FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE COMPLETE SPECIFICATION
(See section 10)
1. A PROCESS FOR THE PREPARATION OF CARVEDILOL.
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

A PROCESS FOR THE PREPARATION OF CARVEDILOL
Abstract
The invention relates to a process for the preparation of carvedilol (l-(9H-carbazol-4-yloxy)-3-[[2- (2-methoxyphenoxy) ethyl]amino]-2-propanol) of 99% purity and in yield >55%, in the reaction of 4-(oxyran-2-ylmethoxy)-9H-carbazole with 2-(2-Methoxyphenoxy)-ethylamine, which comprises carrying out said reaction in 1,4-dioxane as a solvent, wherein said ethylamine is at a molar excess over said carbazole.
Field of The Invention
The present invention relates to an improved commercially feasible method of preparation of Carvedilol.
Background of the Invention
Carvedilol is a nonselective P-adrenergic blocking agent with α1 blocking activity and is indicated in the treatment of congestive heart failure and hypertension.
Carvedilol is chemically known as l-(9H-carbazol-4-yloxy)-3-[[2- (2-methoxyphenoxy) ethyl]amino]-2-propanol and has the structure as shown below as formula-I

Formula-I According to US 4503067 carvedilol is prepared by the reaction of 4-(2,3-Epoxypropoxy)-carbazole (II) with 2-(2-methoxyphenoxy)-ethylamine (III), which is described in Scheme-1 as follows. Scheme-1

4-(oxyran-2-ylmethoxy)-9H-carbazole
Formula II

2-(2-Methoxyphenoxy)-ethylamine
Formula III

Carvedilol [ Formula-I]
However the side reaction of Carvedilol with the epoxide produces an impurity-B (IV).


Impurity-B (IV)
EP 912055 discloses the preparation of Carvedilol in which 4-(oxirane-2-ylmethoxy)-9H-carbazole is coupled with N-benzylated 2-(2-methoxyphenoxy) ethylamine to give N-benzylated Carvedilol which on debenzylation with Palladium on charcoal gives Carvedilol. The two additional steps make this process cumbersome.
WO 2004/041783 describes the process of preparation of carvedilol wherein the epoxide (II) is reacted with a salt of amine (III) in presence of alkaline earth metal carbonate in alcoholic solvent. The product after two recrystallizations in ethyl acetate gives Carvedilol in 41%.
This method suffers from possibilities of salt contamination despite an additional step for their separation.
It is a long-standing need to provide a process of preparing Carvedilol with high purity and yield by direct reaction of 2-(2-methoxyphenoxy) ethylamine with 4-(oxirane-2-ylmethoxy)-9H-carbazole

Summary of the invention
The present invention provides a process for preparing Carvedilol comprising a step of reacting a compound of formula II, 4-(oxiran-2ylmethoxy)-9H-carbazole [also known as 4-(2,3-Epoxypropoxy)-carbazole] with a compound of formula III, 2-(2-methoxyphenoxy) ethylamine, wherein the Compound of formula III is at a molar excess over the compound of formula II.
Another object is to use 1,4-dioxane as solvent for the reaction of an epoxy compound (II) with primary amine (III) to give Carvedilol. The solvent is distilled and the carvedilol is isolated after two successive purifications in ethyl acetate with yields>55% and purity>99%, impurity of tertiary amine in <0.1%.
Detailed description of the invention
The synthetic scheme of the present invention is described in scheme-2

4-(2,3-Epoxypropoxy)-carbazole Formula- II

2-(2-methoxyphenoxy)-ethylamine
Formula-Ill Solvent -1,4-Dioxane
Distillation of Dioxane and "Trituration with EtOAc or MeCN


Carvedilol Crude Formula -1

According to present invention, a process for preparing Carvedilol comprises a step of reacting
a compound of, 4-(oxiran-2-ylmethoxy)-9H-carbazole (formula II) with a compound of, 2-(2-
methoxyphenoxy) ethylamine (formula III).
The compound of formula (III) used, is in molar excess with respect to compound of formula
(II), preferably at molar ratio from about 1.5:1 to about 2:1. The solvent for the reaction is 1,4-
dioxane and the reaction is preferably carried out at around the reflux temperature of the
solvent.
Ethylacetate, acetonitrile and methylisobutylketone are preferably used as solvents for
crystallization of carvedilol.
The purified carvedilol has melting point of 114-115°C and is identified as polymorph form-
II.
Table-1 presents the data on carvedilol crystallized from various solvents.
TABLE-1

Solvent for trituration HPLC analysis

Purity Imp-B
Diethylether
Diisopropylether
Ethylacetate
Acetonitrile 85.55% 81.56% 97.90% 98.50% 6.75% 8.74% 0.84% 0.90%
The process of preparation of carvedilol is illustrated by following examples, which do not limit the scope of the invention.
Example-1
A mixture of 25 gm 4-(2,3-Epoxypropoxy)-carbazole (II), 33 gm of 2-(2-methoxyphenoxy)-ethylamine (III) in 175 ml of 1,4-dioxane is stirred at 100°C for 5.5 hours. After completion of reaction, the reaction mixture is cooled to 55°C and 1,4-dioxane is distilled out under vacuum to give an oily mass. This oily mass is then cooled to 35°C and to this, 125 ml ethyl acetate is added and obtained a clear solution. This clear solution is stirred for some time at room temperature during which precipitation is observed. After precipitation of solid, it is further stirred for 2 to 3 hrs at RT and chilled to 0 to 5°C. Filtration of solid and washing with

chilled ethyl acetate gives 30 gm of crude carvedilol (HPLC contents > 97.90% area%, HPLC content of impurity-B is 0.84% by area%)
Example-2
A mixture of 25 gm of 4-(2,3-Epoxypropoxy)-carbazole (II), and 35 gm of 2-(2-methoxyphenoxy)-ethylamine (III) in 175 ml 1,4-dioxane is stirred at 100°C for 5.5 hrs. After completion of reaction, the reaction mixture is cooled to 55°C and 1,4-dioxane is distilled out under vacuum to give an oily mass. This oily mass is then cooled to 35°C and to this mixture 125 ml acetonitrile is added and a clear solution obtained. This clear solution is stirred for some time at room temperature. After precipitation of solid it is further stirred for 2 to 3 hrs at room temperature and chilled to 0 to 5°C and maintained at this temperature. Filtration of solid and washing with chilled acetonitrile results in 30 gm of crude carvedilol (HPLC contents > 97.5% area%, HPLC content of impurity-B 0.9% area%)
The crude Carvedilol produced by a process described in examples 1 and 2 is given further two successive purifications in ethyl acetate to give Carvedilol with melting point of 114-115°C and is identified as polymorph form-II.
On production scale, when the same process is followed i.e. reaction of epoxide (II) with amine of formula (III) in 1,4-dioxane, followed by trituration / isolation using ethyl acetate, it results into crude Carvedilol with lower percentage of impurity B which on single purification in ethyl acetate gives Carvedilol of passing quality (with less than 0.1 % impurity). As the centrifugation on plant scale is more effective in removing mother liquor containing impurities, rather than suction filtration on a lab scale, the reaction on production scale gives high purity Carvedilol in single purification (instead of two purifications required on a laboratory scale). The results of scale up batches describing the yield and purity of Carvedilol and percentage of impurity -B are summarized in the table-2 as shown below.

TABLE-2
Yield with respect to 4-(2,3-Epoxypropoxy)-carbazole(II) (on mole basis) Using ethylacetate as a solvent for trituration.

Trial No. Carvedilol -crude HPLC analysis Purification
in ethylacetate
Carvedilol-Purified HPLC analysis
%Yield 1 70.74%
HPLC purity Imp-B 96.21% 0.67% 58.30%
HPLC purity Imp-B 99.48% 0.05%
%Yield 2 70.64%
HPLC purity Imp-B 97.45% 0.63% 57.64%
HPLC purity Imp-B 99.59% 0.08%
%Yield 3 70.61
HPLC puri. Imp-B 97.87% 0.65% 57.73%
HPLC purity Imp-B 99.64% 0.04%

Claims:
We claim:
1. A process for preparing Carvedilol, which comprises reaction of 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methoxyphenoxy)-ethylamine in 1,4-dioxane followed by crystallization in organic solvents to obtain carvedilol (99% purity) with yields >55% with respect to 4-(2,3-epoxypropoxy)-carbazole as input.
2. The solvent for crystallization as claimed in claim-1 is selected from ethylacetate, acetonitrile and methylisobutylketone.
3. The solvent for crystallization as claimed in claim-1, is preferably ethylacetate and acetonitrile.
4. The solvent for crystallization as claimed in claim-1, is more preferably ethylacetate.
5. The process as claimed in claim-1, wherein the carvedilol obtained is of polymorphic form-II.
6. The process as claimed in claim-1, wherein the reaction is carried at temperature of about 25°C to about 110°C.
7. The process as claimed in claim-1, wherein the reaction is carried out preferably at around the reflux temperature of solvent.

Dr. Bakulesh M Khamar
Director - Research
FOR CADILA PHARMACEUTICALS LIMITED.