CN104181252A - Method for separating and detecting CETP (Cholesteryl Ester Transfer Protein) inhibitor - Google Patents
Method for separating and detecting CETP (Cholesteryl Ester Transfer Protein) inhibitor Download PDFInfo
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- CN104181252A CN104181252A CN201410441412.9A CN201410441412A CN104181252A CN 104181252 A CN104181252 A CN 104181252A CN 201410441412 A CN201410441412 A CN 201410441412A CN 104181252 A CN104181252 A CN 104181252A
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Abstract
The invention discloses a method for separating and detecting Anacetrapib and isomers of Anacetrapib. According to the method, with a CHIRALPAK AD-H Chiral chromatographic column (250P*4.6mm) serving as a separating chromatographic column, and n-hexane: isopropanol=95:5(V/V) serving as a mobile phase, the baseline separation of Anacetrapib from three optical isomers of Anacetrapib can be achieved, so that the content of isomer impurities and diastereoisomers of Anacetrapib can be effectively controlled. The method is capable of simply, rapidly and accurately separating and detecting Anacetrapib and the optical isomers of Anacetrapib.
Description
Technical field
The application relates to pharmaceutical chemistry field, is specifically related to the synthetic method that suppresses the compound of cholesterol ester transfer protein (CETP).
Background technology
Chinese patent application CN 200580022618.7 discloses a series of cholestery ester transfer protein inhibitors (CETP), wherein Ansai is bent, can increase high-density lipoprotein (HDL) (HDL) cholesterol and Apolipoprotein A1, and reduce low-density lipoprotein (LDL) cholesterol and apolipoprotein B, can potential treatment dyslipidemia and prevention of arterial 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-yl] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone, its chemical constitution is suc as formula shown in (1):
In the molecule that Ansai is bent, there are 2 chiral centers, therefore, have an enantiomter impurity and two diastereo-isomerisms.In the process of bent of production Ansai, need to carry out quality control, 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 better to control more accurately the content of Isomers In Products, guarantee the quality of bulk drug and formulation products, inventor has developed the analytical approach of the content of isomer mensuration that is suitable for the bent bulk drug in Ansai.Method of the present invention can be simply, quickly and accurately 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, with CHIRALPAK AD-H chiral chromatographic column (250*4.6mm), it is separation chromatography post, normal hexane: the isopropyl alcohol=95:5 (V/V) of take is mobile phase, baseline separation can be carried out to its 3 optical isomers in bent of Ansai, can effectively control the bent isomer impurities in Ansai and diastereo-isomerism content.Method of the present invention can be simply, separation fast and accurately detects 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-yl] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone.
In the context of the invention, no matter whether use wordings such as " approximately " or " approximately ", all numerals that disclose at this are approximate value.Each digital numerical value likely there will be 1%, 2%, 5% or 10% etc. difference.
Detailed Description Of The Invention
A separated method that detects bent of Ansai and isomeride thereof, is characterized in that, with the chiral chromatographic column that filler is coating amylose class or bonding cellulose family, is separation chromatography post, take lower paraffin hydrocarbon and/or alcohols solvent as mobile phase.
In certain embodiments, described chiral chromatographic column is CHIRALPAK AD-H.
In certain embodiments, described lower paraffin hydrocarbon is one or more of normal hexane, cyclohexane, n-pentane, normal heptane.
In certain embodiments, described alcohols solvent is one or more of methyl alcohol, ethanol, n-propanol, isopropyl alcohol.
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, in order to realize separated detection of the present invention, the present invention adopts following detecting instrument and testing conditions:
Chromatographic column is CHIRALPAK AD-H.
Detecting device is DAD detecting device, detects wavelength 230nm-270nm, preferably 250nm.
Flow velocity is 0.3-1.1ml/min, preferential 0.6mL/min.
Column temperature is 20-40 ℃, preferential 30 ℃.
Sample size is 2-30 μ L, preferably 15 μ L.
Be in 80 minutes working time.
Test liquid preparation: with thinning agent, test sample is mixed with to 0.3-5mg/ml, preferably the solution of 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, with normal heptane, as thinning agent, dissolve and be diluted to scale, shake up, as need testing solution,
B) get need testing solution, by following condition, carry out efficient liquid phase chromatographic analysis:
The CHIRALPAK AD-H (4.6x 250mm) of take is separating column; It is 250nm that ultraviolet detects wavelength;
Mobile phase is normal hexane: isopropyl alcohol=95:5 (V/V);
30 ℃ of column temperatures;
Sampling volume is 15 μ L;
Flow velocity 0.6ml/min;
C) record chromatogram.
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.
The present invention adopts take CHIRALPAK AD-H as chiral chromatographic column, the mixed solution of lower paraffin hydrocarbon and lower alcohol of take is mobile phase, effective separation can be carried out in bent of Ansai and isomeride thereof, degree of separation reaches more than 1.5 or more than 2.5, complete baseline separation, go out peak position stable, thereby can accurate and effective control the quality of bent of Ansai and isomeride thereof.Adopt separation method of the present invention, the separated time of detecting bent of Ansai and isomeride thereof is in 80 minutes, be in 50 minutes in certain embodiments, be in 30 minutes in certain embodiments, method of the present invention can be simply, separation fast and accurately detects 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 Ansais.
Fig. 3 shows the high-efficient liquid phase chromatogram of the bent test sample in embodiment 3 Ansais.
Fig. 4 shows the high-efficient liquid phase chromatogram of the bent test sample in embodiment 4 Ansais.
Embodiment
In order to make those skilled in the art understand better technical scheme of the present invention, below further disclose some unrestricted embodiment the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can obtain by method preparation described in the invention.
In the present invention, mg represents milligram, and ml represents milliliter, and μ L represents microlitre.
Embodiment 1
Instrument and condition
U.S. Agilent 1260 type highly effective liquid phase chromatographic system and workstations; Auto injection;
The CHIRALPAK AD-H (4.6x 250mm) of take is separating column; Ultraviolet detects wavelength: 250nm;
Mobile phase: normal hexane: isopropyl alcohol=95:5;
30 ℃ of column temperatures;
Sampling volume is 15 μ L;
Flow velocity 0.6ml/min;
Experimental procedure
Thinning agent/blank solvent: normal heptane;
Get the bent about 25mg of optical isomer system suitability reference substance in Ansai, accurately weighed to 25mL volumetric flask, with thinning agent, dissolve and be diluted to scale, shake up, as need testing solution.
Get respectively blank solution and system suitability solution, by above-mentioned condition, carry out efficient liquid phase chromatographic analysis, 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 is described: toward finished product API, add respectively a certain amount of enantiomter, diastereo-isomerism 1, diastereo-isomerism 2.
Two, the qualitative detection of enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 is taked following method:
Determining of A steric configuration: prepare respectively certain density enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 solution, by nmr analysis, above-mentioned sample is carried out to determining 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 respectively certain density enantiomter, diastereo-isomerism 1, diastereo-isomerism 2 solution, by normal-phase chromatography analytical approach, position respectively, determine the peak position that of each isomer impurities.Final definite, 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 about 25mg of the bent test sample in Ansai, accurately weighed to 25mL volumetric flask, with thinning agent, dissolve and be diluted to scale, shake up, as need testing solution.
Get need testing solution, according to the condition of example 1, carry out efficient liquid phase chromatographic analysis, record chromatogram, the results are shown in Figure 3.
Embodiment 3
Get the about 25mg of the bent test sample in Ansai that different batches optical siomerism body burden is different, accurately weighed to 25mL volumetric flask, with thinning agent, dissolve and be diluted to scale, shake up, as need testing solution.
Get need testing solution, according to the facts the condition of example 1 is carried out efficient liquid phase chromatographic analysis, records 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 apply the technology of the present invention.Those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.
Claims (9)
1. a separated method that detects bent of Ansai and isomeride thereof, is characterized in that, with the chiral chromatographic column that filler is coating amylose class or bonding cellulose family, is separation chromatography post, take lower paraffin hydrocarbon and/or alcohols solvent as mobile phase.
2. the method for claim 1, described chiral chromatographic column is CHIRALPAK AD-H.
3. the method for claim 1, described lower paraffin hydrocarbon is one or more of normal hexane, cyclohexane, n-pentane, normal heptane.
4. the method for claim 1, described alcohols solvent is one or more of methyl alcohol, ethanol, n-propanol, isopropyl alcohol.
5. the method for claim 1, the volume ratio of described lower paraffin hydrocarbon and alcohols solvent is 100:0 to 80:20.
6. the method for claim 1, the volume ratio of described lower paraffin hydrocarbon and alcohols solvent is 95:5.
7. the method for claim 1, described mobile phase is normal hexane and isopropyl alcohol, its volume ratio is 95:5.
8. 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, with normal heptane, as thinning agent, dissolve and be diluted to scale, shake up, as need testing solution;
B) get need testing solution, by following condition, carry out efficient liquid phase chromatographic analysis:
Chromatographic column is CHIRALPAK AD-H,
Detecting device is DAD detecting device, detects wavelength 230nm-270nm,
Flow velocity is 0.3-1.1ml/min,
Column temperature is 20-40 ℃,
Sample size is 2-30 μ L
Be in 80 minutes working time,
Test liquid preparation: with thinning agent, test sample is mixed with to 0.3-5mg/ml, preferably the solution of 1mg/ml;
C) record chromatogram.
9. method as claimed in claim 8, 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, with normal heptane, as thinning agent, dissolve and be diluted to scale, shake up, as need testing solution;
B) get need testing solution, by following condition, carry out efficient liquid phase chromatographic analysis:
The CHIRALPAK AD-H (4.6x 250mm) of take is separating column; It is 250nm that ultraviolet detects wavelength;
Mobile phase is normal hexane: isopropyl alcohol=95:5;
30 ℃ of column temperatures;
Sampling volume is 15 μ L;
Flow velocity 0.6ml/min;
C) record chromatogram.
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| CN201410441412.9A CN104181252B (en) | 2014-09-01 | 2014-09-01 | A kind of method being separated bent of detection Ansai and isomeride thereof |
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| CN201410441412.9A CN104181252B (en) | 2014-09-01 | 2014-09-01 | A kind of method being separated bent of detection Ansai and isomeride thereof |
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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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2014
- 2014-09-01 CN CN201410441412.9A patent/CN104181252B/en not_active Expired - Fee Related
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 |
|---|
| CAMERON J. SMITH 等: "Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| RAJESH KRISHNA 等: "Assessment of the CYP3A-Mediated Drug Interaction Potential of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Volunteers", 《JOURNAL OF CLINICAL PHARMACOLOGY》 * |
| RAMESH MULLANGI 等: "Review of the quantitative analysis of cholesteryl ester transfer protein inhibitors", 《BIOMED. CHROMATOGR.》 * |
| SANJEEV KUMAR 等: "Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans", 《DRUG METABOLISM AND DISPOSITION》 * |
| 肖桂芝 等: "胆固醇酯转移蛋白抑制剂Anacetrapib", 《现代药物与临床》 * |
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