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Preparation method for olmensartan medoxomil with low-level impurity

A technology of olmesartan medoxomil and esterification reaction, which is applied in the production of organic chemistry and bulk chemicals, can solve the problems of high price, high toxicity, unfavorable industrial production, etc., and achieve the goal of avoiding the use of highly toxic solvents and mild conditions Effect

Inactive Publication Date: 2011-10-05
SHANGHAI SHYNDEC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The olmesartan medoxomil impurity amount prepared by the above method is large, and the content is relatively high, which requires column chromatography purification, which is not conducive to industrial production; in addition, the solvent acetonitrile used in the reaction is not only expensive, but also highly toxic, which is harmful to the operation. Both personnel and environmental protection have put forward higher requirements

Method used

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  • Preparation method for olmensartan medoxomil with low-level impurity
  • Preparation method for olmensartan medoxomil with low-level impurity
  • Preparation method for olmensartan medoxomil with low-level impurity

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Experimental program
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Effect test

Embodiment 1

[0024] 1-[[[2′-(trityl)-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl-1- Preparation and Purification of Ethyl Methyl)imidazole-5-carboxylate (IV)

[0025] 7.0g calcium oxide, 15.0g 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylate ethyl ester (II) and 38.30g 4-[2-(trityl tetrazole -5-yl)phenyl]benzyl bromide (III), suspended in 90ml of N,N-dimethylacetamide, heating the reaction mixture to 60°C to 65°C, insulated and stirring the reaction until the end of the reaction (3~ 5 hours). The reaction solution was filtered hot, and the filtrate was cooled to 20°C and then poured into 400ml of ice water. A large amount of solids were precipitated, filtered and dried to obtain 49.60g of crude product (IV).

[0026] Add the crude product of (IV) to 300ml of acetone, heat to reflux, and after dissolving, heat filter, and the filtrate is gradually cooled to 20°C, kept at this temperature for 3 hours, then continued to cool to 0°C to 5°C, and kept for 2 hours...

Embodiment 2

[0029] 1-[[[2′-(trityl)-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl-1- Preparation and Purification of Ethyl Methyl)imidazole-5-carboxylate (IV)

[0030] 11.2g alumina, 17.6g ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (II) and 45.0g 4-[2-(trityl tetrazole -5-yl)phenyl]benzyl bromide (III), suspended in 100ml N,N-dimethylacetamide, heating the reaction mixture to 60°C to 65°C, keeping the temperature and stirring the reaction until the end of the reaction (3~ 5 hours). The reaction solution was filtered hot, and the filtrate was cooled to 20°C and then poured into 450ml of ice water. A large amount of solids were precipitated, filtered and dried to obtain 52.60g of crude product (IV).

[0031] Add the crude product of (IV) to 300ml of acetone, heat to reflux, and after dissolving, heat filter, and the filtrate is gradually cooled to 20°C, kept at this temperature for 3 hours, then continued to cool to 0°C to 5°C, and kept for 2 hours,...

Embodiment 3

[0038] 1-[[[2′-(trityl)-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl-1- Preparation and Purification of Methylethyl)imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (VI)

[0039]36.0 g of high-purity compound (IV) and 3.0 g of sodium hydroxide powder were suspended in 270 ml of dimethylacetamide, stirred at a temperature of 30°C to 35°C for 3 hours, and compound (IV) was completely reacted. The reaction mixture was cooled to 0°C, 6.90 g of potassium carbonate was added, and under stirring, 13.91 g of 4-chloromethyl-5-methyl-2-oxo-1,3 - Dioxole (V), after the addition is completed, the reaction mixture is slowly heated to 60° C. to 65° C., and the reaction is kept for 3 to 5 hours. After the reaction, the reaction mixture was cooled to 5°C-10°C, poured into 800ml of ice water, a large amount of solid precipitated, filtered, and dried to obtain 43.10g of crude product (VI).

[0040] Add the crude product of (VI) to 150ml of acetone, hea...

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Abstract

The invention relates to the technical field of a preparation method for an olmensartan medoxomil with a low-level impurity. With the invention, 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester and 4-[12-(triphenylmethyl tetrazole-5-yl) phenyl] benzyl bromide are adopted as raw materials, and are sequentially subjected to an alkylating, a hydrolysis and a esterification, and a last process of a protective group removing to obtain the olmensartan medoxomil with high impurity. Content of single impurity of the olmensartan medoxomil is less than 0.1%. In the prior art, the olmensartan medoxomil has disadvantages of a variety of the impurities, high content of the impurities, and a requirement of a purification by a column chromatography so as to go against an industrial production. According to the present invention, problems of the prior art are solved. In addition, the preparation method provided by the present invention is mild, and avoids using solvents with high toxicity so as to comply with environmental requirements of the industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation methods of olmesartan medoxomil. Background technique [0002] Olmesartan medoxomil (olmensartan medoxomil) is a novel angiotensin II receptor (AT1) antagonist, its chemical name is 4-(1-hydroxy-1-methylethyl)-2-propyl-1 -{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxole -4-yl) methyl ester. Its chemical structure is: [0003] [0004] Japanese patent publication JP (31) 27098, European patent EP0503785, CN101238119A, CN1976926A, CN101094849A, Journal of Medical Chemistry, 1996, Vol.39, 323-338 have all reported the preparation method of olmesartan medoxomil. These methods all focus on the alkylation reaction between the imidazole intermediate and the substituted biphenylmethylene bromide, the alkylated product is hydrolyzed and esterified under alkaline conditions, and the trityl protecting group is removed under acidic conditions to obtain...

Claims

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Application Information

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IPC IPC(8): C07D405/14
CPCY02P20/55
Inventor 邹强郑少军戈耘侯建王国平
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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