Analysis method of 4-[[(4-fluorophenyl)imine]methyl]-phenol, the key intermediate of ezetimibe

Abstract

The invention discloses a method for analyzing and detecting 4-[[(4-fluorophenyl)imine]methyl]-phenol, a key intermediate of ezetimibe, and its application. The method uses silica gel to bond cellulose- The tris(3,5-dichlorophenylcarbamate) chiral column can analyze and detect 4-[[(4-fluorophenyl)imine]methyl]-phenol, which can monitor the focus of the target well Impurities: chlorinated impurities, defluorinated impurities and meta-fluorine impurities, and the operation is simple and convenient, with strong specificity, suitable for daily application of 4-[[(4-fluorophenyl)imine]methyl]-phenol related substances and Content testing.

Description

technical field

[0001] The invention belongs to the technical field of analysis, and in particular relates to an analysis and detection method of 4-[[(4-fluorophenyl)imine]methyl]-phenol, a key intermediate of ezetimibe, and an application thereof. Background technique

[0002] 4-[[(4-fluorophenyl)imine]methyl]-phenol is the key intermediate in the synthesis of ezetimibe, which is a selective cholesterol absorption inhibitor and has been widely used clinically. The three impurities contained in 4-[[(4-fluorophenyl)imine]methyl]-phenol-chlorinated impurities, defluorinated impurities and meta-fluorine impurities will participate in the reaction and be carried to the final product, affecting the purity of the final product and yield, so the above-mentioned impurities are preferably controlled in the starting material.

[0003] 4-[[(4-fluorophenyl)imine]methyl]-phenol, CAS: 3382-63-6

[0004] Chlorinated impurities Defluorinated impurities Fluorine impurity

[0005] ...

Examples

Embodiment 1

[0022] Instruments and Conditions

[0023] Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance

[0024] Chromatographic column: Daice lChiralpak IC columns 150 x 4.6mm, 5μm

[0025] Column temperature: 35°C

[0026] UV detection wavelength: 284nm

[0027] Mobile phase: n-hexane: isopropanol 98:2

[0028] Flow rate: 1.0ml / min

[0029] experiment procedure

[0030] Prepare impurity reference substance stock solution: take about 10 mg of each of p-fluoroaniline, p-hydroxyformaldehyde, defluorinated, defluorinated, and meta-fluorinated impurities, put them in a 100ml volumetric flask, dissolve them with isopropanol: n-hexane (10:90) and Dilute to the mark, shake well, and get it;

[0031] Prepare the impurity reference substance solution: accurately pipette 1.0ml of the reference substance stock solution, put it in a 10ml volumetric flask, dissolve in isopropanol:n-hexane (10:90) and dilute to the mark, shake well, and you get it;...

Embodiment 2

[0039] Instruments and Conditions

[0040] Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance

[0041] Chromatographic column: Daicel Chiralpak IC columns 250 x 4.6mm, 5μm

[0042] Column temperature: 20°C

[0043] UV detection wavelength: 284nm

[0044] Mobile phase: n-hexane: isopropanol 96:4

[0045] Flow rate: 1.0ml / min

[0046] experiment procedure

[0047] Take 10 μl of the 4-[[(4-fluorophenyl)imine]methyl]-phenol mixed solution prepared in Example 1, perform HPLC analysis according to the above conditions, and record the chromatogram.

[0048] test results

[0049]

[0050] Conclusion: 4-[[(4-fluorophenyl)imine]methyl]-phenol can be baseline separated from each impurity to be detected and each impurity to be detected.

Embodiment 3

[0052] Instruments and Conditions

[0053] Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance

[0054] Chromatographic column: Daicel Chiralpak IC columns 150 x 2.1mm, 5μm

[0055] Column temperature: 40°C

[0056] UV detection wavelength: 275nm

[0057] Mobile phase: n-hexane: isopropanol 99:1

[0058] Flow rate: 0.5ml / min

[0059] experiment procedure

[0060] Take 10 μl of the 4-[[(4-fluorophenyl)imine]methyl]-phenol mixed solution prepared in Example 1, perform HPLC analysis according to the above conditions, and record the chromatogram.

[0061] test results

[0062]

[0063] Conclusion: 4-[[(4-fluorophenyl)imine]methyl]-phenol can be baseline separated from each impurity to be detected and each impurity to be detected.

technical field

[0001] The invention belongs to the technical field of analysis, and in particular relates to an analysis and detection method of 4-[[(4-fluorophenyl)imine]methyl]-phenol, a key intermediate of ezetimibe, and an application thereof. Background technique

[0002] 4-[[(4-fluorophenyl)imine]methyl]-phenol is the key intermediate in the synthesis of ezetimibe, which is a selective cholesterol absorption inhibitor and has been widely used clinically. The three impurities contained in 4-[[(4-fluorophenyl)imine]methyl]-phenol-chlorinated impurities, defluorinated impurities and meta-fluorine impurities will participate in the reaction and be carried to the final product, affecting the purity of the final product and yield, so the above-mentioned impurities are preferably controlled in the starting material.

[0003] 4-[[(4-fluorophenyl)imine]methyl]-phenol, CAS: 3382-63-6

[0004] Chlorinated impurities Defluorinated impurities Fluorine impurity

[0005] ...

Examples

Embodiment 1

[0022] Instruments and Conditions

[0023] Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance

[0024] Chromatographic column: Daice lChiralpak IC columns 150 x 4.6mm, 5μm

[0025] Column temperature: 35°C

[0026] UV detection wavelength: 284nm

[0027] Mobile phase: n-hexane: isopropanol 98:2

[0028] Flow rate: 1.0ml / min

[0029] experiment procedure

[0030] Prepare impurity reference substance stock solution: take about 10 mg of each of p-fluoroaniline, p-hydroxyformaldehyde, defluorinated, defluorinated, and meta-fluorinated impurities, put them in a 100ml volumetric flask, dissolve them with isopropanol: n-hexane (10:90) and Dilute to the mark, shake well, and get it;

[0031] Prepare the impurity reference substance solution: accurately pipette 1.0ml of the reference substance stock solution, put it in a 10ml volumetric flask, dissolve in isopropanol:n-hexane (10:90) and dilute to the mark, shake well, and you get it;...

Embodiment 2

[0039] Instruments and Conditions

[0040] Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance

[0041] Chromatographic column: Daicel Chiralpak IC columns 250 x 4.6mm, 5μm

[0042] Column temperature: 20°C

[0043] UV detection wavelength: 284nm

[0044] Mobile phase: n-hexane: isopropanol 96:4

[0045] Flow rate: 1.0ml / min

[0046] experiment procedure

[0047] Take 10 μl of the 4-[[(4-fluorophenyl)imine]methyl]-phenol mixed solution prepared in Example 1, perform HPLC analysis according to the above conditions, and record the chromatogram.

[0048] test results

[0049]

[0050] Conclusion: 4-[[(4-fluorophenyl)imine]methyl]-phenol can be baseline separated from each impurity to be detected and each impurity to be detected.

Embodiment 3

[0052] Instruments and Conditions

[0053] Instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance

[0054] Chromatographic column: Daicel Chiralpak IC columns 150 x 2.1mm, 5μm

[0055] Column temperature: 40°C

[0056] UV detection wavelength: 275nm

[0057] Mobile phase: n-hexane: isopropanol 99:1

[0058] Flow rate: 0.5ml / min

[0059] experiment procedure

[0060] Take 10 μl of the 4-[[(4-fluorophenyl)imine]methyl]-phenol mixed solution prepared in Example 1, perform HPLC analysis according to the above conditions, and record the chromatogram.

[0061] test results

[0062]

[0063] Conclusion: 4-[[(4-fluorophenyl)imine]methyl]-phenol can be baseline separated from each impurity to be detected and each impurity to be detected.

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