HPLC method for the analysis of related substances of Fimasartan and the use of these impurities as reference standards

A technology for Fimasartan and impurities, which is applied in the field of drug synthesis and can solve problems such as inappropriate determination

Active Publication Date: 2019-01-01
BEIJING CREATRON INST OF PHARMA RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method for determining the content of main components of the compound preparation of fimasartan and amlodipine besylate was reported in the public literature (ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES 9(2014) 123-128), but this method is not suitable for the analysis of fimasartan Determination of related substances in its hydrates

Method used

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  • HPLC method for the analysis of related substances of Fimasartan and the use of these impurities as reference standards
  • HPLC method for the analysis of related substances of Fimasartan and the use of these impurities as reference standards
  • HPLC method for the analysis of related substances of Fimasartan and the use of these impurities as reference standards

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1: Compound A: Synthesis of (E)-2-(2-butyl-6 methyl-4-carbonylpyrimidinyl-5-(4H)-subunit)-N,N-dimethylacetamide .

[0124]Add 20ml of a mixed solvent of N,N-dimethylformamide and ethyl acetate (volume ratio 1:1) to a 100mL three-necked flask, and add 1.00g of SM1(2-(2-butyl-4-methanol) under stirring Base-6-oxo-1,6-dihydropyrimidin-5-yl)-N,N-dimethylacetamide), nitrogen protection, cooling to 0-10°C, adding 0.48 g of LiH, and continuing to stir for 20-30 Minutes, add 2.08 grams of SM2 (5-(4'-(bromomethyl)-[1,1'-diphenyl]-2-yl)-1-triphenyl-1H-tetrazolium), warming up to Stir at 60° C. for 48 hours; sample TLC (methanol:dichloromethane=1:10) detects that the starting material disappears. After adding 20ml of water, a large amount of solids precipitated, and the stirring was continued for 30 minutes. Filtrate, drain, and blow dry at 40°C for 30 minutes to obtain a solid crude product, which is purified by column chromatography, the elution ratio is: methanol:dic...

Embodiment 2

[0125] Example 2: Compound L: 2-(1-((2'-(1H-tetrazol-5-yl)-[1,1'-diphenyl]-4-yl)methyl)-2- Preparation of butyl-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetylmethyl ester

[0126] Add 20ml of N, N-dimethylformamide and ethyl acetate (volume ratio 1: 1) mixed solvent into the three-necked flask of 100mL, add the impurity of 1.00g SM1 under stirring Shown SM1 impurity), nitrogen protection, cooling to 0~10 ℃, adding 0.48 gram of LiH, continuing to stir for 20~30 minutes, adding 2.08 gram of SM2, heating up to 60 ℃, stirring for 48 hours; sampling TLC detection (methanol: dichloro methane=1:10) the starting material disappeared. After adding 20ml of water, a large amount of solids precipitated, and the stirring was continued for 30 minutes. Filtered, pumped dry, and air-dried at 40°C for 30 minutes to obtain 2.18 g of a solid crude product, which was dissolved in 100 mL of toluene, and 1.57 g of Lawesson's reagent was added. Under nitrogen protection, the reaction solution was...

Embodiment 3

[0127] Example 3: Compound I: 2-(2-butyl-1-((2'-cyano-[1,1'-diphenyl]-4-yl)methyl)-4-methyl-6 Preparation of -Oxy-1,6-dihydropyrimidin-5-yl)-N,N-dimethylthioacetamide

[0128] Add 20ml of a mixed solvent of N,N-dimethylformamide and ethyl acetate (volume ratio 1:1) into a 100mL three-necked flask, add 1.00g of SM1 under stirring, protect with nitrogen, cool to 0-10°C, add 0.30 g of LiH, continue to stir for 20 to 30 minutes, add 1.30 g of 4'-(bromomethyl)-[1,1'-diphenyl]-2-carbonitrile (SM2-impurity-1), heat up to 60 ° C, Stir for 48 hours; sample TLC (methanol:dichloromethane=1:20) detects that the starting material disappears. 15ml of water was added, a large amount of solids were precipitated, and the stirring was continued for 30 minutes. Filtered, pumped dry, and air-dried at 40°C for 30 minutes to obtain 1.41 g of a solid crude product. Dissolve the crude product in 50 mL of toluene, add 1.28 g of Lawesson's reagent, and under nitrogen protection, heat the reaction sol...

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Abstract

The invention discloses a method for analyzing impurities that are produced during the preparation of fimasartan potassium(2-butyl-5-dimethylaminothioformylmethyl-6-methyl-3-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-ketosylvite) or a hydrate thereof, wherein the impurities are selected from compounds A-L, and the method comprises the following steps: (1) dissolving a sample that contains the fimasartan or the hydrate thereof in a solvent to prepare a sample solution; (2) dissolving samples of any one or more of the compounds A-L in the solvent to prepare a reference standard solution or a reference substance solution; (3) performing a chromatography technology on the sample solution and the reference standard solution; (4) measuring the presence of any one or more of the compounds A-L in the sample by referring to one or more of known compounds A-L that are present in the reference standard solution.

Description

technical field [0001] The invention belongs to the field of medicine synthesis. Specifically, the present invention relates to Fimasartan potassium (2-butyl-5-dimethylaminothioformylmethyl-6-methyl-3-[[2'-(1H-tetrazole-5- base) biphenyl-4-yl]methyl]pyrimidin-4(3H)-one potassium salt) or a method for analyzing the impurities that appear during the preparation of its hydrate. Background technique [0002] Fimasartan (Fimasartan) is a novel selective AT1 receptor blocker, which exhibits rapid and effective antihypertensive effects in various types of hypertension, and is very safe and well tolerated. superior to other drugs of the same type. In September 2011, Fimasartan (potassium salt) of South Korea's Boryeong Pharmaceutical Co., Ltd. (BorYung) was launched in South Korea. In 2013, it was listed in Russia, Mexico, Brazil, Cuba and other countries. It is currently undergoing phase III clinical trials in the United States and is expected to be declared by the FDA by 2016....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02G01N30/06
CPCG01N30/02G01N30/06G01N2030/027
Inventor 贾慧娟王艳鑫李衍
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD
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