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Novel preparation method for azilsartan and intermediate thereof

An intermediate, bromomethyl technology, applied in the field of preparation of pharmaceutical compounds, can solve problems such as instability of the 2-position ethoxy group, difficulty in product purification, and carbonyl conversion, and achieve easy procurement, industrial mass production, and route shortened effect

Inactive Publication Date: 2016-06-15
CHONGQING LAND TOWER PHARMA
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0019] The key intermediate 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1 of the above two routes H The 2-ethoxy group on the benzimidazole of -benzimidazole-7-carboxylic acid methyl ester (II) is unstable, and it is easy to drop the ethyl group in the following four-step reaction and become a carbonyl group, so that in the subsequent reaction Generate a series of other impurities, thereby reducing the yield and bringing great difficulties to the purification of the product

Method used

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  • Novel preparation method for azilsartan and intermediate thereof
  • Novel preparation method for azilsartan and intermediate thereof
  • Novel preparation method for azilsartan and intermediate thereof

Examples

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example 1

[0044] example 1( Z )-4'-(bromomethyl)- N’ Preparation of -Hydroxy-[1,1'-biphenyl]-2-amidine

[0045] Add 100ml of dimethyl sulfoxide to the dry reaction bottle, add 182g of hydroxylamine hydrochloride, stir to dissolve, add 60g of raw material 2-cyano-4'-bromomethylbiphenyl, control the internal temperature at 25-30°C, add 302g of anhydrous sodium carbonate, heat up to 75-80°C, keep warm for reaction, and use HPLC to control (until 2-cyano-4'-bromomethylbiphenyl≤0.5%). Cool down to 20-30°C, slowly add 3L of water, and continue stirring for 1 hour after the addition is complete. Suction filtration, the filter cake was washed with about 200ml of water, suction filtration to dryness, and drying under reduced pressure at 50±5°C to obtain ( Z )-4'-(bromomethyl)- N’ -Hydroxy-[1,1'-biphenyl]-2-amidine dry product 57g. Yield 85.4%, purity 96.7%.

example 2

[0046] Example 2 ( Z )-4'-(bromomethyl)- N’ Preparation of -Hydroxy-[1,1'-biphenyl]-2-amidine

[0047] Add 69.5g of hydroxylamine hydrochloride to 400ml of tetrahydrofuran and stir to dissolve, add dropwise 210g of 27% sodium methoxide in methanol at room temperature, stir for 10 minutes, add 54.2g of 2-cyano-4'-bromomethylbiphenyl, at 90 Stir the reaction at ~95°C, use HPLC to control (until 2-cyano-4'-bromomethylbiphenyl≤0.5%), cool down to 20-30°C, add 1.2L water dropwise at room temperature, and stir for 30 minutes. Filter, wash with 100°C of water, and dry under reduced pressure at 50-60°C to obtain ( Z )-4'-(bromomethyl)- N’ -Hydroxy-[1,1'-biphenyl]-2-amidine dry product 54.6g, yield 89.9%, purity 95.8%

example 3

[0048] Example 3 ( Z )-4'-(bromomethyl)- N’ Preparation of -Hydroxy-[1,1'-biphenyl]-2-amidine

[0049] Add 139g of hydroxylamine hydrochloride to 750ml of ethanol and stir to dissolve, add dropwise 220g of triethylamine at room temperature, stir at 35~40 for 60 minutes, add 66g of 2-cyano-4'-bromomethylbiphenyl, and stir at 65~70 The reaction was controlled by HPLC (until 2-cyano-4'-bromomethylbiphenyl≤0.5%), cooled to room temperature, 2L water was added dropwise at room temperature, stirred for 1h, filtered, washed with 150ml water, at 50 ~60 decompression drying, get ( Z )-4'-(bromomethyl)- N’ -Hydroxy-[1,1'-biphenyl]-2-amidine dry product 59.2g, yield 79.8%, purity 96.4%

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Abstract

The invention relates to an intermediate for preparing azilsartan and a novel preparation method for the azilsartan. The method includes the following steps: 1) reducing 2-cyano-4'-bromomethylbiphenyl with hydroxylamine hydrochloride to generate (Z)-4'-bromomethyl-(N')-hydroxy-[1,1'-biphenyl]-2-amidine; 2) performing esterification with ethyl chloroformate to generate (Z)-4'-bromomethyl-(N')-((ethoxycarbonyl)oxyl)-[1,1'-biphenyl]-2-amidine; 3) performing ring closing to prepare 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazole-5-(4H)-one; 4) performing a condensation reaction to 2-ethoxy-1H-benzimidazole-7-methyl carboxylate and the 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazole-5-(4H)-one to prepare 2-ethoxy-1-((2'-(2,5-dihydro-5-oxy-1,2,4-oxadiazole-3-yl)biphenyl-4-yl)methyl)benzimidazole-7-methyl carboxylate; and 5) finally performing hydrolysis to prepare the azilsartan. The method employs the raw material being easy to obtain, is short in synthetic route, is low in device cost, is less in side products, is low in toxicity and pollution, is environment-friendly, is high in product purity and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of an intermediate of azilsartan and a new preparation method of azilsartan. Background technique [0002] In recent years, with the continuous improvement of people's living standards and the growth of the elderly population, hypertension is becoming a common disease with a high prevalence rate. At present, there is no effective means to cure high blood pressure at home and abroad. Therefore, once high blood pressure is diagnosed, it will be accompanied for life and cause many other related diseases. According to the World Health Organization (WHO) statistics on the death of various diseases in the world, the proportion of the death toll of cardiovascular and cerebrovascular diseases represented by hypertension in the total death toll will rise from 28.8% in 1997 to 36.0% in 2002, a high Blood pressure is seriously endangering human healt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C257/18C07D271/07C07D413/10
Inventor 孟文学龙道兵孙文靖
Owner CHONGQING LAND TOWER PHARMA
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