FIELD OF INVENTION

The invention relates to an improved process for the purification of trityl candesartan of formula I

formula I which is a useful as an intermediate in the preparation of Candesartan Cilexetil.

BACKGROUND OF INVENTION

The chemical name of Candesartan Cilexetil is l-[[(Cyclohexyloxy) carbonyl] oxy] ethyl 2-ethoxy-l-[|2-(l lI-tetazole-5-yl)| 1, 1 '-biphcnyl-4-yl]mcthyl|-III-benzimida-zole-7-carboxylate. Its molecular formula is C33I I3-4NO6 and mol wt is 610.66. Candesartan Cilexetil is represented by the following structural formula

Candesartan Cilexetil is an ester pro drug of 2-ethoxy-l-(|2-(lH-tetrazole-5-yl)[l,-biphenyl-4-yl]mcthyl [-111 benzimida/ole-7-carboxylic acid (candesartan), known as a potent angiotensin II receptor antagonist. It is useful in the treatment of cardiovascular complaints such as liyperlension 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 AstraZencca under trade name ATACANO.

U.S.Pal. No. 5,196,444 describes a process of preparation of tritylated candesarlan acid of formula (I) by reacting candesartan acid of formula (II)

Formula 11 with trityl chloride in the presence of base in a solvent which is selected from halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride, ethers such as dioxane and tetrahydrofuran, acetonitrile, pyridine to obtain tritylated candesartan acid of formula (1) in 66% yield after column chromatography. The yield obtained by this process is very low due to the presence of 10-20% impurities.

Moreover, the purification of final product by chromatography is commercially not suitable and is cumber some at an industrial scale.

The complexity and high cost of the prior art procedures has created a need for the purification of tritylated candesartan acid of formula (I). The present invention provides a solution to the problem presented by the prior art,

Through experimentation, the present inventors have observed that the tritylation step in the process for the preparation of tritylated Candesartan acid is sensitive generating lot of impurities thus affecting the quality and yield of the final product. Therefore, we directed our research work toward developing a process which avoids these difficulties during tritylation .step for the preparation of tritylated candesartan acid of formula (I). Surprisingly, the present inventors have found a robust method of purification of trityl candesartan resulting in increase in yield and quality of tritylated candesartan acid of formula (I).

OBJECTIVE OF THE INVENTION

An object of the present invention is to provide an improved process for the purification of trityl candesartan of formula I.

Another object of the present invention is to provide a process for the preparation of trityl candesartan in high purity.

SUMMARY OF THE INVENTION

Accordingly present invention provides a process for purification of trityl candesartan to obtain trityl candesartan of at least 99% purity, said process comprising the steps of:

(i) Dissolving trityl candesartan in an organic solvent
(ii) Adding anti-solvent to the reaction mixture
(iii) Washing the filtered product obtained in step (ii) with a solvent selected from the group consisting of mixture of an ester and halogenated hydrocarbons.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of the present invention there is provided a process for the preparation of trityl candesartan which comprises the steps of

i) Dissolving trityl candesartan in an organic solvent
ii) Adding anti-solvent to the reaction mixture
iii) Washing the filtcred product obtained in step (ii) with a solvent selected from the group consisting of mixture of an ester and halogenated hydrocarbons.

In the present invention, trityl candesartan is dissolved in Methylene dichloride at 25-30 °C and subsequently heated at reflux temperature. The reaction mixture is stirred for 30 min at reflux temperature and cooled lo ambient temperature. Then ethyl acetate is added and again the whole reaction mixture is heated to reflux and stirred for 30 min followed by cooling to ambient temperature. The cooled reaction mixture is stirred for 1 hr and filtered to obtain trityl candesartan. This filtered material is subsequenlly washed with a mixture of solvents like esters and halogenated hydroearbons.

The ester solvents preferably employed are ethyl acetate, butyl acetate etc. The halogcnated hydrocarbons employed are methylene dichloride, ethylene dichloride etc.

EXAMPLE

Trityl candesartan (100 gms) and methylene dichloride arc stirred at 25-30 °C and heated to reflux temperature. The reaction mixture is stirred at reflux temperature for 35-30 °C and cooled and subsequently cooled to ambient temperature. To the reaction mixture, ethyl acetate (1000 ml) was added and stirred for 30 min at reflux temperature followed by cooling to room temperature. The obtained solid was filtered and washed with chilled ethyl acetate and methylene dichloride to obtain 70 gms of pure trityl candesarlan.

CLAIMS

1. An improved process for purification of trilyl candcsarlan to obtain trityl candesartan of

at least 99% purity, said process comprising the steps of

i) Dissolving trityl candesartan in an organic solvent at ambient temperature
ii) Adding anti-solvent to the reaction mixture
iii) Washing the filtered product obtained in step (ii) with a solvent selected from the group consisting of mixture of an ester and halogenated hydrocarbons

2. A process according to claim 1 slep(i). where in said organic solvent is selected from a group comprising halogenated hydrocarbons like methylene dichloride.

3. A process according claim 1 step (ii). wherein said anti-solvent is selected from ester solvents like ethyl acetate.

4. A process according to claim 1 step(iii), wherein said organic solvent is selected from a mixture of an acetate and hydrocarbon solvents.

5. A process according to claim 4. wherein said organic solvent is a mixture of a ethyl acetate and dichloromethane.