CN103018349B - Hydrindene amide compound detection analysis method - Google Patents
Hydrindene amide compound detection analysis method Download PDFInfo
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- CN103018349B CN103018349B CN201110283460.6A CN201110283460A CN103018349B CN 103018349 B CN103018349 B CN 103018349B CN 201110283460 A CN201110283460 A CN 201110283460A CN 103018349 B CN103018349 B CN 103018349B
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- -1 Hydrindene amide compound Chemical class 0.000 title claims description 12
- 238000004458 analytical method Methods 0.000 title description 2
- 238000001514 detection method Methods 0.000 title description 2
- 239000000243 solution Substances 0.000 claims description 50
- 239000012071 phase Substances 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 150000001408 amides Chemical class 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 238000012360 testing method Methods 0.000 claims description 22
- 239000013558 reference substance Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 9
- 239000012467 final product Substances 0.000 claims description 9
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 7
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- 238000004811 liquid chromatography Methods 0.000 claims description 7
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 7
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Abstract
The invention belongs to the technical field of medical technology, and discloses raw materials and a preparation detection analysis method of a compound (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-hydrindene-5 amide sesquisulfate. The method has the advantages such as precise detection content, convenient operation, and the like.
Description
Technical field
The present invention relates to drug quality analysis field, be specifically related to a kind of determination method of dihydroindene amides compound.
Background technology
Protein tyrosine kinase (PTK) is the member in the cancer protein and proto-protein family played an important role in normal and abnormality proliferation process, it is a kind of a kind of enzyme that optionally can make the tyrosine residue phosphorylation of different substrate, γ-the phosphate of their catalysis ATP is transferred on the tyrosine residue of many key proteins, makes phenolic hydroxyl group phosphorylation.Protein tyrosine kinase is divided into receptor tyrosine kinase (receptor tyrosine kinase, RTK), nonreceptor tyrosine kinase (nrPTK) and IR and Janus kinases etc.RTK comprises active region in Bao Wai part district, cross-film district and born of the same parents, and nrPTKs is a kind of plasmosin, does not generally have cell membrane extracellular portion, and what nrPTKs had now confirmed about has 30 kinds, is divided into 10 extended familys.To cells survival with breed relevant nrPTKs and mainly contain Abl, Src kinase families (as Src, Fyn, Yes, Blk, Yrk, Lck, Lyn and Csk etc.) and other tyrosine kinase as Jak, FAK, Ack, Fes, Rak and Brk etc.Their principal biological function is the signal transduction in mediated cell.NrPTKs plays a part different in cell proliferation, differentiation and dead regulation and control, and some wide expression, some then only expresses in specific tissue.In tumor tissues, nrPTKs is often activated, the signal transduction pathway in reactivation downstream, promotes cell proliferation, opposing Apoptosis, impels generation and the development of tumour.At present, external drugmaker has developed the tens of kinds of targeting anticarcinogens for tyrosine kinase, such as Gleevec (gleevec), Iressa (iressa), Erlotinib (tarceva), with SU11248 (sutent) etc., they are definite to specific tyrosine kinase high expressed type tumor efficiency, and toxic and side effect is less than classical anticarcinogen.
Patent WO2010072166 discloses the tyrosine protein kinase inhibitor of all new generation: dihydroindene amides compound, instructions embodiment 16 discloses (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the synthetic method of 3-dihydroindene-5 acid amides sesquisulfates, but this patent documentation does not openly ensure the quality of this compound, namely this compound and the content detection analytical approach containing this compound formulation are not disclosed.
Summary of the invention
For these reasons, applicant is according to (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the character of 3-dihydroindene-5 acid amides sesquisulfates, in efficient liquid phase testing process, we find, in order to improve (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the peak purity of 3-dihydroindene-5 acid amides sesquisulfates, keep (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the stability of 3-dihydroindene-5 acid amides sesquisulfates, a certain amount of salt should be added in mobile phase, adopt specific mobile phase wash-out, so just can well by (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate content are determined, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 can be kept simultaneously, the stability of 3-dihydroindene-5 acid amides sesquisulfates, make (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the content of 3-dihydroindene-5 acid amides sesquisulfates is measured accurately, but the salt adding too many amount in mobile phase can be larger to packed column damage, and the amount adding salt just can not produce good peak purity within the specific limits, we are determined by long-term experiment: mobile phase is that the aqueous phase of organic solvent and saliferous forms, can well by (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the magazins' layout that 3-dihydroindene-5 acid amides sesquisulfates are close with its character is opened, ensure that (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the accuracy of 3-dihydroindene-5 acid amides sesquisulfate content, and the utilization rate of chromatographic column can well be kept.
The present invention is achieved through the following technical solutions.
A kind of determination method of dihydroindene amide compound, comprise (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfates, containing (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2, the high performance liquid chromatography of the pharmaceutical preparation of 3-dihydroindene-5 acid amides sesquisulfates detects to be analyzed, and its method is for adopting C
18chromatographic column, mobile phase is that the aqueous phase of organic solvent and saliferous forms.
Wherein said organic solvent preferably includes methyl alcohol or acetonitrile.
Wherein said salt aqueous solution phase is selected from following salt: diethylamine, triethylamine.
The concentration of wherein said diethylamine or triethylamine is 0.1%-1.0%.
The concentration of wherein said diethylamine or triethylamine is 0.5%.
Wherein in mobile phase, the volume ratio of organic solvent and salt aqueous solution phase is 30-40:70-60.
Wherein the pH value of salt aqueous solution phase is 5.0-7.0.
Wherein the preferable ph of salt aqueous solution phase is 6.5.
Wherein adjust pH reagent is phosphoric acid.
A determination method for dihydroindene amide compound, its method is:
Chromatographic column: C
18chromatographic column;
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 0.5-1.0ml/min; Column temperature 20-40 DEG C; Determined wavelength 267 nm.
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.1-1mg;
The preparation of need testing solution: precision takes sample, is mixed with the solution of every 1ml containing 0.1-1mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 2-50 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
Wherein flow velocity 1.0ml/min; Column temperature 30 DEG C.
Accompanying drawing explanation
Fig. 1: the efficient liquid phase of embodiment 1 detects collection of illustrative plates.
Fig. 2: the efficient liquid phase of embodiment 2 detects collection of illustrative plates.
Fig. 3: the efficient liquid phase of embodiment 3 detects collection of illustrative plates.
Fig. 4: the efficient liquid phase of embodiment 4 detects collection of illustrative plates.
Fig. 5: the efficient liquid phase of embodiment 5 detects collection of illustrative plates.
Preparation embodiment
Embodiment 1
(1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate determination methods are:
Chromatographic column: C
18chromatographic column;
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 0.5/min; Column temperature 25 DEG C; Determined wavelength 267nm, mobile phase: with acetonitrile-0.2% triethylamine aqueous solution volume ratio be: 30:70(phosphoric acid adjust ph to 5.0).
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.1mg;
The preparation of need testing solution: precision takes sample, is mixed with the solution of every 1ml containing 0.1mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 5 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
Embodiment 2
(1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate determination methods are:
Chromatographic column: C
18chromatographic column;
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 1.0/min; Column temperature 30 DEG C; Determined wavelength 267nm, mobile phase: with methyl alcohol-0.5% diethylamine aqueous solution volume ratio be: 35:65(phosphoric acid adjust ph to 6.0).
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.5mg;
The preparation of need testing solution: precision takes sample, is mixed with the solution of every 1ml containing 0.5mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 20 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
Embodiment 3
(1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate determination methods are:
Chromatographic column: C
18chromatographic column;
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 1/min; Column temperature 30 DEG C; Determined wavelength 267nm, mobile phase: with acetonitrile-1% triethylamine aqueous solution volume ratio be: 35:65(phosphoric acid adjust ph to 6.5).
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.2mg;
The preparation of need testing solution: precision takes sample, is mixed with the solution of every 1ml containing 0.2mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 40 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
Embodiment 4
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate 10g, filling agent lactose 17g, microcrystalline cellulose 41g, pregelatinized starch 3.7g, disintegrating agent carboxymethyl base sodium starch 3.4g, magnesium stearate lubricant 0.75g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfates, lactose, microcrystalline cellulose, pregelatinized starch, 3g sodium carboxymethyl starch mixes, with water softwood, granulate, add 0.4g sodium carboxymethyl starch, add lubricant, mix, compressing tablet, to obtain final product.
Chromatographic column: C
18chromatographic column;
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 1.0/min; Column temperature 30 DEG C; Determined wavelength 267nm, mobile phase: with acetonitrile-0.5% diethylamine aqueous solution volume ratio be: 35:65(phosphoric acid adjust ph to 6.0).
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.5mg;
The preparation of need testing solution: precision takes sample tablet, is mixed with the solution of every 1ml containing 0.5mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 20 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
Embodiment 5
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate 25g, filling agent lactose 50g, microcrystalline cellulose 100g, disintegrant polyvinylpolypyrrolidone 12.5g, lubricant superfine silica gel powder 2.3g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfates, lactose, microcrystalline celluloses, 10.6g polyvinylpolypyrrolidone mixes, with water softwood, granulate, add 1.9g polyvinylpolypyrrolidone, add lubricant, mix, compressing tablet, to obtain final product.
Chromatographic column: C
18chromatographic column;
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 1/min; Column temperature 30 DEG C; Determined wavelength 267nm, mobile phase: with methyl alcohol-0.5% triethylamine aqueous solution volume ratio be: 35:65(phosphoric acid adjust ph to 6.5).
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.2mg;
The preparation of need testing solution: precision takes tablet, is mixed with the solution of every 1ml containing 0.2mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 40 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
Described embodiment includes but not limited to above-mentioned.
Claims (4)
1. the determination method of a dihydroindene amide compound, comprise (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfates, containing (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2, the high performance liquid chromatography of the pharmaceutical preparation of 3-dihydroindene-5 acid amides sesquisulfates detects to be analyzed, and it is characterized in that: adopt C
18chromatographic column, mobile phase is that the aqueous phase of organic solvent and saliferous forms;
Wherein said organic solvent is methyl alcohol or acetonitrile;
Wherein said salt aqueous solution phase is selected from following alkali: diethylamine, triethylamine, and the concentration of diethylamine or triethylamine is 0.1%-1.0%;
Wherein in mobile phase, the volume ratio of organic solvent and salt aqueous solution phase is 30-40:70-60;
Wherein the pH value of salt aqueous solution phase is 5.0-7.0, and adjust pH reagent is phosphoric acid;
Determination method is:
Chromatographic condition and system suitability are tested: take octadecylsilane chemically bonded silica as filling agent; Flow velocity 0.5-1.0ml/min; Column temperature 20-40 DEG C; Determined wavelength 267nm;
The preparation of reference substance solution: precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 acid amides sesquisulfate reference substances are in volumetric flask, add mobile phase dissolving to shake up, and be diluted to scale, prepare the solution of every 1ml containing 0.1-1mg;
The preparation of need testing solution: precision takes sample, is mixed with the solution of every 1ml containing 0.1-1mg as need testing solution with mobile phase;
Determination method: accurate absorption reference substance solution and need testing solution 2-50 μ l respectively, injection liquid chromatography, record chromatogram, calculates content by external standard method with peak area or peak height and get final product.
2. the determination method of a kind of dihydroindene amide compound according to claim 1, the concentration of wherein said diethylamine or triethylamine is 0.5%.
3. the determination method of a kind of dihydroindene amide compound according to claim 1, wherein the pH value of salt aqueous solution phase is 6.5.
4. the determination method of a kind of dihydroindene amide compound according to claim 1, wherein flow velocity 1.0ml/min; Column temperature 30 DEG C.
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