Preparation and purification method of olmesartan medoxomil key intermediate

A technology for olmesartan medoxomil and a purification method, applied in the field of chemical synthesis, can solve the problems of difficult separation and removal of by-products, difficult to realize industrialized production, poor product quality, etc., and achieves easy control of process conditions, simple post-processing and low production cost. Effect

Inactive Publication Date: 2020-06-09
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Related reports in existing literature 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2'-(trityl-1H-tetrazol-5-yl)(1 ,1'-biphenyl)-4-yl]methyl}-1H-imidazole-5-ethyl carboxylate has the following preparation methods: Chinese Patent Publication Nos. CN1532195A, CN1045770C and CN1381453A etc. provide preparations for the treatment of hypertension The preparation method of olmesartan has been reported on the medicine olmesartan, and Japanese patent JP[31]27098, European patent EP503785, Journal nbl of Medicinalchemistry 1996, Vo1.39, No.1323-338, described method It is formed by linking the imidazole part and the biphenyl part. During the reaction, side reactions easily occur to form by-products, which brings difficulties to subsequent processing, making it difficult to separate and remove the by-products. The quality of the obtained product is poor, and the yield is also low, which is difficult to achieve Industrial production

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  • Preparation and purification method of olmesartan medoxomil key intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] A. Add 660kg acetonitrile in the 1000L glass-lined reaction kettle equipped with devices such as agitator, thermometer vacuum pressure gauge, etc., add 30.0kg compound (II), 84kg compound (III) and 34.8kg potassium hydroxide powder under stirring, close the feeding After nitrogen replacement, keep the nitrogen positive pressure, the temperature is raised to 90 ℃ under stirring, the reaction process control pressure is ≥0.01Mpa≤0.3Mpa, and the temperature is maintained and stirred for 12 hours. After the reaction finishes, the temperature in the reaction mixture is lowered to 45~50 ℃, the insoluble by-product is removed by pressure filtration, the filtrate is concentrated under reduced pressure to recover the solvent to 3 / 4 of the added amount, the concentrated solution is cooled for crystallization, and the crystallization is incubated at 3 ℃ for 1 hour, Centrifuge to obtain the wet crude product of compound (I).

[0015] B, add 180kg of acetonitrile to the 500L refinin...

Embodiment 2

[0017] A. Add 600kg acetonitrile in the 1000L glass-lined reactor equipped with devices such as agitator, thermometer vacuum pressure gauge, etc., add 30.0kg compound (II), 76.6kg compound (III) and 30.2kg potassium hydroxide powder under stirring, close At the feeding port, after nitrogen replacement, keep nitrogen positive pressure, heat up to 85°C under stirring, control pressure ≥0.01Mpa≤0.3Mpa in the reaction process, keep stirring for 14 hours. After the reaction finishes, the temperature in the reaction mixture is lowered to 45~50 ℃, the insoluble by-product is removed by pressure filtration, the filtrate is concentrated under reduced pressure to recover the solvent to 3 / 4 of the added amount, the concentrated solution is cooled for crystallization, and the crystallization is incubated at 5 ℃ for 1 hour, Centrifuge to obtain the wet crude product of compound (I).

[0018] B, add 150kg of acetonitrile to the 500L refining kettle, start stirring, add the wet crude product...

Embodiment 3

[0020] A. Add 750kg of acetonitrile in the 1000L glass-lined reactor equipped with devices such as agitator, thermometer vacuum pressure gauge, add 30kg of compound (II), 84kg of compound (III) and 34.8kg of potassium hydroxide powder under stirring, close the feeding port , after nitrogen replacement, keep nitrogen positive pressure, heat up to 80 ℃ under stirring, control pressure ≥0.01Mpa≤0.3Mpa in the reaction process, keep stirring for 15 hours. After the reaction finishes, the temperature in the reaction mixture is reduced to 45~50 ℃, the insoluble by-product is removed by pressure filtration, the filtrate is concentrated under reduced pressure to recover the solvent to 3 / 4 of the added amount, the concentrated solution is cooled for crystallization, and the crystallization is incubated at 0 ℃ for 1 hour, Centrifuge to obtain the wet crude product of compound (I).

[0021] B, add 165kg of acetonitrile to the 500L refining kettle, turn on stirring, add the wet crude produ...

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Abstract

The invention relates to a preparation and purification method of a key intermediate 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2' -(triphenylmethyl-1H-tetrazole-5-yl) (1, 1'-biphenyl)-4-yl] methyl}-1H-imidazole-5-ethyl formate (I) for preparing a chemical drug olmesartan medoxomil for treating hypertension. The invention provides a preparation and purification method for generating a compound (I) by reacting 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) with N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl) tetrazole (III) in the presence of an organic solvent and an acid-binding agent. According to the preparation and purification method of the compound (I), the impurity content is effectively reduced, and the quality of a subsequent target productis improved. The method is stable in process, high in yield, good in quality, simple to operate, less in three wastes, low in production cost and suitable for industrial production, and the recoveredsolvent can be continuously used.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a key intermediate 4-(1-hydroxy-1-methylethyl)-2-propyl-1 for preparing a chemical drug olmesartan medoxomil for treating hypertension -{[2'-(Trityl-1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl]methyl}-1H-imidazole-5-carboxylic acid ethyl ester compound ( I) preparation and purification method. Background technique [0002] Reports related to existing literature 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2'-(trityl-1H-tetrazol-5-yl)(1 ,1 '-biphenyl)-4-yl] methyl}-1H-imidazole-5-ethyl carboxylate preparation method has the following several kinds: Chinese Patent Publication No. CN1532195A, CN1045770C and CN1381453A etc. provide can be prepared to treat hypertension The drug olmesartan, as well as Japanese Patent Publication JP [31] 27098, European Patent EP503785, Jour nbl of Medicinalchemistry 1996, Vol.39, No.1323-338 have reported the preparation method of olmesartan. It is formed b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 朱连博郑忠辉
Owner SHANDONG XINHUA PHARMA CO LTD
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