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Process for the Preparation of Candesartan Cilexetil

a technology of candesartan and cilexetil, which is applied in the field of process for the preparation of candesartan cilexetil, can solve the problems of low yield of the process, insufficient completion of the deprotection reaction, and insufficient processing of the reaction mixture, so as to achieve short reaction time, lower impurity levels, and high yield

Inactive Publication Date: 2010-08-05
ZUPANCIC SILVO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]It has unexpectedly been found that in the preparation of candesartan and its pharmaceutically active esters and salts, preferably candesartan cilexetil, the deprotection reaction of the tetrazolyl protecting group, especially when the tetrazolyl protecting group is trityl, leads to much higher yields if performed in a polar organic solvent, and in the presence of a Lewis acid. The reaction times are shorter when compared to prior art deprotection procedures and consequently, candesartan cilexetil with lower levels of impurities is prepared.

Problems solved by technology

The setbacks of this procedure are very low yields and the product needs to be purified by means of chromatography.
The drawbacks of the above mentioned methods are that they include the use of strongly corrosive acids and also the need to process the reaction mixture by complex extractions or chromatographic purification.
The reported conversion to candesartan cilexetil is between 76% and 91% which is still not optimal in industrial production, and the reported reaction time is 24 hours, which is another setback from the industrial point of view.
The drawbacks of these procedures are that the deprotection reaction is not completed properly and that the product is mostly isolated in form of a viscous oil due to impurities present.

Method used

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  • Process for the Preparation of Candesartan Cilexetil
  • Process for the Preparation of Candesartan Cilexetil
  • Process for the Preparation of Candesartan Cilexetil

Examples

Experimental program
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Effect test

example 1

[0077]The mixture of 0.43 g (0.5 mmol) of trityl candesartan cilexetil, 15 ml of methanol, 0.05 g (0.37 mmol) of ZnCl2 and 0.4 ml of water is stirred under reflux temperature for 2.5 h. The reaction mixture is analyzed (Area % HPLC: candesartan cilexetil: 75.5%, trityl candesartan cilexetil: 1.2%, 2-oxo candesartan cilexetil: 1.6%) and cooled to room temperature. Then, the mixture is neutralized to pH 6.11 by addition of a saturated solution of NaHCO3 and methanol is evaporated. Ethyl acetate (15 ml) and water (10 ml) are added and the mixture is stirred. After the separation of phases, the organic phase is washed with 10 ml of water. The organic phase is dried over Na2SO4, filtered and evaporated to ¼ of the starting volume. To the oily remainder, 10 ml of heptane are added and cooled below 0° C. The precipitated product is collected by filtration and dried.

example 2

[0078]A mixture of 1.55 g (1.8 mmol) of trityl candesartan cilexetil, 5.4 ml of methanol, 22 ml of methylene chloride, 0.05 g (1.61 mmol) of ZnCl2 and 0.5 ml of water is stirred under reflux temperature for 5 h. The reaction mixture is analyzed (Area % HPLC: candesartan cilexetil: 76.3%, trityl candesartan cilexetil: 1.8%, 2-oxo candesartan cilexetil: 0.7%, ethyl ester of candesartan 0.09%.) and cooled to room temperature. Then, to the mixture 36 ml of methylene chloride and 55 ml of water is added. The phases were separated and organic phase is washed with 2×55 ml of water. Organic phase is dried over Na2SO4, filtered and evaporated to the oily residue. This residue is dissolved in 1.6 ml of methylene chloride and then 16 ml of isopropyl acetate is added. The mixture is stirred at 0° C. for 24 h. The precipitated product is collected by filtration and dried. After that the product was suspended in 5 ml of tert-butyl methyl ether. The mixture is stirred for 2 h. The product is colle...

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Abstract

The present invention provides an improved synthesis for the manufacture of candesartan and pharmaceutically acceptable salts and esters thereof as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions which comprises the removal of the tetrazolyl protecting group in an organic solvent, and in the presence of a Lewis acid.

Description

FIELD OF THE INVENTION [0001]The present invention relates to an improved process for the manufacture of candesartan and pharmaceutically acceptable salts and esters thereof as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions.TECHNICAL PROBLEMS [0002]Candesartan cilexetil of formula (I) is chemically described as (+ / −)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. Because of its ability to inhibit the angiotensin-converting enzyme it is widely used for the treatment of hypertension and related diseases and conditions. As an angiotensin II receptor antagonist, candesartan cilexetil avoids the side-effects of calcium antagonists, and shows high stability and obvious curative effects. At the time being it is sold as the racemic mixture. It is produced according to published patents, e.g. EP 0 720 982 B1 and EP 0 459 136.[0003]As is indicated here...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D403/10
CPCC07D403/10Y02P20/55A61P9/00A61P9/12
Inventor ZUPANCIC, SILVO
Owner ZUPANCIC SILVO
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