AN IMPROVED PROCESS FOR THE PURIFICATION OF CARVEDILOL INTERMEDIATE
Field of the Invention
The present invention relates to an improved process for the purification of 4-(2,3-epoxypropoxy)carbazole compound of formula (I)

which is a key intermediate for l-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethyl amino]propan-2-ol of formula (II) (Carvedilol), which is a nonselective β-adrenergic blocking agent with al-blocking activity.

US Patent No. 4503067 discloses preparation of carbazolyl-(4)-oxypropanolamine compound and the salts thereof with physiologically acceptable acids and methods for the treatment and prophylaxis of circulatory and cardiac diseases, e.g., hypertension and angina pectoris.
Background of the invention
British patent GB 1369580 discloses the preparation of 4-(2, 3-epoxypropoxy) carbazole by reacting 4-hydroxy carbazole with epichlorohydrin in presence of sodium hydroxide in dioxane solvent. The process as shown below:


US 4697022 disclose the similar process for the preparation of R&S isomers of 4-(2,3-epoxypropoxy)carbazole. In Ex-3 of 022 patent disclosed the process of (S)-(+)-4-(2,3-epoxypropoxy)carbazole by reacting 4-hydroxy carbazole with R (-) epichlorohydrin in presence of sodium hydroxide in dimethylsulfoxide solvent, the obtained crude compound was recrystallized from ethyl acetate to get (S)-(+)-4-(2,3-epoxypropoxy)carbazole (melting point is 163-164°C).
PCT Application number WO 2005/113502A1 describes synthesis as

And PCT Application number WO 2005/115981A2 describes synthesis of formula (I) by reacting 4-hydroxy carbazole with epichlorohydrin in presence of sodium hydroxide in isopropyl alcohol; the obtained precipitate was filtered and washed with IP A


All the prior art references disclose only the process for preparation of 4-(2,3-epoxypropoxy)carbazole where the chance of getting impurities like l-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol of formula (HI), 4-(oxiran-2-ylmethoxy)-9-(oxiran-2-ylmethyl)-9H-carbazole of formula (IV), l,3-bis(9H-carbazol-4-yloxy)propan-2-ol of formula (V), for the convenient now onwards compound of formula (III) called as chloro impurity, compound of formula (IV) called as diepoxy impurity and compound of formula (V) called as dimmer impurity; the structures of these impurities as given below.

We repeated the processes in the prior art and found that no process produces the pure compound of formula (I) like the present process, where in the present process impurities of (IV) and (V) are minimized and impurity (III) able to remove completely. The data captured in the detail description.
Therefore, there is a definite reason to develop a process to get pure compound of formula (I) which reduces the above impurities to minimum level, this indirectly helps to prepare Carvedilol in pure form. We focused our research to develop an improved and efficient process for the purification of the compound of formula (I) in commercial scale.
Summary of the Invention
The main objective of the present invention is to provide 4-(2,3-epoxypropoxy)carbazole compound of formula (I),
Substantially free of compound of l-(9H~carbazoI-4-yloxy)-3-chloropropan-2-ol of formula (III)


Another objective of the present invention to prepare substantially pure compound of formula (I) having more than 99.60% purity by HPLC.
Yet another object of the present invention is an improved process for the preparation of compound of formula (I) having substantially free of chloro impurity of formula (III), having less than 0.06% of diepoxy impurity of compound of formula (IV) and less than 0.03% of dimmer impurity of compound of formula (V).
Yet another embodiment of the present invention is to prepare Carvedilol by using purified key intermediate 4-(2,3-epoxypropoxy)carbazole compound of formula (I).
Detailed Description of the Invention
The main objective of the present invention is to provide 4-(2,3-epoxypropoxy)carbazole compound of formula (I),

Another objective of the present invention to prepare substantially pure compound of formula (I) having more than 99.60% purity by HPLC.

Yet another object of the present invention is an improved process for the preparation of compound of formula (I) having substantially free of chloro impurity of formula (III), having less than 0,06% of diepoxy impurity of compound of formula (IV) and dimmer impurity of compound of formula (V).
The present process for the purification of compound of formula (1) involves recrystallizations by treating an alcohol solvent followed by a ketone/water mixture.
The crude compound of 4-(2,3-epoxypropoxy)carbazole obtained by reacting I hydroxy carbazole with epichlorohydrin in presence of sodium hydroxide and dimethyl
sulfoxide solvent is separated into two portions. One portion repeated the crystallization process as given in Ex-3 of US 4697022 patent in which, S-isomer of formula (I) purified using ethyl acetate and other portion purified as per the present invention.
The process includes treating of crude 4-(2,3-epoxypropoxy)carbazoie with first organic solvent at room temperature, then the contents are allowed to reflux for some time. After complete dissolution of the crude compound of formula (I), charcoal is added to it and the reflux is continued at the same temperature for 30-45 min. Filter the reaction mass through hyflowbed in hot condition and wash the residue with first organic solvent. Cool the filtrate to 0-5°C and continue to maintain the same for 1hr. Filter the product obtained and wash with pre-cooled first organic solvent. Take a clean 4-necked RB . charge it with a second organic solvent and add the product obtained above at the room temperature. Heat the contents to 30-40°C as soon as it dissolves completely in the second organic solvent add charcoal at 35-40°C and maintain for 20-30 min at same temperature. Filter the reaction mass through hyflow bed in hot condition and wash the residue with second organic solvent, take the filtrate obtained in to clean RBF and slowly add drop wise water to the reaction mass at 25-30°C. After the complete addition of water allow it to stay for lh-2hrs at room temperature. Filter the product obtained and wash with water.
The first organic solvent selected from the group of alcohols like methanol. ethanol, isopropyl alcohol and butanol, preferably isopropyl alcohol.
Second organic solvent selected form the group of water miscible solvents like acetone, tetrahydrofuron, acetonitrile, more preferably acetone.

Room temperature in the present invention can varies from 18-40 C. particularly
25-30°C.
The compared results of the present invention with prior art processes are
captured in table-1

From the above results one can conclude the importance of the present invention. I IK
HPLC conditions employed in this invention are
System Name : ADEQP-015
Column : Inertisil C87 250X4.6, 5.0µm
Processed channel deser : PDA 240.0nm

Reference example-1 (Ex-9 of GB 1369580)

A solution of 16.3g of 4-hydroxy carbazole in a mixture of 190 ml of dioxane and 98 ml of IN sodium hydroxide is added 66 ml of epichlorohydrin, after the addition stirred for 2hrs at 40-50°C. The reaction mixture is then diluted with water and shaken out with methylene chloride. The methylene chloride phase was washed with water, dried over anhydrous sodium sulphate and evaporated. There are obtained 16.3g of 4-(2,3-Epoxy propoxy)carbazole.

27.5g 4-hydroxycarbozole is dissolved in mixture of 150 ml of IN NaOH solution and 70 ml DMSO. To this is added at ambient temperature 13.9g of (R)-(-)-epichlorohydrin, followed by stirring for 18hrs at ambient temperature. 280ml of water then added thereto, followed by stirring for 15 min and filtering off with suction. The filter residue is washed with 0.1N NaOH solution and subsequently dissolved in methylene chloride. The DCM solution is dried over anhydrous sodium sulphate, treated with active charcoal and floridin and evaporated. The residue is purified by recrystallising twice from ethyl acetate. Yield 15.2g; M.P: 163-164°C.

Example 1
Preparation of 4-(2,3-Epoxy propoxy)carbazole
To a stirred solution of sodium hydroxide (22.9g, 0.57moles) and water (300ml) added 4-hydroxy carbazole (100g, 0.545moles), stirred for 10-15min, to this slowly added DMSO (150ml) and continued the stirring for another 30-45min. slowly added epichlorohydrin (75,7g, 0.82moles) to the reaction mixture, maintained stirring at 25-30°C slowly raised the temperature to 45°C, maintained the reaction for 8hrs. after completion of the reaction, cooled to 25-30°C. slowly added water (400ml) and stirred for 30min, filter the product, washed with water (100ml) to get wet 4-(2,3-Epoxy propoxy)carbazole.
The above wet compound was taken in isopropyl alcohol (300 ml) heat the reaction mass to 60°C and maintained the stirring for 20-30min at same temperature. Cool the reaction mass to 25-30°C maintained the stirring for 20-30min at same temperature filter the product dried at 60-70°C to get crude 4-(2,3-Epoxy propoxy)carbazole (90g, Yield: 69.2%)
Example 2
Purification of 4-(2,3-epoxypropoxy)carbazole compound of formula (I) using ethyl
acetate.
25.0g of crude 4-(2,3-Epoxy propoxy)carbazole obtained from the above step taken in ethyl acetate (75 ml) heated to 65-70°C to get clear solution, allow to cool to room temperature, the obtained solid was filtered and washed with pre-cold ethyl acetate (20ml), compound dried under vacuum at 45-50°C to get (12.5g)
Example 3
Purification of 4-(2,3-epoxypropoxy)carbazole compound of formula (I)
Step-1: Take a clean RBF and charge with 800 ml of IPA at room temperature of 25-
30°C. Add the 200g crude 4-(2,3-Epoxy propoxy)carbazole obtained in the above step at
the same temperature. Reflux the contents at 80-85°C.After its complete dissolution add
charcoal to the reaction mass at 80-85°C,continue the reflux for 30-45 min at the same
temperature. Filter the reaction mass through hyflowbed in hot condition and wash the

residue with IPA (50ml). Cool the filtrate to 0-5°C and maintain the same for lhr.Filter the product obtained and wash with cooled IPA (50ml),
Step-2: In to a clean 4-necked RBF take 500 ml of acetone and add the product obtained in step-1 at room temperature. Heat the contents to 35-40 °C, after its complete dissolution add charcoal at 35-40°C and maintain for 20-30 min at same temperature .Filter the reaction mass through hyflow bed in hot condition and wash the residue with acetone (50ml). Take the filtrate obtained in to RBF and slowly add drop wise water (1000ml) to the reaction mass at 25-30°C. (Note: addition of water is critical, if water is added quickly there is a chance of formation of lumps) after the complete addition of water, maintain it for 1 h at room temperature. Filter the product and wash with water. Dry the product obtained at 50-60°C for 6- 8hrs to get pure 4-(2,3-Epoxy propoxy)carbazole (80,0g) Example 4
Preparation of Carvedilol
To a stirred solution of 2-(2-Methoxyphenoxy)ethylamine (76,9g, 0.46 moles) in monoglyme (150 ml) was added pure 4-(2,3-epoxypropoxy)carbazole (100g, 0.418 moles) at 25-30°C, heat the reaction mixture to 75-80°C maintained the reaction mass 10-12 hrs at same temperature, check the TLC for the absence of 4-(2,3-epoxypropoxy)carbazole. After completion of the reaction distill of monoglyme from the reaction at below 80°C, cool the reaction mass to 55-60°C, add ethyl acetate (400 ml) and heat the reaction mass up to 65-70°C to get clear solution add charcoal (5.0g) stir for 25-30 min at 55-60°C and filter through celite bed, wash the bed with ethyl acetate (50 ml), cool the filtrate to 25-30°C under stirring for l-2hrs. Further cool the solution to 0-5°C, maintain it for 2-3hrs, filter the product and washed with pre cooled ethyl acetate (50ml). To the wet cake of the above obtained product add ethyl acetate (400 ml), heat the reaction mixture to 65-70°C to get clear solution, add charcoal (5.0g) stir for 25-30 min at 55-60°C and filter through celite bed, wash the bed with ethyl acetate (50 ml), cool the solution to 25-30°C and maintained stirring for 2-3hrs, Filter the obtained product at 25-30°C, wash the material with ethyl acetate (50 ml), suck dry the compound for l-2hrs at 25-30°C, dry the material at 55-60°C till constant weight obtains to get Carvedilol (62.0g, 36.5%)

We claim:
1. A compound of formula (I),

having substantially free of compound of formula (III)

2. A compound of formula (I),

having substantially free of compound of formula (III),

less than 0.06% of compound of formula (IV)

and less than 0.03% of compound of formula (V)


3. A method for the purification of compound of formula (I)

comprises of:
a) dissolve or suspend the crude carbazole of formula (I) in a first organic solvent
b) reflux the above solution
c) add charcoal to the refluxing mass of (b)

d) filter the solution of (c) through high flow bed in hot condition
e) cool the filterate to obtain the solid; filter the solid
f) dissolve the solid obtained from step (e) in a second organic solvent
g) After its complete dissolution add charcoal and allow it to heat
h) filter the solution of step (g) in hot condition; cool to room temperature
i) take the filterate obtained in step (h) and add water to it in drop wise manner; observe
the solid formation
j) filter the solid obtained and wash with water and dry the product.
4. Process according to claim 3, where first organic solvent is alcohol selected from
methanol, ethanol, propanol, butanol, isopropylalcohol etc.,
5. Process according to claim 4, where the alcohol preferably isopropyl alcohol,
6. process according to claim 3, where, the second organic solvent is a ketone solvent
selected from acetone, methyl ethyl ketone.methyl isobutylketone, ethyl butyl ketone etc.,
7. Process according to claim 6, where the ketone preferably acetone
8. Process according to claim 3, where the reflux temperature is in between 75-95°C ,
more preferably at 80-85°C .

Dated this seventh (7) day of March 2008 for Inogent Laboratories Private Limited