FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of tctrazole biphenyl compound of general Formula (I).

wherein, R is selected from a group consisting of:

* Asymmetric centre

BACKGROUND OF THE INVENTION

(+)-1 -[[(Cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1 -[[2'-( 1 H-tetrazol-5-yl)biphenyl-4-yl] methyl]benzimidazole-7-carboxylate (Candesartan cilexetil) is generically disclosed in US 5,705,517 and specifically disclosed in US 5,196,444; 2-Butyl-3-fp-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4.4]non-l-en-4-one (Irbesartan) is disclosed in US 5,270,317; 2-Butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]-1 H-imidazole-5-methanol (Losartan) is disclosed in US 5,138,069: (5-Methyl-2-oxo-l,3-dioxolen-4-yl)methyl-4-(l-hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(tetrazole-5-yl)phenyl]phenyl]- methylimidazole-5-carboxylate (Olmesartan medoxomil) is disclosed in US 5,616,599; N-( 1 -oxopentyl)-N-[[2'-( 1 H-tetrazol-5-yl)[l, 1 '-biphenyl]-4-yl]methyl] -L-valine (Valsartan) is disclosed in US 5,399,578.

These compounds are belongs to non-peptide ATi-subtype angiotensin II receptor antagonists and indicated for the treatment of hypertension. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATi receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

Candesartan cilexetil is marketed under the trade name, ATACAND®; Irbesartan is marketed with the trade Name, Avapro®; Losartan potassium is marketed with the trade name, Cozaar®; Olmesartan medoxomil is marketed with the trade name, Benicar®; Valsartan is marketed with the trade name, DIOVAN®.

According to the process disclosed in US 5,196,444, trityl Candesartan cilexetil (11a) is detritylated using IN HC1 in methanol to produce Candesartan cilexetil (I), followed by purification using column chromatography.

The process is as shown in Scheme-I below:
Scheme-I

The disadvantage with the above process is the use of column chromatography in the purification of Candesartan cilexetil (I). Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.

US 5,270,317 discloses a process for the deprotection of trityl Irbesartan (Ilia) using methanol/THF and 4N HC1 to produce Irbesartan (III). The process is as shown in Scheme-II below:

US 5.138,069 discloses a process for the deprotection of trityl Losartan (IVa) using methanol and 4N HC1 to produce Losartan (IV). The process is as shown in Scheme-III below:

US 5,616,599 discloses a process for the deprotection of trityl Olmesartan (Va) using aqueous acetic acid to produce Olmesartan (V), followed by purification using column chromatography.

The process is as shown in Scheme-IV below:

US 5,399,578 discloses a process for the deprotection of trityl Valsartan benzyl ester (Via) using dioxane and IN HC1 to produce Valsartan benzyl ester (VIb), followed by hydrogenation using methanol and palladium on carbon to produce Valsartan (VI).

The process is as shown in Scheme-V below:

US 5,578,733, discloses a process for the deprotection of trityl Candesartan cilexetil (IIa) using mineral acids under substantially anhydrous conditions in the presence of an alcohol to produce Candesartan cilexetil (II).

The disadvantage with the above process is that detritylation of trityl Candesartan cilexetil (IIa) requires acidic conditions, which leads to the formation of unwanted impurity such as desethyl Candesartan cilexetil (IIb). It is difficult to remove the impurity from the Candesartan cilexetil (II). Hence, extra purification is required to remove the unwanted impurity to obtain Candesartan cilexetil (II) of pharmaceutical grade.

* Asymmetric centre

US 6,710,183 B1 discloses a process for the deprotection of trityl Losartan (IVa) in the presence of KOH in an alcohol.

US 7,041,832 B2 discloses a process for the deprotection of trityl Losartan (IVa) in the presence of acid in a diluent comprising a liquid ketone.

US 2005/0250827 Al discloses a process for the deprotection of trityl Candesartan cilexetil (IIa) in the presence of water/methanol mixture under heating to reflux.

US 2006/0287537 Al discloses a process for the deprotection of trityl Candesartan cilexetil (Ila) using solvolysis in a simple anhydrous C1-C5 alcohol in a neutral or slightly basic medium.

The disadvantage with the above process is the use of basic medium, which can cause to cleave the cilexetil ester to form Candesartan acid and longer reaction time is required for deprotection of trityl group under neutral conditions, which leads to the formation of undesired byproducts.

US 2006/0020005 Al discloses a process for the deprotection of trityl Losartan (IVa) in the presence of an aqueous acid.

US 2006/0194858 Al discloses a process for the deprotection of trityl Candesartan cilexetil (Ha) by heating a solution of trityl Candesartan cilexetil (Ha) in toluene in the presence of at least one C1-C4 alcohol; combining the solution with a second portion of water to obtain a two-phase system comprising an organic phase and an aqueous phase; separating two said two-phase system; and recovering Candesartan cilexetil (II) from the organic phase.

US 2006/0148870 Al discloses a process for the deprotection of trityl Olmesartan (Va) using mixture of an organic solvent, water and a pH of at least 2.5.

WO 2006/097121 Al discloses a process for the deprotection of trityl tetrazole biphenyl compound (la) in the presence of hydroxylammonium sulfates and hydroxylammonium chlorides in a solvent.

US 2006/0252939 Al discloses a process for the deprotection of trityl Candesartan cilexetil (Ha) in the presence of at least one organic acid and at least one organic solvent.

WO 2007/057919 A2 discloses a process for the deprotection of trityl Valsartan (Via) using of PTC in the presence of acid or base.

WO 2009/157001 A2 discloses a process for the deprotection of trityl Candesartan (IIa) by hydrogenating in alcohol in the presence of palladium catalyst.

I Icnce, there is need to have a process, which restricts the formation of unwanted impurities and formation of tetrazole biphenyl compound of Formula (I) with high purity and good yield.

The present invention is specifically directed towards a process, wherein deprotection of trityl tetrazole biphenyl compound of Formula (la) is carried out in the presence of silica gel supported alkali metal sulfate and in the presence of cation exchange resin to produce tetrazole biphenyl compound of Formula (I) with high purity and good yield.

Reagents employed are less corrosive, inexpensive, readily available and it can be easily prepared.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and effective process for the preparation of tetrazole biphenyl compound of Formula (I) with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of tctra/ole biphenyl compound of Formula (I),

wherein, R is selected from a group consisting of:

which comprises:

(i) treating trityl tetrazole biphenyl compound of Formula (la);

wherein, R is same as defined above; with silica gel supported alkali metal sulfate in a solvent; (ii) isolating the tetrazole biphenyl compound of Formula (I).

In another embodiment, the present invention also relates to an improved process for the preparation of tetrazole biphenyl compound of Formula (I),

wherein, R is same as defined above; which comprises: (i) treating trityl tetrazole biphenyl compound of Formula (la);

wherein, R is same as defined above; with cation exchange resin in a solvent; (ii) isolating the tetrazole biphenyl compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of pure tetrazole biphenyl compound of Formula (I).

The process comprises, treating trityl tetrazole biphenyl compound of Formula (la) with silica gel supported alkali metal sulfate in a solvent to produce tetrazole biphenyl compound of Formula (I).

The alkali metal sulfate used in the above reaction is selected from sodium hydrogen sulfate, potassium hydrogen sulfate, ammonium hydrogen sulfate, iron (III) sulfate, aluminium sulfate, or manganese sulfate. Preferably, sodium hydrogen sulfate. The solvent used in the above reaction is selected from methanol, ethanol, isopropanol, n-butanol, methylene chloride, and mixtures thereof.

The reaction may be performed at a temperature ranging from about 25 °C to about 40°C. Preferably, at about 34° to about 38°C based on the solvent or mixture of solvents used for the reaction. The sufficient period of time necessary for obtaining compound (I) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 2 to 8 hours.

After completion of reaction, the byproducts are precipitated and removed by filtration, followed by subjected to carbon treatment and distillation of solvents to produce tetrazole biphenyl compound of Formula (I) and is purified by conventional means, for example, by recrystallization.

In another embodiment, tetrazole biphenyl compound of Formula (I) are produced by treating trityl tetrazole biphenyl compound of Formula (la) with a cation exchange resin in a solvent.

The cation exchange resin for the above reaction is selected from LEWATITK 2629, DOWEX MARATHON 650 (H), DOWEX MARATHON C, and any other DOWEX type strong acidic cation resins or week acid cation resins and other acidic cation resin. The reaction may be performed at a temperature ranging from about 35°C to about 45°C, Preferably about 38° to about 41°C based on the solvent or mixture of solvents used for the reaction. The solvent is selected from methanol, ethanol, isopropanol, n-butanol, methylene chloride, and mixtures thereof.

The sufficient period of time necessary for obtaining compound of Formula (I) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 6 hours.

After completion of the reaction, the product is further purified by conventional means, for example, by recrystallization.

It has been observed that the preparation of Candesartan cilexetil (II) produced by the process having desethyl Candesartan cilexetil impurity less than about 0.05% by HPLC and the resulting finished product has high purity according to high performance liquid chromatography (HPLC).

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE - 1

Step 1:

Preparation of silica gel supported sodium hydrogen sulfate (NaHSO4 SIO2)
Sodium hydrogen sulfate (NaHSO4. H20) (4.14g, 0.03 mol) was added to DM water (20 ml) and Si02 (10g) (column chromatographic grade; 60 A°, 200-400 mesh) was added to the reaction mass. The mixture was stirred for 15-20 min and the water was distilled at 70-90°C until free flowing white solid was obtained. The above white solid was further dried in an oven at 120°C for 24h to remove maximum amount of water.

Step 2:

Preparation of Candesartan cilexetil

(±)-1 -[[(Cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1 -[[2'-N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (trityl Candesartan cilexetil 30 g) was added to a mixture of methanol and methylene chloride (7.0 volume, 68:32 v/v ratio). Above catalytic amount of silica gel supported sodium hydrogen sulfate (0.30 g) was added to the reaction mass and stir the reaction mass at 34-38°C till the reaction was completed (it takes about 8 hrs). After completion of reaction, reaction mass was cooled to 15-20°C and pH was adjusted to 7.5 with aqueous ammonia. The methanol and methylene chloride were distilled up to certain volume. Byproducts were precipitated and removed by filtration. Filtrate was subjected to carbon treatment and distillation of solvents to produce Crude Candesartan cilexetil. Crude Candesartan cilexetil was treated with aqueous ethanol to produce pure Candesartan cilexetil Form I (C-type crystal) (16.9g, 78.5%) with HPLC purity of 99.80%.

EXAMPLE - 2

Preparation of Candesartan cilexetil

Trityl Candesartan cilexetil (5 g) was added to a mixture of methanol and methylene chloride (7.0 volume, 68:32 v/v ratio). Catalytic amount of cation exchange resin (100 mg, LEWATITK 2629) was added to the above reaction mass and reaction mass was maintained at 38-41°C till the reaction was completed (it takes 6 hrs). After completion of reaction, reaction mass was cooled to 15-20°C, pH was adjusted to 7.5 with aqueous ammonia. The methanol and methylene chloride were distilled up to certain volume. Byproducts were precipitated and removed by filtration and filtrate was subjected to carbon treatment and distillation of solvents to produce crude Candesartan cilexetil. Crude Candesartan cilexetil was treated with aqueous ethanol to produce pure Candesartan cilexetil Form I (C-type crystal) (2.76 g, 77%) with HPLC purity of 99.85%.

We claim:

1. A process for the preparation of tetrazole biphenyl compound of Formula
(I),

wherein, R is selected from a group consisting of:

which comprises: (i) treating trityl tetrazole biphenyl compound of Formula (la)
wherein, R is same as defined above; with silica gel supported alkali metal sulfate in a solvent; (ii) isolating the tetrazole biphenyl compound of Formula (I).

2. The process according to claim 1 wherein, the silica gel supported metal
alkali sulfate is prepared by reacting metal alkali sulfate with SiO2 in a solvent.

3. The process according to claim 2 wherein, the solvent is water.

4. The process according to claim 2 wherein, the alkali metal sulfate is selected from sodium hydrogen sulfate, potassium hydrogen sulfate, ammonium hydrogen sulfate, iron (III) sulfate, aluminium sulfate, or manganese sulfate.

5. The process according to claim 1 wherein, the solvent used in step-(i) is selected from methanol, ethanol, isopropanol, n-butanol, methylene chloride, and mixtures thereof.

6. A process for the preparation of tetrazole biphenyl compound of Formula (I),
wherein, R is selected from a group consisting of:

which comprises:

(i) treating trityl tetrazole biphenyl compound of Formula (la);
wherein, R is same as defined above; with cation exchange resin in a solvent;

(ii) isolating the tetrazole biphenyl compound of Formula (I).

7. The process according to claim 6 wherein, the cation exchange resin is selected from LEWATITK 2629, DOWEX MARATHON 650 (H), DOWEX MARATHON C, and any other DOWEX type strong acidic cation resins or week acid cation resins and other acidic cation resin.
8. The process according to claim 6 wherein, the solvent is selected from methanol, ethanol, isopropanol, n-butanol, methylene chloride, and mixtures thereof.