WO2009157015A2 - Synthesis of 1-(carbazol-4-yloxy)-3-[[2-(o- methoxyphenoxy)ethyl]amino]-2-propanol - Google Patents

Abstract

The present invention relates to an improved process for the preparation of Carvedilol, wherein, the process involves the use of organic base in the reaction of 4-(oxirane-2ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy) ethylamine in presence of a solvent. While preparing Carvedilol minimum amount of bis-impurity was obtained without purification.

Description

SYNTHESIS OF l-(CARBAZOL-4-YLOXY)-3-[[2-(O- METHOXYPHENOXY)ETHYL]AMINO]-2-PROPANOL

BACKGROUND OF THE INVENTION

Technical field

The present invention relates to an improved process for the preparation of Carvedilol of formula (I) in high purity. Particularly the invention relates to a process of Carvedilol wherein the process involves the use of organic base in the reaction of 4- (oxirane-2-ylmethoxy)-9H-carbazole (II) with 2-(2-methoxyphenoxy) ethylamine (III) in presence of a solvent. This invention in particular to minimize bis-impurity to less than around 1.0% without any purification.

Description of the related art

Carvedilol, (±) l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]- amino]-2-propanol having structure (I), is a non selective β-adrenergic blocker with α_r blocking activity.

Carvedilol has a chiral centre and can exist either as individual stereo isomer or in

® racemic form. Racemic Carvedilol is the active ingredient of COREG , which is indicated for the treatment of congestive heart failure and for the management of hypertension. Since Carvedilol is a multiple action drug, its beta-blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is also known to be a vasodilator resulting primarily from alfa-adrenoceptor blockade. The multiple actions of Carvedilol are responsible for the anti hypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure. The nonselective β-adrenergic activity of Carvedilol is present in the S (-) enantiomer and the αi blocking activity is present in both the R(+) and S(-) enantiomers at equal potency. U.S. Pat. No. 4,503,067, which is incorporated herein by reference, discloses a process for preparation of Carvedilol by reacting 4-(oxirane-2-ylmethoxy)-9H-carbazole (II) with 2-(2-methoxyphenoxy) ethylamine (III).

By the method described in this patent, Carvedilol is prepared in low yields, Moreover, it is contaminated with high amount of bis-derivative of formula (IV).

Various routes of synthesis of Carvedilol has been proposed for reduction of bis- impurity and increasing the yield of the product. The applicants of EP 918 055 Bl, EPl 142873 Bl, WO2005113502 Al and WO2004113296 Al tried to minimize the amount of bisimpurity by reacting 4-(oxirane-2-ylmethoxy)-9H-carbazole (II) with N- benzylated 2-(2-methoxyphenoxy) ethylamine of formula (V); by this method creation of bis-impurity is minimized and the yield of Carvedilol is increased, but a disadvantage of this method is the introduction of additional steps for protection and deprotection of N- benzyl group.

Use of N-benzylated 2-(2-methoxyphenoxy) ethylamine is used for its reaction with 4-(2,3-epoxypropoxy) carbazole for preparation of Carvedilol (I). Due to the toxic nature of N-benzyl impurity, European pharmacopeia has fixed the limits of this impurity to not more than 0.02% and practically it is very difficult to produce this impurity. Further, the catalytic hydrogenation in final stage is not advisable.

(V)

The applicants of WO200200216 decreased the amount of bis-derivative by reaction of an epoxide (II) with an amine (III) in 1:1.5 to 1:100 molar ratios without solvent in neat condition at 100 C to minimize the formation of compound (IV) as a byproduct. This patent does not disclose the yield and purity of the Carvedilol obtained. At higher temperature, in the absence of solvent there is a possibility of degradation which results in low yield. Also use of large amount of amine (III) makes the process uneconomical.

Patent Applications WO2004094378, WO2005080329 and WO2008038301 disclose the formation of organic acid salts of Carvedilol followed by salt cleavage and then purification of the resulting product for the reduction of bis-impurity. But, the formation and cleavage of salt further increases two steps of the process and its reaction time which is not economical in large scale.

The applicant of international application WO2004041783 discloses a method of preparation of Carvedilol by reacting epoxide (II) with salt of amine (III) in the presence of base, which is an alkali metal or alkaline earth metal carbonate.

The applicant of international application WO2005115981 discloses a method of preparation of Carvedilol by reacting epoxide (II) with salt of amine (III) in the presence of base, which is an alkali metal hydroxide in alcoholic solvent. Both these processes are restricted to inorganic base. It is evident from the above matter that although prior art looks very comfortable, it is very difficult to reproduce it practically at commercial scale production. According to the US Patent 4503067, the reaction time itself is 25 hours with lesser yields. While in WO 02/00216 the product is crystallized out in 40 hours at 4⁰C and according to the European Patent EP 918055, the final stage involves catalytic hydrogenation for debenzylation. Thus these processes are not feasible on production scale and prove to lack industrial applicability. Therefore, there is long standing need in industry to provide a simple, economical, precise, reproducible, and industrially feasible process for the preparation and purification of Carvedilol that can meet the standards stipulated by ICH. After painstaking research, the inventors have arrived at an improved process for the preparation and purification of Carvedilol that can meet the standards stipulated by ICH. The novelty of the present invention resides in preparing Carvedilol in which the tedious work-up, extraction steps, and repeated purifications are avoided in order to get increased purity along with reduced reaction steps for reduction in batch time cycle and avoiding any degradation of the final product. Additionally, by reacting 4-(2,3- epoxypropoxy)carbazole with 2-(2-methoxyphenoxy) ethylamine in a suitable organic solvent in presence of a base while maintaining the ratio of 4-(2,3-epoxypropoxy) carbazole to 2-(2-methoxyphenoxy)ethylamine more than 1: 1.0-1.102, formation of bis- impurity (IV) is minimized to less than 1.0% thereby getting crude with high purity more than 98% and avoiding repeated purifications steps.

SUMMARY OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of Carvedilol obviating the drawbacks of the existing processes. Other object of the present invention is to provide a process for the preparation of

Carvedilol in high HPLC purity. Particularly the bis-impurity (IV) is minimized to less than 1.0% thereby getting crude with high purity more than 98% and avoiding repeated purifications steps.

Another object is to provide a more simplified, time saving, cost effective and commercially feasible process for the manufacture of Carvedilol (I).

Yet another object of the invention is to provide a process that can be reproducible and which will overcome the anomalies of the reported processes to provide Carvedilol (I) of high purity (ICH grade) without increasing the reaction steps.

The present invention relates to a process for the preparation of Carvedilol by reacting 4-(oxirane-2-ylmethoxy)-9H-carbazole (H) with 2-(2-methoxyphenoxy) ethylamine (III).

in presence of an organic base and solvent, to minimize the bis-impurity of formula (IV)

The starting material 4-(oxirane-2-ylmethoxy)-9H-carbazole (II) can be prepared according to the process disclosed in the Indian patent application IN 606/CHE/2008 and 2-(2-methoxyphenoxy) ethylamine (III) can be prepared from the hydrochloride salt by using aqueous sodium hydroxide and extracting it with organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention gives the method for the preparation of Carvedilol by reacting 2-(2-methoxyphenoxy) ethylamine (III) with 4-(oxirane-2-ylmethoxy)-9H- carbazole (II) in presence of an organic base and organic solvent. The molar equivalents of the amine of formula (III) are in an amount of 1 to 2 equivalents with respect to the carbazole of formula (II), preferably 1 to 1.102 and more preferably 1 to 1.1 equivalents. The organic solvents can be taken from the group of ethereal solvents, preferably monoglyme. The said organic base used for the present invention is selected from primary, secondary and tertiary amines, preferably tertiary amines. Tertiary amines are selected from the group of N,N-dimethylbenzylamine, N,N-dimethylbutylamine, N₅N- dimethylcyclohexylamine, triethylamine, N-methyl-2-piperidone and tribenzylamine, preferably N,Ndiisopropylethylamine and tribenzylamine are used. The amount of organic base employed is about 0.8 to 1.2 equivalents, more particularly 1.0 equivalent with respect to the carbazole of the formula (II). The reaction is carried out at temperature range of room temperature to 85⁰C, preferably at 80-85⁰C. The reaction typically takes about 8-12 hours for the completion. The progress of the reaction can be monitored by conventional methods like HPLC/ TLC.

After the reaction is completed, the reaction mixture is cooled to room temperature and the organic solvent is added to the mixture and further cooled to 0°- 5⁰C with stirring. The obtained solid is filtered after slurry in ethylacetate to get crude Carvedilol. The organic solvent employed for isolation of Carvedilol is taken from esters solvent, preferably ethyl acetate. The Purity of crude Carvedilol obtained in this process is more than 98 % and having bis-impurity less than 1.0 %, particularly less than 0.7%. The obtained crude Carvedilol can be purified by the conventional techniques.

A surprising new fact in this inventive method of production is that, the method is advantageous in obtaining crude Carvedilol having very less amount of the bis-derivative than by using the existing known methods.

The method of preparation of Carvedilol by this invention is also advantageous in that the new conditions of preparation in combination with purification and isolation of the Carvedilol increase purity and guarantee reliability of the production of an acceptable substance in required pharmacopeia quality and with a defined particle size. Methods of production of this invention will be clear from the following examples, which, however, do not limit the same in any case.

EXAMPLES Example 1:

Process for the preparation of 2-(2-methoxyphenoxy) ethylamine: To a solution of 2-(2-methoxyphenoxy) ethylamine hydrochloride (100 g) in water (200 mL), was added 10% aqueous NaOH at 0⁰C till the pH of the solution is 12-14 and then extracted into dichloromethane (3 x 100 mL). The organic layer was washed with brine (2 X 100 mL). The organic layer was dried over Na₂SO₄ and concentrated to obtain 2-(2-methoxyphenoxy) ethylamine (97%). Example 2:

Process for the preparation of Carvedilol:

2-(2-Methoxyphenoxy)ethyl amine (15.09 g), N,N-diisopropylethyl amine (10.8 g), 4-(oxiran-2yl-methoxy)-9H-carbazole (20.0 g) and monoglyme (30 mL) were heated to 80-85⁰C. After 8-12 hours, the reaction mixture was cooled to room temperature and ethyl acetate (40 mL) was added. The contents were cooled to 0-5⁰C. The solid is filtered after slurry in ethylacetate to get crude Carvedilol (100 mL). (Purity: 98.62%; Yield: 36.26 %; Bis-impurity: 0.65%.)

Example 3:

Recrystalization of Carvedilol: A mixture of Crude Carvedilol (11.0 g) and Ethyl acetate (66 ml) were stirred for

10 min and the reaction mass was heated to 70-75° C for 30 min. It was Filtered and washed with 6 ml of hot ethyl acetate, cooled to room temperature and further cooled to 0-5⁰C. The reaction mass was maintained at 0-5⁰C for 2-3 hrs. The Product was filtered and washed with 6 ml of chilled ethyl acetate and dried. (Purity: 99.6%; Yield: 85%.)

It is understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the features and advantages appended hereto. Industrial Applicability

This invention can be used in the pharmaceutical industry for the production of Carvedilol, which is a nonselective β-adrenergic blocking agent with αi blocking activity.

Claims

We Claim :

1. A method for preparation of Carvedilol, comprising reacting 4-(oxirane-2- ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy) ethylamine in an amount of 1.0- 1.102 equivalents with respect to the starting carbazole, in presence of an organic base, in an amount of 0.8-1.2 equivalents with respect to the starting carbazole in a solvent.

2. The method of claim 1, where in the organic base is selected from the group of N,Ndimethylbenzylamine, N,N-dimethylbutylamine, N,N-dimethylcyclohexylamine, triethylamine, N-methyl-2-piperidone and tribenzylamine, preferably N,N- diisopropylethylamine , tribenzylamine.

3. The method of claim 1, where in the solvent is monoglyme.

4. The method of claim 1, wherein the reaction temperature is maintained in the range of 80°Cto85°C.

5. The method of claim 1, wherein the crude Carvedilol is having less than about 0.7 % of the bis-impurity.