FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - "An improved process for the preparation of
Candesartan Cilexetil."
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company
(c) ADDRESS: Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

Field of invention:
The present invention relates to an improved process for the preparation of Candesartan cilexetil.
Background of the invention:
The chemical name of Candesartan Cilexetil is l-[[(Cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-l-[[2-(lH-tekazole-5-yl)[l,1’-biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate. Its molecular formula is C33H34N6O6 and mol wt is 610.66. Candesartan Cilexetil is represented by structural formula (I)

Candesartan Cilexteil is an ester prodrug of 2-ethoxy-l-[[2-(lH-tetrazole-5-yl)[l,l'-biphenyl-4-yl]methyl]-lH benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin II receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure. Candesartan cilexetil is a white to off-white powder and is sparingly soluble in water and in methanol. It is marketed by AstraZeneca under tradename ATACAND® .
U.S. Pat. No. 5,196,444 describes a process of preparation of Candesartan cilexetil in which it is formed by reacting 2-ethoxy-l-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl -4-yl]methyl]benzimidazole-7-carboxylic acid in dimethylformamide with cyclohexyl-1-iodoethyl carbonate to form cilexetil trityl candesartan and its subsequent deprotection with a methanolic hydrochloric acid gives candesartan cilexetil in 47% yield after column chromatography. The yield obtained by this process is very low. Moreover, the
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purification of final product by chromatography is commercially not suitable and is cumbersome at an industrial scale.
U.S.Pat. No. 5,578,733, describes a process of preparation of candesartan cilexetil comprising deprotection of cilexetil trityl candesartan with mineral acids is done under substantially anhydrous conditions in the presence of alcohol. The purification of candesartan cilexetil involves a variety of extraction steps with solvents such as ethyl acetate, ethanol, and acetone prior to crystallizing candesartan cilexetil from aliphatic hydrocarbon such as hexane. Such purification process is tedious, laborious to perform and time consuming.
The complexity and high cost of the prior art procedures has created a need for an improved process for the preparation of candesartan cilexetil. The present invention provides a solution to the problem presented by the prior art.
Through our experimentation present inventors have observed that the detritylation step, wherein the trityl group from Candesartan cilexetil of formula II, in the process for the preparation of Candesartan Cilexetil is sensitive and directly related to the formation of impurities, quality and yield of the final product. Therefore, we directed our research work toward developing a process which avoids these difficulties during detritylation step.

Surprisingly, present inventors have found that a selective molar proportion and concentration of HC1 utilized in the step of detritylation, substantially increase the yield and quality of the product.
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Summary of the invention:
A primary object of the present invention is to provide an improved process for the preparation of candesartan cilexetil.
Another object of the present invention is to provide a process for the preparation of Candesartan Cilexetil having purity of more than 99%.
Another object of the present invention is to provide an improved process for cleaving the trityl group from tritylated Candesartan cilexetil of formula II, which is simple, easy to handle and feasible at commercial scale.

(II)
Yet another object of the present invention is to provide an improved process for the preparation of Candesartan Cilexetil comprising a step of cleaving the trityl group from tritylated Candesartan cilexetil of formula II, in the presence of methanol containing 30-35% hydrochloride acid with 3 to 5 moles in dichloromethane.
Detailed description of the invention:
According to the present invention, it provides a process for the preparation of Candesartan cilexetil comprising a step of cleaving the trityl group from tritylated Candesartan cilexetil of formula II, in the presence of methanol containing 30-35% hydrochloric acid with 3 to 5 moles in dichloromethane.
The reaction is carried out by adding a solution of hydrochloric acid in methanol to tritylated Candesartan cilexetil of formula II at -5°C slowly for a period of time sufficient
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to maintain the temperature. The reaction is carried out at the same temperature for period of time sufficient to complete. After completion of the reaction,-reaction mixture is neutralized with 5% aqueous sodium hydrogen carbonate to pH ranging from about 6 to about 7. An organic layer washed with water and evaporated to dryness. The residue is diluted with ethanol and cyclohexane and stirred for 3 hrs to crystallize the final product. The product is isolated by the methods known in the art such as filtration, decantation or centrifugation. The solid is optionally washed with crystallizing solvent and dried preferably under reduced pressure.
The present invention process has advantages over prior art such as:
(i) It provides a process which is operationally simple and industrially applicable.
(ii) This process avoids the use of dry HC1 gas which is a tedious process.
(iii) It involves less reaction time then prior art process.
(iv) It controls the formation of impurities in detritylation step.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Examples-1
Preparation of l-(cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- l-[(2'-{lH- tetrazole-5-yl}bipheny1-4-yl)-methyl] benzimidazole-7-carboxylate (Candesartan Cilexetil)
A solution of 1-(cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-l-[(2'-{N-tri phenyl methyl
tetrazole-5-yl}biphenyl-4-yl)-methyl]benzimidazole-7-carboxylate(100g) in
dichloromethane (50ml) is cooled to -5°C. A solution of 30-35% hydrochloric acid (1.5-1.75g on dry basis-3.0 to 5.0 moles) (5ml) in methanol (50ml) is added dropwise to the above reaction solution at -5°C over a period of 30-60 minutes and stirred for 3 hours at the same temperature. The reaction mixture is neutralized to pH 6 to 7 with 5% aq. NaHCC3. Organic layer is separated. Aqueous layer is extracted with dichloromethane (50ml). The combined organic layer is washed with water, evaporated to dryness. The
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residue is diluted with a mixture of ethanol and cyclohexane and stirred for 3 hours. The crystals are filtered, washed with mixture of ethanol and cyclohexane. The product is dried in oven under reduced pressure to provide 6.0 g of the title compound.
Yield: 84%
Purity: 99.7%
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We Claim:
1. A process for the preparation of Candesartan cilexetil having purity of at least 99%, comprising a step of cleaving the trityl group of tritylated Candesartan cilexetil of formula II,

in the presence of methanol containing 30-35%) hydrochloric acid in dichloromethane.
Dated this 04th day of May 2006.
Ashwini Sandu
Of S. Majumdar & Co.
Applicant's Agent
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Abstract:
An improved process for the preparation of Candesartan cilexetil having purity of more than 99%. The improved process which comprises a step of cleaving the trityl group from tritylated Candesartan cilexetil of formula II is simple, easy to handle and feasible at commercial scale.
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