FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of crystalline Azilsartan kamedoxomil of Formula la.

The present invention relates to an invention disclosed in our co-pending application IN 4226/CHE/2012, wherein present invention is an improvement for the preparation of Azilsartan kamedoxomil of formula (la).

BACKGROUND OF THE INVENTION
Azilsartan kamedoxomil is chemically known as (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4yl]methyl}-l//-benzimidazole-7-carboxylate, monopotassium salt.

Azilsartan medoxomil (I) is an ATi-subtype angiotensin II receptor blocker (ARB). 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. Azilsartan medoxomil blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT) 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. Azilsartan medoxomil is approved for the treatment of hypertension and is marketed under the brand name Edarbi®.

Azilsartan medoxomil of Formula I.
Formula I

US patent No. 5,583,141 disclosed Azilsartan and pharmaceutically acceptable esters and salts thereof.

US 7,157,584 disclose Azilsartan kamedoxomil. US '584 also disclose a process for the preparation of Azilsartan kamedoxomil by treating Azilsartan medoxomil (I) with potassium 2-ethyl hexanoate in acetone. However, there are no any specific crystalline forms or its characteristic properties are disclosed in US '584.

WO 2013/042067 disclose Azilsartan kamedoxomil polymorphic Form-I prepared by treating Azilsartan medoxomil with potassium source in the presence of at least one C4.9 ketone solvent; and isolation of the potassium salt of Azilsartan medoxomil.

The major disadvantage in WO '067 is the use of C4.9 ketone solvents to prepare Azilsartan kamedoxomil Form-I which leads to lower yield.

However, there is always a need for alternative preparative routes, which for example, involve the use of solvents that are less expensive and /or easier to handle, consume smaller amounts of solvents, provide a higher yield of product, having more bioavailability and high dissolution rates than the prior art products.

The present invention directed towards a process for the preparation of crystalline Azilsartan kamedoxomil (la) by treating Azilsartan medoxomil with a potassium source in presence of a solvent, which leads to high yield and high purity.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple and cost-effective improved process for the preparation of crystalline Azilsartan kamedoxomil (la) with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

One embodiment of the present invention provides an improved process for the preparation of crystalline Azilsartan kamedoxomil, which comprises,

(i) treating Azilsartan medoxomil with a potassium source in presence of a solvent; (ii) isolating the crystalline Azilsartan kamedoxomil from the reaction mixture; (iii) optionally, purifying the crystalline Azilsartan kamedoxomil;
with the proviso that the solvent is not a ketone.

Another embodiment of the present invention provides crystalline Azilsartan kamedoxomil can be characterized by Powder X-Ray Diffraction Pattern with peaks at 6.21, 6.68, 12.64, 12.67, 13.37, 14.04, 14.52, 14.75, 15.50, 16.02, 16.42, 16.70, 17.38, 17.83, 18.13, 18.47, 18.75, 19.09, 19.65, 20.34, 21.39, 22.82, 23.31, 23.81, 24.00, 24.38, 24.57, 24.87, 25.14, 25.60, 26.11, 26.60, 27.00, 27.53, 28.19, 28.85, 29.19, 30.02, 30.86, 31.31, 31.93, 33.03, 33.84, 36.04, 37.27 and 38.00 degrees of 2-theta, substantially as depicted in Figure 1.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the Powder X-Ray Diffraction pattern of crystalline Azilsartan kamedoxomil (la).

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention provides an improved process for the preparation of crystalline Azilsartan kamedoxomil (la).

The process comprises, Azilsartan medoxomil (I) is suspended in a solvent, and the reaction mass temperature is raised until the mass becomes a clear solution. This clear solution is treated with carbon enoanticromos, followed by filtration to remove carbon and washed with the solvent. The filtrate is treated with a potassium source in a solvent to produce crystalline Azilsartan kamedoxomil.

In another embodiment of the present invention, with the proviso that the solvent is not a ketone solvent and the solvent comprises ether, alcohol, ester, halo hydrocarbon, hydrocarbon solvent, water or mixtures thereof.

In another embodiment of the present invention, the solvent comprises tetrahydrofuran (THF), dimethyl ether, diethyl ether, dimethoxyethane (DME), dioxane, anisole (methoxy benzene), crown ethers, polyethylene glycol (PEG), methanol, ethanol, isopropanol, ethyl acetate, methylene chloride, chloroform, toluene, o-xylene, w-xylene, p-xylene, n-hexane, cyclohexane, n-heptane, n-octane or mixtures thereof.

In yet another embodiment of the present invention, the potassium source is an organic or inorganic in nature. The inorganic potassium source is potassium hydroxide, potassium carbonate or potassium bicarbonate. An organic potassium source is potassium acetate, potassium ascorbate, potassium benzoate, or potassium 2-ethylhexanoate.

In still another embodiment of the present invention, the obtained crystalline Azilsartan kamedoxomil (la) is suspended in an organic solvent, followed by filtration and dried.

In still another embodiment of the present invention, the organic solvent comprises alcohol, ester, ether, halo hydrocarbon, ketone, and nitrile or mixture thereof.

In still another embodiment of the present invention, the organic solvent comprises methanol, ethanol, isopropanol, ethyl acetate, acetone, toluene, tetrahydrofuran, methylene chloride, acetonitrile or mixture thereof.

In another embodiment of the present invention, the crystalline Azilsartan kamedoxomil (la) obtained by the process of present invention is crystalline Azilsartan kamedoxomil Form-I characterized by an X-ray powder diffraction pattern as depicted in Figure-1, having peaks at 6.21, 6.68, 12.64, 12.67, 13.37, 14.04, 14.52, 14.75, 15.50, 16.02, 16.42, 16.70, 17.38, 17.83, 18.13, 18.47, 18.75, 19.09, 19.65, 20.34, 21.39, 22.82, 23.31, 23.81, 24.00, 24.38, 24.57, 24.87, 25.14, 25.60, 26.11, 26.60, 27.00, 27.53, 28.19, 28.85, 29.19, 30.02, 30.86, 31.31, 31.93, 33.03, 33.84, 36.04, 37.27 and 38.00 degrees of angle 20.

In still another embodiment of the present invention, the crystalline Azilsartan kamedoxomil (la) is optionally purified by known methods, for example recrystallization by dissolving in a solvent selected from methanol, ethanol, dimethyl formamide (DMF), dimethyl acetamide (DMAc) and dimethyl sulfoxide (DMSO) or mixture thereof and precipitating pure crystalline Azilsartan kamedoxomil Form-I by cooling the solution or by adding an anti solvent selected from the group of ketone, ether and esters such as acetone, THF and ethyl acetate.

In still another embodiment of the present invention, the crystalline Azilsartan kamedoxomil (la) is optionally purified by stirring in a mixture of solvents selected from methanol-acetone or methanol-THF.

In still another embodiment of the present invention, the Azilsartan medoxomil (I) used in the preparation of crystalline Azilsartan kamedoxomil (la), can be prepared by the known methods or the methods disclosed in our co-pending patent application IN 4226/CHE/2012.

In still another embodiment of the present invention, the Azilsartan medoxomil (I) used in the preparation of crystalline Azilsartan kamedoxomil (la), can be prepared by cyclising (5-methyl-2-oxo-2//-1,3-dioxol-4-yl)methyl-2-ethoxy-1-[(4-(2-[N-hydroxycarbamimidoyl] phenyl)phenyl)methyl]-l//-l,3-benzodiazole-7-carboxylate (Azilsartan amidoxime) (XII) using a carbonyl source comprises N,N-disuccinimidyl carbonate, diphenyl carbonate, N,N-carbonyldiimidazole, dialkyl carbonate, phosgene equivalents, alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide, N,N-di cyclohexyl carbodiimide, diphenyl carbodiimide, ditolyl carbodiimide and the like; in presence of an organic solvent selected from chloroform, methylene chloride, dioxane, tetrahydrofuran, ethyl acetate, DMF, DMSO, DMAc, acetonitrile and pyridine and in presence or absence of a base, wherein the base comprises triethylamine, pyridine, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, DBU to produce Azilsartan medoxomil (I).

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.

EXAMPLES:
Example-1:
Process for the preparation of Azilsartan medoxomil
(5-Methyl-2-oxo-2//-l,3-dioxol-4-yl)methyl2-ethoxy-l-[(4-(2-[N-hydroxy carbamimidoyl] phenyl)phenyl)methyl]-l//-l,3-benzodiazole-7-carboxylate (Azilsartan amidoxime, 100 g, 0.185 moles,) was dissolved in N,N-dimethylformamide (500 ml) at 25-30°C and stirred for 5-10 min. N,N-Disuccinimidyl carbonate (56.68 g, 0.22moles) was added to the reaction mixture at 25-30°C and stirring was continued at this temperature for ~ 10 min. The reaction mass temperature was slowly raised to 40-45 °C and stirring was continued at this temperature till starting material, Azilsartan amidoxime and reactive intermediate each left unreacted (<1% by qualitative HPLC analysis). DM water(2000 ml) was added to the reaction mixture after completion of the reaction, at 25-30°C and stirred for ~ 30 min at 25-30°G The product was filtered and washed with DM water (250 ml) at 25-30°C. Ethanol (500 ml) was added to the wet material at 25-30°C and stirred for ~ 10 min at the same temperature. The product was dried at 40-45°C under reduced pressure (-20 mm Hg) till Loss On Drying < 0.5% w/w (determined on 1 g at 105°C for 2 hr). (Yield: 80 g).

Example-2:
Process for the preparation of crystalline Azilsartan kamedoxomil (la) Azilsartan medoxomil (100 g, 0.176 mmol) was suspended in tetrahydrofuran (1000 ml) at 25-30°C. Temperature was raised to 50-55°C and continued the stirring at this temperature until the reaction mass becomes a clear solution. Carbon enoanticromos (5g) was added to the reaction mass and continued the stirring at 45-55°C for ~ 30 min. The carbon was removed by filtration through hyflo and the residue was washed with tetrahydrofuran (100 ml) at 25-30°C. The combined filtrate was cooled tol0-15°C under nitrogen atmosphere and a solution of potassium 2-ethylhexanoate in tetrahydrofuran (70.5 g, Assay: 50%) was added slowly to the resulting reaction mass. The precipitated product was stirred for 1 hr at 10-15° C. The product was filtered and washed with tetrahydrofuran (100 ml) at a temperature of 25-30°C. The wet material was suspended in acetone (400 ml) at 25-30°C and the stirring was continued for 1 hr at the same temperature. The product was filtered and washed with acetone (100 ml). The product was dried at 40-45 °C under reduced pressure (~20 mm Hg) till Loss On Drying < 0.2% w/w (determined on 1 g at 105°C for 2 hr). (Yield: 90 g)

Example-3:
Process for the preparation of crystalline Azilsartan kamedoxomil (la) Azilsartan medoxomil (100 g, 0.176 mmol) was suspended in tetrahydrofuran (1000 ml) at 25-30°C. Temperature was raised to 50-55°C and continued the stirring at this temperature until the reaction mass becomes a clear solution. Carbon enoanticromos (5 g) was added to the reaction mass and continued the stirring at 45-55°C for ~ 30 min. The carbon was removed by filtration through hyflo and the residue was washed with tetrahydrofuran (100 ml) at 25-30°C. The combined filtrate was cooled tolO-15°C under nitrogen atmosphere and a solution of potassium acetate (19 g potassium acetate dissolved in 60 ml of methanol) was added slowly to the resulting reaction mass. The precipitated product was stirred for 2 hr at 10-15° C. The product was filtered and washed with tetrahydrofuran (100 ml), followed by acetone (100 ml) at 25-30°C. The product was dried at 40-45°C under reduced pressure (-20 mm Hg) till Loss On Drying < 0.2% w/w (determined on 1 g at 105°Cfor2hr).(Yield:70g)

WE CLAIM:

1. An improved process for the preparation of crystalline Azilsartan kamedoxomil, which comprising the steps of,

(i) treating Azilsartan medoxomil with a potassium source in presence of a solvent; (ii) isolating the crystalline Azilsartan kamedoxomil from the reaction mixture; (iii) optionally purifying the crystalline Azilsartan kamedoxomil;
with the proviso that the solvent is not a ketone solvent.

2. The process according to claim 1, wherein the crystalline Azilsartan kamedoxomil is characterized by Powder X-ray Diffraction Pattern having peaks at 6.21, 6.68, 12.64, 12.67, 13.37, 14.04, 14.52, 14.75, 15.50, 16.02, 16.42, 16.70, 17.38, 17.83, 18.13, 18.47, 18.75, 19.09, 19.65, 20.34, 21.39, 22.82, 23.31, 23.81, 24.00, 24.38, 24.57, 24.87, 25.14, 25.60, 26.11, 26.60, 27.00, 27.53, 28.19, 28.85, 29.19, 30.02, 30.86, 31.31, 31.93, 33.03,33.84, 36.04, 37.27 and 38.00 degrees of angle 20.

3. The process according to claim 1, the crystalline Azilsartan kamedoxomil is crystalline Azilsartan kamedoxomil Form-I.

4. The process according to claim 1, wherein the solvent used in step-(i) comprises ether, alcohol, ester, halo hydrocarbon, hydrocarbon solvent, water or mixtures thereof.

5. The process according to claim 4, wherein the solvent comprises tetrahydrofuran (THF), dimethyl ether, diethyl ether, dimethoxyethane (DME), dioxane, anisole (methoxy benzene), crown ethers, polyethylene glycol (PEG), such as methanol, ethanol, isopropanol, ethyl acetate, methylene chloride, chloroform, toluene, o-xylene, m- xylene, p-xylene, n-hexane, cyclohexane, n-heptane, n-octane or mixtures thereof.

6. The process according to claim 1, wherein the potassium source is organic or inorganic in nature.

7. The process according to claim 6, wherein the inorganic potassium source is potassium hydroxide, potassium carbonate or potassium bicarbonate.

8. The process according to claim 6, wherein the organic potassium source is potassium 2-ethylhexanoate, potassium acetate, potassium ascorbate, potassium benzoate, preferably potassium 2-ethylhexanoate.

9. A process for the preparation of Azilsartan medoxomil which comprises, cyclising (5-methyl-2-oxo-2//-1,3-dioxol-4-yl)methyl2-ethoxy-1 -[(4-(2-[N-hydroxycarbamimidoyl] phenyl)phenyl)methyl]-l//-l,3-benzodiazole-7-carboxylate using a carbonyl source in presence of an organic solvent and in presence or absence of a base.

10. The process according to claim 9, wherein the carbonyl source comprising N,N-disuccinimidyl carbonate, diphenyl carbonate, N,N-carbonyldiimidazole, dialkyl carbonate, phosgene equivalents, alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide, N,N-dicyclohexyl carbodiimide, diphenyl carbodiimide, ditolyl carbodiimide.