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4-[(4- fluorophenylimino) methyl]-phenol related substance detection method and application thereof

A technology of fluorophenylimine and detection method, which is applied in the field of drug analysis and achieves the effects of high sensitivity, simple operation and high specificity

Inactive Publication Date: 2015-10-14
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, conventional reversed-phase high-performance liquid chromatography is not suitable for the detection of related substances of 4-[(4-fluorophenylimine) methyl]-phenol, and it is necessary to invent a new method to monitor the quality of its related substances

Method used

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  • 4-[(4- fluorophenylimino) methyl]-phenol related substance detection method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The choice of solvent and the choice of the concentration of the solution:

[0025] For the choice of solvent for dissolving samples, we used dimethyl sulfoxide, dimethylformamide, ethanol, isopropanol, and acetonitrile to dissolve samples respectively, all of which are easily soluble to samples. Dimethyl sulfoxide and dimethyl formamide produce large solvent peaks on the liquid chromatography column, and are likely to remain in the syringe and column to affect detection. Ethanol or isopropanol should be considered as the preferred choice. After investigation, it was found that the sample would decompose after being placed in ethanol and isopropanol solutions for a period of time, so acetonitrile was chosen to dissolve the sample, and it was prepared and tested immediately.

[0026] We use acetonitrile as the solvent of the sample, and they are formulated into 0.2mg / mL, 1.0mg / mL and 5mg / mL respectively. Although they can be separated, the response of 0.2mg / mL is too sma...

Embodiment 2

[0028] Selection of mobile phase type and flow rate:

[0029] We choose the commonly used normal phase liquid chromatography mobile phase system: n-hexane-isopropanol, n-hexane-ethanol, n-heptane-isopropanol, n-heptane-ethanol, cyclohexane-isopropanol, cyclohexane —Ethanol screening, the results show that the main peak of the sample in the n-hexane and cyclohexane systems is relatively wide, and the separation degree from impurities cannot reach more than 1.5; Plate number, n-heptane-ethanol system is higher than n-heptane-isopropanol system, so n-heptane-ethanol is selected as mobile phase system.

[0030] We have investigated the flow rate, and the technical solution can be realized in the range of 0.2-2.0mL / min, but the flow rate of 0.2mL / min is too slow, the peak time of the sample is too long, and the peak shape is too broad; the flow rate of 2.0mL / min leads to The peak eluting time of the sample is too early and cannot be completely separated from impurities. Selecting...

Embodiment 3

[0032] 1) Instruments and testing conditions

[0033] E2695 high-performance liquid chromatograph produced by American Waters Company, autosampler, Chiralpak IA chiral analysis column produced by Daicel Company (4.6×250mm, 5μm); mobile phase ratio n-heptane:ethanol (95:5) ;Column temperature: 35°C; Flow rate: 1.0mL / min; Detection wavelength: 232nm; Injection volume: 20μL.

[0034] 2) Experimental steps

[0035] Accurately weigh 10mg of 4-[(4-fluorophenylimine)methyl]-phenol into a 10mL volumetric flask, dissolve with acetonitrile, dilute to the mark, and mix well to obtain the test solution (1mg / ml).

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Abstract

The invention provides a liquid chromatography detection method of 4-[(4-fluorophenylimino) methyl]-phenol. The liquid chromatography detection method is implemented under the following chromatographic conditions: a chromatographic column is formed by a silica gel column, an amino column, a cyano column, a phenyl column and a chiral column, a mobile phase is formed by n-hexane (A) and isopropanol (B), n-hexane (A) and ethanol (B), n-heptane (A) and isopropanol (B), or n-heptane (A) and ethanol (B), a ratio of A to B in the mobile phase is (95:5) to (70:30), the mobile speed of the mobile phase is 0.2-2.0mL / min, the detection wavelength is 200-400nm, the column temperature is 25-40 DEG C, and an ultraviolet detector or a diode array detector is adopted. The detection method is normal-phase liquid chromatography. The detection method is high in sensitivity and specificity, is simple and convenient in operation, has a degree of separation meeting the standards, can be used for rapidly and accurately detecting related substances and the content of 4-[(4-fluorophenylimino) methyl]-phenol, can be applied to quality control of 4-[(4-fluorophenylimino) methyl]-phenol, and has important significance to synthesis of a cholesterol absorption inhibitor, namely ezetimibe.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, and in particular relates to a method for detecting related substances of 4-[(4-fluorophenylimine)methyl]-phenol and an application thereof. Background technique [0002] 4-[(4-fluorophenylimine)methyl]-phenol (English name: 4-[(4-Fluorophenylimino)methyl]phenol), molecular formula is C13H10FNO, molecular weight is 215.22, CAS registration number: 3382-63- 6. The pure product of 4-[(4-fluorophenylimine)methyl]-phenol is light yellow crystal with a melting point of 173-176°C. Its structure is shown below. [0003] [0004] 4-[(4-Fluorophenylimine)methyl]-phenol is an important intermediate of ezetimibe, a drug for the treatment of primary hypercholesterolemia. Ezetimibe is a new class of cholesterol-lowering drugs. Compared with statins that inhibit the synthesis of cholesterol in the liver, ezetimibe works by selectively inhibiting the absorption of cholesterol in the intestine. In ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/62
Inventor 郝英魁金松子吴学丹蒋庆峰
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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