CN105806967A - Analysis method of ezetimibe key intermediate 4-[[(4-fluorophenyl)imine]methyl]-phenol - Google Patents
Analysis method of ezetimibe key intermediate 4-[[(4-fluorophenyl)imine]methyl]-phenol Download PDFInfo
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- CN105806967A CN105806967A CN201410844917.XA CN201410844917A CN105806967A CN 105806967 A CN105806967 A CN 105806967A CN 201410844917 A CN201410844917 A CN 201410844917A CN 105806967 A CN105806967 A CN 105806967A
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Abstract
The invention discloses an analysis and detection method of an ezetimibe key intermediate 4-[[(4-fluorophenyl)imine]methyl]-phenol and application thereof. The method employs silica gel bonded cellulose-tris(3, 5-dichlorophenyl carbamate) chiral chromatographic column to conduct analysis and detection on 4-[[(4-fluorophenyl)imine]methyl]-phenol, can well monitor target key impurities: chlorinated impurities, defluorinated impurities and m-fluoro impurities, also is simple and convenient to operate and has strong specificity, thus being suitable for daily application to 4-[[(4-fluorophenyl)imine]methyl]-phenol related substance and content detection.
Description
Technical field
The invention belongs to analysis technical field, be specifically related to analyzing detecting method and the application thereof of a kind of key ezetimibe intermediate 4-[[(4-fluorophenyl) imines] methyl]-phenol.
Background technology
4-[[(4-fluorophenyl) imines] methyl]-phenol is the key intermediate of Ezetimibe synthesis, and Ezetimibe is selectivity cholesterol absorption inhibitor, is widely used clinically.3 impurity-chloro impurity, defluorinate impurity and a fluora matter that 4-[[(4-fluorophenyl) imines] methyl]-phenol contains can be participated in reaction and be taken in finished product, affecting purity and the yield of finished product, therefore above-mentioned impurity preferably controls in initiation material.
4-[[(4-fluorophenyl) imines] methyl]-phenol, CAS:3382-63-6
Chloro impurityDefluorinate impurityBetween fluora matter
Existing 4-[[(4-fluorophenyl) imines] methyl]-phenol method for detecting purity is for adding interior target nuclear magnetic resonance method (enterprise of An Run Pharmaceutical Technology Co., Ltd internal control method), each impurity range go-on-go cannot be surveyed by the method, degree of accuracy is low, and the use of nuclear magnetic resonance analyser is not yet common, method complex operation.At present, in domestic and international open source literature, also the analysis method of this compound is reported by needleless.
Summary of the invention
For solving above-mentioned technical problem, the present invention provides one application convenient, accurately and reliably, specificity strong-analyzing detecting method of [[(4-fluorophenyl) imines] methyl]-phenol, described method is high performance liquid chromatography, its chromatographic condition is: adopt silica gel bonded cellulose-three (3, 5-Dichlorobenzene base carbamate) chiral chromatographic column, the mixed solvent of normal hexane and isopropanol is mobile phase, wherein normal hexane and isopropanol volume ratio are 96 ~ 99:4 ~ 1, and adopt UV-detector to detect, flow velocity is 0.5 ~ 2.0ml/min, the column temperature of chromatographic column is 15 ~ 40 DEG C.
Above-mentioned detection method, silica gel bonded cellulose-three (3,5-Dichlorobenzene base carbamate) chiral chromatographic column is chosen as DaicelChiralpakICcolumns.
Above-mentioned detection method, the specification of silica gel bonded cellulose-three (3,5-Dichlorobenzene base carbamate) chiral chromatographic column may select 150x4mm, 5 μm or 250x4mm, 5 μm.
Above-mentioned detection method, wherein the volume ratio of normal hexane and isopropanol is chosen as 98:2.
Above-mentioned detection method, the detection wavelength selectable of UV-detector is 284nm.
Above-mentioned detection method, flow velocity is chosen as 1.0ml/min.
Above-mentioned detection method, the column temperature of chromatographic column is chosen as 35 DEG C.
Above-mentioned detection method, what can be applicable to 4-[[(4-fluorophenyl) imines] methyl]-phenol has related substance detection and assay.
4-[[(4-fluorophenyl) imines] methyl]-phenol is containing imine structure, and meeting water decomposition is para-fluoroaniline and to hydroxy carbaldehyde,
Use reversed-phase liquid chromatography cannot direct analysis.As adopted the method destroyed by unstable compound or be analyzed after derivatization again, operating more complicated, and compare complete or its degradation pathway the toleration of degrading being difficult to ensure its compound of card, impurity monitoring aspect has certain difficulty and risk；And need the diversity of checked for impurities little, use the normal phase column of routine to separate and be difficult to reach desirable effect.Use silica gel bonded cellulose-three (3,5-Dichlorobenzene base carbamate) chiral chromatographic column to be analyzed detection, achieve beyond thought good result unexpectedly, each impurity is successfully separated, can monitoring objective emphasis impurity well, and simple and convenient, be suitable for daily use.
Accompanying drawing explanation
Fig. 1 is impurity reference substance HPLC figure in embodiment 1；
Fig. 2 is 4-in embodiment 1 [[(4-fluorophenyl) imines] methyl]-phenol HPLC figure；
Fig. 3 is the HPLC figure that in embodiment 1, impurity mixes with 4-[[(4-fluorophenyl) imines] methyl]-phenol.
Detailed description of the invention
Again the foregoing of the present invention is described in further detail below by way of specific embodiment.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is limited only to Examples below.Without departing from the idea case in the present invention described above, the various replacements made according to ordinary skill knowledge and customary means or change, all should be included within the scope of the invention.
Embodiment 1
Instrument and condition
Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance
Chromatographic column: DaicelChiralpakICcolumns150x4.6mm, 5 μm
Column temperature: 35 DEG C
Ultraviolet detection wavelength: 284nm
Mobile phase: normal hexane: isopropanol 98:2
Flow velocity: 1.0ml/min
Test procedure
Configuration impurity reference substance storing solution: take para-fluoroaniline, to hydroxy carbaldehyde, remove fluorine, defluorinate, each about 10mg of a fluora matter, be placed in 100ml volumetric flask, with isopropanol: normal hexane (10:90) dissolves and is diluted to scale, shakes up, to obtain final product；
Configuration impurity reference substance solution: precision pipettes reference substance storing solution 1.0ml and puts in 10ml volumetric flask, isopropanol: normal hexane (10:90) dissolves and is diluted to scale, shakes up, to obtain final product；
Configuration 4-[[(4-fluorophenyl) imines] methyl]-phenol solution: take 4-[[(4-fluorophenyl) imines] methyl]-phenol 10mg and put in 20ml volumetric flask, with isopropanol: normal hexane (10:90) dissolves and is diluted to scale, shake up, to obtain final product.
Configuration impurity and 4-[[(4-fluorophenyl) imines] methyl]-phenol mixed solution: take test sample 10mg and put in 20ml volumetric flask, use a small amount of isopropanol: normal hexane (10:90) dissolves, pipette 2.0ml reference substance storing solution and put in volumetric flask, with isopropanol: normal hexane (10:90) is diluted to scale, shake up, to obtain final product；
Take impurity reference substance solution, 4-[[(4-fluorophenyl) imines] methyl]-phenol solution and impurity and 4-[[(4-fluorophenyl) imines] methyl]-phenol mixed solution 10 μ l respectively, carry out high-efficient liquid phase analysis by above-mentioned condition, record chromatogram (accompanying drawing 1,2,3) respectively.
Result of the test
Conclusion: in analyte detection process, 4-[[(4-fluorophenyl) imines] methyl]-phenol is undegraded；All can baseline separation between itself and each impurity to be measured, each impurity to be measured.
Embodiment 2
Instrument and condition
Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance
Chromatographic column: DaicelChiralpakICcolumns250x4.6mm, 5 μm
Column temperature: 20 DEG C
Ultraviolet detection wavelength: 284nm
Mobile phase: normal hexane: isopropanol 96:4
Flow velocity: 1.0ml/min
Test procedure
4-[[(4-fluorophenyl) imines] the methyl]-phenol mixed solution 10 μ l of Example 1 configuration, carries out high-efficient liquid phase analysis by above-mentioned condition, records chromatogram.
Result of the test
Conclusion: 4-[[(4-fluorophenyl) imines] methyl] all can baseline separation between-phenol and each impurity to be measured, each impurity to be measured.
Embodiment 3
Instrument and condition
Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance
Chromatographic column: DaicelChiralpakICcolumns150x2.1mm, 5 μm
Column temperature: 40 DEG C
Ultraviolet detection wavelength: 275nm
Mobile phase: normal hexane: isopropanol 99:1
Flow velocity: 0.5ml/min
Test procedure
4-[[(4-fluorophenyl) imines] the methyl]-phenol mixed solution 10 μ l of Example 1 configuration, carries out high-efficient liquid phase analysis by above-mentioned condition, records chromatogram.
Result of the test
Conclusion: 4-[[(4-fluorophenyl) imines] methyl] all can baseline separation between-phenol and each impurity to be measured, each impurity to be measured.
Embodiment 4
Instrument and condition
Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance
Chromatographic column: DaicelChiralpakICcolumns250x4.6mm, 5 μm
Column temperature: 30 DEG C
Ultraviolet detection wavelength: 284nm
Mobile phase: normal hexane: isopropanol 97:3
Flow velocity: 2.0ml/min
Test procedure
4-[[(4-fluorophenyl) imines] the methyl]-phenol mixed solution 10 μ l of Example 1 configuration, carries out high-efficient liquid phase analysis by above-mentioned condition, records chromatogram.
Result of the test
Conclusion: 4-[[(4-fluorophenyl) imines] methyl] all can baseline separation between-phenol and each impurity to be measured, each impurity to be measured.
Claims (9)
1. the analysis method of key ezetimibe intermediate 4-[[(4-fluorophenyl) imines] methyl]-phenol, described method is high performance liquid chromatography, it is characterized in that, the method includes adopting silica gel bonded cellulose-three (3,5-Dichlorobenzene base carbamate) chiral chromatographic column, the mixed solvent of normal hexane and isopropanol is mobile phase, wherein normal hexane and isopropanol volume ratio are 96 ~ 99:4 ~ 1, and adopt UV-detector to detect, flow velocity is 0.5 ~ 2.0ml/min, and the column temperature of chromatographic column is 15 ~ 40 DEG C.
2. detection method according to claim 1, it is characterised in that: described silica gel bonded cellulose-three (3,5-Dichlorobenzene base carbamate) chiral chromatographic column is DaicelChiralpakICcolumns.
3. detection method according to claim 1, it is characterised in that: the specification of described silica gel bonded cellulose-three (3,5-Dichlorobenzene base carbamate) chiral chromatographic column is 150x4.6mm, 5 μm or 250x4.6mm, 5 μm.
4. detection method according to claim 1, it is characterised in that: the volume ratio of described normal hexane and isopropanol is 98:2.
5. detection method according to claim 1, it is characterised in that: the detection wavelength of described UV-detector is 284nm.
6. detection method according to claim 1, it is characterised in that: described flow velocity is 1.0ml/min.
7. detection method according to claim 1, it is characterised in that: the column temperature of described chromatographic column is 35 DEG C.
8. the detection method described in any one of claim 1-7, it has the application in related substance detection at 4-[[(4-fluorophenyl) imines] methyl]-phenol.
9. the detection method described in any one of claim 1-7, its application in 4-[[(4-fluorophenyl) imines] methyl]-phenol content detects.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107677753A (en) * | 2017-11-24 | 2018-02-09 | 中山奕安泰医药科技有限公司 | A kind of detection method of ezetimibe intermediate |
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| CN103760281A (en) * | 2014-01-14 | 2014-04-30 | 北京万全德众医药生物技术有限公司 | Method for separating ezetimibe optical isomer by liquid-phase process |
| CN103760282A (en) * | 2014-01-14 | 2014-04-30 | 北京万全德众医药生物技术有限公司 | Method for separating and measuring ezetimibe intermediate related substances by liquid chromatography |
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| US20090209492A1 (en) * | 2004-11-12 | 2009-08-20 | Trustees Of Tufts College | Lipase Inhibitors |
| CN103207248A (en) * | 2012-12-21 | 2013-07-17 | 北京万全德众医药生物技术有限公司 | Method of separating optical isomers of ezetimibe intermediate by using HPLC |
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| CN104230978A (en) * | 2014-09-22 | 2014-12-24 | 上海现代制药股份有限公司 | Preparation midbody for Ezetimibe and preparation method of preparation midbody |
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| KAMESWARA RAO CHIMALAKONDA 等: "Development and Validation of Chiral HPLC Method for Identification and Quantification of (R)-Enantiomer in Ezetimibe", 《AMERICAN JOURNAL OF ANALYTICAL CHEMISTRY》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107677753A (en) * | 2017-11-24 | 2018-02-09 | 中山奕安泰医药科技有限公司 | A kind of detection method of ezetimibe intermediate |
| CN107677753B (en) * | 2017-11-24 | 2021-03-16 | 中山奕安泰医药科技有限公司 | Detection method of ezetimibe intermediate |
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