Title of Invention

A COST EFFECTIVE PROCESS FOR PRODUCTION OF CARVEDILOL

Abstract ABSRACT: A cost effective process for preparation of highly pure carvedilol substantially free from impurities is described herein; l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propan- 2-ol is catalytically hydrogenated using inexpensive catalyst like Raney Nickel and isolating crude carvedilol free from penultimate and other major impurity; which is purified in an ethyl acetate/ Methyl ethylketone to obtain pure Carvedilol. 8
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A cost effective process for production of Carvedilol."
.2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies Act, 1956
(c) ADDRESS: B- Wing, 10tb Floor, BSEL Tech Park, Sector 30 A, Plot no.39/5
& 39/5A. Opp. Vashi Railway Station, Navi- Mumbai- 400 703, Maharashtra,
India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to a process for synthesis of l-(9H-carbazol-4yloxy)-3-[[2-(2- methoxyphenoxy)ethyl] amino]-propan-2-ol, (carvedilol) of formula (I) which is substantially free from penultimate impurities, by catalytic debenzylation of 3-[9H-carbazol-4-yloxy] -1 - [N- { benzyl} -2-( { 2-methoxyphenoxy)-ethyl} -amino]- propan-2-ol (benzyl carvedilol) of formula (VIII) over Raney Nickel.
Background of invention: -
Carvedilol, the first beta blocker labeled in the United States for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality. Carvedilol is chemically known as l-(9H-carbazol-4yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl] amino]-propan-2-ol, which has the following structure (I).

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The patent DE 2815926 and its equivalent patents (US 4,503,067, EP- 004920) describe preparation of carvedilol by reacting 4-(2,3-epoxypropoxy)-carbazole of formula (III) with 2-(2-methoxyphenoxy)-ethylamine of formula (IV) using ethylene glycol and dimethyl ether as solvent. A major drawback of the process reported is the formation of bis- compound of formula VII by reaction of carvedilol with one more molecule of 4-(2,3-epoxypropoxy)-carbazole. This problem is partly overcome by using N-benzyl derivative of 2-(2-methoxyphenoxy)- ethylamine instead of the free amine to obtain benzyl carvedilol which is subsequently debenzylated to get carvedilol.


The European patent EP 0 918 055 describes the formation of the bis side product (VII) can be avoided by mono protecting the N atom in 2-(2'-(methoxy)-phenoxy)-ethylamine before reaction with 4-(oxiranylmethoxy)-9H-carbazol using a benzyl group as protection group. Reaction of 4-(oxiranylmethoxy)-9H-carbazole with the N-2-(2-methoxy-phenoxy)ethyl benzyl amine was carried out in a protic organic solvent to obtain benzyl-carvedilol which is debenzylated with palladium/Carbon to obtain carvedilol.

VII H
Patent application US2002/0143045 Al and patent US6699997 discloses preparation of Carvedilol by reaction of 4- (oxiran-2-ylmethoxy)-9H carbazole with 2- (2-methoxyphenoxy) ethylamine in 1: 1.5 to 1:100 molar ratio without solvent in neat condition atl00°C to minimize the formation of bis compound as by-product. Use of large amount of 2- (2-methoxyphenoxy) ethylamine makes the process uneconomical.
According to literature knowledge, N-debenzylation reaction over pd/C never goes for 100% completion, leading the traces of N-benzyl Carvedilol as major impurity along with some additional impurity in final product. The amount of impurity formation depends on the catalyst, temperature and pressure used in the hydrogenation reaction. The European pharmacopoeia has covered the limit of this benzyl carvedilol impurity not more than 0. 02% due to its toxic nature and practically it is very difficult to achieve this impurity level.
Methods known in the literature involve expensive precious metal catalysts. Hence the problem underlying to the invention is to provide a new cost effective process for catalytic hydrogenation for preparing carvedilol. The present invention does not involve
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expensive precious metal catalyst. Moreover this invention can be easily implemented in large scale operation and also the product has low impurity profile.
Summary of the invention:
The present invention discloses a cost effective process for production of carvedilol. The process involves catalytic hydrogenation of benzyl carvedilol over specially prepared Raney-Nickel followed by isolation of carvedilol.
The present invention is further aimed to reduce the other impurities by performing the reaction under moderate reaction conditions, whereby achieving the product in good yields and desired purity and the undesired benzyl impurity is less than detection limit.
Detailed description of the invention:
The present invention describes a cost effective preparation of Carvedilol. The process of the present invention comprises the steps of;
i) Condensation of N-2-(2-methoxy- phenoxy)ethyl benzyl amine with the 4-
(2,3-epoxypropoxy)-carbazole to obtain benzyl carvedilol.
ii) Debenzylation of 3-[9H-carbazol-4-yloxy]-l-[N-{benzyl}-2-({2-
methoxyphenoxy)-ethyl}-amino]- propan-2-ol to obtain crude carvedilol. iii) Treatment of Toluene to crude carvedilol.
iv) Purification of crude carvedilol in ethyl acetate or Methyl ethyl ketone to get pure carvedilol.
The preferred embodiment of the present invention comprises debenzylation of 3-[9H-carbazol-4-yloxy]-l-[N-{benzyl}-2-({2-methoxyphenoxy)-ethyl}-amino]- propan-2-ol using Raney Nickel as a hydrogenating catalyst being carried out under hydrogen pressure range of 50-125 psi; preferably at 100 psi. and at a temperature range of 25-90°C, preferably at 75°C. The debenzylation can be carried out in polar or non-polar solvents. The catalyst is used in a quantity of 5-25 % of the substrate in the reaction preferably 15 %. Debenzylation was carried for 30 mins - 2 hrs to give carvedilol, substantially free of penultimate and other impurities.
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The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example 1
3-[9H-carbazol-4-yloxy]-1 -[N- {benzyl} -2-({2-methoxyphenoxy)-ethyl} -amino]-
propan-2-ol (Benzyl carvedilol)
100 gm. (0.4179 moles) 4-(oxiranylmethoxy)-9H-carbazole is reacted with 123.7
gm.(0.4807 moles) N-2-(2-methoxyphenoxy) ethyl benzyl amine in 1 liter isopropyl
alcohol at reflux for 6-8 hrs. There after heating discontinued and reaction mass cooled to
room temperature, stirred for 12-15 hrs. at room temperature. Filtered the product and
washed with 25 ml isopropyl alcohol and dried in vacuum to yield 198 gm (0.3987
moles) (95.6 % of theoretical) as a white solid. Purity: Not less than 98.5 %
Example 2
Crude Carvedilol
100 gm (0.2013 moles) 3-[9H-carbazol-4-yloxy]-l-[N-{benzyl}-2-({2-methoxyphenoxy)-ethyl} -amino]- propan-2-ol,l liter isopropyl alcohol and 15 gm(15%) Raney Nickel were charged in an autoclave. Vessel was pressurized to 100 PSI with hydrogen at 75°C under stirring for 1-2 hr. There after vessel was cooled, depressurized and the reaction mass was filtered and wash with hot 50 ml isopropyl alcohol. Isopropyl alcohol was recovered by distillation and stirred overnight at 0-5°C. The material was filtered suck dried. Again taken in flask added 350 ml toluene stirred for 30 mins., filtered and wash with toluene to obtain 76.9 gm.(0.1891) crude carvedilol. (95.0% of theoretical). Purity: Not less than 98.5 %
Example 3
Crude Carvedilol
100 gm (0.2013 moles) 3-[9H-carbazol-4-yloxy]-l-[N-{benzyl}-2-({2-
methoxyphenoxy)-ethyl}-amino]- propan-2-ol, 1 liter toluene and 15 gm (15%) Raney
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Nickel were charged in an autoclave. Vessel was pressurized to 100 PSI with hydrogen at 75°C under stirring for 4-6 hr. There after vessel was cooled, depressurized and the reaction mass was filtered and wash with hot toluene. The filtrate was stirred overnight at room temperature. The material was filtered to obtain 77 gm.(0.1894 moles) crude carvedilol. (95.06% of theoretical). Purity: Not less than 98.5 %
Example 4
Carvedilol pure
77 gm crude carvedilol was charged to 770 ml ethyl acetate. Added 4 gm activated
carbon in clear solution. Heated at 60 °C for 1 hr and filter through hyflo, wash with 15
ml ethyl acetate. The filtrate was cooled to 0-5°C gradually and stir for 10-12 hrs. The
material was filtered to yield 72 grams of pure carvedilol (88 % of theoretical) Percentage
Purity: NLT 99.5 %. Contents of benzyl carvedilol are observed below detection limit.
Example 5 Carvedilol pure
77 gm crude carvedilol was charged to 144 ml Methylethylketone. Added 4 gm activated carbon in clear solution. Heated at 60 °C for 1 hr and filter through hyflo, wash with 15 ml Methylethylketone. The filtrate was cooled to 50°C added 770 ml toluene. Cooled to 0-5°C gradually and stir for 10-12 hrs. The material was filtered to yield 72 grams of pure carvedilol (88 % of theoretical) Percentage Purity: NLT 99.7 %. Contents of benzyl carvedilol are observed below detection limit.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. A process for preparation of highly pure carvedilol substantially free from
impurities, comprising the steps of;
i) debenzylation of l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-
methoxyphenoxy)-ethylamino]-propan- 2-ol by using inexpensive hydrogenation catalyst in an organic solvent.
ii) removing the impurities of crude carvedilol in non polar solvents.
2. The process as claimed in claim 1, wherein, hydrogenation catalyst is Raney Nickel.
3. The process as claimed in claim 1, wherein, hydrogenation reaction is carried out at 50-125 psi, preferably 100 psi.
4. The process as claimed in claim 1, wherein, hydrogenation reaction is carried out at 25-90°C preferably at 75°C.
5. The process as claimed in claim 1, wherein, quantity of the catalyst used is 5-25% of the substrate, preferably 15%.
6. The process as claimed in claim 1, wherein, said organic solvent used for debenzylation is selected from non polar solvent or polar solvents.
7. The process as claimed in claim 1, removing the impurity of carvedilol by the treatment with toluene, or mixture of Methylethylketone and Toluene.
8. The process as claimed in claim 1, wherein Carvedilol is isolated with benzyl carvedilol impurity below detection limit.
9. The process for preparation of highly pure carvedilol substantially free from impurities as substantially described herein with reference to the foregoing examples 1 to 5.
Dated this 22nd day of May, 2006
Dr. Gopakumar G. Nair Agent for the applicant
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ABSRACT:
A cost effective process for preparation of highly pure carvedilol substantially free from impurities is described herein; l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propan- 2-ol is catalytically hydrogenated using inexpensive catalyst like Raney Nickel and isolating crude carvedilol free from penultimate and other major impurity; which is purified in an ethyl acetate/ Methyl ethylketone to obtain pure Carvedilol.
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Documents:

771-mum-2006-abstract(22-05-2006).pdf

771-mum-2006-abstract.doc

771-mum-2006-abstract.pdf

771-mum-2006-cancelled pages(22-05-2006).pdf

771-mum-2006-claims(granted)-(22-05-2006).doc

771-mum-2006-claims(granted)-(22-05-2006).pdf

771-mum-2006-claims.doc

771-mum-2006-claims.pdf

771-mum-2006-correspondance-received-ver-070806.pdf

771-mum-2006-correspondance-received.pdf

771-mum-2006-correspondence(10-04-2008).pdf

771-mum-2006-correspondence(ipo)-(19-12-2008).pdf

771-mum-2006-description (complete).pdf

771-mum-2006-form 1(22-05-2006).pdf

771-mum-2006-form 18(30-08-2006).pdf

771-mum-2006-form 2(granted)-(22-05-2006).doc

771-mum-2006-form 2(granted)-(22-05-2006).pdf

771-mum-2006-form 26(16-06-2005).pdf

771-mum-2006-form 3(29-10-2007).pdf

771-mum-2006-form-1.pdf

771-mum-2006-form-2.doc

771-mum-2006-form-2.pdf

771-mum-2006-form-26.pdf

771-mum-2006-form-3.pdf

771-mum-2006-form-9-ver-030806.pdf

771-mum-2006-form-9-ver-070806.pdf


Patent Number 226869
Indian Patent Application Number 771/MUM/2006
PG Journal Number 10/2009
Publication Date 06-Mar-2009
Grant Date 26-Dec-2008
Date of Filing 22-May-2006
Name of Patentee WANBURY LIMITEED
Applicant Address B-Wing,10thFloor,BSEL Tech Park, Sector 30 A, Plot no.39/5 & 39/5A. Opp.Vashi-Mumbai-400703, Maharashtra,India
Inventors:
# Inventor's Name Inventor's Address
1 Sanganabhatla, Shankar 402,Plot No.51,Sector-12 B, Khoparkhairane, Navi Mumbai-400 709 Maharashtra, India
2 Suryavanshi,Jitendra Pandurang Khardeo Nagar, Chembur(E), Mumbai-400 071. Maharashtra,India
3 Koduru,Ramanarasimha Moorthy 4,Udayagiri,Cheddanagar, Chembur, Mumbai-400 089 Maharashtra,India
PCT International Classification Number C07D 209/00, C07D 209/88
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA