DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141041083 filed on September 10, 2021; the disclosure of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of carvedilol or its pharmaceutical acceptable salts thereof. The present invention particularly relates to an improved process for the preparation and purification of 4-(oxiran-2-ylmethoxy)-9H-carbazole, an intermediate used in the preparation of carvedilol or its pharmaceutical acceptable salts thereof.
BACKGROUND OF THE INVENTION
Carvedilol is chemically known as (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol that is mentioned below as formula I.

Carvedilol, a nonselective ß-adrenergic blocking agent with a1-blocking activity was approved for the treatment for congestive heart failure and hypertension. It was developed by Boehringer Mannheim GmbH and marketed in USA by Smithkline Beecham under the brand name Coreg. Carvedilol exits in different dosages in tablet as 3.12 mg, 6.25 mg, 12.5 mg, and 25 mg.
Carvedilol was first disclosed in the Patent US4503067. This Patent discloses a process for the preparation of carvedilol involving the step of reacting 4-(oxiran-2-ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy) ethylamine at a temperature 70°C as mentioned below.

The process for preparing the intermediate 4-(oxiran-2-ylmethoxy)-9H-carbazole, used in the preparation of carvedilol is disclosed in the Patent GB 1369580 as mentioned below.

There is a possibility for the formation of impurities like impurity I, Impurity II, Impurity III and Impurity IV during the reaction of 4-hydroxy carbazole with epichlorohydrin in the presence of base with a suitable solvent system.

These impurities along with unreacted intermediates carried over to next stage increasing the total amount of impurities at the final stage that requires cumbersome purification methods. Hence, purification of the intermediate 4-(oxiran-2-ylmethoxy)-9H-carbazole avoids purification processes at the final stage and also increases the yield of the reaction in further stages.
The Patent US4697022 discloses a process for the purification of 4-(oxiran-2-ylmethoxy)-9H-carbazole using ethyl acetate during the preparation of carvedilol. Though some impurities were removed during this purification process, 4-hydroxy carbazole, the unreacted intermediate was not removed significantly.
The PCT Publication WO2005115981 and the Patent US6777559 disclose the purification process of 4-(oxiran-2-ylmethoxy)-9H-carbazole using isopropyl alcohol.
The Publication Journal of Medicinal Chemistry 1996, 39, 3256-3262 discloses the purification of 4-(oxiran-2-ylmethoxy)-9H-carbazole by using in a mixture of chloroform and hexane.
The Patent application IN 606/CHE/2008 discloses the purification involving the charcoalization of 4-(oxiran-2-ylmethoxy)-9H-carbazole followed by using ethyl acetate. This purification process large amount of ethyl acetate during purification process and also 4-hydroxy carbazole, the unreacted intermediate was not removed significantly.
The Patent application IN 2280/CHE/2008 discloses the purification of the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole by using methanol.
The Journal of Applicable Chemistry (Lumami, India), 8(6), 2328-2335 in 2019; discloses the purification of 4-(oxiran-2-ylmethoxy)-9H-carbazole by using acetone.
Besides, the prior art processes for the purification of 4-(oxiran-2-ylmethoxy)-9H-carbazole in different solvents, there lies a definite necessity to develop a purification process of 4-(oxiran-2-ylmethoxy)-9H-carbazole that reduces the all the impurities to minimum level, thereby providing an improved and efficient process for the preparation of carvedilol or its pharmaceutically acceptable salts thereof in commercial scale. Further, there is a need for an improved purification process of 4-(oxiran-2-ylmethoxy)-9H-carbazole for meeting the regulatory criteria of the final carvedilol API, which is commercially significant.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of carvedilol of formula I or its pharmaceutically acceptable salts thereof.
Yet another objective of the present invention is to provide an improved process for the preparation and purification of carvedilol intermediate of formula IV.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of carvedilol or its pharmaceutically acceptable salts and intermediates thereof.

An aspect of the present invention is to provide a process for the preparation of carvedilol of formula -I or its pharmaceutically acceptable salts thereof,

comprising the steps of:
(i) reacting compound 4-hydroxy carbazole of formula V

with epichlorohydrin of formula VI,

in the presence of base in a suitable solvent system to obtain compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV;

(ii) purifying the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (i), comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in step (e).
(iii) reacting the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (ii) with a compound 2-(2-methoxyphenoxy) ethylamine of formula III

in the presence of organic solvents to obtain Carvedilol of formula I or its pharmaceutical acceptable salts thereof; and
(iv) optionally purifying the compound Carvedilol of formula I or its pharmaceutical acceptable salts thereof obtained in step (iii) in an organic solvent.
According to one embodiment, the base is sodium hydroxide.
In an alternative embodiment according to the present invention, the base is selected from the group comprising: hydroxides, carbonate salts of alkaline, and alkaline earth metals. The hydroxides, carbonate salts of alkaline, and alkaline earth metals are selected from the group comprising: lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, disodium carbonate, sodium hydrogen carbonate, calcium carbonate, caesium carbonate.
According to one embodiment, the organic solvent is ethyl acetate.
In an alternative embodiment according to the present invention, the organic solvent is selected from the group comprising: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, and organosulphur, and mixture thereof.
According to one embodiment, the aromatic hydrocarbon solvent is toluene.
In an alternative embodiment according to the present invention, the aromatic hydrocarbon solvent is selected from the group comprising: toluene, benzene, xylene and mixtures thereof.
According to one embodiment, the alcoholic solvent is methanol.
In an alternative embodiment according to the present invention, the alcoholic solvent is selected from the group comprising: C1-C5 alcohols include methanol, ethanol, propanol, and mixtures thereof.
Another aspect of the process for the preparation of the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV,

an intermediate useful in the preparation of carvedilol or its pharmaceutically acceptable salts thereof, comprising the steps of:
(i) reacting compound 4-hydroxy carbazole of formula V

with epichlorohydrin of formula VI

in the presence of base in a suitable solvent system to obtain the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV;

(ii) purifying the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (i) comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (e).
DETAIL DESCRIPTION OF THE INVENTION
First embodiment of the present invention is to provide a process for the preparation of Carvedilol of formula (I) or its pharmaceutically acceptable salts thereof,

comprising the steps of:
(i) reacting compound 4-hydroxy carbazole of formula V

with epichlorohydrin of formula VI

in the presence of base in a suitable solvent system to obtain compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV;

(ii) purifying the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (i), comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in step (e).
(iii) reacting the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (ii) with a compound 2-(2-methoxyphenoxy) ethylamine of formula III,

in the presence of organic solvents to obtain Carvedilol of formula I or its pharmaceutical acceptable salts thereof; and
(iv) optionally purifying the compound Carvedilol of formula I or its pharmaceutical acceptable salts thereof obtained in step (iii) in an organic solvent.

According to the embodiment, the base used in step (i) is selected from the group consisting of hydroxides, carbonate salts of alkaline, and alkaline earth metals. The hydroxides or carbonate salts of alkaline or alkaline earth metals base are selected from the group including, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, disodium carbonate, sodium hydrogen carbonate, calcium carbonate, and caesium carbonate. Preferably the base is sodium hydroxide.
According to the embodiment, the suitable solvent used in step (i) selected from the group comprising of aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane and cyclopentane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and trichloromethane; esters such as ethyl acetate, methyl acetate and isopropyl acetate; ethers such as diethyl ether, diisopropyl ether and methyl tert-butyl; organosulphur such as dimethyl sulfoxide and sulfolane; and its mixture thereof. Preferably the suitable solvent is dimethyl sulfoxide.

According to the embodiment, a plurality of different methods such as suspending the wet solid or dry solid or gummy solid in a mixture of alcoholic solvent, and aromatic hydrocarbon solvent is used for providing a suspension of compound of formula IV as in step (a).

According to the embodiment, the alcoholic solvent used in step (a) is selected from the group comprising C1-C5 alcohols such as methanol, ethanol, propanol and its mixtures thereof. Preferably the alcoholic solvent is methanol.

According to the embodiment, the aromatic hydrocarbon solvent used in step (a) is selected from the group comprising toluene, benzene, xylene and its mixture thereof. Preferably the aromatic hydrocarbon solvent is toluene.

According to the embodiment, the mixture of alcoholic solvent and aromatic hydrocarbon solvent is preferably the mixture of methanol and toluene.

According to the embodiment, the alcoholic solvent used in step (c) is selected from the group comprising C1-C9 carbon linear chain alcohols such as methanol, ethanol, propanol and butanol; branched carbon chain alcohols such as isopropanol and isobutanol; and its mixture thereof. Preferably the alcoholic solvent is methanol.

According to the embodiment, the heated suspension temperature as in step-(c) is accomplished at a temperature between 40°C to 80°C, preferably the suspension is heated at a temperature between 45° to 70°C and more preferably the suspension is heated at a temperature of between 55°C to 70°C.

According to the embodiment, the maintained temperature as in step-(d) is accomplished by heating the suspension at a temperature between 40°C to 80°C, preferably the maintained temperature as in step-(d) between 45° to 70°C and more preferably the maintained temperature as in step-(d) between 55°C to 70°C.

According to the embodiment, in step-(e) is accomplished by cooling the suspension while stirring at a temperature between -5°C to 20°C for a time period of at least 30 minutes, preferably at a temperature between 0°C to 10°C for a time period from 60 minutes to 180 minutes, and more preferably at a temperature between 0°C to 5°C for a time period from 45 minutes to 60 minutes.

According to the embodiment, the isolation of the solid in step-(f) is carried out by the techniques known in the arts such as filtration, filtration under vacuum, decantation, centrifugation; and their combinations.

According to the embodiment the organic solvent used in the step (iii) is selected from the group comprising of aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane and cyclopentane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and trichloromethane; esters such as ethyl acetate, methyl acetate and isopropyl acetate; ethers such as diethyl ether, diisopropyl ether and methyl tert-butyl; and its mixture thereof. Preferably the organic solvent is ethyl acetate.

Second embodiment of the present invention is to provide a process for the preparation of the compound of formula (IV), useful in the preparation of carvedilol or its pharmaceutically acceptable salts thereof,

comprising the steps of:
(i) reacting compound 4-hydroxy carbazole of formula V,

with epichlorohydrin of formula VI

in the presence of base in a suitable solvent system to obtain the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV;

(ii) purifying the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (i), comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension to obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in step (e).
According to the embodiment the base used in step (i) is selected from the group consisting of hydroxide or carbonate salts of alkaline or alkaline earth metals. Hydroxide or carbonate salts of alkaline or alkaline earth metal base including, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, disodium carbonate sodium hydrogen carbonate, calcium carbonate, and cesium carbonate. Preferably the base is sodium hydroxide.

According to the embodiment, the suitable solvent used in step (i) selected from the group comprising of aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane and cyclopentane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and trichloromethane; esters such as ethyl acetate, methyl acetate and isopropyl acetate; ethers such as diethyl ether, diisopropyl ether and methyl tert-butyl; organosulphur such as dimethyl sulfoxide and sulfolane; and its mixture thereof. Preferably the suitable solvent is dimethyl sulfoxide.

According to the embodiment, a plurality of different methods such as dissolving the wet solid or dry solid or gummy solid in a mixture of alcoholic solvent and aromatic hydrocarbon solvent is used for providing a suspension of compound of formula IV as in step (a).

According to the embodiment, the alcoholic solvent used in step (a) is selected from the group comprising C1-C5 alcohols such as methanol, ethanol, propanol and its mixtures thereof, preferably the alcoholic solvent is methanol.

According to the embodiment, the aromatic hydrocarbon solvent used in step (a) is selected from the group comprising toluene, benzene, xylene and its mixture thereof, preferably the aromatic hydrocarbon solvent is toluene.

According to the embodiment, the mixture of alcoholic solvent and aromatic hydrocarbon solvent is preferably the mixture of methanol and toluene.

According to the embodiment, the alcoholic solvent used in step (c) is selected from the group comprising C1-C9 carbon linear chain alcohols such as methanol, ethanol, propanol and butanol; branched carbon chain alcohols such as isopropanol and isobutanol; and its mixture thereof. Preferably the alcoholic solvent is methanol.

According to the embodiment, the heated suspension temperature as in step-(c) is accomplished at a temperature between 40°C to 80°C, preferably the suspension is heated at a temperature between 45° to 70°C, and more preferably the suspension is heated at a temperature between 55°C to 70°C.

According to the embodiment, the maintained temperature as in step-(d) is accomplished by heating the suspension at a temperature between 40°C to 80°C, preferably the maintained temperature as in step-(d) between 45° to 70°C and more preferably the maintained temperature as in step-(d) between 55°C to 70°C.

According to the embodiment, in step-(e) is accomplished by cooling the suspension while stirring at a temperature between -5°C to 20°C for a time period of at least 30 minutes, preferably at a temperature between 0°C to 10°C for a time period from 60 minutes to 180 minutes, and more preferably at a temperature between 0°C to 5°C for a time period from 45 minutes to 60 minutes.

According to the embodiment, the isolation of the solid in step-(f) is carried out by the techniques known in the arts such as filtration, filtration under vacuum, decantation, centrifugation; and their combinations.

Third and last embodiment of the present invention is to provide a process for the purification of carvedilol intermediate of formula (IV)

comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension to obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in step (e).

According to the embodiment, is a plurality of different methods such as dissolving the wet solid or dry solid or gummy solid in a mixture of alcoholic solvent and aromatic hydrocarbon solvent is used for providing a suspension of compound of formula IV as in step (a).

According to the embodiment, the alcoholic solvent used in step (a) is selected from the group comprising C1-C5 alcohols such as methanol, ethanol, propanol and its mixtures thereof, preferably the alcoholic solvent is methanol.

According to the embodiment, the aromatic hydrocarbon solvent used in step (a) is selected from the group comprising toluene, benzene, xylene and its mixture thereof, preferably the aromatic hydrocarbon solvent is toluene.

According to the embodiment, the mixture of alcoholic solvent and aromatic hydrocarbon solvent is preferably the mixture of methanol and toluene.

According to the embodiment, the alcoholic solvent used in step (c) is selected from the group comprising C1-C9 carbon linear chain alcohols such as methanol, ethanol, propanol and butanol; branched carbon chain alcohols such as isopropanol and isobutanol; and its mixture thereof. Preferably the alcoholic solvent is methanol.

According to the embodiment, the heated suspension temperature as in step-(c) is accomplished at a temperature between 40°C to 80°C, preferably the suspension is heated at a temperature between 45° to 70°C, and more preferably the suspension is heated at a temperature between 55°C to 70°C.

According to the embodiment, the maintained temperature as in step-(d) is accomplished by heating the suspension at a temperature between 40°C to 80°C, preferably the maintained temperature as in step-(d) between 45° to 70°C and more preferably the maintained temperature as in step-(d) between 55°C to 70°C.

According to the embodiment, in step-(e) is accomplished by cooling the suspension while stirring at a temperature between -5°C to 20°C for a time period of at least 30 minutes, preferably at a temperature between 0°C to 10°C for a time period from 60 minutes to 180 minutes, and more preferably at a temperature between 0°C to 5°C for a time period from 45 minutes to 60 minutes.

According to the embodiment, the isolation of the solid in step-(f) is carried out by the techniques known in the arts such as filtration, filtration under vacuum, decantation, centrifugation; and their combinations.

The formation of impurities such as Impurity I, II and III as mentioned below,

during preparation of the compound of formula IV as mentioned below
are difficult to separate from the compound of formula IV by purification techniques in the prior art. The genotoxic impurity Impurity-I should be within the regulatory limit in the final API. Further the carry-over of impurities I, II and III till the final stage of the process produces other undesired impurities during the process that requires multiple purification methods or cumbersome purification methods at the final stage, thereby causes a reduction in yield of the final product.
Inventors of the Present invention have tried purification methods of the compound of formula IV resulted from the reaction, with different solvents such as ethyl acetate, acetone, and isopropyl alcohol and tabulated the results in Table-1.
Table-1: Comparative table on the Purity of the compound after purification by different solvents
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Initial Purity (by HPLC) of the compound of formula IV before purification
Purity (by HPLC) of the compound of formula IV after purification

1. Ethyl acetate 88.13 94.54
2. Acetone
88.13 94.07
3. Isopropyl alcohol
88.13 83.70

The solvents ethyl acetate and acetone had an advantage over the isopropyl alcohol in the purification of the compound of formula IV resulted from the reaction. Hence the content of the Impurities I, II and III in the compound of formula IV resulted from the reaction before and after were determined and the results were tabulated in Table-2, 3, and 4.
Table-2: Comparative table on the Content of Impurity I in the compound after purification by solvents ethyl acetate and acetone.
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Content of Impurity I (by HPLC) in the compound of formula IV before purification
Content of Impurity I (by HPLC) in the compound of formula IV after purification

1. Ethyl acetate
0.67 1.06
2. Acetone
0.67 0.97

Table-3: Comparative table on the Content of Impurity II in the compound after purification by solvents ethyl acetate and acetone.
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Content of Impurity II (by HPLC) in the compound of formula IV before purification
Content of Impurity II (by HPLC) in the compound of formula IV after purification

1. Ethyl acetate
1.18 0.36
2. Acetone
1.18 0.34

Table-4: Comparative table on the Content of Impurity II in the compound after purification by solvents ethyl acetate and acetone.
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Content of Impurity III (by HPLC) in the compound of formula IV before purification
(from Batch A) Content of Impurity III (by HPLC) in the compound of formula IV after purification
(from Batch A)
1. Ethyl acetate
5.48 1.52
2. Acetone
5.48 2.68

Though, the purification methods using the solvents such as ethyl acetate and acetone are reduced impurities II and III in the compound of formula IV resulted from the reaction. These purification methods using the solvents such as ethyl acetate and acetone are not capable of reducing the impurity I in the compound of formula IV resulted from the reaction. Further, the purification methods using the solvents such as ethyl acetate and acetone are increased the Impurity I in the compound of formula IV resulted from the reaction.
Inventors of the Present invention compared the purification methods of the compound of formula IV resulted from the reaction with methanol and a mixture of toluene and methanol and tabulated the findings in the Table 5, 6, 7 and 8.

Table-5: Comparative table on the Purity of the compound after purification in mixture of toluene and methanol & Methanol
S. No Solvent or its mixtures used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Initial Purity (by HPLC) of the compound of formula IV before purification
Purity (by HPLC) of the compound of formula IV after purification

1. Methanol
91.86 98.79
2. Mixture of Toluene and Methanol
94.21 99.32

Table-6: Comparative table on the Content of Impurity I in the compound after purification in mixture of toluene and methanol & Methanol
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Content of Impurity I (by HPLC) in the compound of formula IV before purification
Content of Impurity I (by HPLC) in the compound of formula IV after purification

1. Methanol
0.43 0.34
2. Mixture of Toluene and Methanol
0.42 0.02

Table-7: Comparative table on the Content of Impurity II in the compound after purification in mixture of toluene and methanol & Methanol
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Content of Impurity II (by HPLC) in the compound of formula IV before purification
Content of Impurity II (by HPLC) in the compound of formula IV after purification

1. Methanol
0.29 0.20
2. Mixture of Toluene and Methanol 0.19 0.02

Table-8: Comparative table on the Content of Impurity III in the compound after purification in mixture of toluene and methanol & Methanol
S. No Solvents used for the purification of the compound of formula IV during the process for preparation of Carvedilol or its pharmaceutically salts thereof Content of Impurity II (by HPLC) in the compound of formula IV before purification
Content of Impurity II (by HPLC) in the compound of formula IV after purification

1. Methanol
0.98 0.20
2. Mixture of Toluene and Methanol
1.71 0.38

The purification method in the solvent mixture of methanol and toluene is significantly reduced the impurities I and II in the compound of formula IV resulted from the reaction than the purification method using methanol as the solvent.
Thus, the inventors of the present invention surprisingly found the improved purification process of 4-(oxiran-2-ylmethoxy)-9H-carbazole that is the compound of formula IV using a mixture of aromatic hydrocarbon and aliphatic alcohol is effective in reducing the impurities I, II and III in the compound of formula IV after the reaction.
Particularly Impurity-I and Impurity-II were significantly reduced after the improved purification process of 4-(oxiran-2-ylmethoxy)-9H-carbazole of the present invention.
Further, the inventors also observed that the 4-(oxiran-2-ylmethoxy)-9H-carbazole that is the compound of formula IV resulted from the process of the invention has an improved colour than the compound of formula IV resulted in prior art process.
Certain specific aspect and embodiment of the present invention will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES OF THE INVENTION
Example-1:
Step (A) Preparation of 4-(oxiran-2-ylmethoxy)-9H-carbazole, compound of formula IV: To a solution of sodium hydroxide (26.2 g) in water (300 ml), dimethyl sulfoxide (125 ml) was slowly added at the temperature of15±5°C under nitrogen atmosphere, followed by the addition of 4-hydroxy carbazole (100 g) at 15±5°C, and stirred for 30 minutes at the temperature of 15±5°C under nitrogen atmosphere. To the reaction mixture, epichlorohydrin (73.2 g) was added at the temperature of 15±5°C and stirred for 2±1 hour at the temperature of 15±5°C. The temperature of the reaction mixture was raised to 25±5°C and stirred for 60±10 minutes. The temperature of the reaction mixture was gradually increased to 45±5°C and maintained for 6±1 hour at a temperature of 45±5° C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 25±5°C, then water (100 ml) was added to the cooled reaction mass at the temperature of 25±5°C and stirred for 30±5 minutes at the temperature of 25±5°C, further methanol (300 ml) was added to the reaction mass at the temperature of 25±5°C and stirred for 60±10 minutes. The resultant solid was filtered; washed with a mixture of water and methanol (60ml of Methanol and 40 ml of water); then washed with water (200 ml) and dried under vacuum at the temperature of 25-35°C for 25 ±5 minutes. Wet solid weight: 149 g. Purity by HPLC: 93.3% area; The contents of the Impurities; impurity I (0.39%) by HPLC; Impurity II (0.33%) by HPLC; Impurity III (3.79%) by HPLC; Impurity IV (0.85%) by HPLC; and the unreacted 4-hydroxy carbazole of formula V (0.04%) by HPLC.
Step (B) Purification of 4-(oxiran-2-ylmethoxy)-9H-carbazole, compound of formula IV: The wet solid of 4-(oxiran-2-ylmethoxy)-9H-carbazole, compound of formula IV obtained in Step (A) (149 g) was suspending in a mixture of toluene (75 ml) and methanol (75 ml) at the temperature of 25±5°C. The contents were slowly heated to 55±5°C. To the heated contents, methanol (75 ml) was added at the temperature of 55±5°C and maintained for 60±5 minutes at the temperature of 55±5°C. The contents were then cooled at the temperature of 5±5°C and stirred for 60±15 minutes at the temperature of 5±5°C. The resultant solid was filtered; washed with water (100 ml); then washed with chilled methanol (100 ml); and dried at the temperature of 55-60°C for 2-3hours. Yield: 103.44g; Off-white solid; Purity by HPLC: 99.21% area; The contents of the impurities; Impurity I (0.07%) by HPLC; Impurity II (0.06%) by HPLC; Impurity III (0.12%) by HPLC; Impurity IV (0.07%) by HPLC; and the unreacted 4-hydroxy carbazole of formula V (Not detected) by HPLC.

Example-2: Preparation of crude Carvedilol
A solution of 2-(2-methoxyphenoxy) ethylamine (69.9 g) in ethyl acetate (350 ml) at the temperature of 25±5°C was gradually heated at the temperature of 70±5°C, followed by the addition of 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in example-1 (b) (50 g) at the temperature of 70±5°C and stirred for 7±1 hour at the same temperature. The progress of the reaction was monitored through HPLC. After completion of the reaction, the reaction mass was cooled at the temperature of 25±5°C; then quenched with water (500 ml) and stirred for 5-10 minutes to form a biphasic mixture. The pH of the biphasic mixture was adjusted to 4.5 to 5.0 using diluted hydrochloric acid solution at the temperature of 25±5°C and stirred for 1 hour at the temperature of 25±5°C. The resultant solid was filtered; washed with water (100 ml) and ethyl acetate (125 ml) respectively. The wet solid was mixed with a mixture of water (500ml) and ethyl acetate (400 ml) and stirred for 5-10 minutes at the temperature of 25±5°C to form a biphasic mixture. The biphasic mixture was then gradually heated at the temperature of 40±5°C. The pH of the heated biphasic mixture was adjusted to 8 to 8.5 by using diluted sodium carbonate solution at the temperature of 40±5°C and stirred for 5-10 minutes at the temperature of 40±5°C. The organic layer was separated at 40±5°C and treated with activated carbon (5g) at the temperature of 45±5°C. The carbon treated organic layer was filtered. The obtained filtrate was concentrated under vacuum to obtain a residue. The residue was mixed with ethyl acetate (250 ml) at the temperature of 25±5°C and stirred for 14±2 hours at the temperature of 25±5°C. The contents were then cooled at the temperature of 5±5°C and stirred for 2±1 hours at the temperature of 5±5°C. The resultant solid was filtered; washed with water (50 ml) and chilled ethyl acetate (50 ml); and dried. Yield 62 g, purity by HPLC (w/w) 98.9% area.
Example-3: Purification of Crude Carvedilol
The crude carvedilol obtained in example-2 (62 g) was dissolved in ethyl acetate (310 ml) at the temperature of 25±5°C and gradually heated at the temperature of 45±5°C. Activated charcoal (6.2 g) was added to the heated contents at the temperature of 45±5°C and stirred for 60 minutes. Then contents were filtered through celite bed. The obtained filtrate was concentrated to remove some amount of ethyl acetate at the temperature of 45±5°C. The concentrated mass was gradually heated at the temperature of 65±5°C. The heated concentrated mass was cooled at the temperature of 25±5°C and stirred for 14±2 hours at the temperature of 25±5°C. The cooled mass was further cooled at the temperature of 5±5°C and stirred for 90±30 minutes at the temperature of 5±5°C. The resultant solid was filtered; washed with pre-chilled ethyl acetate (62 ml). The solid was dried on vacuum at the temperature of 50±5°C. Yield 51.5 g (0.83X), Purity by HPLC (w/w); 99.8% area.
,CLAIMS:1. A process for the preparation of carvedilol of formula-I,

comprising the steps of:
(i) reacting compound 4-hydroxy carbazole of formula V

with epichlorohydrin of formula VI,

in the presence of base in a suitable solvent system to obtain compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV;

(ii) purifying the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (i), comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in step (e).
(iii) reacting the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (ii) with a compound 2-(2-methoxyphenoxy) ethylamine of formula III

in the presence of organic solvents to obtain Carvedilol of formula I; and
(iv) optionally purifying the compound of Carvedilol of formula I obtained in step (iii) in an organic solvent.
2. The process as claimed in claim 1, wherein the base is selected from the group comprising: hydroxides, carbonate salts of alkaline, and alkaline earth metals.
3. The process as claimed in claim 2, wherein the hydroxides, carbonate salts of alkaline, and alkaline earth metals are selected from the group comprising: lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, disodium carbonate, sodium hydrogen carbonate, calcium carbonate, and caesium carbonate.
4. The process as claimed in claim 1, wherein the base is sodium hydroxide.
5. The process as claimed in claim 1, wherein the organic solvent is selected from the group comprising: aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, and organosulphur, and mixture thereof.
6. The process as claimed in claim 1, wherein the organic solvent is ethyl acetate.
7. The process as claimed in claim 1, wherein the aromatic hydrocarbon solvent is selected from the group comprising: toluene, benzene, xylene and mixtures thereof.
8. The process as claimed in claim 1, wherein the aromatic hydrocarbon solvent is toluene.
9. The process as claimed in claim 1, wherein the alcoholic solvent is selected from the group comprising: C1-C5 alcohols include methanol, ethanol, propanol, and mixtures thereof.
10. The process as claimed in claim 1, wherein the alcoholic solvent is methanol.
11. A process for the preparation of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV, useful in the preparation of carvedilol ,

comprising the steps of:
(i) reacting compound 4-hydroxy carbazole of formula V

with epichlorohydrin of formula VI

in the presence of base in a suitable solvent system to obtain the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV;

(ii) purifying the compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV obtained in step (i), comprising the steps of:
(a) providing a suspension of compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV in a mixture of alcoholic solvent and aromatic hydrocarbon solvent;
(b) heating the suspension of the compound obtained in step (a) at a temperature between 40-80°C;
(c) adding alcoholic solvent to the heated suspension obtained in step (b);
(d) maintaining the suspension obtained in step (c) at a temperature between 40-80°C;
(e) cooling the suspension obtained in step (d) to a temperature between 0-20°C, thereby obtaining a solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole of formula IV; and
(f) isolating the solid compound 4-(oxiran-2-ylmethoxy)-9H-carbazole obtained in step (e).
12. The process as claimed in claim 11, wherein the base is selected from the group comprising: hydroxides, carbonate salts of alkaline, and alkaline earth metals.
13. The process as claimed in claim 12, wherein the hydroxides, carbonate salts of alkaline, and alkaline earth metals are selected from the group comprising: lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, disodium carbonate, sodium hydrogen carbonate, calcium carbonate, and caesium carbonate.
14. The process as claimed in claim 11, wherein the base is sodium hydroxide.
15. The process as claimed in claim 11, wherein the aromatic hydrocarbon solvent is selected from the group comprising toluene, benzene, xylene, and mixtures thereof.
16. The process as claimed in claim 11, wherein the aromatic hydrocarbon solvent is toluene.
17. The process as claimed in claim 11, wherein the alcoholic solvent is selected from the group comprising C1-C5 alcohols include methanol, ethanol, propanol, and mixtures thereof.
18. The process as claimed in claim 11, wherein the alcoholic solvent is methanol.