Title of Invention

PROCESS FOR THE PREPARATION OF CARVEDILOL FREE FROM BIS IMPURITY

Abstract The present invention discloses a cost-effective, industrially feasible process for preparation of carvedilol of high HPLC purity (>99.5%), absolutely free from bisimpurity. The said process comprises, reacting 4-hydroxy carbazole with epichlorohydrin in presence of aluminium or Lewis acid; further the resultant 4-(2,3-epoxy propoxy) carbazole with 2-(2-methoxyphenoxy) ethylamine in presence of phase transfer catalyst or aluminium alkoxides or Lewis acid, followed by purification in ethyl acetate.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF CARVEDILOL FREE FROM
BIS IMPURITY"

2. APPLICANT(S):

(a) NAME: IPCA LABORATORIES LIMITED

(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956

(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West),
Mumbai-400 067, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:

The following specification describes the nature of this invention and the manner in
which it is to be performed:
Technical field:
The present invention relates to a cost-effective, industrially feasible and improved method for preparation of l-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxy phenoxy)ethyl]amino]-2-propanol of high HPLC purity (>99.5%), absolutely free from bis-impurity.
Background and prior art:
l-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxy phenoxy)ethyl]amino]-2-propanol (CAS No. 72956-09-3) is also known as carvedilol and has the structure of formula I:

H
Formula-I
Carvedilol is known to be both a competitive non-selective b-adrenoceptor antagonist and a vasodilator. The vasodilatory actions of carvedilol result primarily from a1-adrenoceptor blockade, whereas the b-adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug.
Carvedilol was reported in EP 0004920, wherein the compound 4-(2,3-epoxy propoxy)carbazole of Formula II is reacted with 2-(2-methoxy-phenoxy)ethylamine of Formula III to prepare the carvedilol as per the reaction sequence shown in Scheme I:


















The known processes produce carvedilol in lower yield with formation of a bis-impurity of Formula IV, which in most cases cannot be avoided, in about 10-15% of the total product. This necessitates additional purification procedures for the isolation of carvedilol free from contamination of high percentage of bis-impurity and therefore the process may not be ideal for industrialization.



Formula IV
The process for the preparation of 4-(2,3-epoxy propoxy)carbazole, which is the key intermediate of carvedilol, is reported in GB 1974/1369580 and WO 2002/059089 A3. The process discloses the reaction of 4-hydroxy carbazole (Formula V) and epichlorohydrin (Formula VI) using aqueous sodium hydroxide in solvents like 1,4-dioxan and DMSO as shown in Scheme II. 1, 4-dioxan and DMSO are expensive and high boiling solvents and their removal from the product are quite tedious. These known processes use undesirable solvents such as 1, 4-dioxan and DMSO in view of environmental hygiene.
On the basis of the growing conscious to international environmental conservation in recent years, great demands become arisen in a chemical industry to make every effort decreasing use of the solvents and reagents pointed out the harmfulness, and preventing those materials from discharging into the environment. Under the circumstances with these social demands, the present inventors have made a study of the process being safer for the environment, for producing 4-(2, 3-epoxy propoxy)carbazole with using C1-C4 alcohols as solvents in place of 1,4-dioxan and DMSO.


Scheme-II

H H
Formula V Formula VI Formula II
EP 0918055 Al, EP 01142873 A2 and WO 02/059089 A3 disclose a process by which the formation of bis-impurity is avoided (Scheme III) by reacting a benzyl protected 2-(2-methoxy phenoxy)ethyl amine (Formula VII) with 4-(2,3-epoxy propoxy)carbazole. The intermediate benzyl carvedilol (Formula VIII) is subjected to the catalytic N-debenzylation by using costly metal catalyst or hydrazine hydrate at the final stage. This process leads to the formation of N-benzyl carvedilol (Formula VIII) as major impurity in final product, which is toxic in nature.
Scheme-III




Formula VIII
Debenzylation
CARVEDILOL Formula I
WO 01/87837 describes the preparation of carvedilol from 4-hydroxy carbazole by reacting it with 5-chloromethyl-3-[2-(2-methoxy phenoxy)ethyl]-oxazolidin-2-one (Formula IX) to yield oxazolidine derivative of Formula X as expressed in Scheme IV. This intermediate is further hydrolyzed to get carvedilol. The preparative process for the intermediate of Formula IX involves various stages, such as reacting 1,3-dichloropropan-2-ol with phenyl chloroformate, which is made to react with 2-[2-(methoxy phenoxy)] ethylamine hydrochloride to yield 2-[2-(methoxy phenoxy)] ethyl carbamic acid-2-chloro-1- chloromethyl ethyl ester. The ester formed is cyclised to get compounds of Formula IX. In order to produce carvedilol, free of bis-impurity, the process introduces number of additional steps making it cumbersome for the industrial production of the compound.


Scheme-IV

Formula X Hydrolysis

CARVEDILOL Formula I
WO 02/00216 describes the preparation of carvedilol from 4-(2, 3-epoxy propoxy) carbazole (Formula II) with 2-(2-methoxy phenoxy) ethylamine (Formula III). The process uses a large molar excess of intermediate of Formula III in the range of 2.80 moles to 10.0 moles per 1.0 mole of 4-(2,3-epoxy propoxy) carbazole (Formula II) to avoid the formation of bis-impurity (Formula IV). The application further discloses the process for isolation of carvedilol as crystalline Hydrochloride, Hydrochloride Hydrate,


and methyl ethyl ketone solvate. The use of large excess of 2-(2-methoxy phenoxy) ethylamine (Formula III) makes the process uneconomical and requires the excess reactant to be recovered and recycled. Moreover, the use of strong mineral acids for the salt formation can lead to decomposition of the product.
Further WO 2004/094378 describes a process for preparation of carvedilol Form-II by reacting 4-(2,3-epoxy propoxy) carbazole (Formula II) with 2-(2-methoxy phenoxy) ethylamine (Formula III) in solvents like isopropyl acetate, monochlorobenzene, monoglyme or mixtures thereof at reflux temperature 125-140 °C. The application does not mention about the bis-impurity formed during the condensation.
To avoid the formation of bis-impurity (Formula IV), WO 2004/094378 Al and WO 2005/080329 A2 disclose the preparation of carvedilol by reacting 4-(2,3-epoxy propoxy) carbazole (Formula II) with 2-(2-methoxy phenoxy) ethylamine (Formula III), followed by acidification with an organic acid such as oxalic acid, salicylic acid, tartaric acid or benzoic acid in an organic solvent to yield acid addition salts, treatment of the said salts with base(s) in presence of organic solvent(s) followed by crystallization from ethyl acetate. The process introduces number of additional steps and affects the cost.
Therefore, it has been a long-standing need in the industry to provide an economical process for the preparation of carvedilol with control over the formation of the bis-impurity of Formula IV and involves minimal workup steps without using mineral and organic acids.
Objectives of the invention:
An object of the present invention is to provide a cost-effective, industrially feasible and improved process for preparation of l-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxy phenoxy)ethyl]amino]-2-propanol, known as carvedilol of high HPLC purity (>99.5%), absolutely free from bis-impurity of Formula IV.
Another object of the present invention is to provide a process for carvedilol, which avoids use of hazardous reagents and use milder conditions.


Further object of the present invention is to provide a process for 4-(2,3-epoxy propoxy) carbazole, which employs use of less expensive, eco friendly solvents.
Yet another objective of the present invention is to provide a process for carvedilol, which avoids use of mineral and organic acids and additional steps in the synthesis.
A further object of the present invention is to provide a process for carvedilol, which allows recovery and recycling of the solvents.
Summary of the invention:
The present inventors have discovered that the prior art processes present substantial difficulties in producing pure carvedilol substantially free from bis-impurity in economically acceptable yield. Accordingly, the present invention discloses a cost-effective and industrially feasible process for the manufacture of carvedilol (Formula I) in high HPLC purity and high yield.
In one aspect, 4-hydroxy carbazole (Formula V) is reacted with epichlorohydrin (Formula VI) in a hydroxylic solvent selected from C1 to C4 alcohols, in presence of a catalyst and an inorganic base at temperatures ranging between 10 to 20 °C.
The catalyst used in the reaction between the compounds of Formula V and Formula VI is selected from aluminium alkoxide or Lewis acid, preferably aluminium alkoxide, more preferably aluminium isopropoxide
The preferred inorganic base is alkali metal hydroxide, more preferably potassium hydroxide in aqueous form.
The C1 to C4 alcohols are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol or butyl alcohol. The volume ratio of the hydroxylic solvent to the water in aqueous solution of the said inorganic base is employed as 1: 1.4.


In another aspect, 4-(2, 3-epoxy propoxy) carbazole (Formula II) reacted with 2-(2-methoxyphenoxy) ethylamine (Formula III) in presence of a catalyst and an organic solvent at temperatures ranging between 20 to 75 °C to obtain carvedilol.
The catalyst used in the above reaction is selected from a phase transfer catalyst, aluminium alkoxide or a Lewis acid. One preferred catalyst is phase transfer catalyst, more preferably tetrabutyl ammonium bromide
The organic solvent is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol or ethyl acetate, more preferably ethyl acetate. The water content of the solvent is made 2.0-5.0%, more preferably 2.0%.
The reaction between the compounds of Formula II and Formula III is carried out at a preferable temperature range of 65 to 70 °C.
In yet another aspect, the crude carvedilol is purified by charcoal treatment in methyl alcohol, isopropyl alcohol or ethyl acetate but more preferably in ethyl acetate at an elevated temperature; followed by cooling to crystallize out the carvedilol with a purity of more than 99.5%. (by HPLC).
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this


invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
The term "isolating" is used to indicate separation or collection or recovery of the compound being isolated in the solid/liquid form either as crude or pure material.
The term "substantially free" in the context of bis-impurity means that the product is free from contamination of the said impurity at least less than 1.0%, preferably less than 0.1% and most preferably less than 0.05%.
Referring now to the present invention, a cost-effective, industrially viable process for preparation of carvedilol of Formula I, free of bis-impurity is disclosed.
In a preferred embodiment, 4-hydroxy carbazole (Formula V) is reacted with epichlorohydrin (Formula VI) in a hydroxylic solvent selected from C1 to C4 alcohols, in presence of a catalyst and an inorganic base at temperatures ranging between 10 to 20 °C.
The preferred inorganic base is alkali metal hydroxide like sodium hydroxide or potassium hydroxide, more preferably potassium hydroxide in aqueous form.
The catalyst used in the reaction between formula (V) and formula (VI) is selected from Lewis acid such as boron trifluoride, ferric chloride, aluminium chloride, aluminium bromide or titanium tetrachloride; or aluminium alkoxide such as aluminium isopropoxide or aluminium tertiarybutoxide, more preferably aluminium isopropoxide.
The hydroxylic solvent is C1-C4 alcohol like methyl alcohol, ethyl alcohol, isopropyl alcohol and butyl alcohol. The volume ratio of the hydroxylic solvent to the water in aqueous solution of the said inorganic base is employed as 1: 1.4.


Epichlorohydrin (Formula VI) is used in slight excess in the range of 1.5 to 2.5 molar equivalents relative to the 4-hydroxy carbazole (Formula V), preferably 2.0 molar equivalents.
The reaction between the compounds of formula V and formula VI is carried out at a preferred temperature range of 10 to 20 °C. The reaction normally completes within a span of 20-25 hours. The progress of the reaction is monitored by HPLC, till the reaction showed complete utilization of 4-hydroxy carbazole (Formula V).
The process of the above reaction thus involves in the use of eco friendly solvents like methyl alcohol, ethyl alcohol and isopropyl alcohol in aqueous inorganic base like potassium hydroxide or sodium hydroxide giving 4-(2,3-epoxy propoxy) carbazole (Formula II) in 84.20 % yield. This process eliminates use of expensive solvents like 1,4-dioxan and obnoxious solvents like dimethyl sulphoxide.
In another preferred embodiment, the resultant 4-(2,3-epoxy propoxy) carbazole (Formula II) is reacted with 2-(2-methoxyphenoxy)ethylamine (Formula III) in presence of a catalyst and an organic solvent at a temperature of 20 to 75 °C to obtain carvedilol.
The molar equivalent of 2-(2-Methoxy phenoxy) ethylamine (Formula III) is employed in the range 1.0 to 2.0 relative to 4-(2,3-Epoxy propoxy) carbazole (Formula II), preferably 1.5 molar equivalents.
The catalyst used in the reaction between the compounds of Formula II and Formula III is selected from Lewis acid such as boron trifluoride, ferric chloride, aluminium chloride, aluminium bromide or titanium tetrachloride; or aluminium alkoxide like aluminium isopropoxide or aluminium tertiarybutoxide; or phase transfer catalyst like tetrabutyl ammonium bromide or benzyl triethyl ammonium chloride but more preferably tetrabutyl ammonium bromide.
The organic solvent is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol or ethyl acetate but more preferably ethyl acetate. The water content of the organic solvent is made 2.0-5.0 %, more preferably 2.0%. The said water content facilitates the function of


catalyst. The reaction carried out in the said solvent in the presence of the said catalyst has found to limit the formation of the bis-impurity to about 1.0% in comparison with 5-20% in neat condition or in reported solvents without using any catalyst.
The reaction of compound of formula II with compound of formula III is carried out preferably at a temperature range of 65 to 70 °C. The reaction normally completes within a span of 20 to 25 hours. The progress of the reaction is monitored by HPLC, till the reaction showed complete utilization of 4-(2,3-Epoxy propoxy) carbazole (Formula II).
The crude carvedilol so obtained has purity of more than 98.5% (by HPLC) and bis-impurity of about 1.0%. Thus the process of the present invention involves less number of steps since crude carvedilol can be directly isolated without going through the additional steps of converting crude carvedilol into an acid addition salt, followed by its isolation as acid addition salt and final conversion into free base. Moreover, the process of the present invention completes in lesser reaction times.
In another preferred embodiment, the crude carvedilol is purified by charcoal treatment in methyl alcohol, isopropyl alcohol or ethyl acetate but more preferably in ethyl acetate at an elevated temperature of 68 to 72 °C. The carvedilol solution is filtered, concentrated and subsequently cooled to 20 to 30 °C to crystallize out the pure product. The carvedilol obtained by the crystallization according to this procedure is absolutely free from bis-impurity and has purity of more than 99.5% (by HPLC).
The organic solvents used in the process of the present invention are recyclable. The process has also been carried out with recovered ethyl acetate having water content 2.0 to 5.0%. The carvedilol obtained by the use of recovered ethyl acetate is also absolutely freed from bis-impurity and has purity of more than 99.5% (by HPLC).
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.


Example-1 :
Preparation of 4-(2,3-Epoxy propoxy) carbazole
37.0 gm (0.66 mole) of potassium hydroxide was dissolved in 320.0 ml of water at room temperature and further cooled to 14 °C. To this 100.0 gm (0.54 mole) of 4-hydroxy carbazole was added. The reaction mass was stirred for 30.0 min. at 14 °C. To this a solution of 230.0 ml isopropyl alcohol and 0.5 gm (0.002 mole) of aluminium isopropoxide were added. The reaction mass was stirred for 30.0 min. at 14 °C. To this solution 100.0 gm (1.08 moles) of epichlorohydrin added all at once and the reaction mixture was then stirred at 17 °C for 22.0 hours. The reaction mixture was monitored by HPLC, till the reaction showed complete utilization of 4-hydroxy carbazole. 4-(2,3-Epoxy propoxy) carbazole, thus formed, filtered at 17 °C and the cake was washed with water followed by isopropyl alcohol. The product dried at 70 °C for 12.0 hours.
Yield: 110.0 gm (84.20%) Purity by HPLC: 98.6 %
Example-2 :
Preparation of 4-(2,3-epoxy propoxy) carbazole
37.0 gm (0.66 mole) of potassium hydroxide dissolved in 320.0 ml of water at room temperature and the alkali solution was cooled to 14 °C. To that 100.0 gm (0.54 mole) of 4-hydroxy carbazole added and the reaction mass was stirred for 30.0 min. at 14 °C. To this a solution of 230.0 ml isopropyl alcohol and 0.5 gm (0.037 mole) of aluminium trichloride were added. The reaction mass was stirred for 30.0 min. at 14 °C. To this solution 100.0 gm (1.08 mole) of epichlorohydrin was added all at once and the reaction mixture was then stirred at 17 °C for 22.0 hours. The reaction mixture was monitored by HPLC, till the reaction showed complete utilization of 4-hydroxy carbazole. 4-(2,3-Epoxy propoxy) carbazole, thus formed, filtered at 17 °C and the cake was washed with water followed by isopropyl alcohol. The product was dried at 70 °C for 12.0 hours.
Yield : 108.0 gm (82.69 %) Purity by HPLC : 98.4 %


Example-3 :
Preparation of 4-(2,3-Epoxy propoxy) carbazole
37.0 gm (0.66 mole) of potassium hydroxide dissolved in 320.0 ml of water at room temperature and the alkali solution was cooled to 14 °C. To that 100.0 gm (0.54 mole) of 4-hydroxy carbazole was added. The reaction mass was stirred for 30.0 min. at 14 °C. To this a solution of 230.0 ml methyl alcohol and 0.5 gm (0.002 mole) of aluminium isopropoxide were added and the reaction mass was stirred for 30.0 min. at 14 °C. To this solution 100.0 gm (1.08 mole) of epichlorohydrin was added all at once and the reaction mixture was then stirred at 17 °C for 22.0 hours. The reaction mixture was monitored by HPLC, till the reaction showed complete utilization of 4-hydroxy carbazole. 4-(2,3-Epoxy propoxy) carbazole, thus formed, filtered at 17 °C and the cake was washed with water followed by methyl alcohol. The product was dried at 70 °C for 12.0 hours.
Yield : 108.0 gm (82.69 %) Purity by HPLC : 98.1%
Example-4:
Preparation of 4-(2,3-Epoxy propoxy) carbazole
37.0 gm (0.66 mole) of potassium hydroxide dissolved in 320.0 ml of water at room temperature and the alkali solution was cooled to 14 °C. To this 100.0 gm (0.54 mole) of 4-hydroxy carbazole was added and the reaction mass was stirred for 30.0 min. at 14 °C. To this a solution of 230.0 ml methyl alcohol and 0.5 gm (0.037 moles) of aluminium trichloride were added. The reaction mass was stirred for 30.0 min. at 14 °C. To this, solution 100.0 gm (1.08 mole) of epichlorohydrin was added all at once and the reaction mixture was then stirred at 17 °C for 22.0 hours. The reaction mixture was monitored by HPLC, till the reaction showed complete utilization of 4-hydroxy carbazole. 4-(2,3-Epoxy propoxy) carbazole, thus formed, filtered at 17 °C and the cake was washed with water followed by methyl alcohol. The product was dried at 70 °C for 12.0 hours.
Yield: 106.0 gm (81.16%)


Purity by HPLC : 98.2 %
Example-5 :
Preparation of l-(9H-Carbazol-4-yloxy)-3-[[2(2-methoxyphenoxy) ethyl] amino]-2-
propanol (Carvedilol)
100.0 gm (0.42 mole) of 4-(2,3-Epoxy propoxy) carbazole was dissolved in 500.0 ml of ethyl acetate at 30 °C. To this, solution 105.0 gm (0.63 moles) of 2-(2-Methoxy phenoxy) ethylamine, 10.0 ml of water and 0.6 gm (0.002 mole) of tetrabutyl ammonium bromide were added. The reaction mixture was heated to 70 °C and then maintained at 70 °C for 20.0 hours. The reaction was monitored to completion by HPLC and then cooled to 50 °C. The reaction mass was concentrated and cooled to 30 °C. The reaction mass was further cooled to 23 °C. The solid obtained was filtered and washed with ethyl acetate and dried at 54-56 °C. Crude carvedilol so obtained was dissolved in about 500.0 ml of ethyl acetate and heated to 70 °C to obtain a clear solution. The clear solution was treated with charcoal and filtered. The clear filtrate was concentrated and cooled to 23 °C. The solid so obtained was filtered and washed with ethyl acetate. The product was dried at 54-56 °C for 10.0 hours.
Yield: 98.0 gm
Purity by HPLC : 99.9 %
Bis-impurity {Impurity-B} = Not detected
Benzyl carvedilol {Impurity-C} = Not detected
l-[[9-[2-Hydroxy-3-[[2(2-methoxyphenoxy) ethyl] amino] propyl]-9H-carbazol-4-
yl]oxy]-3-[[2(2-methoxyphenoxy) ethyl] amino]-2-propanol {Impurity-A} = 0.05%
Example-6:
Preparation of l-(9H-Carbazol-4-yloxy)-3-[[2(2-methoxyphenoxy) ethyl] amino]-2-
propanol (Carvedilol)
100.0 gm (0.42 mole) of 4-(2,3-Epoxy propoxy) carbazole was dissolved in 500.0 ml of ethyl acetate at 30°C. To this solution 105.0 gm (0.63 moles) of 2-(2-Methoxy phenoxy)


ethylamine, 10.0 ml of water and 0.25 gm (0.07 moles) of benzyl triethyl ammonium chloride were added. The reaction mixture was heated to 70 °C and then maintained at 70 °C for 20.0 hours. The reaction was monitored to completion by HPLC and then cooled to 50 °C. The reaction mass was concentrated and cooled to 30 °C. The reaction mass was further cooled to 23 °C. The solid thus obtained was filtered and washed with ethyl acetate and dried at 54-56 °C. Crude carvedilol so obtained was dissolved in about 500.0 ml of ethyl acetate and heated to 70 °C to obtain a clear solution. The clear solution was treated with charcoal and filtered. The clear filtrate was concentrated and cooled to 23 °C. The product thus obtained was filtered and washed with ethyl acetate. The product was dried at 54-56 °C for 10.0 hours.
Yield: 97.0 gm
Purity by HPLC : 99.8 %
Bis-impurity {Impurity-B} = Not detected
Benzyl carvedilol {Impurity-C} = Not detected
l-[[9-[2-Hydroxy-3-[[2(2-methoxyphenoxy) ethyl] amino] propyl]-9H-carbazol-4-
yl]oxy]-3-[[2(2-methoxyphenoxy) ethyl] amino]-2-propanol {Impurity-A}= 0.06%
Example-7:
Preparation of l-(9H-Carbazol-4-yloxy)-3-[[2(2-methoxyphenoxy) ethyl] amino]-2-
propanol (Carvedilol)
100.0 gm (0.42 mole) of 4-(2,3-Epoxy propoxy) carbazole was dissolved in 500.0 ml of isopropyl alcohol at 30 °C. To this solution 105.0 gm (0.63 mole) of 2-(2-Methoxy phenoxy) ethylamine and 0.6 gm (0.002 mole) of tetrabutyl ammonium bromide were added. The reaction mixture was heated to 75 °C and then maintained at 75 °C for 20.0 hours. The reaction was monitored to completion by HPLC and then cooled to 55 °C. Isopropyl alcohol was distilled out under vacuum to obtain a residue. 300.0 ml of ethyl acetate was added to the resulting residue at 50 °C. The reaction mass was degassed for 2.0 hours at 50 °C. 300.0 ml of ethyl acetate was further added to the reaction mass and cooled to 23 °C. The product was filtered and washed with ethyl acetate and dried at 54 to 56 °C. Crude carvedilol so obtained was dissolved in about 500.0 ml of ethyl acetate and


heated to 70 °C to obtain a clear solution. The clear solution was treated with charcoal and filtered. The filtrate thus obtained was concentrated and cooled to 23 °C. The material was filtered and washed with ethyl acetate. The product was dried at 54 to 56 °C for 10.0 hours.
Yield: 98.0 gm
Purity by HPLC: 99.8%
Bis-impurity {Impurity-B} = Not detected
Benzyl carvedilol {Impurity-C} = Not detected
l-[[9-[2-Hydroxy-3-[[2(2-methoxyphenoxy) ethyl] amino] propyl]-9H-carbazol-4-yl]
oxy]-3-[[2(2-methoxyphenoxy) ethyl] amino]-2-propanol {Impurity-A} = 0.05%
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.


We claim:
1. A process for the preparation of carvedilol (Formula I), substantially free from bis-impurity comprising the steps of

H
Formula I
(a) reacting 4-hydroxy carbazole (Formula V) with epichlorohydrin (Formula VI) in
presence of a catalyst, a base and a hydroxylic solvent at temperatures between 10
to 20 °C;







(b) further reacting the resultant 4-(2,3-Epoxy propoxy) carbazole (Formula II) with
2-(2-Methoxy phenoxy) ethylamine (Formula III) in presence of a catalyst and an
organic solvent at temperatures between 20 to 75 °C; and





Formula III
Formula II
(c) isolating the pure carvedilol free from bis impurity by recovering the same from suitable organic solvents.
2. The process as claimed in claim 1(a), wherein the molar equivalent of epichlorohydrin (Formula VI) is employed in the range of 1.5 to 2.5 relative to the 4-hydroxy carbazole (Formula V), preferably 2.0 molar equivalents.
3. The process as claimed in claim 1(a), wherein the said catalyst is Lewis acid or aluminium alkoxide.
4. The process as claimed in claim 3, wherein said Lewis acid is selected from boron trifluoride, ferric chloride, aluminium chloride, aluminium bromide or titanium Tetrachloride.
5. The process as claimed in claim 3, wherein said aluminium alkoxide is selected from aluminium isopropoxide or aluminium tertiarybutoxide, more preferably aluminium isopropoxide.
6. The process as claimed in claim 1(a), wherein the said hydroxylic solvent is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol or butyl alcohol.
7. The process as claimed in claim 1(a), wherein the volume ratio of the hydroxylic solvent to the water in aqueous solution of the said inorganic base is employed as 1.0: 1.4.
8. The process as claimed in claim 1(a), wherein the reaction between 4-hydroxy carbazole (Formula V) and epichlorohydrin (Formula VI) in the presence of catalyst is carried out at a preferred temperature range of 10 to 20 °C.
9. The process as claimed in claim 1(b), wherein the molar equivalent of 2-(2-Methoxy phenoxy) ethylamine (Formula III) is employed in the range of 1.0 to 2.0


relative to 4-(2,3-Epoxy propoxy) carbazole (Formula II), preferably 1.5 molar equivalents.
10. A process as claimed in claim 1(b), wherein the catalyst is selected from Lewis acid, alluminium alkoxide or phase transfer catalyst.
11. The process as claimed in claim 10, wherein said Lewis acid is selected from boron trifluoride, ferric chloride, aluminium chloride, aluminium bromide or titanium tetrachloride.
12. The process as claimed in claim 10, wherein said alluminium alkoxide is selected from aluminium isopropoxide or aluminium tertiarybutoxide.
13. The process as claimed in claim 10, wherein said phase transfer catalyst is selected from tetrabutyl ammonium bromide or benzyl triethyl ammonium chloride, more preferably tetrabutyl ammonium bromide.
14. The process as claimed in claim 1(b), wherein the said organic solvent is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol or ethyl acetate, more preferably ethyl acetate.
15. The process as claimed in claim 1(b) or 14, wherein the water content of the said organic solvent is 2.0-5.0 %, more preferably 2.0%.
16. The process as claimed in claim 1(c), wherein the solvent used to recover the pure carvedilol free from bis-impurity is selected from methyl alcohol, isopropyl alcohol or ethyl acetate.
17. A pharmaceutical composition comprising carvedilol, absolutely free from the bis-impurity of formula IV, wherein the carvedilol is obtained according to claim 1.

ABSTRACT
The present invention discloses a cost-effective, industrially feasible process for preparation of carvedilol of high HPLC purity (>99.5%), absolutely free from bis-impurity. The said process comprises, reacting 4-hydroxy carbazole with epichlorohydrin in presence of aluminium alkoxide or Lewis acid; further reacting the resultant 4-(2,3-epoxy propoxy) carbazole with 2-(2-methoxyphenoxy)ethylamine in presence of phase transfer catalyst or aluminium alkoxide or Lewis acid, followed by purification in ethyl acetate.


Documents:


Patent Number 256708
Indian Patent Application Number 1683/MUM/2007
PG Journal Number 30/2013
Publication Date 26-Jul-2013
Grant Date 19-Jul-2013
Date of Filing 03-Sep-2007
Name of Patentee IPCA LABORATORIES LIMITED
Applicant Address 48, KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (WEST), MUMBAI
Inventors:
# Inventor's Name Inventor's Address
1 CHOUBEY AJIT IPCA LABORATORIES LIMITED, VILLAGE : SEJAVATA, DISTRICT : RATLAM 457002
2 SHARMA DEEPAK IPCA LABORATORIES LIMITED, VILLAGE : SEJAVATA, DISTRICT : RATLAM 457002
3 MOHAMMAD SAFI AHMAD IPCA LABORATORIES LIMITED, VILLAGE : SEJAVATA, DISTRICT : RATLAM 457002
4 MARMAT VIJAY IPCA LABORATORIES LIMITED, VILLAGE : SEJAVATA, DISTRICT : RATLAM 457002
PCT International Classification Number C07D209/88; C07D209/
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA