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Preparation method of losartan impurity

A technology for losartan potassium and impurities, applied in the field of drug synthesis, can solve the problems of human toxicity, influence on the raw material drug of losartan potassium, no preparation method reported in literature, etc., and achieves short reaction steps, improved selectivity, and easy availability of raw materials. Effect

Inactive Publication Date: 2021-09-10
润都制药荆门有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the present research and development work, the inventors have found that alkylation impurities will inevitably appear in the losartan potassium synthesized by the existing synthetic route, and the chemical structural formula of the impurities is: , because impurities may have potential toxicity to the human body, impurity research is an important part of drug research, this impurity will affect the purity of losartan potassium API, the generation of this impurity should be controlled during the synthesis process, but there is no literature The preparation method of this impurity is reported, but it is an important impurity standard in the quality study of losartan potassium

Method used

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  • Preparation method of losartan impurity
  • Preparation method of losartan impurity
  • Preparation method of losartan impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Add 40g of losartan potassium (0.0868mol, 1eq) and 200ml of acetone into a 500ml four-neck flask, stir and cool down to 10°C, add 7.2g of K 2 CO 3 (0.0511mol, 0.7 equivalent), stir evenly, continue to add 12.9g of iodomethane (0.0911mol, 1.05 equivalent) in 20ml of acetone solution to the reaction solution, return to room temperature after adding, and react at room temperature for 6h. TLC monitors the completion of the reaction of losartan potassium. Concentrate the reaction solution to dryness under reduced pressure, add 100ml of dichloromethane and 100ml of water, stir evenly, add 13g of glacial acetic acid to the reaction solution to adjust pH=4~5, and cool down only 0~5℃ Stir and crystallize for 2 hours, filter, mix the wet product with 60ml of acetone, heat to reflux to dissolve, then cool down naturally, stir and crystallize at room temperature for 4 hours, filter and wash the filter cake with water, continue to filter until dry, and dry the filter cake to obtain ...

Embodiment 2

[0023] Add 40g of losartan potassium (0.0868mol, 1eq) and 200ml of acetone into a 500ml four-neck flask, stir and cool down to 10°C, add 7.2g of K 2 CO 3 (0.0511mol, 0.7 equivalent), stir well, continue to add 19.5g of isopropyl p-toluenesulfonate (0.0911mol, 1.05 equivalent) to the reaction solution in 20ml of acetone solution, return to room temperature after adding, and react at room temperature for 8h . TLC monitors that the reaction of losartan potassium is complete, concentrate the reaction solution to dryness under reduced pressure, add 100ml of dichloromethane and 100ml of water, stir well, add glacial acetic acid to the reaction solution to adjust pH=4~5, and cool down to 0~5°C Stir and crystallize for 2 hours, filter, mix the wet product with 60ml of acetone, heat to reflux to dissolve, then cool down naturally, stir and crystallize at room temperature for 4 hours, filter and wash the filter cake with water, continue to filter until dry, and dry the filter cake to o...

Embodiment 3

[0026] Add 40g of losartan potassium (0.0868mol, 1eq) and 200ml of acetone into a 500ml four-neck flask, stir and cool down to 10°C, add 7.2g of K 2 CO 3 (0.5211mol, 0.7 equivalent), stir evenly, continue to add 14.2g iodoethane (0.0911mol, 1.05 equivalent) in 20ml acetone solution to the reaction solution, return to room temperature after adding, and react at room temperature for 8h. TLC monitors the completion of the reaction of losartan potassium. Concentrate the reaction solution to dryness under reduced pressure, add 100ml of dichloromethane and 100ml of water, stir well, add glacial acetic acid to the reaction solution to adjust pH=4~5, and cool down only 0~5℃ Stir and crystallize for 2 hours, filter, mix the wet product with 60ml of acetone, heat to reflux to dissolve, then cool down naturally, stir and crystallize at room temperature for 4 hours, filter and wash the filter cake with water, continue to filter until dry, and dry the filter cake to obtain 32.02g of N Eth...

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Abstract

The invention relates to a preparation method of a losartan potassium impurity. In the production process, a novel losartan alkylation impurity is found, and the impurity has obvious influence on the quality of a finished product and is a key impurity in the preparation process. A synthesis method of the impurity is not reported at present. The invention provides a synthesis method of the losartan impurity, and the synthesis method has the advantages of short reaction steps, easily available raw materials, high yield and good regioselectivity.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing losartan impurities. Background technique [0002] Losartan potassium (Losartan), the chemical name is 2-butyl-4-chloro-5-(hydroxymethyl)-1-{[2'-(1H-tetrazol-5-)biphenyl]} Imidazole, is the first marketed non-peptide angiotensin II receptor antagonist. Jointly developed by Merck Company and Dupont Merck Pharmaceutical Company, it was first listed in Switzerland in 1994. In 2000, the State Food and Drug Administration approved the production of Merck Pharmaceutical Co., Ltd., and in 2004 it was approved by the US Food and Drug Administration (FDA). In recent years, it has been the first-line drug for the clinical treatment of hypertension, and its clinical application in China has also made great progress. It can be used to treat patients with mild, moderate and severe hypertension. Its antihypertensive effect is similar to that of the current first-line anti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor 蔡强阎智勇乐东张春亮陶少君徐晨廷谢立
Owner 润都制药荆门有限公司
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