CN100516868C - Method for detecting content of 3,5-substituted oxaolidones compound - Google Patents
Method for detecting content of 3,5-substituted oxaolidones compound Download PDFInfo
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- CN100516868C CN100516868C CNB200710088396XA CN200710088396A CN100516868C CN 100516868 C CN100516868 C CN 100516868C CN B200710088396X A CNB200710088396X A CN B200710088396XA CN 200710088396 A CN200710088396 A CN 200710088396A CN 100516868 C CN100516868 C CN 100516868C
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- Prior art keywords
- compound
- oxo
- phenyl
- fluoro
- oxazole alkyl
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- -1 oxaolidones compound Chemical class 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000012071 phase Substances 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 82
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims description 37
- 238000001514 detection method Methods 0.000 claims description 29
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 239000003495 polar organic solvent Substances 0.000 claims description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000012360 testing method Methods 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000007791 liquid phase Substances 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 28
- 239000000523 sample Substances 0.000 description 17
- 239000013558 reference substance Substances 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000007788 liquid Substances 0.000 description 9
- ABCGRFHYOYXEJV-UHFFFAOYSA-N 4-methylisoindole-1,3-dione Chemical compound CC1=CC=CC2=C1C(=O)NC2=O ABCGRFHYOYXEJV-UHFFFAOYSA-N 0.000 description 8
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000011003 system suitability test Methods 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 3
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Abstract
The invention provides a content testing method of 3, 5-replacing oxazolidone compound, which uses high-efficient liquid-phase chromatogram containing ultraviolet detector to test. Testing wavelength of the ultraviolet detector is 200-400nm. The fixed phase of high-efficient liquid-phase chromatogram is reverse phase pole and mobile of it is intermixture of water and polar organic solution. The method is characterized that sample solvency has high speed and efficiency, components in analyzed sample are separated thoroughly, preparation of corresponding regent is simple, analyzing method is stable and adaptability is strong.
Description
Technical field
The invention provides a kind ofly 3, the high performance liquid chromatogram method of utilizing of 5-substituted oxaolidones compound is carried out the method for content detection.In addition, the present invention also provides 3, and the 5-substituted oxaolidones compound is as the content detection of the antibacterials of effective constituent.
Background technology
All kinds ofly in recent years antibioticly constantly be developed and come out; make the treatment of bacterial infective diseases that a lot of specific aim medicines arranged; certainly can also see that a large amount of drug-fast bacterias at antiseptic also are that development is rapid in its good effect; because after the bacterium contact antibacterials; morph by plasmid or chromosome mediation; obtain drug resistance, brought new difficulty to clinical treatment.As far back as 1978, E.I.Du Pont Company discloses 5-halomethyl-3-Fang oxazolidinone in the US4128654 patent had antibacterial activity to the certain plants germ.Beijing biological technical institute of consonance medical university finishes structure on this basis of reference modifies, and has synthesized 3, the 5-substituted oxaolidones compound.And apply for a patent the patent No.: CN1355165A.Obviously, how to carry out 3, the content detection problem of 5-substituted oxaolidones compound also becomes increasingly conspicuous in research and development.Generally speaking, stratographic analysis is because of it has fast, sensitive, characteristics that degree of separation is high, often be applied to that medicine separates and Quantitative Study work in, be one of important method of Pharmaceutical Analysis, be the requisite method of the desired detection of pharmacopeia.With respect to thin-layered chromatography detection method or additive method, high performance liquid chromatograph (HPLC) method has advantage fast and accurately, so its application is also increasingly extensive, but for the assay of specific compound, screening appropriate H PLC carries out content detection and has sizable difficulty.Through a large amount of literature search, find the method put down in writing in the general disclosed document, for example, and the Liquid Detection condition of the analogs such as sharp naphthalene oxazolone that the compound structure that detects to the present invention is similar, moving phase adopts normal hexane more: ethanol: TFA (65: 35: 1).Although structural similarity adopts above known method to measure 3, the 5-substituted oxaolidones compound, the dissolubility of moving phase is bad, can not effectively separate each component, and main composition can't be detected, and spended time is also longer.Since this 3, the 5-substituted oxaolidones compound is the brand-new compound of a class, so also do not retrieve at present the detection method of this compound.
Summary of the invention
It is a kind of 3 that the object of the invention is to provide, the content detecting method of 5-substituted oxaolidones compound.This method should have following characteristics: sample dissolution speed is fast, the timeliness height; The formulation operations of moving phase is simple, and analytical approach is stable, and adaptability is strong.
Provided by the invention 3, the content detecting method of 5-substituted oxaolidones compound is characterized in that, detects with the high performance liquid chromatography that includes UV-detector, and the detection wavelength is 200-400nm.The stationary phase of described high performance liquid chromatography is a reversed-phase column, and moving phase is the mixed liquor of water and polar organic solvent, and wherein the ratio of organic phase is 30%-90%.
Described polar organic solvent is acetonitrile, methyl alcohol, ethanol, tetrahydrofuran, chloroform, isopropyl alcohol or its potpourri, preferred acetonitrile and/or methyl alcohol; Moving phase is the mixed liquor of any ratio of water and acetonitrile, water and methyl alcohol, water and ethanol, water and tetrahydrofuran, water and chloroform, water and isopropyl alcohol or water and acetonitrile+methyl alcohol in the detection method of the present invention, in moving phase weight is 100%, water shared part by weight in moving phase can be elected 10-70% as, preferred 20-60%, more preferably 20-50%, if organic solvent is acetonitrile and methanol mixture, then this potpourri preferably accounts for the 50-80% of moving phase weight, wherein the ratio of acetonitrile and methyl alcohol is 0.1～3: 1, preferred 0.12～2: 1.
The above-mentioned reversed-phase column of the present invention (stationary phase) preferred C4, C8, C18 chromatographic column, the preferred 20-50 of column temperature ℃; Described moving phase is the mixed liquor of water and polar organic solvent.
Of the present invention 3, the 5-substituted oxaolidones compound can be to contain the final products that this effectively imitates composition, perhaps contains 3, and the 5-substituted oxaolidones compound is as the antibacterials of effective constituent.
Key point of the present invention is: can be under this moving phase and wavelength condition well with 3, and the 5-substituted oxaolidones compound separates with other inactive substances, can measure the content of this material exactly.Adopt detection method of the present invention, use acetonitrile: water (75: 25) is done moving phase sample dissolution rapidly, and the used time of detachment process is shorter, can finish detection in general 15 minutes, very is fit to 3, the detection of 5-substituted oxaolidones compound content.The high performance liquid chromatography that the present invention set up has simple to operate, the accuracy height, and selectivity is strong, etc. characteristics.
Of the present invention 3, what the purity of 5-substituted oxaolidones compound assay separating method and this compound adopted is same moving phase and stationary phase, such advantage is to avoid troublesome poeration, adopt a chromatographic condition both can measure content and also can measure related substance (impurity), bring great convenience for suitability for industrialized production and detecting operation, also relatively save reagent simultaneously.
Of the present invention 3, the 5-substituted oxaolidones compound comprises following compound:
Compound 1:(S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide;
Compound 2:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 3:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 4:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol p-toluenesulfonic esters;
Compound 5:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methanol acetic acid ester;
Compound 6:(S)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methylimidazole;
Compound 7:5-methyl-2-[(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl] sulfydryl-1,3, the 4-thiadiazoles;
Compound 8:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole;
Compound 9:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid H-tetrazole;
Compound 10:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl camphorimide;
Compound 11:1-methyl-5-[(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl mercapto tetrazole;
Compound 12:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl phthalimide;
Compound 13:(S)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methylacetamide;
Compound 14:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl thiophenol;
Compound 15:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide;
Compound 16:(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl benzotriazazole;
Compound 17:(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 18:(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 19:(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl phthalimide;
Compound 20:(S)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methylacetamide;
Compound 21:(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole;
Compound 22:(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl camphorimide;
Compound 23:(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide;
Compound 24:(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 25:(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 26:(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl phthalimide;
Compound 27:(S)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methylacetamide;
Compound 28:(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole;
Compound 29:(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl camphorimide;
Compound 30:(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide;
Compound 31:(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 32:(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 33: compound 39:(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl phthalimide;
Compound 34:(S)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methylacetamide;
Compound 35:(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole;
Compound 36:(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl camphorimide;
Compound 37:(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide;
Compound 38:(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl) phenyl-2-oxo-5-oxazole alkyl) methyl alcohol;
Compound 39:(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl) phenyl-2-oxo-5-oxazole alkyl) the methyl alcohol methanesulfonates;
Compound 40:(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl) phenyl-2-oxo-5-oxazole alkyl) the methyl phthalimide;
Compound 41:(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl) phenyl-2-oxo-5-oxazole alkyl) methyl isophthalic acid, 2, the 4-1H-triazole;
Compound 42:(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl) phenyl-2-oxo-5-oxazole alkyl) the methyl succimide;
Compound 43:(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 44:(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 45:(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methyl phthalimide;
Compound 46:(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, and 2, the 4-1H-triazole;
Compound 47:(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide;
Compound 48:(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 49:(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 50:(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] the methyl phthalimide;
Compound 51:(S)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide;
Compound 52:(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, and 2, the 4-1H-triazole;
Compound 53:(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] the methyl camphorimide;
Compound 54:(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide;
Compound 55:(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] methyl alcohol;
Compound 56:(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] the methyl alcohol methanesulfonates;
Compound 57:(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] methyl phthalimide;
Compound 58:(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole;
Compound 59:(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] the methyl camphorimide;
Compound 60:(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide.
Above-claimed cpd is preferred:
(S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide; (R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methylacetamide; (R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole; (R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazole alkyl] the methyl succimide; (R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazole alkyl] methyl isophthalic acid, 2, the 4-1H-triazole.
In a preferred embodiment, the detection method of content of above-claimed cpd of the present invention is specially:
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filling agent, is moving phase with acetonitrile-water (75: 25); The detection wavelength is 257nm, and number of theoretical plate is by 3, and 5-substituted oxaolidones compound peak meter should be not less than 2500.
Determination method: it is an amount of to get this product, the accurate title, decide, and adds the moving phase dissolving and dilute to make among every 1ml to contain 3 approximately, the solution of 5-substituted oxaolidones compound 100 μ g, precision is measured 20 μ l, inject high performance liquid chromatograph, the record chromatogram, other gets 3,5-substituted oxaolidones compound reference substance is an amount of, measure with method, press external standard method with calculated by peak area, promptly.
Embodiment
Further specify enforcement of the present invention below by embodiment.
Embodiment 1
Detect wavelength determination
With sample (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide is configured to the concentration of 5ug/ml with moving phase; scan with ultraviolet; as can be seen; the maximum absorption wavelength of this compound is 257nm, so assay selects 257nm for detecting wavelength from ultraviolet surface sweeping collection of illustrative plates.
Embodiment 2
(S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] retention behavior of methylacetamide in different reverse phase filler posts.
With acetonitrile-water (70: 30) is moving phase, and flow velocity is 20ul for the 1.0ml/ml. sample size, at 257nm place record chromatogram, investigates the chromatographic behavior in the anti-phase C18 filled column of difference, the results are shown in Table 1.
The retention behavior of table 1 in different ODS chromatographic columns
As can be seen from Table 1, existing C 18 brands all can be used for (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] assay of methylacetamide and preparation.Select Diamonsil ODS (200 * 4.6mm, 5um) be chromatographic column, investigate 20,30,40,50 ℃ of column temperatures respectively, the result show equal can will (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide or its salt and contain the assay of the preparation of this compound.In the practical application, can be in 20-50 ℃ of scope or be below or above a certain suitable column temperature of this scope.
Embodiment 3
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filling agent, is moving phase with acetonitrile-water (75: 25); The detection wavelength is 257nm, number of theoretical plate by (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide peak should be not less than 2500.
The preparation of reference substance solution: learn from else's experience 105 ℃ (S) that be dried to constant weight-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide reference substance; accurate claim fixed, with the moving phase dissolving and be diluted to the solution of 100ug/ml.Shake up, promptly.
The preparation of need testing solution: precision take by weighing (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide is an amount of, with the moving phase dissolving and be diluted to the solution of 100ug/ml, shake up, promptly.
Determination method: precision is measured reference substance solution and each 20 μ l of need testing solution, injects high performance liquid chromatograph, and the record chromatogram is pressed external standard method with calculated by peak area, promptly.According to the dry product meter contain (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide must not be lower than 98.0%.(S) in the preparation-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide should be 95.0%～105.0%.
Embodiment 4
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filling agent, is moving phase with methanol-water (80: 20); The detection wavelength is 257nm, number of theoretical plate by (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide peak should be not less than 2500.
The preparation of reference substance solution: learn from else's experience 105 ℃ (S) that be dried to constant weight-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide reference substance; accurate claim fixed, with the moving phase dissolving and be diluted to the solution of 100ug/ml.Shake up, promptly.
The preparation of need testing solution: precision take by weighing (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide is an amount of, with the moving phase dissolving and be diluted to the solution of 100ug/ml, shake up, promptly.
Determination method: precision is measured reference substance solution and each 20 μ l of need testing solution, injects high performance liquid chromatograph, and the record chromatogram is pressed external standard method with calculated by peak area, promptly.According to the dry product meter contain (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide must not be lower than 98.0%.(S) in the preparation-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide should be 95.0%～105.0%.
Embodiment 5
Chromatographic condition and system suitability test: with octyl silane group silica gel is filling agent, is moving phase with methanol-water (80: 20); The detection wavelength is 257nm, number of theoretical plate by (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide peak should be not less than 2500.
The preparation of reference substance solution: learn from else's experience 105 ℃ (S) that be dried to constant weight-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide reference substance; accurate claim fixed, with the moving phase dissolving and be diluted to the solution of 100ug/ml.Shake up, promptly.
The preparation of need testing solution: precision take by weighing (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide is an amount of, with the moving phase dissolving and be diluted to the solution of 100ug/ml, shake up, promptly.
Determination method: precision is measured reference substance solution and each 20 μ l of need testing solution, injects high performance liquid chromatograph, and the record chromatogram is pressed external standard method with calculated by peak area, promptly.According to the dry product meter contain (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide must not be lower than 98.0%.(S) in the preparation-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide should be 95.0%～105.0%.
Embodiment 6 typical curves
Typical curve: with moving phase is solvent, take by weighing (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide reference substance is mixed with the serial solution of 2.5ug/ml, 12.5ug/ml, 25ug/ml, 50ug/ml, 100ug/ml, 200ug/ml, 500ug/ml; sample introduction 20ul respectively; with concentration (C) is horizontal ordinate, and peak area (A) is an ordinate.
Regression equation: C=31.37A (10-4)+0.3779 R=0.9996 range of linearity 2.5～500ug/ml.
Quantitative limit: get (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide reference substance is an amount of; and be diluted to variable concentrations with moving phase, get 20ul, inject liquid chromatograph; making signal to noise ratio is 10: 1, this moment, solution concentration was 1.5ug/ml.Quantitatively be limited to 30ng.
Embodiment 7 solution stability testings
Get (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide sample and reference substance be an amount of, with the moving phase dissolving and be diluted to the solution of 100ug/ml, gets the 20ul sample introduction, the results are shown in Table 2.Need testing solution in moving phase, place 8 hours basicly stable.
The stability of table 2 in moving phase solution
Embodiment 8 replica tests
Get (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] five parts in methylacetamide sample; with the moving phase dissolving and be diluted to the solution of 100ug/ml; the accurate again reference substance that takes by weighing is in right amount with the moving phase dissolving and be diluted to the solution of 100ug/ml; get the 20ul sample introduction; calculate, the results are shown in Table 3.
Table 3 replica test
Embodiment 9 pharmaceutical adjunct interference tests
(S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] auxiliary material in methylacetamide tablet or the capsule preparations comprises these three kinds of white powders of starch, microcrystalline cellulose and lactose.Make according to capsule formula do not contain (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the blank auxiliary material of methylacetamide; get blank auxiliary material 100mg and put in the volumetric flask of 10ml; press the white opacity liquid of need testing solution course of dissolution dissolving; filter; get filtrate 20ul injecting chromatograph, method is measured according to the above analysis.The result shows that auxiliary material does not all go out the peak in The whole analytical process, and pharmaceutical adjunct does not disturb the test sample analysis.
Embodiment 10 preparation application of sample recovery tests
Precision take by weighing (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide reference substance is an amount of; be respectively 80%, 100%, 120% of recipe quantity; add blank auxiliary material; measure the recovery according to content assaying method, the results are shown in Table 4 according to the prescription ratio.
Table 4 capsule sample recovery test
Test findings shows that this method is feasible, and the recovery is better.
Embodiment 11
Error in a few days: adopt purity 99.5% (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] the methylacetamide bulk drug; by capsule formula be made into (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] methylacetamide capsule (abbreviation capsule sample), get in the accurate title of the 10mg fixation 100ml volumetric flask and dissolve and constant volume, be mixed with concentration: 100.12ug/ml, 100,31ug/ml, 100.28ug/ml sample solution respectively with moving phase.Divide the morning, noon, afternoon sample analysis, the results are shown in Table 5.
Table 5 sample capsules is error at measurment in a few days
Embodiment 12
In the daytime error: adopt purity 99.5% 3,5-substituted oxazolidinone derivative bulk drug, be made into 3 by capsule formula, 5-replaces the oxazolidinone derivative capsule, get in the accurate title of the 10mg fixation 100ml volumetric flask and dissolve and constant volume, be mixed with concentration: 100.04ug/ml, 99.48ug/ml, 98.43ug/ml sample solution respectively with moving phase.One day sample analysis the results are shown in Table 6 at interval.
Table 6 sample capsules is error at measurment in the daytime
The present invention not only is suitable for the bulk drug Determination on content as can be seen from the test results, and this assay method also is applicable to the mensuration of its capsule, tablet or injection simultaneously.
Embodiment 13
The employing octadecyl silane is a filling agent, acetonitrile: water (75: 25), methyl alcohol: water (80: 20), acetonitrile: methyl alcohol: water (10: 70: 20) is respectively moving phase, detects wavelength 257nm; Column temperature: 35 ℃.
Detection compound 1 the results are shown in Table 7 to the content of compound 60.
Table 73,5-substituted oxaolidones compound content detection result
Embodiment 13
Adopting octyl group silane group silica gel is filling agent, and acetonitrile: water (75: 25), methyl alcohol: water (80: 20), acetonitrile: methyl alcohol: water (10: 70: 20) is respectively moving phase, detects wavelength 257nm; Column temperature: 35 ℃ of detection compound 1 the results are shown in Table 8 to the content of compound 60.
Table 83,5-substituted oxaolidones compound content detection result
Adopt acetonitrile-water (75: 25), methanol-water (80: 20), acetonitrile-methanol-water (10: 70: 20) to calculate with reference substance for moving phase C8 or C18 chromatographic column adopting external standard method as can be seen from table 7,8, content is all between 95%-105%.The theoretical plate number average is not less than 2500.Illustrate and adopt acetonitrile-water (75: 25), methanol-water (80: 20), acetonitrile-methanol-water (10: 70: 20) can measure 3, the content of 5-substituted oxaolidones compound.
Claims (4)
1, a kind of (S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazole alkyl] detection method of content of methylacetamide; this method comprises with the high performance liquid chromatography that includes UV-detector and detecting; the detection wavelength of described UV-detector is 220-300nm; the stationary phase of described high performance liquid chromatography is a reversed-phase column; moving phase is the mixed liquor of water and polar organic solvent; described polar organic solvent is acetonitrile and/or methyl alcohol, and wherein the part by weight of organic phase is 50-80%; The column temperature of above-mentioned reversed-phase column is 20-50 ℃.
2, detection method of content as claimed in claim 1, wherein said detection wavelength is 257nm.
3, detection method of content as claimed in claim 1, wherein, described moving phase is water and acetonitrile, is 100% in moving phase weight, acetonitrile shared part by weight in moving phase is 70-75%.
4, detection method of content as claimed in claim 1, wherein, described moving phase is water and acetonitrile and methyl alcohol, is 100% in moving phase weight, and water shared part by weight in moving phase is 20%, and the ratio of acetonitrile and methyl alcohol is 1: 7.
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| TR01 | Transfer of patent right |
Effective date of registration: 20230619 Address after: No.10, Shennong Road, Torch Development Zone, Zhongshan City, Guangdong Province, 528400 Patentee after: GUANGDONG JINCHENG JINSU PHARMACY Co.,Ltd. Address before: Room 401, 4th floor, scientific research building, No.10 Shennong Road, Torch Development Zone, Zhongshan City, Guangdong Province 528400 Patentee before: Guangdong saifaluo Pharmaceutical Co.,Ltd. |