Process For Preparation Of 1-(9h-carbazol-4-yloxy)-3-[[2-(2- Methoxyphenoxy) Ethyl] Amino]-2-propanol

  • Published: Sep 24, 2009
  • Earliest Priority: Feb 04 2008
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Technical field of invention:

The present invention relates to a process for preparation of l-(9H-carbazoM-yloxy}-3- [[2-(2-methoxyphenoxy) ethyl] amino] -2-propanol and its salts, which are pharmaceutically valuable compounds.

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 β-adrenergic blocking agent with vasodilating activity. The chemical structure of Carvedilol is represented in the following formula:

Formula - 1

The compound Carvedilol has one chiral carbon atom and hence it can exist in either as its stereoisomer or in its racemic form.

Carvedilol, its process and pharmaceutical application were reported for the first time in EP0004920. EP0004920 discloses several alternative processes to prepare Carvedilol or its derivatives, one of which includes reaction of 4-(2,3- epoxy propoxy) carbazole of Formula - II with 2-(2-methoxy-phenoxy)ethylamine of Formula - III to prepare the Carvedilol as per the reaction sequence shown in scheme- 1:

Formula - II Formula - III Formula - 1

Scheme - 1

This route reportedly 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 economically ideal for industrialization.

Formula - IV

Another route exemplified in EP '920 patent is by reacting an N-protected 2-(2-methoxy- phenoxy)ethylamine, 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 completely blocked. Thereafter benzyl Carvedilol (Formula VI) intermediate was debenzylated to obtain the product Carvedilol (reaction scheme is represented in Scheme II given below). Although this route adds two more steps, but expected to give the final Carvedilol in higher yield and purity. However, the yield of the benzyl Carvedilol obtained by following the aforementioned pathway is reported to be nearly 80% only. An obvious extension of this route was disclosed in EP 0918055 in 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 (Formula II) as represented in scheme II.


Scheme - II

Modification of the benzyl protected route were extensively studied and reported in US20070112054, WO2005113502, EPl 142873, EPl 142874 [both EP '873 and EP '874 belongs to same family]; WO2004113296 and in Indian Patent Application number 583/BOM/1999.

An alternative to benzyl protective group was also studied for blocking the di-substitution side reaction. For example, WO 01/87837 describes preparation of Carvedilol by first reacting 4-hydroxy carbazol with 5-chloromethyl-3-[2-(2-methoxyphenoxy)ethyl]- oxazoIidin-2-one (Formula - VII) to yield an oxazolidine derivative of Formula - VIII as expressed in scheme III. This intermediate was further hydrolyzed to give Carvedilol. The process for the preparation of intermediate of Formula -VII used in this method involves various stages, such as reacting l,3-dichloropropan-2-ol with phenyl chloroformate, which then reacts 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 cyclized to get compound of Formula - VII. In order to produce Carvedilol free of bis impurity, this alternative process introduces number of additional steps making it cumbersome for the industrial production of Carvedilol.



Scheme - III

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), but with reduced formation of bis-impurity in the reaction. The process accomplishes reduction of bis-impurity formation, however, by using 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 reduce the level of formation of bis impurity (Formula - IV). The side reaction reduces as the molar ratio increases and achieves almost complete reduction large excess amount of one of the expensive reagent. 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 is 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 2 - (2- methoxy phenoxy) ethylamine 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 invention:

In view of the above-mentioned complexities, the 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 comprising the following steps:

a) reacting l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol or its 9-substituted derivative of Formula (IX) with 2-(2-methoxyphenoxy)-compound of Formula (X) to obtain a compound of Formula VIA; and

formula IX

b) deprotecting compound of Formula VIA to obtain Carvedilol of Formula I (R=H) in free form or its acid addition salt.

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 'having', '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 is substantially free from the bis- compound of formula IV. Thus, the present invention provides process according to the following scheme:

formula IX In the scheme, Ar refers to a substituted or unsubtitiuted aryl residue; R is hydrogen or any suitable NH-protecting group, preferably a benzyl 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 IX) with 2-(2- methoxyphenoxy)-haloethane (Formula X), wherein X is a leaving group such as halogen, or activated hydroxyl-group like tosyl.

The details of the process are explained below:

In the process of the present invention, the starting l-(9H-carbazol-4-yloxy)-3- arylmethylamino-2-propanol of (Formula IX) is prepared by reacting 4-(2,3-epoxy propoxy) carbazole (Formula - II) with Arylmethylamine as represented below:

Formula Il A

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, Arylmethylamine may be used in excess which serves the purpose as a solvent. In the process, the Arylmethylamine is otherwise, also preferably used in excess to obtain selective mono-substitution. After completion of the reaction, l-(9H-carbazol-4- yloxy)-3-arylmethylamino-2-propanol or its 9-substitued derivative 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 IX by reacting in a batch of excess of benzyl amine in a suitable solvent, filtering out the l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol of Formula IX as solid component, and feeding 4-(2,3- epoxy propoxy) carbazole of Formula II and the Arylmethylamine in molar amounts to the reactor. The reaction may be performed under ambient to 100 0C, but preferably at about 40 to 70 0C

The starting 4-(2,3- epoxy propoxy) carbazole of Formula II may be obtained by reacting 4-hydroxy-carbazole with epichlorohydrin in a conventional manner.

Form u Ia Il

The reaction is advantageously carried out in a solvent, preferably a polar solvent or aqueous solvents. The intermediate 4-(2,3- epoxy propoxy) carbazole may be isolated and purified in a conventional manner before reacting with Arylmethylamine.

In the process of the present invention, the compound of formula IX, l-(9H-carbazol-4- yloxy)-3-arylmethylamino-2-propanol is reacted with compound of Formula (X) in the presence or absence of a solvent, 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 reaction is advantageously carried out in presence of a base substance.

The process is advantageously carried out in an organic or aqueous solvent, such as those customarily used, for example, chlorinated hydrocarbons, ethyl acetate, toluene, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide 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 tertiary amines like triethylamine, diisopropylethylamine, pyridine, 4-dimethylamino pyridine and mixtures thereof. Examples of inorganic bases include alkali metal carbonate, bicarbonate, hydroxides, 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 halide. 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 halides. 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, and phenyl lower alkyl group.

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 1000C. 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 excess, a design choice according to the conditions of reaction. The condensation may be done in a pressure vessel with a positive pressure.

Arylmethyl Carvedilol or its 9-substituted derivative obtained after the reaction may be optionally isolated before deprotection reaction. In this process, the work up and isolation of the Arylmethyl Carvedilol is carried out either by solvent elimination or filtration or extraction of the product into an organic solvent. The extraction may be optionally 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 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 deprotected 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 HO0C, under hydrogen gas pressure. For 9- substituted derivatives, if necessary the protective group may be removed by hydrolysis or hydrogenolysis in a conventional manner.

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.

The carvedilol obtained by the process of the present invention may be further converted to its pharmaceutically active salts, such as phosphate, sulfate etc. The carvedilol or its salts such as phosphate may be thereafter incorporated in a pharmaceutical composition along with suitable pharmaceutical excipients and made into dosage forms such as tablet, capsules etc.

Further details of the process of the present invention will be apparent from the examples presented below. 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 l-(9H-carbazol-4-yloxy)-3-phenylmethylamino-2-propanoI

Example l(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 600C 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 l(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 600C & 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 bromide 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 1000C & 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%)

Preparation of Carvedϋol

Example 3

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 & 700C 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%)

We Claim,

1. A process for preparation of carvedilol comprising: a) reacting l-(9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol or its 9- substituted derivative of Formula IX with a compound of Formula X to obtain a compound of Formula VIA; and

Formula DC

b) deprotecting compound of Formula VIA to obtain carvedilol of Formula I in free form or its acid addition salt.

2. A process as claimed in claim 1, wherein the group Ar is (un)substituted phenyl group.

3. A process as claimed in claim 1, wherein the leaving group X is any halogen or sulphonyloxy substituted.

4. A process as claimed in claim 3, wherein the leaving group is chloro, bromo, iodo, tosyl, mesyl group.

5. A process as claimed in claim 1, wherein the compound of formula IX is 1-(9H- carbazol-4-yloxy)-3-arylmethylamino-2-propanol.

6. A process as claimed in any one of the preceding claim, wherein the reaction is in presence of a base.

7. A process as claimed in claim 6, wherein the base is organic or inorganic base.

8. A process as claimed in any one of the preceding claim, wherein the reaction is in presence of a catalyst.

9. A process as claimed in claim 8, wherein the catalyst is a phase-transfer catalyst or a metal halide.

10. A process as claimed in claim 9, wherein the catalyst is selected from potassium iodide, sodium iodide and tetrabutyl ammonium bromide.

11. A process as claimed in any one of the preceding claim, wherein the reaction is in the absence of solvent.

12. A process as claimed in any one of the preceding claim, wherein the reaction is in presence of a solvent.

13. A process as claimed in claim 12, wherein the solvent is aqueous or organic solvent.

14. A process as claimed in claim 13, wherein the solvent is chlorinated hydrocarbons, ethyl acetate, toluene, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide or their mixtures.

15. A process for preparation of carvedilol or its pharmaceutical salt comprising: a) reacting l-(9H-carbazol-4-yloxy)-3-benzylamino-2-propanol with 2-(2- methoxyphenoxy)-haloethane to obtain benzyl carvedilol; and b) hydrogenolysis of benzylcarvedilol to obtain carvedilol of Formula I in free form or its acid addition salt.

16. A process for preparation of carvedilol as claimed in claim 15, wherein the 2-(2- methoxyphenoxy)-haloethane is 2-(2-methoxyphenoxy)-chloroethane or 2-(2- methoxyphenoxy)-bromoethane.

17. A process as claimed in any one of the preceding claim, wherein the pharmaceutical salt is carvedilol phosphate or carvedilol sulphate.

18. A process as claimed in any one of the preceding claims, wherein the carvedilol or its salt is further incorporated in a pharmaceutical composition.

19. A process as herein described with reference to the accompanying text, description or examples.

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