FORM-2
THE PATENTS ACT 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. PROCESS FOR THE PREPARATION OF CARVEDILOL VIA SILYL PROTECTION OF SUBSTITUTED AMINE
2. CADILA PHARMACEUTICALS LIMITED.
"CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210 GUJARAT, INDIA NATIONALITY: AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.


FIELD OF INVENTION
The invention relates to an improved process for the preparation of Carvedilol. BACKGROUND OF INVENTION
The present invention relates to process for making Carvedilol, (±)-l-(carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-amino]-2-propanol. Carvedilol is the active ingredient of COREG®. It is nonselective P-adrenergic blocker with a1-blocking activity having following structural formula:

Carvedilol is in racemic mixture form, wherein S-(-) enantiomer is responsible for nonselective b-adrenoreceplor blocking activity and R-(+) and S-(-) enantiomers in both at equal potency shows a-adrenergic blocking activity.
COREG® is indicated for the treatment of mild-to-severe heart failure of ischemic or cardiomyopathic origin. It is also indicated to reduce cardiovascular mortality during the acute phase of myocardial infarction and for the management of essential hypertension. Since Carvedilol is multiple action drug, its P-adrenoreceptor blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is known to be vasodilator resulting primarily from a-adrenoceptor blockade. The multiple drug actions of Carvedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
The US patent 4,503,067 discloses process for preparation of Carvedilol comprising reaction of 4-(2,3-epoxypropoxy)carbazole (compound of formula I) with 2-(2-methoxyphenoxy)-ethylamine (compound of formula II) using ethylene glycol, dimethyl ether as solvent, yields 39% Carvedilol. The draw back of known process is a bis-compound gets formed with the Carvedilol. The bis-compound is formed by the reaction of 2 molar equivalents of 4-(oxiranylmethoxy)-9H-carbazole of the formula I and 1 molar of equivalent of 2-[2'-(methoxy)-phenoxy]-ethyl amine of the formula II. This said reaction can never be avoided. It should also difficult to remove the impurity difficult to remove these impurities by purification of Carvedilol.


In principle, the formation of the bis compound as an impurity can be avoided by using, in stead of primary amine 2[2'-(methoxy)-phenoxy]-ethylamine of formula II, a secondary amine which is a derivative of primary amine of the formula II, containing protective group.



O' "2
H,N C
Carvedilol
SCHEME 1
Formula I

H2
II3CO' Formula II

European patent no. 918055 discloses two processes for preparation of Carvedilol The process (A) as illustrated in scheme 2 comprises the reaction of 4-(oxiranylmethoxy)-9H-carbazole of the formula I with protected N-[2-{2'-(methoxy)-phenoxy}-ethyl]-benzylamine of the formula IV in a protic organic solvent to give benzyl protected Carvedilol of the formula V as shown in scheme 2.

SCHEME 2
Formula I

Formula IV

Formula V I Debenzylation

OCH,

Carvedilol
The process (B) as illustrated in scheme 3 comprisies the reaction of protected N-[2-{2'-(methoxy)-phenoxy}-ethyl]-benzyl amine of the formula VI with epichlorohydrin to form chloro compound, l-[N-{benzyl}-2'-({2"-(methoxy)-phenoxy)-ethyl}-amino]-3-[chloro]-propan-2-ol of the formula VII. The intermediate chloro compound of the formula VII reacts with 4-(hydroxyl)-9H-carbazole of formula V11I and thus forms benzyl protected Carvedilol of the formula V.
The end product is obtained via debenzylation of benzyl protected Carvedilol by catalytic hydrogenation.


OC1I-,
SCHEME 3 Formula VIOCII., Epicn


OCH-,
Formula VIII Formula VII

Formula V
Debenzylation

OCH3

Carvedilol
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 free amine compound is taken at a molar excess ratio to reduce the formation of bis-substituted impurities.
Other processes for making Carvedilol are also known, international application No. WO2004/041783 discloses the process for preparation of Carvedilol wherein the 4-(oxiranylmethoxy)-9H-carbazole (Compound of formula I) reacts with an amine 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-(oxirane-2-ylmethoxy)-9H-carbazole (Compound of formula I) with 2-(2-methoxyphenoxy)-ethylamine using ethyl acetate as solvent.
As the scale-up of the known processes of Carvedilol results in low yields and poor quality end products, they become commercially unattractive. It is therefore desirable to provide processes that are commercially applicable.
SUMMARY OF THE INVENTION
An object of the invention is to provide 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 on desilylation gives Carvedilol.
Yet another aspect of the invention is to provide a novel silyl protected 2-(2-methoxy phenoxy)-ethylamine as key intermediate for the preparation of Carvedilol.


DETAIL DESCRIPTION OF THE INVENTION
In accordance with the present invention, the process for the preparation of Carvedilol as illustrated in scheme 4 comprises:
a. 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.
b. silyl protected Carvedilol on desilylation results into Carvedilol.
SCHEME 4 ^\ H2 H2 H2

^cx ,c\ A-^ ^o
O Cll N C

I I H2
0,1 I IhCO
p H3co
Formula II
H Silyl protected Carvedilol
Formula I
1
Deprotection
1'


Wherein P =■■ Amine protecting silyl derivatives

11,
M7
,0
ll2 ,c.
O Cll N C
011 H,CO
Carvedilol

In a preferred embodiment the reaction involves the use of 2-(2-methoxy phenoxy)-ethylamine intermediate, which is protected by different protecting groups in order to reduce the formation of bis-substituted side product. The preferable protecting groups are different silyl derivatives which includes hexamethyl disilazane, trimethyl chlorosilane, bistrimethyl silyl urea (BSU), bistrimethyl acetamide (BSA), tert-butyl dimethyl silyl (TBDMS) or tert-butyl-diphenyl silyl (TBDPS) groups.
Yet another aspect of the invention is to provide a novel silyl protected 2-(2-methoxy phenoxy)-ethylamine as an intermediate for the preparation of Carvedilol. The silyl protected amine compound preferable prepared via silylation of an amine compound carried out at 20°C to 150°C, preferable at temperature ranging from 25°C to 100°C. In a preferred embodiment the silyl protected amine compound of the formula II is condensed with an epoxy intermediate to give silyl protected Carvedilol. The reverse addition of starting material can also results into the formation of silyl protected Carvedilol intermediate.


The solvent used for condensation is selected from organic solvents such as aromatic hydrocarbon, nitriles, substituted amide, alcohols, esters, ethers, halohydrocarbon or mixture thereof. The substituted or unsubstituted aromatic hydrocarbons can preferable select from toluene, xylene, benzene etc. The nitriles can preferable select from acetonitrile, propionitrile etc. The amide can preferable select from dimethyl formamide, N,N-dimethyl acetamide, N,N'-trimethylene urea, N,N'-ethylene urea, N-methyl-2-pyrrolidone, tetramethyl urea etc. The ethers can preferable select from diethyl ether, THF, dioxane etc. The substituted or unsubstituted alcohols can preferable selected from C2-C6 alcohols and the preferable substituted or unsubstituted esters can select from dimethyl ester, diethyl ether etc.
The silyl protected Carvedilol compound upon deprotection in presence of water at pH 1-14 result into the formation of Carvedilol. Any acid or base may preferable used in the deprotection of silyl protected Carvedilol. The end product is isolated from reaction mass and upon purification or crystallization results into the formation of highly pure Carvedilol.
In preferred embodiment Carvedilol comprising condensation of 4-(oxiran-2-yl-methoxy)-9H-carbazole and substituted silyl derivative of 2-(2-methoxy phenoxy)-ethylamine compound to give corresponding protected Carvedilol intermediate. The silyl protected Carvedilol on desilylation using gives Carvedilol. The more preferable substituted silyl derivative of 2-(2-methoxy phenoxy)-ethyiamine compound includes TBDMS, TBDPS, TMS etc. derivatives of corresponding amine.
The process of invention comprises reaction of 2-(2-methoxyphenoxy)ethyl amine in Toluene with Trimethylsilylchloride. 4-(2,3-epoxypropoxy)carbazole is added to the reaction mass and heated to reflux for 4-5hrs. The reaction mass was allowed to cool and H3PO4 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 0-5°C temperature. The solid was isolated and filtered. The end product was dried at under reduced pressure Carvedilol as resulting end product.
Carvedilol can also prepared by process comprising reaction of bis-trimethylsilylurea or
trimethylsilyl chloride with 2-(2-methoxyphenoxy)ethyl amine in toluene at RT. The reaction
mass is heated at reflux temperature for 3 hrs and allowed to cool at 80 to 85°C temperature. 4-


(2,3-epoxypropoxy)carbazole is added and refluxed for 5-6 hrs. The reaction mass is further allowed to cool to get the temperature of 55 to 60°C. Water was added and stirred for 15 minutes. The solvent was distilled under reduced pressure at 55 to 60°C. Ethyl acetate is added and stirred. The solvent is removed by distillation under reduced pressure to give an oily mass. Ethyl acetate and water is added to oily mass and the layer is allowed separated. The organic layer was washed with water and dried over anhydrous sodium sulphate (l0gm). The 50 % of ethyl acetate was distilled under reduced pressure. 4.81 ml of 85% H3PO4 was added at 20-25°C 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 0-5°C and filtered to give 15.5gm Carvedilol
The present invention is illustrated with the given non-limiting examples.
Example -1 Preparation of Carvedilol
2-(2-methoxyphenoxy)ethyl amine(10.35gm ) was added to Toluene (100ml) in 250ml round bottomed flask and stirred for 15 minutes at 25-30°C. Trimethylsilylchloride (8.4ml) was added slowly and stirred for 2-3 hrs followed by addition of 4-(2,3-epoxypropoxy)carbazole (14.8gms). The reaction mass was heated to reflux for 4-5hrs. The reaction mass was allowed to cool at 45-50°C temperature and H3PO4 solution (4.8ml) was added slowly followed by addition of water (50ml). The layer was allowed to separate and liq. ammonia was added to give pH ~9-9.5. Ethyl acetate (100ml) was added and organic layer was separated and washed with water. The organic layer was dried over anhydrous sodium sulphate (lOgm). The 50% of organic layer was distilled under reduced pressure at 55°C. The mass was allowed to cool at 0-5°C temperature. The solid was isolated and filtered. The product was dried at 50-55°C under reduced pressure to give 7.5gm Carvedilol.
Example -2 Preparation of Carvedilol
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 85°C 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 60°C. Water (25 ml) was added and stirred for 15 minutes. The solvent is removed by distillation under
reduced pressure at 55 to 60°C. 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 (lOgm). The 50 % of ethyl acetate was distilled under reduced pressure. 4.81 ml of 85% H3PO4 was added at 20-25°C 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 0-5°C and filtered to give 15.5gm Carvedilol
Example 3: 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 50°C 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 - 75 C to yield an oily mass. The oily mass was cooled to 25 - 30°C. 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 = 478.5J The oily mass (5 gm) was taken in 25 ml of DM water and stirred with H2S04 (2.56 gm) for 15 minutes and then heated at 65-70°C. The reaction mass was allowed to cool at 15 - 20°C. 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)