CN104181252B - A kind of method being separated bent of detection Ansai and isomeride thereof - Google Patents
A kind of method being separated bent of detection Ansai and isomeride thereof Download PDFInfo
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- CN104181252B CN104181252B CN201410441412.9A CN201410441412A CN104181252B CN 104181252 B CN104181252 B CN 104181252B CN 201410441412 A CN201410441412 A CN 201410441412A CN 104181252 B CN104181252 B CN 104181252B
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Abstract
A kind of method being separated bent of detection Ansai and isomeride thereof, do you use CHIRALPAK? AD-H chiral chromatographic column (250*4.6mm) is separation chromatography post, with normal hexane: isopropyl alcohol=95:5 (V/V) is mobile phase, baseline separation can be carried out bent for Ansai with its 3 optical isomers, effectively can control the content of the bent isomer impurities in Ansai and diastereo-isomerism.Method of the present invention can be separated simply, fast and accurately and detect bent of Ansai and optical isomer thereof.
Description
Technical field
The application relates to medicinal chemistry art, is specifically related to the method for synthesizing the compound suppressing cholesterol ester transfer protein (CETP).
Background technology
Chinese patent application CN200580022618.7 discloses a series of cholestery ester transfer protein inhibitors (CETP), wherein bent of Ansai, high-density lipoprotein (HDL) (HDL) cholesterol and Apolipoprotein A1 can be increased, and reduce low-density lipoprotein (LDL) cholesterol and apolipoprotein B, can potential treatment dyslipidemia prevention of arterial is atherosis.Bent its chemical name in Ansai is (4S, 5R)-5-[3, two (trifluoromethyl) phenyl of 5-]-3-{ [4 '-fluoro-5 '-isopropyl-2 '-methoxyl-4-(trifluoromethyl) xenyl-2-base] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone, its chemical constitution is such as formula shown in (1):
There are 2 chiral centers in the molecule that Ansai is bent, therefore, there are an enantiomter impurity and two diastereo-isomerisms.Need to carry out quality control in the process of bent of production Ansai, but at present, " American Pharmacopeia " USP, " European Pharmacopoeia " EP and " Chinese Pharmacopoeia " Ch.P. all do not record bent of Ansai, do not find the method for separating and detecting of bent of related documents report Ansai and isomeride thereof yet.In order to better control the content of Isomers In Products more accurately, ensureing the quality of bulk drug and formulation products, inventors have developed the analytical approach of the content of isomer mensuration being suitable for the bent bulk drug in Ansai.Method of the present invention can simply, quickly and accurately be separated, detect bent of Ansai and isomer impurities thereof.
Summary of the invention
At present, do not find the report to the bent optical isomer analytical approach in Ansai, we are through repetition test and research, be separation chromatography post with CHIRALPAKAD-H chiral chromatographic column (250*4.6mm), with normal hexane: isopropyl alcohol=95:5 (V/V) is mobile phase, baseline separation can be carried out bent for Ansai with its 3 optical isomers, can effectively control the bent isomer impurities in Ansai and diastereo-isomerism content.Method of the present invention can be separated simply, fast and accurately and detect bent of Ansai and optical isomer thereof.
Term definition
Term " bent of Ansai " refers to (4S, 5R)-5-[3, two (trifluoromethyl) phenyl of 5-]-3-{ [4 '-fluoro-5 '-isopropyl-2 '-methoxyl-4-(trifluoromethyl) xenyl-2-base] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone.
In the context of the present invention, no matter whether use the wording such as " approximately " or " about ", all numerals disclosed at this are approximate value.The numerical value of each numeral likely there will be the difference of 1%, 2%, 5% or 10% etc.
Detailed Description Of The Invention
Being separated the method detecting bent of Ansai and isomeride thereof, it is characterized in that, is separation chromatography post with the chiral chromatographic column that filler is coating amylose class or binding fibers element class, with lower paraffin hydrocarbon and/or alcohols solvent for mobile phase.
In certain embodiments, described chiral chromatographic column is CHIRALPAKAD-H.
In certain embodiments, described lower paraffin hydrocarbon be normal hexane, cyclohexane, n-pentane, normal heptane one or more.
In certain embodiments, described alcohols solvent be methyl alcohol, ethanol, n-propanol, isopropyl alcohol one or more.
In certain embodiments, the volume ratio of described lower paraffin hydrocarbon and alcohols solvent is 100:0 to 80:20, and in certain embodiments, the volume ratio of lower paraffin hydrocarbon and alcohols solvent is 95:5.
In certain embodiments, described mobile phase is normal hexane and isopropyl alcohol, and its volume ratio is 95:5.
Further, detect to realize separation of the present invention, the present invention adopts following detecting instrument and testing conditions:
Chromatographic column is CHIRALPAKAD-H.
Detecting device is DAD detecting device, determined wavelength 230nm-270nm, preferred 250nm.
Flow velocity is 0.3-1.1ml/min, preferential 0.6mL/min.
Column temperature is 20-40 DEG C, preferential 30 DEG C.
Sample size is 2-30 μ L, preferably 15 μ L.
Working time is within 80 minutes.
Test liquid is prepared: with thinning agent, test sample is mixed with 0.3-5mg/ml, the solution of preferred 1mg/ml.
In certain embodiments, the separation of bent of Ansai and isomeride thereof detects and comprises the following steps:
A) get bent of a certain amount of Ansai and isomer mixture thereof, to dissolve as thinning agent with normal heptane and be diluted to scale, shaking up, as need testing solution,
B) get need testing solution, carry out efficient liquid phase chromatographic analysis by following condition:
With CHIRALPAKAD-H (4.6x250mm) for separating column; UV detect wavelength is 250nm;
Mobile phase is normal hexane: isopropyl alcohol=95:5 (V/V);
Column temperature 30 DEG C;
Sampling volume is 15 μ L;
Flow velocity 0.6ml/min;
C) chromatogram is recorded.
Method for separating and detecting of the present invention, Qu Pichu peak position, Ansai retention time (RT) is about 10.2min, and its enantiomter RT is about 8.4min, and the RT of its diastereo-isomerism is about 9.0min and is about 11.9min.
It is chiral chromatographic column that the present invention adopts with CHIRALPAKAD-H, with the mixed solution of lower paraffin hydrocarbon and lower alcohol for mobile phase, bent for Ansai and isomeride effectively can be separated, degree of separation reaches more than 1.5 or more than 2.5, complete baseline separation, go out peak position to stablize, thus accurate and effective can control the quality of bent of Ansai and isomeride thereof.Adopt separation method of the present invention, the time of bent of detection Ansai and isomeride thereof that is separated is within 80 minutes, be within 50 minutes in certain embodiments, be within 30 minutes in certain embodiments, method of the present invention can be separated simply, fast and accurately and detect bent of Ansai and isomeride thereof.
Accompanying drawing explanation
Fig. 1 shows the high-efficient liquid phase chromatogram of blank solution.
Fig. 2 shows the high-efficient liquid phase chromatogram of the bent optical isomer system suitability reference substance in embodiment 2 Ansai.
Fig. 3 shows the high-efficient liquid phase chromatogram of the bent test sample in embodiment 3 Ansai.
Fig. 4 shows the high-efficient liquid phase chromatogram of the bent test sample in embodiment 4 Ansai.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, mg represents milligram, and ml represents milliliter, and μ L represents microlitre.
Embodiment 1
Instrument and condition
U.S. Agilent1260 type highly effective liquid phase chromatographic system and workstation; Auto injection;
With CHIRALPAKAD-H (4.6x250mm) for separating column; UV detect wavelength: 250nm;
Mobile phase: normal hexane: isopropyl alcohol=95:5;
Column temperature 30 DEG C;
Sampling volume is 15 μ L;
Flow velocity 0.6ml/min;
Experimental procedure
Thinning agent/blank solvent: normal heptane;
Get the bent optical isomer system suitability reference substance in Ansai and be about 25mg, accurately weighed to 25mL volumetric flask, dissolve with thinning agent and be diluted to scale, shaking up, as need testing solution.
Get blank solution and system suitability solution respectively, carry out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram, the results are shown in Figure 1, Fig. 2.
One, system suitability reference substance:
Composition: bent of Ansai, enantiomter, diastereo-isomerism 1, diastereo-isomerism 2;
Preparation process describes: add a certain amount of enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 respectively toward finished product API.
Two, the qualitative detection of enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 takes following method:
The determination of A steric configuration: prepare certain density enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 solution respectively, by nmr analysis, above-mentioned sample is carried out to the determination of steric configuration.
The location of the positive Phase Analysis Method of B: determine on nuclear magnetic resonance map on the basis of steric configuration, prepare certain density enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 solution respectively, position respectively by normal-phase chromatography analytical approach, that determines Isomers impurity goes out peak position.Finally determine, Qu Pichu peak position, Ansai retention time (RT) is about 10.24min, and its enantiomter RT is about 8.39min, and the RT of its diastereo-isomerism is about 8.98min and is about 11.95min.
Embodiment 2
Get the bent test sample in Ansai and be about 25mg, accurately weighed in 25mL volumetric flask, dissolve with thinning agent and be diluted to scale, shaking up, as need testing solution.
Get need testing solution, carry out efficient liquid phase chromatographic analysis according to the condition of example 1, record chromatogram, the results are shown in Figure 3.
Embodiment 3
Get the bent test sample in the different Ansai of different batches optical siomerism body burden and be about 25mg, accurately weighed in 25mL volumetric flask, dissolve with thinning agent and be diluted to scale, shaking up, as need testing solution.
Get need testing solution, according to the facts the condition of example 1 carries out efficient liquid phase chromatographic analysis, and record chromatogram, the results are shown in Figure 4.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (6)
1. being separated the method detecting bent of Ansai and isomeride thereof, it is characterized in that, is separation chromatography post with the chiral chromatographic column that filler is coating amylose class, with lower paraffin hydrocarbon and alcohols solvent for mobile phase; Wherein,
Described chiral chromatographic column is CHIRALPAKAD-H,
Described lower paraffin hydrocarbon be normal hexane, cyclohexane, n-pentane, normal heptane one or more,
Described alcohols solvent be methyl alcohol, ethanol, n-propanol, isopropyl alcohol one or more,
Described lower paraffin hydrocarbon and the volume ratio of alcohols solvent are 100:0 to 80:20.
2. the method for claim 1, the volume ratio of described lower paraffin hydrocarbon and alcohols solvent is 95:5.
3. the method for claim 1, described mobile phase is normal hexane and isopropyl alcohol, and its volume ratio is 95:5.
4. the method for claim 1, the separation of bent of Ansai and isomeride thereof detects and comprises the following steps:
A) get bent of a certain amount of Ansai and isomer mixture thereof, to dissolve as thinning agent with normal heptane and be diluted to scale, shaking up, as need testing solution;
B) get need testing solution, carry out efficient liquid phase chromatographic analysis by following condition:
Chromatographic column is CHIRALPAKAD-H,
Detecting device is DAD detecting device, determined wavelength 230nm-270nm,
Flow velocity is 0.3-1.1ml/min,
Column temperature is 20-40 DEG C,
Sample size is 2-30 μ L,
Working time is within 80 minutes,
Test liquid is prepared: with thinning agent, test sample is mixed with 0.3-5mg/ml;
C) chromatogram is recorded.
5. method according to claim 4, wherein said step b) need testing solution preparation: the solution with thinning agent, test sample being mixed with 1mg/ml.
6. method as claimed in claim 4, the separation of bent of Ansai and isomeride thereof detects and comprises the following steps:
A) get bent of a certain amount of Ansai and isomer mixture thereof, to dissolve as thinning agent with normal heptane and be diluted to scale, shaking up, as need testing solution;
B) get need testing solution, carry out efficient liquid phase chromatographic analysis by following condition:
Take CHIRALPAKAD-H as separating column, described chromatographic column specification is 4.6x250mm,
UV detect wavelength is 250nm,
Mobile phase is normal hexane: isopropyl alcohol=95:5,
Column temperature 30 DEG C,
Sampling volume is 15 μ L,
Flow velocity 0.6ml/min;
C) chromatogram is recorded.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130150372A1 (en) * | 2010-01-21 | 2013-06-13 | Hoffmann-La Roche Inc. | 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds |
| WO2013131901A1 (en) * | 2012-03-06 | 2013-09-12 | Boehringer Ingelheim International Gmbh | Benzodioxanes in combination with other actives for inhibiting leukotriene production |
| CN103384663A (en) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130150372A1 (en) * | 2010-01-21 | 2013-06-13 | Hoffmann-La Roche Inc. | 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds |
| CN103384663A (en) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
| WO2013131901A1 (en) * | 2012-03-06 | 2013-09-12 | Boehringer Ingelheim International Gmbh | Benzodioxanes in combination with other actives for inhibiting leukotriene production |
Non-Patent Citations (5)
| Title |
|---|
| Assessment of the CYP3A-Mediated Drug Interaction Potential of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Volunteers;Rajesh Krishna 等;《Journal of Clinical Pharmacology》;20090131;第49卷(第1期);第80-87页 * |
| Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib;Cameron J. Smith 等;《Journal of Medicinal Chemistry》;20110617;第54卷(第13期);第4880-4895页 * |
| Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans;Sanjeev Kumar 等;《DRUG METABOLISM AND DISPOSITION》;20091216;第38卷(第3期);第474-483页 * |
| Review of the quantitative analysis of cholesteryl ester transfer protein inhibitors;Ramesh Mullangi 等;《Biomed. Chromatogr.》;20131031;第27卷(第10期);第1259-1272页 * |
| 胆固醇酯转移蛋白抑制剂Anacetrapib;肖桂芝 等;《现代药物与临床》;20110331;第26卷(第2期);第153-156页 * |
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