Flame ionization ditector
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m ' 0.53mm, 1.5 μm);
Injector temperature: 280 DEG C;
Detector temperature: 280 DEG C;
Carrier gas (nitrogen) flow velocity: 4.0mL/min;
Split ratio: 10.0:1;
Sampling volume: 1 μ L
Column temperature rise program:
| Heating rate (DEG C/min) | Temperature (DEG C) | Retention time (min) |
| / | 40 | 5 |
| 10 | 150 | 8 |
The present invention utilizes vapor-phase chromatography, adopt polysiloxane-based nonpolar capillary chromatographic column (30m ' 0.53mm, 1.5 μm), can fast and effeciently separation determination Minodronate intermediate and related substance thereof, the invention solves the separation determination problem of Minodronate intermediate and related substance thereof, thus decrease the generation of synthesis minodronic acid subsidiary reaction and the yield of product, the results are shown in accompanying drawing 1 ~ 5.
Accompanying drawing explanation
The gas chromatogram of solvent (dimethyl sulfoxide (DMSO)) when Fig. 1 is embodiment 1;
Minodronate intermediate and related substance gas chromatogram thereof when Fig. 2 is embodiment 1;
Minodronate intermediate gas chromatogram when Fig. 3 is embodiment 1;
Minodronate intermediate and related substance gas chromatogram thereof when Fig. 4 is embodiment 2;
Minodronate intermediate and related substance gas chromatogram thereof when Fig. 5 is embodiment 3.
Embodiment:
Following examples are used for understanding the present invention further, but are not limited to the scope of this enforcement.Below by way of example forms, the assay of the Minodronate intermediate that the present invention relates to and related substance detection method thereof are described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Instrument and condition
Chromatograph: Agilent6890N gas chromatograph;
Detecting device: flame ionization ditector;
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m ' 0.53mm, 1.5 μm);
Column temperature: initial temperature 40 DEG C, constant temperature 5min, with the heating rate to 150 DEG C of 10 DEG C per minute, constant temperature 8min;
Injector temperature: 280 DEG C;
Detector temperature: 280 DEG C;
Carrier gas (nitrogen) flow velocity: 4.0mL/min;
Split ratio: 10.0:1;
Sampling volume: 1 μ L
Experimental procedure
Get Minodronate intermediate and related substance thereof appropriate, with dmso solution, be mixed with the solution of every 1mL containing Minodronate intermediate and each 0.1 ~ 10.0mg of related substance thereof; Separately get dimethyl sulfoxide (DMSO) as blank solution.Analyze by above-mentioned chromatographic condition, record chromatogram.The results are shown in accompanying drawing 1 ~ 3, Fig. 1 is blank solution chromatogram; In Fig. 2, the chromatographic peak of retention time 13.163min is Minodronate intermediate, and all the other chromatographic peaks are the related substance of minodronic acid.In Fig. 3, the chromatographic peak of retention time 13.293min is Minodronate intermediate.Fig. 1 ~ Fig. 3 shows: method of the present invention, effectively can be separated with its related substance by Minodronate intermediate, and can accurately quantitatively detect, to calculate the purity of Minodronate intermediate.
Embodiment 2
Instrument and condition
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m ' 0.53mm, 1.5 μm);
Column temperature: initial temperature 40 DEG C, constant temperature 5min, with the heating rate to 150 DEG C of 10 DEG C per minute, constant temperature 8min;
Injector temperature: 280 DEG C;
Detector temperature: 280 DEG C;
Carrier gas (nitrogen) flow velocity: 3.9mL/min;
Split ratio: 10.0:1;
Sampling volume: 1 μ L
Experimental procedure
Get Minodronate intermediate and related substance thereof appropriate, with dmso solution, be mixed with the mixed solution of every 1mL containing Minodronate intermediate and each 0.1 ~ 10.0mg of related substance thereof; Separately get dimethyl sulfoxide (DMSO) as blank solution.By above-mentioned Minodronate intermediate and related substance mixed solution, blank solution inject gas chromatograph respectively, analyze by above-mentioned chromatographic condition, record chromatogram.The chromatographic peak that the results are shown in retention time 13.263min in accompanying drawing 4, Fig. 4 is Minodronate intermediate, and all the other chromatographic peaks are the related substance of minodronic acid.
Embodiment 3
Instrument and condition
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m ' 0.53mm, 1.5 μm);
Column temperature: initial temperature 40 DEG C, constant temperature 5min, with the heating rate to 150 DEG C of 10 DEG C per minute, constant temperature 8min;
Injector temperature: 275 DEG C;
Detector temperature: 280 DEG C;
Carrier gas (nitrogen) flow velocity: 4.0mL/min;
Split ratio: 10.0:1;
Sampling volume: 1 μ L
Experimental procedure
Get Minodronate intermediate and related substance thereof appropriate, with dmso solution, be mixed with the mixed solution of every 1mL containing Minodronate intermediate and each 0.1 ~ 10.0mg of related substance thereof; Separately get dimethyl sulfoxide (DMSO) as blank solution.By above-mentioned Minodronate intermediate and related substance mixed solution, blank solution inject gas chromatograph respectively, analyze by above-mentioned chromatographic condition, record chromatogram.The chromatographic peak that the results are shown in retention time 13.174min in accompanying drawing 5, Fig. 5 is Minodronate intermediate, and all the other chromatographic peaks are the related substance of minodronic acid.
The following items of the present invention to described Minodronate intermediate and Related substance method thereof is verified:
1, system suitability experiment
Get Minodronate intermediate and related substance thereof appropriate, use dmso solution sample respectively, be mixed with the test liquid containing Minodronate intermediate and related substance thereof.Gas chromatographic analysis is carried out, record chromatogram by the chromatographic condition of embodiment 1.Under this condition, between related substance and main peak, degree of separation meets the requirements as seen from Figure 2.
2, sample introduction replica test
By the test liquid of Minodronate intermediate and related substance thereof, by the chromatographic condition of embodiment 1, repeat sample introduction 6 times, the repeatability of investigation method.Can be added by result, the method repeatability is good.
| Number of injections | Main peak (A) | Related substance A peak (A) | Related substance B peak (A) |
| 1 | 650.5 | 251.1 | 706.8 |
| 2 | 655.4 | 251.1 | 715.2 |
| 3 | 639.2 | 244.6 | 696.8 |
| 4 | 652.8 | 249.5 | 717.3 |
| 5 | 634 | 240.6 | 693 |
| 6 | 644.5 | 245.8 | 709.1 |
| Mean value | 646.38 | 247.38 | 705.82 |
| RSD％ | 1.39 | 1.68 | 1.54 |
3, stability of solution
Get the test liquid of Minodronate intermediate and related substance thereof, by the chromatographic condition of embodiment 1, respectively at sample introduction after 0,1,2,4,6 hour, stability of solution when investigating this product quantitative measurement, from result, this sample solution was stablized in 6 hours.
| Time (h) | Minodronate intermediate peak (A) |
| 0 | 65180.0 |
| 1 | 63952.1 |
| 2 | 62523.9 |
| 4 | 63049.5 |
| 6 | 62133.4 |
| Mean value | 63367.8 |
| RSD％ | 1.9 |
4, durability
By fine setting injector temperature, flow rate of carrier gas and chromatographic column brand isochromatic spectrum condition, we have investigated the durability of method further.Found that, the method is to good tolerance under the condition such as chromatographic column, injector temperature change ± 5 DEG C, flow rate of carrier gas change ± 0.1mL/min of different brands.Under different brands chromatographic column, different injector temperature, flow rate of carrier gas condition, Minodronate intermediate and related substance retention time thereof without marked change, and all can reach effective separation.
5, quantitative limit
Get Minodronate intermediate and related substance thereof appropriate, accurately weighed, use dmso solution sample respectively, be mixed with the test liquid of response, then precision to measure test liquid appropriate, stepwise dilution, the chromatographic condition sample introduction of embodiment 1 is investigated.Each material quantitative limit data are as shown in the table.
Claims (9)
1. a method for vapor-phase chromatography separation determination Minodronate intermediate related substance, is characterized in that: with suitable solvent by sample dissolution, adopt polysiloxane-based capillary chromatographic column, and flame ionization ditector detects.
2. method of separating and assaying according to claim 1, solvent can be one or more in dimethyl sulfoxide (DMSO), DMF, methyl alcohol, ethanol, isopropyl ether.
3. method of separating and assaying according to claim 1, chromatographic column is selected from the chromatographic column that brand is Agilent, OHIOVALLEY or SGE.
4. method of separating and assaying according to claim 1, chromatographic column is nonpolar or the polysiloxane-based capillary chromatographic column of low pole.
5. method of separating and assaying according to claim 1, is characterized in that, comprises following step:
1) get Minodronate intermediate and related substance thereof appropriate, dissolved with solvent respectively, be mixed with the sample solution of every 1mL containing Minodronate intermediate and related substance 0.1 ~ 10mg thereof;
2) arranging injector temperature is 180 ~ 300 DEG C, flow rate of carrier gas is 2.0 ~ 5.0mL/min, programmed temperature method, heating schedule is initial temperature 40 DEG C, constant temperature 1 ~ 10min, with the heating rate to 150 DEG C of 5 ~ 15 DEG C per minute, constant temperature 8 ~ 20min, detector temperature is 220 ~ 320 DEG C, and split ratio is 1:1 ~ 50:1;
3) get 1) sample solution 1 ~ 5 μ L, inject gas chromatograph, completes the separation determination of Minodronate intermediate and related substance thereof.
6. method for separating and analyzing according to claim 5, step 2) said carrier gas is nitrogen or helium.
7. method for separating and analyzing according to claim 5, step 2) the preferred 4mL/min of said flow rate of carrier gas.
8. method for separating and analyzing according to claim 5, step 2) said detector temperature preferably 280 DEG C.
9. method for separating and analyzing according to claim 5, step 2) said programmed temperature method,
Preferred following heating schedule.
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| CN114384186A (en) * | 2022-01-21 | 2022-04-22 | 王立强 | Method for measuring content of (2E, 4E) -ethyl-4- (pyridine-2-yl imino) -2-ethyl crotonate |
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