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PROCESS FOR THE PREPARATION OF POTASSIUM SALT OF AZILSARTAN MEDOXOMIL

IP.com Disclosure Number: IPCOM000234868D
Publication Date: 2014-Feb-11
Document File: 5 page(s) / 73K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure provides a process for the preparation of a potassium salt of azilsartan medoxomil.

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PROCESS FOR THE PREPARATION OF POTASSIUM SALT OF AZILSARTAN MEDOXOMIL

Abstract

The present disclosure provides a process for the preparation of a potassium salt of azilsartan medoxomil. ______________________________________________________________________________

Azilsartan medoxomil potassium is chemically described as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium salt of Formula I.

FORMULA I

Azilsartan medoxomil of Formula II

FORMULA II

is a prodrug of azilsartan of Formula III.

FORMULA III

Azilsartan medoxomil is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension.  It may be used alone or in combination with other antihypertensive agents.

The present disclosure provides a process for the preparation of a potassium salt of azilsartan medoxomil.  The present disclosure recognizes that the medoxomil moiety of azilsartan medoxomil is hydrolyzed in the presence of a strong base like potassium hydroxide.  Therefore, there is a need to develop a process for the preparation of azilsartan medoxomil using a base which does not hydrolyze the medoxomil moiety and also results in the formation of pure azilsartan medoxomil with improved yield.

Reported herein is a process for the preparation of a potassium salt of azilsartan medoxomil, wherein the process comprises:

a)      treating azilsartan medoxomil with a potassium source selected from the group consisting of potassium acetate, potassium octanoate, potassium hexanoate, potassium trifluoromethanesulfonate, potassium oleate, potassium stearate, or potassium elaidate; and

b)      isolating the potassium salt of azilsartan medoxomil from the reaction mixture thereof.

Azilsartan medoxomil starting material may be prepared by any method known in the literature, for example, U.S. Patent No. 7,157,584.  

The treatment of azilsartan medoxomil with a potassium source is carried out in the presence of a solvent selected from the group consisting of ketones, esters, ethers, nitriles, halogenated hydrocarbons, dimethyl sulfoxide, dimethyl formamide, and mixtures thereof.  The ketone is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, butanone, and acetophenone.  The ester is selected from the group consisting of ethyl acetate and butyl acetate.  The ether is selected from the group consisting of tetrahydrofuran, methyl tertiary butyl ether, and isopropyl ether.  The halogenated hydrocarbon is dichloromethane.  The nitrile is acetonitrile.

The treatment of azilsartan medoxomil with a potassium source is carried out at -20°C to 50°C, for example, at 0°C to 30°C.  The treatment is carried out for about 2 hours to about 6 hours.  The potassium salt of azilsartan medoxomil may be isolated by techniques such as evaporation, evaporation under vacuum, coolin...