CN105806967B - The analysis method of key ezetimibe intermediate 4 [[(4 fluorophenyl) imines] methyl] phenol - Google Patents
The analysis method of key ezetimibe intermediate 4 [[(4 fluorophenyl) imines] methyl] phenol Download PDFInfo
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- CN105806967B CN105806967B CN201410844917.XA CN201410844917A CN105806967B CN 105806967 B CN105806967 B CN 105806967B CN 201410844917 A CN201410844917 A CN 201410844917A CN 105806967 B CN105806967 B CN 105806967B
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Abstract
The invention discloses the analyzing detecting method of a kind of key intermediate 4 of Ezetimibe [[(4 fluorophenyl) imines] methyl] phenol and its application, this method to use silica gel bonded cellulose iii（3,5 dichlorophenyl carbamates）Chiral chromatographic column carries out analysis detection to 4 [[(4 fluorophenyl) imines] methyl] phenol, being capable of monitoring objective emphasis impurity well:Chloro impurity, defluorinate impurity and a fluorine impurity, and it is simple and convenient, specificity is strong, is suitable for daily use in 4 [[(4 fluorophenyl) imines] methyl] the relevant materials of phenol and content detection.
Description
Technical field
The invention belongs to analysis technical field, and in particular to [[(4- fluorophenyls) is sub- by a kind of key ezetimibe intermediate 4-
Amine] methyl]-phenol analyzing detecting method and its application.
Background technology
4- [[(4- fluorophenyls) imines] methyl]-phenol is the key intermediate of Ezetimibe synthesis, and Ezetimibe is choosing
Selecting property cholesterol absorption inhibitor, is clinically widely used.4- [[(4- fluorophenyls) imines] methyl]-phenol contains
3 impurity-chloro impurity, defluorinate impurity and a fluorine impurity can participate in reaction and take in finished product, influence finished product purity and
Yield, therefore above-mentioned impurity preferably controls in initiation material.
4- [[(4- fluorophenyls) imines] methyl]-phenol, CAS：3382-63-6
Chloro impurityDefluorinate impurity
Between fluorine impurity
Existing 4- [[(4- fluorophenyls) imines] methyl]-phenol method for detecting purity is target nuclear magnetic resonance method in adding
（Enterprise of An Run Pharmaceutical Technology Co., Ltd internal control method）, this method can not survey to each impurity range go-on-go, and accuracy is low, and nuclear-magnetism
The use of resonance instrument is not yet common, and method is cumbersome.At present, also without the analysis for the compound in domestic and international open source literature
Method is reported.
The content of the invention
In order to solve the above technical problems, a kind of application of present invention offer it is convenient, accurately and reliably, specificity it is strong-[[(4-
Fluorophenyl) imines] methyl] and-phenol analyzing detecting method, methods described is high performance liquid chromatography, and its chromatographic condition is：Adopt
With silica gel bonded cellulose-three（3,5- dichlorophenyl carbamates）The mixing of chiral chromatographic column, n-hexane and isopropanol is molten
Agent is mobile phase, and wherein n-hexane and isopropanol volume ratio are 96 ~ 99:4 ~ 1, and detected using UV-detector, flow
Speed is 0.5 ~ 2.0 ml/min, and the column temperature of chromatographic column is 15 ~ 40 DEG C.
Above-mentioned detection method, silica gel bonded cellulose-three（3,5- dichlorophenyl carbamates）Chiral chromatographic column is optional
For Daicel Chiralpak IC columns.
Above-mentioned detection method, silica gel bonded cellulose-three（3,5- dichlorophenyl carbamates）The rule of chiral chromatographic column
Lattice may be selected 150 x 4mm, 5 μm or 250 x 4mm, 5 μm.
The volume ratio of above-mentioned detection method, wherein n-hexane and isopropanol is chosen as 98:2.
Above-mentioned detection method, the Detection wavelength of UV-detector are chosen as 284 nm.
Above-mentioned detection method, flow velocity are chosen as 1.0ml/min.
Above-mentioned detection method, the column temperature of chromatographic column are chosen as 35 DEG C.
Above-mentioned detection method, it can be applied to the relevant material detection of 4- [[(4- fluorophenyls) imines] methyl]-phenol and contain
It is fixed to measure.
4- [[(4- fluorophenyls) imines] methyl]-phenol contains imine structure, meets water decomposition for para-fluoroaniline and to hydroxyl first
Aldehyde,
Can not Direct Analysis using reversed-phase liquid chromatography.Such as using will unstable compound destroy or derivatization after enter again
Row analysis method, operation it is more complicated, and compare be difficult to ensure demonstrate,prove its compound degraded completely or its degradation pathway tolerance,
There are certain difficulty and risk in terms of impurity monitoring；And need the otherness of checked for impurities small, it is difficult using the positive post separation of routine
To reach preferable effect.Use silica gel bonded cellulose-three（3,5- dichlorophenyl carbamates）Chiral chromatographic column is carried out
Analysis detection, unexpectedly achieves unexpected good result, and each impurity is successfully separated, being capable of monitoring objective weight well
Point impurity, and it is simple and convenient, it is suitable for daily use.
Brief description of the drawings
Fig. 1 is that impurity reference substance HPLC schemes in embodiment 1；
Fig. 2 is that 4- [[(4- fluorophenyls) imines] methyl]-phenol HPLC schemes in embodiment 1；
Fig. 3 is the HPLC figures that impurity mixes with 4- [[(4- fluorophenyls) imines] methyl]-phenol in embodiment 1.
Embodiment
The above of the present invention is described in further detail again below by way of specific embodiment.But this should not be managed
The scope solved as the above-mentioned theme of the present invention is limited only to following example.The situation of the above-mentioned technological thought of the present invention is not being departed from
Under, the various replacements or change made according to ordinary skill knowledge and customary means, model of the invention all should be included in
In enclosing.
Embodiment 1
Instrument and condition
Instrument：Shimadzu LC-20A high performance liquid chromatographs, electronic analytical balance
Chromatographic column：Daice lChiralpak IC columns 150 x 4.6mm,5μm
Column temperature：35℃
Ultraviolet detection wavelength：284nm
Mobile phase：N-hexane：Isopropanol 98:2
Flow velocity：1.0ml/min
Test procedure
Configure impurity reference substance storing solution：Take para-fluoroaniline, to hydroxy carbaldehyde, go fluorine, defluorinate, a fluorine impurity each about
10mg, it is placed in 100ml volumetric flasks, uses isopropanol：N-hexane（10:90）Dissolve and be diluted to scale, shake up, produce；
Configure impurity reference substance solution：Precision pipettes reference substance storing solution 1.0ml and put in 10ml volumetric flasks, isopropanol：Just
Hexane（10:90）Dissolve and be diluted to scale, shake up, produce；
Configure 4- [[(4- fluorophenyls) imines] methyl]-phenol solution：Take 4- [[(4- fluorophenyls) imines] methyl]-phenol
10mg is put in 20ml volumetric flasks, uses isopropanol：N-hexane（10:90）Dissolve and be diluted to scale, shake up, produce.
Configure impurity and 4- [[(4- fluorophenyls) imines] methyl]-phenol mixed solution：Test sample 10mg is taken to put 20ml appearances
In measuring bottle, with a small amount of isopropanol：N-hexane（10:90）Dissolving, pipettes 2.0ml reference substance storing solutions and puts in volumetric flask, use isopropyl
Alcohol：N-hexane（10:90）Scale is diluted to, is shaken up, is produced；
Impurity reference substance solution, 4- [[(4- fluorophenyls) imines] methyl]-phenol solutions and impurity and 4- [[(4- are taken respectively
Fluorophenyl) imines] methyl] 10 μ l of-phenol mixed solution, high-efficient liquid phase analysis are carried out by above-mentioned condition, record chromatogram respectively
（Accompanying drawing 1,2,3）.
Result of the test
Conclusion：In analyte detection process, 4- [[(4- fluorophenyls) imines] methyl]-phenol is undegraded；Its with it is each to be measured miscellaneous
Can baseline separation between matter, each impurity to be measured.
Embodiment 2
Instrument and condition
Instrument：Shimadzu LC-20A high performance liquid chromatographs, electronic analytical balance
Chromatographic column：Daicel Chiralpak IC columns 250 x 4.6mm,5μm
Column temperature：20℃
Ultraviolet detection wavelength：284nm
Mobile phase：N-hexane：Isopropanol 96:4
Flow velocity：1.0ml/min
Test procedure
The μ l of 4- [[(4- fluorophenyls) imines] methyl]-phenol mixed solution 10 that Example 1 configures, are entered by above-mentioned condition
Row high-efficient liquid phase analysis, record chromatogram.
Result of the test
Conclusion：4- [[(4- fluorophenyls) imines] methyl] can baseline between-phenol and each impurity to be measured, each impurity to be measured
Separation.
Embodiment 3
Instrument and condition
Instrument：Shimadzu LC-20A high performance liquid chromatographs, electronic analytical balance
Chromatographic column：Daicel Chiralpak IC columns 150 x 2.1mm,5μm
Column temperature：40℃
Ultraviolet detection wavelength：275nm
Mobile phase：N-hexane：Isopropanol 99:1
Flow velocity：0.5ml/min
Test procedure
The μ l of 4- [[(4- fluorophenyls) imines] methyl]-phenol mixed solution 10 that Example 1 configures, are entered by above-mentioned condition
Row high-efficient liquid phase analysis, record chromatogram.
Result of the test
Conclusion：4- [[(4- fluorophenyls) imines] methyl] can baseline between-phenol and each impurity to be measured, each impurity to be measured
Separation.
Embodiment 4
Instrument and condition
Instrument：Shimadzu LC-20A high performance liquid chromatographs, electronic analytical balance
Chromatographic column：Daicel Chiralpak IC columns 250 x 4.6mm,5μm
Column temperature：30℃
Ultraviolet detection wavelength：284nm
Mobile phase：N-hexane：Isopropanol 97:3
Flow velocity：2.0ml/min
Test procedure
The μ l of 4- [[(4- fluorophenyls) imines] methyl]-phenol mixed solution 10 that Example 1 configures, are entered by above-mentioned condition
Row high-efficient liquid phase analysis, record chromatogram.
Result of the test
Conclusion：4- [[(4- fluorophenyls) imines] methyl] can baseline between-phenol and each impurity to be measured, each impurity to be measured
Separation.
Claims (9)
1. a kind of analysis method of key ezetimibe intermediate 4- [[(4- fluorophenyls) imines] methyl]-phenol, methods described
For high performance liquid chromatography, it is characterised in that this method includes using silica gel bonded cellulose-three（3,5- dichlorophenyl amino
Formic acid esters）The mixed solvent of chiral chromatographic column, n-hexane and isopropanol is mobile phase, and wherein n-hexane and isopropanol volume ratio is
96~99:4 ~ 1, and detected using UV-detector, flow velocity is 0.5 ~ 2.0ml/min, and the column temperature of chromatographic column is 15 ~ 40 DEG C.
2. analysis method according to claim 1, it is characterised in that：The silica gel bonded cellulose-three（3,5- dichloro-benzenes
Aminocarbamic acid ester）Chiral chromatographic column is Daicel Chiralpak IC columns.
3. analysis method according to claim 1, it is characterised in that：The silica gel bonded cellulose-three（3,5- dichloro-benzenes
Aminocarbamic acid ester）The specification of chiral chromatographic column is 150x4.6mm, 5 μm or 250x4.6mm, 5 μm.
4. analysis method according to claim 1, it is characterised in that：The volume ratio of the n-hexane and isopropanol is 98:
2。
5. analysis method according to claim 1, it is characterised in that：The Detection wavelength of described UV-detector is
284nm。
6. analysis method according to claim 1, it is characterised in that：The flow velocity is 1.0ml/min.
7. analysis method according to claim 1, it is characterised in that：The column temperature of the chromatographic column is 35 DEG C.
8. the analysis method described in claim any one of 1-7, it is in 4- [[(4- fluorophenyls) imines] methyl] the relevant thing of-phenol
Application in quality detection.
9. the analysis method described in claim any one of 1-7, it is examined in 4- [[(4- fluorophenyls) imines] methyl]-phenol content
Application in survey.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
-
2014
- 2014-12-31 CN CN201410844917.XA patent/CN105806967B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| Development and Validation of Chiral HPLC Method for Identification and Quantification of (R)-Enantiomer in Ezetimibe;Kameswara Rao Chimalakonda 等;《American Journal of Analytical Chemistry》;20120731;第3卷;第479页的2.2-2.4 * |
| Isolation and Characterization of R-Enantiomer in Ezetimibe;Kameswara Rao Chimalakonda 等;《American Journal of Analytical Chemistry》;20130930;第4卷;第488-495页 * |
| RP-HPLC测定依折麦布原料药中的有关物质;周增慧 等;《中国实验方剂学杂志》;20131031;第19卷(第19期);第159-163页 * |
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