FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Novel process for preparation of l-(9H-carbazol - 4 - yloxy)- 3 - [[2 - (2-methoxyphenoxy)ethyl] amino]-2-propanol"
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of invention:
The present invention relates to a preparation method for l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy) ethyl] amino]-2-propanol and its salts.
Background of the invention:
The pharmaceutically valuable compound l-(9H-carbazol—4-yloxy)-3-[[2-(2-methoxyphenoxy) ethyl] amino]-2-propanol, also known as Carvedilol under the international proprietary name, is a non-selective b-adrenergic blocking agent with vasodilating activity. Carvedilol is represented with the following structural formula:

Formula -1
The compound carvedilol has one chiral carbon atom and hence it can exist in either as its stereoisomers or in its racemic form.
Carvedilol was reported for the first time 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-1:

^N^.OCH3
Formula - II Formula - III
Scheme -1.



This route suffers from lower yield due to the formation of a bis-compound of Formula -IV, which in most cases cannot be avoided, in about 10 - 15% of the total product and remains as impurity in the carvedilol. This necessitates additional purification procedures for the isolation of carvedilol free from contamination of bis-impurity of Formula IV and therefore the process may not be ideal for industrialization.

Formula - IV
Another route exemplified in '920 patent is by reacting an N-protected reaction partner, i.e., N-benzyl 2-(2-methoxy-phenoxy)ethylamine of Formula V with 4-(2,3-epoxy propoxy) carbazole, whereby the formation of bis-impurity is blocked. The intermediate benzyl carvedilol (Formula VI) was debenzylated to obtain the product carvedilol. However the yield of the benzyl carvedilol obtained by following this pathway is reported to be nearly 80%.

CARVEDILOL Formula -I
Scheme - II
An obvious extension of this route was disclosed in EP 0918055 by which the formation of bis impurity is similarly avoided by reacting a benzyl protected 2-(2-methoxyphenoxy) ethylamine (Formula V) with 4-(2,3-epoxypropoxy)-carbazole.

Modification to this route were extensively studied and reported in US20070112054, WO2005113502, EP1142873, EP1142874[both 873 and 874 are same family]; WO2004113296 and in Indian patent application number IN583/BOM/1999.
An alternative protective group was also studied for blockage of di-substitution reaction, for example, WO 01/87837 describes the preparation of carvedilol from 4-hydroxy carbazol by reacting it with 5-chloromethyl-3-[2-(2-methoxyphenoxy)ethyl]-oxazolidin-2-one (Formula - VII) to yield oxazolidine derivative of Formula - VIII as expressed in scheme III. This intermediate was further hydrolyzed to get carvedilol. The preparative process for the intermediate of Formula -VII involves various stages, such as reacting 1,3-dichloropropan-2-ol with phenyl chloroformate, which is made to react with 2-[2-(methoxyphenoxy)] ethylamine hydrochloride . to yield [2-(2-methoxy phenoxy)-ethyl]-carbamic acid-2-chloro-l-chloromethyl-ethyl ester. The ester formed is cyclised to get compounds of Formula - VII. 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.

CARVEDILOL Formula -I
Scheme - HI
Yet another improvement reported in 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 100 moles per 1.0 mole of 4-(2,3- epoxy propoxy) carbazole (Formula - II) to avoid the formation of bis impurity (Formula - IV). The use of large excess of 2 - (2- methoxy phenoxy) ethylamine


(Formula III) makes the process uneconomical and requires the wasted reactant to be recovered and recycled, if the process to be economically successful.
The same route was explored in many patent literature, for example WO 2004/094378, however, the problem of bis-impurity remains as a concern to the synthetic chemist except for use of an N-protected intermediate.
Thus the search for a manufacturing process for the preparation of carvedilol resulting in a satisfactory yield / purity of final product remains undoubtedly of interest. It is therefore an object of the present invention to discover an efficient process to prepare carvedilol, apart from simplifying the process for industrial use.
Summary of the present invention:
In view of the above-mentioned present situation, the present inventors have conducted various studies with the aim of achieving the above-mentioned object. Accordingly, the present invention provides a process for preparation of carvedilol comprises the following steps:
a) reacting a l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of formula VII with 2-(2-methoxyphenoxy)-haloethane (formula VIII) to obtain arylmethyl carvedilol of Formula VIA; and.

Ar = (un)substituted phenyl Formula VIII R
R= H, acetyl, benzyl etc.
Formula VIA Formula VII
b) deprotecting benzyl carvedilol to obtain carvedilol of Formula I in free form or its acid addition salt.


Y"'xi\r"x'---'0' ----- -->- /^ OH H

°H I 1' A U /X A /J MeO
J MeO N,
N - \^ AT R
p Formula IA
Formula VIA
The process of the present invention is described herein after in more details substantiating various embodiments and conditions of reaction for better understanding/appreciation of the invention.
Detailed Description of the invention:
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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words 'including', 'includes', 'comprising' and 'comprises' mean 'including without limitation' and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
This invention is thus directed to process for preparation of carvedilol such that, by virtue of the processes of this invention, carvedilol obtained substantially free from the bis-compound of formula IV. Therefore, the present invention provides process according to the following scheme:


OH

-Ar

MH
.0
OH

Ar = (un)substituted phenyl R = H, acetyl, benzyl etc.
Formula VII

MeO
X= Leaving group Formula VIII

Ar
Formula VIA

MeO

MeO

Formula I

OH

N H

MeO

Formula VIA
In the scheme Ar refers to a substituted or unsubtitiuted aryl residue; R is hydrogen or any suitable NH-protecting group; and X is any leaving group including halogen such as chloro, bromo, and iodo, or a tosyl, mesyl group)
The key to the success of the present invention lies in the selective alkylation of 1-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of formula VII with 2-(2-methoxyphenoxy)-haloethane (formula VIII), wherein, X is a leaving group such as halogen, or activated hydroxyl-group like tosyl.
The details of process are explained below:
In the process of the present invention, the starting l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of formula VII is prepared by reacting 4-(2,3-epoxy propoxy) carbazole (Formula - II) with Arylmethylamine as represented below:


R
Formula IIA

Ar-CH2-NH2

OH
N ~
/
R Formula VII

N

-Ar



wherein the groups are as defined previously. The reaction may be conducted in the presence or absence of a solvent, but advantageously in presence of an inert solvent. The solvent may be selected from aqueous or organic solvents. For example, but not limited to, water, alcohols, ketones, amide, sulphoxides, hydrocarbons, chlorinated solvents, nitriles, esters and ethers or their mixtures.
In neat reaction the benzyl amine may be used in excess which serves the purpose as a solvent. In the process, the benzylamine is otherwise, also preferably used in excess to obtain selective mono-substitution. After completion of the reaction, l-(9Z/-carbazol-4-yloxy)-3-arylmethylamino-2-propanol is isolated by any conventional methods like filtration. Like-wise the present invention provides a continuous process for preparation of l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of Formula VII by reacting in a batch of excess of benzyl amine in a suitable solvent, filtering out the \-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of Formula VII as solid component, and feeding 4-(2,3- epoxy propoxy) carbazole and the benzyl amine in molar amounts to the reactor. The reaction may be performed under ambient to 100 degree Celsius, but preferably at about 40 to 70 degrees.
The starting 4-(2,3- epoxy propoxy) carbazole may be obtained by reacting 4-hydroxy-carbazole with epichlorohydrin in a conventional manner.

Formula II
The reaction is advantageously carried out in a solvent, preferably aqueous solvent. The 4-(2,3- epoxy propoxy) carbazole may be isolated and purified in a conventional manner before reacting with benzyl amine in the following step.


In the process of the present invention, the l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of Formula VII is reacted with compound of Formula (VIII) in presence of a base, wherein Ar is defined as above and X is any leaving group such as halogen, for example, chloro, bromo, iodo, or an activated hydroxyl ester group, for example tosyl, mesyl group.
The process is advantageously carried out in an organic or aqueous solvent, such as those customarily used, for example, chlorinated hydrocarbons, ethyl acetate, toluene, diethylether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl acetamide, N-methyl pyrollidone or toluene etc. The reaction may be done in presence of water or mixture of water miscible solvents.
The base used in the reaction may be an inorganic or an organic base; examples of organic base include triethylamine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (l,5-diazabicyclo-[4.3.0]- non-5-ene), 4-dimethylamino pyridine and mixtures thereof. Examples of inorganic bases include alkali metal carbonate, bicarbonate, hydroxide, alkoxides and mixtures thereof. Examples of alkali metal carbonates include sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate. Examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Organic bases are preferred for this application and especially suitable bases are amines, preferably triethylamine or N,N-diisopropylethylamine. The amount of base added to the reaction mixture is not very critical but should be adjusted with respect to the molar amounts of respective substrates or can be established by trial.
In a further embodiment of the invention, the reaction is preferably carried out in the presence of a catalyst. The catalyst may be selected from among the phase-transfer catalyst or metal iodide. The selection or presence of said catalysts accelerate the reaction and reduces the time cycle. However, the same results are obtained in its absence; however, owing to the economy of the process it is preferred to be used. Sodium or potassium iodide is especially preferred among the metal iodides. As the phase transfer catalyst, mention can be made of, for example, quaternary ammonium salts substituted


with a residue selected from the group consisting of straight or branched chain alkyl
group having 1-18 carbon atoms, phenyl lower alkyl group and phenyl group, such as
tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium
fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide,
tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride,
tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium
bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride,
methyltrihexylammonium chloride, benzylmethyloctadecanylammonium chloride,
methyltridecanylammonium chloride, benzyltripropylammonium chloride,
benzyltriethylammonium chloride, phenyltriethylammonium chloride,
tetraethylammonium chloride, tetramethylammonium chloride and the like; phosphonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms such as tetrabutylphosphonium chloride and the like; and pyridinium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as 1-dodecanylpyridinium chloride and the like or from a crown ether.
The reaction is preferably performed by heating the reactants in the said solvent medium and the preferred temperature for carrying out the reaction is by maintaining the reaction mass at reflux of the solvent, but preferably between 60 to 100 degrees. The reaction normally completes in a span of 5 - 10 hours. Both the reactants are used in molar amounts or one of the reactant in slight excess, a design choice according to the conditions of reaction.
The benzyl carvedilol obtained after the reaction may be optionally isolated before deprotection reaction. In this process, the work up and isolation of the benzyl cavedilol is carried out either by solvent elimination or filtration or extraction of the product into an organic solvent. The extraction my be performed by following an acid-base treatment to purify the product, and crystallization from a suitable solvent, known to a skilled artisan. In another alternative method, the crude product may be directly subjected to a debenzylation reaction.


In the process, the arylmethyl substituted carvedilol obtained according to the present invention is deprtoected by hydrogenation in presence of a catalyst to obtain carvedilol of high purity, essentially free from bis-compound of Formula IV.
The catalyst may be selected from any known ones customarily used for the debenzylation, preferably the catalyst is palladium on charcoal. The debenzylation reaction may be advantageously carried out in a suitable solvent, preferably alcohols. The hydrogenation reaction is performed at suitable temperature and pressure. The reaction temperature may be from ambient to 110 °C, preferably at positive pressure.
On complete debenzylation, the crude carvedilol is isolated by first filtration of the catalyst, and solvent distillation, followed by leaching or crystallization in solvent selected from ethyl acetate, toluene, water or its mixture thereof. The preferred solvent for leaching is a mixture of toluene and water. The preferred crystallization solvent is ethyl acetate. The carvedilol is purified further from a suitable solvent by crystallization, preferably from ethyl acetate.
Further details of about process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Examples:
Preparation of 1 -(9H-carbazol-4-yloxy)-3-phenylmethylamino-2-propanol
Example 1(a)
To a four neck R.B.flask 5.6gm benzyl amine and 25 ml water, 5.0gm of 4-(2,3-epoxy-propoxy) carbazole were added .The reaction mass was heated to about 60°C and maintained for 10 hours. The mixture containing solid was filtered, washed with water and dried. Weight of the product obtained was 7.2 gm. (Yield 98.7 %.)


Example 1(b)
To a four neck R.B.flask containing 112gm benzyl amine, 25.0gm of 4-(2,3-epoxy propoxy) carbazole were added. The reaction mass was heated to 60°C & maintained for about 3 hrs. Product was isolated by pouring the reaction mixture in water and dichloromethane mixture. The precipitate obtained was filtered and dried. Weight of the product obtained was 22.35gm (Yield 61.7%)
Preparation of benzyl carvedilol
Example 2(a).
To a four neck R.B.flask containing 30ml toluene, 3.46 gm l-(9H-carbazol-4-yloxy)-3-phenylmethylamino-2-propanol and 3.5 gm 2-(2methoxy phenoxy) ethyl bromides were added. To this stirred mixture 5 ml water, 6.5 gm potassium carbonate and 0.1 gm triethyl benzyl ammonium chloride were added. The reaction mixture was then heated to about 95°C for about 24 hours. Then the reaction mixture was cooled to room temperature, layers were separated and the organic layer was cooled to get the product. This was filtered and dried to obtain 2.48 gm benzyl carvedilol (Yield: 50%).
Example 2(b).
To the four neck RB flask, a mixture of 10.0 gm l-(9H-carbazol-4-yloxy)-3-phenylmethylamino-2-propanol, 8.0 gm 2-(2methoxy phenoxy) ethyl bromide , 12.0 gm (0.030mmole) potassium carbonate, 0.2 gm Potassium iodide and 100 ml water were added. The mixture was heated to 100°C & maintained for 6 hrs. The mixture was then cooled to room temperature, extracted with dichloromethane, distilled out dichloromethane to obtain a residue. The residue was crystallized from isopropyl alcohol to obtain 12 gm benzylcarvedilol. (Yield: 83.1%)


Example 3. Preparation of Carvedilol
In a pressure vessel, 58.0 gm of benzyl carvedilol & 870 ml methanol were charged. 5.85gm of Pd/C (10%) was added to this mixture and hydrogenated at 4-5 kg/cm2 hydrogen pressure & 70°C temperature. After hydrogenation, the reaction mixture was filtered to remove catalyst and the filtrate was concentrated to remove solvent. The crude product was crystallized from ethyl acetate to obtain 36.3 gm Carvedilol (Yield: 76.7%)