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A modified process to obtain Carvedilol Disclosure Number: IPCOM000130550D
Publication Date: 2005-Oct-26
Document File: 3 page(s) / 81K

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Carvedilol is obtained by reaction of 4-(oxiran-2-yl-methoxy)-9H-carbazole with 2-(2-methoxyphenoxy)ethylamine hydrochloride in a presence of potassium carbonate in toluene solvent.

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Carvedilol, chemically known as (±) 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]-amino]-2-propanol, having structural formula I is a nonselective β-adrenergic blocking agent with α1 blocking activity.





The process of preparing carvedilol is disclosed in US 4503067 by the following reaction:




                   II                                                            III       

in which 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) reacts with 2-(2-methoxyphenoxy)ethylamine (III) in a molar ratio of 1:1,1 to form carvedilol. By this method a considerable amount of by-product bis-derivate (IV) is formed and crude carvedilol requires two or three crystallizations to meet EP specifications. Therefore a low yield of the desired product is obtained.



Moreover, the process to obtain 2-(2-methoxyphenoxy)ethylamine free base involves an additional cost in the manufacture of carvedilol. Due the instability of the 2-(2-methoxyphenoxy)ethylamine, the commercially available raw material is its hydrochloride salt.

Accordingly, the process described herein presents the advantage that uses 2-(2-methoxyphenoxy) ethylamine hydrochloride as a starting material. It has been demonstrated that the hydrochloride salt reacts as well as the free base with 4-(oxiran-2-ylmethoxy)-9H-carbazole.

Furthermore, the present invention provides a method to obtain crude carvedilol with a content of IV lower than 1,0%. According to our know-how this level is the maximum value to assure crystallized carvedilol that meet EP specifications with only one crystallization.

Detailed description

The process for preparing carvedilol comprises:

-          The reaction of 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) with 2-(2-methoxyphenoxy)ethylamine hydrochloride (III) in a molar ratio of 1:1,4 in a presence of  potassium carbonate in a molar ratio of 0,53 to 1,07, more preferably...