FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR PREPARATION OF CANDESARTAN
CILEXETIL
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT,
1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR PREPARATION OF CANDESARTAN CILEXETIL
TECHNICAL FIELD OF THE INVENTION:
The invention relates to the process for the preparation of candesartan ciJexetil, particularly the present invention provides an improved process for the deprotection of trityl candesartan cilexetil to obtain Candesartan cilexetil.
BACKGROUND OF THE INVENTION:
Candesartan cilexetil, which is chemically known as l-[[( cyclohexyloxy)carbony] oxy ] ethyl-2-ethoxy-l-[[2'-(lH-tetrazol-5-yl)-l-l'-biphenyl-4-yl] methyl]-l-H-benzimidazole-7-carboxylate has the formula (I) as given below.

Candesartan cilexetil is an angiotensin II receptor antagonist, useful in the treatment of
hypertension and related disease. It is marketed by Astra Zeneca under the trade name of
ATACAND.
US Patent 5196444 (Takechiko Naka et al, 1991) discloses candesartan cilexetil and a
process for its preparation. The key chemical reaction in the synthetic process described
is de-tritylation or de- protection of1-[[( cyclohexyloxy)carbony] oxy ] ethyl-2-ethoxy-l-

[[2-(N-triphenylmethyltetrazol-5-yl)-1-1 '-biphenyl-4-yl] methyl]-1 -H-benzimidazole-7-carboxylate (trityl candesartan cilexetil). In the said patent de-tritylation was done in methanol by using 1 N HC1, After the reaction is over the reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and dried. After removal of the solvent the residue was purified by column chromatography on silica gel to obtain colorless powder of candesartan cilexetil.
Candesartan cilexetil is highly sensitive to strong acids due to the presence of bulky cilexetil ester group and ether moiety. Under the condition employed in '444 for de-tritylation, the ester group is hydrolysed to acid and the ether linkage to alcohol and there is a possibility of the impurities might be formed and for which purification by column chromatography is required.
US Patent 5763619 (Yasushi Shida et al, 1996) covers a process for producing tetrazolyl compounds and exemplifies a process for the synthesis of Candesartan cilexetil (i.e 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-l-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl] methyl]-lH-benzimidazole-7-carboxylate) by removing the trityl group using mineral acids under anhydrous conditions in presence of an alcohol. As exemplified in comparison example 1, trityl candesartan cilexetil is dissolved in methylene chloride followed by addition of methanol and methanol containing hydrogen chloride and the resulting mass was stirred at a low temperature till completion of the reaction. Methyl ether of triphenyl methanol, substantial amount of alcohol and acid impurity are getting formed as a by products under this reaction conditions. To remove these by products, particularly methyl ether of triphenyl methanol, acetone-hexane is used for

purification. The other disadvantages of this process are use of corrosive hydrochloric acid gas and halogenated solvent for the preparation of Candesartan cilexetil. WO2007/074399A2 (Soldevilla Madrid, Nuria, 2006) discloses a process for preparing candesartan cilexetil by removing the trityl group from trityl candesartan cilexetil by using Lewis acids like AICI3, TiCI4, ZnBr2 and ZnCI2 in presence of an inert solvent and alcohol. The Lewis acids are used in excess and are expensive which negates its use in commercial scale.
WO2007/094015A1 (Gorantla, Seeta, Ramajaneyulu et al, 2006) discloses a process for the preparation of Candesartan cilexetil in which detritylation was done by using phosphoric acid or boric acid in ethanol. The acids used in the said process are costly and higher temperature is required for the reaction which leads to the formation of impurities. WO2009/157001A2 (Parthasaradhi Reddy, Bandi et al, 2008) discloses a process for the preparation of Candesartan cilexetil, wherein the said detritylation was done by hydrogenating the trityl candesartan cilexetil with hydrogen in presence of Pd catalyst. For the purpose of hydrogenation, special pressure reactor is required which limits its use in commercial scale.
In view of the above, there exists a need for to develop an efficient, and cost effective, process which requires minimum capital investment and to avoid the use of corrosive and hazardous chemicals for the synthesis of Candesartan Cilexetil
OBJECT OF THE INVENTION
The object of the present invention is to provide good quality Candesartan cilexetil with high yields

Another object of the present invention is to provide a simple process which avoids the stringent conditions like maintaining anhydrous conditions during reaction and can be scaled up easily.
SUMMARY OF INVENTION
The present invention relates to an improved process for the preparation of candesartan cilexetil (I)

which comprises de-tritylation of trityl candesartan cilexetil in an ethereal solvent by using inorganic acids, and in presence of water or methanol
DETAILED DESCRIPTION
The present invention relates to an improved process for the preparation of l-[[( cyclohexyloxy)carbony] oxy ] ethyl-2-ethoxy-l-[[2'-(lH-tetra2ol-5-yl)-l-1'-biphenyl-4-yl] methyl ]-l-H-benzimidazole-7-carboxyIate (I) known as Candesartan cilexetil. The present invention also relates to an improved and economical process for the synthesis of Candesartan cilexetil with high yield
The present invention provides high quality Candesartan cilexetil by selective de-tritylation or removal of protecting group of1-[[( cyclohexyloxy)carbony] oxy ] ethyl-2-

ethoxy-l-[[2'-(N-triphenylmethyltetrazol-5-yl)-l-r-biphenyl-4-yl]methyl]-l-H-benzimidazole-7-carboxylate (trityl candesartan cilexetil).
The present invention relates to an improved process for the preparation of Candesartan cilexetil having formula (I), comprising

de-tritylation of 1 -[[(cyclohexyloxy)carbony]oxy]ethyl-2-ethoxy-1 -[[2'-(N-
triphenylmethyltetrazol -5 -yl)-1-1' -bipbenyl-4-yl] methyl] -1 -H-benzimi dazole-7-
carboxylate (trityl candesartan cilexetil) carried out in an ethereal solvent under acidic
condition.
The starting material which is trityl candesartan cilexetil may be prepared according to
procedure known in the art (e.g. J. Med. Chem, 1993, 36, 2343-2349)
In the present invention the protecting group which is triphenyl methyl group is removed
by dissolving the trityl candesartan cilexetil in an ethereal solvent like tetrahydrofuran, 2-
methyl tetrahydrofuran, methyl tert-butyl ether, preferably tetrahydrofuran.
The acid used in the present invention is an inorganic acid and is sulphuric acid. Further,
to accelerate the rate of reaction, water or methanol is added to the reaction mixture.
When water is added to the reaction mixture, triphenyl methanol formation take place as
a by-product. The amount of water used for this process is 1.0 molar equivalent to 5.0
molar equivalents, preferably 1.25 molar equivalents. When methanol is used in the

reaction medium, methyl ether of triphenyl methanol formation takes place as a by-product The amount of methanol used for the reaction is in the range of 1.0 molar equivalent to 10.0 molar equivalents, preferably 5.0 molar equivalents. However, the excess of methanol has no adverse effect on the reaction. The progress of the reaction can be monitored by HPLC or TLC. After the reaction is over, the reaction mass can be quenched in methylene chloride and water and the organic layer having the product is separated from aqueous layer. The product, Candesartan cilexetil is obtained by distilling the organic layer under reduced pressure. The product thus obtained can be crystallized from suitable solvents like ethanol and n-hexane.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example-1: Preparation of candesartan cilexetil
To a three neck round bottomed flask equipped with thermometer and overhead stirrer, were added 1 -(cyc!ohexyIoxycarbonyloxy)ethyi-2-Ethoxy-1-[[2'-(N-triphenylmethyl tetrazol-5-yl)biphenyl-4-yl]methyl] benzimimidazole-7-carboxylate (25.0 gm) and tetrahydrofuran (250 ml) at RT, stirred to get a clear solution and water (0.659 ml) was added to the reaction mass. To the solution, added coned sulphuric acid (7.8 ml) drop-wise at 0-5 °C and stirred for 8-9 hrs. The progress of the reaction was monitored by HPLC. After the completion of the reaction, methylene chloride (200 ml) and water (250 ml) was charged to the reaction mass, stirred for 10-15 minutes and separated the

aqueous layer at RT. The aqueous layer was extracted with methylene chloride (50.0 ml). Both the organic layers were combined, washed with water (250 ml) and brine solution (250 ml) and distilled out the organic layer under reduced pressure to get thick oil. Ethanol (50 ml) added to it and heated at 75-80 °C to get a clear solution. Charged hexane (50 ml) to the clear solution and stirred for 24.0 hours at RT. It was filtered and washed with 25 ml hexane. It was unloaded and dried at 35-40 °C to give 15.0 gm of candesartan cilexetil with a purity of 98.0%.
Example-2: Preparation of candesartan cilexetil
To a three neck round bottomed flask equipped with thermometer and overhead stirrer, were added l-(cyclohexyloxycarbonyloxy)ethyl 2-Ethoxy-l-[[2'-(N-triphenylmethyl tetrazol-5-yl)biphenyl-4-yl]methyl] benzimimidazole-7-carboxylate (25.0 gm) and tetrahydrofuran (250 ml) at RT. Stirred to get a clear solution and methanol (6.0 ml) was added to the reaction mass. To the solution, coned Sulphuric acid (5.0 ml) was added drop-wise at 0-5 °C and stirred for 8-9 hrs. The progress of the reaction was monitored by HPLC. After the completion of the reaction, methylene chloride (200 ml) and water (250 ml) were added to the reaction mass. Stirred for 10-15 minutes and the aqueous layer was separated at RT. Extracted the aqueous layer with methylene chloride (50.0 ml). Both the organic layers were combined and washed with water (250 ml) and brine solution (250 ml). The organic layer was distilled out under reduced pressure to get the thick oil. Ethanol (50 ml) was added to it and heated to 75-80 °C to get a clear solution. Charged hexane (50 ml) to the clear solution and stirred for 24.0 hours at RT. Filtered and washed

with hexane (25 ml). It was unloaded and dried at 35-40 °C to give candesartan cilexetil (17.0 gm) with a purity of 98.0%.

CLAIMS: We claim
1. An improved process for the preparation of candesartan cilexetil (I)

which comprises de-tritylation of trityl candesartan cilexetil in an ethereal solvent by using inorganic acids, and in presence of water or methanol
2. An improved process according to claim-1, wherein the ethereal solvent selected from tertahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, preferably tetrahydrofuran.
3. An improved process according to claim-1, wherein the inorganic acid is sulfuric acid.
4. An improved process according to claim-1, wherein the amount of water used is 1.0 molar equivalent to 5.0 molar equivalent preferably 1.25 molar equivalent.
5. An improved process according to claim-1, wherein the amount of methanol used is 1.0 molar equivalent to 10.0 molar equivalent preferably 5.0 molar equivalent

6. A process for the preparation of Candesartan Cilexetil substantially as herein described with reference to the examples.