WO2009115902A1

WO2009115902A1 - Process for the preparation of carvedilol via silyl protection of substituted amine

Info

Publication number: WO2009115902A1
Application number: PCT/IB2009/000551
Authority: WO
Inventors: Indravadan Ambalal Modi; Sanjay Laxamanbhai Patel; Sanjay Muktawat; Ramasubbu Chadrasekaran; Ravi Ponnaiah; Bakulesh Mafatlal Khamar
Original assignee: Cadila Pharmaceuticals Ltd.
Priority date: 2008-03-19
Filing date: 2009-03-19
Publication date: 2009-09-24

Abstract

The invention provides new process for preparing Carvedilol by reaction of 4-(oxiran-2- yl-methoxy)-9H-carbazole and substituted silyl protected 2-(2-methoxy phenoxy)-ethylamine compound to give silyl protected Carvedilol intermediate. The silyl protected Carvedilol intermediate on desilylation gives Carvedilol. The invention also provides a novel substituted silyl protected 2-(2-methoxy phenoxy)-ethylamine as key intermediate for the preparation of Carvedilol.

Description

FIELD OF INVENTION

The invention relates to an improved process for preparation of Carvedilol.

BACKGROUND OF INVENTION

The present invention relates to process for making Carvedilol, chemically known as (±)- 1 -(carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-amino]-2-propanol having structural formula -I

Formula-I

It is nonselective β-adrenergic blocker with c^-blocking activity, indicated for the treatment of mild-to-severe heart failure of ischemic or cardiomyopathic origin.lt is marketed in USA as COREG^®-

The US patent 4,503,067 discloses process for preparation of Carvedilol comprising reaction of 4-(2,3-epoxypropoxy)carbazole with 2-(2-methoxyphenoxy)-ethylamine using ethylene glycol dimethyl ether as solvent The reported yield of carvedilol is 39% . The draw back of this process is formation of "bis- impurity" having structural Formula-ll.

Formula-ll

Once formed it is very difficult to remove this impurity and obtain pure carvedilol suitable for pharmaceutical use. Carvedilol contains one chiral center. The racemic mixture containing equal amounts of R(+) and S(-) enantiomers is commercial product.

European patent no. 918055 discloses two processes for preparation of Carvedilol. The process (A) comprises reaction of 4-(oxiranylmethoxy)-9H-carbazole with N-[2-{2'-(methoxy)- phenoxy}-ethyl]-benzylamine in a protic organic solvent to give benzyl protected Carvedilol [ Formula-Ill ], which on debenzylation using catalytic hydrogenation gives carvedilol.

i

Formula-Ill

The process (B) comprisies reaction of protected N-[2-{2'-(methoxy)-phenoxy}-ethyl]- benzyl amine (Formula-IV) with epichlorohydrin to form chloro compound, 1-[N-{benzyl}-2'-({2"- (methoxy)-phenoxy)-ethyl}-amino]-3-chloro-propan-2-ol (Formula-V). The intermediate chloro compound (Formula-V) reacts with 4-(hydroxyl)-9H-carbazole (Formula-VI) in the presence of base to give benzyl protected carvedilol (Formula-Ill) which is converted to carvedilol using catalytic hydrogenation.

Formula-IV Formula-V Formula-VI

Formula-I

The processes disclosed in this patent make use of expensive catalyst in the debenzylation stage.

The US patent 7,126,008 discloses process for preparing Carvedilol comprising reaction of 4- (oxiran-2-yl-methoxy)-9H-carbazole with 2-(2-methoxyphenoxy)-ethylamine, wherein the ethyl amine compound is taken in large excess to minimize the formation of bis impurity (Formula-ll) making the process commercially less attractive. Other processes for making Carvedilol are also known, international application No.

WO2004/041783 discloses the process for preparation of Carvedilol comprising reacting 4- (oxiranylmethoxy)-9H-carbazole with a salt of 2-(2-methoxyphenoxy)-ethylamine in presence of alkaline earth metal carbonate in C₂-C₅ alcohols as solvents. The product on crystallization in ethyl acetate yields 41% Carvedilol. The international application No. WO/2006/061364 discloses reaction of 4-(oxiran-2-ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy)- ethylamine using ethyl acetate as solvent. All the processes reported so far, produce Carvedilol in low yields or make use of expensive catalyst.

Thus, there is a need to provide a commercially viable process which does not make use of expensive catalyst and at the same time produces carvedilol of high purity by limiting formation of bis-impurity [Formula-ll].

SUMMARY OF THE INVENTION

An object of the invention is to provide a novel process for preparing Carvedilol by reaction of 4-(oxiran-2-yl-methoxy)-9H-carbazole [Formula-VII] and substituted silyl protected 2-

(2-methoxy phenoxy)-ethylamine compound [ Formula-VIII] to give substituted silyl protected

Carvedilol [Formula-IX] intermediate . The substituted silyl protected Carvedilol on desilylation gives Carvedilol.

Yet another object of the invention is to provide novel substituted silylated carvedilol intermediate [Formula-IX] The preferred substituents (R₁₁R₂₁S R₃) in silyl protecting group P are R₁=R₂=R₃= -CH₃ ;

R₁=R₂=R₃= -CH₂CH₃; R₁=R₂= -CH₃, R₃= -C(CH₃)₃. The most preferred being one with

Still, yet another object of the invention is to provide a novel substituted silyl protected

2-(2-methoxy phenoxy)-ethylamine as an intermediate for the preparation of Carvedilol and process for the preparation thereof.

DETAILED DESCRIPTION OF THE INVENTION

The novel process of this invention is illustrated in scheme-1. The process comprises of following steps. a) reacting 2-(2-methoxyphenoxy)ethylamine [Formula-Villa ] with silylating agent in an organic solvent to give N-substituted silylated compound of Formula-(VIII), wherein silyl substituent P is - Si(R₁)(R₂)(R₃) wherein Ri,R₂,& R₃ is C₁-C₄ alkyl , b) reacting compound of Formula-(VIII) with 4-(2,3-Epoxypropoxy)-carbazole [Formula- VII] to give substituted silyl protected compound [Formula-IX] , wherein P is as defined above, c) desilylation of substituted silyl protected Carvedilol to give Carvedilol, followed by isolation and purification to give high purity carvedilol.

Yet another aspect of the invention is to provide a novel substituted silyl protected 2-(2- methoxy phenoxy)-ethylamine (Formula-VIII) as an intermediate for the preparation of Carvedilol. The silyl protected amine compound is prepared by silylation of an amine compound using silylating agents such as hexamethyl disilazane, trimethyl chlorosilane, bistrimethyl silyl urea (BSU)₁ bistrimethyl acetamide (BSA), tert-butyl dimethyl silyl chloride.

The reaction is carried out at 2O⁰C to 15O⁰C, preferably at 25⁰C to 100⁰C, more preferably at 50⁰C to 100⁰C. In a preferred embodiment the substituted silyl protected amine compound [Formula-VIII] is reacted with an epoxy intermediate [Formula-VII] to give substituted silyl protected Carvedilol [Formula-IX] .

The reaction is carried out in solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene or mixtures thereof ; ethers such as Tetrahydrofuran [THF] ,dioxane,2- methyl THF, dipropyl ether.di n-butyl ether, Methyl tertiary butyl ether [MTBE], monoglyme or mixtures thereof; chlorinated solvents such as dichloro methane, chloroform, carbon tetra chloride, chlorobenzene or mixtures thereof; amides such as N,N-dimethyl formamide, N₁N- dimethyl acetamide, N-methyl pyrrolidone , N.N'dimethyl imidazoline 2-one, N₁N₁N', N'- tetramethyl urea or mixtures thereof ; nitriles such as acetonitrile, propionitrile or mixtures thereof; the preferred solvent being toluene.

The substituted silyl protected Carvedilol compound gives carvedilol upon deprotection. The deprotection is preferably carried out in aqueous acid followed by isolation of Carvedilol from reaction mass and purification to provide high purity carvedilol.

In one of the preferred embodiments of this invention, 2-(2-methoxyphenoxy)ethyl amine in toluene is reacted with with trimethylsilylchloride in presence of acid scavenger like trialkyl amine, preferably triethyl amine to give trimethyl silyl protected2-(2- methoxyphenoxy)ethyl amine which is then reacted with 4-(2,3-epoxypropoxy)carbazole at about reflux temperature for about 4-5 hrs. The reaction mass is then cooled and acid preferably , phosphoric acid solution is added slowly, followed by addition of water (50ml). The layer is allowed to separate and liq. ammonia is added to give pH -9-9.5. Ethyl acetate is added and organic layer is separated, washed with water and dried over anhydrous sodium sulphate. The 50% of organic layer was distilled under reduced pressure. The mass was allowed to cool at O⁰C -5⁰C temperature. Carvedilol is isolated by filtration and dried.

The present invention is further illustrated by following non-limiting examples. Example -1 Preparation of Carvedilol i

Bis-trimethylsilylurea (21.35gm) was added to 2-(2-methoxyphenoxy)ethyl amine (17.47gm) in toluene (75 ml) at RT. The reaction mass was heated at reflux temperature for 3 hrs and allowed to cool at 80 to 85⁰C temperature. 4-(2,3-epoxypropoxy)carbazole (25gm) was added and refluxed for 5-6 hrs. The reaction mass was further allowed to cool at temperature of 55 to 60⁰C. Water (25 ml) was added and stirred for 15 minutes. The solvent is removed by distillation under reduced pressure at 55 to 6O⁰C. Ethyl acetate (2x 500ml) was added and stirred. The solvent was distilled under reduced pressure to give an oily mass. Ethyl acetate (100ml) and water (50 ml) was added to oily mass and the layer was separated. The organic layer was washed with water and dried over anhydrous sodium sulphate (10gm). The 50 % of ethyl acetate was distilled under reduced pressure. 4.81 ml of 85% H₃PO₄ was added at 20-25⁰C and stirred for 30 minutes. Water (25 ml) and liq ammonia (25%) was slowly added to get pH ~9.5. The reaction mass was cooled to 0-5⁰C and filtered to give 15.5gm Carvedilol Example 2: Preparation of Carvedilol Trimethylsilyl chloride (31.68 ml) was added to a solution of 2-(2-methoxyphenoxy) ethylamine (20 gm) in toluene at RT over 30-45 minutes and stirred for two hours. Triethyl amine (42 ml) was added drop wise in 15-30 min. The reaction mass was heated up at 50⁰C and a solution of 4-(2,3-Epoxypropoxy)carbazole (28.60gm) in 1,4-dioxane (100 ml) was added over 10 minutes. The reaction was heated at reflux temperature and stirred for 4 - 5 hour. On completion of reaction, the solvent was distilled under reduced pressure at 70 - 75⁰C to yield an oily mass. The oily mass was cooled to 25 - 30⁰C. Water (50 ml) and ethyl acetate (50 ml) was added and stirred for 30 minutes. Ethyl acetate layer was separated and washed with water (2x50 ml). Ethyl acetate layer was dried with anhydrous sodium sulfate and distilled under reduced pressure at 50 - 55°C to give result the silylated Carvedilol as oily mass, [m/z = 478.5] Wt. of oil= 18 gms

The oily mass (5 gm) was taken in 25 ml of DM water and stirred with H₂SO₄ (2.56 gm) for 15 minutes and then heated at 65-70⁰C. The reaction mass was allowed to cool at 15 - 20⁰C. The pH was adjusted to ~ 9.5-10 using 10 %NaOH solution. Ethyl acetate (50 ml) was added and the layer was allowed to separate which was washed with water (2x 50 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give residue which were crystallized using ethyl acetate to give pure Carvedilol (3.0gm)

Claims

We claim,

1. A process of preparing carvedilol comprising following steps: a) reacting 2-(2-methoxyphenoxy)ethylamine [Formula-Villa ] with silylating agent in an organic solvent to give the compound of Formula-(VIII),

Formula-VIIIa Formula- VIII wherein, P = - Si(R₁)(R₂)(R₃) wherein R₁₁R₂₁S R₃ is C₁-C₄ alkyl

b) reacting compound of Formula-(VIII) with 4-(2,3-Epoxypropoxy)-carbazole [Formula- VII] to give substituted silyl protected compound [Formula-IX] , wherein P is as defined above,

c) desilylation of substituted silyl protected Carvedilol to give Carvedilol, followed by isolation and purification to give high purity carvedilol.

The process as claimed in claim-1, wherein silylating agent in step-(a) is selected from trimethylchlorosilane, N.N'bistrimethylsilyl urea, N,O-bis trimethylsilyl acetamide, hexamethyidisilazane or combination thereof , the preferred agent being

N.N'bistrimethylsilyl urea or trimethylchlorosilane . 3. The process as claimed in claim-1, wherein the solvent used in step -(a) is selected from aromatic hydrocarbons such as benzene, toluene, xylene or mixtures thereof; ethers such as Tetrahydrofuran,dioxane,2-methyl THF₁ dipropyl ether.di n-butyl ether, methyl tertiarybutyl ether, monoglyme, or mixtures thereof; chlorinated solvents such as dichloro methane, chloroform, carbon tetra chloride, chlorobenzene or mixtures thereof; amides such as N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl pyrrolidone , N.N'dimethyl imidazolidin-2-one, N,N,N',N'-tetramethyl urea or mixtures thereof ; nitriles such as acetonitrile, propionitrile or mixtures thereof.

4. The process as claimed in claim-3, wherein the preferred organic solvent is toluene. 5. The process as claimed in claim-1, wherein the compound of formula-VIII, wherein P is trimethyl silyl or triethyl silyl or tertiarybutyl dimethyl silyl.

6. The process as claimed in claim-1, wherein the silylation is carried out at 20⁰C to 150⁰C preferably at 25⁰C to 100⁰C.

7. The process as claimed in claim-1, wherein the desilylation in step-(c) is carried out using aqueous acid. 8. The process as claimed in claim-1, wherein the desilylation in step-(c) is carried out at

25⁰C to 100⁰C preferably at 50⁰C to 100⁰C.

9. The process of preparing carvedilol as claimed in claim-1 , wherein the purification of carvedilol in step-(c) is carried out in organic solvent selected from toluene.dioxane.acetone acetonitrile, methyl ethyl ketone, methyl /-butyl ketone, ethyl acetate, isopropyl acetate, preferred solvent being ethyl acetate. 10. The compound of the Formula-IX useful in the preparation of carvedilol or related compounds.

Formula-IX wherein, P is -Si(Me)₃, -Si(Et)₃ , -Si(Me)₂C(Me)₃

1. The compound of Fprmula-VIII

Formula-VIII wherein, P is -Si(Me)₃, -Si(Et)₃ , -Si(Me)₂C(Me)₃