FORM-2
THE PATENTS ACT 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. AN IMPROVED PROCESS FOR PREPARATION OF CARVEDILOL INVOLVING HALOHYDRIN DERIVATIVE
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 present invention relates to a cost effective and industrially viable process for the preparation of Carvedilol involving halohydrin derivative
BACKGROUND OF INVENTION
The present invention relates to process for making Carvedilol, (±)-l-(carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-arnino]-2-propanol. Carvedilol is the active ingredient of COREG ®. It is nonselective b-adrenergic blocker with a1-blocking activity having following structural formula:

Carvedilol is in racemic mixture form wherein S-(-) enantiomer is responsible for nonselective b-adrenoreceptor 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-carbazoIe 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, a
secondary amine which is a derivative of primary amine of the formula II, containing protective
Formula
group, in stead of primary amine 2[2'-(methoxy)-phenoxy]-ethylamine of formula II SCHEME 1
European patent no. 918055 discloses two processes for preparation of Carvedilol. The process (A) as illustrated in scheme 2 comprises the reaction of 4-(oxiranylmethoxya)-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.



H2
O" ^ ^O
UN C
H2

SCHEME 2
Formula I

OCH,
Formula IV

H2 H2 H2
CI I N C
II2 OH

Formula V I Debenzylation

OCIh

Carvedilol
The process (B) as illustrated in scheme 3 comprises 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 VIII and thus forms benzyl protected Carvedilol of the formula V.
The end product is obtained via debenzylation of benzyl protected Carvedilol by catalytic hydrogenation.
3


OCTI,

SCHEME 3
Formula VI
Formula VIII

on i,
Epichlorhydrin
►
Formula VII

,x\on
Formula VII

Formula V
Debenzylation
Carvedilol

OCII,

The US patent 7,126,008 discloses process for preparation of Carvedilol comprising reaction of 4-(oxiran-2-yl-methoxy)-9H-carbazole with 2-(2-methoxyphenoxy)-ethylamine, wherein the free amine compound is taken in molar excess ratio to reduce the formation of the 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 a process for the preparation of Carvedilol by reacting l-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or l-(9H-carbazol-4-yloxy)-3-bromopropan-2-ol with 2-(2-methoxyphenoxy)-ethylamine.


Yet another object of the invention is to provide a process for the preparation of Carvedilol by reacting l-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or l-(9H-carbazol-4-yloxy)-3-bromo propan-2-ol with amino protected 2-(2-methoxyphenoxy)-ethylamine
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. reacting 4-(2,3-epoxy propoxy)carbazole with hydrochloric acid or hydrobromic acid to
give l-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol or l-(9H-carbazol-4-yloxy)-3-
bromopropan-2-ol respectively,
b. reacting l-(9H-carbazol-4-yloxy)-3-chloropropan-2-ol (Compound of formula I') or 1-
(9H-carbazol-4-yloxy)-3-bromopropan-2-ol (Compound of formula l")with a compound
of formula- II, to give a compound of formula-Ill
c. separating crude residue results in to Carvedilol or protected Carvedilol. The protected
Carvedilol after suitable deprotection reaction results into the formation of crude
Carvedilol.
d. The crude Carvedilol on purification gives highly pure Carvedilol.

Formula I
wherein,
X = CI for Tor Br for I

wherein,
R = H or Protective group

wherein, R is as defined above Formula III


In a preferred embodiment the reaction involves the use of hydrochloric acid or hydrobromic acid. The reaction is carried out at 0°C to 100°C; preferably temperature is 15°C to 50°C, more preferably at 25°C-30°C. Toluene is added to the reaction mass to remove water under reduced pressure. The residue is cooled to 25°C-30°C. Toluene and 2-(2-methoxyphenoxy)-ethylamine is added followed by addition of potassium carbonate.
The reaction mass is heated to 80°C to 85°C and maintained for 13 hours. Water is added and stirred. Toluene layer is separated and distilled under reduced pressure at 65 - 70°C. Ethyl acetate is added to the residue and stirred at ambient temperature for half an hour. The reaction mass is gradually cooled and stirred. The residue is filtered and washed with chilled ethyl acetate to give Carvedilol (5.5 gm). The end product is dried under reduced pressure to give Carvedilol (> 97% HPLC purity).
When an amino protected 2-(2-methoxyphenoxy)-ethylamine is used in the above reaction instead of 2-(2-methoxyphenoxy)-ethylamine, above reaction results in the formation of protected Carvedilol of high purity (>97%). The protecting groups are selected from benzyl, substituted silyl derivatives etc. wherein the substituted silyl derivatives are preferable selected from hexamethyl disilazane, trimethyl chlorosilane, bistrimethyl silyl urea (BSU), bistrimethyl acetamide (BSA), tert-butyl dimethyl silyl (TBDMS) or tert-butyl-diphenyl silyl (TBDPS) groups. Purification of crude Carvedilol is carried out using any solvent, though ethyl acetate is preferred.
In another embodiment of this reaction, it is possible to provide (S)-isomer of Carvedilol which is obtained by reaction of (S)-1-(9H-carbazol-4-yloxy)-3-halopropan-2-ol with 2-(2-methoxyphenoxy)-ethylamine. The present invention is illustrated with the given non-limiting examples.
Example 1: Preparation of Carvedilol
4-(2,3-Epoxypropoxy)carbazole (10 gms) was added to a solution of hydrochloric acid [25 ml] at 25-30°C. The reaction mass was stirred for 5 hours at 25 - 30°C, then the reaction mass was heated to 75-80°C. Water was distilled out at 75 - 85°C and then Toluene was added to remove water under reduced pressure at 75-80°C. The residue was cooled to 25-30°C. Toluene (100 ml) and 2-(2-methoxyphenoxy)-ethylamine (10.45 gm) was added followed by addition of K2CO3 (9.45 gm). The reaction mass was heated to 80 - 85°C and maintained for about 13 hours. Water


(100 ml) was added and stirred for 5 - 10 minutes. Toluene layer was separated and distilled out under reduced pressure at 65 - 70°C. Ethyl acetate was added to the residue and stirred at ambient temperature for half an hour. The reaction mass was gradually cooled to 0-5°C and stirred for 2 hrs. The reaction mass was filtered, washed with chilled ethyl acetate to obtain Carvedilol (5.5 gm). The product was dried under reduced pressure to give Carvedilol (>97% HPLC purity).
Example-2 Preparation of Carvedilol
48 % HBr solution [35 ml] was added to 4-(2,3-Epoxy propoxy)carbazole (25 gm) in Isopropyl alcohol (50 ml ) at 25-30°C and heated to 60°C and maintained for about one hour with stirring. The solvent was distilled under reduced pressure and allow the reaction mass to cool at room temperature. Triethyl amine (16 gm) and 2-(2-methoxyphenoxy)-ethylamine (35 gm) were added to reaction mass and heated to 60°C and maintained for about 2 hours with stirring. Traces of Isopropyl alcohol was distilled under reduced pressure at 45-50°C. Water (50 ml), Toluene (100 ml) and 50 ml ethyl acetate were added at 50°C, and stirred for 15 minutes. The organic layer was allowed to separate and washed with water at 50°C then dried with sodium sulfate (10 gm). Solvent was distilled under reduced pressure up to 55°C. Ethyl acetate (55 ml) was added to residue and stirred for 30 minutes. The reaction mass was cooled to 0-5°C and filtered to get Carvedilol (12 gm). The product was dried to give Carvedilol (>97% HPLC purity).