Preparation method of fimasartan impurities

A Fimasartan and impurity technology, which is applied in the field of chemical substance preparation, can solve the problems of no preparation method and achieve the effect of high purity

Active Publication Date: 2019-03-19
合肥创新医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0022] Although impurities E and K are reported in the patent CN105784867A, they are only used for the analysis of the detection method, and there is no related preparation method

Method used

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  • Preparation method of fimasartan impurities
  • Preparation method of fimasartan impurities
  • Preparation method of fimasartan impurities

Examples

Experimental program
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Effect test

Embodiment 1

[0043]A preparation method of Fimasartan impurity E, comprising the steps of: adding Lawesson reagent to the FMST-1 toluene solution with a concentration of 0.17g / ml in a nitrogen atmosphere, heating up to 70°C, and stirring for 5h to obtain a reaction solution , vacuum-dry the reaction solution to obtain the crude product, then add ethyl acetate 5 times the weight of the crude product and water 5 times the weight of the crude product, heat up to dissolve, reflux, add activated carbon, reflux 1h, slowly cool to room temperature, stir 2h, filter, rinse the filter cake with ethyl acetate, adjust the temperature to 45°C, and blow dry for 6h to obtain impurity E, wherein the amount of Lawesson reagent is 0.6eq, the weight ratio of FMST-1 and activated carbon is 26.07:3, the impurity The yield of E is 63.8%;

[0044] The impurity E was detected by proton nuclear magnetic spectrum, and the detection result of proton nuclear magnetic spectrum was: 1H-NMR (400Mz, CDCl3) δ: 7.850~7.827...

Embodiment 2

[0051] A preparation method of Fimasartan impurity K, comprising the steps of: adding Lawesson reagent to the FMST-1 toluene solution with a concentration of 0.17g / ml in a nitrogen atmosphere, heating up to 70°C, and stirring for 5h to obtain a reaction solution , the reaction solution was evaporated to dryness in vacuo to obtain the crude product, the crude product was subjected to column chromatography, the eluate was collected, the temperature was adjusted to 40°C, and the impurity K was obtained by vacuum drying, wherein the mobile phase of the column chromatography was a mixture of methanol and dichloromethane Solution, wherein, the volume ratio of methanol and dichloromethane is 1:15, the amount of Lawesson reagent is 1.2eq, the weight volume (g / L) ratio of FMST-1 and eluent is 25.88:1, the yield of impurity K 68.3%;

[0052] The impurity K is detected by proton nuclear magnetic spectrum, and the proton nuclear magnetic spectrum detection result is: 1H-NMR (400Mz, CDCl3)...

Embodiment 3

[0056] A preparation method of Fimasartan impurity E, comprising the steps of: adding Lawesson reagent to the FMST-1 acetonitrile solution with a concentration of 0.13 g / ml in a nitrogen atmosphere, heating up to 80° C., and stirring for 4 hours to obtain a reaction solution , the reaction solution was vacuum-dried to obtain the crude product, then adding ethyl acetate 5 times the weight of the crude product and water 5 times the weight of the crude product, heating up to dissolve, reflux, adding activated carbon, refluxing for 0.5h, slowly cooling to room temperature, Stir for 3h, filter, rinse the filter cake with ethyl acetate, adjust the temperature to 50°C, and blow dry for 8h to obtain impurity E, wherein the amount of Lawesson reagent is 0.3eq, and the weight ratio of FMST-1 to activated carbon is 26.07:3, The yield of impurity E was 60.5%, and the purity of impurity E by HPLC analysis was 99.5%.

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Abstract

The invention discloses a preparation method of fimasartan impurities. The preparation method comprises the steps of adding a Lawesson reagent into an FMST-1 solution in an inert gas atmosphere, heating to 70-80 DEG C for reaction so as to obtain reaction liquid, and purifying the reaction liquid, so as to obtain an impurity E or an impurity K, wherein the impurity E is obtained under the conditions that the use amount of the Lawesson reagent is 0.3eq-0.6eq and the reaction time is 4-5 hours, and the impurity K is obtained under the conditions that the use amount of the Lawesson reagent is 1.2eq-1.25eq and the reaction time is 4-5 hours. The purifies of the prepared impurities E and K are high and are both higher than 95%, and the high-purity impurity reference substances can be provided for the research of the fimasartan impurities.

Description

technical field [0001] The invention relates to the technical field of chemical substance preparation, in particular to a method for preparing fimasartan impurities. Background technique [0002] Hypertension is one of the common cardiovascular diseases that seriously endanger human health, and it is also a major public health problem worldwide. In recent years, with the acceleration of global integration and the continuous improvement of people's living standards, hypertension has shown a growing trend worldwide. If active and effective treatment measures are not taken, it is estimated that by 2025, the number of patients with hypertension worldwide may Another 80% increase, so the outlook is not optimistic. In the past 50 years, the prevalence of hypertensive drugs in my country has also been showing an obvious upward trend. According to the report survey data on the nutrition and health status of Chinese residents in 2002, the prevalence of hypertension in adults over th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 曹明成年帅黄顺旺曹阳
Owner 合肥创新医药技术有限公司
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